CN101312965B

CN101312965B - Morpholine type cinnamide compound

Info

Publication number: CN101312965B
Application number: CN2006800440217A
Authority: CN
Inventors: 木村祯治; 川野弘毅; 土井江梨子; 北泽则孝; 高石守; 伊藤康一; 金子敏彦; 佐佐木健雄; 佐藤信明; 宫川武彦; 萩原博昭
Original assignee: Eisai R&D Management Co Ltd
Current assignee: Eisai R&D Management Co Ltd
Priority date: 2005-11-24
Filing date: 2006-10-27
Publication date: 2011-07-20
Anticipated expiration: 2026-10-27
Also published as: CN101312965A; ZA200803939B

Abstract

The present invention relates to a compound represented by the formula (I): or a pharmacologically acceptable salt thereof, wherein R<1>, R<2>, R<3>, and R<4 >are the same or different and each represent a hydrogen atom or a C1-6 alkyl group; X1 represents a C1-6 alkylene group that may be substituted; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, provided that Xb is only an oxygen atom when Xa is a methoxy group; and Ar1 represents an aryl group, pyridinyl group, aryloxy group, or pyridinyloxy group that may have a substituent such as a halogen atom; and to use of the compound or salt as a pharmaceutical agent.

Description

Morpholine type cinnamide compound

Technical field

The present invention relates to morpholine type cinnamide compound and comprise the medicine of described compound as activeconstituents.The present invention more particularly relates to non-peptide two ring cinnamide compounds and comprises the formation inhibitor of described compound as the amyloid-β (hereinafter being called A β) of activeconstituents, it is for the neurodegenerative disease that treatment is caused by A β, and for example alzheimer's disease or mongolism are effective especially.

Background of invention

Alzheimer's disease is the disease that is characterized as neuronal degeneration and disappearance and senile plaque formation and neurofibrillary degeneration.At present, alzheimer's disease only carries out symptomatic treatment by using with acetylcholinesterase depressant as the doing well,improving medicine of representative, the also untapped base therapy that goes out to suppress this progression of disease.In order to set up the base therapy of alzheimer's disease, be necessary to develop the method for the pathological pathogenic factor of control.

Supposition is thought, has participated in the morbidity (referring to non-patent literature 1 and 2) of neuronic sex change and disappearance and dementia to a great extent as amyloid precursor protein (hereinafter being called APP) the A beta-protein of meta-bolites.The A beta-protein has as main component, comprises 40 amino acid whose A β 40 and increase by two A β 42 at C-terminal amino group acid number.A β 40 and A β 42 are known to have high coherency (referring to non-patent literature 3), and is the main component (referring to non-patent literature 3,4 and 5) of senile plaque.In addition, known A β 40 and A β 42 owing to APP and in the familial alzheimer's disease sudden change of observed presenilin gene increase (referring to non-patent literature 6,7 and 8).Therefore, expectation will reduce progression inhibiting agent or the prophylactic agent of the compound of A β 40 and A β 42 generations as alzheimer's disease.

A β cuts APP successively by beta-secretase and gamma-secretase and produces.Therefore, attempt to obtain the inhibitor of beta-secretase and gamma-secretase to reduce the generation of A β.Found many inhibitor of these Secretasess, the analogue of peptide class and peptide for example, as L-685,458 (referring to non-patent literatures 9) and LY-411575 (referring to non-patent literature 10,11 and 12).

[non-patent literature 1] Klein WL and other seven people, the brain that influenced by alzheimer's disease: exist oligomerization A beta ligands (ADDL) to point out the molecular basis of reversible loss of memory (Alzheimerdisease-affected brain:Presence of oligomeric A β Ligands (ADDLs) suggests a Molecular basis for reversible Memory Loss), NAS's minutes (Proceding National Academy of Science USA), 2003, Sep 2; 100 (18), p.10417-10422;

[non-patent literature 2] Nitsch RM and other 16 people, the antibody of anti-beta amyloid has slowed down the cognitive decline in the alzheimer's disease (Antibodies against β-amyloid slow cognitivedecline in Alzheimer ' s disease), neurone (Neuron), 2003, May 22; 38, p.547-554;

[non-patent literature 3] Jarrett JT and other two people, the C-terminal of amyloid beta is very crucial for the beginning that amyloid forms: for the pathogenetic hint of alzheimer's disease (Thecarboxy terminus of the β amyloid protein is critical for the seeding ofamyloid formation:Implications for the pathogenesis of Alzheimer ' sdisease), biological chemistry (Biochemistry), 1993,32 (18), p.4693-4697;

[non-patent literature 4] Glennerg GG and other people, alzheimer's disease: to the purifying of new cerebrovascular amyloid and the initial report of evaluation (Alzheimer ' s disease:initialreport of the purification and characterization of a Novel cerebrovascularamyloid protein), biological chemistry and biophysical studies news in brief (Biochemical andbiophysical research communications), 1984, May 16,120 (3), p.885-890;

[non-patent literature 5] Masters CL and other five people, the core protein of the amyloid plaque in alzheimer's disease and mongolism (Amyloid plaque core protein inAlzheimer disease and Down syndrome), NAS's minutes (Proceding National Academy of Science USA), 1985, Jun, 82 (12), p.4245-4249;

[non-patent literature 6] Gouras GK and other 11 people, the accumulating of A β 42 (Intraneuronal A β 42 accumulation in human brain) in the neurone of human brain, U.S.'s pharmacology magazine (American Journal of Pathology), 2000, Jan, 156 (1), p.15-20;

[non-patent literature 7] Scheuner D and other 20 people, the presenilin 1 relevant with the familial alzheimer's disease and 2 and the sudden change of APP increased the amyloid beta protein (Secreted amyloid β-protein similar to thatin the senile plaques of Alzheimer ' s disease increased in vivo by thepresenil in 1 and 2 and APP Mutations Linked to familial Alzheimer ' sdisease) of the secretion in the old patch that is similar to alzheimer's disease in the body, natural drug (Nature Medicine), 1996, Aug, 2 (8), p.864-870;

[non-patent literature 8] Forman MS and other four-players, the amyloid precursor protein of swedish mutant body is accumulated and excretory same-action (Differential effects of the swedish Mutant amyloid precursor protein on β-amyloid accumulation and secretion in Neurons and nonneuronal cells) not amyloid beta in neurone and the non-neuronal cell, journal of biological chemistry (The Journal of Biological Chemistry), 1997, Dec 19,272 (51), p.32247-32253;

[non-patent literature 9] Shearman MS and other nine people, a kind of aspartyl protease transition state analog L-685,458, be the active effective inhibitor (L-685 of amyloid beta protein precursor gamma-secretase, 458, an Aspartyl Protease Transition State Mimic, Is a PotentInhibitor of Amyloid β-Protein Precursor γ-Secretase Activity), biological chemistry (Biochemistry), 2000, Aug 1,39 (30), p.8698-8704;

[non-patent literature 10] Shearman MS and other six people, the gamma-secretase mixture inhibitor of catalytic site orientation can not be distinguished the cracking (CatalyticSite-Directed γ-Secretase Complex Inhibitors Do Not DiscriminatePharmacologically betweeen Notch S3 and β-APP Cleavages) of Notch S3 and β-APP on pharmacology, biological chemistry (Biochemistry), 2003, Jun 24,42 (24), p.7580-7586;

[non-patent literature 11] Lanz TA and other three people use inhibitors of gamma-secretase N2-[(2S)-2-(3, the 5-difluorophenyl)-2-hydroxyacetyl]-N1-[(7S)-and 5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepine

-7-yl]-L-alanimamides (LY-411575), brain (no patch) Tg2576 mouse childhood, carry out pharmacodynamic study (the Studies of A β pharmacodynamics in the brain of A β in cerebrospinal fluid and the blood plasma, cerebrospinal fluid, and plasma in young (plaque-free) Tg2576 mice using the γ-secretase inhibitorN2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d] azepin-7-yl]-L-alaninamide (LY-411575)), pharmacology and experimental therapeutic magazine (The journal of pharmacology and experimentaltherapeutics), 2004, Apr, 309 (1), p.49-55;

[non-patent literature 12] Wong GT and other 12 people, adopt inhibitors of gamma-secretase LY-411,575 chronic treatment suppresses differentiation (the Chronic treatment with the γ-secretase inhibitor LY-411 that beta-amyloyd peptide generated and changed lymphocyte generation and intestinal cells, 575inhibits β-amyloid peptide production and alters Lymphopoiesis andintestinal cell differentiation), journal of biological chemistry (The journal of biologicalchemistry), 2004, Mar 26,279 (13), p.12876-12882.

Summary of the invention

The problem to be solved in the present invention

As mentioned above, the compound that inhibition A β 40 and A β 42 generate from APP is supposed to be used as the disease that is caused by A β, as the treatment or the prophylactic agent of alzheimer's disease.But, also find the highly active non-peptide compound that inhibition A β 40 and A β 42 generate.Therefore, need to suppress the new low-molecular weight compound of A β 40 and A β 42 generations.

The approach that addresses this problem

Through extensive studies, the present invention finds to suppress the non-peptide class morpholine type cinnamide compound that A β 40 and A β 42 generate from APP first, and has found the disease that prevention or treatment cause by A β such as the medicine of alzheimer's disease thus.This discovery has caused of the present invention finishing.

Particularly, the present invention relates to

1) compound of representing by formula (I), or its pharmaceutically useful salt:

Wherein

(a) R ¹, R ², R ³And R ⁴Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately;

X ₁Represent the C1-6 alkylidene group, wherein said C1-6 alkylidene group can be replaced by 1-3 oh group or C1-6 alkyl group, wherein said C1-6 alkyl group can be replaced by 1-3 oh group, or forms the C3-13 group of naphthene base jointly by two on the same carbon atom that is connected the C1-6 alkylidene group described C1-6 alkyl groups and this carbon atom;

X _aRepresentation methoxy group or fluorine atom;

X _bRepresention oxygen atom or methylene group, condition are to work as X _aWhen being methoxy group, X _bIt only is Sauerstoffatom; And

Ar ₁Represent aromatic yl group, pyridyl group, aryloxy group or pyridyloxy group, it can replace by selected 1-3 substituting group from substituting group A1;

(b) Ar ₁-X ₁-representative and phenyl ring condensed C3-8 group of naphthene base, wherein a methylene group on the C3-8 group of naphthene base can be replaced by Sauerstoffatom, described C3-8 group of naphthene base can be replaced by 1-3 oh group and/or C1-6 alkyl group, and described phenyl ring can be replaced by 1-3 substituting group that is selected from substituent A 1; And R ¹, R ², R ³, R ⁴, X _aAnd X _bSuch as in (a) definition;

(c) R ¹And R ²In one of them and R ³And R ⁴One of them identical or differently represents hydrogen atom or C1-6 alkyl group separately; R ¹And R ²In another and R ³And R ⁴In another carbon atom that connects respectively with them form the C3-8 group of naphthene base, wherein said C3-8 group of naphthene base can be replaced by the substituting group that 1-3 is selected from substituent A 1; And X ₁, X _a, X _bAnd Ar ₁Such as (a) or (b) in definition;

(d) Ar ₁-X ₁-and R ⁴With Ar ₁-X ₁-the nitrogen-atoms and the R that are connected ⁴The carbon atom that is connected forms 4-to 8-member heterocyclic ring containing nitrogen group together, it can be replaced by aryl or pyridyl, wherein a methylene group on this 4-to 8-member heterocyclic ring containing nitrogen group can be replaced by following radicals: the methylene radical that is replaced by 1 or 2 substituting group that is selected from substituent A 1, the vinylidene, Sauerstoffatom or the selected imino-that substituting group replaced that are replaced by 1 or 2 substituting group that is selected from substituent A 1 from substituting group A1, and described aryl or pyridyl can be replaced by 1-3 substituting group that is selected from substituent A 1; X _bRepresention oxygen atom; And R ¹, R ², R ³And X _aSuch as (a) or (b) in definition;

(e) R ¹And R ²Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ³, R ⁴, X ₁, X _a, X _bAnd Ar ₁Such as (a) or (b) in definition; Perhaps

(f) R ³And R ⁴Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ¹, R ², X ₁, X _a, X _bAnd Ar ₁Such as (a) or (b) in definition

(substituent A 1 comprises: (1) halogen atom, (2) oh group, (3) cyano group, (4) C3-8 group of naphthene base, (5) C3-8 cycloalkyloxy group, (6) C1-6 alkyl group, wherein this C1-6 alkyl group can be replaced by 1-5 halogen atom or 1-3 C1-6 alkoxy base, (7) amino group, it can be replaced by one or two C1-6 alkyl group, wherein said C1-6 alkyl group can be replaced by 1-5 halogen atom, (8) C1-6 alkoxy base, wherein this C1-6 alkoxy base can be replaced and (9) formamyl group by 1-5 halogen atom, it can be replaced by one or two C1-6 alkyl group, and wherein said C1-6 alkyl group can be replaced by 1-3 halogen atom);

2) as mentioned 1) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (I-a) is represented:

R wherein ¹, R ², R ³, R ⁴, X ₁And Ar ₁As mentioned 1) defines in;

3) as mentioned 1) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (II) is represented:

R wherein ¹, R ², R ³, R ⁴, X _aAnd X _bAs mentioned 1) defines in; R ⁵And R ⁶Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately, and wherein said C1-6 alkyl group can be replaced by 1-3 oh group; And Ar _1-aExpression phenyl group or pyridyl group, it can be selected from as mentioned 1 by 1-3) in the substituting group of defined substituent A 1 replace;

4) as mentioned 3) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (II-a) is represented:

R wherein ¹, R ², R ³And R ⁴As mentioned 1) defines in; And R ⁵, R ⁶And Ar _1-aAs mentioned 3) define in;

5) as mentioned 3) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (II-b) is represented:

6) as mentioned 3) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (II-c) is represented:

R wherein ¹, R ², R ³And R ⁴As mentioned 1) defines in; R ⁷Represent hydrogen atom or C1-6 alkyl group; And Ar _1-aAs mentioned 3) define in;

7) as mentioned 3) described compound or its pharmacologically acceptable salt, wherein said compound through type (II-d) is represented:

8) as mentioned 3) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (II-e) is represented:

R wherein ¹, R ², R ³And R ⁴As mentioned 1) defines in; Ar _1-aAs mentioned 3) define in; And R ⁷As mentioned 6) define in;

9) as mentioned 1) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (I-b) is represented:

R wherein ¹, R ², R ³And R ⁴As mentioned 1) defines in; R ¹³And R ¹⁴Identical or different ground is represented hydrogen atom separately or is selected from as mentioned 1) in the substituting group of defined substituent A 1; And Y represents methylene group or Sauerstoffatom;

10) as mentioned 9) described compound or pharmaceutically acceptable salt thereof, wherein R ¹³And R ¹⁴Identical or different ground is represented hydrogen atom, halogen atom or C1-6 alkoxy base separately;

11) as mentioned 1) described compound or pharmaceutically acceptable salt thereof, wherein said compound through type (I-c) is represented:

R wherein ¹And R ²As mentioned 1) defines in; Ar _1-cRepresent phenyl group or pyridyl group, it can be replaced by 1-3 substituting group that is selected from substituent A 1 identical or differently; Z ₁Representative can be selected from as mentioned 1 by 1 or 2) in defined substituent A 1 the methylene radical that substituting group replaced or vinylidene, Sauerstoffatom or can be selected from the imino-that substituting group replaced of A1;

And n and m identical or differently represent the integer of 0-2 separately;

12) as mentioned 11) described compound or pharmaceutically acceptable salt thereof, wherein Z ₁Represent methylene group, wherein said methylene group can be replaced by 1 or 2 substituting group that is selected from C1-6 alkyl group and oh group identical or differently; And n and m represent 1 separately;

13) as mentioned 11) described compound or pharmaceutically acceptable salt thereof, wherein Z ₁Represention oxygen atom, and n and m represent integer 1;

14) as mentioned 1) described compound or pharmaceutically acceptable salt thereof, wherein Ar ₁Aromatic yl group or the pyridyl group representing aromatic yl group or pyridyl group or replaced by 1-3 halogen atom;

15) as mentioned 1) described compound or pharmaceutically acceptable salt thereof, wherein Ar ₁Phenyl group or the pyridyl group representing phenyl group or pyridyl group or replaced by 1-3 halogen atom;

16) as mentioned 1) described compound or pharmaceutically acceptable salt thereof, wherein said compound is selected from following compounds:

1) (Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone,

2) (Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone,

3) (Z)-(S)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone,

4) (Z)-(R)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone,

5) (Z)-(S)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone,

6) (Z)-(R)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone,

7) (Z)-4-[(S)-1-(4-fluorophenyl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

8) (Z)-(R)-4-[(S)-1-(4-fluorophenyl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

9) (Z)-(S)-4-[(S)-1-(4-fluorophenyl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

10) (Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(S)-and 1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone,

11) (Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(R)-and 1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone,

12) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

13) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

14) (Z)-(R)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

15) (Z)-(6S, 9aR)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone,

16) (Z)-(6R, 9aS)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone,

17) (Z)-(S)-4-[(S)-1-(6-chloropyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

18) (Z)-(S)-4-[(R)-1-(6-chloropyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

19) (Z)-(S)-4-[(S)-1-(5-chloropyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

20) (Z)-(S)-4-[(R)-1-(5-chloropyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

21) (Z)-(S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

22) (Z)-(S)-4-[(R)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

23) (Z)-(S)-4-[(S)-1-(2,3-difluoro pyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

24) (Z)-(S)-4-[(R)-1-(2,3-difluoro pyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

25) (Z)-(S)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

26) (Z)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

27) (Z)-4-[(R)-1-(4-fluorophenyl)-2-hydroxyethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

28) (Z)-(6R)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

29) (Z)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical] morpholine-3-ketone,

30) (Z)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical] morpholine-3-ketone,

31) (Z)-(S)-4-[(1R, 2R)-1-(4-fluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

32) (Z)-4-[(1R, 2R)-1-(4-fluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

33) (Z)-(S)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

34) (Z)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(Methylimidazole-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

35) (Z)-(S)-4-[(S)-2-hydroxyl-1-methyl isophthalic acid-(3,4, the 5-trifluorophenyl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

36) (Z)-(6S)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-methyl-4-[(S)-1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone,

37) (Z)-(6S)-4-[1-(4-fluorophenyl)-1-methylethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

38) (Z)-(6S)-4-[1-(4-fluorophenyl) cyclopropyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

39) (Z)-(6S, 9aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene]-6-(3,4, the 5-trifluorophenyl) hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone,

40) (Z)-(6S, 9aR)-6-(3, the 4-difluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone,

41) (Z)-(6S, 9aR)-6-(2,6-difluoro pyridine-3-yl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone,

42) (Z)-(S)-4-[(S)-1-(5-fluorine pyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

43) (Z)-(S)-4-[(S)-1-(2-chloropyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

44) (Z)-(S)-4-[(S)-1-(2-chloro-3-fluorine pyridin-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

45) (Z)-(S)-4-[(S)-1-(2,6-difluoro pyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

46) (Z)-4-[(S)-1-(2-chloropyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

47) (Z)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

48) (Z)-4-[(S)-1-(6-fluorine pyridin-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

49) (Z)-4-[(S)-1-(6-chloropyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

50) (Z)-4-[(S)-1-(2,3-difluoro pyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

51) (Z)-4-[(S)-1-(5-chloropyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

52) (Z)-(R)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

53) (Z)-(S)-and 4-(4-luorobenzyl)-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

54) (Z)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(S)-and 1-(4-trifluorophenyl) ethyl]-6,6-thebaine-3-ketone,

55) (Z)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

56) (Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

57) (Z)-(S)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-6-methylmorpholine-3-ketone,

58) (Z)-(S)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone,

59) (Z)-(S)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(1R, 2R)-1-(4-fluorophenyl)-2-hydroxypropyl]-6-methylmorpholine-3-ketone,

60) (Z)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-6,6-thebaine-3-ketone,

61) (Z)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone,

62) 1-[1-(2,4 difluorobenzene base) ethyl]-3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(E)-and methylene radical } piperidines-2-ketone,

63) (E)-(S)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-5-methyl piperidine-2-ketone,

64) (E)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group] piperidines-2-ketone,

65) (E)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[(2R, 3R)-3-hydroxyl-1,1-dimethyl indane-2-yl] piperidines-2-ketone,

66) (E)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[(S)-and 2-hydroxyl-1-methyl isophthalic acid-(3,4, the 5-trifluorophenyl) ethyl] piperidines-2-ketone,

67) (E)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[1-(4-fluorophenyl)-1-methylethyl] piperidines-2-ketone,

68) (E)-(R)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-5-methyl piperidine-2-ketone,

69) (E)-(S)-1-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-5-methyl piperidine-2-ketone,

70) (Z)-(6S, 8aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene]-6-(3,4, the 5-trifluorophenyl) Pyrrolidine also [2,1-c] [1,4] oxazine-4-ketone,

71) (6S, 9aR)-6-(4-chloro-phenyl-)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone,

72) (6R, 9aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical-6-(3,4, the 5-trifluorophenyl)-tetrahydrochysene [1,4] oxazine also [3,4-c] [1,4] oxazine-4-ketone,

73) (6R, 9aR)-6-(3, the 4-difluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical-tetrahydrochysene [1,4] oxazine also [3,4-c] [1,4] oxazine-4-ketone,

74) (6R, 9aR)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical-tetrahydrochysene [1,4] oxazine also [3,4-c] [1,4] oxazine-4-ketone and

75) (6R, 9aR)-6-(4-chloro-phenyl-)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical-tetrahydrochysene [1,4] oxazine also [3,4-c] oxazine-4-ketone;

17) comprise above 1)-16) in any described compound or pharmaceutically acceptable salt thereof as the medicine of activeconstituents;

18) be used to prevent or treat the disease that causes by amyloid beta as mentioned 17) described medicine; With

19) as mentioned 17) described medicine, wherein the disease that is caused by amyloid beta is alzheimer's disease, senile dementia, mongolism or amyloidosis.

The medicine of the disease that the compound or pharmaceutically acceptable salt thereof of general formula of the present invention (I) and prevention of the present invention or treatment amyloid beta cause is the new invention of also not describing in any document.

The implication of the symbol that uses in the specification sheets of the present invention, term etc. will be explained hereinafter, and the present invention will be described in detail.

In specification sheets of the present invention, for convenience, the structural formula of compound can be represented certain isomer.Yet, the present invention includes all isomer and isomer mixture, for example the geometrical isomer that can produce, optically active isomer, steric isomer and tautomer based on unsymmetrical carbon from the structure of compound.The invention is not restricted to the description of the chemical formula that carries out for convenience, this class description can comprise any one isomer or their mixture.Therefore, compound of the present invention can have unsymmetrical carbon in molecule, and exists with the compound or the racemoid of optically active, and the present invention comprises the compound and the racemoid of each optically active without restriction.Though can there be polymorph in described compound, compound is not limited thereto, and it can exist with the mixture of monocrystalline form or monocrystalline form.Described compound can be dehydrate or hydrate.

" C1-6 alkylidene group " is meant the alkylidene group with 1-6 carbon atom.The example of preferred described group comprises methylene radical, ethylidene, propylidene, butylidene and pentylidene.

" C1-6 alkyl " is meant the alkyl group with 1-6 carbon atom.The example of preferred described group comprises the straight or branched alkyl group, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, 1-methyl-propyl, 1,2-dimethyl propyl, 1-ethyl propyl, 1-methyl-2-ethyl propyl, 1-ethyl-2-methyl-propyl, 1,1,2-trimethylammonium propyl group, 1-methyl butyl, 2-methyl butyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 2-ethyl-butyl, 1,3-dimethylbutyl, 2-methyl amyl and 3-methyl amyl.

" C3-13 cycloalkyl " is meant the group of naphthene base with 3-13 carbon atom.The example of preferred described group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, ring nonyl, ring decyl, ring undecyl, cyclo-dodecyl and ring tridecyl.

" aryl " is meant " 6-to 14-unit Polycyclic aromatic hydrocarbons group " or " 5-to 14-unit heteroaromatic group "." 6-to 14-unit Polycyclic aromatic hydrocarbons group " used herein is meant the monocyclic, bicyclic or tricyclic aromatic hydrocarbon group with 6-14 carbon atom.The example of preferred described group comprises the monocyclic, bicyclic or tricyclic aromatic hydrocarbon group of 6-to 14-unit, for example phenyl, indenyl, naphthyl, Azulene base, heptalenyl, xenyl, fluorenyl, non-that thiazolinyl, phenanthryl and anthryl." 5-to 14-unit heteroaromatic group " is meant the monocyclic, bicyclic or tricyclic aromatic heterocyclic group with 5-14 carbon atom.The example of preferred described group comprises: the aromatic heterocycle group that (1) is nitrogenous, for example pyrryl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, pyrazolinyl, imidazolyl, indyl, pseudoindoyl, indolizine base, purine radicals, indazolyl, quinolyl, isoquinolyl, quinolizinyl, phthalazinyl, naphthyridine base, quinoxalinyl, quinazolyl, cinnolines base, pteridyl, imidazo-triazine base, pyrazine and pyridazinyl, acridyl, phenanthridinyl, carbazyl, The pyridine base, phenanthroline base and phenacyl, (2) aromatic heterocycle group of sulfur-bearing, for example thienyl and benzothienyl, (3) oxygen containing aromatic heterocycle group, furyl for example, pyranyl, the cyclopenta pyranyl, benzofuryl and isobenzofuran-base, and (4) are contained two or more and are selected from nitrogen-atoms, the heteroatomic aromatic heterocycle group of sulphur atom and Sauerstoffatom, for example thiazolyl, isothiazolyl, benzothiazole quinoline base, the diazosulfide base, benzothiazine base isoxazolyl, furazan base phenoxazinyl, Bi Zuo Bing oxazolyl, the Imidazothiazole base, the thienofuran base, furo pyrryl and Bi Ding Bing oxazinyl.

" aryloxy group " is meant at the aromatic hydrocarbons ring hydrogen atom of " 6-to 14-unit Polycyclic aromatic hydrocarbons group " or the hydrogen atom on the heteroaromatic of " 5-to 14-unit heteroaromatic group " by the displaced group of Sauerstoffatom.

" with phenyl ring condensed C3-8 group of naphthene base " can be, for example the group of following formula:

Described phenyl ring can be replaced by 1-3 substituting group that is selected from substituent A 1; A methylene radical on the described C3-8 group of naphthene base can be replaced by Sauerstoffatom; And described C3-8 group of naphthene base can be replaced by 1-3 hydroxyl and/or C1-6 alkyl.

By Ar ₁-X ₁-and R ⁴With Ar ₁-X ₁-the nitrogen-atoms and the R that are connected ⁴" 4-to 8-member heterocyclic ring containing nitrogen group " that the carbon atom that is connected forms together can be, for example the group of following formula:

Described 4-to 8-member heterocyclic ring containing nitrogen group can be replaced by aromatic yl group or pyridyl group, and wherein said aromatic yl group or pyridyl group can be replaced by 1-3 substituting group that is selected from substituent A 1.In addition, a methylene radical on this 4-to 8-member heterocyclic ring containing nitrogen group can be replaced by following radicals: the imino-of the methylene radical that is replaced by 1 or 2 substituting group that is selected from A1, the vinylidene, the Sauerstoffatom that are replaced by 1 or 2 substituting group that is selected from A1 or the substituting group replacement that is selected from A1.

Described 4-to 8-member heterocyclic ring containing nitrogen group, the methylene radical that it comprised can be replaced by following radicals: the imino-of the methylene radical that is replaced by 1 or 2 substituting group that is selected from A1, the vinylidene, the Sauerstoffatom that are replaced by 1 or 2 substituting group that is selected from A1 or the substituting group replacement that is selected from A1, this class 4-to 8-member heterocyclic ring containing nitrogen group can be, for example following formula the group of concrete expression:

" C1-6 acyl group " used herein is meant the carboxyl groups with 1-6 carbon atom.The example of preferred described group comprises formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl and caproyl.

" R ¹And R ²The C3-8 group of naphthene base that forms with the carbon atom that they connected " or " R ³And R ⁴The C3-8 group of naphthene base that forms with the carbon atom that they connected " can be, for example following formula the group of concrete expression:

" C1-6 alkylidene group; wherein said C1-6 alkylidene group can be replaced by 1-3 hydroxyl or C1-6 alkyl group; wherein said C1-6 alkyl group can be replaced by 1-3 hydroxyl; or form the C3-13 group of naphthene base jointly by two on the same carbon atom that is connected the C1-6 alkylidene group described C1-6 alkyl groups and this carbon atom " can be, for example following formula the group of concrete expression:

Substituent A 1 is meant following group.

Substituent A 1 comprises: (1) halogen atom; (2) oh group; (3) cyano group; (4) C3-8 group of naphthene base; (5) C3-8 cycloalkyloxy group; (6) C1-6 alkyl group; wherein this C1-6 alkyl group can be replaced by 1-5 halogen atom or 1-3 C1-6 alkoxy base; (7) amino group; it can be replaced by one or two C1-6 alkyl; wherein said C1-6 alkyl can be replaced by 1-5 halogen atom; (8) C1-6 alkoxy base, wherein this C1-6 alkoxy base can be replaced by 1-5 halogen atom, and (9) formamyl group; it can be replaced by one or two C1-6 alkyl, and wherein said C1-6 alkyl can be replaced by 1-3 halogen atom.

" halogen atom " used herein is meant fluorine atom, chlorine atom, bromine atoms, iodine atom etc., and preferred fluorine atom, chlorine atom or bromine atoms.

" C3-8 group of naphthene base " is meant the group of naphthene base with 3-8 carbon atom.The example of preferred described group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.

" C3-8 cycloalkyloxy group " be meant one of them hydrogen atom by Sauerstoffatom the group of naphthene base of the displaced 3-8 of a having carbon atom.The example of preferred described group comprises ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base and ring octyloxy.

" C1-6 alkyl group " as hereinbefore defined and the object lesson of group as indicated above.

" C1-6 alkoxy base " is meant that one of them hydrogen atom is by the alkyl group of the displaced 1-6 of having of a Sauerstoffatom carbon atom.The example of preferred described group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, secondary pentyloxy, uncle's pentyloxy, positive hexyloxy, different hexyloxy, 1,2-dimethyl propoxy-, 2-ethyl propoxy-, 1-methyl-2-ethyl propoxy-, 1-ethyl-2-methyl propoxy-, 1,1,2-trimethylammonium propoxy-, 1,1,2-trimethylammonium propoxy-, 1,1-dimethyl butoxy, 2,2-dimethyl butoxy, 2-ethyl butoxy, 1,3-dimethyl butoxy, 2-methyl pentyloxy, 3-methyl pentyloxy and hexyloxy.

" amino group that can be replaced by one or two C1-6 alkyl " is meant that one of them or two hydrogen atoms are had the amino group that alkyl replaced of 1-6 carbon atom by one or two.The example of preferred described group comprises methylamino, dimethylamino, ethylamino, diethylamino, n-propyl amino and di amino.

" the formamyl group that can be replaced by one or two C1-6 alkyl " is meant that one of them or two hydrogen atoms are had the formamyl group that alkyl replaced of 1-6 carbon atom by one or two.The example of preferred described group comprises methylamino formyl radical, formyl-dimethylamino, ethylamino formyl radical, diethylamino formyl radical, n-propyl formamyl and di formamyl.

In specification sheets of the present invention, be not particularly limited for the scope of the compound formed " pharmacologically acceptable salt " of the general formula (I) of the medicine of the disease that causes by A β as prevention or treatment.The object lesson of preferred described salt comprises: hydrohalogen (hydrofluoride for example, hydrochloride, hydrobromide and hydriodide), inorganic acid salt (vitriol for example, nitrate, perchlorate, phosphoric acid salt, carbonate and supercarbonate), organic carboxylate (acetate for example, oxalate, maleate, tartrate, fumarate and Citrate trianion), organic sulfonate (mesylate for example, fluoroform sulphonate, esilate, benzene sulfonate, tosylate and camsilate), amino acid salts (for example aspartic acid and glutaminate), quaternary ammonium salt, an alkali metal salt (for example sodium salt and sylvite) and alkaline earth salt (for example magnesium salts and calcium salt).

Various details formula (I) compound.

In formula (I) compound or pharmaceutically acceptable salt thereof, preferred

X ₁Represent the C1-6 alkylidene group, wherein this C1-6 alkylidene group can be replaced by 1-3 hydroxyl or C1-6 alkyl group, described C1-6 alkyl group can be replaced by 1-3 hydroxyl, or two described C1-6 alkyl groups are connected together on the same carbon atom of C1-6 alkylidene group and form the C3-13 group of naphthene base;

X _aRepresentation methoxy or fluorine atom;

X _bRepresention oxygen atom or methylene radical, condition are to work as X _aWhen being methoxyl group, X _bIt only is Sauerstoffatom; And

Ar ₁Represent aromatic yl group, pyridyl group, aryloxy group or pyridyloxy group, it can be replaced by 1-3 substituting group that is selected from substituent A 1;

(b) Ar ₁-X ₁-representative and phenyl ring condensed C3-8 group of naphthene base, wherein a methylene radical on this C3-8 group of naphthene base can be replaced by Sauerstoffatom, this C3-8 group of naphthene base can be replaced by 1-3 hydroxyl and/or C1-6 alkyl group, and described phenyl ring can be replaced by 1-3 substituting group that is selected from substituent A 1; And R ¹, R ², R ³, R ⁴, X _aAnd X _bSuch as in (a) definition;

(c) R ¹And R ²One of them and R ³And R ⁴One of them identical or differently represents hydrogen atom or C1-6 alkyl group separately; R ¹And R ²In another and R ³And R ⁴In another carbon atom that connects respectively with them form the C3-8 group of naphthene base, wherein this C3-8 group of naphthene base can be replaced by the substituting group that 1-3 is selected from substituent A 1; And X ₁, X _a, X _bAnd Ar ₁Such as (a) or (b) in definition;

(d) Ar ₁-X ₁-and R ⁴The carbon atom that is connected with R4 with the nitrogen-atoms that Ar1-X1-connected forms 4-to 8-member heterocyclic ring containing nitrogen group, it can be replaced by aromatic yl group or pyridyl group, a methylene radical on wherein said 4-to the 8-member heterocyclic ring containing nitrogen group can be replaced by following radicals: by 1 or 2 methylene radical that is selected from the substituting group replacement of A1, can be by 1-3 the vinylidene that substituting group replaced that is selected from A1, Sauerstoffatom or can be selected from the imino-that the substituting group of A1 replaces, and described aromatic yl group or pyridyl group can be replaced by 1-3 substituting group that is selected from A1; X _bRepresention oxygen atom; And R ¹, R ², R ³And X _aSuch as (a) or (b) in definition;

(e) R ¹And R ²Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ³, R ⁴, X ₁, X _a, X _bAnd Ar ₁Such as (a) or (b) in definition; Or

(f) R ³And R ⁴Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ¹, R ², X ₁, X _a, X _bAnd Ar ₁Such as (a) or (b) in definition,

And it is preferred especially,

X ₁Represent the C1-6 alkylidene group, wherein this C1-6 alkylidene group can be replaced by 1-3 hydroxyl or C1-6 alkyl group, and wherein said C1-6 alkyl group can be replaced by 1-3 hydroxyl;

X _aRepresentation methoxy or fluorine atom;

(b) Ar ₁-X ₁-representative and phenyl ring condensed C3-8 group of naphthene base, wherein a methylene radical on this C3-8 group of naphthene base can be replaced by Sauerstoffatom, this C3-8 group of naphthene base can be replaced by 1-3 hydroxyl and/or C1-6 alkyl group, and described phenyl ring can be replaced by 1-3 substituting group that is selected from substituent A 1; And R ¹, R ², R ³, R ⁴, X _aAnd X _bSuch as in (a) definition; Or

(d) Ar ₁-X ₁-and R ⁴The carbon atom that is connected with R4 with the nitrogen-atoms that Ar1-X1-connected forms 4-to 8-member heterocyclic ring containing nitrogen group, it can be replaced by aromatic yl group or pyridyl group, wherein a methylene radical on this 4-to 8-member heterocyclic ring containing nitrogen group can be replaced by following radicals: the methylene radical that is replaced by 1 or 2 substituting group that is selected from A1, can be selected from the vinylidene that substituting group replaced, the Sauerstoffatom of A1 or can be selected from the imino-that the substituting group of A1 replaces by 1-3, and described aromatic yl group or pyridyl group can be replaced by 1-3 substituting group that is selected from A1; X _bRepresention oxygen atom; And R ¹, R ², R ³And X _aSuch as (a) or (b) in definition;

In formula (I) compound or pharmaceutically acceptable salt thereof,

Ar ₁Preferred aryl groups group or pyridyl group, or by the aromatic yl group or the pyridyl group of 1-3 halogen atom replacement.

In formula (I) compound or pharmaceutically acceptable salt thereof,

Ar ₁Be more preferably phenyl group or pyridyl group, or by the phenyl group or the pyridyl group of 1-3 halogen atom replacement.

In formula (I) compound or pharmaceutically acceptable salt thereof,

X _aPreferably representation methoxy or fluorine atom.

In formula (I) compound or pharmaceutically acceptable salt thereof,

X _bPreferably represention oxygen atom or methylene radical, condition is to work as X _aWhen being methoxyl group, X _bIt only is Sauerstoffatom.

In formula (I) compound or pharmaceutically acceptable salt thereof,

Preferably, 1) R ¹, R ², R ³And R ⁴Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately; 2) R ¹And R ²One of them and R ³And R ⁴One of them identical or differently represents hydrogen atom or C1-6 alkyl group separately; And R ¹And R ²In another and R ³And R ⁴In another carbon atom that connects respectively with them form the C3-8 group of naphthene base, wherein this C3-8 group of naphthene base can be replaced by the substituting group that 1-3 is selected from A1; 3) R ¹And R ²Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ³And R ⁴Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately; Or 4) R ³And R ⁴Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ¹And R ²Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately.

In formula (I) compound or pharmaceutically acceptable salt thereof,

X ₁Preferably represent the C1-6 alkylidene group, wherein this C1-6 alkylidene group can be replaced by 1-3 hydroxyl or C1-6 alkyl group, and wherein said C1-6 alkyl group can be replaced by 1-3 hydroxyl; X ₁Representative-CR more preferably ⁵R ⁶-, R wherein ⁵And R ⁶Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately, and wherein said C1-6 alkyl group can be replaced by 1-3 hydroxyl; And X ₁Representative-CH-C (OH) R most preferably ⁷-, R wherein ⁷Represent the C1-6 alkyl group.

In formula (I) compound or pharmaceutically acceptable salt thereof,

Ar ₁Preferably represent aromatic yl group, pyridyl group, aryloxy group or pyridyloxy group, it can be replaced by 1-3 substituting group that is selected from substituent A 1; And Ar ₁More preferably representative can be by 1-3 aromatic yl group that substituting group replaced or pyridyl group that is selected from substituent A 1.

In formula (II) compound or pharmaceutically acceptable salt thereof,

Ar _1-aPreferably representative can be by 1-3 phenyl group that substituting group replaced or pyridyl group that is selected from substituent A 1; And

Ar _1-aMore preferably represent phenyl group or pyridyl group unsubstituted or that can be replaced by 1-3 halogen atom.

In formula (II) compound or pharmaceutically acceptable salt thereof,

Preferably, R ⁵And R ⁶Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately, and wherein said C1-6 alkyl group can be replaced by 1-3 hydroxyl.

In formula (II) compound or pharmaceutically acceptable salt thereof,

X _aPreferably representation methoxy or fluorine atom.

In formula (II) compound or pharmaceutically acceptable salt thereof,

In formula (I-a) compound or pharmaceutically acceptable salt thereof,

Preferably, 1) R ¹, R ², R ³And R ⁴Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately; 2) R ¹And R ²One of them and R ³And R ⁴One of them identical or differently represents hydrogen atom or C1-6 alkyl group separately; And R ¹And R ²In another and R ³And R ⁴In another, the carbon atom that connects respectively with them forms the C3-8 group of naphthene base, wherein this C3-8 group of naphthene base can be replaced by the substituting group that 1-3 is selected from A1; 3) R ¹And R ²Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ³And R ⁴Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately; Or 4) R ³And R ⁴Form the C3-8 group of naphthene base with the carbon atom that they connected; And R ¹And R ²Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately.

In formula (I-b) compound or pharmaceutically acceptable salt thereof,

Preferably, R ¹³And R ¹⁴Represent hydrogen atom identical or differently or be selected from the substituting group of substituent A 1; And more preferably, R ¹³And R ¹⁴Identical or different ground is represented hydrogen atom, halogen atom or C1-6 alkoxy base separately.

In formula (I-b) compound or pharmaceutically acceptable salt thereof,

Y preferably represents methylene radical or Sauerstoffatom.

In formula (I-b) compound or pharmaceutically acceptable salt thereof,

In formula (I-c) compound or pharmaceutically acceptable salt thereof,

Ar _1-cPreferably represent phenyl group or pyridyl group, it can be replaced by 1-3 substituting group that is selected from substituent A 1; And

Ar _1-cMore preferably represent unsubstituted or can be by 1-3 phenyl group that halogen atom replaced or pyridyl group.

In formula (I-c) compound or pharmaceutically acceptable salt thereof,

Z ₁Preferably representative can be by 1 or 2 imino-that substituting group replaced that is selected from the methylene radical that substituting group replaced or vinylidene, the Sauerstoffatom of A1 or can be selected from A1; Z ₁More preferably representative can be by 1 or 2 methylene radical that substituting group replaced or Sauerstoffatom that is selected from A1; And

Z ₁Most preferably represent methylene radical or Sauerstoffatom, wherein this methylene radical can be replaced by 1 or 2 substituting group that is selected from C1-6 alkyl group and hydroxyl identical or differently.

In formula (I-c) compound or pharmaceutically acceptable salt thereof,

Preferably, n and m identical or differently represent the integer of 0-2 separately; And be more preferably n and m and represent 1 separately.

In formula (I-c) compound or pharmaceutically acceptable salt thereof,

Preferably, 1) R ¹And R ²Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately; Or 2) R ¹And R ²Form the C3-8 group of naphthene base with the carbon atom that they connected.

In formula (II-a), (II-b) or compound or pharmaceutically acceptable salt thereof (II-d),

Ar _1-aPreferably represent phenyl group or pyridyl group, it can be replaced by 1-3 substituting group that is selected from substituent A 1; And

In formula (II-c) or compound or pharmaceutically acceptable salt thereof (II-e),

In formula (II-c) or (II-e) in the compound or pharmaceutically acceptable salt thereof,

R ⁷Preferably represent hydrogen atom or C1-6 alkyl group.

Ar _1-aPreferably represent phenyl group or pyridyl group, it can be replaced by 1-3 substituting group that is selected from A1; And

Ar _1-aMore preferably represent unsubstituted or can be by 1-3 phenyl group that halogen atom replaced or pyridyl group.

Particularly, be selected from following compound or pharmaceutically acceptable salt thereof, as treatment or the disease that for example caused by amyloid beta of prevention, is specially suitable and effective as the medicine of alzheimer's disease, senile dementia, mongolism or amyloidosis for it.

75) (6R, 9aR)-6-(4-chloro-phenyl-)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical-tetrahydrochysene [1,4] oxazine also [3,4-c] oxazine-4-ketone.

The preferred embodiment of the compound of general formula (I) is as indicated above.Active constituents of medicine of the present invention is not limited to specifically described compound in this specification sheets, can be chosen in the interior any embodiment of compound definition of general formula (I) arbitrarily.

The method for preparing general formula of the present invention (I) compound will be described below.

Described compound is represented with general formula (I):

R wherein ¹, R ², R ³, R ⁴, X ₁, X _a, X _bAnd Ar ₁As hereinbefore defined, synthesize described compound according to for example following general preparation method 1 or general preparation method's 2 method.It is evident that, in order to prepare The compounds of this invention easily, this method comprises the step of protective reaction and the step of deprotection reaction aptly, it has used and well known to a person skilled in the art and (for example be suitably for protecting group that each step selects, referring to people such as T.greene, " Protective groups in OrganicSynthesis ", John Wiley ﹠amp; Sons, Inc., New York, 1981).Same apparent, in order to prepare compound of the present invention easily, all isomer and isomer mixture, the for example geometrical isomer that can produce from compound structure, optically active isomer, steric isomer and the tautomer based on unsymmetrical carbon can be used as the simplification compound and are prepared by well known to a person skilled in the art the technology that is suitable for each step such as Steppecd crystallization and column chromatography.

General preparation method 1

The general preparation method 1 who is generally used for the compound of general formula of the present invention (I) will be described below.

In following formula, R ¹, R ², R ³, R ⁴, X ₁(work as X ₁When containing oh group, it can have protecting group), X _a, X _bAnd Ar ₁As hereinbefore defined.

Above-mentioned general preparation method 1 is an example of the compound method of preparation general formula (I), it is included in the aldol reaction among the step 1-1, be converted into aldol adducts (3) with aldehyde cpd (1) with corresponding to the normal amide compound of 0.3-3.0 (2a) of aldehyde cpd (1), and subsequently adducts dewatered.

Aldol adducts (3) is converted into compound (I)

The compound of general formula (I) can be by the dehydration reaction among the step 1-2 with aldol adducts (3) preparation that is converted.Particularly, the dehydration reaction of step 1-2 changes according to raw material, and is no particular limitation within the scope with reaction conditions like this response class.This reaction can use the known preparation method that describes in many documents (for example, referring to Jikken Kagaku Koza (Courses inExperimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [I], TheChemical Society of Japan edits Maruzen Co., Ltd., June 1992, p.194-226).The example of preferred this method comprises: i) method of usefulness acid treatment aldol adducts (3) (for example, referring to Jikken Kagaku Koza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [I], The Chemical Society of Japan edits Maruzen Co., Ltd., June 1992, p.194-196); Ii) the alcohol groups with aldol adducts (3) is converted into leavings group, for example sulfonate ester group or halogen atom, and then with the method for alkaline purification adducts (for example, referring to Jikken Kagaku Koza (Courses in ExperimentalChemistry), vol.19, Yuki Gosei (Organic Synthesis) [I], The ChemicalSociety of Japan edits Maruzen Co., Ltd., June 1992, p.198-205).

At method i) in, used acid, solvent and temperature condition change according to raw material, and have no particular limits.With regard to aldol adducts (3), use the normal acid of 0.1-10, for example hydrochloric acid, sulfuric acid, phosphoric acid, potassium hydrogen sulfide, oxalic acid, tosic acid, boron trifluoride-ether complex, thionyl chloride or aluminum oxide.This method can be carried out under the condition of solvent not having, perhaps inhibited reaction not and allow raw material in a certain scope, be dissolved in wherein solvent or its mixture in carry out.The example of preferred solvent for use comprises water, acetone, dimethyl sulfoxide (DMSO) and hexamethylphosphoramide.In addition, can promote speed of reaction and reaction yield with respect to the normal acid of 0.1-10 of aldol adducts (3) and the combination of organic bases such as pyridine.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference such as room temperature to 200 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

Method ii) in, the example of preferred leavings group comprises ethanoyl, methylsulfonyl, p-toluenesulfonyl, chlorine atom, bromine atoms and iodine atom.The method that is converted into this leavings group changes according to raw material, and has no particular limits.Can use the method for the method of well known to a person skilled in the art as this conversion.For example, preferably at halogenated solvent for example methylene dichloride and chloroform; Non-polar solvent is toluene and benzene for example; Ether solvent is tetrahydrofuran (THF) or ethylene glycol dimethyl ether for example; Or in its mixed solvent; preferably use the normal acetylation reagent of 1.0-10 such as Acetyl Chloride 98Min. and acetic anhydride with respect to aldol adducts (3); or sulfonated reagent for example methylsulfonyl chloride and p-methyl benzene sulfonic chloride, or the normal halide reagent of 1.0-10 thionyl chloride for example.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as-78 to 100 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 1-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.In the reaction of leaving away in second step, for example, preferably at halogenated solvent methylene dichloride for example; Non-polar solvent is toluene for example; Polar solvent such as acetonitrile, dimethyl formamide or dimethyl sulfoxide (DMSO); Ether solvent is tetrahydrofuran (THF) or ethylene glycol dimethyl ether for example; Or in its mixed solvent, preferably will be with respect to the normal organic bases of 0.1-10 of aldol adducts (3), for example diazabicylo undecylene, pyridine, 4-dimethylaminopyridine and triethylamine; Quaternary ammonium salt is TBAH for example; Alkali alcoholate, for example sodium methylate or potassium tert.-butoxide; Alkali metal hydroxide is sodium hydroxide for example; Alkaline carbonate is Quilonum Retard or salt of wormwood for example; Or organometallic reagent for example lithium diisopropylamine use as alkali.

Organic bases for example pyridine can also be used as solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as-78 to 100 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 1-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of aldol adducts (3)

For example, aldol adducts (3) can prepare from aldehyde cpd (1) and amide compound (2a) according to step 1-1.Particularly, the aldol reaction of step 1-1 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction (for example can be used the method for well known to a person skilled in the art, referring to Jikken Kagaku Koza (Courses in ExperimentalChemistry), vol.20, Yuki Gosei (Organic Synthesis) [II], The ChemicalSociety of Japan edits Maruzen Co., Ltd., July 1992, p.94-100).The preferred example of this method comprises i) for example, preferably use the normal alkali of 1.0-5.0, for example preferred lithium diisopropylamine, sodium hydride or sodium methylate, (2a) is converted into the basic metal enolate with amide compound, and subsequently (for example with the method for this enolate and aldehyde cpd (1) reaction, referring to Jikken KagakuKoza (Courses in Experimental Chemistry), vol.20, Yuki Gosei (OrganicSynthesis) [II], The Chemical Society of Japan edits Maruzen Co., Ltd., July 1992, p.97-98); And ii) for example, preferably use the normal alkali of 1.0-5.0, for example preferred lithium diisopropylamine, sodium hydride or sodium methylate, (2a) is converted into the basic metal enolate with amide compound, with this enolate and for example preferred trimethylchlorosilane of silicon halide reagent or TERT-BUTYL DIMETHYL CHLORO SILANE reaction, prepare the silylation enol ether, and subsequently with this ether and aldehyde cpd (1) at Lewis acid, the method of reacting under the existence of for example preferred titanium tetrachloride or boron trifluoride (for example, referring to Jikken Kagaku Koza (Courses in Experimental Chemistry), vol.20, YukiGosei (Organic Synthesis) [II], The Chemical Society of Japan edits, Maruzen Co., Ltd., July 1992, p.96-97).

Used solvent and temperature of reaction change according to raw material, and have no particular limits.For solvent, it is inhibited reaction and allow raw material to be dissolved in wherein in a certain scope not, for example, can preferably use ether solvent, tetrahydrofuran (THF), 1 for example, 4-diox or ether; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride or chloroform; Non-polar solvent is toluene or dimethylbenzene for example; Or its mixed solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference as-78 ℃ to room temperature.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of aldehyde cpd (1)

In following formula, X _aAs hereinbefore defined; L ₁Represent fluorine atom, chlorine atom, bromine atoms, iodine atom, sulfonate ester group such as trifluoromethanesulfonic acid ester group, trialkyltin group, boric acid base group or borate group; And L ₂Represent the C1-C3 alkoxycarbonyl groups, for example methyl ester group, aldehyde groups or cyano group.

The preparation of aldehyde cpd (1)

Aldehyde cpd (1) can be according to step 2-5 from compound (1a) preparation as raw material.Particularly, step 2-5 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.For example, work as L ₂During for alkoxycarbonyl groups, can use the reduction reaction in many known references, described (for example, referring to Jikken Kagaku Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], The Chemical Society of Japan edits, Maruzen Co., Ltd., April 1992, p.159-266).For example, required aldehyde cpd can preferably use the method for reducing of metal hydride such as diisobutyl aluminium hydride to obtain.For example, more preferably, required aldehyde compound can use lithium aluminum hydride or aluminum hydride complex compound, in the presence of amine by method of reducing obtain effectively (for example, referring to people such as T.Abe, " Tetrahedron ", 2001, vol.57, p.2701-2710).

For example, work as L ₂When being cyano group, can use the reduction reaction in many known references, described (for example, referring to Jikken Kagaku Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], The Chemical Society ofJapan edits, Maruzen Co., Ltd., April 1992, p.159-266).For example, required aldehyde cpd can preferably use metal hydride, and for example two (2-methoxy ethoxy) sodium aluminum hydride or diisobutyl aluminium hydride (for example obtains by method of reducing, referring to Jikken Kagaku Koza (Coursesin Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], The Chemical Society of Japan edits, Maruzen Co., Ltd., April 1992, p.231).

Perhaps, required aldehyde cpd can use the technology of well known to a person skilled in the art, by compound (1a) (for example is reduced to alkylol cpd, referring to Jikken Kagaku Koza (Courses inExperimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], The Chemical Society of Japan edits Maruzen Co., Ltd., April 1992, p.159-266) step that also subsequently alkylol cpd is oxidized to aldehyde is synthesized (for example, referring to JikkenKagaku Koza (Courses in Experimental Chemistry), vol.23, Yuki Gosei (Organic Synthesis) [V], The Chemical Society of Japan edits Maruzen Co., Ltd., October 1991, p.1-550).

Alkali used in reduction reaction changes according to raw material, and has no particular limits.Secondary amine can be used as alkali.For example, when preferably using, can obtain required aldehyde cpd effectively with respect to the normal straight chain of 0.1-1.0 of described compound (1a) or ring-type secondary alkyl amine such as diethylamine or tetramethyleneimine.Used solvent and temperature of reaction change according to raw material, and are not particularly limited.For solvent, it is inhibited reaction and allow raw material to be dissolved in wherein in a certain scope not, can preferably use for example ether solvent, as tetrahydrofuran (THF), 1, and 4-diox or ether; Non-polar solvent is toluene or dimethylbenzene for example; Or its mixed solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference as-78 ℃ to room temperature.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The amount of used oxidising agent changes according to raw material in oxidation step, and has no particular limits.Described amount is preferably the 0.1-10 equivalent with respect to described compound (1a).Solvent and temperature of reaction change according to raw material, and have no particular limits.For solvent, it is inhibited reaction and allow raw material to be dissolved in wherein in a certain scope not, can preferably use for example ether solvent, tetrahydrofuran (THF), 1 for example, 4-diox or ether; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride or chloroform; Non-polar solvent is toluene or dimethylbenzene for example; Or its mixed solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as-78 ℃ to 100 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (1a)

For example, can be according to step 2-1 from preparing described compound (1a) from compound (4d) as raw material as the compound (4a) of raw material or according to step 2-4.

Step 2-1

Step 2-1 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.For example, the method in step 2-1 can be used the normal Methylimidazole of 0.3-10 with respect to described compound (4a), carries out substitution reaction from the compound (4a) as raw material.Used solvent and temperature of reaction change according to raw material in this step, and have no particular limits.For solvent, it is inhibited reaction and allow raw material to be dissolved in wherein in a certain scope not, can preferably use for example ether solvent, as tetrahydrofuran (THF), 1, and 4-diox or ether; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride or chloroform; Polar solvent, for example dichlorobenzene, dimethyl formamide or N-Methyl pyrrolidone; Non-polar solvent, for example toluene, dimethylbenzene or sym-trimethylbenzene; Organic bases solvent, for example diazabicylo undecylene, pyridine or triethylamine; Or its mixed solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as 0 ℃ to 200 ℃.In this step, for example can use the normal organic bases of 0.1-10, for example diazabicylo undecylene, pyridine or triethylamine with respect to described compound (4a); Alkali metal alcoholates, for example sodium methylate or potassium tert.-butoxide; Alkali metal hydroxide is sodium hydroxide for example; Or alkaline carbonate for example cesium carbonate or salt of wormwood.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (4a)

Described compound (4a) can be buied or by well known to a person skilled in the art method preparation from commercial.For example, work as X _aWhen being methoxyl group, if can't can prepare described compound (4a) by well known to a person skilled in the art that method methylates corresponding phenolic compound from commercial purchase.

Step 2-4

Step 2-4 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.For example, can prepare required compound (1a) by heating with compound (4d) with respect to the normal ammonia of 1.0-20 of described compound (4d) or ammonium salt.Used solvent and temperature of reaction change according to raw material, and have no particular limits.For solvent, it is inhibited reaction and allow raw material to be dissolved in wherein in a certain scope not, can preferably use for example ether solvent, tetrahydrofuran (THF), 1 for example, 4-diox or ether; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride or chloroform; Alcoholic solvent is ethanol or Virahol for example; Polar solvent, for example dimethyl formamide or N-Methyl pyrrolidone; Non-polar solvent is toluene or dimethylbenzene for example; Organic acid, for example acetate, propionic acid or trifluoroacetic acid; Or its mixed solvent.For example, can be preferably by using the normal ammonium acetate of 1.0-10 in acetic acid solvent to obtain described compound (1a) effectively with respect to described compound (4d).Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference such as room temperature to 200 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 1-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (4d)

For example, can prepare described compound (4d) from compound (4c) according to step 2-3 as raw material.Particularly, step 2-3 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.For example, can be by in the presence of alkali, agitate compounds (4c) and 2-halogen acetone (for example with respect to the normal 2-monochloroacetone of the 0.5-5.0 of described compound (4c), 2-martonite or 2-iodoacetone) obtain described compound (4d).The preferred normal alkali of 0.5-5.0 that uses with respect to described compound (4c).The example of used alkali comprises: alkalimetal hydride, for example sodium hydride and lithium hydride; An alkali metal salt, for example salt of wormwood, yellow soda ash and cesium carbonate; And metal alkoxide for example sodium methylate and tertiary butyl potassium.Used solvent and temperature of reaction change according to raw material, and have no particular limits.For solvent, it is inhibited reaction and allow raw material to be dissolved in wherein in a certain scope not, can preferably use for example ether solvent, tetrahydrofuran (THF), 1 for example, 4-diox or ether; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride or chloroform; Polar solvent, for example dimethyl formamide or N-Methyl pyrrolidone; Non-polar solvent is toluene or dimethylbenzene for example; Or its mixed solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference such as room temperature to 200 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 1-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (4c)

For example, can perhaps use formic acid and dehydrating condensation reagent for example to be preferably the method for acid anhydrides or dicyclohexylcarbodiimide, obtain required compound (4c) by the method for reflux compound (4b) in formic acid.For example, can obtain described compound (4c) effectively by using for example to be preferably the normal formic acid of 1-20 and to be preferably 1-3 normal dehydrating condensation reagent.Used solvent changes according to raw material, and has no particular limits.For solvent, it is inhibited reaction and allow raw material to be dissolved in wherein in a certain scope not, can preferably use for example ether solvent, tetrahydrofuran (THF), 1 for example, 4-diox or ether; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride or chloroform; Polar solvent, for example dimethyl formamide or N-Methyl pyrrolidone; Non-polar solvent is toluene or dimethylbenzene for example; Or its mixed solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference such as room temperature to 100 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 1-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (4b)

Described compound (4b) can be buied or by well known to a person skilled in the art method preparation by commercial.For example, work as X _aWhen being methoxyl group,, can corresponding nitrophenol compound being methylated, and reduce nitryl group subsequently and prepare described compound (4b) by well known to a person skilled in the art method if can't be from commercial purchase.

The preparation of amide compound (2a)

In formula, L ₁, R ¹, R ², R ³, R ⁴, R ⁵(work as R ⁵When containing oh group, it can have protecting group); X ₁(work as X ₁When containing oh group, it can have protecting group); Ar ₁, Ar _1-C, Z ₁, m and n as hereinbefore defined; X _bRepresention oxygen atom; V ₁The protecting group of represention oxygen atom, for example methyl, ethyl, benzyl, allyl group, trityl group, the tertiary butyl or tertiary butyl dimethylsilyl; And V ₂Represent the blocking group of nitrogen-atoms, for example tert-butoxycarbonyl or benzyloxycarbonyl.

Above-mentioned reaction formula has shown the example of the method for preparing amide compound (2a).Particularly, this reaction formula has shown following method: (i) comprise according to step 3-1 and will be converted into compound (5c) as the amine compound (5a) of raw material, and in step 3-2, form the method for oxo morpholine ring subsequently, described amine compound (5a) be from commercial buy or use well known to a person skilled in the art the method preparation; (ii) comprise according to step 3-3 and will be converted into compound (5c), and work as X subsequently as the compound (5b) of raw material ₁When substituting group comprises at least one hydrogen atom, in step 3-2, form the method for oxo morpholine ring, described compound (5b) be from commercial buy or use well known to a person skilled in the art the method preparation; Or (iii) comprise according to step 3-4 and will be converted into compound (5p) by reacting as the compound (5m) of raw material with organometallic reagent (5n); in step 3-5, deprotection reaction and the intramolecularly reductive amination process of compound (5p) by nitrogen-atoms is converted into compound (5q); in step 3-6, the deprotection reaction of compound (5q) by Sauerstoffatom is converted into compound (5c); and in step 3-2, form the method for oxo morpholine ring subsequently, described compound (5m) be from commercial buy or use well known to a person skilled in the art the method preparation.

Compound (5c) is converted into amide compound (2a)

Step 3-2 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be undertaken by well known to a person skilled in the art method.For example, this reaction is preferred in the two-phase solvent that comprises organic solvent and alkaline solution, carry out easily by vigorous stirring compound (5c) with respect to the normal compound of 1.0-10 (5f) of described compound (5c).Used solvent and temperature of reaction change according to raw material, and have no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent wherein in a certain scope.The example of operable preferred solvent comprises: ether solvent is ether for example; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride and chloroform; And non-polar solvent, for example toluene and dimethylbenzene.The example of operable preferred alkaline solution comprises alkali metal salt soln, for example sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, cesium carbonate and sodium bicarbonate.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference as-78 ℃ to room temperature.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

For example, preferably, when mixing with compound (5c) with respect to the normal compound of 1.0-10 (5f) of described compound (5c) under alkaline condition, this reaction can be carried out easily.Used solvent and temperature of reaction change according to raw material, and have no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent wherein in a certain scope.The example of operable preferred solvent comprises: ether solvents, for example ether and tetrahydrofuran (THF); Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride and chloroform; With non-polar solvent for example toluene and dimethylbenzene.Used alkali changes according to raw material, and has no particular limits.The amount of described alkali is preferably with respect to the 1.0-10 equivalent of described compound (5c).The example of operable alkali comprises an alkali metal salt, for example sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, cesium carbonate and sodium bicarbonate; And organic bases, for example diazabicylo undecylene, pyridine, 4-dimethylaminopyridine and triethylamine.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference as-78 ℃ to room temperature.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (5f)

Compound (5f) can or can prepare by well known to a person skilled in the art method by commercial purchase.For example, preferably chloro-acetyl chloride or bromo acetyl bromide of described compound (5f).

The preparation of compound (5c)

Compound (5c) can or can prepare by well known to a person skilled in the art method from commercial purchase.For example, described compound (5c) can preferably prepare by the following method: (i) will be converted into compound (5c) as the aminated compounds (5a) of raw material according to step 3-1, described compound (5a) is to buy or by well known to a person skilled in the art method preparation from commercial; (ii) will be converted into compound (5c) as the aminated compounds (5b) of raw material according to step 3-3, described compound (5b) is to buy or by well known to a person skilled in the art method preparation from commercial; Or (iii) will be converted into compound (5p) by reacting as the compound (5m) of raw material with organometallic reagent (5n) according to step 3-4; in step 3-5, deprotection reaction and the intramolecularly reductive amination process of compound (5p) by nitrogen-atoms is converted into compound (5q); in step 3-6 compound (5q) is converted into compound (5c) by the Sauerstoffatom deprotection reaction, described compound (5m) is to buy or by well known to a person skilled in the art method preparation from commercial.

Compound (5a) is converted into compound (5c)

Step 3-1 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.The preferred example of this method comprises and uses compound (5a) and with respect to the ring-opening reaction of the normal oxirane compound of 1.0-10 (5d) of described compound (5a).Used solvent and temperature of reaction change according to raw material, and have no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent wherein in a certain scope, or its mixed solvent.The example of solvent for use comprises for example ether of ether solvent; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride and chloroform; And non-polar solvent, for example toluene and dimethylbenzene.Do not having can to obtain result preferably under the condition of solvent yet.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference such as room temperature to 300 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.Also preferred by adding Lewis acid, for example boron trifluoride, tetraisopropoxy titanium or lithium perchlorate carry out this reaction (for example, referring to Synthesis, 2004, vol.10, p.1563-1565).

The preparation of compound (5a)

Compound (5a) can or can prepare by well known to a person skilled in the art method from commercial purchase.If not from commercial purchase, described compound (5a) can by described in the document and well known to a person skilled in the art that method (for example prepares, referring to Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu NoGosei To Hannou (Synthesis and Reaction of Organic Compounds) [III], The Chemical Society of Japan edits, Maruzen Co., Ltd., February 1978, p.1332-1399).The preferred example of this method comprises: the method that i) corresponding carbonyl derivative is converted into compound (5a) by reductive amination process; Ii) the carbonyl derivative with correspondence is reduced to alcohol derivate, by well known to a person skilled in the art that substitution reaction (for example prepares the amine Equivalent from alcohol derivate, preferred azido group or imine group), and subsequently the amine Equivalent is converted into the method for compound (5a) by well known to a person skilled in the art conversion reaction; Iii) the carbonyl derivative with correspondence is converted into 9 oxime derivate, and subsequently 9 oxime derivate is reduced to the method for compound (5a) by well known to a person skilled in the art reduction reaction; Iv) alkane compound is converted into alcohol derivate by oxidizing reaction, by well known to a person skilled in the art that substitution reaction (for example prepares the amine Equivalent from alcohol derivate, preferred azido group or imine group), and subsequently the amine Equivalent is converted into the method for compound (5a) by well known to a person skilled in the art conversion reaction; V) the alkane compound with correspondence is converted into aminoalcohol derivative by addition reaction, and aminoalcohol derivative is converted into the method for compound (5a) by well known to a person skilled in the art conversion reaction.Described compound (5a) can from the optically active compound of commercial purchase or by well known to a person skilled in the art method prepare (for example, referring to Chem.Rev., 1994, vol.94, p.2483-2547; Tetrahedron Letters, 1996, vol.37, p.3219-3222; With Organic Letters, 2000, vol.2, p.2821-2824).Can prepare optically active The compounds of this invention from described material as raw material.

The preparation of oxirane compound (5d)

Oxirane compound (5d) can or can prepare by well known to a person skilled in the art method from commercial purchase.If not from commercial purchase, this oxirane compound (5d) can by described in the document and well known to a person skilled in the art that method (for example prepares, referring to ShinJikken Kagaku Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of OrganicCompounds) [I], The Chemical Society of Japan edits, Maruzen Co., Ltd., November 1977, p.567-611).Described compound (5d) is as activity of optically active compounds, can be from commercial purchase or by well known to a person skilled in the art that method (for example prepares, referring to K.B.Sharpless etc., " Comprehensive Organic Synthesis ", B.M.Trost, Pergamon, 1991, vol.7, ch.3-2).Can prepare optically active The compounds of this invention from described material as raw material.

Compound (5b) is converted into compound (5c)

Step 3-3 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.Preferably, this method can be compound (5b) with the reductive amination process of carbonyl reaction thing (5e) (for example, referring to ShinJikken Kagaku Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction of OrganicCompounds) [III], The Chemical Society of Japan edits, Maruzen Co., Ltd., February 1978, p.1380-1384).For example, this method is reflux carbonyl compound (5e) and the normal compound of 0.5-5.0 (5b) in the presence of acid catalyst preferably, mineral acid example hydrochloric acid or sulfuric acid that for example described acid catalyst is more preferably commonly used, organic acid is methylsulfonic acid for example, tosic acid or camphorsulfonic acid, or organic acid salt tosic acid pyridinium salt (for example preferred 0.01-0.5 equivalent) for example, to cause dehydration reaction, and pass through preferably with respect to the normal metal hydride of imine derivative 1.0-10, for example lithium aluminum hydride or sodium borohydride are reduced to required sulfonamide derivatives with the gained imine derivative.Can also inert solvent for example in the tetrahydrofuran (THF), in the presence of for example preferred tetraisopropoxy titanium of lewis acid catalyst (for example preferred 0.01-0.5 equivalent), with carbonyl compound (5e) and the normal compound of 0.5-5.0 (5b) reaction, and pass through for example sodium borohydride reduction resultant of the normal metal hydride of 1.0-10 subsequently.For example, also preferred the use for example passed through the normal metal hydride of preferred 1.0-10 for example sodium triacetoxy borohydride or sodium cyanoborohydride, at for example preferred methylene dichloride, 1 of inert solvent, in 2-ethylene dichloride, tetrahydrofuran (THF), methyl alcohol or the ethanol, with carbonyl derivative (5e) and the preferred normal compound of 0.5-5.0 (5b) reductive method, obtain required sulfonamide derivatives.For example, carry out easily, preferably add the normal acidic substance of 1.0-10, for example acetate or hydrochloric acid in order to make reaction.Temperature of reaction changes according to raw material, and has no particular limits.But temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference such as room temperature to 100 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (5b)

Compound (5b) can or can prepare by well known to a person skilled in the art method from commercial purchase.If not from commercial purchase, described compound (5b) can by describe in the document and well known to a person skilled in the art that method (for example prepares, referring to Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu NoGosei To Hannou (Synthesis and Reaction of Organic Compounds) [III], The Chemical Society of Japan edits, Maruzen Co., Ltd., February 1978, p.1332-1399).Described compound (5b) as activity of optically active compounds can from commercial purchase or by well known to a person skilled in the art method prepare (for example, referring to Tetrahedron Letters, 1996, vol.37, p.3219-3222).Can prepare optically active The compounds of this invention from described material as raw material.

The preparation of carbonyl compound (5e)

Carbonyl compound (5e) can or can prepare by well known to a person skilled in the art method from commercial purchase.If not from commercial purchase, carbonyl compound (5e) can by describe in the document and well known to a person skilled in the art that method (for example prepares, referring to Shin Jikken KagakuKoza (New Courses in Experimental Chemistry), vol.14, Yuki KagobutsuNo Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [II], The Chemical Society of Japan edits, Maruzen Co., Ltd., December 1977, p.633-875).

Compound (5q) is converted into compound (5c)

Step 3-6 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.Can use well known to a person skilled in the art guard method (for example, referring to people such as T.Greene, " Protective Groups in Organic Synthesis ", John Wiley ﹠amp; Sons, Inc., New York, 1981).Perhaps, work as R ¹And R ²Each for example can be preferably by preparing wherein R naturally during hydrogen atom ¹And R ²The compound (5q) (as ester derivative) that forms carbonyl carries out step 3-6, and subsequently by well known to a person skilled in the art that reduction reaction reduces this ester derivative.

The preparation of compound (5q)

Compound (5q) can or can prepare by well known to a person skilled in the art method from commercial purchase.For example, if not from commercial purchase, can preferably prepare described compound (5q) from compound (5p) as raw material according to step 3-5.Particularly, described compound (5q) can be preferably by well known to a person skilled in the art that guard method sloughs blocking group (for example referring to T.Greene etc. to the nitrogen-atoms of compound (5p), " Protective Groups in Organic Synthesis ", John Wiley ﹠amp; Sons, Inc., New York, 1981), two steps of subsequently described compound being carried out the intramolecularly reductive amination process (for example are prepared, referring to Shin Jikken KagakuKoza (New Courses in Experimental Chemistry), vol.14, Yuki KagobutsuNo Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [III], The Chemical Society of Japan edits, Maruzen Co., Ltd., February 1978, p.1380-1384).Perhaps, for example can preferably use wherein R ¹And R ²The compound (5p) that forms carbonyl carries out these steps as raw material.

The preparation of compound (5p)

Compound (5p) can or can prepare by well known to a person skilled in the art method from commercial purchase.For example, if not from commercial purchase, can preferably prepare described compound (5q) from compound (5m) as raw material according to step 3-4.For example, described compound (5p) can be by preparing compound (5m) and the normal organometallic reagent of 0.5-5.0 (5n) through well known to a person skilled in the art nucleophilic reaction easily, and described compound (5m) can be buied or by well known to a person skilled in the art the method preparation by commercial.Used solvent changes according to raw material, and has no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent wherein in a certain scope, or its mixed solvent.The example of solvent for use comprises ether solvent, for example ether and tetrahydrofuran (THF); Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride and chloroform; And non-polar solvent, for example toluene and dimethylbenzene.Temperature of reaction changes according to raw material, and has no particular limits.But temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as-78 ℃ to 50 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.Perhaps, for example preferably use wherein R ¹And R ²The compound (5m) that forms carbonyl is as raw material.

The preparation of compound (5m)

Compound (5m) can or can prepare by well known to a person skilled in the art method from commercial purchase.If not from commercial purchase, for example can be preferably by corresponding raw material being well known to a person skilled in the art protective reaction (for example obtains described compound (5m), referring to people such as T.Greene, " Protective Groups in Organic Synthesis ", John Wiley ﹠amp; Sons, Inc., New York, 1981; Or people such as T.Sakamoto, " J.Org.Chem. ", 1996, vol.61, p.8496).Perhaps, for example preferably use wherein R ¹And R ²The compound that forms carbonyl is as raw material.

General preparation method 2

Will be described below the general preparation method 2 of the compound that is generally used for general formula of the present invention (I).

In formula, Ar ₁, R ¹, R ², R ³, R ⁴, L ₁, X ₁, X _aAnd X _bAs hereinbefore defined; L ₃Represent triphenyl phosphonium group, phosphorous acid ester group or silylation; And the blocking group of V representation carboxy group, for example methyl, ethyl, benzyl, allyl group, trityl group, the tertiary butyl or tertiary butyl dimethyl are silica-based.

Above-mentioned general preparation method 2 comprises: the method that for example aldehyde cpd (1) and amide compound (2b) condensation in step 4-1 is prepared the compound of general formula (I), perhaps for example with aldehyde cpd (1) and ester cpds (6a) condensation in step 4-1, and subsequently gained compound (6b) and amine compound (5a) are reacted the method for the compound for preparing general formula (I) in step 4-2.

Step 4-1

The condensation reaction of step 4-1 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.The currently known methods of describing in a lot of documents can be used for this reaction.The preferred example of this method (for example comprises Wei Dixi (Wittig) reaction, Huo Na-Ai Mengsi (Horner-Emmons) reaction and Peter gloomy (Peterson) reaction, referring to Jikken Kagaku Koza (Courses inExperimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [I], TheChemical Society of Japan edits Maruzen Co., Ltd., June 1992, p.57-85).

Wittig reaction carries out by use compound (2b) or (6a), wherein L ₃It is the triphenyl phosphonium halogen; For example, preferably use the normal aldehyde cpd of 0.8-1.5 (1); And for example preferably use the normal alkali of 1.0-5.0.This reaction can be following method: i) at first form phosphorus ylide with compound (2b) or (6a) with alkali reaction, subsequently aldehyde cpd (1) is added ylide; Or (ii) add alkali at compound (2b) or (6a) and in the presence of the aldehyde cpd (1).From operability and mixing effect, this reaction is preferably carried out in the presence of solvent.Used solvent changes according to raw material and used alkali, and solvent has no particular limits except inhibited reaction and permission raw material are not dissolved in wherein in a certain scope.The preferred example of solvent comprises polar solvent, for example Nitromethane 99Min., acetonitrile, 1-Methyl-2-Pyrrolidone, N, dinethylformamide and dimethyl sulfoxide (DMSO); Ether solvent, tetrahydrofuran (THF), 1 for example, 4-diox and 1,2-glycol dimethyl ether; Non-polar solvent, for example benzene, toluene and dimethylbenzene; Alcoholic solvent is ethanol and methyl alcohol for example; Halogenated solvent, for example chloroform and methylene dichloride; Water; And mixed solvent.Used alkali changes according to raw material and solvent.The example of preferred alkali comprises alkali metal hydroxide, for example sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline carbonate, for example yellow soda ash, salt of wormwood and sodium bicarbonate; Alkali metal alcoholates is sodium methylate and potassium tert.-butoxide for example; Organic bases, for example triethylamine, pyridine and Diazabicyclononene; Organometallic compound is butyllithium and diisobutyl acid amides lithium for example; With alkalimetal hydride sodium hydride for example.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preferably for example-78 to 150 ℃.Under preferred reaction conditions, this is reflected in 1-24 hour and finishes, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

Huo Na-Ai Mengsi reaction is used compound (2b) or (6a) is carried out, wherein L ₃It is phosphorous acid ester; For example preferably use the normal aldehyde cpd of 0.8-1.5 (1); And for example preferably use the normal alkali of 1.0-5.0.This reaction can be following method: i) at first form carbanion with compound (2b) or (6a) with alkali reaction, subsequently aldehyde cpd (1) is added carbanion; (ii) compound (2b) or (6a) and aldehyde cpd (1) in the presence of add alkali.From operability and mixing effect, this reaction is preferably carried out in the presence of solvent.Solvent for use changes according to raw material and used alkali, and solvent has no particular limits except inhibited reaction and permission raw material are not dissolved in wherein in a certain scope.The preferred example of solvent comprises polar solvent, for example 1-Methyl-2-Pyrrolidone, N, dinethylformamide and dimethyl sulfoxide (DMSO); Ether solvent is tetrahydrofuran (THF), 1 for example, 4-diox and 1,2-glycol dimethyl ether; Non-polar solvent, for example benzene, toluene and dimethylbenzene; Alcoholic solvent is ethanol and methyl alcohol for example; Water; And mixed solvent.Used alkali changes according to raw material and solvent.The example of preferred alkali comprises alkali metal hydroxide, for example sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline carbonate, for example yellow soda ash, salt of wormwood and sodium bicarbonate; Alkali metal alcoholates is sodium methylate and potassium tert.-butoxide for example; Organic bases, for example triethylamine, pyridine and Diazabicyclononene; Organometallic compound, for example butyllithium and diisobutyl acid amides lithium; Alkalimetal hydride is sodium hydride for example; With basic metal ammonium salt sodium amide for example.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as-78 to 150 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 1-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The gloomy reaction of Peter is used compound (2b) or (6a) is carried out, wherein L ₃It is silylation; For example preferably use the normal aldehyde cpd of 0.8-1.5 (1); And for example preferably use the normal alkali of 1.0-5.0.This reaction can be following method: i) at first form carbanion with compound (2b) or (6a) with alkali reaction, subsequently aldehyde cpd (1) is added carbanion; (ii) compound (2b) or (6a) and aldehyde cpd (1) in the presence of add alkali.From operability and mixing effect, this reaction is preferably carried out in the presence of solvent.Solvent for use changes according to raw material and used alkali, and solvent has no particular limits except inhibited reaction and permission raw material are not dissolved in wherein in a certain scope.The preferred example of solvent comprises polar solvent, for example 1-Methyl-2-Pyrrolidone, N, dinethylformamide and dimethyl sulfoxide (DMSO); Ether solvent, tetrahydrofuran (THF), 1 for example, 4-diox and 1,2-glycol dimethyl ether; Non-polar solvent, for example benzene, toluene and dimethylbenzene; Alcoholic solvent is ethanol and methyl alcohol for example; Water; And mixed solvent.Used alkali changes according to raw material and solvent.The example of preferred alkali comprises alkali metal hydroxide, for example sodium hydroxide, potassium hydroxide and lithium hydroxide; Alkaline carbonate, for example yellow soda ash, salt of wormwood and sodium bicarbonate; Alkali metal alcoholates, for example sodium methylate and potassium tert.-butoxide; Organic bases, for example triethylamine, pyridine and Diazabicyclononene; Organo-metallic is butyllithium and diisobutyl acid amides lithium for example; Alkalimetal hydride is sodium hydride for example; With basic metal ammonium salt sodium amide for example.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as-78 to 150 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 1-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

Step 4-2

Step 4-2 is the example that compound (6b) and amine compound (5a) is reacted the method for the compound that also subsequently reaction product is converted into general formula (I).The example of this step comprises following method: i) by well known to a person skilled in the art that blocking group that method sloughs compound (6b) (for example, referring to people such as T.Greene, " Protective Groups in Organic Synthesis " (John Wiley ﹠amp; Sons.Inc., New York, 1981), by well known to a person skilled in the art method described compound and amine compound (5a) (are for example carried out dehydration condensation, referring to Shin Jikken Kagaku Koza (NewCourses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei ToHannou (Synthesis and Reaction of Organic Compounds) [III], TheChemical Society of Japan edits, Maruzen Co., Ltd., February 1978, p.1136-1162; With " Yukikagaku Jikken No Tebiki (Introduction to OrganicChemistry Experiments) [4] ", Kagaku-Dojin Publishing Company, Inc., September 1990, p.27-52), handle the compound that condenses is converted into general formula (I) down by alkaline condition subsequently; Ii), resultant is converted into the compound of general formula (I) by follow-up intramolecularly amination reaction by well known to a person skilled in the art that method with compound (6b) and amine compound (5a) coupling, sloughs blocking group.In this step, compound (6b) and amine compound (5a) are selecting can be converted into the compound of general formula (I) through single step reaction under the proper reaction conditions.

The preparation of amides (2b)

In following formula, Ar ₁, L ₁, L ₃, R ¹, R ², R ³, R ⁴, X ₁And X _bAs hereinbefore defined; And R ⁷Represent low-grade alkyl group.

Above-mentioned reaction formula has shown the example of the method for preparing amide compound (2b).Particularly, can prepare amide compound (2b) by well known to a person skilled in the art method, but this method changes according to raw material.The preferred example of this method comprises: according to step 5-1 from prepare the method for amide compound (2b) as the amide compound (2a) of raw material; In step 5-2, will be converted into compound (2c), and in step 5-3, described compound (2c) will be converted into the method for amide compound (2b) subsequently as the compound (5c) of raw material; And in step 5-2, will be converted into compound (5k), and in step 5-4, described compound (5k) is converted into the method for amide compound (2b) subsequently as the compound (5j) of raw material.

Amide compound (2a) is converted into amide compound (2b)

Step 5-1 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.Preferably, for example step 5-1 is i) wittig reaction, wherein L ₃It is the triphenyl phosphonium group, this reaction is by well known to a person skilled in the art that method with amide compound (2a) halogenation (for example, referring to Jikken KagakuKoza (Courses in Experimental Chemistry), vol.19, Yuki Gosei (OrganicSynthesis) [I], The Chemical Society of Japan edits, Maruzen Co., Ltd., June 1992, p.430-438), and subsequently with the method for described compound and triphenylphosphine reaction (for example, referring to Organic Reaction, 1965, vol.14, p.270).Perhaps, step 5-1 is that ii) Huo Na-Ai Mengsi reacts, wherein L ₃It is phosphorous acid ester, this reaction is by well known to a person skilled in the art that method with amide compound (2a) halogenation (for example, referring to Jikken Kagaku Koza (Courses inExperimental Chemistry), vol.19, Yuki Gosei (Organic Synthesis) [I], TheChemical Society of Japan edits, Maruzen Co., Ltd., June 1992, p.430-438), and subsequently described compound and alkyl phosphite are reacted (for example, referring to Chemical Review, 1981 by A Buzuofu (Arbuzov), vol.81, p.415), or with described compound and metal phosphinates by your (Becker) reaction of Bake (for example, referring to Journal of theAmerican Chemical Society, 1945, p.1180) vol.67 prepares the method for amide compound (2b).Perhaps, step 5-1 can use in the presence of alkali, from amide compound (2a) and chloro phosphoric acid ester prepare amide compound (2b) method (for example, referring to The Journal of OrganicChemistry, 1989, vol.54, p.4750).Perhaps, step 5-1 is the iii) gloomy reaction of Peter, wherein L ₃Be silylation, this reaction be in the presence of alkali from amide compound (2a) and trialkyl silyl muriate prepare amide compound (2b) method (for example, referring to Journal of OrganometallicChemistry, 1983, vol.248, p.51).

Amide compound (2c) is converted into amide compound (2b)

Step 5-3 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.Preferably, for example the method for step 5-3 can (for example be reduced to alkylol cpd with the carbonyl moiety of ester, referring to JikkenKagaku Koza (Courses in Experimental Chemistry), vol.26, Yuki Gosei (Organic Synthesis) [VIII], The Chemical Society of Japan edits, MaruzenCo., Ltd., April 1992, p.159-266), again alkylol cpd (for example is converted into halogen compounds, referring to Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.14, Yuki Kagobutsu No Gosei To Hannou (Synthesis and Reaction ofOrganic Compounds) [I], The Chemical Society of Japan edits MaruzenCo., Ltd., November 1977, p.331-450), and halogen compounds (for example are converted into Wei Dixi reagent (2b), referring to Organic Reaction, 1965, vol.14, p.270), perhaps (for example by the A Buzuofu reaction, referring to Chemical Review, 1981, p.415) vol.81 is converted into Huo Na-Ai Mengsi reagent (2b).Perhaps, this alcohol compound can by with the basic Phosphonium hydrobromate reaction of three alkene third, be converted into Wei Dixi reagent (2b) (for example, referring to Synth.Commun., 1996, vol.26, p.3091-3095; With Tetrahedron Lett., 2001, vol.42, p.1309-1331).

The preparation of amide compound (2c)

Amide compound (2c) can prepare by well known to a person skilled in the art method, but this method changes according to raw material.Preferably, for example can prepare amide compound (2c) from compound (5c) by step 5-2 as raw material.Preferably, for example in this step, carry out this reaction easily by vigorous stirring compound (5c) in comprising the two phase reaction solvent of organic solvent and basic solution with respect to the normal compound of 1.0-10 (5g) of described compound (5c).Used solvent and temperature of reaction change according to raw material, and have no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent or its mixed solvent wherein in a certain scope.The preferred example of operable organic solvent comprises for example ether of ether solvent; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride and chloroform; And non-polar solvent, for example toluene and dimethylbenzene.Preferably use 1.0 or bigger normal basic solution.The preferred example of operable basic solution comprises alkali metal salt soln, for example sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, cesium carbonate and sodium bicarbonate.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, preference as-78 ℃ to room temperature.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

Step 5-2 also can use following method: for example, compound (5c) at interior organic amine (is for example for example preferably included triethylamine, sec.-propyl ethylamine or pyridine at alkali, preferred 1.0-5.0 equivalent) exists down, preferably react with the normal compound of 1.0-5.0 (5g).Used solvent and temperature of reaction change according to raw material, and have no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent wherein in a certain scope.The preferred example of operable organic solvent comprises for example ether of ether solvent; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride and chloroform; And non-polar solvent, for example toluene and dimethylbenzene.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as-78 ℃ to 100 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

In step 5-2, heating compound (5c) and with respect to the normal compound of 1.0-20 (5h) of described compound (5c), wherein R ⁷Be low alkyl group, this reaction can be carried out easily.Used solvent and temperature of reaction change according to raw material, and have no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent wherein in a certain scope, or its mixed solvent.The preferred example of operable organic solvent comprises for example ether of ether solvent; Halogenated solvent, methylene dichloride, 1 for example, 2-ethylene dichloride and 1,2-dichlorobenzene; Non-polar solvent, for example toluene and dimethylbenzene; Polar solvent, for example dimethyl formamide and N-Methyl pyrrolidone; And alcoholic solvent, for example methyl alcohol, ethanol, 2-propyl alcohol and the trimethyl carbinol.This reaction can also be carried out under the condition of solvent easily not having.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as 50 ℃ to 200 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

In step 5-2, when using compound (5c) and the normal compound of 1.0-5.0 (5i) under the condition of above-mentioned reaction conditions or its combination, this reaction also can be carried out easily.This reaction can also be by adding phase-transfer catalyst, as quaternary ammonium salt for example tetrabutylammonium chloride or benzyltriethylammoinium chloride, or acidic cpd for example tosic acid or camphorsulfonic acid and carry out easily.

Compound (5g), (5h) and preparation (5i)

Compound (5g), (5h) and (5i) can or can prepare from commercial purchase by well known to a person skilled in the art method.If not from commercial purchase, can be by well known to a person skilled in the art that method is carried out esterification with corresponding oxalic acid derivative or halogenation prepares described compound.

Compound (5k) is converted into oxo morpholinium compound (2b)

Step 5-4 changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.This reaction can be used the method for well known to a person skilled in the art.Preferably, for example the method for step 5-4 can be by oxidative cracking reaction and intramolecular cyclization the alkene of compound (5k) (for example partly to be converted into the hemiacetal derivative, referring to Shin Jikken KagakuKoza (New Courses in Experimental Chemistry), vol.14, Yuki KagobutsuNo Gosei To Hannou (Synthesis and Reaction of Organic Compounds) [I], The Chemical Society of Japan edits, Maruzen Co., Ltd., November 1977, p.331-450), and with the hemiacetal derivative be converted into Wei Dixi reagent (2b) (for example, referring to OrganicReaction, 1965, vol.14, p.270) or by the A Buzuofu reaction be converted into Huo Na-Ai Mengsi reagent (2b) (for example, referring to Chemical Review, 1981, vol.81, p.415).This hemiacetal derivative can also by with the basic Phosphonium hydrobromate reaction of three alkene third be converted into Wei Dixi reagent (2b) (for example, referring to Synth.Commun., 1996, vol.26, p.3091-3095; With Tetrahedron Lett., 2001, vol.42, p.1309-1331).The oxidative cracking reaction of alkene part changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.For example, preferred ozone oxidation is (for example referring to Shin Jikken Kagaku Koza (New Courses in ExperimentalChemistry), vol.15, Sanka To Kangen (Oxidation and Reduction) [I-2], The Chemical Society of Japan edits Maruzen Co., Ltd., September 1976, p.563-603).Oxidative cracking reaction and intramolecular cyclization can carry out under proper reaction conditions continuously, and it is very convenient for preparation compound (2b).

The preparation of compound (5k)

For example, compound (5k) can be according to step 5-2, from compound (5j) with preferably prepare with respect to the normal compound of 1.0-5.0 (5i) of described compound (5j).

The preparation of compound (5j)

Compound (5j) can or can prepare by well known to a person skilled in the art method from commercial purchase.If, for example work as R not from commercial purchase ⁴And X ₁During interconnection formation nitrogen heterocyclic ring, described compound (5i) is preferably by using metal catalyst, to contain the aminated compounds of propadiene base or sulfamide compound carries out the intramolecularly hydroamination reaction and (for example prepares, referring to Journal ofThe American Chemical Society, 2003, vol.125, p.11956; And TetrahedronLett., 1998, vol.39, p.5421-5424).This reaction changes according to raw material, and is no particular limitation within the scope of the reaction conditions that is similar to this reaction.For example, metal catalyst is the normal palladium complex of 0.001-0.1 preferably, for example acid chloride (II), dichloro two (triphenylphosphine) palladium (II), tetrakis triphenylphosphine palladium (0) or allyl palladium chloride dimer.For example, this reaction can also be by preferably adding the normal phosphorus part of 0.001-0.1, for example preferred 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl or 1,1 '-two (diphenylphosphino) ferrocene carries out easily.For example, this reaction can also be carried out easily by preferably adding normal acetate of 0.001-10 or hydrochloric acid.Used solvent and temperature of reaction change according to raw material, and have no particular limits.Preferred not inhibited reaction and permission raw material are dissolved in solvent or its mixed solvent wherein in a certain scope.The preferred example of operable organic solvent comprises ether solvent for example ether and tetrahydrofuran (THF); Halogenated solvent, methylene dichloride and 1 for example, 2-ethylene dichloride; Non-polar solvent is toluene and dimethylbenzene for example; Polar solvent is dimethyl formamide and N-Methyl pyrrolidone for example; And alcoholic solvent, for example methyl alcohol, ethanol, 2-propyl alcohol and the trimethyl carbinol.Temperature of reaction must make the by product that reacts completely and can not promote not expect form, and preference is as 50 ℃ to 200 ℃.Under preferred reaction conditions, this reaction is preferably for example finished in 0.5-24 hour, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can be by well known to a person skilled in the art technology, and for example Chang Gui chromatographic technique, extraction are or/and the removal of crystalline method.

The preparation of compound (6a)

In formula, R ¹, R ², R ³, R ⁴, V, L ₁, L ₃And X _bAs hereinbefore defined; And L ₄As L ₁Define.

Above-mentioned reaction formula has shown the example of preparation compound (6a).Particularly, described compound (6a) can from commercial purchase maybe can by above-mentioned reaction formula represented and well known to a person skilled in the art technology obtain (for example, referring to people such as C.Patois, " Synth.Commun. ", 1991, vol.22, p.2391; With people such as J.A.Jackson, " J.Org.Chem. ", 1989, vol.20, p.5556).For example, step 6-1 be under alkaline condition, by with phosphate compound (6c) with obtain required compound (6a) with respect to the reaction of the normal compound of 1.0-2.0 (6d) of phosphate compound (6c).Perhaps, for example step 6-2 is under alkaline condition, by compound (6e) and the normal ester cpds of 1.0-2.0 (6f) reaction are obtained required compound (6a).For example, required compound (6a) can also obtain from compound (6g) according to step 5-1 mentioned above.

Alkali used in this step changes according to raw material, and without limits.For example, preferably use the normal alkali of 1.0-1.5, for example sodium hydride, n-Butyl Lithium, lithium diisopropylamine, two (trimethyl silicon based) acid amides lithium or two (trimethyl silicon based) acid amides sodium.The solvent used in this step changes according to raw material, and it has no particular limits except inhibited reaction and permission raw material are not dissolved in wherein in a certain scope.The preferred example of solvent comprises hexane, toluene, ether, tetrahydrofuran (THF), N, dinethylformamide, hexamethyl phosphoric triamide and aforesaid mixed solvent.Temperature of reaction must make the by product that reacts completely and can not promote not expect form preferred-78 ℃ to 150 ℃.Under preferred reaction conditions, it is complete that this is reflected at 1-24 hour internal reaction, and the process of this reaction can be monitored by known chromatographic technique.The by product of not expecting can by well known to a person skilled in the art technology for example the conventional chromatogram technology or/and crystallization process remove.

Phosphate compound (6c), compound (6d), compound (6e), ester cpds (6f) and compound (6g) used in this step can maybe can obtain by well known to a person skilled in the art technology from commercial purchase.

The compound or pharmaceutically acceptable salt thereof of general formula of the present invention (I) has the effect that reduces A β 40 or A β 42 generations, therefore as the medicine that prevents or treat the disease that causes by amyloid beta, and for the neurodegenerative disease that is caused by A β, for example alzheimer's disease or mongolism are effective especially as prevention or medicine for it.

Comprise that compound in the present invention demonstrates extraordinary medicine usefulness aspect for example external activity, activity in vivo, solubleness, stability, pharmacokinetics and reduction toxicity.

The prevention of the present invention or the curative drug that are used for the disease that A β causes can prepare by ordinary method.The example of preferred formulation comprises tablet, pulvis, microgranules, granule, coated tablet, capsule, syrup, lozenge, inhalation, suppository, injection, ointment, ophthalmic solution agent, ophthalmic ointment, nasal drop, ear drop, paste and lotion.Can be by using the conventional batching of using for example vehicle, tackiness agent, lubricant, tinting material and correctives, and the batching of just using in case of necessity for example stablizer, emulsifying agent, absorption enhancer, tensio-active agent, pH regulator agent, sanitas and antioxidant prepare described treatment or preventive medicine, and can be by preparing described medicine with the batch mixes that is commonly used for the pharmaceutical preparation material.The example of described batching comprises animal and plant oil, for example soybean oil, butter and synthetic glyceryl ester; Hydrocarbon polymer, for example whiteruss, squalane and solid paraffin; Ester class oil, for example tetradecanoic acid octyl group dodecyl ester and Isopropyl myristate; Higher alcohols for example cetostearyl alcohol with behenyl alcohol; Silicone resin; Silicone oil; Tensio-active agent, for example polyoxyethylene fatty acid ester, sorbitan-fatty acid ester, glycerol fatty acid ester, polyoxyethylene sorbitan aliphatic ester, polyoxyethylene hydrogenated castor oil and polyox-yethylene-polyoxypropylene block copolymer; Water-soluble polymers, for example Natvosol, polyacrylic acid, carboxyvinyl polymer, polyoxyethylene glycol, polyvinylpyrrolidone and methylcellulose gum; Lower alcohol, for example ethanol and Virahol; Polyvalent alcohol, for example glycerine, propylene glycol, dipropylene glycol and sorbyl alcohol; Carbohydrate is dextrose plus saccharose for example; Inorganic powder, for example silica anhydride, neusilin and pure aluminium silicate; And pure water.The example of used excipient comprises lactose, W-Gum, sucrose, glucose, seminose, sorbyl alcohol, crystalline cellulose and silicon-dioxide.The example of adhesive therefor comprises polyoxyethylene glycol, polyvingl ether, methylcellulose gum, ethyl cellulose, gum arabic, tragakanta, gelatin, shellac, HYDROXY PROPYL METHYLCELLULOSE, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene block copolymer and meglumine.Used examples of disintegrants comprises starch, agar, jelly powder, crystalline cellulose, lime carbonate, sodium bicarbonate, citrate of lime, dextrin, pectin and calcium carboxymethylcellulose.Example with lubricator comprise Magnesium Stearate, talcum powder, polyoxyethylene glycol, silica and hydrogenated vegetable oil.The example of used tinting material comprises that those allow to add the tinting material in the medicine.The example of used correctives comprises cocoa powder, menthol, empasma, spearmint oil, borneol and Cortex Cinnamomi powder.

For example, the preparation of oral preparations is to add the compound or its salt of activeconstituents or hydrate, the vehicle of this compound or salt, and if necessary, also have for example tackiness agent, disintegrating agent, lubricant, tinting material and correctives, subsequently this mixture is made for example pulvis, microgranules, granule, tablet, coated tablet or capsule by ordinary method.It is evident that if necessary, tablet or granule be dressing suitably, for example sweet tablet.Can by ordinary method add for example pH regulator agent, solubilizing agent and isotonic agent and add dissolution aids where necessary, stablizer prepares syrup or injection formulations.External preparation can prepare by ordinary method, and has no particular limits.For substrate material, any various materials that are generally used for medicine, quasi drug, makeup etc. all can use.The example of substrate material comprises for example animal and plant oil, mineral oil, ester class oil, wax class, higher alcohols, lipid acid, silicone oil, tensio-active agent, phosphatide, alcohols, polyvalent alcohol, water-soluble polymers, clay mineral and pure water.Where necessary, can add pH regulator agent, antioxidant, sequestrant, sanitas and mycocide, tinting material, spices etc.In addition, also can sneak into composition in case of necessity, for example blood flow toughener, sterilant, antiphlogistic, cell activator, VITAMIN, amino acid, wetting Agent for Printing Inks or keratolytic with induction of differentiation.The dosage of treatment of the present invention or preventive medicine changes according to for example type of symptom degree, age, sex, body weight, administering mode, salt and the particular type of disease.Usually, formula of the present invention (I) compound or pharmaceutically acceptable salt thereof is with the form of single dose or multidose, respectively to the oral administration of grownup about 30 μ g-10g every day, preferred 100 μ g-5g and more preferably 100 μ g-100mg, or to grownup's drug administration by injection about 30 μ g-1g every day, preferred 100 μ g-500mg and more preferably 100 μ g-30mg.

Optimum embodiment of the present invention

Describe the present invention in detail referring now to embodiment and experimental example.But embodiment that provides and experimental example only are used to illustrate purpose of the present invention.Under any circumstance, the medicine of the disease that caused by A β of the present invention prevention or treatment all is not limited to following specific embodiment.Those skilled in the art can be by being not only the multiple modification that following embodiment and experimental example are carried out, also have the multiple modification that the claim of this specification sheets is made fully to implement the present invention, these are revised within the scope of the claim that all is covered by this specification sheets.

Below abbreviation is used for the following example.

DMF: dimethyl formamide

THF: tetrahydrofuran (THF)

LAH: lithium aluminum hydride

WSC:1-ethyl-3-(3-dimethylamino-propyl) carbodiimide hydrochloride

The HOBT:1-hydroxybenzotriazole

DIEA: diisopropyl ethyl amine

TEA: triethylamine

TBAF: tetrabutyl ammonium fluoride

DBU:1,8-diazabicylo [5.4.0] 11 carbon-7-alkene

T: uncle

LDA: lithium diisopropylamine

Embodiment 1

(Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-(3,4, the 5-trifluoro Benzyl) morpholine-3-ketone is synthetic

Synthesizing of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde

Synthesizing of 3-methoxyl group-4-nitrobenzoic acid methyl esters

At room temperature methyl iodide (463g) is dropwise added in 3-hydroxyl-4-nitrobenzoic acid (199g) and the mixture of salt of wormwood (450g) in DMF (1L).This reaction soln at room temperature stirred spend the night, in reaction soln, add methyl iodide (230g) then.This reaction soln further at room temperature stirred 6 hours.Reaction soln added in the frozen water and by filtering the solid of collecting precipitation.The gained solid 50 ℃ of dried overnight, is obtained the 178g title compound.The value of its character meets the value of having reported (CAS#5081-37-8).

Synthesizing of 4-amino-3-methoxyl methyl benzoate

10% palladium-carbon (is contained 50% water, 15g) adds in the 3-methoxyl group-solution of 4-nitrobenzoic acid methyl esters (150g) in methyl alcohol (600mL) and THF (300mL), and reaction soln was stirred 6.5 hours down in 50 ℃-64 ℃ under the hydrogen pressure of 0.9MPa.Reaction soln placed be cooled to room temperature, with after diatomite filtration.The gained filtrate decompression concentrates, and obtains the 134g title compound.The value of its character meets the value of having reported (CAS#41608-64-4).

Synthesizing of 4-formamido group-3-methoxyl methyl benzoate

At room temperature diacetyl oxide (268mL) is dropwise added in the formic acid (401mL), and reaction soln was at room temperature stirred 40 minutes.At room temperature the 4-amino-solution of 3-methoxyl methyl benzoate (134g) in THF (600mL) is dropwise added reaction soln, and reaction soln was stirred 1 hour.The 3.8L frozen water is added in the reaction soln, precipitated solid is filtered and further water (2L) washing.The gained solid obtains the 111g title compound 50 ℃ of following dried overnight.The value of its character meets the value of having reported (CAS#700834-18-0).

4-[formyl radical-(2-oxopropyl) amino]-3-methoxyl methyl benzoate synthetic

At room temperature monochloroacetone (84.5mL) is dropwise added 4-formamido group-3-methoxyl methyl benzoate (111g), cesium carbonate (346g) and potassiumiodide (8.78g) in the mixture of DMF (497mL), and reaction soln was stirred 3 hours.Cesium carbonate (173g) and monochloroacetone (42.0mL) are added in the reaction soln, and it at room temperature stirred 2 hours subsequently.Frozen water is added reaction soln and separates organic layer with ethyl acetate.Ethyl acetate is added water layer and separates organic layer.Merging organic layer and water and salt solution washs successively.With gained organic layer concentrating under reduced pressure behind anhydrous magnesium sulfate drying.Resistates is concentrated with dilution with toluene and with this solution decompression.T-butyl methyl ether and heptane are added in the gained resistates, by filtering the collecting precipitation solid, and wash with the n-heptane solution of 50% t-butyl methyl ether.Gained solid air dried overnight obtains the 118g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

2.19(s，3H)，3.91(s，3H)，3.94(s，3H)，4.49(s，2H)，7.31(d，J＝8.0Hz，1H)，7.63(d，J＝2.0Hz，1H)，7.69(dd，J＝8.0，2.0Hz，1H)，8.33(s，1H)。

Synthesizing of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) methyl benzoate

With 4-[formyl-(2-oxopropyl) amino]-3-methoxyl methyl benzoate (118g) and the solution heating of ammonium acetate (172g) in acetate (255mL), and under 140 ℃, stirred 1 hour.After reacting completely, reaction soln is neutralized with ammoniacal liquor down ice-cooled.Ethyl acetate is added reaction soln and separates organic layer.The gained organic layer also filters on layer of silica gel subsequently through anhydrous magnesium sulfate drying, and filtrate decompression is concentrated.With in t-butyl methyl ether and the heptane adding resistates and by filtering the collecting precipitation solid, with the n-heptane solution washing of 50% t-butyl methyl ether.Gained solid air dried overnight obtains the 68.4g title compound.In addition, with the crystalline mother solution concentrating under reduced pressure, and with resistates (eluting solvent: purifying heptane-ethyl acetate system) obtains the 22.3g title compound through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

2.30(s，3H)，3.94(s，3H)，3.96(s，3H)，6.98(brs，1H)，7.32(d，J＝8.4Hz，1H)，7.71-7.73(m，2H)，7.79(brs，1H)。

At-5 ℃ or more under the low temperature, go through and the solution of tetramethyleneimine (18mL) in THF (45mL) was dropwise added two (2-methoxy ethoxy) sodium aluminum hydride in 15 minutes (65% toluene solution is 56mL) in the solution of THF (60mL).Reaction soln was at room temperature stirred 1 hour.Then, at room temperature the suspension of tert butoxide (2.10g) in THF (15mL) dropwise added reaction soln, and reaction soln was stirred 15 minutes.Ice-cooled down, go through above-mentioned reaction soln dropwise joined 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) methyl benzoate (20g) in the solution of THF (50mL) in 30 minutes.Reaction soln at room temperature stirred 2 hours, and the sodium hydroxide solution (150mL) with 5N dropwise adds reaction soln subsequently.Ethyl acetate is added reaction soln and separates organic layer.Organic layer washs successively with saturated ammonium chloride solution and salt solution.Organic layer filters through anhydrous magnesium sulfate drying and with layer of silica gel, subsequently filtrate decompression is concentrated.Dilute this resistates with ethyl acetate, by filtering the collecting precipitation solid.Gained solid air dried overnight obtains the 7.10g title compound.In addition, (eluting solvent: heptane/ethyl acetate/2-propyl alcohol system) purifying obtains the 2.65g title compound through silica gel column chromatography with the crystalline mother solution concentrating under reduced pressure and with resistates.

¹H-NMR(CDCl ₃)δ(ppm)：

2.31(s，3H)，3.97(s，3H)，7.02(brs，1H)，7.44(d，J＝8.0Hz，1H)，7.55(dd，J＝1.6，8.0Hz，1H)，7.58(d，J＝1.6Hz，1H)，7.84(brs，1H)，10.00(s，1H)。

2-[(3,4,5-trifluoro-benzyl) amino] alcoholic acid is synthetic

Down sodium triacetoxy borohydride (14.1g) is added 3,4 ice-cooled, 5-trifluro benzaldehyde (5.0mL), thanomin (3.52g) and acetate (10.1mL) and at room temperature stirred reaction soln 4 hours 30 minutes in the solution of THF (100mL).Frozen water is added reaction soln.Sodium hydroxide solution and saturated sodium bicarbonate solution with 5N are adjusted to pH 7-8 with reaction soln, use chloroform extraction subsequently.Organic layer is through anhydrous magnesium sulfate drying and subsequent filtration, with the mother liquor concentrating under reduced pressure.(chloroform: methyl alcohol=1: 100-1: 5) purifying obtains the 6.91g title compound to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

2.80(t，J＝4.8Hz，2H)，3.69(t，J＝4.8Hz，2H)，3.78(s，2H)，6.96-7.00(m，2H)。

4-(3,4, the 5-trifluoro-benzyl) morpholine-2,3-diketone synthetic

Under 170 ℃ with 2-[(3,4,5-trifluoro-benzyl) amino] mixture of ethanol (6.91g) and oxalic acid diethyl ester (20mL) stirred 1 hour.With the reaction soln concentrating under reduced pressure, in resistates, add ether subsequently.Also air-dry subsequently by the crystal that filters collecting precipitation, obtain the 7.38g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

3.61(t，J＝4.8Hz，2H)，4.49(t，J＝4.8Hz，2H)，4.63(s，2H)，6.95-6.99(m，2H)。

Synthesizing of 2-hydroxyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone

THF (31.4mL) solution with the 3-sec-butyl lithium borohydride of 1M under-15 ℃ dropwise adds 4-(3,4, the 5-trifluoro-benzyl) morpholine-2, and 3-diketone (7.38g) and stirs reaction soln 2 hours in the solution of THF.At 20 ℃ or more under the low temperature, 5N sodium hydroxide solution (2.85mL) and 30% aqueous hydrogen peroxide solution (968 μ L) are dropwise added reaction soln, it stirred 1 hour at 10 ℃ subsequently.Sodium bisulfite (888mg) is added reaction soln, and it stirred 30 minutes subsequently.Salt solution is added reaction soln and separates organic layer with chloroform.Organic layer is concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(heptane: ethyl acetate=1: 1 to 0: 100) purifying obtains the 3.94g title compound to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

3.11-3.16(m，1H)，3.47-3.54(m，1H)，3.80-3.86(m，1H)，4.28-4.35(m，1H)，4.40(d，J＝14.8Hz，1H)，4.67(d，J＝14.8Hz，1H)，5.37(s，1H)，6.90-6.94(m，2H)。

Under 50 ℃, thionyl chloride (16.1mL) is joined 2-hydroxyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone (3.94g) in the solution of methylene dichloride, and reaction soln was stirred 1 hour.Dilute this resistates with the reaction soln concentrating under reduced pressure and with methylene dichloride.Then, add triphenylphosphine (5.2g) down ice-cooled, and reaction soln was at room temperature stirred 4.5 hours.The concentrating under reduced pressure reaction soln.Ethanol (64.6mL), TEA (4.2mL) and 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (2.72g) is added in the resistates, and with reaction soln reflux 2 hours.The reaction soln concentrating under reduced pressure, and with 2N aqueous hydrochloric acid and ethyl acetate dilution resistates.Then, separate water layer.Organic layer washs with the 2N aqueous hydrochloric acid.Then, merge whole water layers and alkalize with strong caustic.With separating organic layer behind the chloroform extraction alkaline solution, with after anhydrous magnesium sulfate drying and concentrating under reduced pressure.(heptane: ethyl acetate=1: 1-0: 100) purifying obtains the 1.92g title compound to resistates through the NH silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

2.34(s，3H)，3.56(t，J＝4.8Hz，2H)，3.87(s，3H)，4.28(t，J＝4.8Hz，2H)，4.66(s，2H)，6.93(s，1H)，6.95-6.99(m，3H)，7.23(d，J＝8.0Hz，1H)，7.40(dd，J＝8.0，1.2Hz，1H)，7.42(d，J＝1.2Hz，1H)，7.85(s，1H)。

ESI-MS；m/z?444[M ⁺+H]。

Embodiment 2

(Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-(2,3, the 4-trifluoro Benzyl) morpholine-3-ketone is synthetic

2-[(2,3,4-trifluoro-benzyl) amino] alcoholic acid is synthetic

Adopt the method identical with embodiment 1, from 2,3,4-trifluro benzaldehyde (1.0g), thanomin (573mg), acetate (1.79mL) and sodium triacetoxy borohydride (2.65g) react the title compound that obtains 891mg.

¹H-NMR(CDCl ₃)δ(ppm)：

2.80(t，J＝5.2Hz，2H)，3.69(t，J＝5.2Hz，2H)，3.88(s，2H)，6.94-6.96(m，1H)，7.07-7.09(m，1H)。

4-(2,3, the 4-trifluoro-benzyl) morpholine-2,3-diketone synthetic

Adopt the method identical,, 3,4-trifluoro-benzyl from 2-[(2 with embodiment 1) amino] ethanol (891mg) and oxalic acid diethyl ester (8.0mL) react and obtain the 903mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

3.70(t，J＝5.2Hz，2H)，4.50(t，J＝5.2Hz，2H)，4.73(s，2H)，6.97-7.04(m，1H)，7.18-7.25(m，1H)。

Synthesizing of 2-hydroxyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone

Adopt the method identical with embodiment 1, from 4-(2,3, the 4-trifluoro-benzyl) morpholine-2, THF (1.49mL) solution reaction of 3-diketone (350mg) and 1M 3-sec-butyl lithium borohydride obtains the 126mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

3.20-3.25(m，1H)，3.53-3.59(m，1H)，3.81-3.86(m，1H)，4.26-4.33(m，1H)，4.60(d，J＝15.2Hz，1H)，4.67(d，J＝15.2Hz，1H)，5.31(s，1H)，6.96-7.01(m，1H)，7.13-7.15(m，1H).

Adopt the method identical with embodiment 1, from 2-hydroxyl-4-(2,3,4-trifluoro-benzyl) morpholine-3-ketone (126mg), thionyl chloride (516 μ L), triphenylphosphine (166mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (93.9mg) obtain the 95.8mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

2.35(s，3H)，3.64(t，J＝4.8Hz，2H)，3.86(s，3H)，4.28(t，J＝4.8Hz，2H)，4.75(s，2H)，6.89(s，1H)，6.95(s，1H)，6.97-7.02(m，1H)，7.17-7.24(m，2H)，7.38(dd，J＝8.4，1.2Hz，1H)，7.41(d，J＝1.2Hz，1H)，7.88(s，1H)。

ESI-MS；m/z?444[M ⁺+H]。

Embodiment 3

(Z)-(S)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-methyl Synthesizing of-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone

(S)-1-(3,4,5-trifluoro-benzyl amino) propan-2-ol synthetic

Adopt the method identical with embodiment 1, from 3,4,5-trifluro benzaldehyde (370mg), (S)-1-amino-2-propyl alcohol (260mg), acetate (0.662mL) and sodium triacetoxy borohydride (981mg) react, and obtain the 410mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.17(d，J＝6.4Hz，3H)，2.45(dd，J＝12.0，9.2Hz，1H)，2.72(dd，J＝12.0，2.8Hz，1H)，3.75(d，J＝13.2Hz，1H)，3.80(d，J＝13.2Hz，1H)，3.82-3.85(m，1H)，6.96-7.00(m，2H)。

(S)-and 6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-2,3-diketone synthetic

Adopt the method identical, react, obtain the 439mg title compound from (S)-1-(3,4,5-trifluoro-benzyl amino) propan-2-ol (410mg) and oxalic acid diethyl ester (2.0mL) with embodiment 1.

¹H-NMR(CDCl ₃)δ(ppm)：

1.44(d，J＝6.4Hz，3H)，3.35(dd，J＝13.6，3.2Hz，1H)，3.55(dd，J＝13.6，9.6Hz，1H)，4.55(d，J＝15.2Hz，1H)，4.67(d，J＝15.2Hz，1H)，4.73-4.78(m，1H)，6.94-6.98(m，2H)。

(S)-2-hydroxyl-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone synthetic

Adopt the method identical with embodiment 1, from (S)-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-2, THF (1.70mL) solution reaction of 3-diketone (400mg) and 1M 3-sec-butyl lithium borohydride obtains the 308mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.26(d，J＝6.0Hz，3H)，3.06(dd，J＝12.0，3.2Hz，1H)，3.22(dd，J＝12.0，12.0Hz，1H)，4.36(d，J＝14.8Hz，1H)，4.46-4.52(m，1H)，4.66(d，J＝14.8Hz，1H)，5.37(s，1H)，6.90-6.94(m，2H)。

(Z)-(S)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-methyl Synthesizing of 4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone

Adopt the method identical with embodiment 1, from (S)-2-hydroxyl-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone (308mg), thionyl chloride (817 μ L), triphenylphosphine (353mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (218mg) obtain the 339mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.46(d，J＝6.4Hz，3H)，2.34(s，3H)，3.28(dd，J＝12.8，2.8Hz，1H)，3.50(dd，J＝12.8，9.6Hz，1H)，3.87(s，3H)，4.36-4.40(m，1H)，4.58(d，J＝14.8Hz，1H)，4.69(d，J＝14.8Hz，1H)，6.90(s，1H)，6.94-6.98(m，3H)，7.23(d，J＝8.4Hz，1H)，7.37(dd，J＝8.4，2.0Hz，1H)，7.54(d，J＝2.0Hz，1H)，7.85(s，1H)。

ESI-MS；m/z?458[M ⁺+H]。

Embodiment 4

(Z)-(R)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-methyl Synthesizing of-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone

(R)-1-(3,4,5-trifluoro-benzyl amino) propan-2-ol synthetic

Adopt the method identical with embodiment 1, from 3,4,5-trifluro benzaldehyde (1.0g), (R)-1-amino-2-propyl alcohol (704mg), acetate (1.79mL) and sodium triacetoxy borohydride (2.65g) react, and obtain the 1.1g title compound.The NMR value of described compound meets the NMR value of S isomer.

(R)-and 6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-2,3-diketone synthetic

Adopt the method identical, react, obtain the 1.15g title compound from (R)-1-(3,4,5-trifluoro-benzyl amino) propan-2-ol (1.1g) and oxalic acid diethyl ester (4.0mL) with embodiment 1.The NMR value of described compound meets the NMR value of S isomer.

(R)-2-hydroxyl-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone synthetic

Adopt the method identical with embodiment 1, from (R)-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-2, THF (1.70mL) solution reaction of 3-diketone (400mg) and 1M 3-sec-butyl lithium borohydride obtains the 323mg title compound.The NMR value of described compound meets the NMR value of S isomer.

Adopt the method identical with embodiment 1, from (R)-2-hydroxyl-6-methyl-4-(3,4, the 5-trifluoro-benzyl) morpholine-3-ketone (323mg), thionyl chloride (853 μ L), triphenylphosphine (368mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (228mg) obtain the 346mg title compound.The NMR value of described compound meets the NMR value of S isomer.

Embodiment 5

(Z)-(S)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-methyl Synthesizing of-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone

(S)-1-(2,3,4-trifluoro-benzyl amino) propan-2-ol synthetic

Adopt the method identical with embodiment 1, from 2,3,4-trifluro benzaldehyde (1.0g), (S)-1-amino-2-propyl alcohol (704mg), acetate (1.79mL) and sodium triacetoxy borohydride (2.65g) react, and obtains the 968mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.16(d，J＝6.0Hz，3H)，2.47(dd，J＝11.6，9.2Hz，1H)，2.72(dd，J＝11.6，2.8Hz，1H)，3.83-3.88(m，1H)，3.89(s，2H)，6.92-6.99(m，1H)，7.06-7.10(m，1H)。

(S)-and 6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-2,3-diketone synthetic

Adopt the method identical, react, obtain the 917mg title compound from (S)-1-(2,3,4-trifluoro-benzyl amino) propan-2-ol (968mg) and oxalic acid diethyl ester (8.0mL) with embodiment 1.

¹H-NMR(CDCl ₃)δ(ppm)：

1.45(d，J＝6.4Hz，3H)，3.48(dd，J＝13.6，3.2Hz，1H)，3.62(dd，J＝13.6，10.0Hz，1H)，4.66(d，J＝15.2Hz，1H)，4.74-4.80(m，1H)，4.75(d，J＝15.2Hz，1H)，7.00-7.03(m，1H)，7.21-7.27(m，1H)。

(S)-2-hydroxyl-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone synthetic

Adopt the method identical with embodiment 1, from (S)-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-2, THF (1.49mL) solution reaction of 3-diketone (350mg) and 1M 3-sec-butyl lithium borohydride obtains the 196mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.25(d，J＝7.2Hz，3H)，3.13(dd，J＝12.0，3.2Hz，1H)，3.26(dd，J＝12.0，12.0Hz，1H)，4.47-4.51(m，1H)，4.58(d，J＝15.6Hz，1H)，4.64(d，J＝15.6Hz，1H)，5.33(s，1H)，6.95-7.00(m，1H)，7.12-7.15(m，1H)。

Adopt the method identical with embodiment 1, from (S)-2-hydroxyl-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone (196mg), thionyl chloride (500 μ L), triphenylphosphine (243mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (139mg) obtain the 197mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.46(d，J＝6.4Hz，3H)，2.31(s，3H)，3.39(dd，J＝12.8，2.8Hz，1H)，3.55(dd，J＝12.8，9.6Hz，1H)，3.85(s，3H)，4.37-4.40(m，1H)，4.68(d，J＝15.2Hz，1H)，4.77(d，J＝15.2Hz，1H)，6.86(s，1H)，6.93(s，1H)，6.94-7.03(m，1H)，7.16-7.24(m，1H)，7.21(d，J＝8.4Hz，1H)，7.33(dd，J＝8.4，2.0Hz，1H)，7.52(d，J＝2.0Hz，1H)，7.75(s，1H)。

ESI-MS；m/z?458[M ⁺+H]。

Embodiment 6

(Z)-(R)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-methyl Synthesizing of-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone

(R)-1-(2,3,4-trifluoro-benzyl amino) propan-2-ol synthetic

Adopt the method identical with embodiment 1, from 2,3,4-trifluro benzaldehyde (1.0g), (R)-1-amino-2-propyl alcohol (704mg), acetate (1.79mL) and sodium triacetoxy borohydride (2.65g) react, and obtain the 1.09g title compound.The NMR value of described compound meets the NMR value of S isomer.

(R)-and 6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-2,3-diketone synthetic

Adopt the method identical, react, obtain the 874mg title compound from (R)-1-(2,3,4-trifluoro-benzyl amino) propan-2-ol (1.09g) and oxalic acid diethyl ester (8.0mL) with embodiment 1.The NMR value of described compound meets the NMR value of S isomer.

(R)-2-hydroxyl-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone synthetic

Adopt the method identical with embodiment 1, from (R)-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-2, THF (1.49mL) solution reaction of 3-diketone (350mg) and 1M 3-sec-butyl lithium borohydride obtains the 213mg title compound.The NMR value of described compound meets the NMR value of S isomer.

Adopt the method identical with embodiment 1, from (R)-2-hydroxyl-6-methyl-4-(2,3, the 4-trifluoro-benzyl) morpholine-3-ketone (213mg), thionyl chloride (500 μ L), triphenylphosphine (264mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (151mg) obtain the 187mg title compound.The NMR value of described compound meets the NMR value of S isomer.

Embodiment 7

(Z)-4-[(S)-1-(4-fluorophenyl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) Phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

1-[(S)-1-(4-fluorophenyl) ethylamino]-2-methyl propan-2-ol synthetic

At room temperature and (S) with oxidation iso-butylene (1.0g)-1-(4-fluorophenyl) ethamine (2.25mL) adds lithium perchlorate (14.8g) in the solution of ether (27.8mL), and reaction soln at room temperature stirred 1.5 hours.Oxidation iso-butylene (0.5mL) is added reaction soln, then its stirring is spent the night.Frozen water is added reaction soln and separates organic layer with chloroform.After this, organic layer concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(chloroform: 2-propyl alcohol=100: 1-1: 1) purifying obtains the 2.13g title compound to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.13(s，3H)，1.16(s，3H)，1.35(d，J＝6.8Hz，3H)，2.32(d，J＝11.6Hz，1H)，2.44(d，J＝11.6Hz，1H)，3.75(q，J＝6.8Hz，1H)，6.99-7.10(m，2H)，7.23-7.30(m，2H)。

4-[(S)-and 1-(4-fluorophenyl) ethyl]-6,6-thebaine-2,3-diketone synthetic

Adopt the method identical, from 1-[(S with embodiment 1)-1-(4-fluorophenyl) ethylamino]-2-methyl propan-2-ol (2.13g) and oxalic acid diethyl ester (7.0mL) react, and obtains the 1.44g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.19(s，3H)，1.44(s，3H)，1.56(d，J＝6.8Hz，3H)，3.00(d，J＝13.6Hz，1H)，3.31(d，J＝13.6Hz，1H)，6.02(q，J＝6.8Hz，1H)，7.06-7.10(m，2H)，7.30-7.36(m，2H)。

4-[(S)-1-(4-fluorophenyl) ethyl]-2-hydroxyl-6,6-thebaine-3-ketone synthetic

Adopt the method identical, from 4-[(S with embodiment 1)-1-(4-fluorophenyl) ethyl]-6,6-thebaine-2, THF (4.97mL) solution reaction of 3-diketone (1.20g) and 1M 3-sec-butyl lithium borohydride obtains the 1.22g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

0.97(s，1.5H)，1.08(s，1.5H)，1.24(s，1.5H)，1.31(s，1.5H)，1.52(d，J＝6.8Hz，1.5H)，1.53(d，J＝6.8Hz，1.5H)，2.05(s，3H)，2.79(d，J＝12.8Hz，0.5H)，2.87(d，J＝12.8Hz，0.5H)，3.08(d，J＝12.8Hz，0.5H)，3.13(d，J＝12.8Hz，0.5H)，3.77(brs，1H)，5.26(d，J＝4.0Hz，0.5H)，5.29(d，J＝4.0Hz，0.5H)，5.93(q，J＝6.8Hz，0.5H)，5.99(q，J＝6.8Hz，0.5H)，7.03-7.07(m，2H)，7.26-7.35(m，2H)。

Adopt the method identical with embodiment 1, from 4-[(S)-1-(4-fluorophenyl) ethyl]-2-hydroxyl-6, the reaction of 6-thebaine-3-ketone (1.21g), thionyl chloride (3.3mL), triphenylphosphine (1.42g) and 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (880mg) obtains the 500mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.35(d，J＝6.8Hz，3H)，1.57(d，J＝7.2Hz，3H)，2.30(s，3H)，2.89(dd，J＝12.8，9.2Hz，1H)，3.18(dd，J＝12.8，2.8Hz，1H)，3.85(s，3H)，4.31-4.36(m，1H)，6.11(q，J＝7.2Hz，1H)，6.88(s，1H)，6.93(s，1H)，7.03-7.08(m，2H)，7.20(d，J＝8.0Hz，1H)，7.29-7.35(m，3H)，7.52(d，J＝2.0Hz，1H)，7.75(s，1H)。

ESI-MS；m/z?450[M ⁺+H]。

Embodiment 8 and 9

(Z)-(R)-4-[(S)-1-(4-fluorophenyl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1- Base) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(S)-1-(4-fluorophenyl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone Synthetic

1-[(S)-and 1-(4-fluorophenyl) ethylamino] third-2-ketone synthetic

At room temperature the mixture stirring of (S)-1-(4-fluorophenyl) ethamine (5.0g), monochloroacetone (4.78mL), cesium carbonate (13.9g) and DMF (50mL) is spent the night.Water and ethyl acetate diluting reaction solution separate organic layer subsequently.Organic layer is concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(hexane: ethyl acetate=5: 1-0: 100) purifying obtains the 5.1g title compound to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.37(d，J＝6.8Hz，3H)，2.07(s，3H)，3.37(s，2H)，3.74(q，J＝6.8Hz，1H)，6.97-7.03(m，2H)，7.24-7.29(m，2H)。

ESI-MS；m/z?196[M ⁺+H]。

1-[(S)-and 1-(4-fluorophenyl) ethylamino] propan-2-ol synthetic

Ice-cooled down, sodium borohydride (2.39g) is added 1-[(S)-1-(4-fluorophenyl) ethylamino] third-2-ketone (2.5g) in the solution of ethanol (25mL), and subsequently reaction soln was at room temperature stirred 1 hour.With frozen water and ethyl acetate diluting reaction solution, separate organic layer subsequently.Organic layer is concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(chloroform: 2-propyl alcohol=100: 1-0: 100) purifying obtains the title compound that 1.18g is a non-enantiomer mixture to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.09(d，J＝6.4Hz，0.9H)，1.10(d，J＝6.0Hz，2.1H)，1.35(d，J＝7.2Hz，0.9H)，1.36(d，J＝6.4Hz，2.1H)，2.22(dd，J＝12.0，9.6Hz，0.3H)，2.33(dd，J＝12.0，9.2Hz，0.7H)，2.52(dd，J＝12.4，3.6Hz，0.7H)，2.59(dd，J＝11.6，2.8Hz，0.3H)，3.61-3.66(m，0.3H)，3.74-3.80(m，0.7H)，6.99-7.03(m，2H)，7.24-7.29(m，2H)。

4-[(S)-1-(4-fluorophenyl) ethyl]-6-methylmorpholine-2,3-diketone synthetic

Adopt the method identical, from 1-[(S with embodiment 1)-1-(4-fluorophenyl) ethylamino] propan-2-ol (1.18g) and oxalic acid diethyl ester (4.06mL) react, and obtains the title compound that 1.20g is a non-enantiomer mixture.

¹H-NMR(CDCl ₃)δ(ppm)：

1.31(d，J＝6.8Hz，1.8H)，1.37(d，J＝6.8Hz，1.2H)，1.55(d，J＝6.8Hz，1.2H)，1.56(d，J＝6.8Hz，1.8H)，2.96(dd，J＝12.0，9.6Hz，0.6H)，3.04(dd，J＝12.0，3.6Hz，0.4H)，3.26(dd，J＝12.0，3.6Hz，0.6H)，3.38(dd，J＝12.0，9.6Hz，0.4H)，4.42-4.52(m，0.4H)，4.64-4.74(m，0.6H)，5.93-6.02(m，1H)，7.09-7.12(m，2H)，7.29-7.39(m，2H)。

4-[(S)-1-(4-fluorophenyl) ethyl]-2-hydroxyl-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 1, from 4-[(S)-1-(4-fluorophenyl) ethyl]-6-methylmorpholine-2, THF (2.19mL) solution reaction of 3-diketone (500mg) and 1M 3-sec-butyl lithium borohydride obtains the title compound that 382mg is a non-enantiomer mixture.

¹H-NMR(CDCl ₃)δ(ppm)：

1.19(d，J＝6.8Hz，1.5H)，1.20(d，J＝6.8Hz，1.5H)，1.53(d，J＝6.8Hz，3H)，2.61(dd，J＝12.4，10.8Hz，0.5H)，2.74(dd，J＝12.0，2.8Hz，0.5H)，2.94(dd，J＝12.4，2.8Hz，0.5H)，3.12(dd，J＝12.0，11.2Hz，0.5H)，4.11-4.26(m，0.5H)，4.37-4.42(m，0.5H)，5.35(s，0.5H)，5.37(s，0.5H)，5.95(q，J＝6.8Hz，0.5H)，5.99(q，J＝6.8Hz，0.5H)，7.02-7.07(m，2H)，7.25-7.32(m，2H)。

Adopt the method identical with embodiment 1, from 4-[(S)-1-(4-fluorophenyl) ethyl]-2-hydroxyl-6-methylmorpholine-3-ketone (382mg), thionyl chloride (330 μ L), triphenylphosphine (504mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (294mg), obtain the title compound that 628mg is a non-enantiomer mixture.The part of non-enantiomer mixture is passed through by DaicelChemical Industries the CHIRALCEL that Ltd. produces ^TMOJ-H (2cm * 25cm; Moving phase: hexane: ethanol=80: 20) separate, the title compound and the retention time that obtain retention time and be the optically active of 25 minutes (de＞95%) are the title compound of the optically active of 29 minutes (de＞95%).

Retention time is that the property value of title compound (embodiment 8) of 25 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.38(d，J＝6.4Hz，3H)，1.55(d，J＝7.2Hz，3H)，2.30(s，3H)，2.97(dd，J＝12.8，2.4Hz，1H)，3.33(dd，J＝12.8，9.6Hz，1H)，3.85(s，3H)，4.09-4.12(m，1H)，6.13(q，J＝7.2Hz，1H)，6.89(s，1H)，6.94(s，1H)，7.03-7.09(m，2H)，7.21(d，J＝8.4Hz，1H)，7.32-7.36(m，3H)，7.53(d，J＝2.8Hz，1H)，7.74(s，1H)。

ESI-MS；m/z?436[M ⁺+H]。

Retention time is that the property value of title compound (embodiment 9) of 29 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

ESI-MS；m/z?436[M ⁺+H]。

Embodiment 10 and 11

(Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene Base]-4-[(S)-and 1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone and (Z)-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-4-[(R)-and 1-(3,4, the 5-trifluorophenyl) ethyl] the closing of morpholine-3-ketone Become

2-[1-(3,4, the 5-trifluorophenyl) ethylamino] alcoholic acid is synthetic

With 3,4, the mixture of 5-trifluoroacetophenone (2.0g), thanomin (2.0g) and toluene (20mL) reflux 2.5 hours in the Dean-Stark device.With the reaction soln concentrating under reduced pressure, dilute resistates at ice-cooled ethanol (30mL) and the sodium borohydride (1.0g) of adding down subsequently.This mixture was at room temperature stirred 3 hours, subsequently with 2N sodium hydroxide solution and chloroform dilution.After this, separate organic layer.Organic layer is concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(chloroform: methyl alcohol=50: 1-5: 1) purifying obtains the 860mg title compound to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.36(d，J＝6.8Hz，3H)，2.56-2.68(m，1H)，2.68-2.73(m，1H)，3.62-3.80(m，3H)，6.92-7.00(m，2H)。

4-[1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-2,3-diketone synthetic

Adopting the method identical, from 2-[1-(3,4, the 5-trifluorophenyl) ethylamino with embodiment 1] ethanol (860mg) and oxalic acid diethyl ester (5.0mL) react, and obtains the 340mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.55(d，J＝6.4Hz，3H)，3.15-3.21(m，1H)，3.52-3.59(m，1H)，4.31-4.37(m，1H)，4.41-4.46(m，1H)，5.90(q，J＝6.4Hz，1H)，6.97-7.01(m，2H)。

2-hydroxyl-4-[1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone synthetic

Adopt the method identical with embodiment 1, from 4-[1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-2, THF (1.45mL) solution reaction of 3-diketone (340mg) and 1M 3-sec-butyl lithium borohydride obtains the title compound that 273mg is a non-enantiomer mixture.

¹H-NMR(CDCl ₃)δ(ppm)：

1.52(d，J＝7.2Hz，3H)，2.78-2.83(m，0.5H)，2.95-3.03(m，0.5H)，3.10-3.15(m，0.5H)，3.43-3.50(m，0.5H)，3.78-3.84(m，0.5H)，4.12-4.18(m，0.5H)，4.22-4.28(m，0.5H)，4.24(brs，1H)，5.34(s，0.5H)，5.36(s，0.5H)，5.88-5.98(m，1H)，6.92-6.99(m，1H)。

(Z)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene Base]-4-[(S)-and 1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone and (Z)-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-4-[(R)-1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone Close Become

Adopt the method identical with embodiment 1, from 2-hydroxyl-4-[1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone (273mg), thionyl chloride (1.12mL), triphenylphosphine (360mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (204mg), obtain the title compound that 145mg is a racemoid.

¹H-NMR(CDCl ₃)δ(ppm)：

1.55(d，J＝6.8Hz，3H)，2.29(s，3H)，3.08-3.13(m，1H)，3.48-3.55(m，1H)，3.85(s，3H)，4.08-4.14(m，1H)，4.23-4.27(m，1H)，6.06(q，J＝6.8Hz，1H)，6.90(s，1H)，6.92(s，1H)，6.96-7.02(m，2H)，7.20(d，J＝8.0Hz，1H)，7.37(dd，J＝8.0，1.6Hz，1H)，7.38(d，J＝1.6Hz，1H)，7.71(s，1H)。

ESI-MS；m/z?458[M ⁺+H]。

A part of racemoid is passed through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=80: 20) separate, obtain the title compound that title compound that retention time is 21 minutes a optically active (ee＞99%: embodiment 11) and retention time are 24 minutes optically active (ee 95%: embodiment 10).The NMR value of described activity of optically active compounds meets the value of described racemoid.

Embodiment 12

(Z)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] Asia Methyl]-6,6-thebaine-3-ketone synthetic

1-[[(S)-and chroman-4-yl] amino]-2-methyl propan-2-ol synthetic

Adopt the method identical with embodiment 7, from lithium perchlorate (29.6g), ether (55.6mL), the amino chroman (4.13g) of (S)-4-and oxidation iso-butylene (3.46mL) reaction, obtain the 5.62g title compound, the amino chroman of described (S)-4-according to document (for example is, referring to people such as T.Mukaiyama, " A EuropeanJournal of Chemistry ", 2003, vol.9, p.4485-4509) described method preparation.

¹H-NMR(CDCl ₃)δ(ppm)：

1.20(s，6H)，1.93-1.98(m，1H)，2.04-2.09(m，1H)，2.69(s，2H)，3.80-3.85(m，1H)，4.19-4.32(m，2H)，6.83(d，J＝8.4Hz，1H)，6.91(t，J＝8.4Hz，1H)，7.17(t，J＝8.4Hz，1H)，7.33(d，J＝8.4Hz，1H)。

4-[(S)-and chroman-4-yl]-6,6-thebaine-2,3-diketone synthetic

Adopt the method identical, from 1-[[(S with embodiment 7)-chroman-4-yl] amino]-2-methyl propan-2-ol (5.62g) and oxalic acid diethyl ester (20mL) react, and obtains the 1.53g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.45(s，3H)，1.48(s，3H)，2.10-2.17(m，1H)，2.23-2.27(m，1H)，3.23(s，2H)，4.18-4.30(m，2H)，5.96(dd，J＝8.4，7.2Hz，1H)，6.90(d，J＝8.4Hz，1H)，6.95(t，J＝8.4Hz，1H)，7.05(d，J＝8.4Hz，1H)，7.23(t，J＝8.4Hz，1H)。

4-[(S)-chroman-4-yl]-2-hydroxyl-6,6-thebaine-3-ketone synthetic

Adopt the method identical, from 4-[(S with embodiment 7)-chroman-4-yl]-6,6-thebaine-2, THF (6.0mL) solution reaction of 3-diketone (1.50g) and 1M 3-sec-butyl lithium borohydride obtains the 1.11g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.26(s，3H)，1.31(s，1.5H)，1.32(s，1.5H)，2.10-2.25(m，2H)，2.99(d，J＝13.2Hz，0.5H)，3.05(d，J＝13.2Hz，1H)，3.12(d，J＝13.2Hz，0.5H)，4.17-4.25(m，1H)，4.26-4.35(m，1H)，5.36(s，0.5H)，5.37(s，0.5H)，5.89-5.99(m，1H)，6.84-6.87(m，1H)，6.90-6.94(m，1H)，7.01-7.04(m，0.5H)，7.08-7.11(m，0.5H)，7.16-7.21(m，1H)。

Bromination triphenyl phosphonium (292mg) is added 4-[(S)-chroman-4-yl]-2-hydroxyl-6, in acetonitrile (10mL) solution of 6-thebaine-3-ketone (196mg), and with reaction soln reflux 2 hours.The concentrating under reduced pressure reaction soln.Ethanol (15mL), TEA (221 μ L) and 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (138mg) are added in this resistates, and with reaction soln reflux 2.5 hours.The reaction soln concentrating under reduced pressure is also used saturated sodium bicarbonate solution and the ethyl acetate dilution, separates organic layer subsequently.Organic layer is through anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resistates is through NH silica gel column chromatography (heptane: ethyl acetate=1: 1-0: 100) purifying, and further (heptane: ethyl acetate=1: 1-0: 100) purifying obtains the 167mg title compound through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(s，3H)，1.44(s，3H)，2.14-2.22(m，2H)，2.33(s，3H)，3.12(d，J＝12.8Hz，1H)，3.19(d，J＝12.8Hz，1H)，3.87(s，3H)，4.22-4.34(m，2H)，6.13(dd，J＝8.8，6.8Hz，1H)，6.86-6.95(m，4H)，7.10(d，J＝7.2Hz，1H)，7.19(d，J＝7.2Hz，1H)，7.22(d，J＝8.4Hz，1H)，7.37(dd，J＝8.4，1.6Hz，1H)，7.57(d，J＝1.6Hz，1H)，7.80(s，1H)。

ESI-MS；m/z?460[M ⁺+H]。

Embodiment 13 and 14

(Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzene Base] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(R)-4-[(S)-chroman-4-yl]-the 2-[1-[3-methoxyl group -4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical, react, obtain the title compound that 70.3mg is a non-enantiomer mixture from amino chroman (1.0g) of lithium perchlorate (3.56g), ether (6.7mL), (S)-4-and propylene oxide (609 μ L) as raw material with embodiment 7.This mixture passes through Daicel ChemicalIndustries, the CHIRALPAK that Ltd. produces ^TMAD-H (2cm * 25cm; Moving phase: ethanol 100%) separate, obtaining title compound that retention time is 18 minutes a optically active (de＞99%) and retention time is the title compound (de 95%) of 20 minutes optically active.

Retention time is that 18 minutes the property value of optically active title compound (embodiment 13) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.41(d，J＝6.0Hz，3H)，2.28-2.10(m，2H)，2.33(s，3H)，3.09(dd，J＝13.2，3.2Hz，1H)，3.17(dd，J＝13.2，8.8Hz，1H)，3.87(s，3H)，4.20-4.40(m，3H)，6.07(dd，J＝9.2，6.8Hz，1H)，6.86-6.95(m，4H)，7.06(d，J＝7.6Hz，1H)，7.18(d，J＝8.4Hz，1H)，7.23(d，J＝8.0Hz，1H)，7.38(d，J＝8.4Hz，1H)，7.55(s，1H)，7.81(s，1H)。

ESI-MS；m/z?446[M ⁺+H]。

Retention time is that 20 minutes the property value of optically active title compound (embodiment 14) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.41(d，J＝6.4Hz，3H)，2.10-2.21(m，2H)，2.36(s，3H)，3.09(dd，J＝12.8，2.8Hz，1H)，3.33(dd，J＝12.8，10.0Hz，1H)，3.87(s，3H)，4.21-4.38(m，3H)，6.14(dd，J＝9.2，7.2Hz，1H)，6.86-6.96(m，4H)，7.06(d，J＝7.6Hz，1H)，7.18-7.26(m，2H)，7.38(d，J＝8.4Hz，1H)，7.57(s，1H)，7.89(s，1H)。

ESI-MS；m/z?446[M ⁺+H]。

Embodiment 15

(Z)-(S)-4-(6-chloropyridine-2-ylmethyl)-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) Phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

(S)-and 1-[(6-chloropyridine-2-ylmethyl) amino] propan-2-ol synthetic

Adopt the method identical, react, obtain the 394mg title compound from 2-chloro-6-formyl radical pyridine (500mg), (S)-1-amino-2-propyl alcohol (318mg), acetate (0.808mL) and sodium triacetoxy borohydride (1.12g) with embodiment 1.

¹H-NMR(CDCl ₃)δ(ppm)：

1.16(d，J＝6.0Hz，3H)，2.49(dd，J＝12.0，9.2Hz，1H)，2.78(dd，J＝12.0，2.8Hz，1H)，3.83-3.87(m，1H)，3.93(s，2H)，7.23(d，J＝8.0Hz，1H)，7.24(d，J＝8.0Hz，1H)，7.64(t，J＝8.0Hz，1H)。

(S)-and 4-(6-chloropyridine-2-ylmethyl)-6-methylmorpholine-2,3-diketone synthetic

Adopt the method identical, from (S)-1-[(6-chloropyridine-2-ylmethyl with embodiment 1) amino] propan-2-ol (394mg) and oxalic acid diethyl ester (3.0mL) react, and obtains the 411mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.46(d，J＝6.8Hz，3H)，3.71(dd，J＝13.6，3.2Hz，1H)，3.79(dd，J＝13.6，9.6Hz，1H)，4.69(d，J＝15.2Hz，1H)，4.77(d，J＝15.2Hz，1H)，4.84-4.90(m，1H)，7.30(d，J＝8.0Hz，1H)，7.32(d，J＝8.0Hz，1H)，7.68(t，J＝8.0Hz，1H)。

(S)-4-(6-chloropyridine-2-ylmethyl)-2-hydroxyl-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 1, from (S)-4-(6-chloropyridine-2-ylmethyl)-6-methylmorpholine-2, THF (1.64mL) solution reaction of 3-diketone (411mg) and 1M 3-sec-butyl lithium borohydride obtains the 273mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.27(d，J＝6.0Hz，3H)，3.30(dd，J＝12.0，3.2Hz，1H)，3.39(dd，J＝12.0，10.8Hz，1H)，4.48-4.52(m，1H)，4.49(d，J＝15.2Hz，1H)，4.81(d，J＝15.2Hz，1H)，5.35(s，1H)，7.27(d，J＝7.6Hz，1H)，7.28(d，J＝7.6Hz，1H)，7.66(t，J＝7.6Hz，1H)。

Adopt the method identical with embodiment 1, from the reaction of (S)-4-(6-chloropyridine-2-ylmethyl)-2-hydroxyl-6-methylmorpholine-3-ketone (237mg), thionyl chloride (1.01mL), triphenylphosphine (315mg) and 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (21.6mg), obtain the 27.9mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.47(d，J＝6.4Hz，3H)，2.34(s，3H)，3.57(dd，J＝12.8，2.8Hz，1H)，3.68(dd，J＝12.0，10.0Hz，1H)，3.86(s，3H)，4.43-4.46(m，1H)，4.76(s，2H)，6.85(s，1H)，6.95(s，1H)，7.22(d，J＝8.0Hz，1H)，7.31(d，J＝7.6Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.35(dd，J＝7.6，1.6Hz，1H)，7.55(d，J＝1.6Hz，1H)，7.66(t，J＝8.0Hz，1H)，7.84(s，1H)。

Embodiment 16 and 17

(Z)-(6S, 9aR)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) Asia Benzyl] hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone and (Z)-(6R, 9aS)-6-(4-fluorophenyl)-3-{1-[3- Methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone Synthetic

1-(4-fluorophenyl) heptan-5,6-dialkylene-1-amine synthetic

According to Journal of the American Chemical Society, 2003, vol.125, p.11956. the method described in, from (4-luorobenzyl)-(4-fluorine benzylidene) amine (3g) and 6-iodine oneself-1,2-diene (2.97g) reaction obtains the 2.65g title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.25-1.37 (m, 1H), 1.39-1.50 (m, 1H), 1.63-1.75 (m, 2H), and 1.95-2.04 (m, 2H), 3.88 (d, J=6.8Hz, 1H), 4.63 (dt, J=6.8,2.8Hz, 2H), 5.04 (quintet, J=6.8Hz, 1H), 6.99 (t, J=8.8Hz, 2H), 7.26 (dd, J=8.8,5.6Hz, 2H).

(2R ^*, 6S ^*Synthesizing of)-2-(4-fluorophenyl)-6-vinyl piperidines

Acetate (0.74mL) is added allyl palladium chloride dimer (472mg) and 1,1 '-two (diphenylphosphino) ferrocene (1.43g) in the solution of THF (200mL), and reaction soln was at room temperature stirred 10 minutes.With 1-(4-fluorophenyl) heptan-5, THF (50mL) solution of 6-dialkylene-1-amine (2.65g) adds in the reaction soln, stirs 1.5 hours down at 70 ℃ subsequently.Make reaction soln be cooled to room temperature.Then, ether is added reaction soln and separates water layer with the 1N aqueous hydrochloric acid.The gained water layer washs with ether, subsequently the 5N sodium hydroxide solution is added water layer and transfers to 11 or lower until pH.Chloroform is added water layer and separates organic layer.The gained organic layer obtains the 2.4g title compound through dried over mgso and concentrating under reduced pressure.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.24-1.60(m，3H)，1.67-1.77(m，2H)，1.88-1.95(m，1H)，3.24-3.30(m，1H)，3.67(dd，J＝11.2，2.8Hz，1H)，5.01(brd，J＝10.4Hz，1H)，5.17(brd，J＝16.8Hz，1H)，5.88(ddd，J＝16.8，10.4，6.4Hz，1H)，6.98(t，J＝8.8Hz，2H)，7.35(dd，J＝8.8，5.6Hz，2H)。

ESI-MS；m/z?206[M ⁺+H]。

[(2R ^*, 6S ^*)-2-(4-fluorophenyl)-6-vinyl piperidines-1-yl] oxo ethyl acetate synthetic

Ethyl oxalyl chloride (0.5mL) is added (2R ^*, 6S ^*)-2-(4-fluorophenyl)-6-vinyl piperidines (520mg) and DIEA (0.66mL) and at room temperature stirred reaction soln 1 hour in the solution of methylene dichloride (10mL).Chloroform is added reaction soln and separates organic layer with the 1N aqueous hydrochloric acid.The gained organic layer washs with saturated sodium bicarbonate aqueous solution, concentrating under reduced pressure after dried over mgso.(eluting solvent: heptane-heptane: ethyl acetate=1: 1) purifying obtains the 426mg title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

ESI-MS；m/z?306[M ⁺+H]。

(6R ^*, 9aS ^*)-6-(4-fluorophenyl)-3-hydroxyl hexahydropyridine is [2,1-c] [synthesizing of 1,4] oxazine-4-ketone also

With [(2R ^*, 6S ^*)-2-(4-fluorophenyl)-6-vinyl piperidines-1-yl] methyl alcohol (5mL) solution of oxo ethyl acetate (220mg) is cooled to-78 ℃, and ozone gas fed reaction soln 20 minutes.In-78 ℃ of stirrings, sodium borohydride (164mg) is added reaction soln, and reaction soln was stirred 30 minutes under this temperature.Ethyl acetate and saturated ammonium chloride solution are added reaction soln, and separate organic layer.Gained organic layer concentrating under reduced pressure after dried over mgso.Resistates obtains the 26mg title compound through silica gel column chromatography (eluting solvent: heptane: ethyl acetate=1: 1-〉ethyl acetate) purifying.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.35-1.50(m，2H)，1.57-1.67(m，2H)，2.05-2.26(m，2H)，3.57(brs，1H)，3.80(dd，J＝11.6，3.6Hz，1H)，3.88-3.98(m，1H)，4.11(t，J＝11.6Hz，1H)，5.22(t，J＝4.0Hz，1H)，5.28(s，1H)，7.01(t，J＝8.8Hz，2H)，7.19(dd，J＝8.8，5.6Hz，2H)。

ESI-MS；m/z?220[M ⁺+H]。

[(6R ^*, 9aS ^*)-6-(4-fluorophenyl)-4-oxo hexahydropyridine is synthesizing of [2,1-c] [1,4] oxazine-3-yl] triphenyl phosphonium bromide also

With (6R ^*, 9aS ^*)-6-(4-fluorophenyl)-3-hydroxyl hexahydropyridine is [2,1-c] [1,4] oxazine-4-ketone (26mg) and the solution reflux of three phenyl phosphonium bromides (40mg) in acetonitrile (3mL) 1 hour 30 minutes also.Reaction soln is cooled to room temperature, and solvent evaporated under reduced pressure obtains the 57mg title compound subsequently.The value of the character of described compound is as follows.

ESI-MS；m/z?510[M ⁺]。

(Z)-(6S ^*, 9aR ^*)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine [2,1-c] [1,4] oxazine-4-ketone synthetic also

Triethylamine (0.03mL) is added [(6R ^*, 9aS ^*)-6-(4-fluorophenyl)-4-oxo hexahydropyridine also [2,1-c] [1,4] oxazine-3-yl] in ethanol (5mL) solution of tri-phenyl-phosphorus bromide (57mg) and 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (21mg), and reaction soln at room temperature stirred 2 hours.The concentrating under reduced pressure reaction soln.Then, with resistates through silica gel column chromatography (carrier: ChromatorexNH; Eluting solvent: heptane: ethyl acetate=1: 1-〉ethyl acetate) purifying, obtain the 27mg title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.40-1.58(m，2H)，1.65-1.76(m，2H)，2.18-2.25(m，2H)，2.31(s，3H)，3.85(s，3H)，4.07(q，J＝10.8Hz，1H)，4.07-4.15(m，1H)，4.34(dd，J＝10.8，2.4Hz，1H)，5.38(t，J＝4.0Hz，1H)，6.82(s，1H)，6.92(brs，1H)，7.02(t，J＝8.4Hz，2H)，7.20(d，J＝8.0Hz，1H)，7.22(dd，J＝8.0，3.6Hz，2H)，7.37(dd，J＝8.0，1.2Hz，1H)，7.39(d，J＝1.2Hz，1H)，7.74(d，J＝1.2Hz，1H)。

ESI-MS；m/z?448[M ⁺H]。

With racemoid (Z)-(6S that obtains above ^*, 9aR ^*)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone (27mg) passes through Daicel Chemical Industries, CHIRALCELTM OJ-H (2cm * 25cm that Ltd. makes; Moving phase: hexane: ethanol=1: 1) separate, the retention time that obtains optically active is 24 minutes title compound (6.7mg; Ee＞99%) and the retention time of optically active be 31 minutes title compound (4.9mg; Ee＞99%).

The retention time of optically active is that 24 minutes the property value of title compound (embodiment 16) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

ESI-MS；m/z?448[M ⁺+H]。

The retention time of optically active is that 31 minutes the property value of title compound (embodiment 17) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

ESI-MS；m/z?448[M ⁺+H]。

Embodiment 18 and 19

(Z)-(S)-4-[(S)-1-(6-chloropyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(6-chloropyridine-3-yl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone Synthetic

(S)-and 1-[1-(6-chloropyridine-3-yl) ethylamino] propan-2-ol synthetic

Adopt the method identical with embodiment 7, from lithium perchlorate (340mg), ether (0.64mL), 1-(6-chloropyridine-3-yl) ethamine (100mg:CAS#132219-51-3) and (S)-propylene oxide (61 μ L) reacts, and obtains the 44.9mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.11(d，J＝6.4Hz，1.5H)，1.12(d，J＝6.4Hz，1.5H)，1.39(d，J＝6.8Hz，1.5H)，1.40(d，J＝6.8Hz，1.5H)，2.21(dd，J＝12.0，9.2Hz，0.5H)，2.38(dd，J＝12.0，8.8Hz，0.5H)，2.49(dd，J＝12.0，2.4Hz，0.5H)，2.63(dd，J＝12.0，2.8Hz，0.5H)，3.68-3.87(m，2H)，7.31(d，J＝8.0Hz，0.5H)，7.32(d，J＝8.0Hz，0.5H)，7.67(dd，J＝8.0，2.0Hz，0.5H)，7.68(dd，J＝8.0，2.0Hz，0.5H)，8.30(d，J＝2.0Hz，0.5H)，8.31(d，J＝2.0Hz，0.5H)。

(S)-4-[1-(6-chloropyridine-3-yl) ethyl]-6-methylmorpholine-2,3-diketone synthetic

Adopting the method identical, from (S)-1-[1-(6-chloropyridine-3-yl) ethylamino with embodiment 7] propan-2-ol (44.8mg) and oxalic acid diethyl ester (1.0mL) react, and obtains the thick title compound of 37.4mg.

¹H-NMR(CDCl ₃)δ(ppm)：

1.36(d，J＝6.0Hz，1.5H)，1.41(d，J＝6.0Hz，1.5H)，1.62(d，J＝7.2Hz，1.5H)，1.65(d，J＝7.2Hz，1.5H)，3.03-3.11(m，1H)，3.34(dd，J＝14.0，3.2Hz，0.5H)，3.47(dd，J＝13.6，10.4Hz，0.5H)，4.52-4.55(m，0.5H)，4.71-4.76(m，0.5H)，5.94-5.99(m，1H)，7.37(d，J＝8.4Hz，1H)，7.64(dd，J＝8.4，2.4Hz，0.5H)，7.68(dd，J＝8.4，2.4Hz，0.5H)，8.37(d，J＝2.4Hz，0.5H)，8.39(d，J＝2.4Hz，0.5H)。

(S)-4-[1-(6-chloropyridine-3-yl) ethyl]-2-hydroxyl-6-methylmorpholine-3-ketone synthetic

Adopt the method identical, from (S)-4-[1-(6-chloropyridine-3-yl) ethyl with embodiment 7]-6-methylmorpholine-2, the THF of 3-diketone (37.4mg) and 1M 3-sec-butyl lithium borohydride (153 μ L) solution reaction obtains the 3.9mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.22(d，J＝7.2Hz，1.5H)，1.23(d，J＝7.2Hz，1.5H)，1.57(d，J＝8.4Hz，3H)，2.68(dd，J＝12.0，10.8Hz，0.5H)，2.75(dd，J＝12.0，2.8Hz，0.5H)，3.02(dd，J＝12.0，2.8Hz，0.5H)，3.18(dd，J＝12.0，10.8Hz，0.5H)，4.26-4.30(m，0.5H)，4.43-4.47(m，0.5H)，5.34(s，0.5H)，5.36(s，0.5H)，5.96(q，J＝7.2Hz，0.5H)，5.99(q，J＝7.2Hz，0.5H)，7.33(d，J＝8.4Hz，0.5H)，7.34(d，J＝8.4Hz，0.5H)，7.59(dd，J＝8.4，2.4Hz，0.5H)，7.63(dd，J＝8.4，2.4Hz，0.5H)，8.34(d，J＝2.4Hz，0.5H)，8.35(d，J＝2.4Hz，0.5H)。

Adopt and embodiment 16 and 17 identical methods, from (S)-4-[1-(6-chloropyridine-3-yl) ethyl]-2-hydroxyl-6-methylmorpholine-3-ketone (3.9mg), three phenyl phosphonium bromides (5.81mg) and the reaction of 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (3.43mg), obtain title compound into non-enantiomer mixture.Non-enantiomer mixture is passed through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMAD-H (2cm * 25cm; Moving phase: ethanol 100%) separate, the retention time that obtains optically active is 19 minutes title compound (1.25mg; De＞80%) and the retention time of optically active be 25 minutes title compound (0.85mg; De＞84%).

Retention time is that 19 minutes the property value of optically active title compound (embodiment 19) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.39(d，J＝6.8Hz，3H)，1.62(d，J＝6.8Hz，3H)，2.36(s，3H)，2.96(dd，J＝13.2，4.8Hz，1H)，3.26(dd，J＝13.2，2.4Hz，1H)，3.86(s，3H)，4.31-4.40(m，1H)，6.13(q，J＝6.8Hz，1H)，6.88(s，1H)，6.96(s，1H)，7.22(d，J＝8.4Hz，1H)，7.34(d，J＝8.0Hz，1H)，7.36(d，J＝8.0Hz，1H)，7.52(s，1H)，7.64(dd，J＝8.4，2.8Hz，1H)，7.93(s，1H)，8.38(d，J＝2.8Hz，1H)。

ESI-MS；m/z?453[M ⁺+H]。

Retention time is that 25 minutes the property value of optically active title compound (embodiment 18) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.0Hz，3H)，1.61(d，J＝7.2Hz，3H)，2.39(s，3H)，2.99(dd，J＝12.8，2.4Hz，1H)，3.41(dd，J＝12.8，10.4Hz，1H)，3.87(s，3H)，4.10-4.20(m，1H)，6.15(q，J＝7.2Hz，1H)，6.89(s，1H)，6.97(s，1H)，7.23(d，J＝8.4Hz，1H)，7.35(d，J＝7.6Hz，1H)，7.37(d，J＝7.6Hz，1H)，7.55(s，1H)，7.67(dd，J＝8.4，2.4Hz，1H)，7.99(s，1H)，8.39(d，J＝2.4Hz，1H)。

ESI-MS；m/z?453[M ⁺+H]。

Embodiment 20 and 21

(Z)-(S)-4-[(S)-1-(5-chloropyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(5-chloropyridine-2-yl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone Synthetic

1-(5-chloropyridine-2-yl) alcoholic acid is synthetic

Cupric iodide (148mg), 1-vinyl ethyl ether base tri-n-butyl tin (2.97mL) and two (triphenylphosphine) Palladous chloride (II) (183mg) are added in the solution of 2-bromo-5-chloropyridine (1g) in acetonitrile (30mL), and reaction soln was stirred 3 hours under nitrogen at 100 ℃.Reaction soln is returned to room temperature.Add the 5N hydrochloric acid of 10mL and with reaction soln reflux 30 minutes.Reaction soln returns to room temperature and neutralizes with the 5N sodium hydroxide solution.Ether is added reaction soln and separates organic layer.Organic layer is through anhydrous magnesium sulfate drying, subsequently solvent evaporated under reduced pressure.Resistates is dissolved in tetrahydrofuran (THF) (30mL) and the methyl alcohol (10mL).Add sodium borohydride (492mg) and reaction soln was at room temperature stirred 1 hour.Water is added reaction soln and separates organic layer with ether.Organic layer is with the salt water washing and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, and with resistates (eluting solvent: purifying hexane-ether) obtains the 503mg title compound through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.50(d，J＝6.8Hz，3H)，4.90(q，J＝6.8Hz，1H)，7.28(dd，J＝0.8，0.8Hz，1H)，7.67(dd，J＝8.4，2.8Hz，1H)，8.50(dd，J＝2.8，0.8Hz，1H)。

Synthesizing of 2-(1-azido-ethyl)-5-chloropyridine

In nitrogen, diphenyl phosphoryl azide (1.0mL) is added 1-(5-chloropyridine-2-yl) ethanol (503mg) in the solution of toluene (8mL).Reaction soln is ice-cooled, dropwise add 1 to this solution, 8-diazabicylo [5,4,0] 11 carbon-7-alkene (0.69mL).Reaction soln was stirred 3 hours.Then, this solution is returned to room temperature and stir and to spend the night.Water is added reaction soln and separates organic layer with ether.Organic layer is solvent evaporated under reduced pressure after dried over mgso.(eluting solvent: purifying hexane-ether) obtains the 337mg title compound to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.60(d，J＝6.8Hz，3H)，4.66(q，J＝6.8Hz，1H)，7.32(d，J＝8.4Hz，1H)，7.69(dd，J＝8.4，2.8Hz，1H)，8.54(d，J＝2.8Hz，1H)。

Synthesizing of 1-(5-chloropyridine-2-yl) ethamine

Water (3mL) and triphenylphosphine (702mg) are added in tetrahydrofuran (THF) (10mL) solution of 2-(1-azido-ethyl)-5-chloropyridine (333mg), and reaction soln was stirred 2 hours at 60 ℃.Reaction soln is returned to room temperature.Methylene dichloride is added reaction soln and separates water layer with 5N hydrochloric acid.With the 5N sodium hydroxide solution with water layer alkalization (pH 14).Then, methylene dichloride is added reaction soln and separate organic layer.Organic layer obtains the 260mg title compound through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.4Hz，3H)，4.18(q，J＝6.4Hz，1H)，7.28(d，J＝8.4Hz，1H)，7.63(dd，J＝8.4，2.4Hz，1H)，8.50(d，J＝2.4Hz，1H)。

(Z)-(S)-4-[(S)-1-(5-chloropyridine-2-yl) ethyl]-2-[1-(3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(5-chloropyridine-2-yl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone Synthetic

Adopt and embodiment 18 and 19 identical methods, 1-(5-chloropyridine-2-yl) ethamine (200mg) reaction from as raw material obtains the 115mg title compound into non-enantiomer mixture.The part of non-enantiomer mixture is passed through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMLA (2cm * 25cm; Moving phase: ethanol 100%) separate, the retention time that obtains optically active is 17 minutes title compound (12.3mg; De＞99%) and the retention time of optically active be 20 minutes title compound (21.4mg; De 94%).

Retention time is that 17 minutes the property value of optically active title compound (embodiment 20) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.38(d，J＝6.4Hz，3H)，1.61(d，J＝7.2Hz，3H)，2.31(s，3H)，3.19(dd，J＝13.2，9.6Hz，1H)，3.52(dd，J＝13.2，2.4Hz，1H)，3.85(s，3H)，4.33-4.42(m，1H)，6.04(q，J＝7.2Hz，1H)，6.83(s，1H)，6.93(s，1H)，7.20(d，J＝8.0Hz，1H)，7.32(dd，J＝8.0，1.6Hz，1H)，7.33(d，J＝8.4Hz，1H)，7.51(d，J＝1.6Hz，1H)，7.65(dd，J＝8.4，2.4Hz，1H)，7.77(s，1H)，8.52(d，J＝2.4Hz，1H)。

ESI-MS；m/z?453[M ⁺+H]。

Retention time is that 20 minutes the property value of optically active title compound (embodiment 21) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.45(d，J＝6.4Hz，3H)，1.60(d，J＝7.2Hz，3H)，2.55(s，3H)，3.48(dd，J＝12.8，10.0Hz，1H)，3.60(dd，J＝12.8，2.4Hz，1H)，3.89(s，3H)，4.20-4.27(m，1H)，5.97(q，J＝7.2Hz，1H)，6.81(s，1H)，7.02(s，1H)，7.22(d，J＝7.6Hz，1H)，7.37(d，J＝8.4Hz，1H)，7.38(dd，J＝7.6，1.2Hz，1H)，7.60(d，J＝1.2Hz，1H)，7.66(dd，J＝8.4，2.4Hz，1H)，8.48(s，1H)，8.51(d，J＝2.4Hz，1H)。

ESI-MS；m/z?453[M ⁺+H]。

Embodiment 22 and 23

(Z)-(S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(2, the 6-difluoro Pyridin-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-first Synthesizing of base morpholine-3-ketone

Down (2.62M, 29.1mL) drips of solution is added to the solution of Diisopropylamine (11.7mL) in tetrahydrofuran (THF) (310mL) with the THF of n-Butyl Lithium in nitrogen ice-cooled.Ice-cooled down reaction soln the stirring also was cooled to-78 ℃ in 1 hour subsequently.With 2, the solution of 6-difluoro pyridine (8g) in tetrahydrofuran (THF) (10mL) dropwise adds reaction soln.Reaction soln was stirred 3 hours at-78 ℃.Then, under nitrogen gas stream, add excessive broken dry ice, and reaction soln was stirred 20 minutes and at room temperature stirred 3 hours at-78 ℃.Water is added reaction soln and separates water layer with ether.With concentrated hydrochloric acid water layer is transferred to pH 1.Ethyl acetate is added water layer and separates organic layer.Organic layer obtains the 10.4g title compound through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure.

¹H-NMR(CD ₃OD)δ(ppm)：

7.08(dd，J＝8.4，2.8Hz，1H)，8.58(dd，J＝17.2，8.4Hz，1H)。

2,6-two fluoro-N-methoxyl group-N-methylnicotinamides synthetic

With N, O-dimethyl hydroxylamine hydrochloride (14.7g), WSC (28.9g) and HOBt (20.4g) add 2, and 6-two fluorine nicotinic acids (6g) and diisopropylethylamine (10mL) and at room temperature stirred reaction soln 2 days in the solution of DMF (100mL).Water is added reaction soln and separates organic layer with ethyl acetate.Organic layer is through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure.The gained resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: ethyl acetate) purifying obtains the 7.01g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

3.37(s，3H)，3.58(brs，3H)，6.90(dd，J＝8.0，2.8Hz，1H)，8.02(dd，J＝16.0，8.0Hz，1H)。

1-(2,6-difluoro pyridine-3-yl) ethyl ketone

Ice-cooled down with methyl-magnesium-bromide THF (0.96M, solution 88.1mL) adds 2,6-two fluoro-N-methoxyl groups-N-methylnicotinamide (7.01g) and stirs reaction soln 2 hours down ice-cooled in the solution of tetrahydrofuran (THF) (180mL).Saturated ammonium chloride solution is added reaction soln down and separates organic layer ice-cooled with ethyl acetate.Organic layer is with the salt water washing and through anhydrous magnesium sulfate drying.Solvent evaporated under reduced pressure, (eluting solvent: hexane-ethyl acetate) purifying obtains the 4.74g title compound through silica gel column chromatography with this resistates.

¹H-NMR(CDCl ₃)δ(ppm)：

2.05(s，3H)，6.93-6.97(m，1H)，8.46-8.52(m，1H)。

1-(2,6-difluoro pyridine-3-yl) ethyl ketone oxime

With oxammonium sulfate (13.1g) and sodium-acetate (10.9g) add 1-(2,6-difluoro pyridine-3-yl) ethyl ketone (4.18g) moisture THF (50%, in solution 200mL), and reaction soln at room temperature stirred spends the night.Water is added reaction soln and separates organic layer with ethyl acetate.Organic layer is through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure.The gained resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: ethyl acetate) purifying obtains the 2.44g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

2.05(s，3H)，6.93-6.97(m，1H)，8.46-8.52(m，1H)。

1-(2,6-difluoro pyridine-3-yl) ethylamine

Divide three parts to add 1-(2,6-difluoro pyridine-3-yl) ethyl ketone oxime (2.44g) in the solution of trifluoroacetic acid (100mL) on zinc (9.29g), and reaction soln was at room temperature stirred 2 hours.With 5N sodium hydroxide alkalization reaction soln (pH 14),, wash diatomite with chloroform through diatomite filtration.Separate organic layer and through anhydrous magnesium sulfate drying, solvent evaporated under reduced pressure obtains the 1.61g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.8Hz，1H)，4.39(q，J＝6.8Hz，1H)，6.82(dd，J＝8.0，2.8Hz，1H)，8.02(dd，J＝17.2，8.0Hz，1H)。

Adopt and embodiment 18 and 19 identical modes, 1-(2,6-difluoro pyridine-3-yl) ethylamine (330mg) reaction from as raw material obtains the title compound (170mg) into non-enantiomer mixture.The non-enantiomer mixture of gained (10mg) passes through Daicel ChemicalIndustries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=7: 3) separate, obtain the title compound (3.8mg) that title compound that retention time is 33 minutes a optically active (4.7mg) and retention time are 39 minutes optically active.

The property value of the non-enantiomer mixture of title compound is as follows.

ESI-MS；m/z?455[M ⁺+H]。

Retention time is that 33 minutes the property value of optically active title compound (embodiment 22) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.44(d，J＝6.4Hz，3H)，1.67(d，J＝7.2Hz，3H)，2.31(s，3H)，3.23(dd，J＝12.8，10.0Hz，1H)，3.42(dd，J＝12.8，2.8Hz，1H)，3.84(s，3H)，4.37(m，1H)，5.74(q，J＝7.2Hz，1H)，6.81(s，1H)，6.87(dd，J＝8.0，2.8Hz，1H)，6.93(dd，J＝1.2，1.2Hz，1H)，7.20(d，J＝8.0Hz，1H)，7.31(dd，J＝8.4，1.6Hz，1H)，7.50(d，J＝1.6Hz，1H)，7.77(s，1H)，8.00(m，1H)。

Retention time is that 39 minutes the property value of optically active title compound (embodiment 23) is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.46(d，J＝6.4Hz，3H)，1.65(d，J＝7.2Hz，3H)，2.32(s，3H)，3.32(dd，J＝12.8，2.8Hz，1H)，3.50(dd，J＝12.8，9.6Hz，1H)，3.85(s，3H)，4.29(m，1H)，5.80(q，J＝7.2Hz，1H)，6.82(s，1H)，6.87(dd，J＝8.0，2.8Hz，1H)，6.93(dd，J＝1.2，1.2Hz，1H)，7.20(d，J＝8.0Hz，1H)，7.31(dd，J＝8.0，1.6Hz，1H)，7.51(d，J＝1.6Hz，1H)，7.79(s，1H)，7.99(m，1H)。

The another kind of synthetic method of embodiment 22

(Z)-(S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

1-(2,6-difluoro pyridine-3-yl) alcoholic acid is synthetic

At-60 ℃ or low temperature more, (2.62M is 368mL) and in the mixing solutions of tetrahydrofuran (THF) (800mL) at hexane Diisopropylamine (134mL) dropwise to be added n-Butyl Lithium under nitrogen.Reaction soln was stirred 30 minutes, subsequently-60 ℃ or more under the low temperature with 2, the solution of 6-difluoro pyridine (100g) in tetrahydrofuran (THF) (100mL) dropwise adds reaction soln.Stirring reaction solution 1 hour dropwise adds reaction soln with acetaldehyde (97.6mL) subsequently.Then with the 2N aqueous hydrochloric acid (1,000mL) dropwise add reaction soln.After this, with ethyl acetate (1,000mL) and toluene (1,000mL) add reaction soln and separate organic layer.With the organic layer concentrating under reduced pressure, obtain the 129g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.51(d，J＝5.6Hz，3H)，2.00(s，1H)，5.13-5.16(m，1H)，6.84(dd，J＝8.0，2.1Hz，1H)，8.05(dd，J＝16.0，8.0Hz，1H)。

(S)-1-[(S)-and 1-(2,6-difluoro pyridine-3-yl) ethylamino] propan-2-ol (+)-two-right-toluoyl Synthesizing of-D-tartrate

The ice-cooled toluene that down solution of 1-(2,6-difluoro pyridine-3-yl) ethanol (216g) in toluene (300mL) is added thionyl bromide (337g) (1,500mL) in the solution, and reaction soln at room temperature stirred 3 hours.Frozen water is added reaction soln and separates organic layer with toluene.(1,000mL) washing is three times for the organic layer water.With organic layer with anhydrous magnesium sulfate drying and with after layer of silica gel filter.With (S)-1-amino-2-propyl alcohol (157g), cesium carbonate (1.28kg) and DMF (2,500mL) add in the filtrate, and reaction soln at room temperature stirred spend the night.Filtering reacting solution is also subsequently with the mother liquor concentrating under reduced pressure.Resistates ethanol (1,000mL) dilution.Then, add ethanol (500mL) solution of (+)-two-right-toluoyl-D-tartrate (152g) and reaction soln at room temperature stirred 1 hour.By filtering the collecting precipitation crystal and using washing with alcohol.With crystal 80 ℃ of dryings 2 hours and be suspended in ethanol (2,000mL)/heptane (1, in mixed solvent 000mL).Then, reacting by heating solution and 80 ℃ of stirrings.After 1 hour, reaction soln is returned to room temperature, collect crystal by filtering.Crystal obtains the 155g title compound with washing with alcohol and 80 ℃ of dried overnight.

¹H-NMR(DMSO-d ₆)δ(ppm)：

1.02(d，J＝6.0Hz，6H)，1.37(d，J＝6.8Hz，6H)，2.36(s，6H)，2.37-2.51(m，4H)，3.67-3.71(m，2H)，4.14-4.16(m，2H)，5.65(s，2H)，7.21(dd，J＝8.0，2.0Hz，2H)，7.31(d，J＝8.4，Hz，4H)，7.82(d，J＝8.4，Hz，4H)，8.27(dd，J＝17.6，8.0Hz，2H)。

(S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-6-methylmorpholine-2,3-diketone synthetic

With (S)-1-[(S)-1-(2,6-difluoro pyridine-3-yl) ethylamino] propan-2-ol (+)-two-toluoyl-D-tartrate (199g) is dissolved in 5N aqueous sodium hydroxide solution (450mL), water (1,000mL) and 50% toluene-THF (2,000mL) in, separate organic layer.Water layer washs three times with 50% toluene-THF (800mL).Merge organic layer and concentrating under reduced pressure.Then, (200mL) adds this resistates with oxalic acid diethyl ester, and reacting by heating solution also stirs under 140-150 ℃.After 3 hours,, use ice-cooled subsequently while stirring with toluene (500mL) diluting reaction solution.By filtering the crystal of collecting precipitation,, obtain the 103g title compound with toluene and ether washing and air-dry subsequently.

¹H-NMR(CDCl ₃)δ(ppm)：

1.43(d，J＝6.8Hz，3H)，1.70(d，J＝6.8Hz，3H)，3.36(dd，J＝13.2，8.8Hz，1H)，3.52(dd，J＝13.2，2.1Hz，1H)，4.72-4.78(m，1H)，5.59(q，J＝6.8Hz，1H)，6.88(dd，J＝8.0，2.8Hz，1H)，8.01(dd，J＝16.8，8.0Hz，1H)。

(S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-hydroxyl-6-methylmorpholine-3-ketone synthetic

At-50 ℃ or more under the low temperature, THF (20mL) solution of 1M 3-sec-butyl lithium borohydride is dropwise added (S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-6-methylmorpholine-2,3-diketone (4.5g) and stirs reaction soln 2 hours in the solution of THF.At-10 ℃ or more under the low temperature, the aqueous hydrogen peroxide solution (6.78mL) of 5N sodium hydroxide solution (1.66mL) and 30% is dropwise added reaction soln, and reaction soln was stirred 1 hour.Sodium bisulfite (520mg) is added reaction soln, stirred subsequently 30 minutes.Salt solution is added reaction soln and separates organic layer with 50% toluene-THF.Water layer washs with 50% toluene-THF.Merge organic layer and concentrating under reduced pressure.(heptane: ethyl acetate=1: 1-0: 100) purifying obtains the 4.52g title compound to resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.25(d，J＝6.8Hz，2.58H)，1.30(d，J＝6.8Hz，0.42H)，1.60(d，J＝6.8Hz，2.58H)，1.62(d，J＝6.8Hz，0.42H)，2.90(dd，J＝12.8，8.8Hz，0.86H)，3.09(dd，J＝12.8，8.8Hz，0.14H)，3.11(dd，J＝12.8，2.1Hz，0.86H)，3.31(dd，J＝12.8，2.1Hz，0.14H)，4.39-4.49(m，1H)，5.14(s，0.14H)，5.30(s，0.86H)，5.50(q，J＝6.8Hz，0.14H)，5.71(q，J＝6.8Hz，0.86H)，6.87(dd，J＝8.0，2.8Hz，1H)，7.96(dd，J＝16.8，8.0Hz，1H)。

Three phenyl phosphonium bromides (6.52g) are added (S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-hydroxyl-6-methylmorpholine-3-ketone (4.3g) is in the solution of acetonitrile, and with reaction soln reflux 1 hour.Triethylamine (5.28mL) and 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (3.42g) are added reaction soln, and reflux is 1.5 hours subsequently.With the reaction soln concentrating under reduced pressure, and with 2N aqueous hydrochloric acid and ethyl acetate dilution resistates.Separate water layer then.Organic layer washs with the 2N aqueous hydrochloric acid.Then, merge whole water layers and alkalize with strong caustic.With this basic solution of ethyl acetate extraction, separate organic layer and also wash with saturated sodium bicarbonate subsequently.Organic layer is through anhydrous magnesium sulfate drying and concentrating under reduced pressure.(heptane: ethyl acetate=1: 1-0: 100) purifying obtains the 4.06g title compound to resistates through the NH silica gel column chromatography.The value of its character meets the value of embodiment 22.

Embodiment 24 and 25

(Z)-(S)-4-[(S)-1-(2,3-difluoro pyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(2, the 3-difluoro Pyridin-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-first Synthesizing of base morpholine-3-ketone

1-(2,6-difluoro pyridine-3-yl) ethylamine

Adopt and embodiment 22 and 23 identical methods, from known compound 2,3-difluoro Yi Yansuan (2.49g) (for example, referring to Journal of Organic Chemistry, 2005, vol.70, p.3039-3045) reaction obtains the 1.13g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.44(d，J＝6.8Hz，3H)，4.50(q，J＝6.8Hz，1H)，7.33(dd，J＝4.8，4.8Hz，1H)，7.94(d，J＝4.8Hz，1H)。

Adopt and embodiment 18 and 19 identical methods, 1-(2,6-difluoro pyridine-3-yl) ethylamine (500mg) reaction from as raw material obtains the title compound (500mg) into non-enantiomer mixture.Gained non-enantiomer mixture (10mg) is passed through Daicel ChemicalIndustries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=7: 3) separate, obtain the title compound (3.0mg) that title compound that retention time is 39 minutes a optically active (2.6mg) and retention time are 43 minutes optically active.

ESI-MS；m/z?455[M ⁺+H]。

Retention time is that the property value of title compound (embodiment 24) of 39 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.46(d，J＝6.8Hz，3H)，1.67(d，J＝7.2Hz，3H)，2.31(s，3H)，3.24(dd，J＝13.2，9.6Hz，1H)，3.43(dd，J＝13.2，2.8Hz，1H)，3.85(s，3H)，4.39(m，1H)，5.93(q，J＝7.2Hz，1H)，6.83(s，1H)，6.94(dd，J＝0.8，0.8Hz，1H)，7.19-7.27(m，2H)，7.32(dd，J＝8.4，1.6Hz，1H)，7.51(d，J＝1.6Hz，1H)，7.79(d，J＝1.2Hz，1H)，7.99(dd，J＝5.2，0.8Hz，1H)。

Retention time is that the property value of title compound (embodiment 25) of 43 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.49(d，J＝6.4Hz，3H)，1.66(d，J＝7.2Hz，3H)，2.32(s，3H)，3.29(dd，J＝12.8，2.8Hz，1H)，3.54(dd，J＝12.8，9.6Hz，1H)，3.85(s，3H)，4.34(m，1H)，5.97(q，J＝7.2Hz，1H)，6.84(s，1H)，6.94(s，1H)，7.18-7.23(m，2H)，7.33(dd，J＝8.4，1.6Hz，1H)，7.51(d，J＝1.6Hz，1H)，7.80(d，J＝1.2Hz，1H)，7.99(dd，J＝5.2，0.8Hz，1H)。

Embodiment 26

(Z)-(S)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-the 2-[1-[3-methoxyl group -4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

1,2,3-three fluoro-5-[(E)-and propenyl] benzene synthetic

Under nitrogen with tetra-triphenylphosphine palladium (0) (4.66g) and cesium fluoride (21.4g) add 1-bromo-3,4,5-trifluoro-benzene (8.5g) and anti-form-1-propylene-1-ylboronic acid (in the solution of 4.1g) Zai diox (95mL) and water (5mL), and stirs reaction soln 5 hours at 80 ℃.Reaction soln is returned to room temperature.Then, hexane and water are added reaction soln, and by removing by filter insolubles.Separate organic layer and also wash with water subsequently, once more by removing by filter insolubles.Separate organic layer, water and salt water washing successively subsequently.Organic layer is through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure subsequently.The gained crude product obtains the 5.83g title compound through silica gel column chromatography (hexane) purifying.

¹H-NMR(CDCl ₃)δ(ppm)：

1.88(d，J＝6.0Hz，3H)，6.18(qd，J＝6.0，16.0Hz，1H)，6.24(d，J＝16.0Hz，1H)，6.85-6.96(m，2H)。

(1S, 2S)-1-(3,4, the 5-trifluorophenyl) propane-1,2-glycol synthetic

With 1,2,3-three fluoro-5-[(E)-propenyl]-benzene (5.83g) adds ice-cooled AD-Mix-α (47.5g) and Toluidrin (3.22g) in the mixing solutions of the trimethyl carbinol (170mL) and water (170mL), and reaction soln spent the night 5 ℃ of stirrings.Then, S-WAT (51g) is added reaction soln, stirred subsequently 1 hour.With reaction soln dichloromethane extraction 3 times.The organic layer that merges extracts the sodium hydroxide layer with methylene dichloride subsequently once more with the washing of 2N sodium hydroxide solution.Merge organic layer, through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure subsequently.(hexane: ethyl acetate=9: 1-1: 1) purifying obtains the 5.54g title compound to the gained crude product through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.12(d，J＝6.4Hz，3H)，2.20(brs，1H)，2.79(brs，1H)，3.78(qd，J＝6.4，6.4Hz，1H)，4.34(d，J＝6.4Hz，1H)，6.96-7.05(m，2H)。

(1R, 2S)-1-azido--1-(3,4, the 5-trifluorophenyl) propan-2-ol synthetic

In nitrogen, sodium hydroxide small pieces (110mg) are added that (1S, 2S)-1-(3,4, the 5-trifluorophenyl) propane-1,2-glycol (5.54g) and stirs reaction soln 45 minutes at 70 ℃ in the solution of methylcarbonate (15mL).Then, outside temperature is risen to 100 ℃, spray into nitrogen to remove methylcarbonate.Once more methylcarbonate (5mL) is added this resistates and sprays into nitrogen to remove methylcarbonate.THF is added this resistates, remove insolubles by diatomite filtration.Then, solvent evaporated under reduced pressure obtains the 6.13g carbonate products.

In nitrogen, water (0.5mL) and sodiumazide (1.92g) are added in DMF (20mL) solution of described carbonate products, and reaction soln is spent the night 110 ℃ of stirrings.Reaction soln returns to room temperature, ether is added and water (three times) and salt solution washing reaction solution successively.Organic layer is through anhydrous magnesium sulfate drying, subsequently solvent evaporated under reduced pressure.(hexane: ethyl acetate=19: 1-9: 1) purifying obtains the 5.16g title compound to the gained resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.14(d，J＝6.4Hz，3H)，1.79(brs，1H)，3.97(qd，J＝6.4，4.8Hz，1H)，4.42(d，J＝4.8Hz，1H)，6.96-7.05(m，2H)。

[(1R, 2S)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group] t-butyl carbamate synthetic

In nitrogen, triphenylphosphine (5.85g) is added (1R, 2S)-THF (75mL) solution of 1-azido--1-(3,4, the 5-trifluorophenyl) propan-2-ol (5.16g) in, and reaction soln at room temperature stirred 10 minutes.After this, water (5mL) is added reaction soln, stirred 3.5 hours at 60 ℃ subsequently.Reaction soln returns to room temperature, and di-tert-butyl dicarbonic acid ester (5.35g) is added reaction soln, at room temperature stirs subsequently 45 minutes.Also (toluene: ethyl acetate=9: 1) purifying obtains the 5.88g title compound to solvent evaporated under reduced pressure through silica gel column chromatography with the gained resistates subsequently.

¹H-NMR(CDCl ₃)δ(ppm)：

1.07(d，J＝6.4Hz，3H)，1.41(s，9H)，4.10(brs，1H)，4.47(brs，1H)，5.44(brs，1H)，6.92-7.01(m，2H)。

(1R, 2R)-2-tert-butoxycarbonyl amino-1-methyl-2-(3,4, the 5-trifluorophenyl) ethyl 4-oil of mirbane Synthesizing of manthanoate

Under ice-cooled, in nitrogen, diisopropyl azodiformate (6mL) is dropwise added [(1R, 2S)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group] t-butyl carbamate (5.88g), 4-nitrobenzoic acid (4.84g) and triphenylphosphine (7.59g) in the solution of THF (100mL), and reaction soln at room temperature stirred 2 hours.Solvent evaporated under reduced pressure and with the gained resistates through silica gel column chromatography (toluene: ethyl acetate=97: 3) purifying.Then, the gained powder is ground with toluene-hexane, obtain the 6.69g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.37(s，9H)，1.38(d，J＝6.4Hz，3H)，4.85(brs，1H)，5.16(d，J＝9.2Hz，1H)，5.41(qd，J＝6.4，6.0Hz，1H)，6.92-7.01(m，2H)，8.16(d，J＝8.8Hz，2H)，8.29(d，J＝8.8Hz，2H)。

[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group] t-butyl carbamate synthetic

Potassium carbonate powder (6.43g) is added (1R, 2R)-2-tert-butoxycarbonyl amino-1-methyl-2-(3,4,5-trifluorophenyl) ethyl 4-nitrobenzoyl acid esters (7.03g) is in the mixing solutions of methyl alcohol (90mL)-THF (10mL), and reaction soln was at room temperature stirred 1 hour.Ethyl acetate is added reaction soln, subsequently water and salt solution (twice) washing successively.Organic layer is through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure.Add ether in the gained resistates and by removing by filter insolubles.Concentrated filtrate and with the gained resistates (toluene: ethyl acetate=6: 1) purifying obtains the 4.49g title compound through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.28(d，J＝6.4Hz，3H)，1.44(s，9H)，4.01(brs，1H)，4.48(brs，1H)，5.35(brs，1H)，6.90-7.00(m，2H)。

[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group] the carboxylamine uncle Synthesizing of butyl ester

In nitrogen, divide four parts to add [(1R tert-butyl diphenyl chlorosilane (2.0mL), 2R)-2-hydroxyl-1-(3,4,5-trifluorophenyl) propyl group] t-butyl carbamate (610mg) and imidazoles (817mg) in the solution of DMF (3mL), and reaction soln at room temperature stirred 3 hours.Ethyl acetate is added reaction soln, subsequently water, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and salt water washing successively.Organic layer is through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure subsequently.(hexane: ether=49: 1-19: 1) purifying obtains the 684mg title compound to the gained resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

0.95(s，9H)1.13(d，J＝6.4Hz，3H)，1.47(s，9H)，4.02(brs，1H)，4.46(brs，1H)，5.34(brs，1H)，6.69-6.80(m，2H)，7.28-7.46(m，8H)，7.55(d，J＝8.4Hz，2H)。

(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amine

Trifluoroacetic acid (0.5mL) is added [(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group] t-butyl carbamate (370mg) in the solution of methylene dichloride (2mL), and reaction soln at room temperature stirred 11 hours.Saturated sodium bicarbonate solution is added reaction soln, use ethyl acetate extraction subsequently.Organic layer saturated sodium bicarbonate solution and salt water washing, solvent evaporated under reduced pressure obtains the 275mg title compound subsequently.

¹H-NMR(CDCl ₃)δ(ppm)：

0.93(d，J＝6.4Hz，3H)，1.02(s，9H)，3.81(d，J＝4.8Hz，1H)，3.91(dq，J＝4.8，6.0Hz，1H)，6.88-6.97(m，2H)，7.32-7.46(m，6H)，7.57(d，J＝8.0Hz，2H)，7.55(d，J＝8.0Hz，2H)。

(S)-1-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amino] third Synthesizing of-2-alcohol

With (S)-(-)-propylene oxide (0.1mL) and (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amine (212mg) joins lithium perchlorate (750mg) in the suspension of ether (1mL) at the solution of ether (1mL), and reaction soln is stirred under room temperature in nitrogen spend the night.Methylene dichloride and frozen water are added reaction soln.Behind the stirring reaction solution, separate organic layer.Water layer extracts once more with methylene dichloride.Merge organic layer and use anhydrous magnesium sulfate drying, subsequently with the solvent concentrating under reduced pressure.(ethyl acetate: heptane=9: 1-4: 1) purifying obtains the 172mg title compound to the gained resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

0.83(d，J＝6.0Hz，3H)，1.06(s，9H)，1.08(m，3H)，2.20-2.50(m，3H)，3.47(brs，1H)，3.59(brs，1H)，3.86(brs，1H)，6.78-6.95(m，2H)，7.36-7.48(m，6H)，7.67(d，J＝6.8Hz，4H)。

(S)-4-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group]-the 6-methyl Morpholine-2,3-diketone synthetic

Under ice-cooled, in nitrogen, oxalyl chloride (45 μ l) is dropwise added (S)-1-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amino] propan-2-ol (171mg), TEA (0.17mL) and 4-(N, the N-dimethylamino) pyridine (8mg) is in the solution of methylene dichloride (2mL), and reaction soln was stirred 2 hours under same temperature.Frozen water is added reaction soln, use ethyl acetate extraction subsequently.Then, with organic layer water successively, 1N hydrochloric acid, water, saturated sodium bicarbonate solution and salt water washing.Organic layer is through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure.(heptane: ethyl acetate=9: 1-3: 1) purifying obtains the 96mg title compound to the gained resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.02(s，9H)，1.19(d，J＝6.0Hz，3H)，1.28(d，J＝6.4Hz，3H)，3.20(dd，J＝5.6，13.2Hz，1H)，3.68(dd，J＝2.4，13.2Hz，1H)，4.42(dq，J＝5.6，6.0Hz，1H)，4.62(ddq，J＝2.4，5.6，6.4Hz，1H)，5.51(d，J＝5.6Hz，1H)，6.82-6.94(m，2H)，7.40-7.54(m，6H)，7.62(d，J＝8.0Hz，2H)，7.67(d，J＝8.0Hz，2H)。

(S)-4-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group]-the 2-hydroxyl Synthesizing of-6-methylmorpholine-3-ketone

In nitrogen, dropwise add (S)-4-[(1R in-20 ℃ of THF (0.25mL) solution with 3-sec-butyl lithium borohydride (1.06mol), 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group]-6-methylmorpholine-2,3-diketone (95mg) and stirs reaction soln 30 minutes under uniform temp in the solution of THF (3mL).5N sodium hydroxide solution (0.03mL) and 30% aqueous hydrogen peroxide solution (0.07mL) are added reaction soln, stirred 1 hour down ice-cooled subsequently.After this, add sodium bisulfite powder (20mg) and reaction soln at room temperature stirred 30 minutes.Salt solution is added reaction soln, use ethyl acetate extraction subsequently.Organic layer is with the salt water washing and use anhydrous magnesium sulfate drying, solvent evaporated under reduced pressure subsequently.(heptane: ethyl acetate=1: 1) purifying obtains the 93mg title compound to the gained resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.01 (s, 9H), 1.11 (d, J=6.0Hz, 3H), 1.19 (d, J=6.4Hz, 3H), 2.88 and 2.99 (dd, J=12.0,12.0Hz, 1H), 3.12 and 3.48 (dd, J=2.4,12.0Hz, 1H), 3.16 and 3.91 (d, J=2.8Hz, 1H), 4.35-4.55 (m, 2H), 5.11 and 5.30 (d, J=3.6Hz, 1H), 5.40 and 5.49 (d, J=6.8Hz, 1H), 6.79-6.94 (m, 2H), 7.38-7.54 (m, 6H), 7.65 (d, J=8.0Hz, 2H), 7.69 (d, J=8.0Hz, 2H).

In nitrogen with (S)-4-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4,5-trifluorophenyl) propyl group]-2-hydroxyl-6-methylmorpholine-3-ketone (92mg) and triphenylphosphine hydrobromate (68mg) the solution reflux 1 hour of (4mL) in acetonitrile.Solvent evaporated under reduced pressure also is dissolved in ethanol (4mL) with the gained resistates.In this reaction soln, add the 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (40mg) and the TEA (0.12mL) that from embodiment 1, obtain, and reaction soln stirred under room temperature in nitrogen spend the night.Solvent evaporated under reduced pressure.The gained resistates is dissolved in trifluoroacetic acid (1mL) and reaction soln was at room temperature stirred 2 hours.Reaction soln is poured in the saturated sodium bicarbonate solution, used ethyl acetate extraction subsequently.Organic layer saturated sodium bicarbonate solution and salt water washing, solvent evaporated under reduced pressure subsequently.(heptane: ethyl acetate=1: 1-0: 1) purifying obtains the 61.9mg title compound to the gained resistates through the NH silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.33(d，J＝6.0Hz，3H)，1.42(d，J＝6.0Hz，3H)，2.34(s，3H)，3.20(dd，J＝9.6，12.8Hz，1H)，3.61(dd，J＝2.4，12.8Hz，1H)，3.85(s，3H)，4.42-4.52(m，2H)，5.35(d，J＝6.8Hz，1H)，6.85(s，1H)，6.95(s，1H)，7.06-7.15(m，2H)，7.22(d，J＝8.0Hz，1H)，7.33(dd，J＝1.6，8.0Hz，1H)，7.53(d，J＝1.6Hz，1H)，7.86(s，1H)。

ESI-MS；m/z?502[M ⁺+H]。

Embodiment 27

(Z)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-2-[1-[3-methoxyl group-4-(4-first Base-1H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 26, from embodiment 26, obtain (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amine (280mg) and oxidation iso-butylene (63 μ l) react as raw material, obtain the 3.15mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.28(s，3H)，1.34(d，J＝6.0Hz，3H)，1.47(s，3H)，2.31(s，3H)3.19(d，J＝12.8Hz，1H)，3.61(d，J＝12.8Hz，1H)，3.85(s，3H)，4，46(dq，J＝6.8，6.0Hz，1H)，5.40(d，J＝6.8Hz，1H)，6.91(s，1H)，6.93(s，1H)，7.09-7.17(m，2H)，7.21(d，J＝8.4Hz，1H)，7.32(dd，J＝1.6，8.4Hz，1H)，7.53(d，J＝1.6Hz，1H)，7.77(s，1H)。

ESI-MS；m/z?516[M ⁺+H]。

Embodiment 28

(Z)-4-[(R)-1-(4-fluorophenyl)-2-hydroxyethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

Adopt the method identical, react, obtain the 3.48mg title compound from (R)-2-tert-butyl diphenyl siloxy-1-(4-fluorophenyl) ethamine (300mg) and oxidation iso-butylene (101 μ L) as raw material with embodiment 26.

¹H-NMR(CDCl ₃)δ(ppm)：

1.25(s，3H)，1.43(s，3H)，2.34(s，3H)，3.06(d，J＝12.8Hz，1H)，3.39(d，J＝12.8Hz，1H)，3.84(s，3H)，4.12-4.23(m，2H)，5.87(dd，J＝6.0，2.4Hz，1H)，6.88(s，1H)，6.94(s，1H)，7.04-7.09(m，2H)，7.19(dd，J＝8.4，4.8Hz，1H)，7.29-7.34(m，3H)，7.52(d，J＝4.8Hz，1H)，7.92(s，1H)。

ESI-MS；m/z?466[M ⁺+H]。

Embodiment 29

(Z)-(6R)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-the 2-[1-[3-methoxyl group -4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from embodiment 26, obtain (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amine (500mg) and (R)-(+)-propylene oxide (0.12mL) reacts as raw material, obtains the 144mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.33(d，J＝6.4Hz，3H)，1.42(d，J＝6.4Hz，3H)，2.30(s，3H)，3.25(dd，J＝12.8，2.4Hz，1H)，3.62(dd，J＝12.8，10.0Hz，1H)，3.84(s，3H)，4.19(ddd，J＝10.0，6.4，2.4Hz，1H)，4.50(td，J＝6.4，6.0Hz，1H)，5.41(d，J＝6.0Hz，1H)，6.86(s，1H)，6.93(s，1H)，7.05-7.16(m，2H)，7.20(d，J＝8.0Hz，1H)，7.32(dd，J＝8.0，1.6Hz，1H)，7.51(d，J＝1.6Hz，1H)，7.74(s，1H)。

Embodiment 30

(Z)-4-[(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-2-[1-[3-methoxyl group-4-(4-first Base-1H-imidazoles-1-yl) phenyl] methylene radical] morpholine-3-ketone synthetic

[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amino] acetate second Synthesizing of ester

Cesium carbonate (242mg) and ethyl bromoacetate (103 μ l) are added in (1R that obtains among the embodiment 26,2R)-2-tert-butyl diphenyl siloxy-1-(3,4,5-trifluorophenyl) propyl group amine (274mg) is in the solution of DMF (5mL), and reaction soln was at room temperature stirred 11 hours.Frozen water is added reaction soln and separates organic layer with ethyl acetate.Organic layer is used half saturated brine and salt water washing and successively through anhydrous magnesium sulfate drying, subsequently solvent evaporated under reduced pressure.(hexane: purifying ether=19: 1) obtains the 190mg title compound to the gained resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

0.75(d，J＝6.4Hz，3H)，1.09(s，9H)，1.26(t，J＝7.2Hz，3H)，3.03(d，J＝16.8Hz，1H)，3.24(d，J＝16.8Hz，1H)，3.57(d，J＝6.8Hz，1H)，3.80-3.92(m，1H)，4.19(q，J＝7.2Hz，2H)，6.88-6.98(m，2H)，7.36-7.48(m，6H)，7.67-7.77(m，4H)。

2-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amino] ethanol Synthetic

In nitrogen, lithium borohydride (20mg) is added [(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amino] ethyl acetate (158mg) at room temperature stirred 1 day in the solution of THF (3mL) and with reaction soln.Saturated metabisulfite solution is added reaction soln, with after diatomite filtration is removed sedimentary insolubles.Methyl alcohol is added filtrate and solvent evaporated under reduced pressure subsequently.(heptane: ethyl acetate=4: 1) purifying obtains the 103mg title compound to the gained resistates through silica gel column chromatography.

ESI-MS；M/Z?488[MH ⁺]

4-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group] morpholine-2,3- Synthesizing of diketone

With 2-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group amino] solution of ethanol (102mg) in oxalic acid diethyl ester (2mL) stirred 1 hour 30 minutes at 170 ℃.The reduction vaporization oxalic acid diethyl ester, and with the gained resistates (heptane: ethyl acetate=9: 1-6: 1) purifying obtains the 48mg title compound through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

0.99(s，9H)，1.18(d，J＝6.0Hz，3H)，3.47(ddd，J＝14.0，5.6，3.2Hz，1H)，3.83(ddd，J＝14.0，8.0，3.6Hz，1H)，4.27-4.43(m，3H)，5.54(d，J＝5.2Hz，1H)，6.80-6.90(m，2H)，7.36-7.54(m，6H)，7.62(d，J＝8.0Hz，2H)，7.67(d，J＝8.0Hz，2H)。

Adopt the method identical with embodiment 26, from 4-[(1R, 2R)-and 2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group] morpholine-2,3-diketone (47mg) reacts, and obtains the 18mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.33(d，J＝6.0Hz，3H)，2.40(s，3H)，3.41(ddd，J＝13.2，6.4，3.2Hz，1H)，3.81(ddd，J＝13.2，7.2，3.2Hz，1H)，3.87(s，3H)，4.17(ddd，J＝11.2，7.2，3.2Hz，1H)，4.30(ddd，J＝11.2，6.4，3.2Hz，1H)，4.51(dt，J＝6.4，6.0Hz，1H)，5.42(d，J＝6.4Hz，1H)，6.88(s，1H)，6.98(s，1H)，7.08-7.17(m，2H)，7.23(d，J＝8.0Hz，1H)，7.40(dd，J＝8.0，1.6Hz，1H)，7.43(d，J＝1.6Hz，1H)，8.04(s，1H)。

Embodiment 31

(Z)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-first Base-1H-imidazoles-1-yl) phenyl] methylene radical] morpholine-3-ketone synthetic

(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3, the 4-difluorophenyl) propyl group amine synthetic

Adopt the method identical with embodiment 26, from 1-bromo-3,4-two fluorobenzene (19g) react, and obtain the 5.37g title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

0.86(d，J＝6.4Hz，3H)，1.03(s，9H)，3.82(d，J＝6.0Hz，1H)，3.89(dq，J＝6.4，6.0Hz，1H)，6.95-7.13(m，3H)，7.32-7.44(m，6H)，7.59(dd，J＝7.2，2.8Hz，2H)，7.65(dd，J＝7.2，2.8Hz，2H)。

(Z)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical] morpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3, the 4-difluorophenyl) propyl group amine (825mg) reacts, and obtains the 7.3mg title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.33(d，J＝6.4Hz，3H)，2.29(s，3H)，3.38(m，1H)，3.76(m，1H)，3.84(s，3H)，4.13(m，1H)，4.27(m，1H)，4.51(dq，J＝7.6，6.4Hz，1H)，5.44(d，J＝7.6Hz，1H)，6.87(s，1H)，6.92(s，1H)，7.14-7.20(m，3H)，7.27-7.39(m，3H)，7.70(s，1H)。

Embodiment 32

(Z)-(S)-4-[(1R, 2R)-1-(4-fluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-first Base-1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(4-fluorophenyl) propylamine synthetic

Adopt the method identical, react, obtain the 113mg title compound from 1-bromo-4-fluorobenzene with embodiment 26.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

0.83(d，J＝6.4Hz，3H)，1.03(s，9H)，3.85(d，J＝6.0Hz、1H)，3.92(dq、J＝6.4，6.0Hz，1H)，6.92-6.97(m，2H)，7.21-7.25(m，2H)，7.31-7.43(m，6H)，7.59(dd，J＝7.2，2.8Hz，2H)，7.66(dd，J＝7.2，2.8Hz，2H)。

(Z)-(S)-4-[(1R, 2R)-1-(4-fluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(4-fluorophenyl) propylamine reacts, and obtains title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.30(d，J＝6.0Hz，3H)，1.38(d，J＝6.4Hz，3H)，2.29(s，3H)，3.12(dd，J＝12.8，10.0Hz，1H)，3.51(dd，J＝12.8，2.8Hz，1H)，3.83(s，3H)，4.39-4.50(m，2H)，5.41(d，J＝7.6Hz，1H)，6.84(s，1H)，6.92(s，1H)，7.04-7.08(m，2H)，7.19(d，J＝8.0Hz，1H)，7.30-7.38(m，3H)，7.50(s，1H)，7.70(s，1H)。

Embodiment 33

(Z)-4-[(1R, 2R)-1-(4-fluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 27, from (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(4-fluorophenyl) propylamine reacts, and obtains the 259mg title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.20(s，3H)，1.31(d，J＝6.0Hz，3H)，1.43(s，3H)，2.29(s，3H)，3.15(d，J＝12.8Hz，1H)，3.52(d，J＝12.8Hz，1H)，3.83(s，3H)，4.45(dq，J＝8.8，6.0Hz，1H)，5.47(d，J＝8.8Hz，1H)，6.89(s，1H)，6.91(s，1H)，7.03-7.08(m，2H)，7.18(d，J＝8.0Hz，1H)，7.30(dd，J＝8.0，1.6Hz，1H)，7.36-7.40(m，2H)，7.52(d，J＝1.6Hz，1H)，7.70(s，1H)。

Embodiment 34

(Z)-(S)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(4- Methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3, the 4-difluorophenyl) propylamine reacts, and obtains the 198mg title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.32(d，J＝6.4Hz，3H)，1.40(d，J＝6.0Hz，3H)，2.29(s，3H)，3.16(dd，J＝12.8，10.0Hz，1H)，3.56(dd，J＝12.8，2.8Hz，1H)，3.83(s，3H)，4.41-4.48(m，2H)，5.38(d，J＝7.6Hz，1H)，6.84(s，1H)，6.92(s，1H)，7.11-7.20(m，3H)，7.26-7.32(m，2H)，7.50(s，1H)，7.70(s，1H)。

Embodiment 35

(Z)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-methoxyl group-4-(methyl miaow Azoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 27, from (1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3, the 4-difluorophenyl) propylamine reacts, and obtains the 172mg title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.24(s，3H)，1.33(d，J＝6.4Hz，3H)，1.45(s，3H)，2.29(s，3H)，3.17(d，J＝12.8Hz，1H)，3.56(d，J＝12.8Hz，1H)，3.84(s，3H)，4.45(dq，J＝7.6，6.4Hz，1H)，5.42(d，J＝7.6Hz，1H)，6.89(s，1H)，6.91(s，1H)，7.14-7.20(m，3H)，7.27-7.32(m，2H)，7.52(s，1H)，7.70(s，1H)。

Embodiment 36

(Z)-(S)-4-[(S)-2-hydroxyl-1-methyl isophthalic acid-(3,4, the 5-trifluorophenyl) ethyl]-the 2-[1-[3-methoxyl group -4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, use is according to document (J.Org.Chem.2001 for example, 66, p.8778) Zhi Bei (R)-2-tert-butyl diphenyl siloxy-1-methyl isophthalic acid-(3,4, the 5-trifluorophenyl) ethamine is as raw material, from (S)-4-[(S)-2-tert-butyl diphenyl siloxy-1-methyl isophthalic acid-(3,4, the 5-trifluorophenyl) ethyl] morpholine-2,3-two reactive ketones obtain the 2.2mg title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.43(d，J＝6.4Hz，3H)，1.70(s，3H)，2.32(s，3H)，3.14(m，1H)，3.20(m，1H)，3.72(d，J＝12.8Hz，1H)，3.86(s，3H)，4.14(d，J＝12.8Hz，1H)，4.33(m，1H)，6.79(s，1H)，6.95(s，1H)，6.95-7.01(m，2H)，7.22(d，J＝8.0Hz，1H)，7.34(d，J＝8.0Hz，1H)，7.50(s，1H)，7.85(s，1H)。

Embodiment 37

(Z)-(6S)-and 2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 6-methyl -4-[(S)-and 1-(3,4, the 5-trifluorophenyl) ethyl] morpholine-3-ketone synthetic

(R)-1-(3,4, the 5-trifluorophenyl) alcoholic acid is synthetic

In nitrogen, in the solution of THF (200mL), dropwise add 3,4,5-trifluoroacetophenone (5.0g) [CAS 220141-73-1] to (+)-DIP-muriate (11.8g) that is cooled to 30 ℃.Reaction soln was stirred 5 hours under uniform temp, and at room temperature stirred 1 hour, subsequently reduction vaporization THF.The 6.5mL diethanolamine is dropwise added the gained resistates in the solution of ether (150mL), and reaction soln at room temperature stirred spend the night.By removing by filter insolubles and solvent evaporated subsequently.Hexane is added in the gained resistates also once more by removing by filter insolubles.(heptane: ethyl acetate=19: 1-4: 1) purifying obtains the 3.69g title compound to filtrate through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.46(d，J＝6.8Hz，3H)，4.85(q，J＝6.8，1H)，6.98-7.05(m，2H)。

5-((S)-1-azido-ethyl)-1,2,3-trifluoro-benzene synthetic

In the solution of toluene (70mL), dropwise add 1 to (R)-1-(3,4, the 5-trifluorophenyl) ethanol (3.6g) and phenylbenzene azide phosphorus (6.0mL), 8-diazabicylo [5,4,0] 11-7-alkene (4.1mL) down ice-cooled.Reaction soln was stirred 1 hour under uniform temp, and at room temperature stir and spend the night.Water is added reaction soln and separates organic layer.Then water layer is extracted with toluene once more.Merge organic layer and use 1N hydrochloric acid, water, saturated sodium bicarbonate solution and salt water washing successively.Organic layer is through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure subsequently.(heptane: ethyl acetate=49: 1) purifying obtains the 858mg title compound to the gained resistates through silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.50(d，J＝6.8Hz，3H)，4.56(q，J＝6.8，1H)，6.92-7.01(m，2H)。

(S)-1-(3,4, the 5-trifluorophenyl) ethamine synthetic

Triphenylphosphine (1.23g) added 5-((S)-1-azido-ethyl)-1,2 in nitrogen, 3-trifluoro-benzene (858mg) and at room temperature stirred reaction soln 5 minutes in the solution of THF (20mL).After this, water (2.5mL) is added reaction soln, stirred 2.5 hours at 60 ℃ subsequently.Reaction soln returns to room temperature, uses 2N hcl as extraction agent (twice) subsequently.The hcl as extraction agent layer is washed with ethyl acetate, subsequently with the alkalization of 5N sodium hydroxide solution, then with dichloromethane extraction (twice).Dichloromethane layer with anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure, is obtained the 348mg title compound.In addition, carrying out following operation is in order to collect the title compound in the ethyl acetate diluent that is retained in reaction solution.Ether is added this diluent, water extraction subsequently.The water extract layer with the ether washing and subsequently with the alkalization of 5N sodium hydroxide solution, is used dichloromethane extraction (twice) subsequently.Dichloromethane layer obtains the 413mg title compound through anhydrous magnesium sulfate drying and solvent evaporated under reduced pressure.

¹H-NMR(CDCl ₃)δ(ppm)：

1.33(d，J＝6.4Hz，3H)，4.08(q，J＝6.4，1H)，6.95-7.04(m，2H)。

Adopt and embodiment 18 and 19 identical methods, from as (S)-1-(3,4, the 5-trifluorophenyl) ethamine (1.15g) of raw material and (S)-(-)-propylene oxide (0.46mL) reacts, and obtains the 882mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.40(d，J＝6.4Hz，3H)，1.54(d，J＝7.2Hz，3H)，2.29(s，3H)，2.96(dd，J＝12.8，5.6Hz，1H)，3.20(dd，J＝12.8，3.2Hz，1H)，3.85(s，3H)，4.30-4.40(m，1H)，6.04(q，J＝7.2Hz，1H)，6.88(s，1H)，6.92(d，J＝1.2Hz，1H)，6.92-7.00(m，2H)，7.20(d，J＝8.0Hz，1H)，7.33(dd，J＝8.0，1.6Hz，1H)，7.50(d，J＝1.6Hz，1H)，7.86(d，J＝1.2Hz，1H)。

Embodiment 38

(Z)-(6S)-4-[1-(4-fluorophenyl)-1-methylethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from as 1-(4-the fluorophenyl)-1-methylethyl amine (500mg) [CAS#17797-10-3] of raw material and (S)-(-)-propylene oxide (0.23mL) reacts, and obtains the 97.8mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.50(d，J＝6.0Hz，3H)，1.76(s，3H)，1.77(s，3H)，2.28(s，3H)，3.49(dd，J＝13.2，9.6Hz，1H)，3.56(dd，J＝13.2，2.8Hz，1H)，3.82(s，3H)，4.38(dtd，J＝9.6，6.0，2.8Hz，1H)，6.66(s，1H)，6.91(s，1H)，7.00(dd，J＝8.8，8.8Hz，2H)，7.16(d，J＝8.0Hz，1H)，7.24-7.33(m，3H)，7.45(d，J＝1.2Hz，1H)，7.68(d，J＝1.6Hz，1H)。

Embodiment 39

(Z)-(6S)-4-[1-(4-fluorophenyl) cyclopropyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1- Base) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from as 1-(4-fluorophenyl) cyclopropylamine (726mg) [CAS#474709-83-6] of raw material and (S)-(-)-propylene oxide (0.4mL) reacts, and obtains the 213mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.30-1.42(m，4H)，1.44(d，J＝6.0Hz，3H)，2.29(s，3H)，3.47(dd，J＝12.8，3.2Hz，1H)，3.53(dd，J＝12.8，9.6Hz，1H)，3.84(s，3H)，4.33(dtd，J＝9.6，6.0，3.2Hz，1H)，6.82(s，1H)，6.92(d，J＝1.2Hz，1H)，6.99(dd，J＝8.8，8.8Hz，2H)，7.18(d，J＝8.0Hz，1H)，7.30(dd，J＝8.0，2.0Hz，1H)，7.35(dd，J＝8.8，5.2Hz，2H)，7.49(d，J＝2.0Hz，1H)，7.68(d，J＝1.2Hz，1H)。

Embodiment 40

(Z)-(6S, 9aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene]-6-(3,4,5- Trifluorophenyl) hexahydropyridine [2,1-c] [1,4] oxazine-4-ketone synthetic also

(R)-2-tert-butoxycarbonyl amino-6-oxo-6-(3,4, the 5-trifluorophenyl) methyl caproate synthetic

At-40 ℃ to (R)-6-oxo-piperidine-1,2-dioctyl phthalate 1-tertiary butyl ester 2-methyl ester (CAS No.183890-36-0,7.5g) in the solution of THF (200mL), dropwise add 3,4, (solution of 0.35M in ether 100mL) and with reaction soln at room temperature stirred 6 hours 5-trifluorophenyl magnesium bromide.Saturated ammonium chloride solution is added reaction soln and separates organic layer with ethyl acetate.Gained organic layer concentrating under reduced pressure after dried over mgso.(eluting solvent: heptane-heptane: ethyl acetate=1: 1) purifying obtains the 4.0g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

ESI-MS；m/z?412[M ⁺+Na]。

(2R, 6S)-6-(3,4, the 5-trifluorophenyl) piperidines-2-methyl-formiate synthetic

Ethyl acetate (20mL) solution of 4N hydrochloric acid is added (R)-2-tert-butoxycarbonyl amino-6-oxo-6-(3,4, the 5-trifluorophenyl) methyl caproate (4.0g) in the solution of ethyl acetate (20mL), and reaction soln was at room temperature stirred 14 hours.With the reaction soln concentrating under reduced pressure.Then, ethyl acetate and saturated sodium bicarbonate aqueous solution are added this resistates and separate organic layer.Gained organic layer concentrating under reduced pressure after dried over mgso.Palladium-carbon with 10% (100mg) adds the gained resistates in the solution of ethyl acetate (50mL), and reaction soln was at room temperature stirred 6 hours in hydrogen stream.Reaction soln concentrates filtrate decompression through diatomite filtration, obtains the 2.7g title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?274[M ⁺+H]。

[(2R, 6S)-6-(3,4, the 5-trifluorophenyl) piperidines-2-yl] methyl alcohol synthetic

-20 ℃ go through 15 minutes with LAH (75mg) divide three parts add (2R, 6S)-THF (5mL) solution of 6-(3,4, the 5-trifluorophenyl) piperidines-2-methyl-formiate (270mg) in.Reaction soln is added this reaction soln successively-20 ℃ of stirrings 1 hour and with water (0.1mL), 5N sodium hydroxide solution (0.1mL) and water (0.3mL).With this mixture heating up to room temperature and through diatomite filtration.Filtrate decompression concentrates, and obtains the 242mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?246[M ⁺+H]。

(4R, 6S)-6-(3,4, the 5-trifluorophenyl) hexahydropyridine [2,1-c] [1,4] oxazine-3,4-diketone synthetic also

Heating [(2R, 6S)-6-(3,4, the 5-trifluorophenyl) piperidines-2-yl] mixture of methyl alcohol (242mg) and oxalic acid diethyl ester (1.3mL), and stirred 1 hour at 120 ℃.Reaction soln is cooled to room temperature and passes through to filter the collecting precipitation solid.The gained solid obtains the 228mg title compound with ether washing and air-dry.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.36-1.48(m，1H)，1.58-1.67(m，1H)，1.70-1.87(m，2H)，2.10-2.24(m，2H)，4.09-4.18(m，1H)，4.37(t，J＝11.6Hz，1H)，4.43(dd，J＝11.6，3.6Hz，1H)，5.19(t，J＝4.0Hz，1H)，6.82-6.90(m，2H)。

(4R, 6S)-3-hydroxyl-6-(3,4, the 5-trifluorophenyl) hydroxyl hexahydropyridine [2,1-c] [1,4] oxazine-4-also Synthesizing of ketone

THF (0.79mL) solution with the 1M 3-sec-butyl lithium borohydride under-15 ℃ dropwise add (4R, 6S)-6-(3,4, the 5-trifluorophenyl) hexahydropyridine [2,1-c] [1,4] oxazine-3 also, in THF (10mL) solution of 4-diketone (228mg), and reaction soln stirred 3 hours down at-15 ℃.Under-15 ℃, 5N sodium hydroxide solution (0.25mL) and 20% aqueous hydrogen peroxide solution (0.05mL) are added reaction soln successively.Reaction soln is cooled to room temperature and stirred 1 hour.Ethyl acetate is added reaction solution and separates organic layer with sodium sulfite solution.The salt water washing of gained organic layer, concentrating under reduced pressure after dried over mgso.This resistates obtains the 240mg title compound through silica gel column chromatography (eluting solvent: heptane: ethyl acetate=1: 1-〉ethyl acetate) purifying.The value of the character of described compound is as follows.

ESI-MS；m/z?302[M ⁺+H]。

Will (4R, 6S)-3-hydroxyl-6-(3,4, the 5-trifluorophenyl) hydroxyl hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone (240mg) and the solution reflux of three phenyl phosphonium bromides (328mg) in acetonitrile (10mL) 1 hour, be cooled to room temperature subsequently.In reaction soln, add 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (172mg) and triethylamine (0.33mL), and reaction soln was at room temperature stirred 13 hours.Ethyl acetate is added reaction soln and separates organic layer with saturated sodium bicarbonate aqueous solution.The salt water washing of gained organic layer, concentrating under reduced pressure after dried over mgso.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: heptane: ethyl acetate=1: 1-〉ethyl acetate-ethyl acetate: purifying methyl alcohol=9: 1) obtains 1, the 300mg title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.38-1.58(m，2H)，1.66-1.84(m，2H)，2.06-2.14(m，1H)，2.17-2.28(m，1H)，2.30(s，3H)，3.86(s，3H)，4.04(t，J＝10.0Hz，1H)，4.06-4.14(m，1H)，4.36(brd，J＝8.4Hz，1H)，5.26(t，J＝4.0Hz，1H)，6.83(s，1H)，6.86-6.93(m，2H)，6.94(brs，1H)，7.21(d，J＝8.0Hz，1H)，7.38(dd，J＝8.0，1.6Hz，1H)，7.39(d，J＝1.6Hz，1H)，7.73(brs，1H)。

Embodiment 41

(Z)-(6S, 9aR)-6-(3, the 4-difluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) Benzylidene] hexahydropyridine [2,1-c] [1,4] oxazine-4-ketone synthetic also

(R)-2-tert-butoxycarbonyl amino-6-(3, the 4-difluorophenyl)-6-oxo methyl caproate synthetic

Under-40 ℃ to (R)-6-oxo-piperidine-1,2-dioctyl phthalate 1-tertiary butyl ester 2-methyl ester (CAS No.183890-36-0,5.8g) in the solution of THF (200mL), dropwise add 3, the 4-difluorophenyl magnesium bromide (solution of 0.5M in THF, 50mL), and reaction soln stirred 7 hours at-40 ℃.Saturated ammonium chloride solution and ethyl acetate are added reaction soln, and with this mixture heating up to room temperature.After this, separate organic layer, gained organic layer concentrating under reduced pressure after dried over mgso.(eluting solvent: heptane-heptane: ethyl acetate=1: 1) purifying obtains the 3.8g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

ESI-MS；m/z?394[M ⁺+Na]。

(2R, 6S)-6-(3, the 4-difluorophenyl) piperidines-2-methyl-formiate synthetic

The solution of 4N hydrochloric acid in ethyl acetate (20mL) is added in ethyl acetate (20mL) solution of (R)-2-tert-butoxycarbonyl amino-6-(3, the 4-difluorophenyl)-6-oxo methyl caproate (3.8g), and reaction soln was at room temperature stirred 5.5 hours.The concentrating under reduced pressure reaction soln.Then, ethyl acetate and saturated sodium bicarbonate aqueous solution are added this resistates and separate organic layer.Gained organic layer concentrating under reduced pressure after dried over mgso.10% palladium-carbon (50mg) is added in methyl alcohol (20mL) solution of gained resistates, and reaction soln was at room temperature stirred 2 hours in hydrogen stream.Reaction soln concentrates through diatomite filtration and with filtrate decompression, obtains the 2.1g title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?256[M ⁺+H]。

[(2R, 6S)-6-(3, the 4-difluorophenyl) piperidines-2-yl] methyl alcohol synthetic

Under-15 ℃, go through 15 minutes with LAH (90mg) divide three parts add (2R, 6S)-THF (5mL) solution of 6-(3, the 4-difluorophenyl) piperidines-2-methyl-formiate (300mg) in.Reaction soln is stirred 1 hour also successively with water (0.1mL), 5N sodium hydroxide solution (0.1mL) and water (0.3mL) adding reaction soln at-15 ℃.With this mixture heating up to room temperature and through diatomite filtration.Filtrate decompression concentrates, and obtains the 267mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?228[M ⁺+H]。

(4R, 6S)-6-(3, the 4-difluorophenyl) hexahydropyridine [2,1-c] [1,4] oxazine-3,4-diketone synthetic also

Heating [(2R, 6S)-6-(3, the 4-difluorophenyl) piperidines-2-yl] methyl alcohol (267mg) and oxalic acid diethyl ester (1.6mL) mixture and stirred 1 hour at 120 ℃.Reaction soln is cooled to room temperature, by filtering the collecting precipitation solid.The gained solid obtains the 192mg title compound with ether washing and air-dry.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.38-1.48(m，1H)，1.55-1.66(m，1H)，1.68-1.83(m，2H)，2.12-2.25(m，2H)，3.99-4.18(m，1H)，4.35(t，J＝11.6Hz，1H)，4.42(dd，J＝11.6，3.2Hz，1H)，5.27(t，J＝4.0Hz，1H)，6.94-6.99(m，1H)，7.01-7.07(m，1H)，7.10-7.17(m，1H)。

(4R, 6S)-6-(3, the 4-difluorophenyl)-3-hydroxyl hexahydropyridine [2,1-c] [closing of 1,4] oxazine-4-ketone also Become

Dropwise add at-15 ℃ of THF with the 1M 3-sec-butyl lithium borohydride (0.71mL) solution (4R, 6S)-6-(3, the 4-difluorophenyl) hexahydropyridine also [2,1-c] [1,4] oxazines-3 in THF (10mL) solution of 4-diketone (192mg), and stir reaction soln 3 hours at-15 ℃.At-15 ℃ 5N sodium hydroxide solution (0.25mL) and 20% aqueous hydrogen peroxide solution (0.05mL) are added reaction soln successively.Reaction soln is cooled to room temperature and stirred 1 hour.Ethyl acetate is added reaction soln and separates organic layer with sodium sulfite solution.The salt water washing of gained organic layer, concentrating under reduced pressure after dried over mgso.Resistates obtains the 151mg title compound through silica gel column chromatography (eluting solvent: heptane: ethyl acetate=1: 1-〉ethyl acetate) purifying.The value of the character of described compound is as follows.

ESI-MS；m/z?284[M ⁺+H]。

Will (4R, 6S)-6-(3, the 4-difluorophenyl)-3-hydroxyl hexahydropyridine also [2,1-c] [1,4] oxazine-4-ketone (151mg) and the solution reflux of three phenyl phosphonium bromides (220mg) in acetonitrile (7mL) 1 hour, be cooled to room temperature subsequently.In reaction soln, add 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (115mg) and triethylamine (0.22mL), and reaction soln was at room temperature stirred 12 hours.Ethyl acetate is added reaction soln and separates organic layer with saturated sodium bicarbonate aqueous solution.The salt water washing of gained organic layer, concentrating under reduced pressure after dried over mgso.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: heptane: ethyl acetate=1: 1-〉ethyl acetate) purifying, obtain the 150mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?466[M ⁺+H].

¹H-NMR(CDCl ₃)δ(ppm)：

1.38-1.58(m，2H)，1.66-1.80(m，2H)，2.10-2.28(m，2H)，2.30(s，3H)，3.85(s，3H)，4.03(t，J＝10.4Hz，1H)，4.05-4.16(m，1H)，4.35(dd，J＝10.4，2.0Hz，1H)，5.33(t，J＝4.0Hz，1H)，6.82(s，1H)，6.92(brs，1H)，6.98-7.02(m，1H)，7.04-7.16(m，2H)，7.20(d，J＝8.0Hz，1H)，7.35(d，J＝2.0Hz，1H)，7.36(dd，J＝8.0，2.0Hz，1H)，7.71(d，J＝1.2Hz，1H)。

Embodiment 42

(Z)-(6S, 9aR)-6-(2,6-difluoro pyridine-3-yl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles -1-yl) benzylidene] hexahydropyridine [2,1-c] [1,4] oxazine-4-ketone synthetic also

(R)-the closing of 2-tert-butoxycarbonyl amino-6-(2,6-difluoro pyridine-3-yl)-6-oxo methyl caproate Become

(solution of 1.5M in THF 3.2mL) adds 2, in THF (25mL) solution of 6-difluoro pyridine (492mg), and reaction soln is stirred 2.5 hours at-78 ℃ with LDA at-78 ℃.-78 ℃ with (R)-6-oxo-piperidine-1, (CAS No.183890-36-0, THF 1.0g) (5mL) solution add reaction soln to 2-dioctyl phthalate 1-tertiary butyl ester 2-methyl ester.Reaction soln was stirred 1 hour and stirred 2.5 hours at 0 ℃ at-78 ℃.Saturated ammonium chloride solution and ethyl acetate added reaction soln and with this mixture heating up to room temperature.After this, separate organic layer, with gained organic layer concentrating under reduced pressure after dried over mgso.Resistates obtains the 148mg title compound through silica gel column chromatography (eluting solvent: heptane: ethyl acetate=1: 1-〉ethyl acetate) purifying.The value of the character of described compound is as follows.

ESI-MS；m/z?395[M ⁺+Na]。

Adopt the method identical, react, obtain the 18mg title compound from (R)-2-tert-butoxycarbonyl amino-6-(2,6-difluoro pyridine-3-yl)-6-oxo methyl caproate (148mg) with embodiment 41.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.44-1.63(m，2H)，1.68-1.81(m，1H)，1.85-1.94(m，1H)，2.09-2.27(m，2H)，2.29(s，3H)，3.84(s，3H)，4.05(t，J＝10.0Hz，1H)，4.07-4.15(m，1H)，4.39(brd，J＝8.4Hz，1H)，5.25(t，J＝5.2Hz，1H)，6.76(s，1H)，6.79(dd，J＝8.0，3.2Hz，1H)，6.92(brs，1H)，7.19(d，J＝7.6Hz，1H)，7.35(dd，J＝7.6，1.6Hz，1H)，7.36(d，J＝1.6Hz，1H)，7.70(brs，1H)，7.73(dd，J＝17.2，8.0Hz，1H)。

Embodiment 43 and 44

(Z)-4-[(R)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-morpholine-3-ketone and (Z)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-morpholine-3-ketone synthetic

Adopt the method identical with the another kind of synthetic method of embodiment 22, from as 2 of raw material, the reaction of 6-difluoro pyridine, monoethanolamine and 3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde obtains the racemoid of title compound.The racemoid of gained passes through Daicel ChemicalIndustries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=6: 4) separate, obtain the title compound (37.9mg) that title compound that retention time is 18 minutes a optically active (38.7mg) and retention time are 22 minutes optically active.

Retention time is that the property value of title compound (embodiment 43) of 18 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.68(d，J＝6.8Hz，3H)，2.29(s，3H)，3.41-3.47(m，1H)，3.63-3.68(m，1H)，3.85(s，3H)，4.22-4.28(m，2H)，5.77(q，J＝6.8Hz，1H)，6.83(s，1H)，6.87(dd，J＝8.4，2.8Hz，1H)，6.92(s，1H)，7.20(d，J＝8.4Hz，1H)，7.35(d，J＝8.4Hz，1H)，7.38(s，1H)，7.71(s，1H)，8.00(dd，J＝16.8，8.4Hz，1H)。

Retention time is that the property value of title compound (embodiment 44) of 22 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

Embodiment 45 and 46

(Z)-(S)-4-[(S)-1-(2-fluorine pyridine-5-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(2-fluorine pyridine-5-yl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone Synthetic

Synthesizing of 1-(6-fluorine pyridin-3-yl) ethamine

Adopt the method identical, synthesize 1-(6-fluorine pyridin-3-yl) ethyl ketone (7.8g) from 6-fluorine nicotinic acid (10g) with embodiment 22.From the reaction of 1-(6-fluorine pyridin-3-yl) ethyl ketone (1.09g), obtain title compound (457mg).The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.40(d，J＝6.4Hz，3H)，4.21(q，J＝6.4Hz，1H)，6.90(dd，J＝3.2，8.4Hz，1H)，7.84(m，1H)，8.17(d，J＝0.8Hz，1H)。

(Z)-(S)-4-[(S)-1-(6-fluorine pyridin-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(6-fluorine pyridin-3-yl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone Synthetic

Adopt the method identical, react, obtain the crude product (48mg) of the non-enantiomer mixture of title compound from 1-(6-fluorine pyridin-3-yl)-ethamine (457mg) with embodiment 22.Gained non-enantiomer mixture (45mg) passes through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=8: 2) separate, obtain the title compound (6.8mg) that title compound that retention time is 57 minutes a optically active (20mg) and retention time are 63 minutes optically active.

ESI-MS；m/z?437[M ⁺+H]。

Retention time is that 57 minutes the property value of title compound of optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.39(d，J＝6.4Hz，3H)，1.62(d，J＝7.6Hz，3H)，2.30(d，J＝0.8Hz，3H)，2.95(dd，J＝9.6，12.8Hz，1H)，3.26(dd，J＝2.8，13.2Hz，1H)，3.85(s，3H)，4.37(m，1H)，6.15(q，J＝7.2Hz，1H)，6.89(s，1H)，6.93(s，1H)，6.96(dd，J＝2.8，8.4Hz，1H)，7.21(d，J＝8.0Hz，1H)，7.34(m，1H)，7.51(d，J＝1.6Hz，1H)，7.72(d，J＝1.2Hz，1H)，7.77(m，1H)，8.21(dd，J＝1.2，1.2Hz，1H)。

Retention time is that 63 minutes the property value of title compound of optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.4Hz，3H)，1.61(d，J＝7.2Hz，3H)，2.30(s，3H)，2.99(dd，J＝2.8，12.4Hz，1H)，3.40(dd，J＝10.0，12.4Hz，1H)，3.86(s，3H)，4.13(m，1H)，6.17(q，J＝6.8Hz，1H)，6.89(s、1H)，6.94(s，1H)，6.96(dd，J＝2.8，8.8Hz，1H)，7.21(d，J＝8.4Hz，1H)，7.34(dd，J＝1.6，8.4Hz，1H)，7.53(d，J＝1.6Hz，1H)，7.73(d，J＝1.2Hz，1H)，7.81(m，1H)，8.22(d，J＝1.6Hz，1H)。

Embodiment 47 and 48

(Z)-(S)-4-[(S)-1-(2-fluorine pyridin-4-yl) ethyl]-2-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical }-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(2-fluorine pyridin-4-yl) Ethyl]-2-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-6-methylmorpholine-3- Synthesizing of ketone

Adopt the mode identical with embodiment 22 to prepare 1-(2-fluorine pyridin-4-yl)-ethamine, the method that employing and embodiment 22 are identical obtains title compound into non-enantiomer mixture from above-claimed cpd.Described compound passes through Daicel Chemical Industries, CHIRALCELOD-H (2cm * 25cm that Ltd. produces; Moving phase: ethanol-hexane system) separate, obtain retention time and be the title compound (embodiment 48) that 23 minutes title compound (embodiment 47) and retention time are 26 minutes.The value of the character of the title compound of embodiment 47 is as follows.

ESI-MS；m/z?437[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.0Hz，3H)，1.60(d，J＝7.2Hz，3H)，2.30(s，3H)，3.03(dd，J＝12.4，9.2Hz，1H)，3.24(dd，J＝13.2，2.8Hz，1H)，3.86(s，3H)，4.34-4.42(m，1H)，6.11(t，J＝7.2Hz，1H)，6.89(brs，1H)，6.90(s，1H)，6.94(brs，1H)，7.14(brd，J＝5.2Hz，1H)，7.22(d，J＝8.0Hz，1H)，7.35(dd，J＝8.0，1.6Hz，1H)，7.52(d，J＝1.6Hz，1H)，7.73(d，J＝1.2Hz，1H)，8.23(d，J＝5.2Hz，1H)。

Embodiment 49 and 50

(Z)-(S)-4-[(S)-1-(5-fluorine pyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone and (Z)-(S)-4-[(R)-1-(5-fluorine pyridine-2-yl) second Base]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone Synthetic

Synthesizing of 1-(5-fluorine pyridine-2-yl) ethyl ketone

Cupric iodide (811mg), 1-vinyl ethyl ether base tri-n-butyl tin (19.2mL) and two (triphenylphosphine) Palladous chloride (II) (1g) are added 2-bromo-5-fluorine pyridine (5g) in the solution of acetonitrile (250mL), and reacting by heating solution also stirred 2 hours at 100 ℃ in nitrogen.Reaction soln is returned to room temperature and solvent evaporated under reduced pressure.Resistates is with the ethyl acetate dilution and use the salt water washing.Organic layer is through dried over mgso and solvent evaporated under reduced pressure.Add reaction soln with acetone (120mL) dilution resistates and with (1S)-(+)-10-camphorsulfonic acid (9.9g).After confirming that through tlc the purpose product generates, solvent evaporated under reduced pressure.Resistates neutralizes with the ether dilution and with yellow soda ash.Water is added reaction soln and separates organic solution.The organic layer dried over mgso, with resistates through silica gel column chromatography (carrier: Chromatorex; Eluting solvent: hexane-ethyl acetate) purifying obtains the 3.55g title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

2.71(s，3H)，7.51(m，1H)，8.11(ddd，J＝0.4，4.8，8.8Hz，1H)，8.51(d，J＝2.8Hz，1H)。

Synthesizing of 1-(5-fluorine pyridine-2-yl) ethamine

Adopt the method identical, react, obtain title compound (483mg) from 1-(5-fluorine pyridine-2-yl) ethyl ketone (525mg) with embodiment 22.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.4Hz，3H)，4.18(q，J＝6.4Hz，1H)，7.30-7.37(m，2H)，8.41(d，J＝2.4Hz，1H)。

Adopt the method identical, react, obtain crude product (248mg) into the title compound of non-enantiomer mixture from 1-(5-fluorine pyridine-2-yl)-ethamine (483mg) with embodiment 22.Gained non-enantiomer mixture (30mg) passes through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMOD-H (2cm * 25cm; Moving phase: hexane: ethanol=8: 2) and DaicelChemical Industries, the CHIRALPAK that Ltd. produces ^TMAD-H (2cm * 25cm; Moving phase: ethanol) separate, obtain the title compound (3.9mg) that title compound that retention time is 23 minutes a optically active (1.7mg) and retention time are 27 minutes optically active.

The property value of the title compound of non-enantiomer mixture is as follows.

ESI-MS；m/z?437[M ⁺+H]。

Retention time is that 23 minutes the property value of title compound of optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.37(d，J＝6.4Hz，3H)，1.61(d，J＝7.2Hz，3H)，2.29(s，3H)，3.17(dd，J＝1.2，13.2Hz，1H)，3.52(dd，J＝2.8，13.2Hz，1H)，3.84(s，3H)，4.37(m，1H)，6.06(q，J＝6.4Hz，1H)，6.84(s、1H)，6.92(s，1H)，7.20(d，J＝8.4Hz，1H)，7.32(m，1H)，7.37-7.40(m，2H)，7.51(d，J＝1.2Hz，1H)，7.71(d，J＝1.2Hz，1H)，8.42(dd，J＝1.2，1.2Hz，1H)。

Retention time is that 27 minutes the property value of title compound of optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.43(d，J＝6.8Hz，3H)，1.60(d，J＝7.2Hz，3H)，2.29(s，3H)，3.43-3.56(m，2H)，3.85(s，3H)，4.17(m，1H)，6.02(q，J＝6.8Hz，1H)，6.83(s、1H)，6.93(s，1H)，7.20(d，J＝8.0Hz，1H)，7.32(d，1H)，7.36-7.43(m，2H)，7.53(d，J＝1.6Hz，1H)，7.71(d，J＝1.2Hz，1H)，8.41(d，J＝1.6Hz，1H)。

Embodiment 51

(Z)-(S)-4-[(S)-1-(2-chloropyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Synthesizing of 1-(2-chloropyridine-4-yl) ethyl ketone

Adopt the method identical, react, obtain title compound (7.18g) from 2-chloroisonicotinic acid (8.5g) with embodiment 22.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

2.63(s，3H)，7.66(m，1H)，7.77(m，1H)，8.59(m，1H)。

(R)-1-(2-chloropyridine-4-yl) alcoholic acid is synthetic

At-20 ℃ the solution of 1-(2-chloropyridine-4-yl) ethyl ketone (7.18g) in tetrahydrofuran (THF) (10mL) is dropwise added in tetrahydrofuran (THF) (340mL) solution of (+)-DIP-muriate (19.2g), and reaction soln stirred under uniform temp spend the night.Reaction soln is returned to room temperature and solvent evaporated under reduced pressure.Dilute this resistates with ether, at room temperature stirred 4 hours with diethanolamine (12.1g) adding diluent and with reaction soln.Through diatomite filtration to separate insolubles and with the mother liquor concentrating under reduced pressure.(carrier: Chromatorex, eluting solvent: heptane-ethyl acetate) purifying obtains title compound (3.84g) to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.50(d，J＝6.8Hz，3H)，4.90(m，1H)，7.21(m，1H)，7.36(m，1H)，8.34(dd，J＝0.4，5.2Hz，1H)。

Synthesizing of 4-((S)-1-azido-ethyl)-2-chloropyridine

In nitrogen, diphenyl phosphoryl azide (6.57mL) is added in (R)-1-(2-chloropyridine-4-yl) alcoholic acid toluene (50mL) solution, and reaction soln is cooled to 0 ℃.DBU (4.52mL) is added reaction soln, and postheating to room temperature and stirring spent the night.Water is added reaction soln and separates organic layer with ether.Organic layer through dried over mgso and with resistates through silica gel chromatography (carrier: Chromatorex; Eluting solvent: hexane-ethyl acetate) purifying obtains title compound (4.44g).The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.55(d，J＝6.8Hz，3H)，4.62(d，J＝6.8Hz，1H)，7.18(m，1H)，7.30(m，1H)，8.39(dd，J＝0.4，5.2Hz，1H)。

(S)-1-(2-chloropyridine-4-yl) ethamine synthetic

Triphenylphosphine (9.56g) is added 4-((S)-1-azido-ethyl)-2-chloropyridine (4.44g), and (4: 1, in solution 50mL), reacting by heating solution also stirred 2 hours at 60 ℃ at tetrahydrofuran (THF)-water.Reaction soln is returned to room temperature and solvent evaporated under reduced pressure.Chloroform and 5N hydrochloric acid are added this resistates and separates water layer.With 5N sodium hydroxide alkalization water layer.Chloroform is added reaction soln and separates organic layer.Organic layer obtains title compound (2.24g) through dried over mgso and solvent evaporated under reduced pressure.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.38(d，J＝6.8Hz，3H)，4.12(d，J＝6.8Hz，1H)，7.36(m，1H)，7.30(m，1H)，8.31(d，J＝5.2Hz，1H)。

Adopt and embodiment 18 and 19 identical methods,, obtain comprising the title compound (518mg) of geometrical isomer from the reaction of (S)-1-(2-chloropyridine-4-yl) ethamine (1.25g).The mixture of gained (54mg) passes through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=7: 3) separate, obtain retention time and be 38 minutes title compound (6.5mg).The value of the character of this compound is as follows

Retention time is that 38 minutes the property value of title compound is as follows.

ESI-MS；m/z?453[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.8Hz，3H)，1.59(d，J＝7.2Hz，3H)，2.30(d，J＝0.8Hz，3H)，3.02(dd，J＝9.6，12.8Hz，1H)，3.23(dd，J＝2.4，13.2Hz，1H)，3.85(s，3H)，4.36(m，1H)，6.07(q，J＝7.2Hz，1H)，6.90(s、1H)，6.94(dd，J＝1.2，1.2Hz，1H)，7.17(m，1H)，7.22(d，J＝8.0Hz，1H)，7.28(m，1H)，7.36(m，1H)，7.52(d，J＝1.2Hz，1H)，7.73(d，J＝1.2Hz，1H)，8.39(dd，J＝0.8，5.2Hz，1H)。

Embodiment 52

(Z)-(S)-4-[(S)-1-(2-chloro-3-fluorine pyridin-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Synthesizing of 2-chloro-3-fluorine Yi Yansuan

Adopt the method identical, react, obtain title compound (6.34g) from 2-chloro-3-fluorine pyridine (5g) with embodiment 22.The value of the character of described compound is as follows.

¹H-NMR(DMSO-d ₆)δ(ppm)：

7.78(dd，J＝4.8，4.8Hz，1H)，8.27(d，J＝4.8Hz，1H)。

(S)-1-(2-chloro-3-fluorine pyridin-4-yl) ethamine synthetic

Adopt the method identical, react, obtain title compound (3.13g) from 2-chloro-3-fluorine Yi Yansuan (6.34g) with embodiment 51.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.8Hz，3H)，4.45(q，J＝6.8Hz，1H)，7.40(ddd，J＝0.4，4.8，4.8Hz，1H)，8.18(d，J＝4.8Hz，1H)。

Adopt and embodiment 18 and 19 identical methods,, obtain comprising the title compound (623mg) of geometrical isomer from the reaction of (S)-1-(2-chloro-3-fluorine pyridin-4-yl) ethamine (1.2g).The mixture of gained (14mg) passes through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=1: 1) separate, obtain retention time and be 24 minutes title compound (9.5mg).The value of the character of described compound is as follows.

ESI-MS；m/z?471[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.46(d，J＝6.4Hz，3H)，1.67(d，J＝7.2Hz，3H)，2.29(s，3H)，3.23(dd，J＝9.6，12.4Hz，1H)，3.41(dd，J＝2.4，12.8Hz，1H)，3.85(s，3H)，4.38(m，1H)，5.87(q，J＝7.2Hz，1H)，6.83(s，1H)，6.93(s，1H)，7.20(d，J＝8.4Hz，1H)，7.30-7.33(m，2H)，7.50(d，J＝1.2Hz，1H)，7.72(s，1H)，8.23(d，J＝5.2Hz，1H)。

Embodiment 53

(Z)-(S)-4-[(S)-1-(2,6-difluoro pyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the mode identical with embodiment 51 to obtain (S)-1-(2,6-difluoro pyridine-4-yl) ethamine, employing and embodiment 18 and 19 identical methods obtain title compound from above-claimed cpd.

ESI-MS；m/z?455[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.44(d，J＝6.4Hz，3H)，1.61(d，J＝7.2Hz，3H)，2.30(s，3H)，3.09(dd，J＝9.2，12.8Hz，1H)，3.27(dd，J＝2.4，12.8Hz，1H)，3.86(s，3H)，4.34-4.44(m，1H)，6.09(q，J＝7.2Hz，1H)，6.78(s，2H)，6.90(s，1H)，6.94(s，1H)，7.22(d，J＝8.0Hz，1H)，7.35(d，J＝8.0Hz，1H)，7.52(s，1H)，7.72(s，1H)。

Embodiment 54

(Z)-4-[(S)-1-(2-chloropyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles -1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

4-[(S)-and 1-(2-chloropyridine-4-yl) ethyl]-6,6-thebaine-2,3-diketone synthetic

Lithium perchlorate (10.2g) is added in ether (18.5mL) solution of (S)-1-(2-chloropyridine-4-yl) ethamine (1g) that from embodiment 51, obtains, and reaction soln was stirred 5 minutes.Oxidation iso-butylene (1.7mL) is added reaction soln, stir subsequently and spend the night.Under 0 ℃, the 5N sodium hydroxide solution is added reaction soln, use chloroform extraction subsequently.With organic layer through dried over mgso and solvent evaporated under reduced pressure.Methylene dichloride (20mL) and pyridine (20mL) are added resistates, and reaction soln is cooled to 0 ℃.Oxalyl chloride (669 μ L) is added reaction soln, after stirring 1 hour under 0 ℃, at room temperature stirred 1 hour subsequently.Oxalyl chloride (0.4mL) is added reaction soln, once more it was stirred 1 hour.Solvent evaporated under reduced pressure.Water and ethyl acetate are added this resistates and separate organic layer.Organic layer is through dried over mgso, and with resistates through silica gel column chromatography (Chromatorex; Eluting solvent: heptane-ethyl acetate) purifying obtains title compound (1.07g).The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.31(s，3H)，1.49(s，3H)，1.59(d，J＝7.2Hz，3H)，3.05(d，J＝13.6，1H)，3.35(d，J＝14.0Hz，1H)，5.97(q，J＝7.2Hz，1H)，7.21(ddd，J＝0.8，1.2，5.2Hz，1H)，7.30(dd，J＝0.8，0.8Hz，1H)，8.42(d，J＝5.2Hz，1H)。

Adopt and embodiment 18 and 19 identical methods, from 4-[(S)-1-(2-chloropyridine-4-yl) ethyl]-6,6-thebaine-2,3-diketone (1.07g) reacts, and obtains comprising the title compound (1.33g) of geometrical isomer.Gained mixture (56mg) passes through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=7: 3) separate, obtain retention time and be 36 minutes title compound (13mg).The value of the character of described compound is as follows.

ESI-MS；m/z?467[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.31(s，3H)，1.46(s，3H)，1.57(d，J＝7.2Hz，3H)，2.30(s，3H)，2.95(d，J＝12.8Hz，1H)，3.29(d，J＝12.8Hz，1H)，3.86(s，3H)，6.13(q，J＝7.2Hz，1H)，6.93(dd，J＝1.2，1.2Hz，1H)，6.94(s，1H)，7.20-7.23(m，2H)，7.31(dd，J＝0.8，0.8Hz，1H)，7.35(dd，J＝1.6，8.0Hz，1H)，7.53(d，J＝1.6Hz，1H)，7.72(d，J＝1.2Hz，1H)，8.40(d，J＝4.8Hz，1H)。

Embodiment 55

(Z)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

(S)-1-(2,6-difluoro pyridine-3-yl) ethamine synthetic

Adopt the method identical with embodiment 52, from 2,6-difluoro pyridine (15g) reacts, and obtains title compound (9.36g).The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.40(d，J＝6.8Hz，3H)，4.37(q，J＝6.8Hz，1H)，6.81(dd，J＝2.8，8.0Hz，1H)，8.02(dd，J＝8.0，8.0Hz，1H)。

Adopt and embodiment 18 and 19 identical methods,, obtain comprising the title compound (422mg) of geometrical isomer from the reaction of (S)-1-(2,6-difluoro pyridine-3-yl) ethamine (500mg).The mixture of gained (10mg) passes through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMIA (2cm * 25cm; Moving phase: hexane: ethanol=7: 3) separate, obtain retention time and be 28 minutes title compound (6.8mg).The value of the character of described compound is as follows.

ESI-MS；m/z?469[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.35(s，3H)，1.46(s，3H)，1.65(d，J＝7.2Hz，3H)，2.30(d，J＝0.8Hz，3H)，3.20(d，J＝12.8Hz，1H)，3.43(d，J＝12.4Hz，1H)，3.84(s，3H)，5.86(q，J＝7.2Hz，1H)，6.86(s，1H)，6.88(dd，J＝2.8，8.4Hz，1H)，6.92(m，1H)，7.19(d，J＝8.4Hz，1H)，7.31(dd，J＝2.0，8.4Hz，1H)，7.51(d，J＝1.6Hz，1H)，7.71(d，J＝1.6Hz，1H)，8.01(dd，J＝8.0，9.2Hz，1H)。

Embodiment 56

(Z)-4-[(S)-1-(6-fluorine pyridin-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles -1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

(S)-1-(6-fluorine pyridin-3-yl) ethamine synthetic

Adopt the method identical, react, obtain title compound (3.95g) from 6-fluorine nicotinic acid (10g) with embodiment 52.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

Adopt and embodiment 18 and 19 identical methods,, obtain comprising the title compound (1.02g) of geometrical isomer from the reaction of (S)-1-(6-fluorine pyridin-3-yl) ethamine (500mg).The mixture of gained (1.01g) recrystallization from ethylacetate/ether obtains the title compound (120mg) of optically active.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.23(s，3H)，1.45(s，3H)，1.61(d，J＝7.2Hz，1H)，2.30(s，3H)，2.92(d，J＝12.8Hz，1H)，3.32(d，J＝12.4Hz，1H)，3.85(s，3H)，6.21(q，J＝7.2Hz，1H)，6.92-6.97(m，3H)，7.21(d，J＝8.0Hz，1H)，7.33(dd，J＝0.8，8.0Hz，1H)，7.52(d，J＝1.2Hz，1H)，7.71(d，J＝0.8Hz，1H)，7.81(m，1H)，8.22(s，1H)。

Embodiment 57

(Z)-4-[(S)-1-(6-chloropyridine-3-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles -1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

(S)-1-(6-chloropyridine-3-yl) ethamine synthetic

Adopt the method identical, react, obtain title compound (7.04g) from 6-chlorine apellagrin (13g) with embodiment 52.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.39(d，J＝6.4Hz，3H)，4.19(q，J＝6.4Hz，1H)，7.29(d，J＝8.0Hz，1H)，7.70(dd，J＝2.4，8.0Hz，1H)，8.36(d，J＝2.4Hz，1H)。

Adopt and embodiment 18 and 19 identical methods, react from (S)-1-(6-chloropyridine-3-yl) ethamine (600mg), obtain comprising the title compound of geometrical isomer, it was stirred 4 hours in the trifluoroacetic acid/chloroform/solution of 4N hydrochloric acid (5/5/2) in ethyl acetate, make E-isomer isomery turn to the Z-isomer.With the NaOH solution neutralization reaction solution of 5N, use ethyl acetate extraction subsequently.Organic layer is through dried over mgso and solvent evaporated under reduced pressure.With resistates through silica gel column chromatography (ChromatorexNH; Heptane/ethyl acetate-ethyl acetate/methanol) purifying obtains title compound (251mg).

¹H-NMR(CDCl ₃)δ(ppm)：

1.24(s，3H)，1.45(s，3H)，1.60(d，J＝7.2Hz，1H)，2.30(s，3H)，2.92(d，J＝12.4Hz，1H)，3.30(d，J＝12.4Hz，1H)，3.85(s，3H)，6.19(q，J＝7.2Hz，1H)，6.92(s、1H)，6.93(d，J＝3.2Hz，1H)，7.20(d，J＝8.4Hz，1H)，7.32-7.36(m，2H)，7.52(s，1H)，7.68(dd，J＝2.4，8.4Hz，1H)，7.71(d，J＝0.8Hz，1H)，8.40(d，J＝2.4Hz，1H)。

Embodiment 58

(Z)-4-[(S)-1-(2,3-difluoro pyridine-4-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

(S)-1-(2,3-difluoro pyridine-4-yl) ethamine synthetic

Adopt the method identical with embodiment 52, from known compound 2,3-difluoro Yi Yansuan (16.6g) (for example, referring to Journal of Organic Chemistry, 2005, p.3039-3045) vol.70 reacts, and obtains title compound (7.09g).The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.4Hz，3H)，4.49(q，J＝6.4Hz，1H)，7.32(dd，J＝4.8，4.8Hz，1H)，7.93(d，J＝4.8Hz，1H)。

Adopt and embodiment 18 and 19 identical methods, from the reaction of (S)-1-(2,3-difluoro pyridine-4-yl) ethamine (1g), obtain comprising the title compound of geometrical isomer, adopt the mode identical with its isomerization, obtain title compound (830mg) with embodiment 57.The value of the character of described compound is as follows.

ESI-MS；m/z?469[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.37(s，3H)，1.47(s，3H)，1.65(d，J＝7.2Hz，1H)，2.30(s，3H)，3.18(d，J＝12.4Hz，1H)，3.42(d，J＝12.4Hz，1H)，3.85(s，3H)，6.04(q，J＝7.2Hz，1H)，6.88(s、1H)，6.93(s，1H)，7.20(d，J＝8.4Hz，1H)，7.23-7.33(m，2H)，7.51(s，1H)，7.71(s，1H)，8.00(d，J＝3.2Hz，1H)。

Embodiment 59

(Z)-4-[(S)-1-(5-fluorine pyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles -1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

(S)-1-(5-fluorine pyridine-2-yl) ethamine synthetic

Adopt the method identical, react, obtain title compound (1.23g) from the 1-described in the embodiment 49 (5-fluorine pyridine-2-yl) ethyl ketone (3.05g) with embodiment 52.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.4Hz，3H)，4.17(q，J＝6.4Hz，1H)，7.30-7.39(m，1H)，8.40(d，J＝2.4Hz，1H)。

Adopt and embodiment 18 and 19 identical methods, react from (S)-1-(5-fluorine pyridine-2-yl) ethamine (700mg), obtain comprising the title compound of geometrical isomer, adopt the mode identical, obtain title compound (640mg) its isomerization with embodiment 57.The value of the character of described compound is as follows.

ESI-MS；m/z?451[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.16(s，3H)，1.46(s，3H)，1.59(d，J＝6.8Hz，1H)，2.29(s，3H)，3.34(d，J＝12.8Hz，1H)，3.47(d，J＝12.8Hz，1H)，3.84(s，3H)，6.10(q，J＝7.2Hz，1H)，6.86(s、1H)，6.92(dd，J＝1.2，1.2Hz，1H)，7.19(d，J＝8.4Hz，1H)，7.31(dd，J＝2.0，8.4Hz，1H)，7.36-7.46(m，2H)，7.53(d，J＝2.8Hz，1H)，7.70(m，1H)，8.41(d，J＝2.8Hz，1H)。

Embodiment 60

(Z)-4-[(S)-1-(5-chloropyridine-2-yl) ethyl]-2-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles -1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

(S)-1-(5-chloropyridine-2-yl) ethamine synthetic

Adopt the method identical, react, obtain title compound (2.72g) from the 1-described in the embodiment 20 (5-chloropyridine-2-yl) ethyl ketone (4.29g) with embodiment 52.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

Adopt and embodiment 18 and 19 identical methods, from the reaction of (S)-1-(5-chloropyridine-2-yl) ethamine (1g), obtain comprising the title compound of geometrical isomer, the identical mode of employing and embodiment 57 obtains title compound (310mg) with its isomerization.The value of the character of described compound is as follows.

ESI-MS；m/z?467[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.19(s，3H)，1.46(s，3H)，1.59(d，J＝6.8Hz，1H)，2.29(s，3H)，3.35(d，J＝12.8Hz，1H)，3.48(d，J＝12.8Hz，1H)，3.84(s，3H)，6.08(q，J＝6.8Hz，1H)，6.86(s、1H)，6.92(s，1H)，7.19(d，J＝8.0Hz，1H)，7.31(d，J＝8.4Hz，1H)，7.38(d，J＝8.0Hz，1H)，7.53(s，1H)，7.66(dd，J＝1.6，8.4，1H)，7.70(s，1H)，8.51(d，J＝2.0Hz，1H)。

Adopt the compound among same way as acquisition table 1-1 and the 1-2.

[table 1-1]

[table 1-2]

Embodiment 65

(Z)-(S)-and 4-(4-luorobenzyl)-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene Base]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical, react, obtain the 9.06mg title compound from (S)-4-(4-luorobenzyl)-2-hydroxyl-6-methylmorpholine-3-ketone, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde with embodiment 5.

¹H-NMR(CDCl ₃)δ(ppm)：

1.44(d，J＝6.8Hz，3H)，2.38(s，3H)，3.26(dd，J＝12.8，3.2Hz，1H)，3.43(dd，J＝12.8，9.6Hz，1H)，4.32-4.40(m，1H)，4.62(d，J＝14.4Hz，1H)，4.73(d，J＝14.4Hz，1H)，6.87(s，1H)，7.01-7.09(m，3H)，7.27-7.35(m，3H)，7.50(d，J＝8.4Hz，1H)，7.77(d，J＝12.8Hz，1H)，7.96(s，1H)。

Embodiment 66

(Z)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(S)-1-(4-trifluoro Phenyl) ethyl]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 7, from 4-[(S)-1-(4-fluorophenyl) ethyl]-2-hydroxyl-6, the reaction of 6-thebaine-3-ketone, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde obtains the 31.55mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.20(s，3H)，1.43(s，3H)，1.55(d，J＝6.8Hz，3H)，2.34(s，3H)，2.90(d，J＝12.8Hz，1H)，3.24(d，J＝12.8Hz，1H)，6.16(q，J＝6.8Hz，1H)，6.87(s，1H)，7.00(s，1H)，7.04-7.08(m，2H)，7.28-7.36(m，3H)，7.47(dd，J＝8.4，1.6Hz，1H)，7.74(dd，J＝12.8，1.6Hz，1H)，7.85(s，1H)。

Embodiment 67

(Z)-and 4-(4-luorobenzyl)-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-6,6- Synthesizing of thebaine-3-ketone

Adopt the method identical with embodiment 7, from 4-(4-luorobenzyl)-2-hydroxyl-6,6-thebaine-3-ketone, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde reacts, and obtains the 44.7mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.39(s，6H)，2.57(s，3H)，3.35(s，2H)，4.67(s，2H)，6.89(s，1H)，7.03-7.08(m，2H)，7.13(s，1H)，7.29-7.33(m，2H)，7.41(dd，J＝8.0，8.0Hz，1H)，7.57(d，J＝8.0Hz，1H)，7.82(d，J＝12.8Hz，1H)，8.70(s，1H)。

Embodiment 68

(Z)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene Base]-6,6-thebaine-3-ketone synthetic

Adopt the method identical, from 4-[(S with embodiment 12)-chroman-4-yl]-2-hydroxyl-6,6-thebaine-3-ketone, three phenyl phosphonium bromides and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde reacts, and obtains the 25.4mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.43(s，3H)，1.45(s，3H)，2.14-2.21(m，2H)，2.34(s，3H)，3.12(d，J＝13.2Hz，1H)，3.19(d，J＝13.2Hz，1H)，4.23-4.33(m，2H)，6.11(t，J＝7.2Hz，1H)，6.86-6.95(m，3H)，7.01(s，1H)，7.09(d，J＝8.0Hz，1H)，7.20(t，J＝8.0Hz，1H)，7.32(t，J＝8.0Hz，1H)，7.49(d，J＝8.0Hz，1H)，7.76(dd，J＝12.8，1.2Hz，1H)，7.82(s，1H)。

Embodiment 69 and 70

(Z)-(S)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene Base]-6-methylmorpholine-3-ketone and (Z)-(R)-4-[(S)-chroman-4-yl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 12,13 and 14, from 4-[(S as raw material)-chroman-4-yl]-2-hydroxyl-6-methylmorpholine-3-ketone, three phenyl phosphonium bromides and the reaction of 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde, obtain 66.4mg title compound into non-enantiomer mixture.This mixture passes through Daicel Chemical Industries, the CHIRALPAK that Ltd. produces ^TMAD-H (2cm * 25cm; Moving phase: ethanol 100%) separate, obtaining title compound that retention time is 20 minutes a optically active (de＞99%) and retention time is the title compound (de＞99%) of 24 minutes optically active.

Retention time is that the property value of title compound (embodiment 69) of 20 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.43(d，J＝6.0Hz，3H)，2.14-2.24(m，2H)，2.35(s，3H)，3.12-3.15(m，2H)，4.24-4.38(m，3H)，6.05(dd，J＝8.8，6.4Hz，1H)，6.86-6.89(m，2H)，6.93(t，J＝7.2Hz，1H)，7.01-7.07(m，2H)，7.20(t，J＝8.0Hz，1H)，7.33(t，J＝8.0Hz，1H)，7.51(d，J＝8.0Hz，1H)，7.78(d，J＝12.8Hz，1H)，7.87(s，1H)。

Retention time is that the property value of title compound (embodiment 70) of 24 minutes optically active is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.42(d，J＝6.0Hz，3H)，2.14-2.20(m，2H)，2.36(s，3H)，3.10(dd，J＝12.8，2.4Hz，1H)，3.32(dd，J＝12.8，10.0Hz，1H)，4.24-4.37(m，3H)，6.13(t，J＝8.4Hz，1H)，6.86-6.94(m，3H)，7.02-7.07(m，2H)，7.20(t，J＝8.4Hz，1H)，7.33(t，J＝8.4Hz，1H)，7.51(d，J＝8.4Hz，1H)，7.78(dd，J＝12.8，1.2Hz，1H)，7.89(s，1H)。

Embodiment 71

(Z)-(S)-4-(6-chloropyridine-2-ylmethyl)-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzene Base] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 15, from the reaction of (S)-4-(6-chloropyridine-2-ylmethyl)-2-hydroxyl-6-methylmorpholine-3-ketone, thionyl chloride, triphenylphosphine and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde, obtain the 24.3mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.48(d，J＝6.0Hz，3H)，2.33(s，3H)，3.59(dd，J＝12.8，2.8Hz，1H)，3.68(dd，J＝12.8，9.6Hz，1H)，4.43-4.47(m，1H)，4.73(d，J＝14.8Hz，1H)，4.78(d，J＝14.8Hz，1H)，6.82(s，1H)，7.00(s，1H)，7.26-7.33(m，3H)，7.47(dd，J＝8.4，1.6Hz，1H)，7.66(dd，J＝8.0，8.0Hz，1H)，7.75(dd，J＝12.8，1.6Hz，1H)，7.80(s，1H)。

Embodiment 72

(Z)-(S)-4-[(S)-1-(6-chloropyridine-3-yl) ethyl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1- Base) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt and embodiment 18 and 19 identical methods, 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) the phenyl aldehyde reaction from as raw material obtains title compound (11.6mg).

¹H-NMR(CDCl ₃)δ(ppm)：

1.40(d，J＝6.4Hz，3H)，1.62(d，J＝7.2Hz，3H)，2.31(s，3H)，2.95(dd，J＝12.8，9.2Hz，1H)，3.28(dd，J＝12.8，2.8Hz，1H)，4.35-4.41(m，1H)，6.12(q，J＝7.2Hz，1H)，6.85(s，1H)，6.99(s，1H)，7.31(t，J＝8.4Hz，1H)，7.34(d，J＝8.4Hz，1H)，7.46(dd，J＝8.4，2.0Hz，1H)，7.63(dd，J＝8.4，2.4Hz，1H)，7.72(dd，J＝13.2，2.0Hz，1H)，7.74(s，1H)，8.38(d，J＝2.4Hz，1H)。

Embodiment 73

(Z)-(S)-4-[(S)-1-(2,6-difluoro pyridine-3-yl) ethyl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-miaow Azoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt with embodiment 22 in the identical method of another kind of synthetic method, react from 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde as raw material, obtain title compound (11.2mg).

¹H-NMR(CDCl ₃)δ(ppm)：

1.45(d，J＝6.4Hz，3H)，1.67(d，J＝6.8Hz，3H)，2.30(s，3H)，3.22(dd，J＝12.8，5.2Hz，1H)，3.44(dd，J＝12.8，3.2Hz，1H)，4.34-4.42(m，1H)，5.73(q，J＝6.8Hz，1H)，6.76(s，1H)，6.87(dd，J＝8.0，3.2Hz，1H)，6.97(s，1H)，7.29(d，J＝8.0Hz，1H)，7.42(d，J＝8.0Hz，1H)，7.70(d，J＝11.2Hz，1H)，7.75(s，1H)，7.99(dd，J＝16.0，8.0Hz，1H)。

Embodiment 74

(Z)-(S)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(1R, 2R)-2- Hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-6-methylmorpholine-3-ketone synthetic

Synthesizing of 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde

At room temperature, add 4-methylimidazole (46.4g) and salt of wormwood (78.0g) in DMF (533mL) solution of 4-difluorobenzaldehyde (40.0g), reaction soln was stirred 6 hours at 90 ℃ to 3.Reaction soln is cooled to room temperature.Ethyl acetate is added reaction soln, subsequently water and salt water washing successively.Gained organic layer concentrating under reduced pressure after dried over mgso.(eluting solvent: purifying and solidify with t-butyl methyl ether heptane-ethyl acetate system) obtains the 10.1g title compound through silica gel column chromatography with resistates.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

2.33(d，J＝0.8Hz，3H)，7.07(brs，1H)，7.57(dd，J＝7.2，7.2Hz，1H)，7.76-7.82(m，2H)，7.87(brs，1H)，10.01(d，J＝1.6Hz，1H)。

With (S)-4-[(1R, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4,5-trifluorophenyl) propyl group]-2-hydroxyl-6-methylmorpholine-3-ketone (2.16g) and the solution of triphenylphosphine hydrobromate (1.61g) in acetonitrile (70mL) reflux 1 hour in nitrogen.Solvent evaporated under reduced pressure also is dissolved in ethanol (80mL) with the gained resistates.3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (869mg) and TEA (2.68mL) are added this reaction soln, under the room temperature reaction soln was stirred 10 hours under nitrogen.Solvent evaporated under reduced pressure.The gained resistates is dissolved in the mixed solvent of trifluoroacetic acid (30mL) and methylene dichloride (30mL), and reaction soln was at room temperature stirred 13 hours.Pour reaction soln into saturated sodium bicarbonate solution, use ethyl acetate extraction subsequently.Organic layer saturated sodium bicarbonate solution and salt water washing, solvent evaporated under reduced pressure subsequently.(heptane: ethyl acetate=1: 1-0: 1) purifying also solidifies with heptane-ethyl acetate the gained resistates, obtains the 1.32g title compound through the NH silica gel column chromatography.

¹H-NMR(CDCl ₃)δ(ppm)：

1.33(d，J＝6.4Hz，3H)，1.42(d，J＝6.0Hz，3H)，2.30(s，3H)，3.19(dd，J＝12.4，9.2Hz，1H)，3.63(dd，J＝12.4，2.0Hz，1H)，4.44-4.49(m，2H)，5.36(d，J＝6.8Hz，1H)，6.80(s，1H)，6.97(s，1H)，7.09(dd，J＝8.4，6.4Hz，2H)，7.29(t，J＝8.4Hz，1H)，7.44(dd，J＝8.4，2.0Hz，1H)，7.71(dd，J＝12.8，1.2Hz，1H)，7.74(s，1H)。

Embodiment 75

(Z)-(S)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl -1H-imidazoles-1-yl) phenyl] methylene radical]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from by 1-bromo-4,5-two fluorobenzene are as prepared (the S)-4-[(1R of raw material, 2R)-2-tert-butyl diphenyl siloxy-1-(3, the 4-difluorophenyl) propyl group]-2-hydroxyl-6-methylmorpholine-3-ketone and the reaction of 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde, obtain the 1.15g title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.31(d，J＝6.4Hz，3H)，1.41(d，J＝6.8Hz，3H)，2.20(d，J＝6.4Hz，1H)，2.30(s，3H)，3.15(dd，J＝12.8，9.6Hz，1H)，3.57(dd，J＝12.8，2.4Hz，1H)，4.42-4.48(m，2H)，5.38(d，J＝7.6Hz，1H)，6.80(s，1H)，6.97(s，1H)，7.12-7.18(m，2H)，7.26-7.31(m，2H)，7.44(dd，J＝8.4，2.0Hz，1H)，7.71(dd，J＝12.8，1.6Hz，1H)，7.73(s，1H)。

Embodiment 76

(Z)-(S)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene Base]-4-[(1R, 2R)-1-(4-fluorophenyl)-2-hydroxypropyl]-6-methylmorpholine-3-ketone synthetic

Adopt the method identical with embodiment 26, from by 1-bromo-4-fluorobenzene as prepared (the S)-4-[(1R of raw material, 2R)-2-tert-butyl diphenyl siloxy-1-(4-fluorophenyl) propyl group]-2-hydroxyl-6-methylmorpholine-3-ketone and the reaction of 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde, obtain the 11.0mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.31(d，J＝6.0Hz，3H)，1.38(d，J＝6.0Hz，3H)，2.30(s，3H)，3.12(dd，J＝12.8，9.6Hz，1H)，3.57(dd，J＝12.8，2.4Hz，1H)，4.46-4.50(m，2H)，5.46(d，J＝8.0Hz，1H)，6.79(s，1H)，6.97(s，1H)，7.05-7.09(m，2H)，7.27-7.31(m，1H)，7.36-7.39(m，2H)，7.43(dd，J＝8.4，1.6Hz，1H)，7.70(dd，J＝13.2，1.6Hz，1H)，7.76(s，1H)。

Embodiment 77

(Z)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(1R, 2R)-the 2-hydroxyl Base-1-(3,4, the 5-trifluorophenyl) propyl group]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 27,4-[(1R from preparation, 2R)-2-tert-butyl diphenyl siloxy-1-(3,4, the 5-trifluorophenyl) propyl group]-2-hydroxyl-6, the reaction of 6-thebaine-3-ketone and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde obtains the 11.6mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.28(s，3H)，1.34(d，J＝6.0Hz，3H)，1.47(s，3H)，2.30(s，3H)，2.35(d，J＝4.8Hz，1H)，3.19(d，J＝12.8Hz，1H)，3.60(d，J＝12.8Hz，1H)，4.41-4.50(m，1H)，5.40(d，J＝7.2Hz，1H)，6.84(s，1H)，6.97(s，1H)，7.12(dd，J＝8.4，6.4Hz，2H)，7.28(t，J＝8.4Hz，1H)，7.43(dd，J＝8.4，2.0Hz，1H)，7.71(dd，J＝12.8，1.2Hz，1H)，7.73(s，1H)。

Embodiment 78

(Z)-4-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-2-[1-[3-fluoro-4-(4-methyl isophthalic acid H- Imidazoles-1-yl) phenyl] methylene radical]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 27, from the 4-[(1R of preparation, 2R)-2-tert-butyl diphenyl siloxy-1-(3, the 4-difluorophenyl) propyl group]-2-hydroxyl-6, the reaction of 6-thebaine-3-ketone and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde obtains the 13.9mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.25(s，3H)，1.32(d，J＝6.0Hz，3H)，1.46(s，3H)，2.15(d，J＝6.4Hz，1H)，2.30(s，3H)，3.17(d，J＝12.8Hz，1H)，3.55(d，J＝12.8Hz，1H)，4.43-4.48(m，1H)，5.42(d，J＝7.6Hz，1H)，6.85(s，1H)，6.97(s，1H)，7.14-7.18(m，2H)，7.27-7.30(m，2H)，7.43(dd，J＝8.4，1.6Hz，1H)，7.71(dd，J＝13.2，1.6Hz，1H)，7.73(s，1H)。

Embodiment 79

(Z)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(1R, 2R)-1-(4- Fluorophenyl)-and the 2-hydroxypropyl]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 27,4-[(1R from preparation, 2R)-2-tert-butyl diphenyl siloxy-1-(4-fluorophenyl) propyl group]-2-hydroxyl-6, the reaction of 6-thebaine-3-ketone and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde obtains the 35.1mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.18(s，3H)，1.31(d，J＝6.0Hz，3H)，1.44(s，3H)，2.31(s，3H)，3.16(d，J＝12.8Hz，1H)，3.56(d，J＝12.8Hz，1H)，4.45-4.49(m，1H)，5.51(d，J＝8.4Hz，1H)，6.84(s，1H)，6.97(s，1H)，7.03-7.09(m，2H)，7.25-7.30(m，1H)，7.35-7.44(m，3H)，7.70(d，J＝12.8Hz，1H)，7.76(s，1H)。

Embodiment 80

(Z)-and 2-[1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-4-[(R)-1-(4-fluorobenzene Base)-and the 2-hydroxyethyl]-6,6-thebaine-3-ketone synthetic

Adopt the method identical with embodiment 28,4-[(R from preparation)-2-tert-butyl diphenyl siloxy-1-(4-fluorophenyl) ethyl]-2-hydroxyl-6, the reaction of 6-thebaine-3-ketone and 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde obtains the 18.6mg title compound.

¹H-NMR(CDCl ₃)δ(ppm)：

1.26(s，3H)，1.44(s，3H)，2.32(s，3H)，3.06(d，J＝12.8Hz，1H)，3.40(d，J＝12.8Hz，1H)，4.09-4.26(m，2H)，5.87(dd，J＝8.0，5.6Hz，1H)，6.85(s，1H)，6.98(s，1H)，7.04-7.10(m，2H)，7.22-7.26(m，1H)，7.33-7.39(m，3H)，7.69(d，J＝12.8Hz，1H)，7.75(s，1H)。

Adopt same way as to obtain the compound of table 2.

[table 2]

Embodiment 82 and 83

1-[1-(2,4 difluorobenzene base) ethyl]-3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzene Base]-(E)-and methylene radical } piperidines-2-ketone synthetic

With 3,4-difluorobenzaldehyde (30.0g) is dissolved among the DMF (400mL), and at room temperature 4-methyl isophthalic acid H-imidazoles (34.8g) and salt of wormwood (58.5g) is added this solution.Reaction soln was stirred 6 hours down at 90 ℃.Reaction soln is cooled to room temperature.Then, ethyl acetate is added reaction soln and separates organic layer with water.The salt water washing of gained organic layer, concentrating under reduced pressure after dried over mgso.(eluting solvent: purifying heptane-ethyl acetate system) with t-butyl methyl ether curing and by filtering separation, obtains the 6.28g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

2.32(d，J＝0.8Hz，3H)，7.07(brs，1H)，7.57(dd，J＝7.2，7.2Hz，1H)，7.76-7.82(m，2H)，7.87(brs，1H)，10.01(d，J＝1.6Hz，1H)。

(E)-and 5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } the valeric acid tert-butyl ester Synthetic

3-fluoro-4-(the 4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (2.29g) and 5-chloro-2-(diethoxy phosphoryl) the valeric acid tert-butyl ester (3.68g) are dissolved in the mixed solvent of THF (30mL) and ethanol (10mL).(1.41g) at room temperature adds reaction soln with the lithium hydroxide mono-hydrate, and reaction soln was at room temperature stirred 18 hours.Saturated sodium bicarbonate aqueous solution solution is added reaction soln, use ethyl acetate extraction subsequently.Gained extract concentrating under reduced pressure after dried over mgso.(eluting solvent: purifying heptane-ethyl acetate system) with t-butyl methyl ether and heptane curing, by filtering separation, obtains the 1.96g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.56(s，9H)，1.98-2.07(m，2H)，2.31(d，J＝0.8Hz，3H)，2.64-2.70(m，2H)，3.59(t，J＝6.4Hz，2H)，7.01(brd，J＝1.2Hz，1H)，7.22-7.31(m，2H)，7.39(dd，J＝8.0Hz，8.0Hz，1H)，7.55(s，1H)，7.77-7.80(m，1H)。

(E)-and 5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid trifluoro second Synthesizing of hydrochlorate

Chloroform (5mL) and TFA (10mL) are added (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } in the valeric acid tert-butyl ester (1.96g), reaction soln was at room temperature stirred 1 hour.The concentrating under reduced pressure reaction soln.Resistates is solidified with methylene dichloride, ethyl acetate and heptane,, obtain the 2.19g title compound by filtering separation.The value of the character of described compound is as follows.

ESI-MS；m/z?323[M ⁺+H]。

(E)-1-[1-(2,4 difluorobenzene base) ethyl]-3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] Methylene radical } piperidines-2-ketone synthetic

At room temperature DIEA (0.12mL), WSC (88mg) and HOBT (62mg) are added (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid trifluoroacetate (100mg) and 1-(2, the 4-difluorophenyl) ethamine (54mg) is in the solution of DMF (5mL), and reaction soln was at room temperature stirred 1 hour.Ethyl acetate is added reaction soln, use saturated sodium bicarbonate aqueous solution, water, saturated ammonium chloride solution and salt water washing subsequently successively.Gained organic layer concentrating under reduced pressure after dried over mgso.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: purifying heptane-ethyl acetate system) obtains (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl of 98mg] methylene radical } valeric acid [1-(2,4 difluorobenzene base) ethyl] acid amides.With (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid [1-(2,4 difluorobenzene base) ethyl] acid amides (98mg) is dissolved among the DMF (3mL).At room temperature 60% sodium hydride (10mg) is added reaction soln, and reaction soln was at room temperature stirred 30 minutes.Saturated sodium bicarbonate aqueous solution is added reaction soln, use ethyl acetate extraction subsequently.The gained extract layer with dried over mgso after concentrating under reduced pressure.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: purifying heptane-ethyl acetate system) obtains the title compound that 69mg is a racemoid.Described compound (20mg) passes through Daicel Chemical Industries, CHIRALCEL OJ-H (2cm * 25cm that Ltd. produces; Moving phase: ethanol-hexane system) separate, obtain the title compound that retention time is 18 minutes a optically active (embodiment 82) (7mg) and retention time be 24 minutes optically active title compound (embodiment 83) (4mg).The value of the character of title compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.59(d，J＝6.8Hz，3H)，1.77-1.87(m，2H)，2.31(d，J＝0.8Hz，3H)，2.69-2.82(m，1H)，2.98-3.06(m，1H)，3.26-3.33(m，1H)，3.69-3.76(m，1H)，6.13(q，J＝6.8Hz，1H)，6.81(ddd，J＝10.4，8.8，2.8Hz，1H)，6.85-6.91(m，1H)，6.98(brs，1H)，7.19-7.28(m，2H)，7.31-7.38(m，2H)，7.74(brs，1H)，7.80(brs，1H)。

Embodiment 84

(E)-(S)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) Ji Ji] methylene radical }-1-[(1R, 2R)-2- Hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-5-methyl piperidine-2-ketone synthetic

Synthesizing of ((R)-3-bromo-2-methyl propoxy-)-tert-butyl diphenyl silane

Ice-cooled down with tert-butyl diphenyl chlorosilane (83mL) and imidazoles (30g) adding (R)-3-bromo-2-methyl isophthalic acid-propyl alcohol (45g) in the solution of THF (150mL), and reaction mixture at room temperature stirred spends the night.Water is added reaction mixture, use ethyl acetate extraction subsequently.Organic layer salt water washing, concentrating under reduced pressure behind anhydrous magnesium sulfate drying.Resistates is through silica gel column chromatography (carrier: ChromatorexNH; Eluting solvent: purifying heptane-ethyl acetate system) obtains the 117g title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.00(dd，J＝0.8Hz，6.8Hz，3H)，1.06(s，9H)，2.00-2.09(m，2H)，3.50-3.65(m，4H)，7.36-7.46(m，6H)，7.65-7.68(m，4H)。

(S)-5-(tert-butyl diphenyl siloxy)-2-(diethoxy phosphoryl)-4-methylvaleric acid tert-butyl ester Synthetic

Ice-cooled down, THF (100mL) solution of the diethyl phosphonoacetic acid tert-butyl ester (64g) is dropwise added sodium hydride (contains 40% mineral oil, 13.2g) in the suspension of THF (400mL), reaction mixture was at room temperature stirred 75 minutes.THF (100mL) solution of ((R)-3-bromo-2-methyl propoxy-)-tert-butyl diphenyl silane (99.4g) is dropwise added in the reaction mixture, and reflux is 23 hours subsequently.Frozen water is added reaction mixture, use ethyl acetate extraction subsequently.Organic layer salt water washing, concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(eluting solvent: purifying heptane-ethyl acetate system) obtains the 74.6g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

0.91-0.95(m，3H)，1.05(s，9H)，1.29-1.35(m，6H)，1.45(s，9H)，1.68-1.79(m，1H)，1.83-2.04(m，1H)，2.16-2.26(m，1H)，2.95-3.14(m，1H)，3.46-3.51(m，2H)，4.09-4.17(m，4H)，7.35-7.42(m，6H)，7.63-7.67(m，4H)。

(E)-(S)-5-(tert-butyl diphenyl siloxy)-2-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] Methylene radical]-the 4-methylvaleric acid tert-butyl ester

In-70 ℃ under nitrogen; THF (50mL) solution of (4S)-5-(tert-butyl diphenyl siloxy)-2-(diethoxy phosphoryl)-4-methylvaleric acid tert-butyl ester is added tert.-butoxy potassium (3.3g) in the solution of THF (50mL), and reaction mixture was stirred 40 minutes.THF (50mL) solution with 3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl aldehyde (6g) under-70 ℃ adds in the reaction mixture, reaction mixture was stirred 100 minutes, and at room temperature stir and spend the night.Water is added reaction mixture, use ethyl acetate extraction subsequently.Organic layer salt water washing, concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(eluting solvent: purifying heptane-ethyl acetate system) obtains the 9.34g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.55(s，9H)，1.99-2.08(m，2H)，2.30(s，3H)，2.63-2.71(m，2H)，3.59(t，J＝6.4Hz，2H)，3.87(s，3H)，6.93(m，1H)，7.00(d，J＝1.2Hz，1H)，7.09(dd，J＝8.4，1.2Hz，1H)，7.27(d，J＝8.4Hz，1H)，7.58(s，1H)，7.72(m，1H)。

(E)-(S)-and 5-chloro-2-[3-fluoro-4-(4-methylimidazole-1-yl) phenyl] methylene radical]-4-methylvaleric acid uncle fourth Synthesizing of base ester

Ice-cooled following with the TBAF (solution of 1M in THF, 22.8mL) add (E)-(S)-5-(tert-butyl diphenyl siloxy)-2-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical]-the 4-methylvaleric acid tert-butyl ester (9.34g) in the solution of THF (100mL), and reaction mixture at room temperature stirred 4 hours.Frozen water is added reaction mixture, use ethyl acetate extraction subsequently.Organic layer salt water washing, concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(eluting solvent: purifying heptane-ethyl acetate system), collection object flow part also concentrates resistates, obtains colorless oil (4.2g) through silica gel column chromatography.Triphenylphosphine (3.15g) is dissolved in this colorless oil in the solution of methylene dichloride (50mL).N-chlorosuccinimide (1.47g) is added reaction soln down ice-cooled, and reaction mixture was stirred 1 hour at 0 ℃.Frozen water is added reaction mixture, use chloroform extraction subsequently.Organic layer salt water washing, concentrating under reduced pressure behind anhydrous magnesium sulfate drying.Resistates is through silica gel column chromatography (carrier: ChromatorexNH; Eluting solvent: purifying heptane-ethyl acetate system) obtains the 2.84g title compound.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

0.96(d，J＝6.8Hz，3H)，1.55(s，9H)，2.12-2.22(m，1H)，2.49(dd，J＝14Hz，8Hz，1H)，2.74(dd，J＝14Hz，6.4Hz，1H)，3.37-3.46(m，2H)，7.00-7.02(m，1H)，7.22-7.29(m，1H)，7.38(t，J＝8Hz，1H)，7.56(s，1H)，7.77(t，J＝1.6Hz，1H)。

(E)-(S)-and 5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-the 4-methyl Synthesizing of valerate acidifying thing

At room temperature with (E)-(S)-5-chloro-2-[3-fluoro-4-(4-methylimidazole-1-yl) phenyl] methylene radical]-solution stirring of the 4-methylvaleric acid tert-butyl ester (2.84g) in trifluoroacetic acid (20mL) 1 hour.With the reaction mixture concentrating under reduced pressure, ethyl acetate (10mL) solution of ethyl acetate (10mL) and 4N hydrochloric acid is added this resistates, and with the reaction soln concentrating under reduced pressure.This operation repeats twice.Ether is added in the resistates, and shovel the scraping reaction mixture with little medicine.Collect solidified and sedimentary insolubles by filtering, obtain the 2.05g title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?337[M ⁺+H]。

(E)-(S)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[(1R, 2R)-2- Hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group]-5-methyl piperidine-2-ketone synthetic

At room temperature DIEA (0.47mL), WSC (257mg) and HOBT (181mg) are added (E)-(S)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-4-methylvaleric acid hydrochloride (250mg) and (1R, 2R)-1-amino-1-(3,4, the 5-trifluorophenyl) propan-2-ol hydrochloride (243mg) is in the suspension of DMF (5mL), and reaction soln was at room temperature stirred 1 hour.Ethyl acetate is added reaction soln, use saturated sodium bicarbonate aqueous solution, water, saturated ammonium chloride solution and salt water washing subsequently successively.Gained organic layer concentrating under reduced pressure after dried over mgso.Resistates is dissolved in DMF (8mL).Stirred 1 hour at 0 ℃ at 0 ℃ of following adding 60% sodium hydride (32mg) and with reaction soln.Ethyl acetate is added reaction soln, use saturated sodium bicarbonate aqueous solution, water, saturated ammonium chloride solution and salt water washing subsequently successively.Gained organic layer concentrating under reduced pressure after dried over mgso.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: purifying heptane-ethyl acetate system-ethyl acetate-methyl alcohol system) obtains the 176mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?488[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.03(d，J＝6.8Hz，3H)，1.32(d，J＝6.4Hz，3H)，1.86-2.00(m，1H)，2.31(s，3H)，2.39(ddd，J＝15.6，11.6，2.8Hz，1H)，2.65(brs，1H)，2.93(brd，J＝15.6，3.6Hz，1H)，3.20-3.29(m，2H)，4.44-4.53(m，1H)，5.32(d，J＝7.2Hz，1H)，6.99-7.02(m，1H)，7.05-7.11(m，2H)，7.22-7.30(m，2H)，7.39(dd，J＝8.0，8.0Hz，1H)，7.75-7.78(m，1H)，7.81(brs，1H)。

Embodiment 85

(E)-and 3-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical }-1-[(1R, 2R)-the 2-hydroxyl Base-1-(3,4, the 5-trifluorophenyl) propyl group] piperidines-2-ketone synthetic

At room temperature the solution in the hydrochloric acid Zai diox (10mL) of 4N is added [(1R, 2R)-2-hydroxyl-1-(3,4,5-trifluorophenyl) propyl group] t-butyl carbamate (in 2.85g) De diox (10mL) solution, and at room temperature stirred reaction soln 5 hours.(80mL) at room temperature adds reaction soln with hexane, and reaction soln was at room temperature stirred 20 minutes.The gained solid by filtration is separated, obtain (1R, 2R)-1-amino-1-(3,4, the 5-trifluorophenyl) propane-2-alcohol hydrochloride (2.16g).At room temperature DIEA (1.59mL), WSC (880mg) and HOBT (620mg) are added (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid trifluoroacetate (1.00g) and (1R, 2R)-1-amino-1-(3,4, the 5-trifluorophenyl) propan-2-ol hydrochloride (664mg) is in the solution of DMF (25mL), and reaction soln was at room temperature stirred 1 hour.Ethyl acetate is added reaction soln, use saturated sodium bicarbonate aqueous solution, water, saturated ammonium chloride solution and salt water washing subsequently successively.Gained organic layer concentrating under reduced pressure after dried over mgso.Gained solid heptane wash obtains (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid [(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group] acid amides (1.10g).With (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid [(1R, 2R)-2-hydroxyl-1-(3,4, the 5-trifluorophenyl) propyl group] acid amides (1.10g) is dissolved in DMF (25mL).(104mg) at room temperature adds in the reaction soln with 60% sodium hydride, and reaction soln was at room temperature stirred 1 hour.Ethyl acetate is added reaction soln, use saturated sodium bicarbonate aqueous solution, water, saturated ammonium chloride solution and salt water washing subsequently successively.Gained organic layer concentrating under reduced pressure after dried over mgso.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: purifying heptane-ethyl acetate system-ethyl acetate-methyl alcohol system), use the curing of ethyl acetate and heptane and, obtain the 780mg title compound by filtering separation.The value of the character of described compound is as follows.

ESI-MS；m/z?474[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.31(d，J＝6.0Hz，3H)，1.77-1.98(m，2H)，2.31(d，J＝0.8Hz，3H)，2.73(brd，J＝6.4Hz，1H)，2.77-2.85(m，2H)，3.27(ddd，J＝12.4，7.2，4.0Hz，1H)，3.54(ddd，J＝12.4，8.0，4.0Hz，1H)，4.43-4.53(m，1H)，5.28(d，J＝7.6Hz，1H)，6.99-7.02(m，1H)，7.04-7.12(m，2H)，7.23-7.31(m，2H)，7.38(dd，J＝8.0，8.0Hz，1H)，7.75-7.77(m，1H)，7.80-7.83(m，1H)。

Embodiment 86

(E)-1-[(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl]-3-{1-[3-fluoro-4-(4-methyl isophthalic acid H- Imidazoles-1-yl) phenyl] methylene radical } piperidines-2-ketone synthetic

At room temperature the solution of 4N hydrochloric acid in ethyl acetate (10mL) is added [(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl] in methyl alcohol (10mL) solution of t-butyl carbamate (960mg), and reaction soln at room temperature stirred 30 minutes.The concentrating under reduced pressure reaction soln, obtain (1R, 2R)-1-amino-1-(3, the 4-difluorophenyl) propan-2-ol hydrochloride (747mg).At room temperature DIEA (1.59mL), WSC (880mg) and HOBT (620mg) are added (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid trifluoroacetate (1.00g) and (1R, 2R)-1-amino-1-(3, the 4-difluorophenyl) propan-2-ol hydrochloride (612mg) is in the solution of DMF (20mL), and reaction soln was at room temperature stirred 1 hour.Ethyl acetate is added reaction soln, use saturated sodium bicarbonate aqueous solution, water, saturated ammonium chloride solution and salt water washing subsequently successively.Gained organic layer concentrating under reduced pressure after dried over mgso.Gained solid heptane wash obtains (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid [(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl] acid amides (977mg).With (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl] methylene radical } valeric acid [(1R, 2R)-1-(3, the 4-difluorophenyl)-2-hydroxypropyl] acid amides (977mg) is dissolved in DMF (25mL).Sodium hydride with 60% (95mg) at room temperature adds reaction soln, and reaction soln was at room temperature stirred 30 minutes.Water is added reaction soln, use ethyl acetate extraction subsequently.Gained extract concentrating under reduced pressure after dried over mgso.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: ethyl acetate-methyl alcohol system) purifying, use the curing of ethyl acetate and heptane and, obtain the 740mg title compound by filtering separation.The value of the character of described compound is as follows.

ESI-MS；m/z?456[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.30(d，J＝6.0Hz，3H)，1.74-1.96(m，2H)，2.31(d，J＝0.4Hz，3H)，2.68-2.85(m，3H)，3.19-3.28(m，1H)，3.47-3.56(m，1H)，4.43-4.52(m，1H)，5.36(d，J＝8.0Hz，1H)，6.99(s，1H)，7.10-7.18(m，2H)，7.21-7.29(m，3H)，7.36(dd，J＝8.4，7.6Hz，1H)，7.75(brs，1H)，7.80(brs，1H)。

Adopt the compound of acquisition table 3-1,3-2 and 3-3 in a like fashion.

[table 3-1]

[table 3-2]

[table 3-3]

Embodiment 106

(Z)-(6S, 8aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene]-6-(3,4,5- Trifluorophenyl) Pyrrolidine [2,1-c] [1,4] oxazine-4-ketone synthetic also

(2R, 5S)-5-(3,4, the 5-trifluorophenyl) tetramethyleneimine-2-ethyl formate synthetic

Go through 20 fens clockwise (R)-5-oxo-pyrrolidines-1 at-40 ℃, 2-dioctyl phthalate 1-tertiary butyl ester 2-ethyl ester (CAS No.128811-48-3; 4.1g) in the solution of tetrahydrofuran (THF) (100mL), dropwise add 3,4, the 5-trifluorophenyl magnesium bromide (solution of 0.35M in ether; 55mL), and with reaction soln stirred 5 hours down at-40 ℃.Saturated aqueous ammonium chloride and ethyl acetate are added this solution.Reaction soln is heated to room temperature and separates organic layer.The salt water washing of gained organic layer, concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(heptane-heptane: ethyl acetate=1: 1) purifying obtains (R)-2-tert-butoxycarbonyl amino-5-oxo-5-(3,4, the 5-trifluorophenyl) Valeric acid ethylester of 4.8g to resistates through silica gel column chromatography.Ethyl acetate (30mL) solution of 4N hydrogenchloride is added resulting (R)-2-tert-butoxycarbonyl amino-5-oxo-5-(3,4, the 5-trifluorophenyl) Valeric acid ethylester in the solution of ethyl acetate (30mL), and with this solution stirring 15 hours.The concentrating under reduced pressure reaction soln.Ethyl acetate and saturated sodium bicarbonate aqueous solution are added this resistates and separate organic layer.Gained organic layer concentrating under reduced pressure behind anhydrous magnesium sulfate drying.10% palladium-carbon (100mg) is added this resistates in the solution of ethyl acetate (50mL), and reaction soln was stirred 6 hours in 1 atmospheric hydrogen stream.Reaction soln is concentrated by diatomite filtration and with filtrate decompression, obtain the 2.91g title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?274[M ⁺+H]。

[(2R, 5S)-5-(3,4, the 5-trifluorophenyl) tetramethyleneimine-2-yl] methyl alcohol synthetic

Under-15 ℃, go through and LAH (483mg) added in 1 hour (2R, 5S)-THF (50mL) solution of 5-(3,4, the 5-trifluorophenyl) tetramethyleneimine-2-ethyl formate (2.91g) in.Reaction soln was stirred 19 hours down at-15 ℃.Water (0.5mL), 5N sodium hydroxide solution (0.5mL) and water (1.5mL) are added reaction soln successively, and this mixture was at room temperature stirred 30 minutes.Reaction soln obtains the 2.4g title compound by diatomite filtration and concentrating under reduced pressure filtrate.The value of the character of described compound is as follows.

ESI-MS；m/z?232[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.51-1.63(m，1H)，1.66-1.77(m，1H)，1.89-2.00(m，1H)，2.10-2.20(m，1H)，3.43(dd，J＝10.0，5.6Hz，1H)，3.47-3.55(m，1H)，3.64(dd，J＝10.0，3.6Hz，1H)，4.23(t，J＝8.0Hz，1H)，7.02(t，J＝8.0Hz，2H)。

Adopt the method identical with embodiment 41, from as raw material [(2R, 5S)-5-(3,4, the 5-trifluorophenyl) tetramethyleneimine-2-yl] methyl alcohol reacts, and obtains the 521mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?470[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.71-1.82(m，1H)，1.92-1.98(m，1H)，2.10-2.20(m，2H)，2.30(s，3H)，2.37-2.48(m，1H)，3.86(s，3H)，4.09-4.13(m，1H)，4.68(d，J＝8Hz，1H)，5.14(d，J＝9.2Hz，1H)，6.75(s，1H)，6.84(dd，J＝8.4Hz，6.4Hz，2H)，6.93-6.94(m，1H)，7.21(d，J＝8Hz，1H)，7.37-7.41(m，2H)，7.72(d，J＝1.2Hz，1H)。

Embodiment 107

(6S, 9aR)-6-(4-chloro-phenyl-)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzene Base]-(Z)-and methylene radical } hexahydropyridine [2,1-c] [1,4] oxazine-4-ketone synthetic also

(2R, 6S)-6-(4-chloro-phenyl-) piperidines-2-methyl-formiate synthetic

Under nitrogen, go through 20 fens clockwise (R)-6-oxo-piperidines-1 in-78 ℃, 2-dioctyl phthalate 1-tertiary butyl ester (CAS No.183890-36-0,9.00g) in the solution of THF (120mL), add 4-chloro-phenyl-magnesium bromide (solution of 1.0M in ether, 42mL).Reaction soln was stirred 1.5 hours at-78 ℃ to-40 ℃, react-40 ℃ of quenchers with saturated ammonium chloride solution subsequently.Water is added reaction soln, use ethyl acetate extraction subsequently.Gained extract concentrating under reduced pressure after dried over mgso.(eluting solvent: purifying heptane-ethyl acetate system) obtains (R)-2-tert-butoxycarbonyl amino-6-(4-chloro-phenyl-)-6-oxo methyl caproate (9.53g) through silica gel column chromatography with resistates.At room temperature ethyl acetate (90mL) solution with the hydrogenchloride of 4N adds (R)-2-tert-butoxycarbonyl amino-6-(4-chloro-phenyl-)-6-oxo methyl caproate (9.53g) in the solution of ethyl acetate (90mL), and reaction soln was at room temperature stirred 12 hours.Concentrating under reduced pressure reaction soln and with the saturated sodium bicarbonate solution resistates that alkalizes.Then, chloroform being added resistates also at room temperature stirred this mixture 2 hours.Separate organic layer, concentrating under reduced pressure after dried over mgso.At 0 ℃ sodium cyanoborohydride (3.29g) and acetate (4.27mL) are added this resistates successively in the solution of methyl alcohol (150mL), and reaction soln was stirred 1 hour and at room temperature stirred 1 hour at 0 ℃.Saturated sodium bicarbonate solution is added reaction soln, use chloroform extraction subsequently.Gained extract concentrating under reduced pressure after dried over mgso.(eluting solvent: heptane-ethyl acetate system) purifying also is cured with heptane-Di Iso Propyl Ether system resistates, obtains the 2.47g title compound through silica gel column chromatography.The value of the character of described compound is as follows.

ESI-MS；m/z?254[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.38-1.60(m，3H)，1.72-1.78(m，1H)，1.96-2.03(m，1H)，2.05-2.12(m，1H)，2.17(brs，1H)，3.49(dd，J＝10.8，2.8Hz，1H)，3.63(dd，J＝11.2，2.8Hz，1H)，3.73(s，3H)，7.25-7.34(m，4H)。

[(2R, 6S)-6-(4-chloro-phenyl-) piperidines-2-yl] methyl alcohol synthetic

Under nitrogen, lithium aluminum hydride (508mg) is suspended among the THF (50mL).-20 ℃ down will (2R, 6S)-6-(4-chloro-phenyl-) piperidines-2-methyl-formiate (2.47g) adds this suspension, and reaction soln was stirred 1 hour at-20 ℃.Under-20 ℃, water (0.51mL), 5N sodium hydroxide solution (0.51mL) and water (1.53mL) are added reaction soln successively and reaction soln was at room temperature stirred 15 minutes.Ethyl acetate is added reaction soln.Then, reaction soln concentrates through diatomite filtration and with filtrate decompression.Resistates is through silica gel column chromatography (carrier: Chromatorex NH; Eluting solvent: purifying heptane-ethyl acetate system) obtains the 1.90g title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?226[M ⁺+H]。

Adopt the method identical with embodiment 40, from [(2R, 6S)-6-(4-chloro-phenyl-) piperidines-2-yl] methyl alcohol (270mg) reacts, and obtains the 199mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?464[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

1.39-1.54(m，2H)，1.66-1.77(m，2H)，2.14-2.25(m，2H)，2.30(s，3H)，3.86(s，3H)，4.03-4.13(m，2H)，4.35(dd，J＝10.4，2.4Hz，1H)，5.37(t，J＝4.0Hz，1H)，6.83(s，1H)，6.93(s，1H)，7.20-7.23(m，3H)，7.30-7.33(m，2H)，7.36-7.40(m，2H)，7.73(s，1H)。

Embodiment 108

(6R, 9aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene [1,4] oxazine is [3,4-c] [synthesizing of 1,4] oxazine-4-ketone also for base-6-(3,4, the 5-trifluorophenyl) tetrahydrochysene

(S)-5-benzyloxymethyl morpholine-3-ketone synthetic

Down bromo Acetyl Chloride 98Min. (5.06mL) is added in the mixing solutions of (R)-(+)-2-amino-3-benzyloxy-1-propyl alcohol (10g) in toluene (100mL) and 2N sodium hydroxide solution (100mL) ice-cooled.Reaction soln was stirred 30 minutes at 0 ℃, stirred 1 hour at 60 ℃ subsequently.Reaction soln is returned to room temperature.Then, the mixing solutions with toluene-THF (1: 1) adds reaction soln and separates organic layer.Gained organic layer concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(eluting solvent: purifying heptane-ethyl acetate system) obtains the 1.36g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

3.42(t，J＝9.2Hz，1H)，3.54(dd，J＝9.2，5.2Hz，1H)，3.62(dd，J＝12.0，6.0Hz，1H)，3.75(m，1H)，3.86(dd，J＝12.0，4.0Hz，1H)，4.12(d，J＝16.8Hz，1H)，4.18(d，J＝16.8Hz，1H)，4.53(s，2H)，6.29(brs，1H)，7.28-7.40(m，5H)。

(S)-3-benzyloxymethyl-5-oxo morpholine-4-t-butyl formate synthetic

TEA (1.72mL), 4-dimethylaminopyridine (189mg) and tert-Butyl dicarbonate (2.02g) are added (S)-5-benzyloxymethyl morpholine-3-ketone (1.36g) in the solution of acetonitrile (25mL).Reaction soln was at room temperature stirred 2 hours.Then, salt solution is added reaction soln and separates organic layer with ethyl acetate.Gained organic layer concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(eluting solvent: purifying heptane-ethyl acetate system) obtains the 1.65g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.50(s，9H)，3.57(dd，J＝8.8，4.8Hz，1H)，3.68-3.75(m，2H)，4.08-4.28(m，4H)，4.53(d，J＝12.0Hz，1H)，4.58(d，J＝12.0Hz，1H)，7.25-7.36(m，5H)。

(S)-and 1-benzyloxymethyl-2-[2-oxo-2-(3,4, the 5-trifluorophenyl) oxyethyl group] ethyl } carboxylamine Synthesizing of the tert-butyl ester

Go through under 40 ℃ 10 minutes clockwise magnesium (249mg) in the suspension of ether (5mL), dropwise add 1-bromo-3,4,5-trifluoro-benzene (446 μ L), and reaction soln stirred 1 hour down at 40 ℃.Under 40 ℃, go through in tetrahydrofuran (THF) (30mL) solution that this solution was dropwise added in 10 minutes (S)-3-benzyloxymethyl-5-oxo morpholine-4-t-butyl formate (1.1g), and reaction soln was stirred 1 hour at-40 ℃.Divide small portion to add this solution saturated ammonium chloride solution at-40 ℃, and reaction soln is returned to room temperature.Ethyl acetate is added reaction soln and separates organic layer.The salt water washing of gained organic layer is with after anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resistates obtains the 952mg title compound through silica gel column chromatography (heptane-ethyl acetate system) purifying.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

1.43(s，9H)，3.54(dd，J＝9.2，6.0Hz，1H)，3.61-3.71(m，3H)，3.96(m，1H)，4.51(s，2H)，4.61(s，2H)，5.02(m，1H)，7.21-7.35(m，5H)，7.50-7.62(m，2H)。

[(3S, 5R)-5-(3,4, the 5-trifluorophenyl) morpholine-3-yl] methyl alcohol synthetic

At room temperature the solution of 4N hydrochloric acid in ethyl acetate (30mL) is added in ethyl acetate (30mL) solution of { (S)-1-benzyloxymethyl-2-[2-oxo-2-(3,4, the 5-trifluorophenyl) oxyethyl group] ethyl } t-butyl carbamate (3.55g).Reaction soln was at room temperature stirred 1 hour and concentrating under reduced pressure subsequently.With 10% palladium-carbon (contain 50% water, 167mg) add the gained resistates in the solution of methyl alcohol (50mL), and with reaction soln in hydrogen, stirring 18 hours under the room temperature.By removing by filter the palladium-carbon in the reaction soln, subsequently filtrate decompression is concentrated.Saturated sodium bicarbonate solution is added the gained resistates and separates organic layer with ethyl acetate.Organic layer salt water washing.Gained organic layer concentrating under reduced pressure behind anhydrous magnesium sulfate drying.(eluting solvent: purifying heptane-ethyl acetate system) obtains the 1.52g title compound to resistates through silica gel column chromatography.The value of the character of described compound is as follows.

¹H-NMR(CDCl ₃)δ(ppm)：

3.13-3.22(m，2H)，3.34(dd，J＝10.8，10.4Hz，1H)，3.53(dd，J＝10.8，6.4Hz，1H)，3.67(dd，J＝10.8，4.0Hz，1H)，3.77(dd，J＝10.8，3.2Hz，1H)，3.85(dd，J＝10.8，3.2Hz，1H)，3.96(dd，J＝10.4，3.2Hz，1H)，7.02-7.25(m，2H)。

(6R, 9aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene Base }-[1,4] oxazine is [3,4-c] [synthesizing of 1,4] oxazine-4-ketone also for 6-(3,4, the 5-trifluorophenyl) tetrahydrochysene

Adopt the method identical with embodiment 40, from [(3S, 5R)-5-(3,4, the 5-trifluorophenyl) morpholine-3-yl] methyl alcohol (250mg) reacts, and obtains title compound (110mg).The value of the character of described compound is as follows.

ESI-MS；m/z?486[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

2.28(s，3H)，3.46-3.55(m，1H)，3.64(dd，J＝7.6，12.4Hz，1H)，3.83(s，3H)，4.06-4.26(m，3H)，4.30(m，1H)，4.36(dd，J＝2.4，10.4Hz，1H)，4.74(dd，J＝4.4，7.2Hz，1H)，6.77(s，1H)，6.91(brs，1H)，6.95-6.99(m，2H)，7.19(d，J＝8.8Hz，1H)，7.31-7.34(m，2H)，7.70(d，J＝0.8Hz，1H)。

Embodiment 109

(6R, 9aR)-6-(3, the 4-difluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzene Base]-(Z)-and methylene radical } [1,4] oxazine is [3,4-c] [synthesizing of 1,4] oxazine-4-ketone also for tetrahydrochysene

Adopt the method identical with embodiment 108, from [(3S, 5R)-5-(3, the 4-difluorophenyl) morpholine-3-yl] methyl alcohol (338mg) reacts, and obtains the 185mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?468[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

2.29(s，3H)，3.53(dd，J＝11.2，11.2Hz，1H)，3.68(dd，J＝12.0，7.2Hz，1H)，3.84(s，3H)，4.04-4.21(m，3H)，4.27-4.37(m，2H)，4.80(dd，J＝7.2，4.4Hz，1H)，6.78(s，1H)，6.91(s，1H)，7.06-7.20(m，4H)，7.31-7.34(m，2H)，7.70(s，1H)。

Embodiment 110

(6R, 9aR)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzene Base]-(Z)-and methylene radical } [1,4] oxazine is [3,4-c] [synthesizing of 1,4] oxazine-4-ketone also for tetrahydrochysene

Adopt the method identical with embodiment 108, from [(3S, 5R)-5-(4-fluorophenyl) morpholine-3-yl] methyl alcohol (311mg) reacts, and obtains the 242mg title compound.The value of the character of described compound is as follows.

ESI-MS；m/z?450[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

2.29(s，3H)，3.55(dd，J＝11.6，11.6Hz，1H)，3.72(dd，J＝12.0，7.6Hz，1H)，3.83(s，3H)，4.02-4.21(m，3H)，4.30-4.36(m，2H)，4.85(dd，J＝7.6，4.0Hz，1H)，6.79(s，1H)，6.91(s，1H)，7.03-7.07(m，2H)，7.19(d，J＝8.8Hz，1H)，7.30-7.34(m，4H)，7.70(s，1H)。

Embodiment 111

(6R, 9aR)-6-(4-chloro-phenyl-)-3-[1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzene Base]-(Z)-methylene radical] tetrahydrochysene [1,4] oxazine also [3,4-c] oxazine-4-ketone synthetic

Adopt the method identical with embodiment 108, from [(3S, 5R)-5-(4-chloro-phenyl-) morpholine-3-yl] methyl alcohol (470mg) reacts, and obtains title compound (357mg).The value of the character of described compound is as follows.

ESI-MS；m/z?466[M ⁺+H]。

¹H-NMR(CDCl ₃)δ(ppm)：

2.29(s，3H)，2.52(t，J＝11.2Hz，1H)，3.68(dd，J＝12.4，8.0Hz，1H)，3.83(s，3H)，4.04(dd，J＝11.2，4.4Hz，1H)，4.09-4.20(m，2H)，4.26-4.36(m，2H)，4.81(dd，J＝7.6，4.4Hz，1H)，6.78(s，1H)，6.91(s，1H)，7.19(d，J＝8.4Hz，1H)，7.23-7.34(m，6H)，7.70(s，1H)。

For the purposes of the compound that shows general formula of the present invention (I), the present inventor has carried out following test.

Experimental example 1

To from A β peptide in the neurone culture of rat fetal brain quantitatively

(1) The primary neuronal of rat is cultivated

The primary neuronal culture is to prepare in the pallium of the Wistar rat (Charles River Japan, Yokohama, Japan) from 18 days.Particularly, from by the conceived rat of etherization with the aseptic separation of embryo.Brain separated from the embryo and be immersed in the ice-cold L-15 substratum (for example, from Invitrogen Corp.Cat#11415-064, Carlsbad, CA, the U.S. or SIGMA L1518).Under stereoscopic microscope, from isolating brain, collect pallium.The pallium fragment of collecting is being comprised 0.25% trypsin Invitrogen Corp.Cat#15050-065, Carlsbad, CA under 37 ℃, the U.S.) and 0.01% DNase (Sigma D5025, St.Louis, MO, the U.S.) enzyme solution in handle 30 minutes with cell dispersion.Add deactivation this moment in this solution horse serum stops this enzymatic reaction.The solution that to handle through enzyme is 1, under the 500rpm centrifugal 5 minutes, removes supernatant liquid.The 5-10mL substratum is added in the cell mass of gained.2% B27 additive (Invitrogen Corp.Cat#17504-044 will have been added, Carlsbad, CA, the U.S.), 2 mercapto ethanol (the 2-ME of 25 μ M, WAKO Cat#139-06861, Osaka, Japan), 0.5mM L-glutaminate (Invitrogen Corp.Cat#25030-081, Carlsbad, CA, the U.S.) and microbiotic-anti-mycotic agent (Invitrogen Corp.Cat#15240-062, Carlsbad, CA, the U.S.) neural basic medium (Neurobasal medium) (Invitrogen Corp.Cat#21103-049, Carlsbad, CA, the U.S.) as substratum (Neurobasal/B27/2-ME).But, the above-mentioned neural basic medium (Neurobasal/B27) that does not add 2-ME is used for this experiment.By soft absorption cell mass is added in the container of substratum, and disperses once more.The nylon leaching net (Cell Strainer, Cat#35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, the U.S.) of this cell dispersion liquid through 40-μ m filtered to remove residual cell mass, obtained neuronal cell suspension thus.Described neuronal cell suspension is diluted with substratum, subsequently with 5 * 10 ⁵Individual cell/cm ²Initial cell density, be fitted in the 96 hole polystyrene culture plates by the volume integral in 100 μ l/ holes, described culture plate has applied poly--L or D-Methionin (Falcon Cat#35-3075 in advance, BectonDickinson Labware, Franklin Lakes, NJ, the U.S. adopts method as follows to apply poly-L-Lysine, or uses BIOCOAT ^TMCellular environment is gathered-D-Methionin cell product 96-orifice plate, Cat#35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, the U.S.).The coating of poly-L-Lysine is carried out as follows.Use poly-L-Lysine (SIGMA P2636, St.Louis, MO, the U.S.) solution of borate buffer solution (pH 8.5) the sterile preparation 100 μ g/ml of 0.15M.Solution by also at room temperature cultivating one or more hours in the 100 μ l/ holes adding 96-hole polystyrene culture plate, is perhaps spent the night under 4 ℃ or the longer time.With sterilized water washing 4 times or more times, subsequent drying or with for example aseptic PBS or substratum cleaning is used for the cell bed board through the 96-hole polystyrene culture plate that applies.The cell of bed board in culture plate in 37 ℃, 5%CO ₂Cultivated 1 day in-95% air.Then, with above-mentioned substratum all with fresh Neurobasal ^TM/ B27/2-ME substratum is replaced, and subsequently cell is cultivated three days again.

(2) Add compound

As follows, at the 4th day that cultivates medicine is added culture plate.From each hole, remove whole substratum, will not comprise 2-ME and the substratum (Neurobasal/B27) that comprises 2%B-27 adds wherein by the amount in 180 μ l/ holes.The solution of testing compound in dimethyl sulfoxide (DMSO) (hereinafter being abbreviated as DMSO) is diluted with Neurobasal/B27, so that initial concentration reaches 10 times of final concentration.Diluent is added by the amount in 20 μ l/ holes, and with the substratum thorough mixing.The final concentration of DMSO is 1% or lower.The hole that only adds DMSO is a control group.

(3) Sampling

After adding compound,, collects whole nutrient solutions, the nutrient solution of gained is used as the sample of ELISA cell cultures three days.Be used for the sample that the ELISA of A β x-42 measures and do not dilute, use 5 times of the diluted that provide by the ELISA test kit and be used for sample that the ELISA of A β x-40 measures.

(4) The evaluation of cell survival

According to following method, test by MTT and to estimate cell survival.After collecting substratum, the substratum of heating is in advance added each hole by the amount in 100 μ l/ holes.Subsequently, by the amount in 8 μ l/ holes the solution of MTT (SIGMA M2128, St.Louis, MO, the U.S.) in D-PBS (-) (Dulbecco phosphate buffered saline buffer, SIGMA D8537, St.Louis, MO, the U.S.) of 8mg/ml is added each hole.With 96-hole polystyrene culture plate in incubator in 37 ℃, 5%CO ₂Hatched in-95% air 20 minutes.The amount of MTT lysis buffer by 100 μ l/ holes added wherein, and make first

Crystal fully is dissolved in the incubator in 37 ℃, 5%CO ₂In-95% airborne this damping fluid.Then, measure the absorbancy of the 550nm in each hole.Described MTT lysis buffer preparation method is as follows.SDS (sodium lauryl sulphate (Sulfuric acid,monododecyl ester, sodium salt) with 100g, WAKO 191-07145, Osaka, Japan) be dissolved in the N of 250mL, in the mixing solutions of N '-dimethyl formamide (WAKO 045-02916, Osaka, Japan) and 250mL distilled water, the concentrated hydrochloric acid and the dense acetic acid that successively respectively add 350 μ l in solution are so that the solution final pH is about 4.7.

According to mensuration, will not add the hole of cell and only comprise damping fluid and the hole of MTT solution is made as background (bkg).The numerical value of being measured according to following formula respectively from wherein deducting background values.Thus, (group of treated with medicaments not, ratio CTRL) (%CTRL) is with relatively and estimate the cell survival activity with respect to control group to calculate it.

%CTRL=(A550_ sample-A550_ background)/(A550_CTRL-background) * 100

(A550_ sample: the absorbancy of sample well under 550nm, A550_ background: the absorbancy of this bottom outlet under 550nm, A550_CTRL: the absorbancy of the hole of control group under 550nm)

(5) The ELISA test of A β

ELISA test for A β, use is available from Wako Pure Chemical Industries, Ltd. people/rat amyloid beta (42) ELISA test kit Wako (#290-62601) and people/rat amyloid beta (40) ELISA test kit or available from Immuno-Biological Laboratories, Co., Ltd. (IBL Co., human amyloid albumen β (1-42) test kit (#27711) Ltd.) and human amyloid albumen β (1-40) test kit (#27713).Carry out the ELISA test of A β according to the method (method of in appended text, describing) that the manufacturer recommends.But, use amyloid beta peptide 1-42 of rat and amyloid beta peptide 1-40 (Calbiochem, the #171596[A β of rat ₄₂], #171593[A β ₄₀]) generate the calibration curve of A β.

(6) The result

In table 4-1,4-2 and 4-3, shown the result, represented for the per-cent (%CTRL) of control group with A β concentration in the nutrient solution.

[table 4-1]

Test compound	Reduce the active IC50 (nM) that A β 42 generates
		Embodiment 1	77
Embodiment 2	187
		Embodiment 3	41
Embodiment 4	69
		Embodiment 5	125
Embodiment 6	156
		Embodiment 7	76
Embodiment 8	113

Embodiment 9	60
		Embodiment 10	84

Embodiment 12	101
		Embodiment 13	129
Embodiment 14	146
		Embodiment 16	201
Embodiment 18	183
		Embodiment 19	54
Embodiment 20	82
		Embodiment 21	195
Embodiment 22	30
		Embodiment 23	130
Embodiment 24	36
		Embodiment 25	141
Embodiment 26	6
		Embodiment 27	5
Embodiment 28	16

[table 4-2]

Test compound	Reduce the active IC50 (nM) that A β 42 generates
		Embodiment 29	23
Embodiment 30	54
		Embodiment 31	31

Embodiment 32	41
		Embodiment 33	63
Embodiment 34	23
		Embodiment 35	23
Embodiment 36	109
		Embodiment 37	20

Embodiment 38	52
		Embodiment 39	130
Embodiment 40	100
		Embodiment 41	141
Embodiment 51	67
		Embodiment 52	86
Embodiment 53	40
		Embodiment 54	74
Embodiment 55	111
		Embodiment 58	67
Embodiment 60	96
		Embodiment 63	103
Embodiment 74	140
		Embodiment 75	146
Embodiment 77	141
		Embodiment 84	37
Embodiment 85	64
		Embodiment 96	89

Embodiment 101	88
		Embodiment 105	61

[table 4-3]

Test compound	Reduce the active IC50 (nM) that A β 42 generates
		Embodiment 107	78
Embodiment 108	60
		Embodiment 109	100
Embodiment 111	129

Result in table 4-1,4-2 and 4-3 has confirmed that The compounds of this invention has the effect that reduces A β 42 generations.

Experimental example 2

Effect for amyloid beta generation in cerebrospinal fluid, brain and the blood plasma of rat

Move animal to laboratory in the day before yesterday (the 0th day) of on-test.On Animal Tails, mark interim individuality numbering with oil pike.Measure its body weight, and the distribution of managing everywhere.Redistribute individual numbering subsequently.During from on-test (the 1st day), go through three days, once a day rat is forced orally give carrier or sample (5mL/kg).Oral administration is after 6 hours the last time, and injection (50mg/kg) Sodital in rat peritoneum (Dainippon Pharmaceutical Co., Ltd., Osaka).Under narcosis, cut nape and, collect the cerebrospinal fluid of about 100 μ L in the 25G syringe needle insertion cerebellomedullary cistern.Collected cerebrospinal fluid placed the pipe of the p-ABSF that contains 1 μ L 100mmol/L and, decompose to prevent A β in the ice preservation.After this, open the abdominal cavity, use the syringe of heparinization to collect the blood of 2.5mL, and be deposited in the ice from aorta abdominalis.At last,, take out brain, softly clean, then measure the weight in wet base of each hemisphere of brain, respectively two hemispheres is placed the 15mL pipe, and use liquid nitrogen freezing with salt solution with the rat broken end.The brain sample that is taken out always stored refrigerated when measuring.With cerebrospinal fluid 4 ℃ with 7, centrifugal 5 minutes of 000rpm collects supernatant liquor subsequently and measures A β.With blood 4 ℃ with 3, centrifugal 5 minutes of 000rpm collects blood plasma subsequently and measures A β.

Measure for A β 40 and A β 42, cerebrospinal fluid or blood plasma are diluted with the thinner that A beta determination test kit is provided.70% formic acid is added in the cerebral tissue (right brain) with the amount of 1mL with every 100mg (weight in wet base), and with the cerebral tissue supersound process.Ultrasonic back is rapidly with Tris damping fluid (pH 12) dilution 20 times and the neutralization of mixture with 0.9mol/L.Be directly used in the mensuration of A β through neutral liquid.

Carry out the mensuration of A β according to the explanation of measuring test kit.Particularly, the original brain liquid adding before dilution cerebrospinal fluid, diluting plasma sample or the neutralization of each 100 μ L is contained in the microwell plate of immobilised A β 40 and A β 42 antibody.The A β standardized solution of the different concns of each 100 μ L is added in the described microwell plate, and will be reflected at 4 ℃ and spend the night.Microwell plate is washed 5 times with measuring the scavenging solution that test kit provided.Then in microwell plate, add the two anti-of HRP-mark, and will be reflected at 4 ℃ and carry out 1 hour.After the reaction, microwell plate is washed 5 times with same scavenging solution, and, stop this color reaction by adding stop buffer with the colour developing of TMB solution.Then by the absorbancy under SPECTRA MAX 190 (Molecular Devices, Sunnyvale, California, the U.S.) the mensuration 450nm.Calculate A β 40 and A β 42 concentration in each sample according to typical curve.

Effect of the present invention

The compound or pharmaceutically acceptable salt thereof of general formula of the present invention (I) has being used as of reduction A β 42 generations such as grades. Yin this, the neurodegenerative disease that the present invention particularly can provide Zhi to treat or the anti-You A β Zao of Yu becomes is the Yao thing of Alzheimer disease or Down syndrome for example.

Industrial usability

The compound of general formula of the present invention (I) has and reduces being used as that A β 40 and A β 42 generate, and Yin this, it is in particular as Zhi treats or the anti-You A β Zao of Yu becomes neurodegenerative disease Yao thing of Alzheimer disease or Down syndrome for example.

Claims

1. the compound of formula (I) expression, or its pharmaceutically useful salt:

Wherein

X ₁Represent methylene group, wherein said methylene group can be replaced by 1-3 C1-6 alkyl group, wherein said C1-6 alkyl group can be replaced by 1 oh group, or forms the cyclopropyl group jointly by two on the same carbon atom that is connected methylene group described C1-6 alkyl groups and this carbon atom;

X _aRepresentation methoxy group or fluorine atom;

Ar ₁Represent phenyl group, it can be replaced by 1-3 halogen atom; Or the pyridyl group, it can be replaced by 1-3 halogen atom;

(b) Ar ₁-X ₁-representative and phenyl ring condensed C3-8 group of naphthene base, wherein said " with phenyl ring condensed C3-8 group of naphthene base " is:

Wherein a methylene group on the C3-8 group of naphthene base can be replaced by Sauerstoffatom, and described phenyl ring can be replaced by 1-3 halogen atom; And R ¹, R ², R ³, R ⁴, X _aAnd X _bSuch as in (a) definition; Or

(d) Ar ₁-X ₁-and R ⁴With Ar ₁-X ₁-the nitrogen-atoms and the R that are connected ⁴The carbon atom that is connected forms 4-to 8-member heterocyclic ring containing nitrogen group together, and described 4-to 8-member heterocyclic ring containing nitrogen group is:

Ar wherein ₁Be phenyl group, and described phenyl group can be replaced by 1-3 halogen atom; X _bRepresention oxygen atom; And R ¹, R ², R ³And X _aSuch as (a) or (b) in definition.

2. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound through type (I-a) is represented:

R wherein ¹, R ², R ³, R ⁴, X ₁And Ar ₁As defined in claim 1.

3. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound through type (II) is represented:

R wherein ¹, R ², R ³, R ⁴, X _aAnd X _bAs defined in claim 1; R ⁵And R ⁶Identical or different ground is represented hydrogen atom or C1-6 alkyl group separately, and wherein said C1-6 alkyl group can be replaced by 1 oh group; And Ar _1-aThe expression phenyl group, it can be replaced by 1-3 halogen atom, or the pyridyl group, and it can be replaced by 1-3 halogen atom.

4. compound or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein said compound through type (II-a) is represented:

R wherein ¹, R ², R ³And R ⁴As defined in claim 1; And R ⁵, R ⁶And Ar _1-aAs defined in claim 3.

5. compound or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein said compound through type (II-b) is represented:

6. the compound or pharmaceutically acceptable salt thereof of formula (II-c):

R wherein ¹, R ², R ³And R ⁴As defined in claim 1; R ⁷Represent the C1-6 alkyl group; And Ar _1-aAs defined in claim 3.

7. compound or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein said compound through type (II-d) is represented:

8. compound or pharmaceutically acceptable salt thereof as claimed in claim 3, wherein said compound through type (II-e) is represented:

R wherein ¹, R ², R ³And R ⁴As defined in claim 1; Ar _1-aAs defined in claim 3; And R ⁷As defined in claim 6.

9. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound through type (I-b) is represented:

R wherein ¹, R ², R ³And R ⁴As defined in claim 1; R ¹³And R ¹⁴Identical or different ground is represented hydrogen atom or halogen atom separately; And Y represents methylene group or Sauerstoffatom.

10. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound through type (I-c) is represented:

R wherein ¹And R ²As defined in claim 1; Ar _1-cRepresent phenyl group, it can be replaced by 1-3 halogen atom; Z ₁Represent methylene radical or Sauerstoffatom; And n and m represent integer 1.

11. compound or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein said compound is selected from following compounds:

15) (Z)-(6S, 9aR)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4]

Piperazine-4-ketone,

16) (Z)-(6R, 9aS)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4]

Piperazine-4-ketone,

39) (Z)-(6S, 9aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene]-6-(3,4, the 5-trifluorophenyl) hexahydropyridine also [2,1-c] [1,4]

Piperazine-4-ketone,

40) (Z)-(6S, 9aR)-6-(3, the 4-difluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene] hexahydropyridine also [2,1-c] [1,4]

Piperazine-4-ketone,

70) (Z)-(6S, 8aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) benzylidene]-6-(3,4, the 5-trifluorophenyl) Pyrrolidine also [2,1-c] [1,4]

Piperazine-4-ketone,

71) (6S, 9aR)-6-(4-chloro-phenyl-)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-and methylene radical } hexahydropyridine also [2,1-c] [1,4]

Piperazine-4-ketone,

72) (6R, 9aR)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical }-6-(3,4, the 5-trifluorophenyl)-tetrahydrochysene [1,4]

Piperazine is [3,4-c] [1,4] also

Piperazine-4-ketone,

73) (6R, 9aR)-6-(3, the 4-difluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical }-tetrahydrochysene [1,4] Piperazine is [3,4-c] [1,4] also Piperazine-4-ketone,

74) (6R, 9aR)-6-(4-fluorophenyl)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical }-tetrahydrochysene [1,4]

Piperazine is [3,4-c] [1,4] also

Piperazine-4-ketone and

75) (6R, 9aR)-6-(4-chloro-phenyl-)-3-{1-[3-methoxyl group-4-(4-methyl isophthalic acid H-imidazoles-1-yl) phenyl]-(Z)-methylene radical }-tetrahydrochysene [1,4]

Piperazine is [3,4-c] [1,4] also

Piperazine-4-ketone.

12. comprise among the claim 1-11 any described compound or pharmaceutically acceptable salt thereof as the pharmaceutical composition of activeconstituents.

13. any described compound or pharmaceutically acceptable salt thereof is used for preventing or treating the purposes of the medicine of the disease that is caused by amyloid beta among the claim 1-11 in preparation.

14. purposes as claimed in claim 13, wherein the disease that is caused by amyloid beta is alzheimer's disease, senile dementia, mongolism or amyloidosis.