CN105294675A

CN105294675A - Preparation method for stepholidine and derivatives thereof

Info

Publication number: CN105294675A
Application number: CN201410276099.8A
Authority: CN
Inventors: 杨玉社; 高锁
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2014-06-19
Filing date: 2014-06-19
Publication date: 2016-02-03

Abstract

The invention provides a preparation method for stopholidine and derivatives thereof. Specifically, the method comprises the following steps: with a chemical compound as shown in a formula A as an intermediate, carrying out B-N cyclization/sodium borohydride reduction reaction and cyclization reaction so as to obtain a skeleton of a stepholidine compound, wherein definitions of all groups are described in the specification. The method provided by the invention has the advantages of simple operation of related reactions, high yield, cheap reagents, and facilitation to enlargement of the preparation method for methylphenethylamine compounds as shown in a general formula I, and specifically for o-bromobenzeneacetic acid compounds corresponding to 9,10-substituted modes, so the method is applicable to large-scale preparation for optically pure stepholidine or the derivatives thereof.

Description

The preparation method of Stopholidine and derivative thereof

Technical field

The invention belongs to pharmaceutical chemistry and asymmetric synthesis chemical field, particularly, the present invention relates to the chemical synthesis process of the natural product Stopholidine or derivatives thereof optical isomer with antipsychotic activity, especially l-spd (L-stepholidine, and the chemical synthesis process of derivative optical isomer, and the new intermediate used in the method L-SPD).

Background technology

Schizophrenia is a kind of serious mental disorder, and its clinical treatment not yet obtains satisfied solution.In the last few years, neuroscientists had demonstrated the dopamine D of schizophrenic brain's cortex prefrontal lobe ₁receptor hypo-function is relevant to negative symptoms, the D of subcortical structure ₂function of receptors hyperfunction (Okubo, Y., Nature, 1997,385:634 relevant to positive symptom; Abi-Dargham, A., Eur.Psychiatry, 2005,20:15).Therefore, people propose schizoid new nosetiology is due to D ₁function of receptors is lowered, simultaneously D ₂receptor function controlling is hyperfunction to be caused.Based on this hypothesis, there is D simultaneously ₁excitement and D ₂the compound of antagonism dual function likely should become the brand-new antipsychotics that a class can match with schizophrenia nosetiology.

Reported first compound of Tetrahydro-proto-berberines class (THPB)---l-spd (L-stepholidine and L-SPD, its structural formula is as follows) is first and has D Jin nation's chapters etc. ₁excitement and D ₂the lead drug (JinGZ, TrendsinPharmacologicalScience, 2002,23:4) of antagonism dual function.Clinical efficacy tentatively shows, L-SPD, to positive and negative symptoms is all effective in cure, to negative symptoms better efficacy, likely becomes the newtype drug meeting the new hypothesis of schizophrenia.

L-SPD is separated (Chin.J.Physiol.1928:203) that obtain from the block root of Menispermaceae stephania plant " Root of Epigeal Srephaia ", content in its root in most of stephania plant drying, stem, leaf is all lower than 1 ‰, what content was the highest also only has about 1% (Acta.Pharm.Sin., 1998,33 (7): 528 ~ 533).

There are synthesis (Hsuch-ChingChiang, J.Org.Chem., 1977,42,19,3190 of bibliographical information SPD raceme very early; Hsuch-ChingChiang, JournaloftheTaiwanPharmaceuticalAssociation, 1976,28,111-120.).Chinese invention patent application publication number CN1115318A and CN1603324A discloses the preparation method and use of the left-handed and dextrorotation chloro Si Kuli quinoline of L-SPD analogue and salt thereof.Chinese invention patent application publication number CN102399166A and international application published WO2012031573A1 discloses the preparation method of Stopholidine and derivative thereof, but when the preparation relating to optical isomer, the method for what above-mentioned patent documentation used is all non-Chiral Separation.The method that existing bibliographical information is committed step with the asymmetric reduction of ruthenium ligand catalysis 3,4-dihydro-isoquinoline prepares L-SPD optical isomer (Jian-JunChengandYu-SheYang, J.Org.Chem., 2009,74,9225-9228; CN200910053220.X), because the conversion of toluylic acid to lactone needs to reflux for solvent carries out band water with benzene or toluene, paraformaldehyde easily gasifies and results in blockage, make operation difficulty, and ruthenium part price costly, the condition of catalyzed reaction is comparatively harsh, makes this route be difficult to amplify, limits the amplification of route.Report by the addition reaction of metallic lithium salt pair chiral imines optical isomer (Jian-JunCheng, Li-qiangFu, the Chen-yuLingandYu-SheYang of the method synthesis L-SPD being committed step subsequently, Heterocycles, 2010,11,2581-2592; CN20101063372.8), but synthetic route is longer, committed step and total recovery lower, need column chromatographic isolation and purification, cause this route be difficult to amplify.

Because the antipsychotic of L-SPD uniqueness is active, need the optically pure compound of a large amount of preparation further to further investigate, because current plant resources is exhausted, in the urgent need to effective chemosynthesis means.

Summary of the invention

The object of this invention is to provide a kind of method of optical purity Stopholidine or derivatives thereof.

Another object of the present invention is to provide a kind of synthetic intermediate that can be used in the pure Stopholidine or derivatives thereof of synthesizing optical, and builds the method for this intermediate.

A first aspect of the present invention, provides a kind of purposes such as formula compound shown in A:

It is characterized in that, the compound for the preparation of having as shown in the formula structure shown in B:

Wherein, R ₃, R ₄, R ₅, R ₆, R ₇, R ₇', R ₉, R ₉', R ₁₀, R ₁₀', R ₁₂, R ₁₃, R ₁₄, R ₁₅be selected from lower group: H independently of one another, the heteroaryl-oxygen base of halogen, the alkyl of substituted or unsubstituted C1-C10, the alkoxyl group of substituted or unsubstituted C1-C10, the aryl of substituted or unsubstituted C6-C10, the aryl-oxygen base of substituted or unsubstituted C6-C10, the heteroaryl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10; And R ₃be not H;

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

Wherein, described replacement refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, alkyl-the amino of substituted or unsubstituted C1-C10, substituted or unsubstituted C6-C10 aryl, benzyl amine, have 1-3 substituent phenyl, described substituting group is selected from lower group: the alkyl of halogen, C1-C10, the alkyl of C1-C10-oxygen base;

R ₈be selected from lower group:

R ₁₁for H;

Y is Br;

represent R configuration or S configuration; And R ₈with formula B configuration be identical.

In another preference, described R ₃, R ₄, R ₁₄, R ₁₅be selected from lower group independently of one another: the heteroaryl-oxygen base of the aryl-oxygen base of the alkyl-oxygen base of substituted or unsubstituted C1-C10, substituted or unsubstituted C6-C10, substituted or unsubstituted C1-C10;

Described R ₅, R ₆, R ₇, R ₇', R ₉, R ₉', R ₁₀, R ₁₀', R ₁₂, R ₁₃be selected from lower group: H independently of one another, the heteroaryl-oxygen base of halogen, the alkyl of substituted or unsubstituted C1-C10, the alkyl-oxygen base of substituted or unsubstituted C1-C10, the aryl of substituted or unsubstituted C6-C10, the aryl-oxygen base of substituted or unsubstituted C6-C10, the heteroaryl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10; Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O.

In another preference, described R ₄it is not methoxyl group.

In another preference, described R ₃, R ₁₄be selected from lower group independently of one another: the alkyl-oxygen base of substituted or unsubstituted C1-C10; Preferably, described R ₃, R ₁₄be selected from lower group independently of one another: the alkyl-oxygen base of substituted or unsubstituted C1-C6; More preferably, described R ₃, R ₁₄for methoxyl group.

In another preference, described R ₄, R ₁₅be selected from lower group independently of one another: the heteroaryl-oxygen base of the aryl-oxygen base of the alkyl-oxygen base of substituted or unsubstituted C3-C10, substituted or unsubstituted C6-C10, substituted or unsubstituted C1-C10, substituted or unsubstituted benzyloxy, allyl group oxygen base; More preferably, described R ₄, R ₁₅for sec.-propyl oxygen base.

A second aspect of the present invention, provides the method for compound shown in a kind of preparation formula B, and described method comprises step:

In inert solvent, with such as formula the compound shown in A through Bischler-Napieralski ring-closure reaction, then through reduction obtain such as formula the compound shown in B, wherein, the definition of each group is as noted before.

In another preference, described method comprises step:

(i) in inert solvent, with such as formula the compound shown in A through Bischler-Napieralski ring-closure reaction, obtain closing ring intermediate formula A3 compound;

(ii) after polar aprotic solvent dissolves, carry out reduction reaction with formula A3 compound, obtain formula B compound.

In another preference, described Bischler-Napieralski reaction is carried out being selected from the solvent of lower group: halohydrocarbon, alkane, ester class, aromatic hydrocarbons, acetone, ethers, acetonitrile, preferably, described solvent is acetonitrile.

In another preference, described reduction reaction be selected from the solvent of lower group carry out, methyl alcohol, ethanol, Virahol, preferably, described solvent is methyl alcohol.

In another preference, described reduction is carried out under metal borohydride exists; Preferably, described metal borohydride is selected from lower group: sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride, acetic acid sodium borohydride, zinc borohydride, or its combination.

In another preference, described reaction comprises step:

(i) in polar aprotic solvent, with such as formula the compound shown in A and ring-closure reaction reagent react, except desolventizing;

(ii), after residue dissolves with polar aprotic solvent, react with metal hydroborates, obtain formula B compound.

In another preference, containing formula A1 compound in the residue obtained in described step (i).

In another preference, described step (i) is carried out under ring-closure reaction reagent exists, and preferably, described reagent is selected from lower group: POCl ₃, P ₂o ₅, PPAT, FAA, POBr ₃, PCl ₅, PCl ₃, SOCl ₂, triphosgene, oxalyl chloride, or its combination.Best, described reagent is POCl ₃.

In another preference, formula A compound and the mol ratio of ring-closure reaction reagent in B-N ring-closure reaction are formula A compound: ring-closure reaction reagent=1:5-10.

In another preference, formula A compound and the metal borohydride mol ratio in reduction reaction is formula A compound: metal borohydride=1:1-20.

In another preference, described reaction is carried out at-80 DEG C-120 DEG C; Preferably, described step (i) is carried out at 10 DEG C-120 DEG C, and described step (ii) is carried out under-80 DEG C-30 DEG C (room temperature).

In another preference, the productive rate of described step is >=50%, is preferably >=70%, is more preferably >=80%.

A third aspect of the present invention, provides a kind of such as formula the compound shown in A:

Wherein, R ₃, R ₄, R ₅, R ₆, R ₇, R ₇', R ₉, R ₉', R ₁₀, R ₁₀', R ₁₁, R ₁₂, R ₁₃, R ₁₄, R ₁₅be selected from lower group: H independently of one another, the alkyl-oxygen base of halogen, the alkyl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10, the heteroaryl-oxygen base of the aryl of substituted or unsubstituted C6-C10, the aryl of substituted or unsubstituted C6-C10-oxygen base, the heteroaryl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10; And R ₃be not H;

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

Wherein, described replacement refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: the alkyl-amino of the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, substituted or unsubstituted C1-C10, substituted or unsubstituted C6-C10 aryl, benzyl amine, have 1-3 substituent phenyl, described substituting group is selected from lower group: the alkyl of halogen, C1-C10, the alkyl of C1-C10-oxygen base.

R ₈be selected from lower group:

represent R configuration or S configuration.

A fourth aspect of the present invention, provides a kind of such as formula the compound shown in B:

Wherein, Y is selected from lower group: the carboxylic acid ester groups of Br, C2-C10;

R ₃, R ₄, R ₅, R ₆, R ₇, R ₇', R ₉, R ₉', R ₁₀, R ₁₀', R ₁₂, R ₁₃, R ₁₄, R ₁₅be selected from lower group: H independently of one another, the alkyl-oxygen base of halogen, the alkyl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10, the heteroaryl-oxygen base of the aryl of substituted or unsubstituted C6-C10, the aryl of substituted or unsubstituted C6-C10-oxygen base, the heteroaryl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10; And R ₃be not H;

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

Wherein, described replacement refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: the alkyl-amino of the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, substituted or unsubstituted C1-C10, substituted or unsubstituted C6-C10 aryl, benzyl amine, have 1-3 substituent phenyl, described substituting group is selected from lower group: the alkyl of halogen, C1-C10, the alkyl of C1-C10-oxygen base;

R ₈be selected from lower group:

represent R configuration or S configuration.

A fifth aspect of the present invention, provides a kind of such as formula the purposes of the compound shown in B for the preparation of the compound had as shown in the formula structure shown in M:

Wherein, R ₃, R ₄, R ₅, R ₆, R ₇, R ₇', R ₉, R ₉', R ₁₀, R ₁₀', R ₁₂, R ₁₃, R ₁₄, R ₁₅be selected from lower group: H independently of one another, the alkyl-oxygen base of halogen, the alkyl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10, the heteroaryl-oxygen base of the aryl of substituted or unsubstituted C6-C10, the aryl of substituted or unsubstituted C6-C10-oxygen base, the heteroaryl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10; And R ₃be not H;

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

Wherein, described replacement refers to that the substituting group that the one or more hydrogen atoms on group are selected from lower group replaces: alkyl-amino of the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, amide group, substituted or unsubstituted C1-C10, substituted or unsubstituted C6-C10 aryl, benzyl amine, have the individual substituent phenyl of 1-3, and described substituting group is selected from lower group: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base;

represent R configuration or S configuration;

And in formula B, Y is the carboxylic acid ester groups of C2-C10.

A sixth aspect of the present invention, provides the method for compound shown in a kind of preparation formula M, and described method comprises step:

In inert solvent, under hydrogen source exists, carry out catalytic hydrogenation with formula B compound, obtain such as formula the compound shown in M;

Wherein, Y is the carboxylic acid ester groups of C2-C10;

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

represent R configuration or S configuration; And above-mentioned various in, each configuration be identical.

In another preference, described hydrogen source is selected from lower group: hydrogen, formic acid or tetrahydrobenzene.

In another preference, described catalytic hydrogenation is carried out under palladium carbon and/or palladium hydroxide/carbon reagent exist.

In another preference, described catalytic hydrogenation is carried out in presence of an acid; Preferably, described acid is selected from lower group: acetic acid, trifluoracetic acid, hydrochloric acid.

In another preference, the mol ratio of described formula B compound and described acid is 1:2-4.

In another preference, described inert solvent is polar protic solvent; Preferably, described solvent is selected from lower group: methyl alcohol, ethanol, tetrahydrofuran (THF), water, or its combination.Be preferably 95% ethanol-water solution.

In another preference, temperature of reaction is 20 DEG C to 50 DEG C.

In another preference, the reaction times is 1 to 24 hour.

A seventh aspect of the present invention, provides a kind of such as formula the compound shown in M:

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

represent R configuration or S configuration.

In another preference, in described formula M, described R ₄be not H.

In another preference, above-mentioned various in, described R ₅it is not methoxyl group.

A eighth aspect of the present invention, provides the preparation method of a kind of SPD (Stopholidine), and described method comprises step:

D (), in inert solvent, under hydrogen source exists, is carried out catalytic hydrogenation with formula V compound, is obtained formula VI compound;

E (), in inert solvent, is reacted with formula VI compound and reductive agent, is obtained formula VII compound;

(f) in inert solvent, with formula VII compound with remove reagent react, remove R ₁, R ₂, obtain compound S PD;

Wherein, R ₁, R ₂be selected from lower group independently of one another: the alkyl of substituted or unsubstituted C1-C10; Wherein, described replacement refers to that the substituting group that the one or more hydrogen atoms on group are selected from lower group replaces: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, have 1-3 substituent phenyl, and described substituting group is selected from lower group: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base;

In another preference, described R ₁be selected from lower group: sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyls, methoxymethyl or benzyloxymethyl; Preferred sec.-propyl.

In another preference, described R ₂be selected from lower group: sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyls, methoxymethyl or benzyloxymethyl; Preferred sec.-propyl.

In another preference, in described step (d), described hydrogen source is selected from lower group: hydrogen, formic acid or tetrahydrobenzene.

In another preference, in described step (d), described catalytic hydrogenation is carried out under palladium carbon and/or palladium hydroxide/carbon reagent exist.

In another preference, in described step (d), described catalytic hydrogenation is carried out in presence of an acid; Preferably, described acid is selected from lower group: acetic acid, trifluoracetic acid, hydrochloric acid.

In another preference, in described step (d), the mol ratio of described formula B compound and described acid is 1:2-4.

In another preference, in described step (d), described inert solvent is polar protic solvent; Preferably, described solvent is selected from lower group: methyl alcohol, ethanol, tetrahydrofuran (THF), water, or its combination.The preferably aqueous ethanolic solution of 95%.

In another preference, in described step (d), temperature of reaction is 20 DEG C to 50 DEG C.

In another preference, in described step (d), the reaction times is 1 to 24 hour.

In another preference, in described step (e), described reductive agent is selected from lower group: lithium aluminium hydride, borane complexes, POTASSIUM BOROHYDRIDE or sodium borohydride, is preferably LiAlH ₄.

In another preference, in described step (e), described inert solvent is polar aprotic solvent; Preferably, described solvent is selected from lower group: tetrahydrofuran (THF), ether, t-butyl methyl ether, or its combination; More preferably, described solvent is tetrahydrofuran (THF).

In another preference, in described step (f), the described reagent that removes is selected from lower group: boron trichloride, aluminum chloride, hydrogen source (under palladium carbon and/or palladium hydroxide/carbon exist), hydrochloric acid.

In another preference, in described step (f), described inert solvent is selected from lower group: methylene dichloride, chloroform, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, methyl alcohol, ethanol, tetrahydrofuran (THF), water, or its combination.

In another preference, described method is further comprising the steps of:

B (), in inert solvent, is reacted with the compound such as shown in formula III and ring-closure reaction reagent/reductive agent, is obtained the compound shown in formula IV;

(c) in inert solvent, with such as formula the compound shown in IV and CH ₃cOO-M reacts, and obtains formula V compound;

Wherein, M is selected from lower group: the alkyl-oxygen base of Cl, Br, C1-C3; R ₁, R ₂definition as noted before.

In another preference, described reaction is carried out being selected from the solvent of lower group: benzene, toluene, acetonitrile, methyl alcohol, ethanol, Virahol; Preferably, described solvent is selected from lower group: acetonitrile, methyl alcohol.

In another preference, described reaction comprises step:

(b1) B-N ring-closure reaction: in polar aprotic solvent, with such as formula the compound shown in A and ring-closure reaction reagent react, except desolventizing;

(b2) reduction reaction: residue reacts with reductive agent, obtains formula B compound after dissolving with polar aprotic solvent.

In another preference, described step (b1) obtains the intermediate be shown below:

In another preference, described step (b) is carried out under ring-closure reaction reagent exists, and preferably, described reagent is selected from lower group: POCl ₃, P ₂o ₅, PPAT, FAA, POBr ₃, PCl ₅, PCl ₃, SOCl ₂, triphosgene, oxalyl chloride, or its combination.Best, described reagent is POCl ₃.

In another preference, described reductive agent is metal borohydride, is preferably sodium borohydride.

In another preference, formula III compound and the mol ratio of phosphorus oxychloride in B-N ring-closure reaction are formula III compound: phosphorus oxychloride=1:5-10.

In another preference, described reaction is carried out at-80 DEG C-120 DEG C; Preferably, described step (b1) is carried out at 10 DEG C-120 DEG C, and described step (b2) is carried out under-80 DEG C-30 DEG C (room temperature).

In another preference, described step (c) comprising: react with such as formula the compound shown in IV and alkyl lithium reagents, then add methyl-chloroformate and/or methylcarbonate, obtain formula V compound.

In another preference, in described step (c), described inert solvent is polar aprotic solvent, is preferably selected from lower group: tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether or methyl tertiary butyl ether ethanol, glycol dimethyl ether, diethylene glycol dimethyl ether, or its combination; Be preferably tetrahydrofuran (THF).

In another preference, in described step (c), described alkyl lithium reagents is selected from lower group: n-Butyl Lithium, s-butyl lithium; Be preferably n-Butyl Lithium.

In another preference, in described step (c), described formula IV compound and the mol ratio of alkyl lithium reagents are 1:1-3, are preferably 1:0.8-1.5.

In another preference, in described step (c), described temperature of reaction is-80 DEG C to-20 DEG C.

In another preference, described step (c) also comprises: process mixture of reaction products with saturated ammonium chloride solution.

In another preference, described method is further comprising the steps of:

A (), in inert solvent, is reacted with formula I and formula II compound, is obtained formula III compound under condensing agent exists:

Wherein, described condensing agent is selected from lower group: oxalyl chloride, sulfur oxychloride, phosphorus oxychloride, DCC, EDCI, HATU, HOBT, or its combination, is preferably oxalyl chloride;

R ₁, R ₂definition as noted before.

In another preference, described formula II compound and the mol ratio of acyl chlorides are 1:1 ~ 10.

In another preference, described inert solvent is selected from lower group: tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether/water, pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), ether, or its combination; Be preferably the mixed solvent of tetrahydrofuran (THF) and water; Preferably, described tetrahydrofuran (THF) and the blending ratio of water are 1:0.01 ~ 10, and more preferably, described blending ratio is 1:1.

In another preference, described reaction is carried out under acid binding agent exists; Preferably, described acid binding agent is selected from lower group: pyridine, p dimethylamino pyridine, triethylamine or diisopropyl ethyl amine, Na ₂cO ₃, NaHCO ₃, K ₂cO ₃, KHCO ₃, NaOH, KOH, or its combination; More preferably, described acid binding agent is sodium bicarbonate.

In another preference, the temperature of reaction of described reaction is-10 DEG C to 20 DEG C, is preferably 0 DEG C.

In another preference, described formula II compound and the mol ratio of formula I are formula II compound: formula I=0.95 ~ 1.1:1.

In another preference, described step (a) comprises sub-step:

(a1) with formula II compound and oxalyl chloride, sulfur oxychloride and/or phosphorus oxychloride reaction, the formula II compound of chloride is obtained;

(a2) use the formula II compound of chloride and formula I to react, obtain formula III compound.

In another preference, described step (a1) is carried out in methylene dichloride.

In another preference, described step (a2) is carried out in tetrahydrofuran (THF)/aqueous solution.

In another preference, described step (a2) is carried out under acid binding agent exists; Preferably, described acid binding agent is sodium bicarbonate.

In another preference, above-mentioned various in, represent S configuration.

A ninth aspect of the present invention, provides and a kind ofly has with the compound of structure shown in following formula A2:

Wherein, R ₃, R ₄, R ₅, R ₆, R ₇, R ₇' be selected from lower group: H independently of one another, the alkyl-oxygen base of halogen, the alkyl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10, the heteroaryl-oxygen base of the aryl of substituted or unsubstituted C6-C10, the aryl of substituted or unsubstituted C6-C10-oxygen base, the heteroaryl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10;

And R ₃be not H;

And R ₄it is not methoxyl group;

A tenth aspect of the present invention, provide a kind of preparation method of formula A compound, described method comprises step:

In inert solvent, react with formula A2 compound and formula A1 compound, obtain formula A compound;

Wherein, the definition of each group is as noted before.

In another preference, described reaction is carried out under condensing agent exists; Preferably, described condensing agent is selected from lower group: oxalyl chloride, sulfur oxychloride, phosphorus oxychloride, DCC, EDCI, HATU, HOBT, or its combination.

In another preference, described reaction comprises the following steps:

I (), in inert solvent, is reacted with formula A2 compound and chloride reagent, is obtained formula A2a compound;

(ii) in inert solvent, formula A2a compound and formula A1 compound are reacted, obtains formula A compound.

Wherein, described chloride reagent is selected from lower group: oxalyl chloride, sulfur oxychloride, phosphorus oxychloride, or its combination.

In another preference, the productive rate of described method is >=70%, is preferably >=80%, is more preferably >=90%.

Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and can combining mutually between specifically described each technical characteristic in below (eg embodiment), thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.

Embodiment

The present inventor, through long-term and deep research, is surprised to find that, the B-N cyclisation/sodium borohydride reduction method of being induced by chiral source, can build the synthetic intermediate that a class can be used in preparing optical purity Stopholidine or derivatives thereof.By above-mentioned synthetic intermediate, can prepare optical purity Stopholidine by highly selective, and syntheti c route is short, yield is high.Based on above-mentioned discovery, contriver completes the present invention.

Term

Unless stated otherwise, in the present invention, term " replacement " refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: C1 ~ C10 alkyl, C3 ~ C10 cycloalkyl, C1 ~ C10 alkoxyl group, halogen, hydroxyl, carboxyl (-COOH), C1 ~ C10 aldehyde radical, C2 ~ C10 acyl group, C2 ~ C10 ester group, amino, phenyl; Described phenyl comprises unsubstituted phenyl or has 1-3 substituent substituted-phenyl, and described substituting group is selected from: halogen, C1-C10 alkyl, cyano group, OH, nitro, C3 ~ C10 cycloalkyl, C1 ~ C10 alkoxyl group, amino.

Term " C1 ~ C10 alkyl " refers to the straight or branched alkyl with 1 ~ 10 carbon atom, such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl or similar group.

Term " C3 ~ C10 cycloalkyl " refers to the cycloalkyl with 3 ~ 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, suberyl or similar group.

Term " C2 ~ C10 thiazolinyl " refers to the thiazolinyl with 1 ~ 10 carbon atom, such as vinyl, propenyl, pseudoallyl, butenyl, isobutenyl, secondary butenyl, tertiary butenyl or similar group.

Term " C2 ~ C10 alkynyl " refers to the alkynyl with 1 ~ 10 carbon atom, such as ethynyl, proyl, isopropynyl, butynyl, butynyl, secondary butynyl, tertiary butynyl or similar group.

Term " C6 ~ C10 aryl " refers to the aryl with 6 ~ 10 carbon atoms, comprises monocycle or aryl bicyclic, such as phenyl, naphthyl, or similar group.

Term " C1 ~ C10 heteroaryl " refers to the heteroaryl with 1 ~ 10 carbon atom, such as pyrryl, pyridyl, furyl, or similar group.

Term " C1 ~ C10 alkoxyl group " refers to the straight or branched alkoxyl group with 1-10 carbon atom, such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy or similar group.

Term " C6 ~ C10 aryl-oxygen base " refers to the straight or branched aryl-oxygen base with 6-10 carbon atom, such as phenyl-oxygen base, naphthyl-oxygen base, or similar group.

Term " C1 ~ C10 heteroaryl-oxygen base " refers to the straight or branched heteroaryl-oxygen base with 1-10 carbon atom, such as pyridyl-oxygen base, furyl-oxygen base, or similar group.

Term " C1 ~ C10 acyl group " refers to have "-CO-alkyl " structure; preferably there is the group of "-CO-C1 ~ C10 alkyl " structure, such as methylacyl, ethyl acyl group, Acryl, sec.-propyl acyl group, butyl acyl group, isobutyl-acyl group, sec-butyl acyl group, tertiary butyl acyl group or similar group.

Term " C1 ~ C10 ester group " refers to have alkyl-COO-structure, preferably has the group of C1 ~ C10 alkyl-COO-structure, such as CH ₃cOO-, C ₂h ₅cOO-, C ₃h ₈cOO-: (CH ₃) ₂cHCOO-, nC ₄h ₉cOO-, tC ₄h ₉cOO-, or similar group.

Term " C1 ~ C10 alkylsulfonyl " refers to have "-SO ₂-alkyl " structure, preferably there is "-SO ₂-C1 ~ C10 alkyl " group of structure, such as methyl sulphonyl, ethylsulfonyl, sulfonyl propyl base, isopropelsulfonyl, butyl alkylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert. butylsulfonyl or similar group.

Term " C1 ~ C20 Heterocyclylalkyl " refers to the Heterocyclylalkyl with 1 ~ 20 carbon atom, as epoxy ethyl, tetrahydrofuran base, Pyrrolidine base, or similar group.

Term " carboxylic acid ester groups of C2 ~ C10 " refers to that the shape with 2-10 carbon atom is as the group of "-COO-C1-C9 alkyl " structure, such as CH ₃cOO-, C ₂h ₅cOO-, C ₃h ₈cOO-: (CH ₃) ₂cHCOO-, nC ₄h ₉cOO-, tC ₄h ₉cOO-, or similar group.

Term " halogen " refers to F, Cl, Br and I.

Term " Bischler-Napieralski ring-closure reaction ", " B-N ring-closure reaction " or " B-N cyclization " are used interchangeably.

Formula A compound and uses thereof

The invention provides the acid amides that 2, a kind of C ring is brominated, the structure of described compound is such as formula shown in A:

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

R ₈be selected from lower group:

R ₁₁for H;

Y is Br;

In another preference, described R ₄it is not methoxyl group.

Described formula A compound can be used for preparing the compound had as shown in the formula structure shown in B:

Wherein, Y is Br, and the definition of all the other each groups is the same.

Wherein, the method for compound shown in described use formula A preparation of compounds of formula B, comprises step: by B-N cyclisation/sodium borohydride reduction reaction, obtain formula B compound.Particularly, described reaction conditions comprises:

Described method can be undertaken by a step, but in the present invention under a kind of possible mechanism, described method comprises step:

Described intermediate A 3 can not be separated to be directly used in carries out next step reaction, also can be separated thus carry out subsequent step.In another preference, described reaction comprises step:

Described formula B compound can carry out other reactions as intermediate, especially, can carry out 9,10 and replace, thus build the skeleton of SPD molecule, prepare Stopholidine and derivative thereof.

Formula B compound and uses thereof

Present invention also offers a kind of such as formula the compound shown in B:

R ₃, R ₄, R ₅, R ₆, R ₇, R ₉, R ₉', R ₁₀, R ₁₀', R ₁₂, R ₁₃, R ₁₄, R ₁₅be selected from lower group: H independently of one another, the alkyl-oxygen base of halogen, the alkyl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10, the heteroaryl-oxygen base of the aryl of substituted or unsubstituted C6-C10, the aryl of substituted or unsubstituted C6-C10-oxygen base, the heteroaryl of substituted or unsubstituted C1-C10, substituted or unsubstituted C1-C10; And R ₃be not H;

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

Wherein, described replacement refers to that the one or more hydrogen atoms on group are selected from the substituting group replacement of lower group: the alkyl-amino of the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, substituted or unsubstituted C1-C10, substituted or unsubstituted C6-C10 aryl, benzyl amine, have 1-3 substituent phenyl, described substituting group is selected from lower group: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base;

R ₈be selected from lower group:

Described various B compound can be changed mutually, and described conversion (namely replacing bromine atoms with the carboxylic acid ester groups of C2-C10) can be undertaken by the method for some this area routines.Especially, a kind of preferred Y is that to prepare Y be the mode of the formula B compound of the carboxylic acid ester groups of C2-C10 is for the formula B compound of bromine atoms: with formula B compound and shape, the compound as " carboxylic acid ester groups-X of C2-C10 " reacts, and obtains formula B2 compound.Wherein, X is selected from lower group: the alkyl-oxygen base of Cl, Br, C1-C3.

May be used for such as formula the compound shown in B the molecule of the skeleton constructing Stopholidine or derivatives thereof, described molecule of the skeleton has as shown in the formula structure shown in M:

Wherein, the definition of each group as previously mentioned.

Shown in a kind of preferred preparation formula M, the method for compound comprises step:

Wherein, Y is selected from lower group: the carboxylic acid ester groups of Br, C2-C10; The definition of all the other each groups as described above.

In another preference, described catalytic hydrogenation is carried out under palladium hydroxide/carbon reagent exists.

In another preference, described catalytic hydrogenation is carried out in presence of an acid; Preferably, described acid is concentrated hydrochloric acid.

In another preference, described inert solvent is polar protic or aprotic solvent; Preferably, described solvent is ethanol.

Described formula M compound, through a series of modification, can prepare Stopholidine derivative.A kind of preferred modification mode comprises: remove ketone carbonyl by reductive agent effect.

Optical purity Stopholidine and preparation thereof

As used herein, term " Stopholidine ", " stepholidine " or " SPD " are used interchangeably, and all refer to the compound with following structure:

Wherein, represent R configuration or S configuration.

The preferred Stopholidine of one class is l-spd (L-stepholidine, L-SPD), and it has the structure be shown below:

The invention provides a kind of optical purity Stopholidine preparation method, a feature of described method is that the B-N cyclisation/sodium borohydride reduction of being induced by chiral source builds chiral carbon configuration, another feature is then exchanged by bromo-lithium to introduce 9,10 substitute modes that carboxyl ester constructs target molecule.

Particularly, described preparation process is realized by midbody compound II ~ VI.

Preparation in accordance with the present invention adopts the adjacent bromo-acid compounds shown in the Methylphenethylamine compounds shown in following general formula I and general formula I I to be raw material, the S-Methylphenethylamine compounds wherein shown in general formula I:

Wherein, R ₁be selected from lower group: the alkyl of substituted or unsubstituted C1-C10; Wherein, described replacement refers to that the substituting group that the one or more hydrogen atoms on group are selected from lower group replaces: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, have 1-3 substituent phenyl, and described substituting group is selected from lower group: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base; Preferably, described R ¹for sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyls, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl; And in Methylphenethylamine class formation, the chirality of methyl can be S type or R type, wavy line represent that this chemical bond can be solid line or dotted line;

Adjacent bromo-acid compounds shown in general formula I I:

Wherein, R ₂be selected from lower group: the alkyl of substituted or unsubstituted C1-C10; Wherein, described replacement refers to that the substituting group that the one or more hydrogen atoms on group are selected from lower group replaces: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base, have 1-3 substituent phenyl, and described substituting group is selected from lower group: the alkyl of halogen, substituted or unsubstituted C1-C10, the alkyl of substituted or unsubstituted C1-C10-oxygen base; Preferably, described R ²for sec.-propyl, benzyl, 4-methoxy-benzyl, 3,4-dimethoxy-benzyls, methoxymethyl or benzyloxymethyl, and preferred sec.-propyl;

The preparation method of described Stopholidine or derivatives thereof optical isomer specifically comprises the steps:

Step 1: the adjacent bromo-acid compounds shown in general formula I I prepares acyl chlorides in the effect of oxalyl chloride or sulfur oxychloride, then acylation reaction is carried out with the Methylphenethylamine compounds of the S configuration shown in general formula I, obtain the compound III of S configuration, or carry out acylation reaction with the Methylphenethylamine compounds of the R configuration shown in general formula I, obtain the compound III of R configuration;

Its reaction formula is as follows:

Step 2: step 1 obtains the compound of S configuration by B-N cyclisation/sodium borohydride reduction, obtain the compound of the S configuration shown in general formula I V, or step 1 obtains the compound III of R configuration by B-N cyclisation/sodium borohydride reduction, obtains the compound of the R configuration shown in general formula I V;

Its reaction formula is as follows:

Step 3: the compound of the S configuration shown in general formula I V carries out bromo-lithium exchange under the alkali effects such as n-Butyl Lithium, methyl-chloroformate or methylcarbonate cancellation subsequently, obtain the methyl benzoate compounds V of the S configuration shown in general formula V, or the compound of the R configuration shown in general formula I V carries out bromo-lithium exchange under the alkali effects such as n-Butyl Lithium, methyl-chloroformate or methylcarbonate cancellation subsequently, obtain the methyl benzoate compounds V of the S configuration shown in general formula V, obtain the methyl benzoate compounds V of the R configuration shown in general formula V;

Its reaction formula is as follows:

Step 4: the methyl benzoate compounds V catalytic hydrogenation of the S configuration that step 3 is obtained sloughs chiral auxiliary, and the compound of the further cyclisation of intramolecular transesterification reaction for the S configuration shown in general formula VI occurs simultaneously; Or the methyl benzoate compounds V catalytic hydrogenation of R configuration sloughs chiral auxiliary, and the compound of the further cyclisation of intramolecular transesterification reaction for the R configuration shown in general formula VI occurs simultaneously,

Its reaction formula is as follows:

Step 5: the compound of the S configuration shown in general formula VI that step 4 is obtained is reduced to the compound of the S configuration shown in general formula VII under reductive agent effect, or the compound of the R configuration shown in general formula VI that step 4 is obtained is reduced to the compound of the R configuration shown in general formula VII under reductive agent effect;

Its reaction formula is as follows:

Step 6: the compound of the S configuration shown in general formula VII removes R ¹, R ², obtain l-spd, or the compound of the R configuration shown in general formula VII removes R ¹, R ², obtain dextrorotation Stopholidine;

Its reaction formula is as follows:

Synthetic method of the present invention is more specifically described below:

In step 1, preferably:

Described acyl chlorides can be oxalyl chloride, sulfur oxychloride, phosphorus oxychloride etc., and preferred oxalyl chloride; The consumption of acyl chlorides is 1 to 10 equivalents relative to the adjacent bromo-acid compounds shown in general formula I I;

Acylation reaction solvent for use is the mixed solvent of tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether and water, or also can be pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc.;

The acid binding agent reacting used is pyridine, p dimethylamino pyridine, triethylamine or diisopropyl ethyl amine, Na ₂cO ₃, NaHCO ₃, K ₂cO ₃, KHCO ₃, NaOH, KOH etc.; And preferred reaction solvent is the mixed solvent of tetrahydrofuran (THF) and water, blending ratio is 1:0 to 1:10, and preferably blending ratio is 1:1; Acid binding agent is NaHCO ₃;

Temperature of reaction is-10 DEG C to 20 DEG C, and preferable reaction temperature is 0 DEG C.

The consumption of the adjacent bromo-acid compounds shown in general formula I I is 0.95 to 1.1 equivalent relative to the Methylphenethylamine compounds shown in general formula I.

In step 2, preferably:

B-N cyclization with benzene, toluene, acetonitriles etc. are solvent, and be preferably acetonitrile;

The acid that Guan Huan adopts is POCl ₃, P ₂o ₅, PPAT, FAA etc., and preferred POCl ₃;

In a preference, the consumption of sodium borohydride is 1 to 20 equivalents relative to the amides shown in general formula I; And preferred 3 times amount;

In another preference, the consumption of sodium borohydride is 1 to 8 equivalents relative to the amides shown in general formula I, and preferred 5 times amount;

Temperature of reaction be 40 DEG C to solvent reflux temperature, the reaction times is 1 to 24 hour;

Close the reduction of ring product with methyl alcohol, ethanol, Virahol etc. are solvent, and particular methanol is solvent;

NaBH ₄reduction reaction temperature is-80 DEG C to-40 DEG C.

In another preference, described step 2 can also carry out recrystallization to described product after terminating.The recrystallization solvent of reduzate can be sherwood oil, toluene, benzene, normal hexane, normal heptane etc., and preferably sherwood oil is recrystallization solvent.

In step 3, preferably:

Reaction solvent is tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether or methyl tertiary butyl ether ethanol, glycol dimethyl ether or diethylene glycol dimethyl ether etc., and preferred tetrahydrofuran (THF);

The alkali reacting used is n-Butyl Lithium or s-butyl lithium, and preferred n-Butyl Lithium;

The consumption of described alkali is 1 to 3 equivalents relative to the bromobenzene compounds shown in general formula I V, and preferred 1.1 times amount;

Temperature of reaction is-80 DEG C to-20 DEG C;

The time of the bromobenzene compounds shown in general formula I V and alkali effect is 10 to 120 minutes;

Cancellation adopts methyl-chloroformate or methylcarbonate; Methyl-chloroformate or methylcarbonate are 1.0 to 1.5 equivalents relative to the bromobenzene compounds shown in general formula I V, and adding the reaction times after methyl-chloroformate is 1h to 3h.

In step 4, preferably:

The methyl benzoate compounds of the S configuration shown in general formula V removes chiral auxiliary, react with methyl alcohol, ethanol, tetrahydrofuran (THF), water or their mixture for solvent, add the racemization that the acetic acid of 2-4 times amount, trifluoracetic acid, hydrochloric acid etc. suppress chirality, with palladium carbon, palladium hydroxide/carbon etc. for catalyzer, with hydrogen, formic acid or tetrahydrobenzene etc. for hydrogen donor removes.

Temperature of reaction is 20 DEG C to 50 DEG C, and the reaction times is 1 to 24 hour.

In steps of 5, preferably:

Reaction make solvent with tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc., with lithium aluminium hydride, borane complexes, POTASSIUM BOROHYDRIDE or sodium borohydride etc. for reductive agent, temperature of reaction be-20 DEG C to solvent refluxing, the reaction times is 1 to 24 hour;

In step 6, preferably, according to R ¹, R ²difference choose appropriate means and remove.

Such as, R is worked as ¹=R ²during=sec.-propyl, with methylene dichloride, chloroform, tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc. for reaction solvent, preferred methylene dichloride; Compound shown in general formula VII and boron trichloride or aluminum chloride react and remove sec.-propyl; Temperature of reaction be-80 DEG C to room temperature, the reaction times is 1 to 24 hour.

Work as R ¹=R ²during=benzyl, react with methyl alcohol, ethanol, tetrahydrofuran (THF), water or their mixture for solvent, with palladium carbon, palladium hydroxide/carbon etc. for catalyzer, with hydrogen, formic acid or tetrahydrobenzene etc. for hydrogen donor removes; Or be solvent with hydrochloric acid, reflux removes; Or the compound shown in general formula VII and boron trichloride or aluminum chloride react, with methylene dichloride, chloroform etc. for solvent, remove at-80 DEG C of temperature to room temperature.

The preparation of formula I and formula II compound

In embodiments of the present invention, the adjacent bromo-acid compounds shown in formula II can be buied by commercially available approach, or is prepared by methods known in the art.The preparation method of the adjacent bromo-acid compounds shown in the Methylphenethylamine compounds shown in a kind of preferred formula I and formula II is as follows respectively:

(1) the Methylphenethylamine compounds shown in general formula I can be prepared by method below:

Wherein, R ¹definition is the same;

Step I: under acyl chlorides effect, toluylic acid a1 is prepared as corresponding phenyllacetyl chloride, carries out acylation reaction with Methylphenethylamine, obtains acid amides b1; Wherein, this reaction solvent for use is the mixed solvent of tetrahydrofuran (THF), methyl tertiary butyl ether, glycol dimethyl ether and water or also can is pyridine, methylene dichloride, chloroform, tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc., the acid binding agent reacting used is pyridine, p dimethylamino pyridine, triethylamine or diisopropyl ethyl amine, Na ₂cO ₃, NaHCO ₃, K ₂cO ₃, KHCO ₃, NaOH, KOH etc.; Temperature of reaction is-10 DEG C to 40 DEG C, and the reaction times is 4 to 12 hours;

Step I i: acid amides b1 borane reduction, obtains the Methylphenethylamine shown in general formula I; Wherein, this reaction solvent for use is tetrahydrofuran (THF), ether or methyl tertiary butyl ether etc., and the consumption of borine is 2 to 4 equivalents relative to acid amides b1, and temperature of reaction is 80 DEG C, and the reaction times is 6 to 14 hours;

(2) the adjacent bromo-acid compounds shown in general formula I I can be prepared by method below:

Wherein, R ²definition the same;

Step I: 3,4-Dihydroxy benzaldehyde is raw material, the protection of phenolic hydroxyl group selectivity sec.-propyl is phenyl aldehyde b, and this reaction take DMF as solvent, and with salt of wormwood, sodium carbonate is alkali, temperature of reaction 50 DEG C to 70 DEG C, and the reaction times is 6 to 10 hours;

Step I i: phenyl aldehyde b by bromo-reaction, and selectivity obtains the compound c of o-brominated, and this reaction take Glacial acetic acid as solvent, and under the iron powder condition of catalytic amount, take bromine as brominated reagent, temperature of reaction is-5 DEG C to 35 DEG C, and the reaction times is 2 to 6 hours;

Step I ii: compound c carries out phenolic hydroxyl group methylates, and obtains compound benzaldehyde compound d.In acetone, tetrahydrofuran (THF) or N,N-dimethylacetamide equal solvent, under the alkali such as salt of wormwood, sodium carbonate exists, compound c and methyl-sulfate chlorine or iodomethane reaction, obtain aldehyde compound d;

Step I v: aldehyde radical d, by reduction reaction, is reduced to benzylalcohol e; Wherein, this reduction reaction with methyl alcohol, ethanol, tetrahydrofuran (THF) for solvent, with sodium borohydride or POTASSIUM BOROHYDRIDE etc. for catalyzer, temperature of reaction be 0 DEG C to room temperature, the reaction times is 1 to 8 hour;

Step v: benzylalcohol e, by chlorination, is converted into benzyl chlorine f.Halogenating reaction carries out in inert solvent, can select methylene dichloride, chloroform, benzene, toluene, ether, tetrahydrofuran (THF), dioxane etc., preferred methylene dichloride, chloroform.Chlorinating agent can select thionyl chloride, phosphorus pentachloride, trimethylchlorosilane, N-chlorosuccinimide, tetracol phenixin/triphenylphosphine etc., preferred thionyl chloride, phosphorus pentachloride.Temperature of reaction be-40 DEG C to room temperature.Reaction times is 4 to 16 hours.

Step vi: benzyl chlorine f, by cyano group substitution reaction, obtains cyano compound g.Halogen replaces generation reaction to carry out in polar aprotic solvent, and can select DMF, methyl-sulphoxide etc., cyano group reagent can select sodium cyanide, third level natural division, potassium cyanide etc.Temperature of reaction is for being room temperature.Reaction times is 6 to 12 hours.

Step vii: cyano compound g by macromolecule alkali for hydrolysis, and acidifying obtains the adjacent bromo-acid compounds shown in general formula I I then.This hydrolysis reaction solvent for use is methyl alcohol, ethanol, water or their mixture, and described alkali is sodium hydroxide, potassium hydroxide, reacts for solvent reflux temperature, and the reaction times is 10 to 24 hours; Described acid is hydrochloric acid or sulfuric acid etc.

Major advantage of the present invention:

B-N cyclisation/the sodium borohydride reduction being chiral source induction by Methylphenethylamine builds chiral carbon configuration, and follow-up phase is exchanged by bromo-lithium and introduces 9,10 substitute modes that carboxyl ester constructs target molecule.

Method provided by the invention can synthesize the optical isomer of Stopholidine or derivatives thereof.Utilize the Methylphenethylamine of S or R configuration for chiral source respectively, available consistent reaction scheme and working method prepare the optical isomer of the Stopholidine or derivatives thereof of left-handed or dextrorotation respectively.

It is pointed out that the brominated acid amides of 2, Late Cambrian C ring can obtain B-N cyclisation/sodium borohydride reduction product that Methylphenethylamine be chiral source induction by high yield.Simultaneously adopt bromo-lithium to exchange successfully to construct 9,10 substitute modes of target molecule first.Adjacent bromo-acid shown in Methylphenethylamine shown in midbody acid amide B, general formula I, phenyl aldehyde b, bromo-derivative c, general formula I I, the compound shown in general formula I V, the compound shown in general formula VI can pass through recrystallization purifying.And the operation involved by route is simple, yield is higher, reagent is cheap, the Methylphenethylamine compounds shown in general formula I; particularly correspond to 9; adjacent bromo-acid compounds shown in the general formula I I of 10 substitute modes easily amplifies, and these are characterized as mass-producing and prepare optically pure Stopholidine or derivatives thereof and paved road.

Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number calculate by weight.

Illustrate the present invention with L-SPD (in general formula A R=H), embodiment is as described below.But need to understand, those skilled in the art can prepare R-SPD (only needing the chiral auxiliary configuration changing the first step can obtain the final product of respective configuration) by same method, or preparation SPD derivative, such change can be obtained in conjunction with prior art according to content disclosed by the invention apparently by those skilled in the art.

In all embodiments, fusing point all uses MEL-TEMP melting point apparatus to measure, and thermometer is not calibrated; ¹h-NMR uses VarianMercuryPlus300MHz nmr determination, ¹³c-NMR uses VarianMercuryPlus400MHz nmr determination, and chemical shift represents with δ (ppm); EI uses FinniganMAT95 mass spectrograph to measure, and ESI uses KratosMS80 mass spectrograph to measure; Separation silica gel is 200 ~ 300 orders.

Route 1

Preparation R ¹the compound of Formula I (i.e. compound 3) of=sec.-propyl, route is as follows:

The preparation of embodiment 1 compound 2

Toluylic acid 1 (41.5g, 185.3mmol) is dissolved in dry methylene chloride (200ml), adds DMF (1ml), is cooled to 0 DEG C.Then, drip oxalyl chloride (35.0ml, 369.5mmol), continue stirring reaction 4 hours.Be cooled to room temperature, decompression steams methylene dichloride and oxalyl chloride, and it is for subsequent use that resistates is dissolved in methyl tertiary butyl ether (100ml).(S)-a-Methylphenethylamine (25.8ml, 200.4mmol) be dissolved in methyl tertiary butyl ether (200ml), add water (100ml), add sodium bicarbonate 31.1g, frozen water cools, drip the ethereal solution of above-mentioned acyl chlorides, drip complete stirring 2 hours.Add sherwood oil (200ml), filter after stirring, the washing of gained solid, sherwood oil are washed, are dried, and obtain white solid 57.6g, yield 95%.Mp107-108 DEG C; [α] ²⁰ _d+ 14.7 (c0.15, CH ₂cl ₂); ¹hNMR (400MHz, CDCl ₃): δ 7.34 – 7.29 (m, 2H), 7.27 – 7.19 (m, 3H), 6.89 (d, J=8.7Hz, 1H), 6.76 (dd, J=6.1,2.1Hz, 2H), 5.66 (d, J=8.5Hz, 1H), 5.15 (p, J=7.0Hz, 1H), 4.53 (p, J=6.1Hz, 1H), 3.83 (s, 3H), 3.54 (s, 2H), (1.42 d, J=6.9Hz, 3H), (1.39 d, J=6.1Hz, 6H); ¹³cNMR (125MHz, CDCl ₃): δ 170.34,150.71,146.56,143.12,128.60,127.73,127.28,125.91,121.55,116.18,112.99,71.53,55.93,48.65,43.52,22.08,21.83; HRMS (ESI): theoretical value C ₂₀h ₂₅nO ₃[M+Na] ⁺350.1732; Experimental value 350.1732.

Embodiment 2 compound 2 is reduced to amine 3

Under nitrogen protection, raw material acid amides 2 (32.0g, 97.8mmol) is dissolved in anhydrous THF (300mL), adds BF ₃-Et ₂o (3.0mL), BH ₃-CH ₃sCH ₃(2MinTHF, 132mL), return stirring 8 hours.Cooling reaction solution, careful dropping 10% hydrochloric acid (100mL), refluxes 10 minutes, is cooled to room temperature, remove THF under reduced pressure, remaining aqueous phase alkalizes with 10% sodium hydroxide, dichloromethane extraction, and extraction liquid merges, saturated common salt is washed, anhydrous sodium sulfate drying, concentrates to obtain oily matter 30.0g, yield 98%.Be directly used in next step reaction.[α] ²⁰ _d-38.3 (c0.52, CH ₂cl ₂); ¹hNMR (400MHz, CDCl ₃): δ 7.36 – 7.29 (m, 2H), 7.29 – 7.22 (m, 3H), 6.83 (d, J=8.7Hz, 1H), 6.69 (d, J=6.5Hz, 2H), 4.49 (p, J=6.1Hz, 1H), 3.83 (s, 3H), 3.79 (d, J=6.7Hz, 1H), 2.74 (qt, J=4.6,9.60Hz, 4H), 1.37 (d, J=6.1Hz, 6H), 1.35 (d, J=6.7Hz, 3H). ¹³cNMR (125MHz, CDCl ₃): δ 150.36,145.59,133.15,128.39,126.86,126.53,120.61,116.19,112.58,71.56,58.22,55.90,48.92,35.95,24.33,22.16.HRMS (ESI): theoretical value C ₂₀h ₂₇nO ₂[M+H] ⁺314.2120; Experimental value 314.2113.

Route 2

Preparation R ²adjacent bromo-acid compounds shown in the general formula I I of=sec.-propyl (i.e. compound 11)

Synthetic route is as follows:

The preparation of the bromo-3-hydroxyl of embodiment 32--4-isopropoxide benzaldehyde (compound 6)

Under nitrogen protection; 3; 4-dihydroxyl benzaldehyde 4 (100.0g, 725mmol), potassiumiodide (5.0g, 30mmol) are dissolved in DMF (600mL); add Anhydrous potassium carbonate (100.0g; 725mmol), be heated to 40 DEG C, drip bromo propane (87.0ml; 944.8mmol), this temperature stirring reaction is kept 12 hours.Then, be cooled to room temperature, filter, filter cake washs with ethyl acetate (300mL), concentrating under reduced pressure.Resistates dissolves with 10%NaOH, petroleum ether extraction three times, remaining alkali lye, and frozen water cools, concentrated hydrochloric acid acidifying, extraction into ethyl acetate, and extraction liquid merges, and saturated common salt is washed, concentrating under reduced pressure.Resistates methyl alcohol: water recrystallization obtains white crystal 5,98.0g, yield 75%.

3-hydroxyl-4-isopropoxide benzaldehyde 5 (50g, 277.7mmol) be dissolved in glacial acetic acid (300ml), under high degree of agitation, add sodium acetate (45.30g, 556.7mol), iron powder (2.0g, 35.7mmol), be cooled to-5 DEG C, drip glacial acetic acid (80ml) solution of bromine (15.0ml, 291.7mmol), finish and continue reaction 6 hours.After having reacted, by slow for reaction suspension impouring mixture of ice and water (2.5L), leave standstill 1 hour.Filter, filter cake is with frozen water (3 × 200mL) washing, and vacuum-drying obtains compound as white solid 6,71.7g, yield 100.0%.Mp114-115 DEG C; ¹hNMR (300MHz, CDCl ₃) δ=10.26 (s, 1H), 7.55 (d, J=8.6Hz, 1H), 6.90 (d, J=8.6Hz, 1H), 6.15 (s, 1H), 4.75 (p, J=6.1Hz, 1H), 1.43 (d, J=6.1Hz, 6H). ¹³cNMR (125MHz, CDCl ₃): δ 190.97,149.98,143.85,126.93,122.45,112.95,110.85,72.67,21.99.HRMS (EI): theoretical value C ₁₀h ₁₁brO ₃[M] ⁺257.9892; Experimental value 257.9892.

The methyl-etherified of the bromo-3-hydroxyl of embodiment 42--4-isopropoxide benzaldehyde (compound 6), to prepare compound 7

2-bromo-3-hydroxyl-4-isopropoxide benzaldehyde (88.0g, 340.6mmol) is dissolved in DMF (350ml), adds Anhydrous potassium carbonate (62.0g, 443.4mmol), methyl iodide (25.0ml, 392.2mmol), 40 DEG C of stirring reactions 8 hours.Be cooled to room temperature, filter, filter cake ethyl acetate (600ml) is washed, and filtrate decompression reclaims DMF. gained resistates washing acetic acid ethyl dissolution, washing, saturated common salt is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure obtains oily matter, and flash column chromatography obtains yellow oily compounds 7,91.0g, yield 98%.Be directly used in next step reaction.Mp36-37 DEG C, ¹hNMR (400MHz, CDCl ₃) δ 10.27 (s, 1H), 7.73 (d, J=8.7Hz, 1H), 6.96 (d, J=8.7Hz, 1H), 4.84 – 4.53 (m, 1H), 3.90 (s, 3H), 1.44 (d, J=6.1Hz, 6H). ¹³cNMR (125MHz, CDCl ₃): δ 190.98,157.12,147.00,127.01,126.21,123.43,112.90,71.70,60.44,21.94.HRMS (EI): theoretical value C ₁₁h ₁₃brO ₃[M] ⁺272.0048; Experimental value 272.0042.

Embodiment 5 compound 7 aldehyde radical is reduced to methylol 8

Compound 7 (90.5g, 332.7mmol) is dissolved in anhydrous methanol (500mL), and ice bath cools, and stirs and adds sodium borohydride (16.0g, 421mmol) in a moment, stirring at room temperature 6 hours in batches.Reclaim under reduced pressure methyl alcohol, resistates is dissolved in extraction into ethyl acetate (500mL), washing, and saturated common salt is washed, and dried over sodium sulfate, concentrating under reduced pressure obtains colorless oil compounds 8,92.5g, yield 100%.Be directly used in next step reaction.

¹hNMR (300MHz, CDCl ₃): δ 7.10 (d, J=8.4Hz, 1H), 6.84 (d, J=8.4Hz, 1H), 4.63 (s, 2H), 4.52 (p, J=6.1Hz, 1H), 3.83 (s, 3H), 1.33 (d, J=6.1Hz, 6H). ¹³cNMR (100MHz, CDCl ₃): δ 153.02,149.47,134.93,125.88,120.39,116.70,73.51,66.82,62.24,23.97.HRMS (EI): theoretical value C ₁₁h ₁₃brO ₃[M] ⁺274.0205; Experimental value 272.0203.

Embodiment 6 compound 8 is converted into benzyl chlorine compound 9

Compound 8 (92.0g, 332.7mmol) be dissolved in anhydrous methylene chloride (500mL), ice bath cools, drip sulfur oxychloride (48mL, 672.8mmol), stirring at room temperature is risen to 6 hours, after having reacted, by in slow for reaction solution impouring mixture of ice and water (2L), and stir 3 hours.Separate dichloromethane layer, ice bath cools, and carefully add saturated sodium bicarbonate (500mL), stirring is spent the night.Separate dichloromethane layer, saturated sodium bicarbonate is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, concentrating under reduced pressure obtains pale yellow oil compound 9,92.2g, yield 94%.

¹hNMR (400MHz, CDCl ₃) δ 7.18 (d, J=8.5Hz, 1H), 6.88 (d, J=8.5Hz, 1H), 4.72 (s, 2H), 4.59 (p, J=6.2Hz, 1H), 3.88 (s, 3H), 1.39 (d, J=6.1Hz, 6H). ¹³cNMR (125MHz, CDCl ₃): δ 152.01,147.90,129.59,125.88,120.32,114.38,71.57,60.33,46.72,22.06.HRMS (EI): theoretical value C ₁₁h ₁₄br _clo ₂[M] ⁺291.9866; Experimental value 291.9875.

The replacement of embodiment 7 compound 9 turns to cyano compound 10

Benzyl chlorine compound 9 (92.0g, 315.6mmol) is dissolved in dry DMF (500mL), carefully adds sodium cyanide (27.0g, 551.0mmol), stirred overnight at room temperature.Then, careful reclaim under reduced pressure DMF, resistates is with acetic acid ethyl dissolution, and saturated sodium bicarbonate is washed, washing, and saturated common salt is washed, and anhydrous sodium sulfate drying, concentrating under reduced pressure obtains sticky oil compounds 10,90.0g, yield 100%.

¹hNMR (400MHz, CDCl ₃) δ=7.17 (d, J=8.5Hz, 1H), 6.88 (d, J=8.6Hz, 1H), 4.56 (p, J=6.1Hz, 1H), 3.85 (s, 3H), 3.78 (s, 2H), 1.36 (d, J=6.1Hz, 6H). ¹³cNMR (100MHz, CDCl ₃): δ 153.52,150.05,126.23,124.45,121.47,119.26,116.66,73.56,62.29,26.44,23.92.HRMS (EI): theoretical value C ₁₂h ₁₄brNO ₂[M] ⁺283.0208; Experimental value 283.0207.

The hydrolysis of the bromo-3-methoxyl group of embodiment 82--4-isopropoxy phenethyl cyanogen (compound 10), to prepare compound 11

2-bromo-3-methoxyl group-4-isopropoxy phenethyl cyanogen (79g, 279.2mmol) is dissolved in ethanol (500mL), adds 25% potassium hydroxide (200mL), return stirring 12 hours.Be down to room temperature, decompression recycling ethanol, remaining aqueous solution thing is with petroleum ether extraction, and water layer ice bath cools, concentrated hydrochloric acid acidifying, extraction into ethyl acetate, washing, saturated common salt is washed, anhydrous sodium sulfate drying, white solid 11,80.0g is obtained, yield 95% with petrol ether/ethyl acetate (9:1) recrystallization after concentrating under reduced pressure.

Mp106 DEG C. ¹hNMR (400MHz, CDCl ₃): δ 7.00 (d, J=8.5Hz, 1H), 6.86 (d, J=8.5Hz, 1H), 4.56 (p, J=6.1Hz, 1H), 3.88 (s, 3H), 3.81 (s, 2H), 1.38 (d, J=6.1Hz, 6H); ¹³cNMR (125MHz, CDCl ₃): δ 176.50,151.09,147.85,126.55,126.05,120.99,114.63,71.62,60.30,40.94,22.12.HRMS (EI): theoretical value C ₁₂h ₁₅brO ₄[M] ⁺302.0154; Experimental value 302.0129.

Route 3:

With compound 3 and compound 11 for L-SPD prepared by raw material, route is as follows:

Embodiment 9 prepares compound 12

Adjacent bromo-acid compound 11 (18.5g, 61.3mmol) is dissolved in anhydrous methylene chloride (200mL), and ice bath cools, and drips oxalyl chloride (12.0ml, 126.7mmol), room temperature reaction 6 hours.Decompression steams methylene dichloride and excessive oxalyl chloride, and it is for subsequent use that resistates is dissolved in tetrahydrofuran (THF) (100ml).

(S)-a-methylbenzene protection amination 3 (19.0g, 60.7mmol) is dissolved in tetrahydrofuran (THF) ether (250ml), and frozen water cools.Add water (150ml), sodium bicarbonate 11.0g, drip the ethereal solution of above-mentioned acyl chlorides, drip complete stirring 2 hours.Decompression steams tetrahydrofuran (THF).Remaining aqueous solution thing is with dichloromethane extraction, and washing, saturated common salt is washed, anhydrous sodium sulfate drying, obtains thick oily matter 12,33.3g, yield 92% after concentrating under reduced pressure.[α] ²⁰ _D-43.7(c0.25,CH ₂Cl ₂)；

Due to rotational isomeric, cause NMR spectrogram complicated.MS-ESI:598.3(M+H).

¹HNMR(400MHz,CDCl ₃):major:1.59(d,J＝7.0,3H),5.21(t,J＝7.0Hz,1H),3.99(s,1H),3.86(s,1H),3.28(m,2H),2.76(td,J＝6.0,11.2,11.7Hz,1H),2.35(m,1H),6.54(d,J＝1.8Hz,1H),6.74(d,J＝8.1Hz,1H),6.48(dd,J＝1.9,8.1Hz,1H),7.11(d,J＝8.5Hz,1H),6.92(d,J＝8.5Hz,1H),7.25(d,J＝7.3Hz,2H),7.35(dd,J＝7.6,6.9Hz,2H),7.31(dd,J＝7.5,7.2Hz,1H),1.35(d,J＝6.1Hz,6H),1.31(d,J＝6.1Hz,6H).

¹³CNMR(125MHz,CDCl ₃):major,δ170.25,150.73,150.26,147.93,145.55,140.3,132.8,128.61,128.54,127.73,127.23,125.6,120.67,120.66,116.04,115.2,112.69,71.72,71.51,60.35,55.89,55.88,45.73,41.03,34.54,22.11,21.75,18.09.

¹HNMR(400MHz,CDCl ₃):minor:1.60(d,J＝7.0,3H),6.11(t,J＝7.0Hz,1H),3.99(s,1H),3.84(s,1H),3.28(m,2H),2.70–2.62(m,1H),2.26–2.17(m,1H),6.39(d,J＝1.8Hz,1H),6.76(d,J＝8.1Hz,1H),6.46(dd,J＝1.9,8.1Hz,1H),7.04(d,J＝8.5Hz,1H),6.88(d,J＝8.50Hz,1H),7.45(d,J＝7.4Hz,2H),7.38(dd,J＝7.8,7.3Hz,2H),7.31(dd,J＝7.5,7.2Hz,1H),1.37(d,J＝6.1Hz,6H),1.32(d,J＝6.1Hz,6H).

¹³CNMR(125MHz,CDCl ₃):minor,δ170.42,150.62，150.43,147.46,145.94,140.8,131.36,128.66,128.46,128.16,127.64,125.7,120.49,120.47,116.18,114.98,112.5,71.64,71.55,60.31,56.02,51.63,46.35,40.91,36.84,16.59.

Embodiment 10 prepares compound 13

Under nitrogen protection, amide compound 12 (37.4g, 62.6mmol) is dissolved in anhydrous acetonitrile (500ml), drips phosphorus oxychloride (37.0mL, 406.3mmol) under room temperature, and return stirring reacts 8 hours.Be cooled to room temperature, remove solvent under reduced pressure, resistates adds toluene (200ml), evaporated under reduced pressure.Residual oil thing is dissolved in anhydrous methanol (400ml), is cooled to-78 DEG C and stirs 1 hour, then add sodium borohydride (12.0g in batches, 315.8mmol), stir 6 hours, slowly add water (100ml) cancellation, rises to room temperature, decompression steams methyl alcohol, remaining aqueous phase is with dichloromethane extraction, and extraction liquid merges, and saturated common salt is washed, anhydrous sodium sulfate drying, concentrating under reduced pressure.Resistates sherwood oil recrystallization obtains white solid 13,32.0g, yield 88%.Mp：98-99℃,[α] ²⁰ _D+53.3(c0.27,CH ₂Cl ₂)；

¹HNMR(400MHz,CDCl ₃):δ7.16–7.02(m,3H),6.89(d,J＝7.8Hz,2H),6.80(d,J＝8.3Hz,1H),6.75(d,J＝8.3Hz,1H),6.63(s,1H),6.39(s,1H),4.57(p,J＝6.1Hz,1H),4.26(p,J＝6.5Hz,1H),3.86(s,3H),3.84(s,3H),3.81(dd,J＝9.0,5.4,1H),3.70(q,J＝6.5Hz,1H),3.46(ddd,J＝15.0,5.7,15.0,1H),3.36(dd,J＝5.7,15.0Hz1H),3.06(dd,J＝9.0,13.9Hz,1H),2.93(ddd,J＝4.8,12.0,16.6Hz,1H),2.46(dd,J＝4.8,16.6Hz,1H),1.42(d,J＝6.5Hz,1H),1.40(d,J＝6.1Hz,3H),1.34(d,J＝6.1Hz,3H),1.30(d,J＝6.5Hz,3H),1.27(d,J＝6.5Hz,3H).

¹³CNMR(125MHz,CDCl ₃):δ149.90,148.76,147.41,146.08,145.02,132.75,129.80,127.96,127.19,126.43,121.01,116.18,114.60,111.81,71.69,71.48,60.19,58.93,57.96,55.90,42.64,39.28,23.09,22.26,22.18,21.98.

Embodiment 11 by bromo-lithium exchange system for compound 14

Under argon shield; compound 13 (7.86g; 13.5mmol) be dissolved in anhydrous THF (200mL); be cooled to-78 DEG C, drip n-Butyl Lithium (1.6Minhexane, 9.4ml) and finish stirring 1 hour; drip methyl-chloroformate (5ml; 64.9mmol), stir and add saturated ammonium chloride solution after 4 hours, rise to room temperature.Decompression steams THF, and remaining alkali lye is with dichloromethane extraction, and extraction liquid merges, and saturated common salt is washed, and anhydrous sodium sulfate drying, concentrating under reduced pressure obtains sticky oil compounds 14,7.50g, yield 100%.[α] ²⁰ _D+56.7(c0.3,CH ₂Cl ₂)；

¹HNMR(400MHz,CDCl ₃):δ7.10–7.03(m,3H),6.93(d,J＝6.5Hz,2H),6.81(d,J＝8.5Hz,1H),6.64(d,J＝8.5Hz,1H),6.58(s,1H),6.24(s,4H),4.53(p,J＝6.1Hz,1H),4.25(p,J＝6.1Hz,1H),3.86(s,3H),3.82(s,3H),3.72(s,3H),3.64(m,2H),3.32((ddd,J＝6.21,14.2,14.2Hz,1H),3.24(dd,J＝6.21,14.2Hz,1H),3.02(dd,J＝9.3,13.9Hz,1H),2.89(ddd,J＝6.21,13.9,17.2Hz,1H),2.63(dd,J＝6.21,13.9Hz,1H),2.41(dd,J＝3.6,16.6Hz,1H),1.38(d,J＝6.1Hz,3H),1.37(d,J＝6.1Hz,3H),1.31(d,J＝6.5Hz,3H),1.28(d,J＝6.0Hz,3H),1.24(d,J＝6.0Hz,3H)

¹³CNMR(100MHz,CDCl ₃)δ170.24,150.74,150.68,148.97,146.94,131.59,129.92,129.19,128.83,128.45,118.91,117.86,113.64,73.18,62.94,61.93,61.12,57.74,53.69,41.29,40.79,25.07,24.10,24.03,23.99,23.90.

Embodiment 12 prepares compound 15

Methyl benzoate compound 14 (6.3g, 11.2mmol) is dissolved in 95% ethanol (100mL), adds concentrated hydrochloric acid (5ml), palladium hydroxide/carbon (20%Pd, 1.0g), and 40 DEG C of normal pressures lead to hydrogen 12 hours.Reacted rear filtration, filtrate reduced in volume, resistates adds 20% sodium hydroxide (20ml), methylene dichloride (100ml), separates organic phase after jolting fully, washing, and saturated common salt is washed, anhydrous sodium sulfate drying, concentrates to obtain oily matter.[α] ²⁰ _d+56.7 (c0.3, CH ₂cl ₂), 1HNMR (400MHz, CDCl3): δ 7.10 – 7.03 (m, 3H), 6.93 (d, J=6.5Hz, 2H), 6.81 (d, J=8.5Hz, 1H), 6.64 (d, J=8.5Hz, 1H), 6.58 (s, 1H), 6.24 (s, 4H), 4.53 (p, J=6.1Hz, 1H), 4.25 (p, J=6.1Hz, 1H), 3.86 (s, 3H), 3.82 (s, 3H), 3.72 (s, 3H), 3.64 (m, 2H), 3.32 ((ddd, J=6.21, 14.2, 14.2Hz, 1H), 3.24 (dd, J=6.21, 14.2Hz, 1H), 3.02 (dd, J=9.3, 13.9Hz, 1H), 2.89 (ddd, J=6.21, 13.9, 17.2Hz, 1H), 2.63 (dd, J=6.21, 13.9Hz, 1H), 2.41 (dd, J=3.6, 16.6Hz, 1H), 1.38 (d, J=6.1Hz, 3H), 1.37 (d, J=6.1Hz, 3H), 1.31 (d, J=6.5Hz, 3H), 1.28 (d, J=6.0Hz, 3H), 1.24 (d, J=6.0Hz, 3H) .13CNMR (100MHz, CDCl3): δ 170.24, 150.74, 150.68, 148.97, 146.94, 131.59, 129.92, 129.19, 128.83, 128.45, 118.91, 117.86, 113.64, 73.18, 62.94, 61.93, 61.12, 57.74, 53.69, 41.29, 40.79, 25.07, 24.10, 24.03, 23.99, 23.90.HRMS (ESI): theoretical value C ₃₄h ₄₃nO ₆[[M+H]+562.3163, experimental value 562.3156.

Embodiment 13 compound 15 is reduced to the L-SPD (16) of two sec.-propyl protection

Under nitrogen protection, compound 17 (54mg, 0.126mmol) is dissolved in anhydrous THF (20mL), adds LiAlH ₄(15mg), return stirring 2 hours.Frozen water cooling reaction solution, carefully add water cancellation, concentrated, and resistates is with dichloromethane extraction, and extraction liquid saturated common salt is washed, anhydrous sodium sulfate drying, and column chromatography after concentrated, obtains faint yellow solid compound 18,47mg, yield 91%.

¹HNMR(300MHz,CDCl ₃):δ6.87-6.78(m,3H),6.63(s,1H),4.57-4.46(m,2H),4.24(d,J＝15.9Hz,1H),3.88(s,3H),3.85(s,3H),3.62-3.50(m,2H),3.31-3.08(m,3H),2.88-2.61(m,3H),1.45–1.34(m,12H)； ¹³CNMR(100MHz,CDCl ₃):δ148.9,148.1,146.4,145.4,129.6,128.8,128.0,127.5,123.7,115.0,113.9,118.8,71.8,71.1,60.0,59.1,55.8,51.4,36.3,29.1,22.1(×4)；

Embodiment 14 compound 16 deprotection is L-SPD

Under nitrogen protection, compound 18 (47mg, 0.114mmol) is dissolved in anhydrous methylene chloride (10mL), is cooled to-78 DEG C, drips BCl ₃dichloromethane solution (1M, 0.5mL), finish and slowly rise to ambient temperature overnight.(3mL) cancellation that adds water is reacted, and add THF (5mL), separate organic phase, anhydrous sodium sulfate drying, evaporating column chromatography, obtains L-SPD32mg, yield 86%.

[α] _D ²⁰＝-281.6(c1.0,CH ₃OH),M.p.128-129℃； ¹HNMR(CD ₃OD)：δ6.78-6.66(m，3H)，6.63(s，1H),4.15(d，J＝15.7Hz，1H)，3.79(s，3H)，3.77(s，3H)，3.50-3.38(m，2H)，3.32-2.98(m，3H)，2.74-2.52(m，3H)； ¹³CNMR(CD ₃OD)：δ149.26，148.31，146.49，145.46，131.21，129.23，127.68，126.73，125.91，116.86，113.61，112.98，61.13，60.91，56.81，55.32，53.33，36.95，29.74；EI-MS(m/z,％):327(84.4),178(100)。

The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.

Claims

1. the purposes such as formula compound shown in A:

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

R ₈be selected from lower group:

R ₁₁for H;

Y is Br;

2. a method for compound shown in preparation formula B, is characterized in that, comprises step:

In inert solvent, with such as formula the compound shown in A through Bischler-Napieralski ring-closure reaction, then through reduction obtain such as formula the compound shown in B, wherein, the definition of each group is as described in the appended claim 1.

3. one kind such as formula the compound shown in A:

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

R ₈be selected from lower group:

represent R configuration or S configuration.

4. one kind such as formula the compound shown in B:

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

R ₈be selected from lower group:

represent R configuration or S configuration.

5. such as formula a purposes for the compound shown in B, it is characterized in that, the compound for the preparation of having as shown in the formula structure shown in M:

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

represent R configuration or S configuration;

And in formula B, Y is the carboxylic acid ester groups of C2-C10.

6. a method for compound shown in preparation formula M, is characterized in that, comprises step:

Wherein, Y is the carboxylic acid ester groups of C2-C10;

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

7. one kind such as formula the compound shown in M:

Or R ₇and R ₇', R ₉and R ₉', R ₁₀and R ₁₀' common formation=O;

represent R configuration or S configuration.

8. a preparation method of SPD (Stopholidine), is characterized in that, described method comprises step:

9. method as claimed in claim 8, it is characterized in that, described method is further comprising the steps of:

Wherein, M is selected from lower group: the alkyl-oxygen base of Cl, Br, C1-C3; R ₁, R ₂definition as claimed in claim 8..

10. the method as described in as arbitrary in claim 8 or 9, it is characterized in that, described method is further comprising the steps of:

R ₁, R ₂definition as claimed in claim 8..