CN103748059A - Process for the preparation of protease inhibitors - Google Patents

Process for the preparation of protease inhibitors Download PDF

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CN103748059A
CN103748059A CN201280034614.0A CN201280034614A CN103748059A CN 103748059 A CN103748059 A CN 103748059A CN 201280034614 A CN201280034614 A CN 201280034614A CN 103748059 A CN103748059 A CN 103748059A
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alkyl
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aliphatic series
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G.J.塔诺里
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Vertex Pharmaceuticals Inc
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Vertex Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

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Abstract

A process for preparing enantioselectively a compound of formula (la) or (Ib) over a compound of formulas I-2-1h.

Description

The method of preparing proteinase inhibitor
the cross reference of related application
The application requires the benefit of priority of the U.S. Provisional Application submitted on May 13rd, 2011 number 61/486,150, and it is incorporated herein by reference.
Invention field
The present invention relates to method and intermediate for the preparation of proteinase inhibitor, particularly serpin.
background of invention
By hepatitis C virus (" HCV "), being infected is a people's medical problem attracting people's attention.Most cases for non-A type or non-hepatitis B, think that HCV is the medium that causes a disease, in the whole world, estimate the human serum positive rate (people such as A. Alberti that is 3%, " Natural History of Hepatitis C (natural history of hepatitis C) " J. Hepatology, 31 (supplementary issues 1), 17-24 page (1999)).The Jin U.S., nearly 4,000,000 individual possibilities are infected.(the people such as M.J. Alter, " The Epidemiology of Viral Hepatitis in the United States (at the epidemiology of U.S.'s viral hepatitis) " Gastroenterol. Clin. North Am., 23, the 437-455 pages (1994); M. J. Alter " Hepatitis C Virus Infection in the United States (infection with hepatitis C virus in the U.S.) " J. Hepatology, 31 (supplementary issues 1), 88-91 page (1999)).
When being exposed to HCV for the first time, only approximately 20% infected individual development goes out acute clinical hepatitis, and other seem the infection of spontaneously disappearing.Yet almost 70% in the situation that, virus is set up the chronic infection of sustainable many decades.(S. Iwarson, " The Natural Course of Chronic Hepatitis (natural process of chronic hepatitis) " FEMS Microbiology Reviews, 14, the 201-204 pages (1994); D. Lavanchy, " Global Surveillance and Control of Hepatitis C (whole world of hepatitis C is detected and controlled) " J. Viral Hepatitis, 6, the 35-47 pages (1999)).Long-term chronic infection can cause the liver inflammation of recurrent and progressive deterioration, and this causes more serious morbid state conventionally, for example sclerosis and hepatocellular carcinoma.(M.C. Kew, " Hepatitis C and Hepatocellular Carcinoma (hepatitis C and hepatocellular carcinoma) " FEMS Microbiology Reviews, 14, the 211-220 pages (1994); I. the people such as Saito, " Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma (infection with hepatitis C virus is relevant with the development of hepatocellular carcinoma) " Proc. Natl. Acad. Sci. USA, 87, the 6547-6549 pages (1990)).Regrettably, for the exhaustion progress of chronic hcv, extensively effectively do not treat.
Proteinase inhibitor (particularly serpin) can be used for treating HCV to be infected, as disclosed in WO 02/18369.WO 02/18369 also discloses for the preparation of the method for these compounds and intermediate.These methods cause some space carbon center racemization.Referring to for example 223-22 page.As a result, still need to be for the preparation of the enantioselectivity method of these compounds.
summary of the invention
The present invention meets this requirement and other requirement, and it relates to method and intermediate for the preparation of proteinase inhibitor (particularly serpin).On the one hand, the invention provides method and the intermediate for the production of the bicyclic derivatives of formula Ia or Ib:
Figure 2012800346140100002DEST_PATH_IMAGE002
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
Ring B is C 3-12heterocycle aliphatic series ring, it contains other 0-2 heteroatoms that is selected from independently of one another O, N and S, and it can optionally be replaced by 1-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group, aryl and hydroxyl;
R 1for H or protecting group; With
R 2for H, protecting group or C 1-12aliphatic series.
It is a kind of for the compound via formula Ic to Ih that aspect relates to, the method for the compound of enantioselectivity ground preparation formula Ia or Ib:
Figure 2012800346140100002DEST_PATH_IMAGE004
。
Under existing, the compound that described method is included in formula III makes the step of the compound carboxylation of formula IIa or IIb:
Figure 2012800346140100002DEST_PATH_IMAGE006
，
R wherein 1afor protecting group,
Figure 2012800346140100002DEST_PATH_IMAGE008
；
R wherein 3and R 4be protecting group, C independently of one another 1-12aliphatic series or be selected from the cyclic group of cyclic aliphatic, heterocycle aliphatic series, aryl and heteroaryl;
Another aspect relates to a kind of method of the compound for the preparation of formula 10:
Figure 2012800346140100002DEST_PATH_IMAGE010
，
R wherein 2as above definition, and Z 2for H or protecting group;
Said method comprising the steps of:
A. under existing, the compound of formula III forms the 2-negatively charged ion of the compound of formula IIa:
Figure 2012800346140100002DEST_PATH_IMAGE012
，
R wherein 1aa as above defines with ring,
Figure DEST_PATH_IMAGE014
，
R wherein 3and R 4as above definition;
B. use the 2-negatively charged ion of carbon dioxide treatment step a, with the compound of enantioselectivity ground production Ia; With
C. make the compound of formula Ia react with the compound of formula 26:
Figure DEST_PATH_IMAGE016
，
Z wherein 3for protecting group.
detailed Description Of The Invention
Definition
For purposes of the present invention, according to the periodic table of elements (CAS version, Handbook of Chemistry and Physics (physics and chemistry handbook), the 75th edition), determine chemical element.In addition, vitochemical generic principles is described in the Organic Chemistry(organic chemistry of Thomas Sorrell), University Science Books, the Advanced Organic Chemistry (Advanced Organic Chemistry) of Sausalito (1999) and M.B. Smith and J. March, the 5th edition, John Wiley & Sons, New York (2001), both are incorporated herein by reference.
Compound of the present invention described herein can optionally be replaced by one or more substituting groups, and described substituting group is summary description above for example, or as illustrated in specific category of the present invention, subclass and thing class.
Have to be noted that unless context clearly indicates other situation, herein and singulative " " and " being somebody's turn to do " of in claim, using comprise plural object.Therefore, for example, mention that " a kind of tackiness agent " comprises two or more tackiness agents, mention that " a kind of pharmaceutical agent " comprises two or more pharmaceutical agents, etc.
Term used herein " compound " refers to the compound that the structural formula by corresponding drafting herein defines.In addition, unless otherwise indicated, otherwise term " compound " can comprise the salt of compound.
Term used herein " aliphatic series " comprises term alkyl, thiazolinyl, alkynyl and cyclic aliphatic, each optional as following being substituted wherein.
" alkyl " used herein refers to the radical of saturated aliphatic alkyl that contains 1-8 (for example, 1-6 or 1-4) carbon atom.Alkyl can be straight chain, ring-type or branching.The example of alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-heptyl or 2-ethylhexyl.Alkyl can be selected from following one or more substituting groups and be replaced (, optionally be substituted): halogen, cyclic aliphatic (for example, cycloalkyl or cycloalkenyl group), heterocycle aliphatic series (for example, Heterocyclylalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxyl group, aroyl, 4-hetaroylpyrazol, acyl group (for example, (aliphatic series) carbonyl, (cyclic aliphatic) carbonyl or (heterocycle aliphatic series) carbonyl), nitro, cyano group, amido (for example, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl is amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino alkyl amino-carbonyl, cycloalkyl amino carbonyl, Heterocyclylalkyl aminocarboxyl, aromatic yl aminocarbonyl or heteroaryl amino carbonyl), amino (for example, aliphatic amino, cyclic aliphatic amino or heterocycle aliphatic amino), alkylsulfonyl (for example, aliphatic series-SO 2-), sulfinyl, sulfanyl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo, carboxyl, formamyl, cyclic aliphatic oxygen base, heterocycle aliphatic series oxygen base, aryloxy, heteroaryloxy, aralkoxy, heteroaryl alkoxyl group, alkoxy carbonyl, alkyl-carbonyl oxygen base and hydroxyl.Some examples of substituted alkyl are not with restriction and comprise carboxyalkyl (for example HOOC-alkyl, alkoxy carbonyl alkyl and alkyl carbonyl oxy alkyl), cyano group alkyl, hydroxyalkyl, alkoxyalkyl, acyl group alkyl, aralkyl, (alkoxy aryl) alkyl, (sulfuryl amino) alkyl ((alkyl-SO for example 2-amino) alkyl), aminoalkyl group, amidoalkyl, (cyclic aliphatic) alkyl and haloalkyl.
" thiazolinyl " used herein refers to the aliphatic carbons group that contains 2-8 (for example, 2-6 or 2-4) carbon atom and at least one two key.As alkyl, thiazolinyl can be straight chain or branching.The example of thiazolinyl includes but not limited to allyl group, prenyl, crotyl and 2-hexenyl.Thiazolinyl can optionally be replaced by one or more substituting groups, described substituting group is halogen for example, cyclic aliphatic (for example, cycloalkyl or cycloalkenyl group), heterocycle aliphatic series (for example, Heterocyclylalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxyl group, aroyl, 4-hetaroylpyrazol, acyl group (for example, (aliphatic series) carbonyl, (cyclic aliphatic) carbonyl or (heterocycle aliphatic series) carbonyl), nitro, cyano group, amido (for example, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl is amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino alkyl amino-carbonyl, cycloalkyl amino carbonyl, Heterocyclylalkyl aminocarboxyl, aromatic yl aminocarbonyl or heteroaryl amino carbonyl), amino (for example, aliphatic amino, cyclic aliphatic is amino, heterocycle aliphatic amino or aliphatic sulfuryl amino), alkylsulfonyl (for example, alkyl-SO 2-, cyclic aliphatic-SO 2-or aryl-SO 2-), sulfinyl, sulfanyl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo, carboxyl, formamyl, cyclic aliphatic oxygen base, heterocycle aliphatic series oxygen base, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, alkoxy carbonyl, alkyl-carbonyl oxygen base and hydroxyl.Some examples of substituted thiazolinyl are not with restriction and comprise cyano group thiazolinyl, alkoxyl group thiazolinyl, acyl group thiazolinyl, hydroxyl thiazolinyl, arylalkenyl, (alkoxy aryl) thiazolinyl, (sulfuryl amino) thiazolinyl ((alkyl-SO for example 2-amino) thiazolinyl), amino thiazolinyl, amido thiazolinyl, (cyclic aliphatic) thiazolinyl and haloalkenyl group.
" alkynyl " used herein refers to the aliphatic carbons group that contains 2-8 (for example, 2-6 or 2-4) carbon atom and have at least one three key.Alkynyl can be straight chain or branching.The example of alkynyl includes but not limited to propargyl and butynyl.Alkynyl can optionally be replaced by one or more substituting groups, for example aroyl, 4-hetaroylpyrazol, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, nitro, carboxyl, cyano group, halogen, hydroxyl, sulfo group, sulfydryl, sulfanyl be (for example for described substituting group, aliphatic series sulfanyl or cyclic aliphatic sulfanyl), sulfinyl (for example, aliphatic series sulfinyl or cyclic aliphatic sulfinyl), alkylsulfonyl (for example, aliphatic series-SO 2-, aliphatic amino-SO 2-or cyclic aliphatic-SO 2-), amido (for example, aminocarboxyl, alkyl amino-carbonyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, Heterocyclylalkyl aminocarboxyl, cycloalkyl amino carbonyl, aromatic yl aminocarbonyl, aryl-amino-carbonyl, aromatic alkyl carbonyl is amino, (Heterocyclylalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkyl carbonylamino, heteroaryl carbonylamino or heteroaryl amino carbonyl), urea, thiocarbamide, sulfamyl, sulphonamide, alkoxy carbonyl, alkyl-carbonyl oxygen base, cyclic aliphatic, heterocycle aliphatic series, aryl, heteroaryl, acyl group (for example, (cyclic aliphatic) carbonyl or (heterocycle aliphatic series) carbonyl), amino (for example, aliphatic amino), sulphur oxygen base, oxo, carboxyl, formamyl, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base and (heteroaryl) alkoxyl group.
" amido " used herein comprise " aminocarboxyl " and " carbonylamino " the two.These terms, while being combined with when independent use or with another group, when using endways, refer to amido for example-N (R x)-C (O)-R yor-C (O)-N (R x) 2, when using in inside they refer to amide group for example-C (O)-N (R x)-or-N (R x)-C (O)-, R wherein xand R yas give a definition.The example of amido comprises alkyl amido (for example alkyl-carbonyl-amino or alkyl amino-carbonyl), (heterocycle aliphatic series) amido, (heteroaralkyl) amido, (heteroaryl) amido, (Heterocyclylalkyl) alkyl amido, aryl amido, aralkyl amido, (cycloalkyl) alkyl amido and cycloalkyl amido.
" amino " used herein refer to-NR xr y, R wherein xand R yeach independently selected from hydrogen, aliphatic series, cyclic aliphatic, (cyclic aliphatic) aliphatic series, aryl, araliphatic, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, heteroaryl, carboxyl, sulfanyl, sulfinyl, alkylsulfonyl, (aliphatic series) carbonyl, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, aryl carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl, (heteroaryl) carbonyl and (araliphatic of mixing) carbonyl, wherein each is substituted as defined herein and optionally.Amino example comprises alkylamino, dialkyl amido and arylamino.For example, when term " amino " is not end group (, alkyl-carbonyl-amino), its be expressed as-NR x-.R xthere is identical meanings as defined above.
A part (as in " aralkyl ", " aralkoxy " or " aryloxy alkyl ") for the part that use or conduct are larger separately, " aryl " used herein refers to that monocycle (for example, phenyl), dicyclo (for example, indenyl, naphthyl, tetralyl, tetrahydro indenyl) and three rings are (for example, fluorenyl, tetrahydrofluorenyl or tetrahydrochysene anthryl, anthryl) member ring systems, wherein monocycle ring body is aromatics, or at least one ring in dicyclo or three ring member ring systems is aromatics.Dicyclo and three cyclic groups comprise 2 yuan of benzo-fused rings to 3 yuan of carbocyclic rings.For example, benzo-fused group comprises and two or more C 4-8the phenyl that isocyclic part condenses.Aryl is optionally replaced by one or more substituting groups, described substituting group for example aliphatic series (for example, alkyl, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, oxo (on the ring of the non-aromatic carbocyclic ring of benzo-fused dicyclo or three cyclophane bases), nitro, carboxyl, amido, acyl group (for example, aliphatic series carbonyl, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), alkylsulfonyl (for example, aliphatic series-SO 2-or amino-SO 2-), sulfinyl (for example, aliphatic series-S (O)-or cyclic aliphatic-S (O)-), sulfanyl (for example, aliphatic series-S-), cyano group, halogen, hydroxyl, sulfydryl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide and formamyl.Or aryl can not be substituted.
The limiting examples of substituted aryl comprises halogenated aryl (for example, (single halo) aryl, (dihalo) aryl is (for example, to dihalo aryl, between dihalo aryl) or (three halos) aryl), (carboxyl) aryl (for example, (alkoxy carbonyl) aryl, ((aralkyl) carbonyl oxygen base) aryl or (alkoxy carbonyl) aryl), (amido) aryl (for example, (aminocarboxyl) aryl, (((alkylamino) alkyl) aminocarboxyl) aryl, (alkyl-carbonyl) aminoaryl, (aromatic yl aminocarbonyl) aryl or (((heteroaryl) amino) carbonyl) aryl), aminoaryl (for example, ((alkyl sulphonyl) amino) aryl or ((dialkyl group) amino) aryl), (cyano group alkyl) aryl, (alkoxyl group) aryl, (sulfamyl) aryl (for example, (amino-sulfonyl) aryl), (alkyl sulphonyl) aryl, (cyano group) aryl, (hydroxyalkyl) aryl, ((alkoxyl group) alkyl) aryl, (hydroxyl) aryl, ((carboxyl) alkyl) aryl, (((dialkyl group) amino) alkyl) aryl, (4-nitro alkyl) aryl, (((alkyl sulphonyl) amino) alkyl) aryl, ((heterocycle aliphatic series) carbonyl) aryl, ((alkyl sulphonyl) alkyl) aryl, (cyano group alkyl) aryl, (hydroxyalkyl) aryl, (alkyl-carbonyl) aryl, alkylaryl, (tri haloalkyl) aryl, to an amino-alkoxy carbonyl aryl, to an amino-cyano-aryl, to a halo-aminoaryl and ((heterocycle aliphatic series)-adjacent (alkyl)) aryl.
" araliphatic " used herein group for example " aralkyl " refers to aliphatic group (for example, the C being replaced by aryl 1-4alkyl).Aliphatic series, alkyl and aryl are as defined herein.An example of araliphatic (for example aralkyl) is benzyl.
" aralkyl " used herein refers to alkyl (for example, the C being replaced by aryl 1-4alkyl).Alkyl and aryl as above define.An example of aralkyl is benzyl.Aralkyl is optionally replaced by one or more substituting groups, and described substituting group for example aliphatic series (for example, is substituted or unsubstituted alkyl, alkenyl or alkynyl, comprises carboxyalkyl, hydroxyalkyl or haloalkyl, for example trifluoromethyl), cyclic aliphatic (for example, be substituted or unsubstituted cycloalkyl or cycloalkenyl group), (cycloalkyl) alkyl, Heterocyclylalkyl, (Heterocyclylalkyl) alkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, aroyl, 4-hetaroylpyrazol, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, amido (for example, aminocarboxyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl is amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino or heteroaralkyl carbonylamino), cyano group, halogen, hydroxyl, acyl group, sulfydryl, alkyl alkylthio base, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" dicyclo member ring systems " used herein comprises 8 yuan to 12 yuan (for example, 9 yuan, 10 yuan or 11 yuan) structures that form two rings, and wherein two rings have at least one common atom (for example, 2 common atoms).Dicyclo member ring systems comprises dicyclo aliphatic series (for example, bicyclic alkyl or bicyclic alkenyl), dicyclo heterolipid family, bicyclic aryl and bicyclic heteroaryl.
" cyclic aliphatic " used herein group comprises " cycloalkyl " and " cycloalkenyl group ", and wherein each is as described belowly optionally substituted.
" cycloalkyl " used herein refers to the saturated carbon ring monocycle of 3-10 (for example, 5-10) carbon atom or dicyclo (condense or bridging) ring.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, adamantyl, norborneol alkyl, cube alkyl (cubyl), octahydro-indenyl, decahydro-naphthyl, dicyclo [3.2.1] octyl group, dicyclo [2.2.2] octyl group, dicyclo [3.3.1] nonyl, dicyclo [3.3.2.] decyl, dicyclo [2.2.2] octyl group, adamantyl, azacycloalkyl and ((aminocarboxyl) cycloalkyl) cycloalkyl." cycloalkenyl group " used herein refers to the ring of the non-aromatic carbocyclic ring of 3-10 (for example, the 4-8) carbon atom with one or more pairs of keys.The example of cycloalkenyl group comprises cyclopentenyl, 1，4-cyclohexadiene base, cycloheptenyl, cyclooctene base, six hydrogen-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl, dicyclo [2.2.2] octenyl and dicyclo [3.3.1] nonene base.Cycloalkyl or cycloalkenyl group can optionally be replaced by one or more substituting groups, and described substituting group is aliphatic series (for example, alkyl for example, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, amido (for example, (aliphatic series) carbonylamino, (cyclic aliphatic) carbonylamino, ((cyclic aliphatic) aliphatic series) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycle aliphatic series) carbonylamino, ((heterocycle aliphatic series) aliphatic series) carbonylamino, (heteroaryl) carbonylamino or ((assorted araliphatic) carbonylamino), nitro, carboxyl (for example, HOOC-, alkoxy carbonyl or alkyl-carbonyl oxygen base), acyl group (for example, (cyclic aliphatic) carbonyl, (cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), cyano group, halogen, hydroxyl, sulfydryl, alkylsulfonyl (for example, alkyl-SO 2-or aryl-SO 2-), sulfinyl (for example, alkyl-S (O)-), sulfanyl (for example, alkyl-S-), sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" loop section " used herein comprises cyclic aliphatic, heterocycle aliphatic series, aryl or heteroaryl, and wherein each is as previously defined.
Term used herein " heterocycle aliphatic series " comprises Heterocyclylalkyl and heterocycloalkenyl, and wherein each is as described belowly optionally substituted.
" Heterocyclylalkyl " used herein (for example refers to 3-10 unit monocycle or dicyclo (condense or bridging), 5 yuan to 10 yuan monocycles or dicyclo) saturated rings structure, wherein one or more annular atomses are heteroatoms (for example, N, O, S or their combination).The example of Heterocyclylalkyl comprises piperidyl, piperazinyl, THP trtrahydropyranyl, tetrahydrofuran base, 1, 4-dioxolane base, 1, 4-dithiane base, 1, 3-dioxolane base, oxazolidinyl, isoxazole alkyl, morpholinyl, thio-morpholinyl, octahydro benzofuryl, octahydro chromenyl, octahydro sulfo-chromenyl, octahydro indyl, octahydro pyrindine base, decahydroquinolyl, octahydro benzo [b] thienyl, 2-oxa--dicyclo [2.2.2] octyl group, 1-aza-bicyclo [2.2.2] octyl group, 3-aza-bicyclo [3.2.1] octyl group and 2, 6-dioxa-tri-encircle [3.3.1.0 3,7] nonyl.Monocyclic heterocycles alkyl can condense with phenyl moiety, for example tetrahydroisoquinoline." heterocycloalkenyl " used herein refers to and has monocycle that one or more pairs of keys and wherein one or more annular atomses are heteroatoms (for example, N, O or S) or dicyclo (for example, 5 yuan to 10 yuan monocycle or dicyclo) non-aromatic ring structure.Monocycle and dicyclo heterolipid family number according to standard chemical nomenclature.
Heterocyclylalkyl or heterocycloalkenyl can optionally be replaced by one or more substituting groups, and described substituting group is aliphatic series (for example, alkyl for example, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, amido (for example, (aliphatic series) carbonylamino, (cyclic aliphatic) carbonylamino, (cyclic aliphatic) aliphatic series) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycle aliphatic series) carbonylamino, ((heterocycle aliphatic series) aliphatic series) carbonylamino, (heteroaryl) carbonylamino or (assorted araliphatic) carbonylamino), nitro, carboxyl (for example, HOOC-, alkoxy carbonyl or alkyl-carbonyl oxygen base), acyl group (for example, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), nitro, cyano group, halogen, hydroxyl, sulfydryl, alkylsulfonyl (for example, alkyl sulphonyl or aryl sulfonyl), sulfinyl (for example, alkyl sulphinyl), sulfanyl (for example, alkyl alkylthio base), sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" heteroaryl " used herein refers to monocycle, dicyclo or the three ring member ring systems with 4-15 annular atoms, wherein one or more annular atomses be heteroatoms (for example, N, O, S or their combination) and wherein monocycle ring body be aromatics, or dicyclo or three rings at least one ring in member ring systems are aromatics.Heteroaryl comprises the benzo-fused member ring systems with 2-3 ring.For example, benzo-fused group comprises and one or two 4-8 unit heterocycle aliphatic series part benzo-fused (for example, indolizine base, indyl, pseudoindoyl, 3H-indyl, indoline base, benzo [b] furyl, benzo [b] thienyl, quinolyl or isoquinolyl).Some examples of heteroaryl be azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrryl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazyl, benzofuryl, isoquinolyl, benzothiazolyl,
Figure DEST_PATH_IMAGE018
ton base, sulfo-
Figure 137432DEST_PATH_IMAGE018
ton base, thiodiphenylamine, indoline, benzo [1,3] dioxole, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, cinnolinyl, quinolyl, quinazolyl, phthalazinyl, quinazolyl, quinoxalinyl, isoquinolyl, 4H-quinolizinyl, phendioxin, 2,5-thiadiazolyl group and 1,8-naphthyridinyl.
Bicyclic heteroaryl is not with restriction and is comprised furyl, thienyl, 2H-pyrryl, pyrryl, oxazolyl, thiazolyl (thazolyl), imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl group, 2H-pyranyl, 4-H-pyranyl (4-H-pranyl), pyridyl, pyridazinyl, pyrimidyl, pyrazolyl, pyrazinyl and 1,3,5-triazinyl.Bicyclic heteroaryl is numbered according to standard chemical nomenclature.
Bicyclic heteroaryl is not with restriction and is comprised indolizine base, indyl, pseudoindoyl, 3H-indyl, indoline base, benzo [b] furyl, benzo [b] thienyl, quinolyl, isoquinolyl, indolizine base, pseudoindoyl, indyl, benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, 4H-quinolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolyl, quinoxalinyl, 1,8-naphthyridinyl and pteridyl.Bicyclic heteroaryl is numbered according to standard chemical nomenclature.
Heteroaryl is optionally replaced by one or more substituting groups, and described substituting group is aliphatic series (for example, alkyl for example, alkenyl or alkynyl), cyclic aliphatic, (cyclic aliphatic) aliphatic series, heterocycle aliphatic series, (heterocycle aliphatic series) aliphatic series, aryl, heteroaryl, alkoxyl group, (cyclic aliphatic) oxygen base, (heterocycle aliphatic series) oxygen base, aryloxy, heteroaryloxy, (araliphatic) oxygen base, (assorted araliphatic) oxygen base, aroyl, 4-hetaroylpyrazol, amino, oxo (on the non-aromatic carbocyclic ring or heterocyclic ring of dicyclo or tricyclic heteroaryl), carboxyl, amido, acyl group (for example, aliphatic carbonyl, (cyclic aliphatic) carbonyl, ((cyclic aliphatic) aliphatic series) carbonyl, (araliphatic) carbonyl, (heterocycle aliphatic series) carbonyl, ((heterocycle aliphatic series) aliphatic series) carbonyl or (assorted araliphatic) carbonyl), alkylsulfonyl (for example, aliphatic alkylsulfonyl or amino-sulfonyl), sulfinyl (for example, aliphatic sulfinyl), sulfanyl (for example, aliphatic sulfanyl), nitro, cyano group, halogen, hydroxyl, sulfydryl, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide and formamyl.Or heteroaryl can not be substituted.
The limiting examples of substituted heteroaryl comprises (halo) heteroaryl (for example, single (halo) heteroaryl and two (halo) heteroaryl), (carboxyl) heteroaryl (for example, (alkoxy carbonyl) heteroaryl), cyanoheteroaryl, aminoheteroaryl (for example, ((alkyl sulphonyl) amino) heteroaryl and ((dialkyl group) amino) heteroaryl), (amido) heteroaryl (for example, aminocarboxyl heteroaryl, ((alkyl-carbonyl) amino) heteroaryl, ((((alkyl) amino) alkyl) aminocarboxyl) heteroaryl, (((heteroaryl) amino) carbonyl) heteroaryl, ((heterocycle aliphatic series) carbonyl) heteroaryl or ((alkyl-carbonyl) amino) heteroaryl), (cyano group alkyl) heteroaryl, (alkoxyl group) heteroaryl, (sulfamyl) heteroaryl (for example, (amino-sulfonyl) heteroaryl), (alkylsulfonyl) heteroaryl ((for example, (alkyl sulphonyl) heteroaryl), (hydroxyalkyl) heteroaryl, (alkoxyalkyl) heteroaryl, (hydroxyl) heteroaryl, ((carboxyl) alkyl) heteroaryl, (((dialkyl group) amino) alkyl) heteroaryl, (heterocycle aliphatic series) heteroaryl, (cyclic aliphatic) heteroaryl, (4-nitro alkyl) heteroaryl, (((alkyl sulphonyl) amino) alkyl) heteroaryl, ((alkyl sulphonyl) alkyl) heteroaryl, (cyano group alkyl) heteroaryl, (acyl group) heteroaryl (for example, (alkyl-carbonyl) heteroaryl), (alkyl) heteroaryl and (haloalkyl) heteroaryl (for example, tri haloalkyl heteroaryl).
" assorted araliphatic " (for example heteroaralkyl) used herein refers to aliphatic group (for example, the C being replaced by heteroaryl 1-4alkyl).Aliphatic series, alkyl and heteroaryl as above define.
" heteroaralkyl " used herein refers to alkyl (for example, the C being replaced by heteroaryl 1-4alkyl).Both as above define " alkyl " and " heteroaryl ".Heteroaralkyl is optionally replaced by one or more substituting groups, described substituting group for example alkyl (comprises carboxyalkyl, hydroxyalkyl and haloalkyl be trifluoromethyl for example), thiazolinyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, Heterocyclylalkyl, (Heterocyclylalkyl) alkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, aroyl, 4-hetaroylpyrazol, nitro, carboxyl, alkoxy carbonyl, alkyl-carbonyl oxygen base, aminocarboxyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl is amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino, cyano group, halogen, hydroxyl, acyl group, sulfydryl, alkyl alkylthio base, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" acyl group " used herein refers to formyl radical or R x-C (O)-(for example alkyl-C (O)-, also referred to as " alkyl-carbonyl "), wherein R xwith alkyl as previously defined.Ethanoyl and valeryl are the examples of acyl group.
" aroyl " used herein or " 4-hetaroylpyrazol " refer to aryl-C (O)-or heteroaryl-C (O)-.Aryl and the heteroaryl moieties of aroyl or 4-hetaroylpyrazol are optionally substituted as previously defined.
" alkoxyl group " used herein refers to alkyl-O-group, and wherein alkyl as previously defined.
" formamyl " used herein refers to have structure-O-CO-NR xr yor-NR x-CO-O-R zgroup, R wherein xand R yas above definition, and R zcan be aliphatic series, aryl, araliphatic, heterocycle aliphatic series, heteroaryl or assorted araliphatic.
" carboxyl " used herein refer to when using endways-COOH ,-COOR x,-OC (O) H or-OC (O) R x, refer to-OC (O) when using in inside-or-C (O) O-.
" halogenated aliphatic " used herein group refers to the aliphatic group being replaced by 1-3 halogen.For example, term haloalkyl comprises group-CF 3.
" sulfydryl " used herein refer to-SH.
" sulfo group " used herein refer to when using endways-SO 3h or-SO 3r x, refer to-S (O) when using in inside 3-.
" sulphonamide " used herein group refers to structure-NR when using endways x-S (O) 2-NR yr z, refer to-NR when using in inside x-S (O) 2-NR y-, R wherein x, R yand R zas above definition.
" sulphonamide " used herein group refers to structure-S (O) when using endways 2-NR xr yor-NR x-S (O) 2-R z, refer to-S (O) when using in inside 2-NR x-or-NR x-S (O) 2-, R wherein x, R yand R zas above definition.
" sulfanyl " used herein refer to when using endways-S-R x, refer to-S-, wherein R when using in inside xas above definition.The example of sulfanyl comprises aliphatic series-S-, cyclic aliphatic-S-and aryl-S-etc.
" sulfinyl " used herein refer to when using endways-S (O)-R x, refer to-S (O) when using in inside-, R wherein xas above definition.The example of sulfinyl comprise aliphatic series-S (O)-, aryl-S (O)-, (cyclic aliphatic (aliphatic series))-S (O)-, cycloalkyl-S (O)-, heterocycle aliphatic series-S (O)-and heteroaryl-S (O)-etc.
" alkylsulfonyl " used herein refer to when using endways-S (O) 2-R x, refer to-S (O) when using in inside 2-, R wherein xas above definition.Exemplary alkylsulfonyl comprises aliphatic series-S (O) 2-, aryl-S (O) 2-, ((cyclic aliphatic (aliphatic series))-S (O) 2-, cyclic aliphatic-S (O) 2-, heterocycle aliphatic series-S (O) 2-, heteroaryl-S (O) 2-and (cyclic aliphatic (amido (aliphatic series)))-S (O) 2-etc.
" sulphur oxygen base " used herein refers to-O-SO-R when using endways xor-SO-O-R x, refer to-O-S (O) when using in inside-or-S (O)-O-, wherein R xas above definition.
" halogen " used herein or " halo " group refer to fluorine, chlorine, bromine or iodine.
" alkoxy carbonyl " used herein (it is included in " carboxyl ", use separately or with another moiety combinations) refer to alkyl-O-C (O) for example-group.
" alkoxyalkyl " used herein refer to alkyl-O-alkyl for example-alkyl, wherein alkyl as above defines.
" carbonyl " used herein refer to-C (O)-.
Refer to=O of " oxo " used herein group.
" aminoalkyl group " used herein refers to structure (R x) 2n-alkyl-.
" cyano group alkyl " used herein refer to structure (NC)-alkyl-.
" urea " used herein group refers to structure-NR x-CO-NR yr z, and " thiocarbamide " group refers to structure-NR when using endways x-CS-NR yr z, refer to-NR when using in inside x-CO-NR y-or-NR x-CS-NR y-, R wherein x, R yand R zas above definition.
" guanidine " used herein group refers to structure N=C (N (R xr y)) N (R xr y) or-NR x-C (=NR x) NR xr y, R wherein xand R yas above definition.
" amidino groups " used herein refers to structure-C=(NR x) N (R xr y), R wherein xand R yas above definition.
Term used herein " neighbour " refers to places substituting group comprising on the group of two or more carbon atoms, and wherein substituting group is connected with adjacent carbon atom.
Term used herein " together with " refer to and place substituting group comprising on the group of two or more carbon atoms, wherein substituting group connects with identical carbon atom.
Term used herein " end " and " inside " refer to the position of group in substituting group.When group is present in substituent end and during not with the other bonding of rest part of chemical structure, this group endways.Carboxyalkyl (that is, R xan example of carboxyl O (O) C-alkyl) using for end.When group is not inner endways time.Alkyl carboxyl (for example, alkyl-C (O)-O-or alkyl-O-C (O)-) and alkyl carboxyl aryl (for example, alkyl-C (O)-O-aryl-or alkyl-O-C (O)-aryl-) are the example of the inner carboxyl using.
" ring " used herein group comprises monocycle, dicyclo and three ring member ring systems, for example cyclic aliphatic, heterocycle aliphatic series, aryl and heteroaryl, and wherein each as above defines.
" the dicyclo member ring systems of bridging " used herein refers to and wherein encircles the heterocycle aliphatic series member ring systems of the dicyclo that is bridging or the cyclic aliphatic member ring systems of dicyclo.The example of the dicyclo member ring systems of bridging includes but not limited to adamantyl, norborneol alkyl, dicyclo [3.2.1] octyl group, dicyclo [2.2.2] octyl group, dicyclo [3.3.1] nonyl, dicyclo [3.2.3] nonyl, 2-oxabicyclo [2.2.2] octyl group, 1-azabicyclo [2.2.2] octyl group, 3-azabicyclo [3.2.1] octyl group and 2,6-dioxa-tri-ring [3.3.1.0 3,7] nonyl.The dicyclo member ring systems of bridging can optionally be replaced by one or more substituting groups, described substituting group for example alkyl (comprises carboxyalkyl, hydroxyalkyl and haloalkyl be trifluoromethyl for example), thiazolinyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, Heterocyclylalkyl, (Heterocyclylalkyl) alkyl, aryl, heteroaryl, alkoxyl group, cycloalkyloxy, heterocycle alkoxyl group, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, aroyl, 4-hetaroylpyrazol, nitro, carboxyl, alkoxy carbonyl, alkyl carbonyl oxy, aminocarboxyl, alkyl-carbonyl-amino, cycloalkyl amino carbonyl, (cycloalkylalkyl) carbonylamino, aryl-amino-carbonyl, aromatic alkyl carbonyl is amino, (Heterocyclylalkyl) carbonylamino, (Heterocyclylalkyl alkyl) carbonylamino, heteroaryl carbonylamino, heteroaralkyl carbonylamino, cyano group, halogen, hydroxyl, acyl group, sulfydryl, alkyl alkylthio base, sulphur oxygen base, urea, thiocarbamide, sulfamyl, sulphonamide, oxo and formamyl.
" aliphatic chain " used herein refers to branching or linear aliphatic group (for example, alkyl, alkenyl or alkynyl).Linear aliphatic chain has structure-(CH 2) v-, wherein v is 1-6.The linear aliphatic chain of the aliphatic chain of branching for being replaced by one or more aliphatic groups.The aliphatic chain of branching has structure-(CHQ) v-, wherein v is 1-6, and Q is hydrogen or aliphatic group; Yet Q should be aliphatic group at least one situation.Term aliphatic chain comprises alkyl chain, alkenylene chain and alkynyl chain, and wherein alkyl, thiazolinyl and alkynyl as above define.
Phrase used herein " is optionally substituted " " to be substituted or not to be substituted " with phrase and is used interchangeably.Compound of the present invention described herein can optionally be replaced by one or more substituting groups, for example summary description above of described substituting group, or specific category of the present invention, subclass and thing class be illustrated.Variable R described herein 1, R 2, R 3and R 4and other variable comprises specific group, for example alkyl and aryl.Unless otherwise indicated, otherwise for variable R 1, R 2, R 3and R 4other variable wherein comprising, each specific group can optionally be replaced by one or more substituting groups described herein.Each substituting group of special groups is further optionally replaced by 1-3 halogen, cyano group, oxo, alkoxyl group, hydroxyl, amino, nitro, aryl, cyclic aliphatic, heterocycle aliphatic series, heteroaryl, haloalkyl and alkyl.For example, alkyl can be replaced by alkyl alkylthio base, and alkyl alkylthio base can optionally be replaced by 1-3 halogen, cyano group, oxo, alkoxyl group, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl.As other example, the cycloalkyl moiety of (cycloalkyl) carbonylamino can optionally be replaced by 1-3 halogen, cyano group, alkoxyl group, hydroxyl, nitro, haloalkyl and alkyl.When two alkoxyl groups and identical atom or adjacent atom in conjunction with time, the atom that two alkoxyl groups can be attached to them forms ring jointly.
Term used herein " is substituted ", no matter whether has term " optionally " above, refers to the substituent group displacement hydrogen group of using appointment in given structure.Concrete substituting group is described in above definition and following compound is described and embodiment in.Unless otherwise indicated, otherwise optional substituted group can have substituting group in each commutable position of group, and when more than one position in any given structure can be replaced by the more than one substituting group that is selected from the group of appointment, can be identical or different at each position substituting group.Ring substituents (for example Heterocyclylalkyl) can encircle with another (for example cycloalkyl) combination, and to form spiral shell-dicyclo member ring systems, that is, two rings are shared a shared atom.The present invention expection substituent be combined as cause forming stable or in those combinations of chemically feasible compound.
Phrase used herein " stable or chemically feasible " refer to when stand certain condition with allow their production, detection and preferably they recovery, purifying and during for the purposes of one or more objects disclosed herein, substantially indeclinable compound.In some embodiments, stable compound or at chemically feasible compound for when remaining at 40 ℃ or lower temperature, moisture or other chemical reactivity condition not in the presence of, it does not substantially change within least one week.
Phrase used herein " enantioselectivity ground preparation " refers to that asymmetric synthesis preparation is rich in enantiotopic compound.This is further defined as one or more technology of using, with the compound of high enantiomerism excessive (that is, 60% or more) preparation expectation.The technology comprising can comprise uses chiral raw material (for example, chirality pond is synthetic), uses chiral auxiliary(reagent) and chiral catalyst, and applies asymmetric induction.
" enantiomerism is excessive " used herein or " e.e. " refer to the optical purity of compound.
" interior type: external form " used herein refers to the ratio of endo isomer and exo isomer.
" enantiomerism ratio " used herein or " e.r. " are the ratio of a kind of per-cent of enantiomer and the per-cent of another kind of enantiomer in mixture.
" protecting group " used herein is defined as to be incorporated in molecule and in chemical reaction subsequently, reacts to prevent it to change the functional group being present in molecule, therefore obtains the group of chemo-selective.In step below in synthetic, it is removed from molecule.For example, the hydrogen on the replaceable amine of carbobenzoxy-(Cbz) (Cbz) group, to prevent that it from reacting with electrophilic reagent, Cbz group can be removed by hydrolysis in the step below subsequently.
Acid used herein and amine protecting group be known in the art (referring to; for example; T.W. Greene and P.G.M Wutz; " Protective Groups in Organic Synthesis (protecting group in organic synthesis) "; the 3rd edition; John Wiley & Sons, Inc. (1999)).Example for sour suitable protecting group comprises tert.-butoxy, benzyloxy, allyloxy and methoxymethoxy.The example that is used for the suitable protecting group of amine comprises 9-fluorenyl methyl carbamate, tertiary butyl carbamate, benzylamino manthanoate, trifluoroacetamide and para toluene sulfonamide.
" significant quantity " used herein is defined as and gives result for the treatment of required amount to the patient through treatment, and the age based on patient, surface-area, weight and situation are determined conventionally.The mutual relationship of animal and human's dosage (based on milli gram/m body surface) is described in the people such as Freireich, Cancer Chemother. Rep., 50:219 (1966).Body surface area can roughly be determined by patient's height and weight.Referring to, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970)." patient " used herein refers to and comprises people by Mammals.
Unless otherwise indicated, otherwise structure described herein is also intended to comprise all isomeric form (for example, enantiomerism, diastereo-isomerism and how much (or conformation) isomeries) of structure; For example,, for the R of each asymmetric center and S configuration, (Z) and (E) double bond isomer and (Z) and (E) conformer.Therefore, the single three-dimensional chemical isomer of compound of the present invention and enantiomerism, diastereo-isomerism and how much (or conformation) heterogeneous mixtures are within the scope of the invention.Unless otherwise indicated, otherwise all tautomeric forms of compound of the present invention within the scope of the invention.
In addition, unless otherwise indicated, otherwise being also intended to comprise difference, structure described herein is only to exist one or more compounds that are rich in isotopic atom.For example,, except being replaced hydrogen or be rich in by deuterium or tritium 13c or 14the carbon displacement carbon of C, has the compound of structure of the present invention within the scope of the invention.Such compound for example can be used as analysis tool or probe in biology is measured.
" EDC " used herein is 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, " HOBt " is I-hydroxybenzotriazole, and " THF " is tetrahydrofuran (THF), and " Cbz " is carbobenzoxy-(Cbz), " DCM " is methylene dichloride, and " Boc " is tert-butoxycarbonyl.
Used herein " 1h NMR " represent proton magnetic resonance (PMR), " TLC " represents thin layer chromatography.
embodiment
On the one hand, the invention provides method and the intermediate for the production of the bicyclic derivatives of formula Ia or Ib:
Figure DEST_PATH_IMAGE020
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
Ring B is C 3-12heterocycle aliphatic series ring, it contains other 0-2 heteroatoms that is selected from independently of one another O, N and S, and it can optionally be replaced by 1-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group, aryl and hydroxyl;
R 1for H or protecting group; With
R 2for H or C 1-12aliphatic series.
In one embodiment, ring A is C 3-6cyclic aliphatic ring.
More especially, ring A is cyclopentyl.
More especially, ring A is .
In another embodiment, ring A is cyclopropyl.
More especially, ring A is 1,1-dimethyl cyclopropyl.
More especially, ring A is
Figure DEST_PATH_IMAGE024
.
In one embodiment, ring B is aryl.
More especially, ring B is phenyl.
More especially, ring B is:
Figure DEST_PATH_IMAGE026
.
In one embodiment, ring B is the ring of 5 yuan of heterocycles.
In one embodiment, ring B is:
Figure DEST_PATH_IMAGE028
.
In another embodiment, ring B is replaced by aryl rings, and described aryl rings is optionally replaced by 1-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group and hydroxyl.
More especially, ring B is:
Figure DEST_PATH_IMAGE030
。
In one embodiment, R 1for H.
In another embodiment, R 1for protecting group.
More especially, R 1for tertiary butyl carbamate (Boc).
In one embodiment, R 2for H.
In another embodiment, R 2for C 1-12aliphatic series.
More especially, R 2for C 1-6alkyl.
In one embodiment, R 2for methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, normal-butyl, the tertiary butyl, n-pentyl or isopentyl.
More especially, R 2for isobutyl-.
In another embodiment, R 2for the tertiary butyl.
In another embodiment, R 2for cyclic aliphatic ring.
Relate on the other hand a kind of for the compound via formula Ic to Ih, the method for the compound of enantioselectivity ground preparation formula Ia or Ib:
Figure DEST_PATH_IMAGE032
。
Under existing, the compound that described method is included in formula III makes the step of the compound carboxylation of formula IIa or IIb:
Figure DEST_PATH_IMAGE034
，
R wherein a1for protecting group,
Figure DEST_PATH_IMAGE036
；
R wherein 3and R 4be protecting group, C independently of one another 1-12aliphatic series or be selected from the cyclic group of cyclic aliphatic, heterocycle aliphatic series, aryl and heteroaryl.
In one embodiment, R 1afor tertiary butyl carbamate (Boc).
In one embodiment, make the step of the compound carboxylation of formula II have the compound of formula III a:
Figure DEST_PATH_IMAGE038
。
In another embodiment, make the step of the compound carboxylation of formula II have the compound of formula III b:
Figure DEST_PATH_IMAGE040
。
In another embodiment, make the step of the compound carboxylation of formula II have the compound of formula III c:
Figure DEST_PATH_IMAGE042
。
In another embodiment, make the step of the compound carboxylation of formula II have the compound of formula III d:
Figure DEST_PATH_IMAGE044
。
In another embodiment, make the step of the compound carboxylation of formula II have the compound of formula III e:
Figure DEST_PATH_IMAGE046
。
In one embodiment, R 3for C 1-12aliphatic series.
More especially, R 3for C 1-4non-branching alkyl.
In one embodiment, R 4for C 1-4non-branching alkyl
In another embodiment, R 4for the C being replaced by cyclic group 1-4branched-alkyl.
More especially, R 4for the C being substituted by phenyl 1-4branched-alkyl.
In one embodiment, R 4for cyclic group.
More especially, R 4for bicyclic radicals.
In one embodiment, carboxylation step comprises and with carbonic acid gas and lithium alkali, under aprotic solvent exists, processes the compound of formula IIa or IIb.
In one embodiment, aprotic solvent is selected from toluene, ethyl acetate, benzene and methyl tertiary butyl ether (MTBE).
More especially, aprotic solvent is MTBE.
In one embodiment, lithium alkali is s-butyl lithium.
In one embodiment, method of the present invention obtains comprising the mixture of the product of I-1a (external form), I-3 (external form), I-2 (interior type) and I-4 (interior type).
In one embodiment, after carboxylation, in the mixture of the compound (endo isomer) of the compound that comprises formula Ia and Id (exo isomer) and formula Ic and Ie, the weight percent of combination is 100 % by weight.
In one embodiment, the ratio of the combination weight per-cent of the combination weight per-cent of Ia and Id (exo isomer) and Ic and Ie (endo isomer) is 60:40 at least.
More especially, external form/interior type ratio is 80:20 at least.
More especially, external form/interior type ratio is 90:10 at least.
More especially, external form/interior type ratio is 95:5 at least.
More especially, external form/interior type ratio is 97:3 at least.
In one embodiment, described method also comprises the step of removing the compound of a part of formula Ic and/or Ie from product mixtures.
More especially, by making the compound crystal of formula Ia or Ib, remove the compound of formula Ic and/or Ie.
In another embodiment, by making the compound recrystallization of formula Ia or Ib, remove the compound of formula Ic and/or Ie.
In one embodiment, the ratio of the weight percent of Ia and Id is 60:40 at least.
More especially, the ratio of the weight percent of Ia and Id is 80:20 at least.
More especially, the ratio of the weight percent of Ia and Id is 90:10 at least.
More especially, the ratio of the weight percent of Ia and Id is 95:5 at least.
More especially, the ratio of the weight percent of Ia and Id is 99:1 at least.
More especially, the ratio of the weight percent of Ia and Id is 99.6:0.4 at least.
More especially, the ratio of the weight percent of Ia and Id is 100:0 at least.
A kind of method that relates on the other hand compound for the preparation of formula 10:
Figure DEST_PATH_IMAGE048
，
R wherein 2for H, C 1-12aliphatic series or protecting group, and Z 2for H or protecting group, said method comprising the steps of:
A. under existing, the compound of formula III forms the 2-negatively charged ion of the compound of formula IIa:
Figure DEST_PATH_IMAGE050
，
R wherein 1aa as above defines with ring,
Figure DEST_PATH_IMAGE052
R wherein 3and R 4as above definition;
B. use the 2-negatively charged ion of carbon dioxide treatment step a, with the compound of enantioselectivity ground production Ia; With
C. make the compound of formula Ia react with the compound of formula 26:
，
Z wherein 3for protecting group.
In one embodiment, the compound of formula III is the compound of formula III a.
In another embodiment, the compound of formula III is the compound of formula III b.
In one embodiment, the compound of formula 26 is the compound of formula 26-a:
。
In another embodiment, the compound of formula 26 is the compound of formula 26-b:
Figure DEST_PATH_IMAGE058
。
Relate in one aspect to the compound of the formula Ia-1 preparing by method disclosed herein:
。
The compound that relates on the other hand the formula Ia-2 preparing by method disclosed herein:
Figure DEST_PATH_IMAGE062
。
The compound that relates on the other hand the formula Ia-3 preparing by method disclosed herein:
Figure DEST_PATH_IMAGE064
。
The compound that relates on the other hand the formula Ia-4 preparing by method disclosed herein:
Figure DEST_PATH_IMAGE066
。
Relate in one aspect to the compound of the formula 10-a preparing by method disclosed herein:
。
In one embodiment, the compound of formula 10 is the compound of formula 10-a, wherein Z 2for H, and R 2for the tertiary butyl.
The compound that relates on the other hand the formula 10-b preparing by method disclosed herein:
Figure DEST_PATH_IMAGE070
。
The compound that relates on the other hand the formula 10-c preparing by method disclosed herein:
Figure DEST_PATH_IMAGE072
。
In one embodiment, the compound of formula 10 is the compound of formula 10-b, wherein Z 2for H, and R 2for the tertiary butyl.
The compound that relates on the other hand the formula 10-d preparing by method disclosed herein:
Figure DEST_PATH_IMAGE074
。
method and intermediate
On the one hand, the invention provides a kind of method and intermediate of the compound for the preparation of formula Ia, as scheme I general introduction, wherein R 1, R 2, R 3, R 4with ring A as previously defined.
Scheme I
Figure DEST_PATH_IMAGE076
By first form the 2-negatively charged ion of formula IIa under the compound of formula III exists, realize the carboxylation of the compound of formula IIa.In order to form similar negatively charged ion, referring to, for example, the people such as Daniel. J. Pippel, J. Org. Chem., 1998,63,2; The people such as Donald J. Gallagher, J. Org. Chem., 1995,60 (22), 7092-7093; The people such as Shawn T. Kerrick, J. Am. Chem. Soc., 1991,113 (25), 9708-9710; The people such as Donald J. Gallagher, J. Org. Chem., 1995,60 (25), 8148-8154; With the people such as Peter Beak, J. Am. Chem. Soc., 1994,116 (8), 3231-3239.Under existing by the compound at formula III, with strong lithium alkali (for example, s-butyl lithium or isopropyl lithium) for example, in suitable aprotic solvent (, MTBE, Anaesthetie Ether or the toluene) compound of processing formula IIa, the 2-negatively charged ion of preparation formula IIa (not showing in scheme I).
The optically active compound of formula III can be induced enantioselectivity carboxylation, with obtain having the enantiomerism excessive (e.e.) of about 10%-approximately 95% product (referring to, for example, the people such as Beak, J. Org. Chem., 1995,60,8148-8154).Under formula III exists, the compound of formula IIa can be used carbon dioxide treatment, and to obtain the mixture of external form/interior type compound, wherein external form/interior type ratio is 60:40,80:20,90:10,95:5 or is greater than 98:2.
Reference scheme I, is used the compound of known method preparation formula IIa, wherein R 1afor for example tert-butoxycarbonyl (Boc).Referring to, for example, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (protecting group in organic synthesis), the 3rd edition, John Wiley and Sons, Inc. (1999).
The compound of formula III can be prepared as shown in scheme IIA.
Scheme IIA
Figure DEST_PATH_IMAGE078
Work as R 3and R 4when identical, the compound of formula III can be prepared by substituted derivative of piperidone and formaldehyde or formaldehyde equivalent condensation.
Or the compound of formula III can be prepared as shown in scheme IIB.
Scheme IIB
Figure DEST_PATH_IMAGE080
Work as R 3and R 4when different, the amine of commercially available two protections can be used for preparing via the sequence of the known selectivity deprotection reaction of professional and technical personnel and other transformation the compound of formula III.
The compound that scheme III describes formula 26 reacts with the compound of formula Ia, to form the compound of formula 28, wherein R 2as above definition.
Scheme III
Figure DEST_PATH_IMAGE082
In scheme III, under coupling reagent exists, the bicyclic amino group ester of formula Ia (R wherein 2for the tertiary butyl) react (Z wherein with the shielded amino acid of formula 26 3for amine protecting group, and can under acidity, alkalescence or hydrogenation conditions, remove, described condition is different from for removing R 2those of protecting group), to obtain the amide-ester of formula 10.From the amide-ester of formula 10, remove protecting group Z 2, to obtain the amine-ester compound of formula 28.
In another embodiment, the compound of formula 28 is the intermediate in synthesizing according to the proteinase inhibitor of scheme IV.
Scheme IV
Figure DEST_PATH_IMAGE084
Scheme IV is disclosed in U.S. Patent number 7,776,887, and its all content is incorporated herein by reference.
In scheme IV, under coupling reagent exists, (it can as described hereinly prepare the bicyclic amino group ester of formula Ia, wherein R 2for the tertiary butyl) react (Z wherein with the shielded amino acid of formula 26 2for amine protecting group, and can under acidity, alkalescence or hydrogenation conditions, remove, described condition is different from for removing R 2those of protecting group), to obtain the amide-ester of formula 10.From the amide-ester of formula 10, remove protecting group Z 2, to obtain the amine-ester compound of formula 28.Under coupling reagent exists, reacting with shielded amino acid 29 containing aminocompound of formula 28, obtains the tripeptides of formula 30.Remove the protecting group Z in the tripeptides of formula 30, the free amino-tripeptides of formula 31 is provided.Under coupling reagent exists, the amino-tripeptides of formula 31 reacts with pyrazine-2-formic acid of formula 32, obtains the acid amides-tripeptide ester of formula 33.Make the ester hydrolysis of the acid amides-tripeptide ester of formula 33, the amido-tripeptide acid of formula 34 is provided.Under coupling reagent exists, the amido-tripeptide acid of formula 34 reacts with the amino-oxyamide of formula 18, obtains the hydroxyl-peptide of formula 35.In last step, make the hydroxyl oxidize of the compound of formula 35, the compound of formula 4 is provided.
In another embodiment, the method for scheme III can be amplified in proportion for scale operation, for example, and in manufactory.Scale operation can for example be amplified in proportion and be greater than 1000 kilograms.
Although in the some parts of scheme I-IV, for some compounds, individual isomer is only described, the present invention is intended to comprise all steric isomers of compound.
Describe following non-limiting example, make to more fully understand the present invention.These embodiment are only for illustration purpose, and should not regard as by any way and limit the scope of the invention.
Embodiment
Embodiment 1:N-tert-butoxycarbonyl-3-azabicyclo [3.3.0] octane (6).
Figure DEST_PATH_IMAGE086
Method 1
Under nitrogen, band stirs, in the 2L tri-neck round-bottomed flasks of outfit mechanical stirrer, 500 mL feed hoppers and thermometer, pack 3-azabicyclo [3.3.0] nonane hydrochloride (100 g into, 0.677 mol), salt of wormwood (187 g, 1.35 mol), MTBE (220 mL) and water (160 mL).Mixture is cooled to 14-16 ℃.In 500 mL Erlenmeyer flasks, pack Boc into 2o (di-tert-butyl dicarbonic acid ester) (145 g, 0.644 mol) and MTBE (190 mL).Stir the mixture, until complete dissolving.Solution poured in feed hopper and join in reaction mixture, keeping temperature of reaction lower than 25 ℃.Add water (290 mL), with dissolved solids, and mixture is stirred to 10-15 minute.Remove after water 5% water-based NaHSO for organic phase 4washing (twice, each 145 mL), then water (145 mL) washing.Organic phase is concentrated, add MTBE (1.3 L), to obtain the MTBE solution of title compound.Referring to, for example, R.Griot, Helv. Chim. Acta., 42,67 (1959).
Method 2
By salt of wormwood (187 g, 1.35 mol) water (160 mL) solution joins 3-azabicyclo [3.3.0] octane hydrochloride (100 g, 0.677 mol) and in the mixture of MTBE (220 mL), by resulting, mixture is cooled to 14-16 ℃.Add Boc 2mTBE (190 mL) solution of O (145 g, 0.644 mol) keeps temperature lower than 35 ℃ simultaneously.After adding, mixture is stirred 1 hour to subsequent filtration.MTBE for solid (50 mL) washing.Separation of phases subsequently, 5% water-based NaHSO for organic phase 4the washing of (twice, each 145 mL) and water (145 mL).Under vacuum, be concentrated into subsequently 300 mL.Add MTBE (300 mL), mixture is concentrated, to reduce water concentration to being less than 550 ppm.With MTBE (400 mL) dilution enriched material, so that the MTBE solution of title compound to be provided.
Embodiment 2:(1S, 3aR, 6aS)-tertiary butyl 2-((S)-2-(benzyl oxygen base carbonylamino)-3,3-dimethyl butyrate acyl group) octahydro pentamethylene [c] pyrroles-1-manthanoate (27) also.
Figure DEST_PATH_IMAGE088
Method 1
Be equipped with the 3L tri-neck round-bottomed flask nitrogen purging several minutes of overhead, condenser, thermopair and nitrogen outlet.In independent flask, the water dilution of 442 mL for sulfuric acid (46.2 mL, 0.867 mol).Make solution slightly cooling.In reaction flask, pack Cbz-L-Terleu dicyclohexyl amine salt (330.0 g, 0.739 mol) into.MTBE (1620 mL) is joined in reactor, stir the mixture, so that salt suspension.The sulphuric acid soln of as above preparation was joined in reactor through approximately 10 minutes, maintain the temperature at 20 ± 5 ℃.At room temperature, by mixture stir about 1 hour, water (455 mL) slowly dilutes subsequently.Stop stirring, make each layer of sedimentation.Take out water, so that the colourless solution of the pH 1 of 1100mL to be provided.In remaining organic phase in flask, pack other water (200 mL) into.At room temperature by mixture stir about 1 hour.Stop stirring, make each layer of sedimentation.Take out water, so that the colourless solution of the pH 2 of 500mL to be provided.Organic phase is heated to approximately 35 ℃, with DMF (300 mL) dilution, under decompression, is concentrated into the point that distillation is significantly slowed down, leave the enriched material of approximately 500 mL.Without rinsing, enriched material is transferred to the Xiao Te bottle of 1L.Enriched material (colourless solution of clarification) weighs 511.6 g.Based on measured in solution analysis and solution weight, solution contains 187.2 g (0.706 mol) carboxyl benzyl-S-Leucines (Cbz-L-Terleu).
To being equipped with in the four neck round-bottomed flasks of 5L of overhead, thermopair, feed hopper and nitrogen inlet, pack HOBTH into 2o (103.73 g, 0.678 mol, 1.20 molar equivalents), EDCHCl (129.48 g, 0.675 mol, 1.20 molar equivalents) and DMF (480 mL).Slurry is cooled to 0-5 ℃.The sour DMF of the Cbz-L-Terleu of 36.6 % by weight (491.3 g, 0.745 mol, 1.32 molar equivalents) solution was joined in reaction mixture through 47 minutes, maintain the temperature at 0-5 ℃ simultaneously.Reaction mixture is stirred 1 hour 27 minutes.The isopropyl acetate of 3-azabicyclo (3.3.0) octane-2-formic acid-tertiary butyl ester (28.8 % by weight, 414.3 g, 0.564 mol) solution was added through 53 minutes, keep temperature of reaction at 0-5.1 ℃ simultaneously.Reaction mixture was warmed to 20 ± 5 ℃ through approximately 1 hour.4-methylmorpholine (34.29 g, 0.339 mol, 0.60 molar equivalent) was added through 5 minutes.Reaction mixture is stirred 16 hours, subsequently isopropyl acetate (980 mL) is joined in reaction soln.In 4 minutes, water (53.02 g) solution of histamine 2 HCl (41.58 g, 0.226 mol, 0.40 molar equivalent) is joined in reaction mixture, then add 4-methylmorpholine (45.69 g, 0.45 mol, 0.80 molar equivalent).After 3.5 hours, to reaction mixture sampling.Add water (758 mL), by mixture stir about 20 minutes, sedimentation subsequently 11 minutes.Separation of phases.Isopropyl acetate for water (716 mL) extraction, merges organic phase.By add 37 % by weight hydrochloric acid (128.3 mL) in water (1435 ml), preparation 1 N water-based hydrochloric acid.Organic phase is used 1N salt acid elution approximately 20 minutes.By dissolving salt of wormwood (171 g, 1.23 mol, 2.19 molar equivalents) in water (1540 mL), preparation 10 % by weight water-based solution of potassium carbonate.Organic phase is washed approximately 20 minutes with 10 % by weight water-based solution of potassium carbonate.The light yellow organic solution (1862.1 g) that samples final clarification, stands measured in solution.Weight based on measured in solution and solution, the product of the title compound that solution contains 238.3 g (0.520 mol).
1H?NMR?(DMSO-d 6，500?MHz)：δ?7.37?ppm?(5?H，s)，7.25-7.33?ppm?(1?H，m)，5.03?ppm?(2?H，s)，4.17?ppm?(1?H，d)，3.98?ppm?(1?H，d)，3.67-3.75?ppm?(2?H，m)，2.62-2.74?ppm?(1?H，m)，2.48-2.56?ppm?(1?H，m)，1.72-1.89?ppm?(2?H，m)，1.60-1.69?ppm?(1?H，m)，1.45-1.58?ppm?(2?H，m)，1.38?ppm?(9?H，s)，1.36-1.42?ppm?(1?H，m)，0.97?ppm?(9?H，s)。
Method 2
The water of salt of wormwood (73.3 g) (220 mL) solution is joined to (1S, 2S, 5R), in isopropyl acetate (400 mL) suspension of 3-azabicyclo [3.3.0] octane-2-carboxyl-tertiary butyl ester-barkite (80.0 g), keep temperature is approximately 20 ℃ simultaneously.Mixture is stirred 0.5 hour, separation of phases, organic phase is washed with 25 % by weight water-based salt of wormwood (80 mL), to obtain the solution of free alkali.In independent flask, sulfuric acid (400 mL, 0.863 M) is joined in t-butyl methyl ether (640 mL) suspension of Cbz-Terleu dicyclohexyl amine salt (118.4g), keep temperature is approximately 20 ℃ simultaneously.Mixture is stirred 0.5 hour to separation of phases, organic phase water (200 mL) washing.Separation of phases, joins N-methylmorpholine (80 mL) in organic phase, it is evaporated at 40 ℃ to 80 mL, to obtain the solution of free acid in N-methylmorpholine.At 0-10 ℃, this solution is joined in the mixture/N-methylmorpholine (280 mL) of EDC HCl (50.8 g) and HOBt hydrate (40.6 g).At approximately 5 ℃, mixture is stirred 1 hour.At 0-20 ℃, add from above 3-azabicyclo [3.3.0] octane-2-carboxyl, the solution of tertiary butyl ester, then adds N-methylmorpholine (32 mL).Mixture being stirred 6 hours, use subsequently isopropyl acetate (600 mL) dilution, is then 1 N hydrochloric acid (400 mL) dilution.Stir after 0.5 hour separation of phases, 25 % by weight water-based salt of wormwood (400 mL) and water (80 mL) washing for organic phase.By mixture stir about 1 hour, separation of phases, to obtain the isopropyl acetate solution of title compound.
Method 3
By (1S, 2S, 5R) 3-azabicyclo [3.3.0] octane-2-carboxyl-tertiary butyl ester-barkite (1.0 equivalent) is suspended in isopropyl acetate (6 volume), at 20-25 ℃, adds water (3.5 volume) solution of salt of wormwood (3.0 equivalent).Mixture is stirred 3 hours, subsequently separation of phases.Organic phase water (2 volume) washing.
Cbz-Terleu dicyclohexyl amine salt (1.05 equivalent) is suspended in isopropyl acetate (6 volume), at 20-25 ℃, adds sulfuric acid (1.3 equivalent)/water (5 volume).Mixture is stirred 30 minutes to separation of phases, organic phase water (2 times, 2.5 volumes) washing.
Two kinds of solution combinations by from above, are cooled to 0-5 ℃ subsequently.HOBt hydrate (1.1 equivalent) and EDC (1.1 equivalent) are suspended in mixture, mixture is stirred 6 hours.Mixture water (5 volume) washing, at 20-25 ℃, resulting 1B (1 equivalent) and N-methylmorpholine (2 equivalent) processing for organic phase, to destroy excessive Acibenzolar.Mixture is used 5% salt of wormwood (5 volume), 1 N hydrochloric acid (5 volume), 5% salt of wormwood (5 volume) and water (twice, 5 volume) washing subsequently, to obtain the isopropyl acetate solution of title compound.
Embodiment 3:(1S, 3aR, 6aS)-tertiary butyl 2-((S)-2-amino-3,3-dimethyl butyrate acyl group)-octahydro pentamethylene [c] pyrroles-1-manthanoate (28) also.
Figure DEST_PATH_IMAGE090
Method 1
Nitrogen purging three times of the Buchi hydrogenator of 1L.To (the 1S that packs 12.8 % by weight of 307.8 g deals in reactor into; 3aR; 6aS)-tertiary butyl 2-((S)-2-(benzyl oxygen base carbonylamino)-3; 3-dimethyl butyrate acyl group) octahydro pentamethylene also [c] pyrroles-1-manthanoate (as embodiment 6; the method preparation of method 1) isopropyl acetate (39.39 g, 0.086 mol) solution.Isopropyl acetate (100 mL) is joined in reactor.Prepare 50% water and wet 20% Pd (OH) 2the slurry of/carbon (3.97 g) in isopropyl acetate (168 mL), and pack in reactor, start to stir.With nitrogen, reactor is forced into 30 psig, ventilates and be down to normal atmosphere.Repeat twice.Then, with hydrogen, reactor is forced into reactor, ventilates and be down to normal atmosphere.Repeat twice.With hydrogen, reactor is forced into 30 psig, and stirs at ambient temperature 1 hour.The Büchner funnel filtering mixt that use contains Whatman #1 filter paper, to remove catalyzer.Isopropyl acetate for filter cake (80 mL) washing.This program repeats twice again, uses the initial compounds solution of 12.8 % by weight of 617 g and 290.6 g.By the combination of materials from three hydrogenations, decompression (28 holder) distillation.Resulting solution (468.68 g) is measured to title compound.
1H?NMR?(DMSO-d 6，500?MHz)：δ?3.96?ppm?(1?H，d)，3.67?ppm?(1?H，dd)，3.53?ppm?(1?H，dd)，3.19?ppm?(1?H，s)，2.66-2.75?ppm?(1?H，m)，2.49-2.53?ppm?(1?H，m)，1.75-1.92?ppm?(2?H，m)，1.66-1.74?ppm?(1?H，m)，1.48-1.60?ppm?(4?H，m)，1.38?ppm?(9?H，s)，1.36-1.42?ppm?(1?H，m)，0.91?ppm?(9?H，s)。
Method 2
In hydrogenation equipment, will be from embodiment 6, the solution of the Cbz derivative 27 of method 2 joins 20% Pd (OH) 2in/water (50%, 12.2 g).Use hydrogen that equipment is forced into 30 psi, at approximately 20 ℃, stir 2 hours subsequently.Filtering mixt, to remove catalyzer, isopropyl acetate for filter cake (160 mL) washing.At 40 ℃, the filtrate of combination is evaporated 2-3 time with the heptane of approximately 4 volumes, to remove isopropyl acetate.By resulting, slurry is cooled to 0 ℃, filters, by product drying under reduced pressure, to obtain title compound.
Method 3
Will be from embodiment 6, (1S, 3aR, 6aS)-tertiary butyl 2-of method 3 ((S)-2-amino-3,3-dimethyl butyrate the acyl group)-octahydro pentamethylene also isopropyl acetate solution of [c] pyrroles-1-manthanoate joins 20% Pd (OH) 2in (2 % by weight loads, 50% wet), by mixture hydrogenation 2 hours at 2 bar and 20-25 ℃.By removing by filter catalyzer, and wash with isopropyl acetate (2 volume).At 40 ℃, concentrate filtrate to 10 volumes, to obtain the isopropyl acetate solution of title compound.
Although we have presented a plurality of embodiment of the present invention, it is evident that, can change our foundation structure, so that other embodiment of utilizing Compounds and methods for of the present invention to be provided.Therefore, it should be understood that scope of the present invention is defined by the following claims, rather than limited by the specific embodiments presenting as an example.

Claims (71)

1. the method for the compound of enantioselectivity ground preparation formula Ia or Ib:
Figure 2012800346140100001DEST_PATH_IMAGE001
，
The method is via the compound of formula Ic to Ih:
Figure 692135DEST_PATH_IMAGE002
，
Under existing, the compound that described method is included in formula III makes the step of the compound carboxylation of formula IIa or IIb:
Figure 2012800346140100001DEST_PATH_IMAGE003
，
Figure 609275DEST_PATH_IMAGE004
，
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
Ring B is C 3-12heterocycle aliphatic series ring, it contains other 0-2 heteroatoms that is selected from independently of one another O, N and S, wherein encircles B and optionally by 0-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group, aryl and hydroxyl, is replaced;
R 1for H or protecting group;
R 1afor protecting group;
R 2for H, protecting group or C 1-12aliphatic series; And
R 3and R 4be protecting group, C independently of one another 1-12aliphatic series or be selected from the cyclic group of cyclic aliphatic, heterocycle aliphatic series, aryl and heteroaryl.
2. the process of claim 1 wherein that ring A is C 3-6cyclic aliphatic ring.
3. the method for claim 2, wherein encircling A is cyclopentyl.
4. the method for claim 3, wherein encircles A and is
Figure 2012800346140100001DEST_PATH_IMAGE005
.
5. the method for claim 2, wherein encircling A is cyclopropyl.
6. the method for claim 5, wherein encircling A is 1,1-dimethyl cyclopropyl.
7. the method for claim 6, wherein encircles A and is .
8. the process of claim 1 wherein that ring B is aryl.
9. the method for claim 8, wherein encircling B is phenyl.
10. the method for claim 9, wherein encircles B and is .
11. the process of claim 1 wherein that ring B is the ring of 5 yuan of heterocycles.
The method of 12. claims 11, wherein encircles B and is .
13. the process of claim 1 wherein that ring B is replaced by aryl rings, and described aryl rings is optionally replaced by 0-4 group that is selected from independently of one another alkyl, halogen, alkoxyl group and hydroxyl.
The method of 14. claims 13, wherein encircle B and be:
Figure DEST_PATH_IMAGE009
。
15. the process of claim 1 wherein R 1for H.
16. the process of claim 1 wherein R 1for protecting group.
The method of 17. claims 16, wherein R 1for tertiary butyl carbamate (Boc).
18. the process of claim 1 wherein R 1afor protecting group.
The method of 19. claims 18, wherein R 1afor tertiary butyl carbamate (Boc).
20. the process of claim 1 wherein R 2for H.
21. the process of claim 1 wherein R 2for C 1-12aliphatic series.
The method of 22. claims 21, wherein R 2for C 1-6alkyl.
The method of 23. claims 22, wherein R 2be selected from methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, the tertiary butyl, normal-butyl, n-pentyl and isopentyl.
The method of 24. claims 23, wherein R 2for the tertiary butyl.
The method of 25. claims 21, wherein R 2for cyclic aliphatic ring.
26. the process of claim 1 wherein that the step of the compound carboxylation that makes formula IIa or IIb exists the compound of formula III a:
。
27. the process of claim 1 wherein that the step of the compound carboxylation that makes formula IIa or IIb exists the compound of formula III b:
。
28. the process of claim 1 wherein that the step of the compound carboxylation that makes formula IIa or IIb exists the compound of formula III c:
Figure 280111DEST_PATH_IMAGE012
。
29. the process of claim 1 wherein that the step of the compound carboxylation that makes formula IIa or IIb exists the compound of formula III d:
Figure 2012800346140100001DEST_PATH_IMAGE013
。
30. the process of claim 1 wherein that the step of the compound carboxylation that makes formula IIa or IIb exists the compound of formula III e:
Figure 875041DEST_PATH_IMAGE014
。
31. the process of claim 1 wherein R 3for C 1-12aliphatic series.
The method of 32. claims 31, wherein R 3for C 1-4non-branching alkyl.
33. the process of claim 1 wherein R 4for C 1-4branched-alkyl.
34. the process of claim 1 wherein R 4for the C being replaced by cyclic group 1-4branched-alkyl.
The method of 35. claims 34, wherein R 4for the C being substituted by phenyl 1-4branched-alkyl.
36. the process of claim 1 wherein R 4for cyclic group.
The method of 37. claims 36, wherein R 4for bicyclic radicals.
38. the process of claim 1 wherein that described carboxylation step comprises the compound of processing formula II with carbonic acid gas and lithium alkali in aprotic solvent.
The method of 39. claims 38, wherein said aprotic solvent is selected from toluene, ethyl acetate, benzene and methyl tertiary butyl ether MTBE.
The method of 40. claims 39, wherein said aprotic solvent is MTBE.
The method of 41. claims 38, wherein said lithium alkali is s-butyl lithium.
42. the process of claim 1 wherein that the weight percent of combination is 100 % by weight in the mixture of the compound (endo isomer) of the compound that comprises formula Ia and Id (exo isomer) and formula Ic and Ie.
The method of 43. claims 42, wherein said external form/interior type ratio is 60:40 at least.
The method of 44. claims 1, described method also comprises the compound of removing a part of formula Ic and Ie from described mixture.
The method of 45. claims 44, wherein by making the compound crystal of formula Ia remove the compound of formula Ic and Ie.
The method of 46. claims 44, wherein by making the compound recrystallization of formula Ia remove the compound of formula Ic and Ie.
47. the process of claim 1 wherein that the ratio of weight percent of Ia and Id is 60:40 at least.
48. 1 kinds of methods for the preparation of the compound of formula 10:
Figure 2012800346140100001DEST_PATH_IMAGE015
，
Said method comprising the steps of:
A. under existing, the compound of formula III forms the 2-negatively charged ion of the compound of formula IIa:
Figure 870678DEST_PATH_IMAGE016
，
Figure 2012800346140100001DEST_PATH_IMAGE017
；
B. use the negatively charged ion of carbon dioxide treatment step a, with the compound of enantioselectivity ground production Ia; With
C. under coupling reagent exists, the compound of formula Ia is reacted with the compound of formula 26,
Figure 539557DEST_PATH_IMAGE018
；
Wherein:
Ring A is C 3-12cyclic aliphatic ring;
R 1for H or protecting group;
R 2for H, protecting group or C 1-12aliphatic series;
R 3and R 4be protecting group, C independently of one another 1-12aliphatic series or be selected from the cyclic group of cyclic aliphatic, heterocycle aliphatic series, aryl and heteroaryl;
Z 2for H or protecting group; With
Z 3for protecting group.
The method of 49. claims 48, the compound of wherein said formula III is formula III a:
Figure 2012800346140100001DEST_PATH_IMAGE019
。
The method of 50. claims 48, the compound of wherein said formula III is formula III b:
Figure 595238DEST_PATH_IMAGE020
。
The method of 51. claims 48, the compound of wherein said formula III is formula III c:
Figure 2012800346140100001DEST_PATH_IMAGE021
。
The method of 52. claims 48, the compound of wherein said formula III is formula III d:
Figure 349567DEST_PATH_IMAGE022
。
The method of 53. claims 48, the compound of wherein said formula III is formula III e:
Figure 2012800346140100001DEST_PATH_IMAGE023
。
The method of 54. claims 48, the compound of wherein said formula 26 is formula 26-a:
Figure 414475DEST_PATH_IMAGE024
。
The method of 55. claims 48, the compound of wherein said formula 26 is formula 26-b:
Figure 2012800346140100001DEST_PATH_IMAGE025
。
The method of 56. claims 48, the compound of wherein said formula 10 is formula 10-a:
Figure 937860DEST_PATH_IMAGE026
。
The method of 57. claims 56, wherein Z 2for H, and R 2for the tertiary butyl.
The method of 58. claims 48, the compound of wherein said formula 10 is formula 10-b:
Figure 2012800346140100001DEST_PATH_IMAGE027
。
The method of 59. claims 48, the compound of wherein said formula 10 is formula 10-c:
Figure 167372DEST_PATH_IMAGE028
。
The method of 60. claims 59, wherein Z 2for H, and R 2for the tertiary butyl.
The method of 61. claims 48, the compound of wherein said formula 10 is formula 10-d:
Figure 2012800346140100001DEST_PATH_IMAGE029
。
62. 1 kinds of methods for the preparation of the compound of formula 4:
Figure 736894DEST_PATH_IMAGE030
，
Said method comprising the steps of:
A. under the compound of formula III exists, make compound and alkali and the CO of formula II-a 2reaction, with the compound of preparation formula I-1a;
B. under coupling reagent exists, the compound of formula Ia is reacted, to form the compound of formula 10 with the compound of formula 26;
C. from the compound of formula 10, remove Z 2, to obtain the compound of formula 28:
Figure 2012800346140100001DEST_PATH_IMAGE031
；
D. under coupling reagent exists, the compound of formula 28 is reacted with the compound of formula 29:
Figure 12017DEST_PATH_IMAGE032
To obtain the compound of formula 30:
Figure 2012800346140100001DEST_PATH_IMAGE033
Wherein Z is amine protecting group;
E. remove the protecting group Z in the compound of formula 30, to obtain the compound of formula 31:
Figure 717805DEST_PATH_IMAGE034
；
F. under coupling reagent exists, the compound of formula 31 is reacted with the compound of formula 32:
Figure 2012800346140100001DEST_PATH_IMAGE035
To obtain the compound of formula 33:
Figure 849709DEST_PATH_IMAGE036
；
G. make the ester hydrolysis of the compound of formula 33, to obtain the compound of formula 34:
；
H. under coupling reagent exists, the compound of formula 34 is reacted with the compound of formula 18:
Figure 578631DEST_PATH_IMAGE038
To obtain the compound of formula 35:
Figure 2012800346140100001DEST_PATH_IMAGE039
; With
I. make the compound oxidation of formula 35, to obtain the compound of formula 4.
The method of 63. claims 62, wherein said method is amplified in proportion for scale operation.
The compound of the 64. formula Ia-1 that prepare by the method for claim 1:
。
The compound of the 65. formula Ia-2 that prepare by the method for claim 1:
Figure 2012800346140100001DEST_PATH_IMAGE041
。
The compound of the 66. formula Ia-3 that prepare by the method for claim 1:
。
The compound of the 67. formula Ia-4 that prepare by the method for claim 1:
Figure 2012800346140100001DEST_PATH_IMAGE043
。
The compound of 68. its formula 10-a that prepare by the method for claim 48:
Figure 51703DEST_PATH_IMAGE044
。
The compound of the 69. formula 10-b that prepare by the method for claim 48:
Figure 2012800346140100001DEST_PATH_IMAGE045
。
The compound of the 70. formula 10-c that prepare by the method for claim 48:
Figure 2342DEST_PATH_IMAGE046
。
The compound of the 71. formula 10-d that prepare by the method for claim 48:
Figure 2012800346140100001DEST_PATH_IMAGE047
。
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