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HK1197229A1 - Process for the preparation of protease inhibitors - Google Patents

Process for the preparation of protease inhibitors Download PDF

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Publication number
HK1197229A1
HK1197229A1 HK14110522.0A HK14110522A HK1197229A1 HK 1197229 A1 HK1197229 A1 HK 1197229A1 HK 14110522 A HK14110522 A HK 14110522A HK 1197229 A1 HK1197229 A1 HK 1197229A1
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Hong Kong
Prior art keywords
formula
compound
ring
group
aliphatic
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HK14110522.0A
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Chinese (zh)
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Gerald J. Tanoury
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Vertex Pharmaceuticals Incorporated
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Publication of HK1197229A1 publication Critical patent/HK1197229A1/en

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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

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

Description

Process for preparing protease inhibitors
cross Reference to Related Applications
This application claims priority to U.S. provisional application No. 61/486,150, filed on 13/5/2011, which is incorporated herein by reference.
Technical Field
The present invention relates to processes and intermediates for the preparation of protease inhibitors, particularly serine protease inhibitors.
Background
Infection by hepatitis c virus ("HCV") is a medical problem of concern. HCV is considered to be a causative agent in most cases of non-A or non-B Hepatitis, with a human serum positivity estimated at 3% globally (A. Alberti et al, "Natural History of Hepatitis C (Natural History of Hepatitis C)", J. Hepatology, 31 (suppl.1), pp.17-24 (1999)). In the united states alone, nearly four million individuals may be infected. (M.J. Alter et al, "The Epidemiology of Viral Hepatitis in The United States" gastroenterol. Clin. North Am., 23, pp 437-455 (1994); M.J. Alter "Hepatitis C Virus Infection in The United States" J.hepatology, 31 (supplement 1), pp 88-91 (1999)).
When exposed to HCV for the first time, only about 20% of infected individuals develop acute clinical hepatitis, while others appear to resolve the infection spontaneously. However, in almost 70% of cases, virus establishment can persist for decades as a chronic infection. (S, Iward, "The Natural coupling of Chronic Hepatitis" FEMS Microbiology Reviews, 14, pp.201-204 (1994); D, Lavanchy, "Global scientific and Control of Hepatitis C)" J, visual Hepatitis, 6, pp.35-47 (1999)). Chronic infection over a long period of time can lead to recurrent and progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma. (M.C. Kew, "hepatis C and hepaticular Carbonisoma" FEMS Microbiology Reviews, 14, pp 211-220 (1994); I. Saito et al, "hepatis C Virus Infection is Associated with the Development of the Hepatocellular Carcinoma" Proc. Natl. Acad. Sci. USA, 87, pp 6547-6549 (1990)). Unfortunately, there is no widely effective treatment for the failure progression of chronic HCV.
Protease inhibitors, in particular serine protease inhibitors, may be used for the treatment of HCV infections as disclosed in WO 02/18369. WO 02/18369 also discloses processes and intermediates for preparing these compounds. These methods result in racemization of certain steric carbon centers. See, e.g., pages 223-22. As a result, there remains a need for enantioselective processes for preparing these compounds.
Summary of The Invention
This and other needs are met by the present invention, which is directed to processes and intermediates for the preparation of protease inhibitors, particularly serine protease inhibitors. In one aspect, the present invention provides processes and intermediates for the production of bicyclic derivatives of formula Ia or Ib:
wherein:
ring A is C3-12A cycloaliphatic ring;
ring B is C3-12A heterocycloaliphatic ring containing an additional 0-2 heteroatoms each independently selected from O, N and S, which may be optionally substituted with 1-4 groups each independently selected from alkyl, halo, alkoxy, aryl, and hydroxy;
R1is H or a protecting group; and
R2is H, a protecting group or C1-12Aliphatic.
One aspect relates to a process for the enantioselective preparation of compounds of formula Ia or Ib via compounds of formulae Ic to Ih:
。
the method comprises the step of carboxylating a compound of formula IIa or IIb in the presence of a compound of formula III:
，
wherein R is1aIs a protective group, and is characterized in that,
；
wherein R is3And R4Each independently is a protecting group, C1-12Aliphatic or cyclic groups selected from cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl;
another aspect relates to a process for preparing a compound of formula 10:
，
wherein R is2As defined above, and Z2Is H or a protecting group;
the method comprises the following steps:
a. forming a 2-anion of a compound of formula IIa in the presence of a compound of formula III:
，
wherein R is1aAnd ring a is as defined above, and,
，
wherein R is3And R4As defined above;
b. treating the 2-anion of step a with carbon dioxide to enantioselectively produce a compound of formula Ia; and
c. reacting a compound of formula Ia with a compound of formula 26:
，
wherein Z3Is a protecting group.
Detailed Description
Definition of
For the purposes of the present invention, the chemical elements are determined according to the periodic Table of the elements (CAS version, Handbook of Chemistry and Physics, 75 th edition). Further, general principles of Organic Chemistry are described in Thomas Sorrell's Organic Chemistry, University Science Books, Sausaltio (1999), and M.B. Smith and J. March's Advanced Organic Chemistry, 5 th edition, John Wiley & Sons, New York (2001), both of which are incorporated herein by reference.
The compounds of the invention described herein may be optionally substituted with one or more substituents, such as those outlined above, or as exemplified by specific classes, subclasses, and species of the invention.
It must be noted that, as used herein and in the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a binder" includes two or more binders, reference to "a pharmaceutical agent" includes two or more pharmaceutical agents, and the like.
The term "compound" as used herein refers to a compound defined by the structural formulae drawn accordingly herein. Furthermore, unless otherwise indicated, the term "compound" may include salts of the compounds.
The term "aliphatic" as used herein includes the terms alkyl, alkenyl, alkynyl and cycloaliphatic, each of which is optionally substituted as described below.
As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group containing 1 to 8 (e.g., 1 to 6 or 1 to 4) carbon atoms. The alkyl group may be linear, cyclic or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. The alkyl group may be substituted (i.e., optionally substituted) with one or more substituents selected from the group consisting of: halogen, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or (heterocycloaliphatic) carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, cycloaliphatic amino, or heterocycloaliphatic amino), sulfonyl (e.g., aliphatic-SO)2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aralkoxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy and hydroxy. Some examples of substituted alkyl groups include, without limitation, carboxyalkyl (e.g., HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl) alkyl, (sulfonylamino) alkyl (e.g., (alkyl-SO)2-amino) alkyl), aminoalkyl, amidoalkyl, (cycloaliphatic) alkyl and haloalkyl.
"alkenyl" as used herein refers to an aliphatic carbon group containing 2 to 8 (e.g., 2 to 6 or 2 to 4) carbon atoms and at least one double bond. As is alkyl, alkenylMay be straight-chain or branched. Examples of alkenyl groups include, but are not limited to, allyl, isoprenyl, 2-butenyl, and 2-hexenyl. The alkenyl group may be optionally substituted with one or more substituents such as halogen, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocycloalkenyl), aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl (e.g., (aliphatic) carbonyl, (cycloaliphatic) carbonyl, or (heterocycloaliphatic) carbonyl), nitro, cyano, amido (e.g., (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl), amino (e.g., aliphatic amino, cycloaliphatic amino, heterocycloaliphatic amino, or aliphatic sulfonylamino), Sulfonyl (e.g. alkyl-SO)2-, cycloaliphatic-SO2-or aryl-SO2-), sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, carboxy, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy and hydroxy. Some examples, without limitation, of substituted alkenyl groups include cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl) alkenyl, (sulfonylamino) alkenyl (e.g., (alkyl-SO)2-amino) alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic) alkenyl, and haloalkenyl.
"alkynyl" as used herein refers to an aliphatic carbon group containing 2-8 (e.g., 2-6 or 2-4) carbon atoms and having at least one triple bond. The alkynyl group may be linear or branched. Examples of alkynyl groups include, but are not limited to, propargyl and butynyl. Alkynyl groups may be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, aralkoxy, nitro, carboxyl, cyano, halogen, hydroxy, sulfo, mercaptoA radical, a sulfanyl group (e.g., aliphatic sulfanyl or cycloaliphatic sulfanyl), a sulfinyl group (e.g., aliphatic sulfinyl or cycloaliphatic sulfinyl), a sulfonyl group (e.g., aliphatic-SO)2-, aliphatic amino-SO2Or cycloaliphatic-SO2-), acylamino (e.g., aminocarbonyl, alkylaminocarbonyl, alkylcarbonylamino, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, cycloalkylcarbonylamino, arylaminocarbonyl, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (cycloalkylalkyl) carbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, or heteroarylaminocarbonyl), urea, thiourea, sulfamoyl, sulfonamide, alkoxycarbonyl, alkylcarbonyloxy, cycloaliphatic, heterocycloaliphatic, aryl, heteroaryl, acyl (e.g., (cycloaliphatic) carbonyl or (heterocycloaliphatic) carbonyl), amino (e.g., aliphatic amino), sulfoxy, oxo, carboxyl, carbamoyl, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, and (heteroaryl) alkoxy.
As used herein, "amido" includes both "aminocarbonyl" and "carbonylamino". These terms, when used alone or in combination with another group, when used terminally refer to an amido group such as-N (R)X)-C(O)-RYor-C (O) -N (R)X)2When used internally they refer to amide groups such as-C (O) -N (R)X) -or-N (R)X) -C (O) -, wherein RXAnd RYAs defined below. Examples of acylamino groups include alkylamido (e.g., alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic) acylamino, (heteroaralkyl) acylamino, (heteroaryl) acylamino, (heterocycloalkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido, and cycloalkylamido.
As used herein, "amino" refers to-NRXRYWherein R isXAnd RYEach of which is independently selected from the group consisting of hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic) aliphatic, aryl, araliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, heteroaryl, carboxy, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonylA group, (cycloaliphatic) carbonyl, a ((cycloaliphatic) aliphatic) carbonyl, arylcarbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, a ((heterocycloaliphatic) aliphatic) carbonyl, (heteroaryl) carbonyl, and a (heteroarylaliphatic) carbonyl, each of which is as defined herein and optionally substituted. Examples of the amino group include alkylamino, dialkylamino and arylamino. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it is denoted-NRX-。RXHave the same meaning as defined above.
As used herein, "aryl" alone or as part of a larger moiety (as in "aralkyl", "aralkoxy", or "aryloxyalkyl"), refers to monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl), and tricyclic (e.g., fluorenyl, tetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems, wherein the monocyclic ring system is aromatic, or at least one ring in the bicyclic or tricyclic ring systems is aromatic. Bicyclic and tricyclic groups include benzo-fused 2-to 3-membered carbocyclic rings. For example, the benzo-fused group includes a group with two or more C4-8Phenyl fused to a carbocyclic moiety. Aryl is optionally substituted with one or more substituents, such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroarylaliphatic) oxy, aroyl, heteroaroyl, amino, oxo (on the non-aromatic carbocyclic ring of the benzo-fused bicyclic or tricyclic aryl), nitro, carboxyl, amido, acyl (e.g., aliphatic carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroarylaliphatic) carbonyl), sulfonyl (e.g., aliphatic-SO)2-or amino-SO2-), sulfinyl (e.g., aliphatic-S (O) -or cycloaliphatic-S (O) -), sulfanyl (e.g., aliphatic-S-), cyano, halogen, hydroxy, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, and carbamoyl. Alternatively, the aryl group may haveIs substituted.
Non-limiting examples of substituted aryl groups include haloaryl (e.g., (monohalo) aryl, (dihalo) aryl (e.g., p-dihaloaryl, m-dihaloaryl), or (trihalo) aryl), (carboxy) aryl (e.g., (alkoxycarbonyl) aryl, ((aralkyl) carbonyloxy) aryl, or (alkoxycarbonyl) aryl), (amido) aryl (e.g., (aminocarbonyl) aryl, (((alkylamino) alkyl) aminocarbonyl) aryl, (alkylcarbonyl) aminoaryl, (arylaminocarbonyl) aryl, or (((heteroaryl) amino) carbonyl) aryl), aminoaryl (e.g., ((alkylsulfonyl) amino) aryl, or ((dialkyl) amino) aryl), (cyanoalkyl) aryl, (alkoxy) aryl, (sulfamoyl) aryl (e.g., (aminosulfonyl) aryl), (alkylsulfonyl) aryl, (cyano) aryl, (hydroxyalkyl) aryl, ((alkoxy) alkyl) aryl, (hydroxy) aryl, ((carboxy) alkyl) aryl, ((dialkyl) amino) alkyl) aryl, (nitroalkyl) aryl, (((alkylsulfonyl) amino) alkyl) aryl, ((heterocycloaliphatic) carbonyl) aryl, ((alkylsulfonyl) alkyl) aryl, (cyanoalkyl) aryl, (hydroxyalkyl) aryl, (alkylcarbonyl) aryl, alkylaryl, (trihaloalkyl) aryl, p-amino-m-alkoxycarbonylaryl, p-amino-m-cyanoaryl, p-halo-m-aminoaryl, and (m- (heterocycloaliphatic) -o (alkyl)) aryl.
As used herein, an "araliphatic" group such as "aralkyl" refers to an aliphatic group (e.g., C) substituted with an aryl group1-4Alkyl groups). Aliphatic, alkyl, and aryl groups are as defined herein. An example of an araliphatic (e.g., aralkyl) group is benzyl.
"aralkyl" as used herein refers to an alkyl group substituted with an aryl group (e.g., C)1-4Alkyl groups). Both alkyl and aryl groups are as defined above. An example of an aralkyl group is benzyl. An aralkyl group is optionally substituted with one or more substituents such as aliphatic (e.g., substituted or unsubstituted alkyl, alkenyl, or alkynyl groups, including carboxyalkyl, hydroxyalkyl, or haloalkyl groups, such as trifluoromethyl), cycloaliphatic (e.g., substituted or unsubstituted cycloalkyl or cycloalkenyl groups) (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, acylamino (e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, heteroarylcarbonylamino, or heteroaralkylcarbonylamino), cyano, halogen, hydroxyl, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, and carbamoyl.
As used herein, a "bicyclic ring system" includes an 8-to 12-membered (e.g., 9-, 10-, or 11-membered) structure forming two rings, wherein the two rings have at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicyclic cycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicyclic heteroaliphatic, bicyclic aryl, and bicyclic heteroaryl.
As used herein, "cycloaliphatic" groups include "cycloalkyl" and "cycloalkenyl", each of which is optionally substituted as described below.
"cycloalkyl" as used herein refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubic alkyl (cubyl), octahydro-indenyl, decahydro-naphthyl, bicyclo [3.2.1]Octyl, bicyclo [2.2.2]Octyl, bicyclo [3.3.1]Nonyl, bicyclo [3.3.2.]Decyl, bicyclo [2.2.2]Octyl, adamantyl, azacycloalkyl and ((aminocarbonyl) cycloalkyl. "cycloalkenyl" as used herein refers to a non-aromatic carbocyclic ring of 3 to 10 (e.g., 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl include cyclopentenyl, 1, 4-cyclohexadienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclicPentenyl, bicyclo [2.2.2]Octenyl and bicyclo [3.3.1]Nonenyl. The cycloalkyl or cycloalkenyl groups can be optionally substituted with one or more substituents, such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroarylaliphatic) oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic) carbonylamino, (cycloaliphatic) carbonylamino, (cycloaliphatically) carbonylamino, (heterocycloaliphatic) carbonylamino, or ((heteroarylaliphatic) carbonylamino), nitro, carboxy (e.g., HOOC-), Alkoxycarbonyl or alkylcarbonyloxy), acyl (e.g., (cycloaliphatic) carbonyl, (cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroarylaliphatic) carbonyl), cyano, halogen, hydroxy, mercapto, sulfonyl (e.g., alkyl-SO)2-or aryl-SO2-), sulfinyl (e.g., alkyl-S (O) -), sulfanyl (e.g., alkyl-S-), sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, and carbamoyl.
As used herein, "cyclic moiety" includes cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which is as previously defined.
The term "heterocycloaliphatic" as used herein includes heterocycloalkyl and heterocycloalkenyl, each of which is optionally substituted as described below.
As used herein, "heterocycloalkyl" refers to a 3-10 membered monocyclic or bicyclic (fused or bridged) (e.g., 5-to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more ring atoms is a heteroatom (e.g., N, O, S or a combination thereof). Examples of heterocycloalkyl include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1, 4-dioxolanyl, 1, 4-dithianyl, 1, 3-dioxolanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, sulfurMorpholino, octahydrobenzofuranyl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydro4-azoindenyl, decahydroquinolinyl, octahydrobenzo [ b ] b]Thienyl, 2-oxa-bicyclo [2.2.2]Octyl, 1-aza-bicyclo [2.2.2]Octyl, 3-aza-bicyclo [3.2.1]Octyl and 2, 6-dioxa-tricyclo [3.3.1.03,7]Nonyl radical. The monocyclic heterocycloalkyl group can be fused to a phenyl moiety, such as tetrahydroisoquinoline. As used herein, "heterocycloalkenyl" refers to a monocyclic or bicyclic (e.g., 5-to 10-membered monocyclic or bicyclic) non-aromatic ring structure having one or more double bonds and in which one or more ring atoms is a heteroatom (e.g., N, O or S). Monocyclic and bicyclic heteroaliphats are numbered according to standard chemical nomenclature.
The heterocycloalkyl or heterocycloalkenyl can be optionally substituted with one or more substituents, such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroarylaliphatic) oxy, aroyl, heteroarylacyl, amino, acylamino (e.g., (aliphatic) carbonylamino, (cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (araliphatic) carbonylamino, (heterocycloaliphatic) carbonylamino, (heteroaryl) carbonylamino, or (heteroarylaliphatic) carbonylamino), nitro, carboxy (e.g., HOOC-), Alkoxycarbonyl or alkylcarbonyloxy), acyl (e.g., (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroarylaliphatic) carbonyl), nitro, cyano, halogen, hydroxy, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, and carbamoyl.
As used herein, "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system having 4-15 ring atoms, wherein one or more ring atomsIs a heteroatom (e.g., N, O, S or a combination thereof) and wherein the monocyclic ring system is aromatic or at least one ring in a bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo-fused ring systems having 2-3 rings. For example, benzo-fused groups include benzo-fused with one or two 4-8 membered heterocycloaliphatic moieties (e.g., indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ]]Furyl, benzo [ b ]]Thienyl, quinolinyl, or isoquinolinyl). Some examples of heteroaryl groups are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolyl, benzothiazolyl, heteroaryl, and the like,Thioxyl, thioXanthyl, phenothiazine, indoline, benzo [1,3 ]]Dioxoles, benzo [ b ]]Furyl, benzo [ b ]]Thienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, cinnolinyl, quinolyl, quinazolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolyl, 4H-quinolizinyl, benzo-1, 2, 5-thiadiazolyl and 1, 8-naphthyridinyl.
Monocyclic heteroaryl groups include, without limitation, furyl, thienyl, 2H-pyrrolyl, oxazolyl, thiazolyl (thiazolidyl), imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3, 4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl (4-H-pranyl), pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl and 1,3, 5-triazinyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.
Bicyclic heteroaryls include, without limitation, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [ b ] furanyl, benzo [ b ] thienyl, quinolinyl, isoquinolinyl, indolizinyl, isoindolyl, indolyl, benzo [ b ] furanyl, benzo [ b ] thienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, and pteridinyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.
Heteroaryl is optionally substituted with one or more substituents such as aliphatic (e.g., alkyl, alkenyl, or alkynyl), cycloaliphatic, (cycloaliphatic) aliphatic, heterocycloaliphatic, (heterocycloaliphatic) aliphatic, aryl, heteroaryl, alkoxy, (cycloaliphatic) oxy, (heterocycloaliphatic) oxy, aryloxy, heteroaryloxy, (araliphatic) oxy, (heteroarylaliphatic) oxy, aroyl, heteroaroyl, amino, oxo (on a non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl), carboxy, amido, acyl (e.g., aliphatic carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (araliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) aliphatic) carbonyl, or (heteroarylaliphatic) carbonyl), sulfonyl (e.g., aliphatic sulfonyl or aminosulfonyl), sulfinyl (e.g., aliphatic sulfinyl), sulfanyl (e.g., aliphatic sulfanyl), nitro, cyano, halogen, hydroxy, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, and carbamoyl. Alternatively, the heteroaryl group may be unsubstituted.
Non-limiting examples of substituted heteroaryl groups include (halo) heteroaryl (e.g., mono (halo) heteroaryl and di (halo) heteroaryl), (carboxy) heteroaryl (e.g., (alkoxycarbonyl) heteroaryl), cyanoheteroaryl, aminoheteroaryl (e.g., ((alkylsulfonyl) amino) heteroaryl and ((dialkyl) amino) heteroaryl), (amido) heteroaryl (e.g., aminocarbonylheteroaryl, ((alkylcarbonyl) amino) heteroaryl, (((((alkyl) amino) alkyl) aminocarbonyl) heteroaryl, (((((((heteroaryl) amino) carbonyl) heteroaryl, ((heterocycloaliphatic) carbonyl) heteroaryl or ((alkylcarbonyl) amino) heteroaryl), (cyanoalkyl) heteroaryl, (alkoxy) heteroaryl, (sulfamoyl) heteroaryl (e.g., (aminosulfonyl) heteroaryl), (sulfonyl) heteroaryl ((e.g., (alkylsulfonyl) heteroaryl), (hydroxyalkyl) heteroaryl, (alkoxyalkyl) heteroaryl, (hydroxy) heteroaryl, ((carboxy) alkyl) heteroaryl, ((dialkyl) amino) alkyl) heteroaryl, (heterocycloaliphatic) heteroaryl, (cycloaliphatic) heteroaryl, (nitroalkyl) heteroaryl, ((((alkylsulfonyl) amino) alkyl) heteroaryl, ((alkylsulfonyl) alkyl) heteroaryl, (cyanoalkyl) heteroaryl, (acyl) heteroaryl (e.g., (alkylcarbonyl) heteroaryl), (alkyl) heteroaryl, and (haloalkyl) heteroaryl (e.g., trihaloalkylheteroaryl).
As used herein, "heteroaraliphatic" (e.g., heteroaralkyl) refers to an aliphatic group (e.g., C) substituted with a heteroaryl group1-4Alkyl groups). Aliphatic, alkyl and heteroaryl groups are as defined above.
As used herein, "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group (e.g., C)1-4Alkyl groups). Both "alkyl" and "heteroaryl" are as defined above. Heteroarylalkyl is optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halogen, hydroxy, acyl, mercapto, etc, Alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, and carbamoyl.
As used herein, "acyl" refers to formyl or RX-C (O) - (e.g. alkyl-C (O) -, also known as "alkylcarbonyl"), wherein RXAnd alkyl is as previously defined. Acetyl and pivaloyl are examples of acyl groups.
As used herein, "aroyl" or "heteroaroyl" refers to aryl-C (O) -or heteroaryl-C (O) -. The aryl and heteroaryl portions of the aroyl or heteroaroyl groups are optionally substituted as previously defined.
"alkoxy" as used herein refers to an alkyl-O-group, wherein alkyl is as previously defined.
"carbamoyl" as used herein refers to a compound having the structure-O-CO-NRxRyor-NRx-CO-O-RzWherein R isxAnd RYAs defined above, and RzAnd may be aliphatic, aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroarylaliphatic.
As used herein, "carboxy" when used terminally means-COOH, -COORX-OC (O) H or-OC (O) RXWhen used internally, means-OC (O) -or-C (O) O-.
As used herein, a "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogens. For example, the term haloalkyl includes the group-CF3。
"mercapto" as used herein refers to-SH.
As used herein, "sulfo", when used terminally, means-SO3H or-SO3RXWhen used internally, means-S (O)3-。
As used herein, a "sulfonamide" group, when used terminally, refers to the structure-NRX-S(O)2-NRYRZWhen used internally means-NRX-S(O)2-NRY-, wherein RX、RYAnd RZAs defined above.
As used herein, a "sulfonamide" group, when used terminally, refers to the structure-S (O)2-NRxRyor-NRx-S(O)2-RzWhen used internally, means-S (O)2-NRx-or-NRx-S(O)2-, wherein Rx、RYAnd RZAs defined above.
Herein make"Thioalkyl" as used herein when used terminally means-S-RXWhen used internally, is intended to mean-S-, wherein R isXAs defined above. Examples of sulfanyl groups include aliphatic-S-, cycloaliphatic-S-, and aryl-S-, and the like.
As used herein, "sulfinyl" when used terminally means-S (O) -RXWhen used internally, refers to-S (O) -, wherein RXAs defined above. Examples of sulfinyl groups include aliphatic-S (O) -, aryl-S (O) -, (cycloaliphatic (aliphatic)) -S (O) -, cycloalkyl-S (O) -, heterocycloaliphatic-S (O) -, and heteroaryl-S (O) -, and the like.
As used herein, "sulfonyl" when used terminally refers to-S (O)2-RXWhen used internally, means-S (O)2-, wherein RXAs defined above. Exemplary sulfonyl groups include aliphatic-S (O)2-, aryl-S (O)2-, ((cycloaliphatic (aliphatic)) -S (O)2-, cycloaliphatic-S (O)2-, heterocycloaliphatic-S (O)2-, heteroaryl-S (O)2And (cycloaliphatic (amido (aliphatic))) -S (O)2-and the like.
As used herein, "sulfoxy" when used terminally means-O-SO-RXor-SO-O-RXWhen used internally, is intended to mean-O-S (O) -or-S (O) -O-, wherein R isXAs defined above.
As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine, or iodine.
As used herein, "alkoxycarbonyl" (which is included within "carboxy", used alone or in combination with another group) refers to a group such as alkyl-O-C (O) -.
"alkoxyalkyl" as used herein refers to an alkyl group such as alkyl-O-alkyl-, wherein alkyl is as defined above.
As used herein, "carbonyl" refers to-C (O) -.
As used herein, an "oxo" group means = O.
As used herein, "aminoalkyl" refers to the structure (R)X)2N-alkyl-.
"cyanoalkyl" as used herein refers to the structure (NC) -alkyl-.
As used herein, the "urea" group refers to the structure-NRX-CO-NRYRZAnd a "thiourea" group when used terminally refers to the structure-NRX-CS-NRYRZWhen used internally means-NRX-CO-NRY-or-NRX-CS-NRY-, wherein RX、RYAnd RZAs defined above.
As used herein, a "guanidine" group refers to the structure N = C (N (R)XRY))N(RXRY) or-NRX-C(=NRX)NRXRYWherein R isXAnd RYAs defined above.
"amidino" as used herein refers to the structure-C = (NR)X)N(RXRY) Wherein R isXAnd RYAs defined above.
The term "ortho" as used herein means that a substituent is placed on a group comprising two or more carbon atoms, wherein the substituent is attached to an adjacent carbon atom.
The term "geminal" as used herein means placing a substituent on a group comprising two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
The terms "terminal" and "internal" as used herein refer to the position of a group within a substituent. A group is terminal when it is present at the terminus of a substituent and is not otherwise bonded to the remainder of the chemical structure. Carboxyalkyl (i.e., R)XO (O) C-alkyl) is an example of a terminally used carboxyl group. Internal when the group is not terminal. Alkylcarboxy (e.g., alkyl-C (O) -O-or alkyl-O-C (O) -) and alkylcarboxylaryl (e.g., alkyl-C (O) -O-aryl-or alkyl-O-C (O) -aryl-) are examples of internally used carboxyl groups。
As used herein, "cyclic" groups include monocyclic, bicyclic, and tricyclic ring systems, such as cycloaliphatic, heterocycloaliphatic, aryl, and heteroaryl, each of which is defined above.
As used herein, "bridged bicyclic ring system" refers to a heterocyclic aliphatic ring system or a bicyclic cycloaliphatic ring system in which the rings are bridged bicyclic. Examples of bridged bicyclic ring systems include, but are not limited to, adamantyl, norbornyl, bicyclo [3.2.1]Octyl, bicyclo [2.2.2]Octyl, bicyclo [3.3.1]Nonyl, bicyclo [3.2.3]Nonyl, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl and 2, 6-dioxa-tricyclo [3.3.1.03,7]Nonyl radical. The bridged bicyclic ring system may be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroarylalkoxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halogen, hydroxy, acyl, and the like, Mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, and carbamoyl.
As used herein, "aliphatic chain" refers to a branched or straight chain aliphatic group (e.g., alkyl, alkenyl, or alkynyl). The linear aliphatic chain has the structure- (CH)2)v-, where v is 1 to 6. A branched aliphatic chain is a straight aliphatic chain substituted with one or more aliphatic groups. The branched aliphatic chain has the structure- (CHQ)v-, wherein v is 1 to 6 and Q is hydrogen or an aliphatic group; however, Q should in at least one occurrence be an aliphatic group. Operation of the artThe term aliphatic chain includes alkyl, alkenyl and alkynyl chains, wherein alkyl, alkenyl and alkynyl are as defined above.
The phrase "optionally substituted" as used herein is used interchangeably with the phrase "substituted or unsubstituted. The compounds of the invention described herein may be optionally substituted with one or more substituents, such as those outlined above or exemplified by particular classes, subclasses, and species of the invention. Variable R as described herein1、R2、R3And R4And other variables include specific groups such as alkyl and aryl. For variable R, unless otherwise stated1、R2、R3And R4And other variables contained therein, each particular group may be optionally substituted with one or more substituents described herein. Each substituent of a given group is further optionally substituted with 1-3 of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl, haloalkyl, and alkyl. For example, alkyl groups may be substituted with alkylsulfanyl groups, which may be optionally substituted with 1-3 of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl groups. As a further example, the cycloalkyl portion of a (cycloalkyl) carbonylamino group can be optionally substituted with 1-3 of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atom to which they are bound.
The term "substituted" as used herein, whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen radical in a given structure with a radical of the indicated substituent. Specific substituents are described in the above definitions and in the following description of the compounds and in the examples thereof. Unless otherwise specified, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified groups, the substituents may be the same or different at each position. A ring substituent (e.g., heterocycloalkyl) can be combined with another ring (e.g., cycloalkyl) to form a spiro-bicyclic ring system, i.e., the two rings share a common atom. Combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds.
The phrase "stable or chemically feasible" as used herein refers to compounds that do not substantially change when subjected to conditions to allow their production, detection and preferably their recovery, purification and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that does not substantially change for at least one week in the absence of moisture or other chemically reactive conditions when maintained at a temperature of 40 ℃ or less.
The phrase "enantioselectively prepared" as used herein refers to asymmetric synthesis to prepare enantiomerically enriched compounds. This is further defined as using one or more techniques to prepare the desired compound in a high enantiomeric excess (i.e., 60% or more). Included techniques may include the use of chiral starting materials (e.g., chiral pool synthesis), the use of chiral auxiliary agents and chiral catalysts, and the application of asymmetric induction.
As used herein, "enantiomeric excess" or "e.e." refers to the optical purity of a compound.
"endo: exo" as used herein refers to the ratio of endo isomers to exo isomers.
As used herein, "enantiomeric ratio" or "e.r." is the ratio of the percentage of one enantiomer to the percentage of another enantiomer in a mixture.
As used herein, "protecting group" is defined as a group that is introduced into a molecule to alter a functional group present in the molecule to prevent it from reacting in a subsequent chemical reaction, thus resulting in chemoselectivity. It is removed from the molecule in a later step in the synthesis. For example, a benzyloxycarbonyl (Cbz) group may replace a hydrogen on an amine to prevent its reaction with an electrophile, and then the Cbz group may be removed by hydrolysis in a later step.
Acid and amine protecting Groups for use herein are known in the art (see, e.g., t.w. Greene and p.g.m Wutz, "Protective Groups in Organic Synthesis", 3 rd edition, John Wiley & Sons, inc. (1999)). Examples of suitable protecting groups for the acid include t-butoxy, benzyloxy, allyloxy, and methoxymethoxy. Examples of suitable protecting groups for amines include 9-fluorenylmethylcarbamate, t-butylcarbamate, benzylcarbamate, trifluoroacetamide, and p-toluenesulfonamide.
As used herein, an "effective amount" is defined as the amount required to confer a therapeutic effect on a treated patient and is typically determined based on the age, surface area, weight and condition of the patient. Dose correlations between animal and human (based on mg/square meter body surface) are described in Freireich et al, Cancer chemi. 219 (1966). The body surface area may be determined approximately by the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.
Unless otherwise indicated, structures described herein are also intended to include all isomeric forms of the structure (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers); for example, the R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers for each asymmetric center. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) isomeric mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
Furthermore, unless otherwise indicated, structures described herein are also intended to include differences only in the presence of one or more isotopically enriched sitesA compound of an atom of a hormone. For example, other than by replacement of hydrogen by deuterium or tritium or by enrichment13C or14C, and compounds having the structure of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
As used herein, "EDC" is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, "HOBt" is 1-hydroxybenzotriazole, "THF" is tetrahydrofuran, "Cbz" is benzyloxycarbonyl, "DCM" is dichloromethane, and "Boc" is tert-butoxycarbonyl.
As used herein "1H NMR "stands for proton nuclear magnetic resonance and" TLC "for thin layer chromatography.
Detailed description of the preferred embodiments
In one aspect, the present invention provides processes and intermediates for the production of bicyclic derivatives of formula Ia or Ib:
wherein:
ring A is C3-12A cycloaliphatic ring;
ring B is C3-12A heterocycloaliphatic ring containing an additional 0-2 heteroatoms each independently selected from O, N and S, which may be optionally substituted with 1-4 groups each independently selected from alkyl, halo, alkoxy, aryl, and hydroxy;
R1is H or a protecting group; and
R2is H or C1-12Aliphatic.
In one embodiment, ring A is C3-6A cycloaliphatic ring.
More particularly, ring a is cyclopentyl.
More particularly, ring A is。
In another embodiment, ring a is cyclopropyl.
More particularly, ring A is 1, 1-dimethylcyclopropyl.
More particularly, ring A is。
In one embodiment, ring B is aryl.
More particularly, ring B is phenyl.
More particularly, ring B is:。
in one embodiment, ring B is a 5-membered heterocyclic ring.
In one embodiment, ring B is:。
in another embodiment, ring B is substituted with an aryl ring optionally substituted with 1-4 groups each independently selected from alkyl, halo, alkoxy, and hydroxy.
More particularly, ring B is:
。
in one embodiment, R1Is H.
In another embodiment, R1Is a protecting group.
More particularly, R1Is tert-butyl carbamate (Boc).
In one embodiment, R2Is H.
In another embodiment, R2Is C1-12Aliphatic.
More particularly, R2Is C1-6An alkyl group.
In one embodiment, R2Is methyl, ethyl, n-propyl, isopropyl, isobutyl, n-butyl, tert-butyl, n-pentyl or isopentyl.
More particularly, R2Is an isobutyl group.
In another embodiment, R2Is a tert-butyl group.
In another embodiment, R2Is a cycloaliphatic ring.
Another aspect relates to a process for the enantioselective preparation of compounds of formula Ia or Ib via compounds of formulae Ic to Ih:
。
the method comprises the step of carboxylating a compound of formula IIa or IIb in the presence of a compound of formula III:
，
wherein R isa1Is a protective group, and is characterized in that,
；
wherein R is3And R4Each independently is a protecting group, C1-12Aliphatic or cyclic groups selected from cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl.
In one embodiment, R1aIs tert-butyl carbamate (Boc).
In one embodiment, the step of carboxylating the compound of formula II presents a compound of formula IIIa:
。
in another embodiment, the step of carboxylating the compound of formula II is in the presence of a compound of formula IIIb:
。
in another embodiment, the step of carboxylating the compound of formula II presents a compound of formula IIIc:
。
in another embodiment, the step of carboxylating the compound of formula II is in the presence of a compound of formula IIId:
。
in another embodiment, the step of carboxylating the compound of formula II presents a compound of formula IIIe:
。
in one embodiment, R3Is C1-12Aliphatic.
More particularly, R3Is C1-4An unbranched alkyl group.
In one embodiment, R4Is C1-4Unbranched alkyl radical
In another embodiment, R4Is C substituted by a cyclic group1-4A branched alkyl group.
More particularly, R4Is C substituted by phenyl1-4A branched alkyl group.
In one embodiment, R4Is a cyclic group.
More particularly, R4Is a bicyclic group.
In one embodiment, the carboxylation step comprises treating a compound of formula IIa or IIb with carbon dioxide and a lithium base in the presence of an aprotic solvent.
In one embodiment, the aprotic solvent is selected from the group consisting of toluene, ethyl acetate, benzene, and methyl tert-butyl ether (MTBE).
More particularly, the aprotic solvent is MTBE.
In one embodiment, the lithium base is sec-butyllithium.
In one embodiment, the process of the invention gives a mixture of products comprising I-1a (exo), I-3 (exo), I-2 (endo) and I-4 (endo).
In one embodiment, the combined weight percentage in the mixture comprising the compounds of formulae Ia and Id (exo isomers) and the compounds of formulae Ic and Ie (endo isomers) after carboxylation is 100 wt%.
In one embodiment, the ratio of the combined weight percent of Ia and Id (exo isomers) to the combined weight percent of Ic and Ie (endo isomers) is at least 60: 40.
More particularly, the ratio of external form to internal form is at least 80: 20.
More particularly, the ratio of the exterior to the interior is at least 90: 10.
More particularly, the ratio of external form to internal form is at least 95: 5.
More particularly, the ratio of external form to internal form is at least 97: 3.
In one embodiment, the process further comprises the step of removing a portion of the compound of formula Ic and/or Ie from the product mixture.
More particularly, the compound of formula Ic and/or Ie is removed by crystallization of the compound of formula Ia or Ib.
In another embodiment, the compound of formula Ic and/or Ie is removed by recrystallization of the compound of formula Ia or Ib.
In one embodiment, the ratio of weight percent of Ia to Id is at least 60: 40.
More particularly, the ratio of weight percent Ia to Id is at least 80: 20.
More particularly, the ratio of weight percent Ia to Id is at least 90: 10.
More particularly, the ratio of weight percent Ia to Id is at least 95: 5.
More particularly, the ratio of weight percent Ia to Id is at least 99: 1.
More particularly, the ratio of weight percent Ia to Id is at least 99.6: 0.4.
More particularly, the ratio of weight percent Ia to Id is at least 100: 0.
Another aspect relates to a process for preparing a compound of formula 10:
，
wherein R is2Is H, C1-12Aliphatic or protecting groups, and Z2Is H or a protecting group, the process comprising the steps of:
a. forming a 2-anion of a compound of formula IIa in the presence of a compound of formula III:
，
wherein R is1aAnd ring a is as defined above, and,
wherein R is3And R4As defined above;
b. treating the 2-anion of step a with carbon dioxide to enantioselectively produce a compound of formula Ia; and
c. reacting a compound of formula Ia with a compound of formula 26:
，
wherein Z3Is a protecting group.
In one embodiment, the compound of formula III is a compound of formula IIIa.
In another embodiment, the compound of formula III is a compound of formula IIIb.
In one embodiment, the compound of formula 26 is a compound of formula 26-a:
。
in another embodiment, the compound of formula 26 is a compound of formula 26-b:
。
one aspect relates to compounds of formula Ia-1 prepared by the methods disclosed herein:
。
another aspect relates to compounds of formula Ia-2 prepared by the methods disclosed herein:
。
another aspect relates to compounds of formula Ia-3 prepared by the methods disclosed herein:
。
another aspect relates to compounds of formula Ia-4 prepared by the methods disclosed herein:
。
one aspect relates to a compound of formula 10-a prepared by the process disclosed herein:
。
in one embodiment, the compound of formula 10 is a compound of formula 10-a, wherein Z is2Is H, and R2Is a tert-butyl group.
Another aspect relates to a compound of formula 10-b prepared by the methods disclosed herein:
。
another aspect relates to compounds of formula 10-c prepared by the methods disclosed herein:
。
in one embodiment, the compound of formula 10 is a compound of formula 10-b, wherein Z is2Is H, and R2Is a tert-butyl group.
Another aspect relates to compounds of formula 10-d prepared by the methods disclosed herein:
。
processes and intermediates
In one aspect, the inventionProvided are processes and intermediates for preparing compounds of formula Ia, as outlined in scheme I, wherein R1、R2、R3、R4And ring a is as previously defined.
Scheme I
Carboxylation of compounds of formula IIa is achieved by first forming the 2-anion of formula IIa in the presence of compounds of formula III. To form similar anions, see, e.g., daniel. j. Pippel et al, j. org. chem., 1998, 63, 2; donald j. Gallagher et al, j. org. chem., 1995, 60(22), 7092-7093; shawn t. Kerrick et al, j. Am. chem. soc., 1991, 113(25), 9708-9710; donald j. Gallagher et al, j. org. chem., 1995, 60(25), 8148-8154; and Peter bead et al, J. Am. chem. Soc., 1994, 116(8), 3231-3239. The 2-anion of formula IIa (not shown in scheme I) is prepared by treating a compound of formula IIa with a strong lithium base (e.g., sec-butyllithium or isopropyllithium) in a suitable aprotic solvent (e.g., MTBE, diethyl ether or toluene) in the presence of a compound of formula III.
The optically active compound of formula III can induce enantioselective carboxylation to give a product with an enantiomeric excess (e.e.) of about 10% to about 95% (see, e.g., Beak et al, j. org. chem., 1995, 60, 8148-8154). The compound of formula IIa may be treated with carbon dioxide in the presence of formula III to obtain a mixture of exo/endo compounds, wherein the exo/endo ratio is 60:40, 80:20, 90:10, 95:5 or greater than 98: 2.
Referring to scheme I, compounds of formula IIa, wherein R is prepared using known methods1aFor example, tert-butoxycarbonyl (Boc). See, e.g., T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3 rd edition, John Wiley and Sons, Inc (1999).
The compounds of formula III can be prepared as shown in scheme IIA.
Scheme IIA
When R is3And R4In the same way, the compounds of the formula III can be prepared by condensing substituted piperidone derivatives with formaldehyde or a formaldehyde equivalent.
Alternatively, compounds of formula III may be prepared as shown in scheme IIB.
Scheme IIB
When R is3And R4At the same time, commercially available di-protected amines can be used to prepare compounds of formula III via sequences of selective deprotection reactions and other transformations known to the skilled artisan.
Scheme III describes the reaction of a compound of formula 26 with a compound of formula Ia to form a compound of formula 28, wherein R2As defined above.
Scheme III
In scheme III, bicyclic amino esters of formula Ia (wherein R is2Is tert-butyl) with a protected amino acid of the formula 26 (wherein Z is3Is an amine protecting group and can be removed under acidic, basic or hydrogenation conditions, which are different fromFor removing R2Those of protecting groups) to give amide-esters of formula 10. Removal of the protecting group Z from the amide-ester of formula 102To give an amine-ester compound of formula 28.
In another embodiment, the compound of formula 28 is an intermediate in the synthesis of a protease inhibitor according to scheme IV.
Scheme IV
Scheme IV is disclosed in U.S. patent No. 7,776,887, the entire contents of which are incorporated herein by reference.
In scheme IV, bicyclic amino esters of formula Ia (which can be prepared as described herein, wherein R is2Is tert-butyl) with a protected amino acid of the formula 26 (wherein Z is2Is an amine protecting group and can be removed under acidic, basic or hydrogenation conditions, which are different from those used to remove R2Those of protecting groups) to give amide-esters of formula 10. Removal of the protecting group Z from the amide-ester of formula 102To give an amine-ester compound of formula 28. The amino group containing compound of formula 28 is reacted with the protected amino acid 29 in the presence of a coupling reagent to give the tripeptide of formula 30. Removal of the protecting group Z in the tripeptide of formula 30 provides a free amino-tripeptide of formula 31. The amino-tripeptide of formula 31 is reacted with pyrazine-2-carboxylic acid of formula 32 in the presence of a coupling reagent to give an amide-tripeptide ester of formula 33. Hydrolyzing the ester of the amide-tripeptide ester of formula 33 to provide the amido-tripeptide acid of formula 34. The amido-tripeptide acid of formula 34 is reacted with an amino-hydroxyamide of formula 18 in the presence of a coupling reagent to give a hydroxy-peptide of formula 35. In the final step, the hydroxy group of the compound of formula 35 is oxidized to provide the compound of formula 4.
In another embodiment, the process of scheme III can be scaled up for large scale production, for example, in a manufacturing plant. Large scale production may be scaled up to greater than 1000 kilograms, for example.
Although in some portions of schemes I-IV, only a single isomer is illustrated for some compounds, the present invention is intended to include all stereoisomers of the compounds.
The following non-limiting examples are described to provide a more complete understanding of the invention. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
Examples
Example 1: n-tert-butoxycarbonyl-3-azabicyclo [3.3.0] octane (6).
Method 1
A2L three-necked round bottom flask equipped with a mechanical stirrer, 500mL addition funnel, and thermometer was charged with 3-azabicyclo [3.3.0] under nitrogen with stirring]Nonane hydrochloride (100 g, 0.677 mol), potassium carbonate (187 g, 1.35 mol), MTBE (220 mL) and water (160 mL). The mixture was cooled to 14-16 ℃. Charging 500mL Erlenmeyer flask with Boc2O (di-tert-butyldicarbonate) (145 g, 0.644 mol) and MTBE (190 mL). The mixture was stirred until dissolution was complete. The solution was poured into an addition funnel and added to the reaction mixture, maintaining the reaction temperature below 25 ℃. Water (290 mL) was added to dissolve the solid and the mixture was stirred for 10-15 minutes. After removal of the aqueous phase, the organic phase was treated with 5% aqueous NaHSO4Wash (twice, 145 mL each time) followed by water (145 mL). The organic phase was concentrated and MTBE (1.3L) was added to give a solution of the title compound in MTBE. See, e.g., r.griot, helv. chim. acta, 42, 67 (1959).
Method 2
Potassium carbonate (187 g, 1.35 mol) in water (160 mL) was added to 3-azabicyclo [3.3.0]Octane hydrochloride (100 g, 0.677 mol) and MTBE (220 mL) and the resulting mixture was cooled to 14-16 ℃. Addition of Boc2O (145 g, 0.644 mol) in MTBE (190 mL) while maintaining the temperature below 35 ℃. After the addition, the mixture was stirred for 1 hour, followed by filtration. The solid was washed with MTBE (50 mL). The phases are subsequently separated, and the organic phase is treated with 5% aqueous NaHSO4(two times, 145 mL each) and water (145 mL). Then concentrated to 300 mL under vacuum. MTBE (300 mL) was added and the mixture was concentrated to reduce the water concentration to less than 550 ppm. The concentrate was diluted with MTBE (400 mL) to provide an MTBE solution of the title compound.
Example 2: (1S,3aR,6aS) -tert-butyl 2- ((S) -2- (benzyloxycarbonylamino) -3, 3-dimethylbutyryl) octahydrocyclopenta [ c ] pyrrole-1-carboxylate (27).
Method 1
A 3L three-necked round bottom flask equipped with an overhead stirrer, condenser, thermocouple, and nitrogen outlet was purged with nitrogen for several minutes. In a separate flask, sulfuric acid (46.2 mL, 0.867 mol) was diluted with 442 mL of water. The solution was allowed to cool slightly. The reaction flask was charged with Cbz-L-tert-leucine dicyclohexylamine salt (330.0 g, 0.739 mol). MTBE (1620 mL) was added to the reactor and the mixture was stirred to suspend the salt. The sulfuric acid solution prepared as above was added to the reactor over about 10 minutes, maintaining the temperature at 20 ± 5 ℃. The mixture was stirred at room temperature for about 1 hour, then slowly diluted with water (455 mL). Agitation was stopped and the layers were allowed to settle. The aqueous phase was removed to provide 1100mL of a colorless solution of pH 1. The remaining organic phase in the flask was charged with additional water (200 mL). The mixture was stirred at room temperature for about 1 hour. Agitation was stopped and the layers were allowed to settle. The aqueous phase was removed to provide 500mL of a colorless solution of pH 2. The organic phase was heated to about 35 ℃, diluted with DMF (300 mL), and concentrated under reduced pressure to a point where distillation slowed significantly, leaving about 500mL of concentrate. Without rinsing, the concentrate was transferred to a 1L schottky bottle. The concentrate (clear colorless solution) weighed 511.6 g. Based on the solution assay and the weight of the solution, the solution contained 187.2 g (0.706 mol) of carboxybenzyl-L-tert-leucine (Cbz-L-tert-leucine).
A5L four-necked round bottom flask equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet was charged with HOBT. H2O (103.73 g, 0.678 mol, 1.20 mol equivalent), EDC & HCl (129.48 g, 0.675 mol, 1.20 mol equivalent), and DMF (480 mL). The slurry was cooled to 0-5 ℃. A36.6% by weight solution of Cbz-L-tert-leucine in DMF (491.3 g, 0.745 mol, 1.32 molar equivalents) in acid was added to the reaction mixture over 47 minutes while maintaining the temperature at 0-5 ℃. The reaction mixture was stirred for 1 hour 27 minutes. A solution of 3-azabicyclo (3.3.0) octane-2-carboxylic acid-tert-butyl ester in isopropyl acetate (28.8% by weight, 414.3 g, 0.564 mol) was added over 53 minutes while maintaining the reaction temperature at 0-5.1 ℃. The reaction mixture was warmed to 20 ± 5 ℃ over about 1 hour. 4-methylmorpholine (34.29 g, 0.339 mol, 0.60 mol equivalent) was added over 5 minutes. The reaction mixture was stirred for 16 hours, then isopropyl acetate (980 mL) was added to the reaction solution. A solution of histamine-2 HCl (41.58 g, 0.226 mol, 0.40 molar equivalents) in water (53.02 g) was added to the reaction mixture over 4 minutes followed by 4-methylmorpholine (45.69 g, 0.45 mol, 0.80 molar equivalents). After 3.5 hours, the reaction mixture was sampled. Water (758 mL) was added and the mixture was stirred for about 20 minutes followed by settling for 11 minutes. The phases were separated. The aqueous phase was extracted with isopropyl acetate (716 mL) and the organic phases were combined. 1N aqueous hydrochloric acid was prepared by adding 37 wt% hydrochloric acid (128.3 mL) to water (1435 mL). The organic phase is washed with 1N hydrochloric acid for about 20 minutes. A 10 wt% aqueous potassium carbonate solution was prepared by dissolving potassium carbonate (171 g, 1.23 mol, 2.19 mol equiv) in water (1540 mL). The organic phase was washed with 10 wt% aqueous potassium carbonate solution for about 20 minutes. Sampling of the finalA clear, light yellow organic solution (1862.1 g) was subjected to solution assay. The solution contained 238.3 g (0.520 mol) of the title compound product, based on solution determination and solution weight.
1H NMR (DMSO-d6，500 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
A solution of potassium carbonate (73.3 g) in water (220 mL) was added to a suspension of (1S,2S,5R) 3-azabicyclo [3.3.0] octane-2-carboxy-tert-butyl ester-oxalate (80.0 g) in isopropyl acetate (400 mL) while maintaining the temperature at about 20 ℃. The mixture was stirred for 0.5 h, the phases were separated and the organic phase was washed with 25 wt% aqueous potassium carbonate (80 mL) to give a solution of the free base. In a separate flask, aqueous sulfuric acid (400 mL, 0.863M) was added to a suspension of Cbz-tert-leucine dicyclohexylamine salt (118.4g) in tert-butyl methyl ether (640 mL) while maintaining the temperature at about 20 ℃. The mixture was stirred for 0.5 h, the phases were separated and the organic phase was washed with water (200 mL). The phases were separated and N-methylmorpholine (80 mL) was added to the organic phase which was concentrated to 80 mL at 40 ℃ under reduced pressure to give a solution of the free acid in N-methylmorpholine. This solution was added to a mixture of EDC & HCl (50.8 g) and HOBt hydrate (40.6 g) in N-methylmorpholine (280 mL) at 0-10 ℃. The mixture was stirred at about 5 ℃ for 1 hour. A solution of 3-azabicyclo [3.3.0] octane-2-carboxy, tert-butyl ester from above was added at 0-20 deg.C followed by N-methylmorpholine (32 mL). The mixture was stirred for 6 hours, then diluted with isopropyl acetate (600 mL) followed by 1N hydrochloric acid (400 mL). After stirring for 0.5 h, the phases were separated and the organic phase was washed with 25 wt% aqueous potassium carbonate (400 mL) and water (80 mL). The mixture was stirred for about 1 hour and the phases were separated to give a solution of the title compound in isopropyl acetate.
Method 3
(1S,2S,5R) 3-azabicyclo [3.3.0] octane-2-carboxy-tert-butyl ester-oxalate (1.0 equiv.) was suspended in isopropyl acetate (6 vol.) and a solution of potassium carbonate (3.0 equiv.) in water (3.5 vol.) was added at 20-25 ℃. The mixture was stirred for 3 hours, and then the phases were separated. The organic phase was washed with water (2 vol).
The Cbz-tert-leucine dicyclohexylamine salt (1.05 eq) was suspended in isopropyl acetate (6 vol) and sulfuric acid (1.3 eq)/water (5 vol) was added at 20-25 ℃. The mixture was stirred for 30 minutes, the phases were separated and the organic phase was washed with water (2 times, 2.5 volumes).
The two solutions from above were combined and subsequently cooled to 0-5 ℃. HOBt hydrate (1.1 equiv.) and EDC (1.1 equiv.) were suspended in the mixture and the mixture was stirred for 6 hours. The mixture was washed with water (5 vol) and the resulting organic phase was treated with L-lysine (1 eq) and N-methylmorpholine (2 eq) at 20-25 ℃ to destroy excess activated ester. The mixture was then washed with 5% potassium carbonate (5 vol), 1N hydrochloric acid (5 vol), 5% potassium carbonate (5 vol) and water (twice, 5 vol) to give a solution of the title compound in isopropyl acetate.
Example 3: (1S,3aR,6aS) -tert-butyl 2- ((S) -2-amino-3, 3-dimethylbutyryl) -octahydrocyclopenta [ c ] pyrrole-1-carboxylate (28).
Method 1
A1L Buchi hydrogenator was purged three times with nitrogen. The reactor was charged with 307.8 g portions of 12.8 wt% of (1S,3aR,6aS) -tert-butyl 2- ((S) -2- (benzyloxycarbonylamino) -3, 3-dimethylbutyryl) octahydrocyclopenta [ c ] S]A solution of pyrrole-1-carboxylate (prepared as in example 6, method 1) in isopropyl acetate (39.39 g, 0.086 mol). Isopropyl acetate (100 mL) was added to the reactor. Preparation of 50% Water and Wet 20% Pd (OH)2Carbon (3.97 g) in isopropyl acetate (168 mL) and charged to the reactor, agitation was started. The reactor was pressurized to 30 psig with nitrogen and vented to atmospheric pressure. This was repeated twice. The reactor was then pressurized with hydrogen to atmospheric pressure with aeration. This was repeated twice. The reactor was pressurized to 30 psig with hydrogen and stirred at ambient temperature for 1 hour. The mixture was filtered using a buchner funnel containing Whatman #1 filter paper to remove the catalyst. The filter cake was washed with isopropyl acetate (80 mL). This procedure was repeated two more times, using 617 g and 290.6 g of a 12.8% by weight solution of the starting compound. The materials from the third hydrogenation were combined and distilled under reduced pressure (28 torr). The obtained solution (468.68 g) was assayed for the title compound.
1H NMR (DMSO-d6，500 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 the hydrogenation apparatus, the Cbz derivative 27 solution from example 6, method 2 was added to 20% Pd (OH)2In water (50%, 12.2 g). The apparatus was pressurized to 30 psi using hydrogen and then stirred at about 20 ℃ for 2 hours. The mixture was filtered to remove the catalyst and the filter cake was washed with isopropyl acetate (160 mL). The combined filtrate was evaporated 2-3 times with about 4 volumes of heptane at 40 ℃ to remove isopropyl acetate. The resulting slurry was cooled to 0 ℃, filtered, and the product was dried under reduced pressure to give the title compound.
Method 3
(1S,3aR,6aS) -tert-butyl 2- ((S) -2-amino-3, 3-dimethylbutyryl) -octahydrocyclopenta [ c ] from example 6, method 3]A solution of pyrrole-1-carboxylate in isopropyl acetate was added to 20% Pd (OH)2(2% by weight load, 50% wet) the mixture was hydrogenated at 2 bar and 20-25 ℃ for 2 hours. The catalyst was removed by filtration and washed with isopropyl acetate (2 volumes). The filtrate was concentrated to 10 volumes under reduced pressure at 40 ℃ to give a solution of the title compound in isopropyl acetate.
While we have presented several embodiments of this invention, it is apparent that our basic structure may be altered to provide other embodiments that utilize the compounds and methods of this invention. It is, therefore, to be understood that the scope of the invention is defined by the appended claims rather than by the specific embodiments presented as examples.

Claims (71)

1. A process for enantioselectively preparing a compound of formula Ia or Ib:
，
the process is via compounds of formulae Ic to Ih:
，
the method comprises the step of carboxylating a compound of formula IIa or IIb in the presence of a compound of formula III:
，
，
wherein:
ring A is C3-12A cycloaliphatic ring;
ring B is C3-12A heterocycloaliphatic ring containing an additional 0-2 heteroatoms each independently selected from O, N and S, wherein ring B is optionally substituted with 0-4 groups each independently selected from alkyl, halo, alkoxy, aryl, and hydroxy;
R1is H or a protecting group;
R1ais a protecting group;
R2is H, a protecting group or C1-12Aliphatic; and is
R3And R4Each independently is a protecting group, C1-12Aliphatic or cyclic groups selected from cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl.
2. The method of claim 1, wherein ring a is C3-6A cycloaliphatic ring.
3. The method of claim 2, wherein ring a is cyclopentyl.
4. The method of claim 3, wherein ring A is。
5. The method of claim 2, wherein ring a is cyclopropyl.
6. The method of claim 5, wherein ring a is 1, 1-dimethylcyclopropyl.
7. The method of claim 6, wherein ring A is。
8. The method of claim 1, wherein ring B is aryl.
9. The method of claim 8, wherein ring B is phenyl.
10. The method of claim 9, wherein ring B is。
11. The method of claim 1, wherein ring B is a 5-membered heterocyclic ring.
12. The method of claim 11, wherein ring B is。
13. The method of claim 1, wherein ring B is substituted with an aryl ring optionally substituted with 0-4 groups each independently selected from alkyl, halo, alkoxy, and hydroxy.
14. The method of claim 13, wherein ring B is:
。
15. the method of claim 1, wherein R1Is H.
16. The method of claim 1, wherein R1Is a protecting group.
17. The method of claim 16, wherein R1Is tert-butyl carbamate (Boc).
18. The method of claim 1, wherein R1aIs a protecting group.
19. The method of claim 18, wherein R1aIs tert-butyl carbamate (Boc).
20. The method of claim 1, wherein R2Is H.
21. The method of claim 1, wherein R2Is C1-12Aliphatic.
22. The method of claim 21, wherein R2Is C1-6An alkyl group.
23. The method of claim 22, wherein R2Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, n-pentyl and isopentyl.
24. The method of claim 23, wherein R2Is a tert-butyl group.
25. The method of claim 21, wherein R2Is a cycloaliphatic ring.
26. The method of claim 1, wherein the step of carboxylating the compound of formula IIa or IIb is in the presence of a compound of formula IIIa:
。
27. the method of claim 1, wherein the step of carboxylating the compound of formula IIa or IIb is in the presence of a compound of formula IIIb:
。
28. the method of claim 1, wherein the step of carboxylating the compound of formula IIa or IIb presents a compound of formula IIIc:
。
29. the method of claim 1, wherein the step of carboxylating the compound of formula IIa or IIb is in the presence of a compound of formula IIId:
。
30. the method of claim 1, wherein the step of carboxylating the compound of formula IIa or IIb is in the presence of a compound of formula IIIe:
。
31. the method of claim 1, wherein R3Is C1-12Aliphatic.
32. The method of claim 31, wherein R3Is C1-4An unbranched alkyl group.
33. The method of claim 1, wherein R4Is C1-4A branched alkyl group.
34. The method of claim 1, wherein R4Is C substituted by a cyclic group1-4A branched alkyl group.
35. The method of claim 34, wherein R4Is C substituted by phenyl1-4A branched alkyl group.
36. The method of claim 1, wherein R4Is a cyclic group.
37. The method of claim 36, wherein R4Is a bicyclic group.
38. The process of claim 1, wherein said carboxylation step comprises treating the compound of formula II with carbon dioxide and a lithium base in an aprotic solvent.
39. The process of claim 38, wherein the aprotic solvent is selected from the group consisting of toluene, ethyl acetate, benzene, and methyl tert-butyl ether MTBE.
40. The process of claim 39, wherein the aprotic solvent is MTBE.
41. The method of claim 38, wherein the lithium base is sec-butyllithium.
42. The process according to claim 1, wherein the combined weight percentage in the mixture comprising the compounds of formulae Ia and Id (exo isomers) and the compounds of formulae Ic and Ie (endo isomers) is 100% by weight.
43. The method of claim 42, wherein the exterior-to-interior ratio is at least 60: 40.
44. The process of claim 1, further comprising removing a portion of the compounds of formulae Ic and Ie from the mixture.
45. The process of claim 44 wherein the compounds of formulae Ic and Ie are removed by crystallizing the compound of formula Ia.
46. The process of claim 44 wherein the compounds of formulae Ic and Ie are removed by recrystallization of the compound of formula Ia.
47. The method of claim 1 wherein the weight percent ratio of Ia to Id is at least 60: 40.
48. A process for preparing a compound of formula 10:
，
the method comprises the following steps:
a. forming a 2-anion of a compound of formula IIa in the presence of a compound of formula III:
，
；
b. treating the anion of step a with carbon dioxide to enantioselectively produce a compound of formula Ia; and
c. reacting a compound of formula Ia with a compound of formula 26 in the presence of a coupling reagent,
；
wherein:
ring A is C3-12A cycloaliphatic ring;
R1is H or a protecting group;
R2is H, a protecting group or C1-12Aliphatic;
R3and R4Each independently is a protecting group, C1-12Aliphatic or cyclic groups selected from cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl;
Z2is H or a protecting group; and
Z3is a protecting group.
49. The method of claim 48, wherein the compound of formula III is of formula IIIa:
。
50. the method of claim 48, wherein the compound of formula III is of formula IIIb:
。
51. the method of claim 48, wherein the compound of formula III is of formula IIIc:
。
52. the method of claim 48, wherein the compound of formula III is of formula IIId:
。
53. the method of claim 48, wherein the compound of formula III is of formula IIIe:
。
54. the method of claim 48, wherein the compound of formula 26 is of formula 26-a:
。
55. the method of claim 48, wherein the compound of formula 26 is of formula 26-b:
。
56. the method of claim 48, wherein the compound of formula 10 is of formula 10-a:
。
57. the method of claim 56, wherein Z2Is H, and R2Is a tert-butyl group.
58. The method of claim 48, wherein the compound of formula 10 is of formula 10-b:
。
59. the method of claim 48, wherein the compound of formula 10 is of formula 10-c:
。
60. the method of claim 59, wherein Z2Is H, and R2Is a tert-butyl group.
61. The method of claim 48, wherein the compound of formula 10 is of formula 10-d:
。
62. a process for preparing a compound of formula 4:
，
the method comprises the following steps:
a. reacting a compound of formula II-a with a base and CO in the presence of a compound of formula III2Reacting to prepare a compound of formula I-1 a;
b. reacting a compound of formula Ia with a compound of formula 26 in the presence of a coupling reagent to form a compound of formula 10;
c. removal of Z from a compound of formula 102To obtain a compound of formula 28:
；
d. reacting a compound of formula 28 with a compound of formula 29 in the presence of a coupling reagent:
to give a compound of formula 30:
wherein Z is an amine protecting group;
e. removing the protecting group Z in the compound of formula 30 to obtain a compound of formula 31:
；
f. reacting a compound of formula 31 with a compound of formula 32 in the presence of a coupling reagent:
to give a compound of formula 33:
；
g. hydrolyzing the ester of the compound of formula 33 to obtain a compound of formula 34:
；
h. reacting a compound of formula 34 with a compound of formula 18 in the presence of a coupling reagent:
to give a compound of formula 35:
(ii) a And
i. oxidizing the compound of formula 35 to obtain the compound of formula 4.
63. The method of claim 62, wherein the method is scaled up for large scale production.
64. A compound of formula Ia-1 prepared by the process of claim 1:
。
65. a compound of formula Ia-2 prepared by the process of claim 1:
。
66. a compound of formula Ia-3 prepared by the process of claim 1:
。
67. a compound of formula Ia-4 prepared by the process of claim 1:
。
68. a compound of formula 10-a prepared by the process of claim 48:
。
69. a compound of formula 10-b prepared by the process of claim 48:
。
70. a compound of formula 10-c prepared by the process of claim 48:
。
71. a compound of formula 10-d prepared by the process of claim 48:
。
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