CN103814001A - Processes and intermediates - Google Patents

Abstract

A method for enantioselectively preparing compounds of formula Ia or Ib from compounds of formulas I-2 to Ih. .

Description

Methods and Intermediates

Cross References to Related Applications

This application claims the benefit of priority to US Provisional Application No. 61/486,125, filed May 13, 2011, which is incorporated herein by reference.

field of invention

The present invention relates to processes and intermediates for the preparation of protease inhibitors, especially serine protease inhibitors.

Background of the invention

Infection with hepatitis C virus ("HCV") is a human medical concern. HCV is considered the causative agent for most cases of non-A or non-B hepatitis, with an estimated human seropositivity rate of 3% worldwide (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 (Suppl 1), pp. 88-91 (1999)).

When first exposed to HCV, only about 20% of infected individuals develop acute clinical hepatitis, while others appear to resolve the infection spontaneously. However, in almost 70% of cases, the virus establishes a chronic infection that can last for decades. (S. Iwarson, "The Natural Course of Chronic Hepatitis" FEMS Microbiology Reviews, 14, pp. 201-204 (1994); D. Lavanchy, "Global Surveillance and Control of Hepatitis C Global Detection and Control of Hepatitis)" J. Viral Hepatitis, 6, pp. 35-47 (1999)). Long-term chronic infection can lead to recurrent and progressively worsening liver inflammation, which often leads to more serious disease states such as cirrhosis and hepatocellular carcinoma. (M.C. Kew, "Hepatitis C and Hepatocellular Carcinoma" FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saito et al., "Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma (Hepatitis C virus infection is associated with the development of hepatocellular carcinoma)" Proc. Natl. Acad. Sci. USA, 87, pp. 6547-6549 (1990)). Unfortunately, there is no widely effective treatment for the debilitating progression of chronic HCV.

Protease inhibitors, especially serine protease inhibitors, are useful in the treatment of HCV infection, as disclosed in WO 02/18369. WO 02/18369 also discloses processes and intermediates for the preparation of these compounds. These methods result in the racemization of certain steric carbon centers. See eg pp. 223-22. As a result, there remains a need for enantioselective methods for the preparation of these compounds.

Summary of the invention

This need and others are met by the present invention, which relates to processes and intermediates for the preparation of protease inhibitors, particularly serine protease inhibitors. In one aspect, the invention provides methods and intermediates for the production of bicyclic derivatives of formula Ia or Ib:

in:

Ring A is a C _3-12 cycloaliphatic ring;

Ring B is a C _3-12 heterocycloaliphatic ring containing an additional 0-2 heteroatoms each independently selected from O, N and S, which may optionally be replaced by 1-4 heteroatoms each independently selected from alkane radical, halogen, alkoxy, aryl and hydroxyl radical substitution;

_R is H or a protecting group; and

R ₂ is H, a protecting group or C _1-12 aliphatic.

One aspect relates to a process for the enantioselective preparation of compounds of formula Ia or Ib via compounds of formulas Ic to Ih:

.

The method comprises the step of carboxylation of a compound of formula IIa or lib in the presence of a compound of formula III:

，

,

Wherein R _1a is a protecting group,

；

;

Wherein R ₃ is a protecting group or C _1-12 aliphatic, and R ₄ is H or C _1-4 unbranched aliphatic.

Another aspect relates to a process for the preparation of compounds of formula 10:

,

wherein R ₂ is as defined above, and Z ₂ is H or a protecting group;

The method comprises the steps of:

a. Form the 2-anion of the compound of formula IIa in the presence of the compound of formula III:

，

,

wherein R _1a and ring A are as defined above,

，

,

Wherein R ₃ and R ₄ are as 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 la with a compound of formula 26:

，

,

Wherein Z ₃ is a protecting group.

Detailed description of the invention

definition

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, 75th edition). Also, the general principles of organic chemistry are described in Thomas Sorrell's Organic Chemistry, University Science Books, Sausalito (1999) and M.B. Smith and J. March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, New York (2001), both incorporated herein by reference.

Compounds of the invention described herein can be optionally substituted with one or more substituents, such as those described generally 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 so on.

As used herein, the term "compound" refers to a compound defined by the corresponding structural formula drawn herein. Furthermore, unless otherwise stated, the term "compound" may include salts of the compound.

As used herein, the term "aliphatic" 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 1-8 (eg, 1-6 or 1-4) carbon atoms. Alkyl groups can be straight chain, 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. Alkyl groups 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., heterocyclic alkyl 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, (heterocycloalkylalkane base) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylaminoalkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl or heteroarylaminocarbonyl), amino (e.g. , aliphatic amino, cycloaliphatic amino or heterocycloaliphatic amino), sulfonyl (eg, aliphatic -SO ₂ -), sulfinyl, sulfanyl, thiooxy, urea, thiourea, sulfamoyl , sulfonamide, oxo, carboxyl, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy, aralkoxy, heteroarylalkoxy, alkoxy Carbonyl, alkylcarbonyloxy and hydroxy. Some examples of substituted alkyl groups include, without limitation, carboxyalkyl (such as HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxy ylalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (eg (alkyl-SO ₂ -amino)alkyl), aminoalkyl, amido Alkyl, (cycloaliphatic)alkyl and haloalkyl.

As used herein, "alkenyl" refers to an aliphatic carbon group containing 2-8 (eg, 2-6 or 2-4) carbon atoms and at least one double bond. Like alkyl, alkenyl can be straight chain or branched. Examples of alkenyl groups include, but are not limited to, allyl, prenyl, 2-butenyl, and 2-hexenyl. Alkenyl can be optionally substituted with one or more substituents such as halogen, cycloaliphatic (e.g., cycloalkyl or cycloalkenyl), heterocycloaliphatic (e.g., heterocycloalkyl or heterocyclic alkenyl), 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, heterocycloaliphatic amino or aliphatic sulfonylamino), sulfonyl (eg, alkyl-SO ₂ -, cycloaliphatic-SO ₂ - or aryl-SO ₂ -), sulfinyl, Sulfanyl, thiooxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, carboxyl, carbamoyl, cycloaliphatic oxy, heterocycloaliphatic oxy, aryloxy, heteroaryloxy , aralkoxy, heteroaralkoxy, alkoxycarbonyl, alkylcarbonyloxy and hydroxy. Some examples of substituted alkenyl groups include, without limitation, cyanoalkenyl, alkoxyalkenyl, acylalkenyl, hydroxyalkenyl, aralkenyl, (alkoxyaryl)alkenyl, (sulfonylamino )alkenyl (eg (alkyl- _SO2 -amino)alkenyl), aminoalkenyl, amidoalkenyl, (cycloaliphatic)alkenyl and haloalkenyl.

As used herein, "alkynyl" refers to an aliphatic carbon group containing 2-8 (eg, 2-6 or 2-4) carbon atoms and having at least one triple bond. Alkynyl groups can be straight chain or branched. Examples of alkynyl include, but are not limited to, propargyl and butynyl. The alkynyl group may be optionally substituted with one or more substituents such as aroyl, heteroaroyl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, Aralkoxy, nitro, carboxy, cyano, halogen, hydroxy, sulfo, mercapto, sulfanyl (e.g., aliphatic or cycloaliphatic sulfanyl), sulfinyl (e.g., aliphatic sulfinyl or cycloaliphatic sulfinyl), sulfonyl (for example, aliphatic -SO ₂ -, aliphatic amino-SO ₂ - or cycloaliphatic -SO ₂ -), amido (for example, aminocarbonyl, alkane 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 (eg, (cycloaliphatic)carbonyl or (heterocycloaliphatic)carbonyl), amino (eg, aliphatic amino) , sulfoxy, oxo, carboxy, carbamoyl, (cycloaliphatic)oxy, (heterocycloaliphatic)oxy and (heteroaryl)alkoxy.

As used herein, "acylamino" 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( ^Rx )-C(O) ^-RY or -C(O)-N(R ^X ) ₂ , when used internally they refer to amido groups such as -C(O)-N( ^Rx )- or -N( ^Rx )-C(O)-, wherein ^Rx and ^Ry are defined below. Examples of amido groups include alkylamido (e.g., alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic)amido, (heteroaralkyl)amido, (heteroaryl)amido, (heteroaryl)amido, Cycloalkyl)alkylamido, arylamido, aralkylamido, (cycloalkyl)alkylamido and cycloalkylamido.

"Amino" as used herein refers to -NR ^X R ^Y , wherein each of R ^X and R ^Y is independently selected from the group consisting of hydrogen, aliphatic, cycloaliphatic, (cycloaliphatic) aliphatic, aryl, araliphatic , heterocycloaliphatic, (heterocycloaliphatic) aliphatic, heteroaryl, carboxyl, sulfanyl, sulfinyl, sulfonyl, (aliphatic) carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) )aliphatic)carbonyl, arylcarbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl, (heteroaryl)carbonyl and (heteroarylaliphatic) Carbonyl, each of which is as defined herein and is optionally substituted. Examples of amino groups include alkylamino groups, dialkylamino groups and arylamino groups. When the term "amino" is not a terminal group (eg, alkylcarbonylamino), it is represented as ^-NRx- . R ^X has the same meaning as defined above.

"Aryl" as used herein refers to a monocyclic ring (e.g., phenyl), bicyclic (for example, indenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl) and tricyclic (for example, fluorenyl, tetrahydrofluorenyl or tetrahydroanthracenyl, anthracenyl) ring systems, wherein A monocyclic ring system is aromatic, or at least one ring in a bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2- to 3-membered carbocyclic rings. For example, benzo-fused groups include phenyl fused to two or more _C4-8 carbocyclic moieties. 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, (heteroaraliphatic) oxy, aroyl, heteroaroyl, amino, oxo (on the non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl), nitro , carboxyl, amido, acyl (e.g., aliphatic carbonyl, (cycloaliphatic) carbonyl, ((cycloaliphatic) aliphatic) carbonyl, (arylaliphatic) carbonyl, (heterocycloaliphatic) carbonyl, ((heterocycloaliphatic) carbonyl, ((hetero cycloaliphatic) aliphatic) carbonyl or (heteroaraliphatic) carbonyl), sulfonyl (for example, aliphatic- _SO2- or amino- _SO2- ), sulfinyl (for example, aliphatic-S(O) - or cycloaliphatic-S(O)-), sulfanyl (e.g., aliphatic-S-), cyano, halogen, hydroxyl, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide and carbamoyl. Alternatively, the aryl group can be unsubstituted.

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 (for example, (alkoxycarbonyl)aryl, ((arylalkyl)carbonyloxy)aryl or (alkoxycarbonyl)aryl), ( Amino)aryl (e.g., (aminocarbonyl)aryl, (((alkylamino)alkyl)aminocarbonyl)aryl, (alkylcarbonyl)aminoaryl, (arylaminocarbonyl)aryl, or ( ((heteroaryl)amino)carbonyl)aryl), aminoaryl (eg, ((alkylsulfonyl)amino)aryl or ((dialkyl)amino)aryl), (cyanoalkyl) Aryl, (alkoxy)aryl, (sulfamoyl)aryl (eg, (aminosulfonyl)aryl), (alkylsulfonyl)aryl, (cyano)aryl, (hydroxyalkyl) )aryl, ((alkoxy)alkyl)aryl, (hydroxy)aryl, ((carboxy)alkyl)aryl, (((dialkyl)amino)alkyl)aryl, (nitro Alkyl)aryl, (((alkylsulfonyl)amino)alkyl)aryl, ((heterocycloaliphatic)carbonyl)aryl, ((alkylsulfonyl)alkyl)aryl, (cyano Alkyl)aryl, (hydroxyalkyl)aryl, (alkylcarbonyl)aryl, alkylaryl, (trihaloalkyl)aryl, p-amino-m-alkoxycarbonyl aryl, 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 (eg, C _1-4 alkyl) substituted with an aryl group. Aliphatic, alkyl and aryl are as defined herein. An example of an araliphatic (eg, aralkyl) group is benzyl.

"Aralkyl" as used herein refers to an alkyl group (eg, C _1-4 alkyl) substituted with an aryl group. Both alkyl and aryl are as defined above. An example of aralkyl is benzyl. Aralkyl is optionally substituted with one or more substituents such as aliphatic (e.g., substituted or unsubstituted alkyl, alkenyl, or alkynyl, including carboxyalkyl, hydroxyalkyl, or haloalkyl , such as trifluoromethyl), cycloaliphatic (for example, substituted or unsubstituted cycloalkyl or cycloalkenyl), (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl , aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, aroyl, heteroaroyl, Nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, amido (e.g., aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, Aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino or heteroaralkylcarbonylamino), cyano, halogen, hydroxy, acyl, mercapto , alkylsulfanyl, thiooxy, urea, thiourea, sulfamoyl, sulfonamide, oxo and carbamoyl.

As used herein, "bicyclic ring system" includes 8- to 12-membered (e.g., 9-, 10-, or 11-membered) structures that form two rings, where the two rings have at least one atom in common (e.g., 2 common atoms). atom). Bicyclic ring systems include bicyclic aliphatic (eg, 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.

As used herein, "cycloalkyl" refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring of 3-10 (eg, 5-10) carbon atoms. Examples of cycloalkyl groups 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, adamantine Alkyl, azacycloalkyl and ((aminocarbonyl)cycloalkyl)cycloalkyl. As used herein, "cycloalkenyl" refers to a non-aromatic carbocyclic ring of 3-10 (eg, 4-8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohexadienyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, cyclopentenyl Alkenyl, bicyclo[2.2.2]octenyl and bicyclo[3.3.1]nonenyl. Cycloalkyl or cycloalkenyl may 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 radical, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, (( Cycloaliphatic)aliphatic)carbonylamino, (aryl)carbonylamino, (aryl)carbonylamino, (heterocycloaliphatic)carbonylamino, ((heterocycloaliphatic)aliphatic)carbonylamino, (heteroaryl radical)carbonylamino or ((heteroaryliphatic)carbonylamino), nitro, carboxy (for example, HOOC-, alkoxycarbonyl, or alkylcarbonyloxy), acyl (for example, (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-SO ₂ -), sulfinyl (e.g., alkyl-S(O)-), sulfanyl (e.g., alkyl-S -), sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo and carbamoyl.

"Ring moiety" as used herein includes cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl, each of which is as previously defined.

As used herein, the term "heterocycloaliphatic" includes heterocycloalkyl and heterocycloalkenyl, each of which is optionally substituted as described below.

"Heterocycloalkyl" as used herein refers to a 3-10 membered monocyclic or bicyclic (fused or bridged) (eg, 5 to 10 membered monocyclic or bicyclic) saturated ring structure in which one or more Ring atoms are heteroatoms (eg, N, O, S, or combinations thereof). Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dithianyl, Oxolyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, octahydrobenzofuranyl, octahydrochromenyl, octahydrothiochromenyl, octahydrochromenyl Hydroindolyl, octahydro-4-indenyl, decahydroquinolinyl, octahydrobenzo[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[3.3.1.0 ^3,7 ]nonyl. Monocyclic heterocycloalkyl groups may be fused with a phenyl moiety, such as tetrahydroisoquinoline. As used herein, "heterocycloalkenyl" refers to a monocyclic or bicyclic ring (for example, 5 to 10 monocyclic or bicyclic) non-aromatic ring structures. Monocyclic and bicyclic heteroaliphatics are numbered according to standard chemical nomenclature.

The heterocycloalkyl or heterocycloalkenyl group may optionally be 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, hetero Aryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido (e.g., (aliphatic)carbonylamino, (cycloaliphatic)carbonylamino, (cycloaliphatic) aliphatic) carbonylamino, (aryl) carbonylamino, (aryl) carbonylamino, (heterocycloaliphatic) carbonylamino, ((heterocycloaliphatic) aliphatic) carbonylamino, (hetero aryl)carbonylamino or (heteroaraliphatic)carbonylamino), nitro, carboxyl (for example, HOOC-, alkoxycarbonyl or alkylcarbonyloxy), acyl (for example, (cycloaliphatic)carbonyl, ( (cycloaliphatic)aliphatic)carbonyl, (araliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic)aliphatic)carbonyl or (heteroarylaliphatic)carbonyl), nitro, cyano radical, halogen, hydroxyl, mercapto, sulfonyl (e.g., alkylsulfonyl or arylsulfonyl), sulfinyl (e.g., alkylsulfinyl), sulfanyl (e.g., alkylsulfanyl), Sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo and carbamoyl.

吨基、硫代

吨基、吩噻嗪、二氢吲哚、苯并[1,3]二氧杂环戊烯、苯并[b]呋喃基、苯并[b]噻吩基、吲唑基、苯并咪唑基、苯并噻唑基、嘌呤基、肉啉基、喹啉基、喹唑啉基、酞嗪基、喹唑啉基、喹喔啉基、异喹啉基、4H-喹嗪基、苯并-1,2,5-噻二唑基和1,8-萘啶基。 As used herein, "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system having 4-15 ring atoms, one or more of which is a heteroatom (e.g., N, O, S, or combinations thereof ) and wherein the monocyclic ring system is aromatic, or at least one ring in the bicyclic or tricyclic ring system is aromatic. Heteroaryl includes benzo-fused ring systems having 2-3 rings. For example, benzo-fused groups include benzo-fused groups with one or two 4-8 membered heterocycloaliphatic moieties (e.g., indolyl, 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 , isoquinolinyl, benzothiazolyl,

Tonyl, Thio

Tonyl, phenothiazine, indoline, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl , benzothiazolyl, purinyl, cinnolinyl, quinolinyl, quinazolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, 4H-quinazinyl, benzo- 1,2,5-thiadiazolyl and 1,8-naphthyridinyl.

Monocyclic heteroaryl includes without limitation furyl, thienyl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-Thiadiazolyl, 2H-pyranyl, 4-H-pyranyl (4-H-pranyl), pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl and 1,3,5-Triazinyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

Bicyclic heteroaryl includes without limitation indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thienyl, quinolyl, Linyl, isoquinolyl, indolyl, isoindolyl, indolyl, benzo[b]furyl, benzo[b]thienyl, indazolyl, benzimidazolyl, benzothiazolyl , purinyl, 4H-quinolinyl, 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, (aryl (group) oxy, (heteroaraliphatic) oxy, aroyl, heteroaroyl, amino, oxo (on the non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl), carboxyl, acyl Amino, acyl (e.g., aliphatic carbonyl, (cycloaliphatic)carbonyl, ((cycloaliphatic)aliphatic)carbonyl, (arylaliphatic)carbonyl, (heterocycloaliphatic)carbonyl, ((heterocycloaliphatic) Aliphatic) carbonyl or (heteroaraliphatic) carbonyl), sulfonyl (for example, aliphatic sulfonyl or aminosulfonyl), sulfinyl (for example, aliphatic sulfinyl), sulfanyl (for example, aliphatic sulfanyl), nitro, cyano, halogen, hydroxyl, mercapto, thiooxy, urea, thiourea, sulfamoyl, sulfonamide and carbamoyl. Alternatively, a heteroaryl group can 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 (for example, ((alkylsulfonyl)amino)heteroaryl and ((dialkyl)amino)heteroaryl), (Acylamino)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, (alk Oxy)heteroaryl, (sulfamoyl)heteroaryl (for example, (aminosulfonyl)heteroaryl), (sulfonyl)heteroaryl ((for example, (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 (eg, (alkylcarbonyl)heteroaryl), (alkyl)heteroaryl and (haloalkyl)heteroaryl (eg, trihaloalkylheteroaryl).

As used herein, "heteroaraliphatic" (eg, heteroaralkyl) refers to an aliphatic group (eg, C _1-4 alkyl) substituted with a heteroaryl group. Aliphatic, alkyl and heteroaryl are as defined above.

As used herein, "heteroaralkyl" refers to an alkyl group (eg, C _1-4 alkyl) substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" are as defined above. Heteroaralkyl 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, hetero Aryloxy, aralkoxy, heteroaralkoxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonyl Amino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaryl Aralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, and carbamoyl.

"Acyl" as used herein is formyl or ^Rx -C(O)- (eg, alkyl-C(O)-, also known as "alkylcarbonyl"), wherein ^Rx and alkyl are as previously defined. Acetyl and pivaloyl are examples of acyl groups.

"Aroyl" or "heteroaroyl" as used herein refers to aryl-C(O)- or heteroaryl-C(O)-. The aryl and heteroaryl portions of the aroyl or heteroaroyl are optionally substituted as defined previously.

"Alkoxy" as used herein refers to an alkyl-O- group in which alkyl is as previously defined.

As used herein, "carbamoyl" refers to a group having the structure -O-CO- ^NRxRy or ^-NRx -CO- ^ORz , where ^Rx and ^Ry are as ^defined above, and ^Rz may be aliphatic , aryl, araliphatic, heterocycloaliphatic, heteroaryl or heteroaryl.

As used herein, "carboxy" means -COOH, ^-COORx , -OC(O)H, or -OC(O) ^Rx when used terminally and -OC(O)- or -OC(O)Rx when used internally 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 .

As used herein, "mercapto" refers to -SH.

As used herein, "sulfo" means -SO ₃ H or -SO ₃ R ^x when used terminally, and -S(O) ₃ - when used internally.

As used herein, a "sulfonamide" group refers to the structure -NR ^X -S(O) ₂ -NR ^Y R ^Z when used terminally and -NR ^X -S(O) ₂ -NR when used internally ^Y -, wherein ^Rx , ^Ry and ^Rz are as defined above.

As used herein, a "sulfonamide" group when used terminally refers to the structure -S(O) ₂ ^{- NRxRy} or ^-NRx -S(O) ₂ - ^Rz when used internally refers to- S(O) ₂ -NR ^x - or -NR ^x -S(O) ₂ -, wherein R ^x , ^RY and R ^Z are as defined above.

As used herein, "sulfanyl" refers to ^-SRx when used terminally and -S- when used internally, wherein ^Rx is as defined above. Examples of sulfanyl groups include aliphatic-S-, cycloaliphatic-S-, aryl-S-, and the like.

As used herein, "sulfinyl" means -S(O) ^-Rx when used terminally and -S(O)- when used internally, wherein ^Rx is as 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)-, etc.

"Sulfonyl" as used herein means -S(O) ₂ - ^Rx when used terminally and -S(O) _2- when used internally, wherein ^Rx is as 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) ₂ -, (cycloaliphatic(amido(aliphatic)))-S(O) ₂ - and the like.

"Sulfuroxy" as used herein means -O-SO- ^Rx or -SO- ^ORx when used terminally and -OS(O)- or -S(O)-O when used internally -, wherein R ^X is as defined above.

As used herein, a "halogen" or "halo" group refers to fluorine, chlorine, bromine or iodine.

As used herein, "alkoxycarbonyl" (which is included in "carboxy", alone or in combination with another group) refers to a group such as alkyl-O-C(O)-.

As used herein, "alkoxyalkyl" 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 refers to =O.

"Aminoalkyl" as used herein refers to the structure (R ^x ) ₂ N-alkyl-.

As used herein, "cyanoalkyl" refers to the structure (NC)-alkyl-.

As used herein, a "urea" group refers to the structure -NR ^X -CO-NR ^Y R ^Z , and a "thiourea" group when used terminally refers to the structure -NR ^X -CS-NR ^Y R ^Z when in When used internally refers to ^-NRx -CO- ^NRy- or ^-NRx -CS- ^NRy- , wherein ^Rx , ^RY and ^Rz are as defined above.

As used herein, a "guanidine" group refers to the structure N=C(N(R ^X R ^Y ))N(R ^X R ^Y ) or -NR ^X -C(=NR ^X )NR ^X R ^Y , where R ^X and R ^Y is as defined above.

"Amidino" as used herein refers to the ^structure -C=( ^NRx )N( ^RxRY ), wherein ^Rx and ^RY are as defined above.

As used herein, the term "ortho" refers to the placement of substituents on a group comprising two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.

As used herein, the term "geminal" refers to the placement of substituents on a group comprising two or more carbon atoms, wherein the substituents are attached to the same carbon atoms.

As used herein, the terms "terminal" and "internal" refer to the position of a group within a substituent. A group is terminal when it is present at the end of a substituent and is not otherwise bonded to the rest of the chemical structure. Carboxyalkyl (ie, R ^x O(O)C-alkyl) is an example of a terminally used carboxy group. Internal when the group is not terminal. Alkylcarboxy (e.g., alkyl-C(O)-O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)-O-aryl- or alk The group -OC(O)-aryl-) is an example of a carboxyl group for internal use.

As used herein, "ring" groups include monocyclic, bicyclic and tricyclic ring systems, such as cycloaliphatic, heterocycloaliphatic, aryl and heteroaryl, each of which is defined above.

As used herein, a "bridged bicyclic ring system" refers to a heterocycloaliphatic 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[3.3.1.0 ^3,7 ]nonyl. 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 radical, heteroaryloxy, aralkoxy, heteroaralkoxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, ring Alkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonyl Amino, heteroaralkylcarbonylamino, cyano, halogen, hydroxy, acyl, mercapto, alkylsulfanyl, thiooxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, and carbamoyl.

As used herein, "aliphatic chain" refers to a branched or straight chain aliphatic group (eg, alkyl, alkenyl, or alkynyl). A straight aliphatic chain has the structure -(CH ₂ ) _v - where v is 1-6. A branched aliphatic chain is a straight aliphatic chain substituted with one or more aliphatic groups. Branched aliphatic chains have the structure -(CHQ) _v- , where v is 1-6 and Q is hydrogen or an aliphatic group; however, Q should be an aliphatic group in at least one instance. The term aliphatic chain includes alkyl chains, alkenyl chains and alkynyl chains, wherein alkyl, alkenyl and alkynyl are as defined above.

As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". 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. The variables R ₁ , R ₂ , R ₃ and R ₄ and other variables described herein include specific groups such as alkyl and aryl. For the variables R ₁ , R ₂ , R ₃ and R ₄ , and other variables subsumed therein, unless otherwise stated, each specific group may be optionally substituted with one or more substituents described herein. Each substituent of a specific group is further optionally replaced by 1-3 halogen, cyano, oxo, alkoxy, hydroxyl, amino, nitro, aryl, cycloaliphatic, heterocycloaliphatic, heteroaryl , haloalkyl and alkyl substitution. For example, an alkyl group can be substituted with an alkylsulfanyl group, which can optionally be substituted with 1-3 halo, cyano, oxo, alkoxy, hydroxyl, amino, nitro, aryl, haloalkyl and alkyl substitution. As a further example, the cycloalkyl portion of a (cycloalkyl)carbonylamino group can be optionally substituted with 1-3 halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl groups. When two alkoxy groups are bonded to the same atom or adjacent atoms, the two alkoxy groups may form a ring together with the atoms to which they are bonded.

As used herein, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen group in a given structure with a group of the specified substituent. Specific substituents are described in the definitions above and in the compound descriptions and examples below. Unless otherwise stated, 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 replaced by more than one selected from the specified When substituents of a group are substituted, the substituents may be the same or different at each position. A ring substituent (eg, heterocycloalkyl) can be bonded to another ring (eg, cycloalkyl) to form a spiro-bicyclic ring system, ie, the two rings share a common atom. Combinations of substituents contemplated by this invention are those that result in the formation of stable or chemically feasible compounds.

As used herein, the phrase "stable or chemically feasible" refers to substantially Compounds that do not change. In some embodiments, a stable compound or chemically feasible compound is one that does not substantially change for at least one week when maintained at a temperature of 40° C. or less in the absence of moisture or other chemically reactive conditions.

As used herein, the phrase "enantioselectively prepared" refers to the asymmetric synthetic preparation of an enantiomerically enriched compound. This is further defined as the use of one or more techniques to prepare the desired compound in high enantiomeric excess (ie, 60% or more). Included techniques may include the use of chiral starting materials (eg, chiral pool synthesis), the use of chiral auxiliaries 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.

As used herein, "endo:exo" refers to the ratio of endo isomer to exo isomer.

As used herein, "enantiomeric ratio" or "e.r." is the ratio of the percentage of one enantiomer to the percentage of the other enantiomer in a mixture.

As used herein, a "protecting group" is defined as a group introduced into a molecule to alter a functional group present in the molecule to prevent it from reacting in a subsequent chemical reaction, thus rendering chemoselectivity. It is removed from the molecule in a later step in the synthesis. For example, a benzyloxycarbonyl (Cbz) group can replace a hydrogen on an amine to prevent it from reacting with an electrophile, and the Cbz group can then be removed by hydrolysis in a later step.

The acid and amine protecting groups used herein are known in the art (see, e.g., T.W. Greene and P.G.M Wutz, "Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis)", 3rd Ed., John Wiley & Sons, Inc. (1999)). Examples of suitable protecting groups for acids 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 the treated patient, and is generally determined based on the age, surface area, weight and condition of the patient. The interrelationship of doses in animals and humans (based on milligrams per square meter of body surface) is described in Freireich et al., Cancer Chemother. Rep., 50:219 (1966). Body surface area can be approximately determined from the patient's height and weight. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). "Patient" as used herein refers to mammals, including humans.

Unless otherwise indicated, structures depicted herein are also intended to include all isomeric forms of the structures (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers); e.g., for each asymmetric center R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) isomeric mixtures of the compounds of the present invention are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

Furthermore, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having structures of the present invention are within the scope of the present invention except for replacement of hydrogen by deuterium or tritium or replacement of carbon by ¹³ C or ¹⁴ C enriched carbon. 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" stands for thin layer chromatography.

implementation plan

In one aspect, the invention provides methods and intermediates for the production of bicyclic derivatives of formula Ia or Ib:

in:

Ring A is a C _3-12 cycloaliphatic ring;

Ring B is a C _3-12 heterocycloaliphatic ring containing an additional 0-2 heteroatoms each independently selected from O, N and S, which may optionally be replaced by 1-4 heteroatoms each independently selected from alkane radical, halogen, alkoxy, aryl and hydroxyl radical substitution;

_R is H or a protecting group; and

R ₂ is H or C _1-12 aliphatic.

In one embodiment, Ring A is a C _3-6 cycloaliphatic ring.

More particularly, ring A is cyclopentyl.

。 More specifically, ring A is

.

In another embodiment, Ring A is cyclopropyl.

More particularly, ring A is 1,1-dimethylcyclopropyl.

。 More specifically, ring A is

.

In one embodiment, Ring B is aryl.

More particularly, ring B is phenyl.

。 More specifically, 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 specifically, ring B is:

。

.

In one embodiment, R ₁ is H.

In another embodiment, R ₁ is a protecting group.

More particularly, R ₁ is tert-butylcarbamate (Boc).

In one embodiment, _R is H.

In another embodiment, R ₂ is C _1-12 aliphatic.

More particularly, R ₂ is C _1-6 alkyl.

In one embodiment, R is _methyl , ethyl, n-propyl, isopropyl, isobutyl, n-butyl, tert-butyl, n-pentyl or isopentyl.

More particularly, _R2 is isobutyl.

In another embodiment, _R2 is tert-butyl.

In another embodiment, _R2 is a cycloaliphatic ring.

Another aspect relates to a process for the enantioselective preparation of compounds of formula Ia or Ib via compounds of formulas Ic to Ih:

.

The method comprises the step of carboxylation of a compound of formula IIa or lib in the presence of a compound of formula III:

,

Wherein R _a1 is a protecting group,

；

;

Wherein R ₃ is a protecting group or C _1-12 aliphatic, and R ₄ is H or C _1-4 unbranched aliphatic.

In one embodiment, R _1a is tert-butylcarbamate (Boc).

In one embodiment, the step of carboxylation of a compound of formula II involves a compound of formula IIIa:

。

.

In another embodiment, the step of carboxylation of a compound of formula II involves a compound of formula IIIb:

。

.

In one embodiment, R ₃ is C _1-12 aliphatic.

More particularly, R ₃ is C _1-6 alkyl.

In one embodiment, R _is selected from methyl, ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, n-butyl, n-pentyl and isopentyl.

More particularly, _R3 is tert-butyl.

In another embodiment, _R3 is a protecting group.

In one embodiment, _R4 is H.

In another embodiment, R ₄ is C _1-4 unbranched aliphatic.

More particularly, _R4 is methyl.

In one embodiment, the carboxylation step comprises treating a compound of formula IIa or lib with carbon dioxide and a lithium base in the presence of an aprotic solvent.

In one embodiment, the aprotic solvent is selected from 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 results in a mixture of products comprising I-1a (exo), I-3 (exo), I-2 (endo) and I-4 (endo).

In one embodiment, after carboxylation, in a mixture comprising compounds of formulas Ia and Id (exo isomers) and compounds of formulas Ic and Ie (endo isomers), the combined weight percent is 100 weight%.

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 exo/endo ratio is at least 80:20.

More particularly, the exo/endo ratio is at least 90:10.

More particularly, the exo/endo ratio is at least 95:5.

More particularly, the exo/endo ratio is at least 97:3.

In one embodiment, the method 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 crystallizing the compound of formula Ia or Ib.

In another embodiment, the compound of Formula Ic and/or Ie is removed by recrystallizing the compound of Formula Ia or Ib.

In one embodiment, the weight percent ratio 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 percentages of Ia to Id is at least 90:10.

More particularly, the ratio of the weight percentages of Ia to Id is at least 95:5.

More particularly, the ratio of the weight percentages of Ia to Id is at least 99:1.

More particularly, the ratio of weight percentages of Ia to Id is at least 99.6:0.4.

More particularly, the ratio of weight percentages of Ia to Id is at least 100:0.

Another aspect relates to a process for the preparation of compounds of formula 10:

，

,

Wherein R ₂ is H, C _1-12 aliphatic or protecting group, and Z ₂ is H or protecting group, the method comprises the following steps:

a. Form the 2-anion of the compound of formula IIa in the presence of the compound of formula III:

，

,

wherein R _1a and ring A are as defined above,

Wherein R ₃ and R ₄ are as 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 la with a compound of formula 26:

,

Wherein Z ₃ is 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 pertains 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 pertains to compounds of formula 10-a prepared by the methods disclosed herein:

。

.

In one embodiment, the compound of formula 10 is a compound of formula 10-a, wherein Z ₂ is H, and R ₂ is tert-butyl.

Another aspect relates to compounds 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 ₂ is H, and R ₂ is tert-butyl.

Another aspect relates to compounds of formula 10-d prepared by the methods disclosed herein:

。

.

Methods and Intermediates

In one aspect, the present invention provides a process and intermediates for the preparation of compounds of formula Ia, as outlined in Scheme I, wherein R ₁ , R ₂ , R ₃ , R ₄ and Ring A are as previously defined.

Option 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. For the formation of similar anions, see, for example, 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 Beak et al., J. Am. Chem. Soc., 1994, 116(8), 3231-3239. 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 , to prepare the 2-anion of formula IIa (not shown in Scheme I).

Optically active compounds of formula III can induce enantioselective carboxylation to give products having an enantiomeric excess (e.e.) of about 10% to about 95% (see, e.g., Beak et al., J. Org. Chem. ., 1995, 60, 8148-8154). Compounds of formula IIa can 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 98:2.

Referring to Scheme I, known methods are used to prepare compounds of formula IIa wherein R _1a is, for example, tert-butoxycarbonyl (Boc). See, eg, T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (Protective Groups in Organic Synthesis), 3rd Edition, John Wiley and Sons, Inc. (1999).

Compounds of formula III can be prepared as shown in Scheme II. See, e.g., D. Stead et al., Org. Letters, 2008, 10, 1409-1412.

Scheme II

In Scheme II, (±)-trans-cyclohexane-1,2-diamine is cleaved with tartaric acid to provide the diamine with the desired stereochemistry. The resulting diamine is then converted into the desired compound of formula III via reactions known to the skilled person.

Scheme III depicts the reaction of a compound of formula 26 with a compound of formula la to form a compound of formula 28, wherein _R2 is as defined above.

Scheme III

In Scheme III, a bicyclic amino ester of formula Ia (where _R is tert-butyl) is reacted with a protected amino acid of formula 26 (where _Z is an amine protecting group and can be , basic or hydrogenation conditions different from those used to remove the _R2 protecting group) to give amide-esters of formula 10. The protecting group _Z2 is removed from the amide-ester of formula 10 to give the amine-ester compound of formula 28.

In another embodiment, the compound of formula 28 is an intermediate in the synthesis of protease inhibitors according to Scheme IV.

Plan IV

Scheme IV is disclosed in US Patent No. 7,776,887, the entire contents of which are incorporated herein by reference.

In Scheme IV, a bicyclic amino ester of formula la (which can be prepared as described herein, wherein _R is tert-butyl) is reacted with a protected amino acid of formula 26, wherein Z _is amine protecting group and can be removed under acidic, basic or hydrogenation conditions different from those used to remove the _R2 protecting group) to give amide-esters of formula 10. The protecting group _Z2 is removed from the amide-ester of formula 10 to give the amine-ester compound of formula 28. The amino-containing compound of formula 28 is reacted with protected amino acid 29 in the presence of a coupling reagent to obtain a tripeptide of formula 30. Removal of the protecting group Z in the tripeptide of formula 30 provides the free amino-tripeptide of formula 31 . Amino-tripeptides of formula 31 are reacted with pyrazine-2-carboxylic acids of formula 32 in the presence of coupling reagents to give amide-tripeptide esters of formula 33. Esters of amide-tripeptide esters of formula 33 are hydrolyzed to provide amido-tripeptide acids of formula 34. Reaction of an amido-tripeptide acid of formula 34 with an amino-hydroxylamide of formula 18 in the presence of a coupling reagent yields a hydroxy-peptide of formula 35. In the final step, the hydroxyl group of the compound of formula 35 is oxidized to provide the compound of formula 4.

In another embodiment, the method of Scheme III can be scaled up for large-scale production, eg, in a manufacturing plant. Large scale production can eg be scaled up to greater than 1000 kg.

Although in some portions of Schemes I-IV, for some compounds only a single isomer is illustrated, the invention is intended to include all stereoisomers of the compounds.

The following non-limiting examples are described so that the invention may be more fully understood. These examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

Example

Example 1: N-tert-butoxycarbonyl-3-azabicyclo[3.3.0]octane (6).

method 1

Under nitrogen, with stirring, a 2 L three-neck round bottom flask equipped with a mechanical stirrer, 500 mL addition funnel, and thermometer was charged with 3-azabicyclo[3.3.0]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°C. A 500 mL Erlenmeyer flask was charged with Boc ₂ O (di-tert-butyl dicarbonate) (145 g, 0.644 mol) and MTBE (190 mL). Stir the mixture until dissolution is complete. The solution was poured into the addition funnel and added to the reaction mixture, keeping the reaction temperature below 25 °C. Water (290 mL) was added to dissolve the solids, and the mixture was stirred for 10-15 minutes. After removal of the aqueous phase, the organic phase was washed with 5% aqueous NaHSO ₄ (twice, 145 mL each), followed by water (145 mL). The organic phase was concentrated and MTBE (1.3 L) was added to give the title compound as a solution in MTBE. See, eg, R. Griot, Helv. Chim. Acta., 42, 67 (1959).

Method 2

A solution of potassium carbonate (187 g, 1.35 mol) in water (160 mL) was added to a mixture of 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°C. A solution of _Boc2O (145 g, 0.644 mol) in MTBE (190 mL) was added while maintaining the temperature below 35 °C. After the addition, the mixture was stirred for 1 hour, then filtered. The solid was washed with MTBE (50 mL). The phases were then separated and the organic phase was washed with 5% aqueous NaHSO ₄ (twice, 145 mL each) and water (145 mL). It was 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 a solution of the title compound in MTBE.

Example 2: (1S, 3aR, 6aS)-tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-3,3-dimethylbutyryl) octahydrocyclopenta[ c] Pyrrole-1-carboxylate (27).

method 1

A 3 L 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. Allow the solution to cool slightly. Charge Cbz-L-tert-leucine dicyclohexylamine salt (330.0 g, 0.739 mol) into the reaction flask. 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, keeping the temperature at 20±5°C. The mixture was stirred at room temperature for about 1 hour, then diluted slowly with water (455 mL). Agitation was stopped and the layers were allowed to settle. The aqueous phase was removed to provide 1100 mL of a colorless solution at pH 1. Charge additional water (200 mL) to the remaining organic phase in the flask. 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 500 mL of a colorless solution at pH 2. The organic phase was heated to about 35 °C, diluted with DMF (300 mL), and concentrated under reduced pressure to the point that the distillation slowed significantly, leaving about 500 mL of concentrate. Without rinsing, the concentrate was transferred to a 1 L Schott bottle. The concentrate (clear colorless solution) weighed 511.6 g. Based on solution assay analysis and solution weight, the solution contained 187.2 g (0.706 mol) carboxybenzyl-L-tert-leucine (Cbz-L-tert-leucine).

A 5 L four-neck 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 molar equivalents), EDC·HCl (129.48 g, 0.675 mol, 1.20 molar equivalents) and DMF (480 mL). Cool the slurry to 0-5 °C. A 36.6 wt% solution of the acid of Cbz-L-tert-leucine in DMF (491.3 g, 0.745 mol, 1.32 molar equivalents) was added to the reaction mixture over 47 minutes while maintaining the temperature at 0-5 °C. The reaction mixture was stirred for 1 hour and 27 minutes. A solution of 3-azabicyclo(3.3.0)octane-2-carboxylic acid-tert-butyl ester in isopropyl acetate (28.8 wt%, 414.3 g, 0.564 mol) was added over 53 minutes while maintaining the reaction temperature at 0 -5.1°C. The reaction mixture was warmed to 20±5°C over about 1 hour. 4-Methylmorpholine (34.29 g, 0.339 mol, 0.60 molar equiv) was added over 5 minutes. The reaction mixture was stirred for 16 hours, and then isopropyl acetate (980 mL) was added to the reaction solution. A solution of histamine·2HCl (41.58 g, 0.226 mol, 0.40 molar equivalents) in water (53.02 g) was added to the reaction mixture within 4 minutes, followed by 4-methylmorpholine (45.69 g, 0.45 mol, 0.80 mol equivalent). After 3.5 hours, the reaction mixture was sampled. Water (758 mL) was added and the mixture was stirred for about 20 minutes, then settled for 11 minutes. The phases were separated. The aqueous phase was extracted with isopropyl acetate (716 mL), and the organic phases were combined. 1 N aqueous hydrochloric acid was prepared by adding 37 wt% hydrochloric acid (128.3 mL) to water (1435 ml). The organic phase was washed with 1N hydrochloric acid for about 20 minutes. A 10% by weight aqueous potassium carbonate solution was prepared by dissolving potassium carbonate (171 g, 1.23 mol, 2.19 molar equivalents) in water (1540 mL). The organic phase was washed with a 10% by weight aqueous potassium carbonate solution for about 20 minutes. The final clear, pale yellow organic solution (1862.1 g) was sampled for solution assay. The solution contained 238.3 g (0.520 mol) of the product of the title compound based on solution assay and weight of the solution.

¹ H 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

A solution of potassium carbonate (73.3 g) in water (220 mL) was added to (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 °C. 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, 0.863 M) was added to a suspension of Cbz-tert-leucine dicyclohexylamine salt (118.4 g) in tert-butyl methyl ether (640 mL) while maintaining the temperature at about 20°C. 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, N-methylmorpholine (80 mL) was added to the organic phase, which was concentrated to 80 mL under reduced pressure at 40 °C to obtain 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)/N-methylmorpholine (280 mL) at 0-10 °C. The mixture was stirred at about 5°C for 1 hour. A solution of 3-azabicyclo[3.3.0]octane-2-carboxy, tert-butyl ester from above was added at 0-20 °C, followed by N-methylmorpholine (32 mL). The mixture was stirred for 6 hours, then diluted with isopropyl acetate (600 mL), then 1 N 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 volumes) in A solution of potassium carbonate (3.0 eq) in water (3.5 vol) was added at 20-25°C. The mixture was stirred for 3 hours, then the phases were separated. The organic phase was washed with water (2 vol).

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°C. The mixture was stirred for 30 minutes, the phases were separated and the organic phase was washed with water (2x, 2.5 vol).

The two solutions from above were combined and then cooled to 0-5°C. 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°C to destroy excess activated ester. The mixture was then washed with 5% potassium carbonate (5 vol), 1 N hydrochloric acid (5 vol), 5% potassium carbonate (5 vol), and water (twice, 5 vol) to give the title compound in isopropyl acetate.

Example 3: (1S,3aR,6aS)-tert-butyl 2-((S)-2-amino-3,3-dimethylbutyryl)-octahydrocyclopenta[c]pyrrole-1- Formate (28).

method 1

A 1 L Buchi hydrogenator was purged three times with nitrogen. A 307.8 g portion of 12.8% by weight of (1S,3aR,6aS)-tert-butyl 2-((S)-2-(benzyloxycarbonylamino)-3,3-dimethyl Butyryl) octahydrocyclopenta[c]pyrrole-1-carboxylate (prepared as in Example 6, method 1) in isopropyl acetate (39.39 g, 0.086 mol) solution. Isopropyl acetate (100 mL) was added to the reactor. A slurry of 50% water and wet 20% Pd(OH) ₂ /carbon (3.97 g) in isopropyl acetate (168 mL) was prepared and charged to the reactor with agitation started. The reactor was pressurized to 30 psig with nitrogen and vented to atmospheric pressure. Repeat twice. Next, the reactor was pressurized to the reactor with hydrogen and vented to atmospheric pressure. Repeat 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 with Whatman #1 filter paper to remove the catalyst. The filter cake was washed with isopropyl acetate (80 mL). The 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 three hydrogenations were combined and distilled under reduced pressure (28 torr). The resulting solution (468.68 g) was assayed for the title compound.

¹ H 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 the hydrogenation apparatus, the solution of Cbz derivative 27 from Example 6, Method 2 was added to 20% Pd(OH) ₂ /water (50%, 12.2 g). The apparatus was pressurized to 30 psi with hydrogen, followed by stirring at about 20°C for 2 hours. The mixture was filtered to remove the catalyst and the filter cake was washed with isopropyl acetate (160 mL). The combined filtrates were evaporated 2-3 times with about 4 volumes of heptane at 40°C to remove isopropyl acetate. The resulting slurry was cooled to 0 °C, filtered, and the product was dried under reduced pressure to afford the title compound.

Method 3

(1S,3aR,6aS)-tert-butyl 2-((S)-2-amino-3,3-dimethylbutyryl)-octahydrocyclopenta[c A solution of pyrrole-1-carboxylate in isopropyl acetate was added to 20% Pd(OH) ₂ (2 wt% loading, 50% wet) and the mixture was hydrogenated at 2 bar and 20-25°C for 2 hours. The catalyst was removed by filtration and washed with isopropyl acetate (2 vol). The filtrate was concentrated to 10 volumes under reduced pressure at 40°C to obtain a solution of the title compound in isopropyl acetate.

While we have presented various embodiments of this invention, it will be apparent that our basic architecture can be altered to provide other embodiments utilizing 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 (65)

1. A method for enantioselectively preparing the compound of formula Ia or Ib:

, The method is via compounds of formulas Ic to Ih:

, The method comprises the step of carboxylation of a compound of formula IIa or lib in the presence of a compound of formula III:

,

, in: Ring A is a C _3-12 cycloaliphatic ring; Ring B is a C _3-12 heterocycloaliphatic ring containing an additional 0-2 heteroatoms each independently selected from O, N and S, wherein Ring B is optionally composed of 0-4 each independently selected from Alkyl, halogen, alkoxy, aryl and hydroxyl radical substitution; R ₁ is H or a protecting group; R _1a is a protecting group; R ₂ is H, a protecting group or C _1-12 aliphatic; R ₃ is a protecting group or C _1-12 aliphatic; and R ₄ is H or C _1-3 unbranched aliphatic. 2. The method of claim 1, wherein ring A is a C _3-6 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 an 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, halogen, alkoxy and hydroxy. 14. The method of claim 13, wherein Ring B is:

. 15. The method of claim 1, wherein _R is H. 16. The method of claim 1, wherein R ₁ is a protecting group. 17. The method of claim 16, wherein R ₁ is tert-butylcarbamate (Boc). 18. The method of claim 1, wherein R _1a is a protecting group. 19. The method of claim 18, wherein R _1a is tert-butylcarbamate (Boc). 20. The method of claim 1, wherein R ₂ is H. 21. The method of claim 1, wherein R ₂ is C _1-12 aliphatic. 22. The method of claim 21, wherein R ₂ is C _1-6 alkyl. 23. The method of claim 22, wherein _R is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, n-butyl, n-pentyl and isopentyl. 24. The method of claim 23, wherein R ₂ is tert-butyl. 25. The method of claim 21, wherein R ₂ is a cycloaliphatic ring. 26. The method of claim 1, wherein a compound of formula IIIa is present in the step of carboxylation of the compound of formula IIa or lib:

. 27. The method of claim 1, wherein a compound of formula IIIb is present in the step of carboxylation of the compound of formula IIa or lib:

. 28. The method of claim 1, wherein R ₃ is C _1-12 aliphatic. 29. The method of claim 28, wherein R ₃ is C _1-6 alkyl. 30. The method of claim 29, wherein R is selected from the _group consisting of methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl, n-butyl, n-pentyl and isopentyl. 31. The method of claim 30, wherein R ₃ is tert-butyl. 32. The method of claim 1, wherein R ₄ is H. 33. The method of claim 1, wherein R ₄ is C _1-4 unbranched alkyl. 34. The method of claim 33, wherein R ₄ is methyl. 35. The method of claim 1, wherein said carboxylation step comprises treating a compound of formula II with carbon dioxide and a lithium base in an aprotic solvent. 36. The method of claim 35, wherein the aprotic solvent is selected from the group consisting of toluene, ethyl acetate, benzene and methyl tert-butyl ether (MTBE). 37. The method of claim 36, wherein the aprotic solvent is MTBE. 38. The method of claim 35, wherein the lithium base is sec-butyllithium. 39. The method of claim 1, wherein in the mixture comprising the compound (exo isomer) of formula Ia and Id and the compound (endo isomer) of formula Ic and Ie, the weight percentage of combination is 100% by weight . 40. The method of claim 39, wherein the exo/endo ratio is at least 60:40. 41. The method of claim 1, further comprising removing a portion of compounds of formulas Ic and Ie from said mixture. 42. The method of claim 41, wherein the compounds of formula Ic and le are removed by crystallizing the compound of formula la. 43. The method of claim 41, wherein the compounds of formula Ic and le are removed by recrystallizing the compound of formula la. 44. The method of claim 1, wherein the weight percent ratio of Ia to Id is at least 60:40. 45. A method for preparing a compound of formula 10:

, The method comprises the steps of: a. Form the 2-anion of the compound of formula IIa in the presence of the compound of formula III:

,

; b. treating the anion of step a with carbon dioxide to enantioselectively produce a compound of formula Ia; and c. in the presence of a coupling reagent, the compound of formula Ia is reacted with the compound of formula 26,

; in: Ring A is a C _3-12 cycloaliphatic ring; R ₁ is H or a protecting group; R ₂ is H, a protecting group or C _1-12 aliphatic; R ₃ is a protecting group or C _1-12 aliphatic; R ₄ is H or C _1-3 unbranched aliphatic; _Z is H or a protecting group; and Z ₃ is a protecting group. 46. The method of claim 45, wherein the compound of formula III is formula IIIa: . 47. The method of claim 45, wherein the compound of formula III is formula IIIb: . 48. The method of claim 45, wherein the compound of formula 26 is formula 26-a: . 49. The method of claim 45, wherein the compound of formula 26 is formula 26-b:

. 50. The method of claim 45, wherein the compound of formula 10 is formula 10-a: . 51. The method of claim 50, wherein Z ₂ is H, and R ₂ is tert-butyl. 52. The method of claim 45, wherein the compound of formula 10 is formula 10-b: . 53. The method of claim 45, wherein the compound of formula 10 is formula 10-c: . 54. The method of claim 53, wherein Z ₂ is H, and R ₂ is tert-butyl. 55. The method of claim 45, wherein the compound of formula 10 is formula 10-d:

. 56. A method for preparing a compound of formula 4: , The method comprises the steps of: a. in the presence of a compound of formula III, the compound of formula II-a is reacted with alkali and _CO to prepare the compound of formula I-1a; 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 _Z2 from a compound of formula 10 to give a compound of formula 28:

; d. In the presence of a coupling reagent, the compound of formula 28 is reacted with the compound of formula 29:

to obtain compounds of formula 30:

Wherein Z is an amine protecting group; e. Removing the protecting group Z in the compound of formula 30, to obtain the compound of formula 31: ; f. In the presence of a coupling reagent, the compound of formula 31 is reacted with the compound of formula 32:

to obtain compounds of formula 33:

; g. hydrolyzing the ester of the compound of formula 33 to give the compound of formula 34:

; h. In the presence of a coupling reagent, the compound of formula 34 is reacted with the compound of formula 18:

To obtain the compound of formula 35: ;and i. Oxidation of the compound of formula 35 to give the compound of formula 4. 57. The method of claim 56, wherein the method is scaled up for large-scale production. 58. The compound of formula Ia-1 prepared by the method of claim 1:

. 59. The compound of formula Ia-2 prepared by the method of claim 1: . 60. The compound of formula Ia-3 prepared by the method of claim 1:

. 61. The compound of formula Ia-4 prepared by the method of claim 1: . 62. The compound of formula 10-a prepared by the method of claim 45:

. 63. The compound of formula 10-b prepared by the method of claim 45:

. 64. The compound of formula 10-c prepared by the method of claim 45:

. 65. The compound of formula 10-d prepared by the method of claim 45: .