KR20050039844A - Process for preparing 5-(4-fluorophenyl)-1-[2-((2r,4r)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1h-pyrrole-3-carboxylic acid phenylamide - Google Patents

Abstract

A method for preparing 5-(4-fluorophenyl)- I-[2-((2R, 4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-2-isopropyl- 4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I), a key intermediate in the synthesis of atorvastatin calcium, is described.

Description

5- (4-fluorophenyl) -1- [2-((2R, 4R) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) ethyl] -2-isopropyl-4- Method for producing phenyl-1H-pyrrole-3-carboxylic acid phenylamide {PROCESS FOR PREPARING 5- (4-FLUOROPHENYL) -1- [2-((2R, 4R) -4-HYDROXY-6-OXO-TETRAHYDRO- PYRAN-2-YL) ETHYL] -2-ISOPROPYL-4-PHENYL-1H-PYRROLE-3-CARBOXYLIC ACID PHENYLAMIDE}

5- (4-fluorophenyl) -1- [2-((2R, 4R) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -ethyl, an important intermediate in the synthesis of atorvastatin calcium ] -2-isopropyl-4-phenyl-1 H-pyrrole-3-carboxylic acid phenylamide.

5- (4-Fluorophenyl) -1- [2-((2R, 4R) -4-hydroxy-6-oxo-tetrahydro-pyran- 2-yl) -ethyl] -2-isopropyl-4 -Phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I) has the chemical name [R- (R ^* , R ^* )]-2- (4-fluorophenyl) -β, δ-dihydroxy-5 Atorvastatin calcium (Lipitor, also known as-(1-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl] -1H-pyrrole-1-heptanate calcium salt (2: 1) trihydrate) ) Is an important intermediate in the synthesis of (registered trademark). Atorvastatin calcium inhibits 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and is therefore useful as a lipid lowering agent and / or cholesterol lowering agent.

A number of patents have been published that disclose atorvastatin as well as methods and important intermediates for the preparation of atorvastatin. This includes U.S. Patents 4,681,893, 5,273,995, 5,003,080, 5,097,045, 5,103,024, 5,124,482, 5,149,837, 5,155,251, 5,216,174, and 5 5,245,047, 5,248,793, 5,280,126, 5,397,792, 5,342,952, 5,298,627, 5,446,054, 5,470,981, 5,489,690, 5,489,691,5,489,691 5,510,488, 5,998,633, 6,087,511, 5,969,156, 6,121,461, 5,273,995, 6,476,235, 5,969,156 and 6,121,461.

Current shortcomings have emerged for the preparation of important intermediates (I). For example, one approach relies on the use of expensive chiral feedstock ((R) -4-cyano-3-hydroxy-butyric acid ethyl ester) and low temperature diastereomer-selective borane reduction.

Scheme 1 summarizes other approaches disclosed in US Pat. No. 6,476,235. Hydrogenation of β, δ diketoester 2 in the presence of a chiral ruthenium catalyst under acidic conditions affords diol 3 in moderate to good yield, with a 1: 1 syn: anti moiety for C-3 and C-5 chiral centers. Provide stereoisomer selectivity. Next, a number of additional modifications are needed to reset the stereochemistry of the C-3 centers in Diol 3 to provide the important intermediate (I). Said step of (a) providing lactone 4 by intramolecular cyclization of 3; (b) removing water from lactone 4 to provide α, β unsaturated lactone 5; (c) surface-selective Michael addition of allyl or benzyl alcohol to α, β unsaturated lactone 5 to provide saturated lactone 6; And removing allyl or benzyl residues in lactone 6 via hydrogenolysis to provide the important intermediate (I).

As a premise, asymmetric hydrogenation of ketones is a known variant in organic synthesis. However, in the case of 1,3,5-tricarbonyl systems, the complexity of the reaction is increased, often resulting in poor efficiency and poor stereoselectivity. In fact, Saburi, Tetrahedron, 1997, 1993; 49] and Carpentier, Eur. J. Org. Chem. 1999; 3421 has demonstrated low to moderate diastereomer- and / or enantiomer-selectivity for diketoester asymmetric hydrogenation.

In addition, the fact that the process disclosed in this document requires high pressure hydrogenation and extended reaction times makes the procedure generally impractical and unacceptable in large scale manufacturing processes where safety, efficiency and cost are critical considerations.

As a result, there is still a need for an approach to the preparation of important intermediates (I) which is efficient and inexpensive, with minimal modifications, and which results in good yields and high levels of diastereomer-selectivity.

Summary of the Invention

Above requirements and other demands

(a) contacting a compound of formula (II) with a transition metal catalyst, a hydrogen source and a base in a solvent to provide a compound of formula (III);

(b) converting a compound of formula (III) to a compound of formula (IV) using a base; And

(c) contacting a compound of formula (IV) with an acid in a solvent to obtain a compound of formula (I), which is satisfied by the present invention relating to a process for the preparation of a compound of formula (I):

Wherein R ¹ is defined as -XR, wherein X is O, S, or Se,

R ¹ is Wherein R ² and R ³ are independently alkyl, cycloalkyl, arylalkyl, or aryl, or

R ² and R ³ combine to form — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — (CH (R ⁴ ) —CH ₂ ) ₃ —, — (CH (R ⁴ ) —CH ₂ ) ₄ − ,-(CH (R ⁴ )-(CH ₂ ) ₂ -CH (R ⁴ ))-,-(CH (R ⁴ )-(CH ₂ ) ₃ -CH (R ⁴ ))-, -CH ₂ -CH ₂ -A-CH ₂ -CH _2- , -CH (R ⁴ ) -CH ₂ -A-CH ₂ CH _2- , -CH (R ⁴ ) -CH ₂ -A-CH ₂ -CH (R ⁴ )- ego,

R ⁴ is alkyl having 1 to 4 carbon atoms, A is O, S, or NH or NR,

R is defined as alkyl, aryl, arylalkyl, or heteroaryl.

In addition, the present invention

(a) contacting a compound of formula (V) with a transition metal catalyst, a hydrogen source and a base in a solvent to provide a compound of formula (VI);

(b) converting a compound of formula (VI) to a compound of formula (IV) using a base; And

(c) contacting a compound of formula (IV) with an acid in a solvent to obtain a compound of formula (I):

<Formula I>

Wherein R ″ is defined as Me, Et, or t-Bu.

As disclosed herein, Applicant surprisingly unexpectedly finds (R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl, which is the diol ester of the present invention. -Pyrrole-1-yl] -3,5-dihydroxy-heptanoic acid esters are highly modified through a gentle and efficient ruthenium-catalyzed asymmetric mobile hydrogenation reaction using a transition metal catalyst with a chiral non-racemic ligand It has been found that it can be obtained directly from the corresponding 1,3,5-tricarbonyl precursor in a stereoselective manner. The reaction proceeds in good yield at ambient temperature and atmospheric pressure. The method of the present invention does not require the use of specialized high pressure equipment and hydrogen gas, making it safer and more efficient than previous approaches on a large scale. Since the transfer hydrogenation reaction occurs with high levels of neodiastereoselectivity, no further modification is required to calibrate the C-3 central stereochemistry as in the previous approach, and the compounds of formula (II) may be The overall number of steps needed to convert to) is minimized. In addition, the process of the present invention is a low temperature and the use of expensive chiral raw material ((R) -4-cyano-3-hydroxy-butyric acid ethyl ester) which was essential in the previous approach for the preparation of the important intermediate (I). It avoids diastereoisomer-selective borane reduction.

The term "alkyl" means a straight or branched hydrocarbon radical having 1 to 8 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- Butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.

The term "cycloalkyl" means a saturated hydrocarbon ring having 3 to 8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

"Alkoxy" and "thioalkoxy" are 0-alkyl or S-alkyl of 1 to 6 carbon atoms as defined for "alkyl" above.

The term "aryl" refers to phenyl groups, phenylalkyl groups, alkyl as defined above, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cya Furnace, as defined above for alkyl ,-(CH ₂ ) n ₂ -N (alkyl) ₂ , where n ₂ is an integer from 1 to 5, alkyl is as defined above, and as defined above for alkyl and n ₂ It means an aromatic radical which is a phenyl group substituted with 1 to 4 substituents selected from.

The term “heteroaryl” refers to 5- and 6-membered heteroaromatic radicals which may optionally be fused to a benzene ring containing 1 to 3 heteroatoms selected from N, O and S, for example as defined above. Alkyl, alkoxy as defined above, thioalkoxy as defined above, halogen, trifluoromethyl, dialkylamino as defined above for alkyl, nitro, cyano, as defined above for alkyl ,-(CH ₂ ) n ₂ -N (alkyl) ₂ , where n ₂ is an integer from 1 to 5, alkyl is as defined above, and as defined above for alkyl and n ₂ 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrrolyl, 2-, 3-, or 4-pyridinyl, 2-pyrazinyl, 2- optionally substituted with a substituent selected from , 4-, or 5-pyrimidinyl, 3- or 4-pyridazinyl, 1H-indol-6-yl, 1H-indol-5-yl, 1H-benzimidazol-6-yl, 1H-benzimi Dazol-5-yl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, Or heteroaromatic radicals such as 5-pyrazolyl, or 2- or 5-thiadiazolyl and the like.

The term "arylalkyl" refers to aromatic radicals in which aryl and alkyl are attached to alkyl radicals as defined above, such as benzyl, phenylethyl, 3-phenylpropyl, (4-chlorophenyl) methyl and the like.

Description of the method of the invention

The process of the invention disclosed herein is shown in Scheme 2, which begins in step (a) with mobile hydrogenation of a compound of formula (II) to form a compound of formula (III). In step (b), in the compound of formula (III) Residues (typically esters or amides) are hydrolyzed to form acids (IV). Finally, in step (c) lactoneization of acid (IV) provides the important intermediate (I).

As foretold, the carbonyl group in the compound of formula (II) is shown in keto form in Scheme 2. However, compounds of formula (II) may experience "keto-enol" tautomerism, and therefore may exist in several tautomeric forms (II, II-a, II-b, II-c and II-d) shown below. All of these forms are included in the present invention:

Step (a)

The process of the invention begins with mobile hydrogenation of a compound of formula (II) to provide a compound of formula (III). In one embodiment, R ¹ in the compound of formula (II) is defined as -XR, wherein X is O, S, or Se,

R ¹ is Wherein R ² and R ³ are independently alkyl, cycloalkyl, arylalkyl, or aryl, or

R ² and R ³ combine to form — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — (CH (R ⁴ ) —CH ₂ ) ₃ —, — (CH (R ⁴ ) —CH ₂ ) ₄ − ,-(CH (R ⁴ )-(CH ₂ ) ₂ -CH (R ⁴ ))-,-(CH (R ⁴ )-(CH ₂ ) ₃ -CH (R ⁴ ))-, -CH ₂ -CH ₂ -A-CH ₂ -CH _2- , -CH (R ⁴ ) -CH ₂ -A-CH ₂ CH _2- , -CH (R ⁴ ) -CH ₂ -A-CH ₂ -CH (R ⁴ )- ego,

R ⁴ is alkyl having 1 to 4 carbon atoms, A is O, S, or NH or NR, and R is defined as alkyl, aryl, arylalkyl, or heteroaryl.

In another embodiment of the invention, R ¹ in the compound of formula (II) is OMe, OEt, or OtBu.

In step (a) of Scheme 2, the compound of formula (II) is contacted with a catalyst such as a transition metal catalyst with a chiral non-racemic ligand in the presence of a hydrogen source and a base. "Contacting" in step (a) involves mixing a compound of formula (II), formic acid, a base and a transition metal catalyst in a solvent to form a homogeneous or heterogeneous mixture.

The solvent in step (a) is typically anhydrous or aqueous polar aprotic, polar protic, or nonpolar solvent, ketone, or hexane. Thus, the solvent in step (a) may be acetonitrile, ethyl acetate, tetrahydrofuran, dimethyl formamide, diethyl ether, methylene chloride, chloroform, methanol, ethanol, isopropanol, toluene or the like with or without water as a cosolvent or Mixtures or combinations thereof.

In step (a), the concentration of the compound of formula (II) in the solvent is generally from about 0.2 molar concentration to about 0.6 molar concentration. Typically, the concentration is about 0.3 molar to about 0.5 molar, preferably about 0.35 molar to about 0.45 molar.

The transition metal catalyst in step (a) is typically a chiral non-racemate transition metal catalyst. "Transition metal catalyst" means a catalyst derived from one of the transition metal elements as shown in columns 1B to 8B of the Periodic Table of the Elements. Chiral non-racemate transition metal catalysts contemplated for use in the process of the present invention include catalysts derived from elemental ruthenium, rhodium, iridium and the like.

Chiral non-racemate transition metal catalysts are, for example, solvents such as methanol, ethanol, isopropanol, and the like, optionally co-solvents such as dichloromethane, tetrahydrofuran, toluene and triethylamine, depending on methods available to those skilled in the art. In the presence of a base such as, the catalyst precursor is prepared by reacting with a chiral non-racemic ligand.

Catalyst precursors contemplated for use in the process of the invention include [dichloro- (1,5-cycloocta-diene)] ruthenium (II) oligomers, [RuCl ₂ benzene] ₂ , [RuCl ₂ p-cymene] ₂ , [RuCl ₂ mesitylene] ₂ , [dibromo- (1,5-cyclooctadiene)] ruthenium (II) dimer, [bis- (2-methallyl) cycloocta-1,5-diene] ruthenium ( II) complexes, pentamethylcyclopenta-dienyl iridium (III) chloride dimers and pentamethylcyclopentadienyl rhodium (III) chloride dimers.

Chiral non-racemic ligands contemplated for use in the methods of the present invention include chiral non-racemic diphosphine ligands as well as chiral diamine ligands. Such ligands are described, for example, in Noyori, Ryoji; Hashiguchi, and Shohei in Acc. Chem. Res. (1997), 30 (2), 97-102; Or in Palmer, Matthew J. and Wills, Martin in Tetrahedron: Asymmetry (1999), 10 (11), 2045-2061. For example, chiral diamine ligands, chiral amino alcohol ligands can be used to prepare chiral non-racemate transition metal catalysts. Chiral diamine ligands include the following compounds 7 and 8. Chiral alcohol amine ligands include norephedrine and the like.

However, any rhodium, iridium, or ruthenium (II) precursor / diphosphine or / diamine ligand combination can be used for the mobile hydrogenation reaction of step (a).

A chiral non-racemate transition metal catalyst, once prepared, is added to a mixture comprising a compound of formula (II), a hydrogen source, a base and a solvent. Hydrogen sources contemplated for use in the process of the invention are selected from isopropanol, formic acid, or ammonium formate. When isopropanol is selected as the hydrogen source, it is typically present in very excess and used with NaOH as the base. When formic acid is selected as the hydrogen source, amine is selected as the base. When ammonium formate is selected as the hydrogen transfer agent, excess ammonia can be used, or only 2 equivalents of base as described herein can be used. Typically, the hydrogen source used in step (a) of the process of the invention is formic acid.

As noted above, when formic acid is selected as the hydrogen source, amines are typically selected as the base for the mobile hydrogenation reaction of step (a). The amine base is typically triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0.] Undes-7-ene (DBU ), Lutidine, collidine, 4-dimethyl aminomethyl pyridine, diisopropyl amine, piperidine, pyrrolidine, tri-n-butyl amine, 4-methylmorpholine and the like. Typically, however, the amine base is triethylamine.

In step (a) of the process of the invention, the molar equivalents of the compound of formula (II), the hydrogen source, the base and the transition metal catalyst are each generally about 1 equivalent of the compound of formula (II); About 2.0 to about 2.5 equivalents of hydrogen source; About 4 to about 5 equivalents of amine base; And about 0.05 to about 2 mol% transition metal catalyst.

Typically, in step (a) of the process of the invention, the molar equivalents of the compound of formula (II), the hydrogen source, the base and the transition metal catalyst are each about 1 equivalent of the compound of formula (II); About 2.1 equivalents of hydrogen source; About 4.1 equivalents of amine base; And about 1 mol% of a transition metal catalyst.

The step (a) mixture comprising a compound of formula (II), a chiral non-racemate transition metal catalyst, a hydrogen source, a base and a solvent, may be, for example, a mechanical stirrer, a magnetic stirrer, Or by using other disturbing means available to those skilled in the art. Typically, the temperature is about 10 to about 40 ° C. Preferably, the temperature is about 20 to about 30 ° C.

The pressure in step (a) is generally at atmospheric pressure, or from about 0.9 to about 1.1 atmospheres. Typically, the pressure is about 0.95 to about 1.05 atmospheres. Preferably, the pressure is about 0.99 to about 1.02 atmospheres.

Step (a) The mixture is typically stirred or otherwise disturbed at the temperature and pressure provided above until the reaction is completed by thin layer chromatography, or any other suitable monitoring method available to those skilled in the art. Generally, the reaction time is in the range of about 6 to about 24 hours. Typically, the reaction time of step (a) is about 12 to about 18 hours.

Step (a) Upon completion of the reaction, the solvent is removed by distillation at atmospheric or reduced pressure to leave the compound of formula (III) as a residue, which residue can be used in the next reaction without further purification or by column chromatography Or by other suitable means known to those skilled in the art.

Step (b)

Step (b) of the method of the present invention is disclosed in US Pat. No. 6,476,235. In step (b), the ester or amide moiety in the compound of formula (III) is converted to the acid moiety in compound (IV) under basic conditions in a solvent. Thus, for example, the ester is dissolved in aqueous methanol tetrahydrofuran and the like and treated with KOH. Alternatively, the ester can be dissolved in an aqueous THF or non-water miscible solvent such as dichloromethane and a phase transfer catalyst. Such methods and conditions are known to those skilled in the art and are readily available.

Step (c)

Step (c) of the method of the present invention is described in US Pat. No. 6,476,235, which provides 1, a convenient precursor to atorvastatin. In step (c) of the process of the invention the lactonation of compound (IV) is carried out in the presence of an aqueous acid to provide the important intermediate (I). Thus, for example, the acid is stirred in toluene in the presence of a catalytic amount of HCl.

The following examples are intended to illustrate various embodiments of the invention and are not intended to limit the scope of the invention.

Example 1

(3R, 5R) -7- [2- (4-Fluorophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -3,5-dihydroxy- Preparation of heptanoic acid, t-butyl ester (VI-A)

7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -3,5-dioxo-heptanoic acid in an argon deactivation reactor, t-butyl ester (VA, 100.0 mmol, prepared as described in US Pat. No. 6,476,235) and toluene (245 ml) were charged. Triethyl amine (55 ml) was added to the reaction mixture, followed by formic acid (7.5 ml) slowly. The vessel and its contents were degassed through three vacuum / argon purges. Under steady flow of argon, ruthenium, [N-[(1R, 2R) -2- (amino-κN) -1,2-diphenylethyl] -4-methylbenzenesulfonamidateto-κN] chloro A complex of [(1,2,3,4,5,6-η))-1,3,5-trimethylbenzene]-(1.25 g) was added and the vessel and its contents were subjected to one vacuum / argon purging. Degassed through. The reaction mixture was stirred for 24 hours and concentrated to an effervescent solid. Crude (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -3,5-dihydroxy Heptanoic acid, t-butyl ester, can be proceeded through the next step without purification, or can be isolated by eluting with an ethyl acetate-heptane mixture, optionally via flash column chromatography on silica gel. HPLC analysis (YMC ODS AQ S5; 1 ml / min; 30 ° C .; 254 nm: CH ₃ CN / H ₂ 0 w / .1% formic acid, 60:40 (0-5 min) to 100: 0 (15-22 Min) to 60:40 (25 min)) showed a syn: anti ratio of 6: 1, t _r (god) = 13.9 min, t _r (anti) = 13.5 min.

Example 2

(3R, 5R) -7- [2- (4-Fluorophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -3,5-dihydroxy- Heptanoic Acid (IV)

Crude (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrol-1-yl] -3,5-dihydroxy Heptanoic acid, t-butyl ester (VI-A) was converted to acid with excess KOH / MeOH / water and then lactonized in toluene with catalytic amount of HCl. Chiral HPLC analysis ((ChiralCel OF; 1 ml / min; 60 ° C; 254 nm; 20% IPA: hexane) t _R (3R, 5R) = 26.97 min / t _R (3S, 5S) = 33.8 min t _R (3R, 5S) = 38.1 min / t _R (3S, 5R) = 61.0 min) showed an enantiomeric excess of 85% of the isomers with a predominant (R, R) shape.

All publications, patents, and patent documents are incorporated herein by reference as if they were individually incorporated by reference. The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may occur within the spirit and scope of the invention.

Cross Reference to Related Application

This application claims priority to US Provisional Application No. 60 / 401,707, filed August 6, 2002.

Claims (13)

(a) contacting a compound of formula (II) with a transition metal catalyst, a hydrogen source and a base in a solvent to provide a compound of formula (III); (b) converting the compound of formula (III) to the compound of formula (IV) using a base in aqueous methanol; And (c) contacting a compound of formula (IV) with an acid in a solvent to obtain a compound of formula (I): <Formula I> <Formula II and III> <Formula III and IV> Wherein R ¹ is defined as -XR, wherein X is O, S, or Se, R ¹ is Wherein R ² and R ³ are independently alkyl, cycloalkyl, arylalkyl, or aryl, or R ² and R ³ combine to form — (CH ₂ ) ₄ —, — (CH ₂ ) ₅ —, — (CH (R ⁴ ) —CH ₂ ) ₃ —, — (CH (R ⁴ ) —CH ₂ ) ₄ − ,-(CH (R ⁴ )-(CH ₂ ) ₂ -CH (R ⁴ ))-,-(CH (R ⁴ )-(CH ₂ ) ₃ -CH (R ⁴ ))-, -CH ₂ -CH ₂ -A-CH ₂ -CH _2- , -CH (R ⁴ ) -CH ₂ -A-CH ₂ CH _2- , -CH (R ⁴ ) -CH ₂ -A-CH ₂ -CH (R ⁴ )- ego, R ⁴ is alkyl having 1 to 4 carbon atoms, A is O, S, or NH or NR, R is defined as alkyl, aryl, arylalkyl, or heteroaryl. The process of claim 1, wherein the contacting in step (a) comprises mixing the compound of formula (I), formic acid, base and transition metal catalyst in a solvent to form a homogeneous or heterogeneous mixture, wherein the solvent is acetone, Pentane, hexane, methylethyl ketone, tetrahydrofuran, dimethyl formamide, diethyl ether, methylene chloride, chloroform, methanol, ethanol, isopropanol, and toluene, acetonitrile, ethyl acetate, water or mixtures or combinations thereof Which is an aqueous or anhydrous polar aprotic, polar protic, or nonpolar solvent. The process of claim 1 wherein R ¹ in the compound of formula (II) or (III) is defined as —XR, wherein X is O and R is alkyl, cycloalkyl, arylalkyl, aryl, or heteroaryl. The method of claim 1, wherein R ¹ in the compound of formula (II) or (III) is defined as —XR, wherein X is O and R is alkyl. The method of claim 1 wherein R ¹ in the compound of formula (II) or (III) is OMe, OEt, or Ot-Bu. The process of claim 1 wherein the transition metal catalyst in step (a) is derived from Ir, Ru, or Rh, [dichloro- (1,5-cycloocta-diene)] ruthenium (II) oligomer, [RuCl ₂ benzene ] ₂ , [RuCl ₂ p-cymene] ₂ , [RuCl ₂ mesitylene] ₂ , [dibromo- (1,5-cyclooctadiene)] ruthenium (II) dimer, [bis- (2-methallyl) ) A transition metal catalyst precursor selected from cycloocta-1,5-diene] ruthenium (II) complex, pentamethylcyclopenta-dienyl iridium (III) chloride dimer and pentamethylcyclopentadienyl rhodium (III) chloride dimer And a chiral non-racemic ligand which is a chiral diamine ligand or a chiral alcohol amine ligand selected from norephedrine or compounds 7 or 8 . The process of claim 1 wherein the transition metal catalyst of step (a) is ruthenium, [N-[(1R, 2R) -2- (amino-κN) -1,2-diphenylethyl] -4-methylbenzenesulfonami Dayto-κN] chloro [(1,2,3,4,5,6-η))-1,3,5-trimethylbenzene]-. The process of claim 1 wherein the hydrogen source in step (a) is selected from formic acid, ammonium formate and isopropanol and the base in step (a) is triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine , Diisopropylethylamine, 1,8-diazabicyclo [5.4.0.] Undes-7-ene (DBU), lutidine, collidine, 4-dimethylaminomethyl pyridine, diisopropyl amine, tri- amine base selected from n-butyl amine, 4-methylmorpholine, piperidine and pyrrolidine. The process of claim 1 wherein the concentration in the solvent of the compound of formula (II) in step (a) is from about 0.2 molar concentration to about 0.6 molar concentration, the molar equivalent of the compound of formula (II) used is about 1, hydrogen Molar equivalents of source, base and transition metal catalyst: About 1 equivalent of compound of formula (II); About 2.0 to about 2.5 equivalents of hydrogen source; About 4.0 to about 5.0 equivalents of amine base; And Transition metal catalyst from about 0.05 to about 2 mol%. The process of claim 1 wherein the concentration in the solvent of the compound of formula (II) in step (a) is from about 0.35 molar concentration to about 0.45 molar concentration, the molar equivalent of the compound of formula (II) used is about 1, hydrogen Molar equivalents of source, base and transition metal catalyst: About 1 equivalent of compound of formula (II); About 2.1 to about 2.4 equivalents of hydrogen source; About 4.1 to about 4.8 equivalents of amine base; And The transition metal catalyst is about 1 mol%. The process of claim 1 wherein the reaction temperature in step (a) is about 0 to about 50 ° C., the reaction pressure of step (a) is about 0.9 to about 1.1 atmospheres, and the reaction time of step (a) is about 6 to about How about 24 hours. The process of claim 1 wherein the reaction temperature in step (a) is about 20 to about 30 ° C., the reaction pressure in step (a) is about 0.95 to about 1.05 atmospheres, and the reaction time of step (a) is about 12 to How about 18 hours. The process of claim 1 wherein step (a) comprises contacting a compound of formula (V) with a transition metal catalyst, a hydrogen source and a base in a solvent to provide a compound of formula (VI): <Formulas V and VI> Wherein R ″ is defined as Me, Et, or t-Bu.