MXPA00003711A - Process for the synthesis of 1,3-diols - Google Patents

Abstract

An improved process for the preparation of cis-1,3-diols is described where a beta hydroxy ketone is treated with a trialkylborane or dialkylalkoxyborane or a mixture of a trialkylborane and a dialkylalkoxyborane followed by recovery and reuse of the alkylborane species to convert additional beta hydroxy ketone to the cis-1,3-diol.

Description

PROCESS FOR THE SYNTHESIS OF 1.3-DIOLES DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing 1,3-diols. More particularly, the present invention relates to the use and subsequent recovery and reuse of a trialkylborane or dialkylalkoxyborane or a mixture of trialkylborane and a dialkylalkoxyborane in the reduction of a beta-hydroxy ketone to obtain a cis-1,3-diol. Additionally, the present invention relates to the use of a synergistic combination of a trialkylborane and a dialkylalkoxyborane in the reduction of a beta-hydroxy ketone to obtain a cis-1,3-diol. The use of trialkylboranes or dialkylalkoxyborane in the stereoselective reduction of 1,3-keto alcohols to the corresponding sin-1,3-diols has been widely described in the literature. This method has given high hetereoselectivity without the use of extraordinarily difficult conditions (Brower PL, Butler DE, Deering CF, Le TV, Millar A., Nanninga TN, and Roth B., Tetrahedron Lett., 1992; 33: 2279; Narasaka K ., and Pai FC, Tetrahedron, 1984; 40: 2233; Chen KM, Hardtmann GE, Prasad K., Repic O., and Shapiro MJ, Tetrahedron Lett., 1987; 28: 155; Chen KM, Gunderson KG, Hardtmann GE , Prasad K., Repic O., and Shapiro MJ, Chem. Lefí., 1987: 1923). The formation of a borate ester from either trialkyl or dialkylalcoxyborane which is to form a cyclic chelate seems to be of general acceptance (Narasaka K., and Pai FC, Tetrahedron, 1984; 40: 2233; Chen KM, Hardtmann GE , Prasad K., Repic O., and Shapiro MJ, Tetrahedron Lett., 1987; 28: 155; Chen KM, Gunderson KG, Hardtmann GE, Prasad K., Repic O., and Shapiro MJ, Chem. Lett., 1987 : 1923, see for example Paterson I., Cumming JG, and Smith JD, Tetrahedron Lett., 1994; 35: 3405). The axial supply of a hydride to the complex is then directed predominantly to the product-syn which can be hydrolyzed to the diol. The diols are valued as intermediates for the preparation of, for example, HMG-CoA reductase inhibitors which are useful hypolipidermic or hypocholesterolemic agents. There is a widely used method of preparing such agents (U.S. Patent Nos. 4,645,854, 5,354,772, 5,155,251, and 4,970,313). Many procedures in the literature describe the working up of the reaction with hydrogen peroxide (U.S. Patent 4,645,854 and 4,970,313). This results in the destruction of the active alkyl borane species. Some procedures describe repeated distillation with methanol and an acid (U.S. Patent Nos. 5,354,772 and 5,155,251). It also dilutes and eventually destroys the active alkylborane species. It has surprisingly and unexpectedly been found that by performing the reduction and processing with a minimum amount of acid, and keeping the distillation stream separated, that the initial distillation can be recovered and reused to obtain very good selectivity in subsequent reductions.

Thus, the present process offers significant advantages over the prior art process. For example, the cost of the additional alkyl borane is eliminated for each bath in which the distilled stream is recycled. Additionally, since alkylborans are dangerous, they must be destroyed before being disposed of. The present process minimizes this expensive and time-consuming procedure. Furthermore, it is especially surprising that very good selectivity is obtained using recovered alkylborans. Finally, it has also surprisingly and unexpectedly been found that a combination of trialkylborane and a dialkylalcoxyborane is synergistic in selectively reducing a beta-hydroxy ketone to obtain a cis-1,3-diol.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, a first aspect for the present invention is a process for the preparation of a compound of Formula I OH OH ! R- CH- CH. -CH-R1 wherein R is alkyl, NC-CH2-, PG-O-CH2- wherein PG is a protecting group, wherein R2 is (H3C) 2 CH- or cyclopropyl, wherein R3 is C6H5, (H3C) 2- N- or (H3C) 2CH- and R4 is hydrogen, H3C-0-CH2-, H3C-CH2-C (CH3) 2-C02CH2-, or H3C-O2C-CH2 -CH (OH) -CH2- CH (OH) -CH = CH-, where R5 is CH ^ CH ^ R6 is hydrogen or CH3, R7 is hydrogen or CH3, R8 is hydrogen, OH, CH3, or H5C6-NHCO-0-, and R9 is hydrogen or CH3, R1 is alkyl, or -CH2-C02R6 wherein R6 is alkyl; comprising: Step (a) treating a compound of Formula II or a compound of the Formula lll wherein R and R1 are as defined above with a trialkylborane or dialkylalkoxyborane or a mixture of a trialkylborane and a dialkylalkoxyborane in a solvent; Step (b) add an alkali metal hydride at about -110 ° C to about -50 ° C; Step (c) concentrating the reaction for distillation to provide a compound of Formula I and a distillate containing alkyl borane species; and Step (d) treating a further compound of Formula II or III with the distillate of Step (c) containing recovered alkyl borane species and repeating Steps (b) and (c) as desired to provide an additional compound of Formula I. A second aspect of the present invention is a process for the preparation of a compound of Formula I OH OH R- CH- CH2-CH-R1 l n R is alkyl, NC-CH2-, PG-O- CH2- where PG is a protective group, wherein R2 is (H3C) 2 CH- or cyclopropyl, wherein R3 is C6H5, (H3C) 2-N- or (H3C) 2CH- and R4 is hydrogen, H3C-0-CH2-, H3C-CH2-C ( CH3) 2-CO2CH2-, or H3C-O2C-CH2-CH (OH) -CH2- where R5 is CH R6 is hydrogen or CH3, R7 is hydrogen or CH3, R8 is hydrogen, OH, CH3l or HsCs-NHCO-O-, and R9 is hydrogen or CH3, R1 is alkyl, or -CH2-CO2R6 wherein R6 is alkyl; comprising: Step (a) treating a compound of the Formula or a compound of the Formula lll wherein R and R1 are as defined above with a synergistic combination of a trialkylborane and a dialkylalkoxyborane in a solvent; and Step (b) adding an alkali metal hydride at about -110 ° C to about -50 ° C to provide a compound of Formula I. A third aspect of the present invention is a synergistic combination comprising a trialkylborane and a dialkylalkoxyborane .

DETAILED DESCRIPTION OF THE INVENTION In this invention the term "alkyl" means a linear or branched hydrocarbon radical having from 1 to 10 carbon atoms and include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, butyl secondary, isobutyl, tertiary butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. "PG" means a protecting group used to protect a portion of alcohol such as, for example, benzyl and the like.

Additional examples of protecting groups for an alcohol moiety are described in Chapter 2 in Greene T. W. "Protective Groups in Organic Synthesis", John Wiley & Sons, Inc., 1981. "Alkali metal" is a metal in Group IA of the periodic table and includes, for example, lithium, sodium, potassium and the like. "Alkaline earth metal" is a metal in the HA Group of the periodic table, and includes for example, calcium, barium, strontium, and the like. "Alkali metal hydride" includes, for example, sodium borohydride, zinc borohydride, lithium borohydride, lithium aluminum borohydride and the like. "Alkylborane species" means a mono-, di- or trialkylborane wherein the mono or dialkylbonaro is further substituted by hydride or alkoxy as defined hereafter or a dimeric borane alkyl species. "Alkoxy" means an alkyl O as defined above for alkyl. As previously described, the compounds of the Formula I are either useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme reductase A (HNG CoA reductase) or are useful as intermediates for preparing HMG CoA reductase inhibitors. In this way, the present process can be used to prepare several HMG CoA reductase inhibitors that contain a cis-1,3-diol portion. For example, atorvastatin published and described in US Patents 4,681,893 and 5,273,995; fluvastatin published and described in U.S. Patent 5,354,772; bervastatin published and described in U.S. Patent 5,082,859; cerivastatin published and described in U.S. Patent 5,177,080; NK-L04 published and described in U.S. Patent 5,011,930; dalvastatin published and described in U.S. Patent 4,863,957; glenvastatin published and described in U.S. Patent 4,925,852; methyl ester of erythritol-7- [5- (2,2-dimethyl-buty-ri-oxy-methyl) 4- (4-fluoroforyl) 2,6-di-isopropyl-pyridin-3-yl] 3, 5- dihydroxy-6 (E) -heptanoic published and described in US Patents 5,006,530, 5,169,857 and 5,401,746; 7,7 '- [2- (dimethylamino) -4- (4-flurophenyl) -6-isopropylpyridine-3,5-diyl] bis [erythro- (E) -3,5-dihydroxy-6-methyl ester -heptanoic published and described in the US Patent 5,145,857; sodium salt of 7- [6-cyclopropyl-4- (4-fluorophenyl) -2- (4-methoxyphenyl) pyrimidin-5-yl] -3,5-dihydroxy-6 (£) -heptanoic acid published and described in U.S. Patent 5,026,708; (E) -7- [4- (4-fluorophenyl) -2-isopropylquinolin-3-yl] -3,5, -dihydroxy-6-heptanoic acid d-lactone published and described in U.S. Patents 5,011,930, 5,102,888 and 5,185,328; frans- (E) -6- [2- [2- (4-fluoro-3-methylphenyl) -6,6-dimethyl-4 - (? / - phenyl-carbamoyloxy) -1-cyclohexanyl] vinyl] -4- hydroxytetrahydropyran-2-one published and described in U.S. Patent 5,001,144; sodium salt of erythritol- (E) -7- [2- (4-fluoro-3-methylphenyl) -4,4,6,6-tetramethyl-1-cyclohexan-1-yl] -3,5-dihydroxy acid -6-heptanoic published and described in U.S. Patent 4,863,957; (E) -Itans-6- [2- [2- (4-fluoro-3,5-dimethylphenyl) 4-hydroxy-6,6-dimethyl-1-cyclohexanyl] vinyl] -4-hydroxytetrahydropyran-2-one published and described in U.S. Patent 4,900,754; ethyl E- (3R, 5S) -7- [4'-fluoro-3,3 ', 5-trimethyl (1,1') biphenyl-2-yl] -3,5-dihydroxy-6-heptanoate published and described in U.S. Patent 4,567,289; 3 (R), 5 (S) -dihydroxy-7- [4- (4-fluorophenyl) -1-isopropyl-3-phenyl-1 / - / - pyrazol-5-yl] hept-6 (E) - acid anoicum published and described in U.S. Patent 4,613,610; and (3R, 5S) -BMY-21950 published and described in U.S. Patent 4,897,490 can be obtained using the present process. The total of the aforementioned US Patents are incorporated herein for reference. The process of the present invention in its first aspect is an improved, economical and commercially feasible method for preparing a compound of Formula I. The process of the present invention in its first aspect is indicated in Scheme I Scheme I.

OH OR OH OH? II f R-CH-CH¿- C- R¡R-CH-CH2- GH-R1 p III In this way, the compound of Formula II of R is alkyl, NC-CH2-, PG-0-CH2- wherein PG is a protecting group, wherein R2 is (H3C) 2 CH or cyclopropyl, wherein R3 is C6H5, (H3C) 2-N- or (H3C) 2CH- and R4 is hydrogen, H3C-O-CH2-, H3C-CH2-C (CH3) 2 -COCH2-, or H3C-O2C-CH2 -CH (OH) -CH2- CH (OH) -CH = CH-, where R5 is R6 is hydrogen or CH3, R7 is hydrogen or CH3, R8 is hydrogen, OH, CH3, or H5C6-NHCO-O-, and R9 is hydrogen or CH3, R1 is alkyl, or -CH2-CO2R6 wherein R6 is alkyl; or a compound of Formula III wherein R and R1 are as defined above, treated with about 0.1 to about 2.0 molecular equivalents of a trialkylborane such as, for example, triethylborane, tripropylborane, tri-n-butylborane, tri-sec. -butylborane and the like or a dialkylalkoxyborane such as, for example, dimethylmethoxyborane, dimethylethoxyborane, dimethylisopropoxyborane, diethylmethoxyborane, diethylethoxyborane, diethylisopropoxyborane, dusopropylmethoxyborane, diisopropylethoxyborane, diisopropylisopropoxyborane, and the like or a mixture of a trialkylborane and a dialkylalkoxyborane as described previously, followed by stereoselective reduction with about 1 molecular equivalent of an alkali metal hydride such as, for example, sodium borohydride, zinc borohydride, lithium borohydride, lithium aluminum hydride, and the like; in a solvent such as hydrocarbon, for example hexane, toluene, cyclohexane and the like; an alkanol, for example methanol, ethanol, isopropanol and the like; or an ether, for example diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, triglyme (triethylene glycol dimethyl ether) and the like, or mixtures thereof at a temperature of about -110 ° C to about -50 ° C to provide after the concentration by distillation of a compound of Formula I. The additional compound of Formula II or III is subsequently treated with the distillate obtained by vacuum distillation of the first run followed by stereoselective reduction carried out as described above for to produce a second bath of a compound of Formula I. In this way, the recovered amounts of the alkylborane species can be used to convert additional amounts of a compound of the Formula II or III to a compound of the Formula I. This procedure uses Recovered alkylborane species can be repeated as desired to obtain additional amounts of a compound of the formula. I. Preferably, the reaction is carried out with about 1.2 to 0.8 molecular equivalents of triethylborane or diethylmethoxyborane or a mixture of a triethylborane and a diethylmethoxyborane as previously described in a solvent, preferably a mixture of tetrahydrofuran and methanol, in a ratio of about 8 volumes of tetrahydrofuran to one volume of methanol. This is followed by the addition of about one molecular equivalent of sodium borohydride at about -110 ° C to about -50 ° C, preferably at -80 ° C, followed by stirring for about 30 minutes at about 3 hours. Under these preferred conditions, more than 90% of the compound of Formula I is produced in the desired stereochemical conformation.

Preferably, the present process is used to prepare [R- (R *, R *)] -1,1-dimethylethyl-6-cyano-3,5-dihydroxy hexane ate which is used as an intermediate to prepare atorvastatin.

The compounds of Formula II or III are either known or capable of being prepared by methods known in the art. The process of the present invention in its second aspect is an improved, economical, and commercially feasible method for preparing a compound of Formula I as previously noted in Scheme I. In this aspect of the invention, it has been found that a combination of trialkylborane and a dialkylalcoxyborane surprisingly and unexpectedly is synergistic in selectively providing the desired cis-1, 3-diol on the unwanted trans-1,3-diol compared to the use of either a trialkylborane or a dialkylalkoxyborane alone. The synergistic combination comprises about 1% to 99% by weight of a trialkyoborane and about 99% to 1% by weight of a dialkylalkoxyborane.; preferably, a combination of about 90% by weight of a trialkylborane and 10% by weight of a dialkylalcoxyborane. This synergistic combination is of particular advantage since it does not require a stir time of the alkyl borane species with the hydroxyketone at room temperature before reduction. The conditions and solvents for carrying out the reaction with a synergistic combination of a trialkylborane and a dialkylborane are as previously described in the foregoing. Thus, for example, in the preparation of [R- (R *, R *)] 1, 1 -dimethylethyl-6-cyano-3,5-dihydroxyhexanoate when pre-agitation is not used, triethylborane provides a mixture from 5 to 10: 1 (cis: trans). When diethylmethoxyborane is used in place of triethylborane, a mixture of 5 to 10: 1 (cis: trans) is obtained. When a combination of 10% diethylmethoxyborane and 90% by weight of triethylborane is used, typically the majority of the 30: 1 (cis: trans) mixture is obtained. This synergistic effect of the combination of a dialkylalkoxyborane and a trialkylborane could not have been anticipated based on the use of any single reagent or preceding literature. The following examples are illustrative to show the present process and show utility in the preparation of (4R-Cis) 1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate which is an intermediate prepared from a 1,3-diol of the present process that can be converted to atorvastatin acid ([R- (R *, R *)] - 2- (4-fluorophenyl) -β, d-dihydroxy-5 - (1-Methylethyl) -3-phenyl-4 - [(phenylamino) carbonyl] -1H-pyrrole-1-heptanoic, calcium salt (2: 1)) (Crystalline Form I) which is useful as a hypolipidemic agent and hypocholesterolemic.

EXAMPLE 1 (4R-CIS) 1.1-Di metyl-6-cyanomethyl-2,2-di methyl-1,3-dioxan-4-acetate Step (1): Preparation of 5R 1, 1-dimethylethyl 6-cyano-5- hydroxy-3-oxohexanoate A mixture containing 80 kg of diisopropylamine in 80 L of tetrahydrofuran is added to a vessel containing 265 kg of 16.8% n-butyllithium which maintains the temperature at less than 20 ° C. The solution is cooled to -55 ° C, and 85 kg of tert-butyl acetate is added to maintain the temperature at -50 ° C ± 5 ° C. A solution of 25 kg of ethyl ester of R 4 -cyano-3-hydroxybutanoic acid in 55 L of tetrahydrofuran is then added, and the temperature is allowed to warm to -20 ° C for at least 20 minutes. The solution is then quenched to transfer to aqueous hydrochloric acid. The organic layer is separated and the aqueous layer is back extracted with ethyl acetate. The combined organic layers are concentrated by vacuum distillation to provide 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate without purification. Step (2): Preparation of IR- (R *, R *) 1-1, 1 -dimethylethyl 6-cyano-3,5-dihydroxy hexanoate Method A: Use triethylborane Step (a): Dissolve 5R 1, 1- Unpurified dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (approximately 150 moles) of Step (1) in 325 L of tetrahydrofuran containing about 20 kg of triethylborane, stirred for about 2 hours at room temperature, is cooled to -75 ° C ± 20 ° C and diluted with 25 L of methanol and 8 g of acetic acid. Sodium borohydride (8 kg) is added slowly as a solution in methanol and aqueous sodium hydroxide. After the addition, the reaction mixture is heated to 0 ° C ± 25 ° C. The reaction mixture is optionally quenched by the addition of 3 kg of acetic acid and 10 L of methanol and concentrated by vacuum distillation, saving the distillate. The residue is dissolved in methanol and acetic acid, optionally diluted with water, and concentrated by vacuum distillation, keeping this distillate separate from the former. The residue is dissolved in methanol and concentrated by vacuum distillation. The residue is dissolved in a mixture of water and ethyl acetate, and the separated aqueous layer. The organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation to give [R- (R *, R *)] -1,1 -dimeti leti I 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was about 30: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate. according to the process described herein in Step 3. Step (b): Reusing the recovered triethylborane Dissolve 5R 1, 1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate without purification (approximately 150 moles) of the Step (1) in the first distillate of Step (a) together with 50 L of tetrahydrofuran, cooled to -75 ° C + 20 ° C and optionally diluted with 25 L of methanol and 10 kg of acetic acid. Sodium borohydride (8 kg) as a solution in methanol and aqueous sodium hydroxide is added slowly. After the addition, the reaction mixture is heated to 0 ° C ± 25 ° C. The reaction mixture is quenched by the addition of 10 kg of acetic acid and 20 L of methanol and concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid, optionally diluted with water, and concentrated by vacuum distillation. The residue is dissolved in methanol and concentrated by vacuum distillation. The residue is dissolved in a mixture of water and ethyl acetate, and the separated aqueous layer. The organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation to give [R- (R *, R *)] -1,1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was about 40: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate. according to the procedure described in this in Stage 3.

Method B: Use Triethylborane Step (a): 5R 1, 1 -dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate is dissolved without purification (approximately 130 mmol) of Step (1) in 10 mL of 1 M triethyl borane in THF and 65 mL of tetrahydrofuran, stirred for about 2 hours at room temperature, then cooled to -75 ° C ± 20 ° C, and diluted with 25 mL of methanol. Sodium borohydride (6 g) as a solution in triglyme (75 mL) is added slowly. After the addition, the reaction mixture is heated from 20 ° C to 25 ° C. The reaction mixture is quenched by the addition of 20 mL of methanol and 8 kg of acetic acid and concentrated by vacuum distillation - saving the distillate. The residue is diluted with 100 mL of water and 200 mL of stirred ethyl acetate, and the phases separated. The organic layer is concentrated by vacuum distillation - keeping this distillate separate from the first one. The residue is dissolved in 200 mL of methanol and 10 mL of acetic acid and concentrated by vacuum distillation. The residue is dissolved in 200 mL of methanol and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by distillation resulting in [R- (R *, R *)] -1,1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was approximately 20: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6- cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate according to to the process described herein in Step 3.

Step (b): Reuse of recovered triethylborane Dissolve 5R 1, 1 -dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate without purification (approximately 130 mmol) of Step (1) is dissolved in the first distillate of the mixture from Stage (a) above and cooled to -75 ° C ± 20 ° C. Sodium borohydride (6 g) is slowly added as a solution in 75 mL of triglyme. After the addition, the reaction mixture is heated to 25 ° C. The reaction mixture is quenched by the addition of 8 g of acetic acid (and optionally 20 mL of methanol) and concentrated by vacuum distillation - saving the distillate. The residue is dissolved in a mixture of water (100 mL) and ethyl acetate (200 mL), the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved with 200 mL of methanol and 10 mL of acetic acid and concentrated by vacuum distillation. The residue is dissolved with 200 mL of methanol and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in [R- (R *, R *) j -1,1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was approximately 30: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6-cyanomethyl-2,2-d-methyl-1,3-dioxan-4- acetate according to the procedure described herein in Step 3.

Stage (c): Reuse of recovered triethylborane Following the procedure of Step (b) previous 5R 1, 1 -dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate without purification (about 130 mmol) of Step (1) are reacted with triethyl borane recovered from Step (b) to provide [R- (R * , R *)] - 1, 1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was approximately 30: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate according to the procedure described herein in Step 3.

Method C: Use diethylmethoxyborane Step (a): 5R 1, 1 -dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate is dissolved without purification (approximately 150 mmol) to add 22 mL of diethylmethoxyborane and 200 mL of tetrahydrofuran. The solution is stirred for about 2 hours at room temperature, then cooled from -70 ° C to -75 ° C, and further diluted with 25 mL of methanol. Sodium borohydride (6 g) is added slowly as a solution in triglyme (75 mL) between -65 ° C to -75 ° C. After the addition, the reaction mixture is heated from 15 ° C to 25 ° C, quenched by the addition of acetic acid and concentrated by vacuum distillation - maintaining this distillate. The residue is diluted with methanol and concentrated by vacuum distillation - keeping this distillate and all subsequent distillates separate from the first. The residue is dissolved in a mixture of water and ethyl acetate, the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in [R- (R *, R *)] -1,1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was approximately 35: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate according to to the process described herein in Step 3.

Step (b): Reuse the recovered diethylmethoxyborane 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate is dissolved without purification (approximately 150 mmol) in the first distillate from the above mixture, allowed to stir room temperature for about 2 hours, and cooled to about -70 ° C. Sodium borohydride (6 g) as a solution in 75 mL of triglyx is slowly added between 65 ° C to -75 ° C. After the addition, the reaction mixture is heated to 15 ° C to 25 ° C, quenched by the addition of acetic acid and concentrated by vacuum distillation. The residue is dissolved with methanol and concentrated by vacuum distillation. The residue was dissolved in a mixture of water and ethyl acetate, the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved with methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in [R- (R *, R *)] -1,1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was about 25: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate from according to the procedure described herein in Step 3. Method D: Using a mixture of diethylmethoxyburan and triethylborane Stage (a): 5R 1, 1 -dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate is dissolved without purification (approximately 150 mmol) in 170 mL of tetrahydrofuran. The solution is cooled from -70 ° C to 75 ° C, and further diluted with 115 mL of 14% of triethylborane in tetrahydrofuran, 4 mL of diethylmethoxyborane, 45 mL of methanol, and 8 mL of acetic acid. Sodium borohydride (7 kg) as a methanol solution (65 mL) containing 50% aqueous sodium hydroxide (3.2 g) is slowly added between -70 ° C to -75 ° C. After the addition, the reaction mixture is heated to 15 ° C to 25 ° C, quenched by the addition of acetic acid and concentrated by vacuum distillation - maintaining the distillate. The residue is diluted with methanol and concentrated by vacuum distillation - keeping this distillate and all subsequent ones separated from the first one. The residue is dissolved in a mixture of water and ethyl acetate, the layers separated, and the organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation resulting in [R- (R *, R *)] -1,1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification. The cis: trans ratio was > 50: 1 as measured after conversion to (4R cis and trans) 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate according to the process described herein in Stage 3 Step (b): Reuse recovered triethyl borane diethylmethoxyborane mixture Following the procedure in Step (2) (b) as described in Method A provides [R- (R *, R *)] -1,1 -dimethylethyl 6- cyano-3,5-dihydroxy hexanoate.

Step (3): Preparation of (4R cis) 1,1 -dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxan-4-acetate. Dilute [R- (R *, R *)] - 1, 1 -dimethylethyl 6-cyano-3,5-dihydroxyhexanoate without purification (about 150 moles) from Step (2) with 100 kg of 2,2-dimethoxypropane and acidified with about 1L of methanesulfonic acid. The reaction is quenched by the addition of an aqueous sodium bicarbonate solution and concentrated by vacuum distillation. The residue is diluted with 150 L of hexane, and the layers separated. The organic layer is washed with a solution of aqueous sodium bicarbonate and cooled to 0 ° C ± 10 ° C to crystallize. The product is collected by filtration and washed with cooled hexane, then dried to provide 28.5 kg of (4R cis) 1,1-dimethylethyl 6-cyan or met i 1-2,2-di methyl-1,3-dioxan- 4-acetate.

EXAMPLE 2 Acid rR- (R * .R *) l-2- (4-fluorophenin-ß.d-dihydroxy-5 (1-methylethyl) -3-phenyl-4-f (phenylamino) carbon.p-1 H -pyrrole-1-heptanoic, calcium salt (2: 1) (crystalline Form I) Stage (1): Preparation of (4R-cis) -1, 1-dimethylethyl 6- (2-am i noetip-2,2 -d methyl-1, 3-dioxan-4-acetate It is converted (4R-cis) -1, 1-dimethylethyl 6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-acetate (Example 1) to the title compound using the methodology described in Column 49, Lines 17-43 of U.S. Patent 5,003,080.

Step (2): Preparation of (4R-cis) -1, 1 -dimethylethyl 6-Í2Í2-fluorophenyl) -5-1 (1-methylthio [3] -phenyl-4-r (phenylamino) carbonill-1 H -pyrrol-1-yl-1-yl-2,2-dimethyl-1,3-dioxan-4-acetate It is converted (4R-cis) -1, 1-dimethylethyl 6- (2-aminoethyl) -2,2-dimethyl-1, 3 -dioxan-4-acetate to the title compound using the methodology described in Column 49, Lines 43-60 of the American Patent 5, i0 w0w3v,? 080.

Step (3): Preparation of (2R-trans) -5- (4-fluorophenyl) -2- (1-methylethyl) -N, 4-diphenyl-1-y2- (tetrahydro-4-hydroxy-6-oxo- 2H-pyran-2-yl) ethill-1 H -pyrryl-3-carboxamide. The (4R-cis) -1,1-dimethyl-6- (2-aminoethyl) -2,2-dimethyl-1,3-dioxan-4-acetate is converted to the title compound using the methodology described in Column 50, Lines 4-30 of the US Patent 5,003,080.

Step (4): Preparation of rR- (R *. R *) l-2- (4-fluorophenin-β-d-dihydroxy-5- (1-methylethyl) -3-phenyl-4-y ( phenylamino) carbonin-1 H -pyrol 1-1-heptanoic, calcium salt (2: 1) (crystalline Form I) is converted (2R-trans) -5- (4-fluorophenyl) -2- (1 - methylethyl) -N, 4-diphenyl-1- [2- (tetrahydro-4-hydroxy-6-oxo-2H-pyrn-2-yl) ethyl] -1H-pyrrole-3-carboxamide to the title compound using the methodology described in the North American Patent Application 08 / 945,812.

Claims (25)

1. CLAIMING IS 1 . A process for the preparation of a compound of the Formula characterized in that R is alkyl, NC-CH2-, PG-0-CH2- wherein PG is a protecting group, wherein R2 is (H3C) 2 CH- or cyclopropyl, wherein R3 is C6H5, (H3C) 2-N- or (H3C) 2CH- and R4 is hydrogen, H3C-O-CH2-, H3C-CH2-C (CH3) 2 -COCH2-, or H3C-O2C-CH2 -CH (OH) -CH2- CH (OH) -CH = CH-, where R5 is R6 is hydrogen or CH3, R7 is hydrogen or CH3, R8 is hydrogen, OH, CH3, or HsCe-NHCO-O-, and R9 is hydrogen or CH3, R1 is alkyl, or -CH2-C02R wherein R6 is alkyl; comprising: Step (a) treating a compound of Formula II or a compound of the Formula lll wherein R and R1 are as defined above with a trialkylborane or dialkylalkoxyborane or a mixture of trialkylborane or a dialkylalkoxyborane in a solvent; step (b) adding an alkali metal hydride at about -110 ° C to about -50 ° C; Step (c) concentrating the reaction by distillation to provide a compound of Formula I and a distillate containing alkyl borane species; and Step (d) treating a further compound of Formula II or III with the distillate of Step (c) containing recovered alkyl borane species and repeating Steps (b) and (c) as desired to provide an additional compound of Formula I. The process according to claim 1, characterized in that the trialkylborane in Step (a) is triethylborane. 3. The process according to claim 1, characterized in that the dialkylalkoxyborane in Step (a) is diethylmethoxyborane. 4. The process according to claim 1, characterized in that the solvent in Step (a) is selected from the group consisting of: tetrahydrofuran, methanol, and a mixture of tetrahydrofuran and methanol. 5. The process according to claim 1, characterized in that the distillation in Step (c) is a vacuum distillation. 6. The process according to claim 1, characterized in that PG is benzyl. 7. The process according to claim 1, characterized in that the alkali metal hydride is sodium borohydride. 8. The process according to claim 1, characterized by the preparation of [R- (R *, R *)] -1,1 -dimethylethyl 6-cyan or -3,5-dihydroxy hexanoate. 9. The process according to claim 1, characterized by the preparation of the compound of the Formula la. -31- 6H5 10. A process for the preparation of a compound of Formula I characterized in that R is alkyl, NC-CH2-, PG-O-CH2- wherein PG is a protecting group, wherein R2 is (H3C) 2 CH- or cyclopropyl, wherein R3 is C6H5, (H3C) 2- N- or (H3C) 2CH- and R4 is hydrogen, H3C-0-CH2-, H3C-CH2-C (CH3) 2 -COCH2-, or H3C-O2C-CH2 -CH (OH) -CH2- CH (OH) -CH = CH-, where Rs is CH. R is hydrogen or CH3, R7 is hydrogen or CH3, R8 is hydrogen, OH, CH3, or HsCe-NHCO-O-, and R9 is hydrogen or CH3, R1 is alkyl, or -CH2-C02R6 wherein R6 is alkyl; comprising: Step (a) treating a compound of Formula II or a compound of the Formula lll O OH II T R- C- -CH2- CH -_D? III wherein R and R1 are as defined above with a synergistic combination of a trialkylborane and a dialkylalcoxyborane in a solvent; and step (b) adding an alkali metal hydride at about -110 ° C to about -50 ° C to provide a compound of Formula I. 11. The process according to claim 10, characterized in that the trialkylborane in the Step (a) is triethylborane. 12. The process according to claim 10, characterized in that the dialkylalkoxyborane in Step (a) is diethylmethoxyborane. The process according to claim 10, characterized in that the solvent in Step (a) is selected from the group consisting of: tetrahydrofuran; methanol; and a mixture of tetrahydrofuran and methanol. 14. The process according to claim 10, characterized in that PG is benzyl. 15. The process according to claim 10, characterized in that the alkali metal hydride is sodium borohydride. 16. The process according to claim 10, characterized by the preparation of [R- (R *, R *)] -1,1 -dimethylethyl 6-cyano-3,5-d-hydroxy hexanoate. 17. The process according to claim 10, characterized by the preparation of the compound of the Formula la. -31- wherein R is alkyl. 18. A synergistic combination characterized in that it comprises a trialkylborane and a dialkylalcoxyborane. 19. A synergistic combination characterized in that it comprises from about 1% to 99% by weight of a trialkylborane and about 99% to 1% of a dialkylalcoxyborane. 20. A synergistic combination characterized in that it comprises approximately 90% by weight of a trialkylborane and approximately 10% by weight of a dialkylalcoxyborane. 21. A synergistic combination characterized in that it comprises triethylborane and diethylmethoxyborane. 22. A method for using a synergistic combination characterized in that it comprises a trialkylborane and a dialkylalkoxyborane to selectively reduce a beta-hydroxy ketone to a cis-1,3-diol. 23. The method according to claim 22, characterized in that it comprises approximately 1% to 99% by weight of a trialkylborane and approximately 99% to 1% by weight of a dialkylalcoxyborane. 24. The method according to claim 22, characterized in that it comprises approximately 90% by weight of a trialkylborane and approximately 10% by weight of a dialkylalcoxyborane. 25. The method according to claim 22, characterized in that it comprises triethylborane and diethylmethoxyborane.