Preparation of S,S and R,S amino acid isosteres

Abstract: The present invention provides compounds and methods that can be used to convert the intermmediate halomethyl ketones (HMKs), e.g ., chloromethyl ketones, to the corresponding S,S- and R,S- diastereomers. More particularly, the present invention provides: (1) reduction methods; (2) inversion methods; and (3) methods involving the epoxidation of alkenes. Using the various methods of the present invention, the R,S-epoxide and the intermediary compounds can be prepared reliably, in high yields and in high purity.

Description: BACKGROUND OF THE INVENTION Human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS), encodes three enzymes, including the well-characterized proteinase belonging to the aspartic proteinase family, the HIV protease. Inhibition of this enzyme has been regarded as a promising approach for treating AIDS. Hydroxyethylamine isosteres have been extensively utilized in the synthesis of potent and selective HIV protease inhibitors. However, this modern generation of HIV protease inhibitors has created an interesting challenge for the synthetic organic chemist. Advanced x-ray structural analysis has allowed for the design of molecules that fit closely into active sites on enzymes creating very effective drug molecules. Unfortunately, these molecules, designed by molecular shape, are often difficult to produce using conventional chemistry. The modem generation of HIV inhibitors has structural similarities in a central three-carbon piece containing two chiral carbons that link two larger groups on each side (see, e.g ., Parkes, et al., J. Org. Chem. 1994 39, 3656). Numerous synthetic routes to these isosteres have been developed. As illustrated below, a common strategy to prepare the linking group starts with an amino acid, such as phenylalanine, to set the chirality of the first carbon. Then, the linking group is completed by a series of reactions including a one-carbon homologization during which the old amino acid carbon is transformed into a hydroxy-functionalized carbon having the correct chirality. However, the commercial production of isosteres by this method presents serious challenges, generally requiring low-temperature organometallic, reactions (Baragua, et al., J. Org. Chem. 1997, 62, 6080 ) or the use of exotic reagents. A second approach, which is illustrated below, is to convert the amino acid to an aldehyde and to add the carbon by use of a Wittig reaction to give an olefin (see, Luly, et al., J. Org . Chem. 1987 , 52, 1487). The olefin is then epoxidized. Alternatively, the aldehyde can be reacted with nitromethane, cyanide (see, Shibata, et al., Chem. Pharm. Bull. 1998 , 46, 733) or carbene sources ( see , Liu, et al., Org. Proc. Res. Dev. 1997, 1, 45). Instability and difficulty in preparation of the aldehyde make these routes undesirable ( see , Beaulieu, et al., J. Org. Chem. 1997 , 62, 3440). Other routes that have been published, but not commercialized are illustrated in Figure 1. One of the best reagents that can be used to add a single carbon to amino acids is diazomethane because it gives high yields and few side-products. In addition, diazomethane reactions are very clean, generating only nitrogen as a by-product. HIV inhibitor molecules need high purity because of the high daily doses required. As such, diazomethane is an ideal reagent for making high purity compounds. In spite of the documented hazards of diazomethane, processes have recently been developed that permit the commercial scale use of diazomethane to convert amino acids to the homologous chloromethyl ketones ( see, U.S. Patent No. 5,817,778, which issued to Archihald, et al. on October 6, 1998; and U.S. Patent No. 5,854,405, which issued to Archibald, et al. on December 29, 1998). Figure 2 illustrates examples of HIV protease inhibitors wherein the central linking group can be synthesized by the commercial use of diazomethane. Figure 3 illustrates a general reaction scheme that can be used to prepare the S,S-epoxide compound using diazomethane. The most useful amino acid isosteres are based on phenylanaline. The key intermediate in the synthesis of Sequinivir® (Roche) and Aprenavir® (Glaxo Wellcome) is the (S,S-)N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine. Several other protease inhibitors, such as those described in Chen, et al. ( J. Med Chem. 1996 , 39, 1991) or those under development ( e.g. , BMS-234475 or BMS-232623). use the diastereomeric (R,S-) N-t-butoxycarbonyl-1,2-epoxy-4-phenyl-3-butanamine. Beginning with readily available (L)-phenylanaline, one is able to manufacture N-t-butoxycarbonyl-1-chloro-2 keto-4-phenylbutanamine (called "chloroketone" or "CMK") using the methods described in the literature ( see, e.g., Parkes, et al., J. Org. Chem. 1994 39, 3656; Shaw, E., Methods in Enzymology (Academic Press, New York, London), 1967 ,11, 677;, and Dufour, et al., J. Chem. Soc. Perkin Trans. I 1986 , 1895, the teachings of which are incorporated herein by reference). However, what are needed in the art are methods that allow one to produce reliably and in high-yields either diastereomer, i.e. , the S,S or the R,S, from the common chloroketone starting material ( see, Figure 4). Quite surprisingly, the present invention fulfills this and other needs. SUMMARY OF THE INVENTION The present invention provides compounds and methods that can be used to convert the intermediate halomethyl ketones (HMKs), e.g. , chloromethyl ketones, to the corresponding S,S- and R,S- diastereomers. It is these chiral centers that determine the chiral centers in the HIV protease inhibitor and, thus, the efficacy of the drug. As explained herein, the present invention provides reduction methods. Using the methods of the present invention, the R,S-epoxide and the intermediary compounds can be prepared reliably, in high yields and in high purity. Described below, not part of the present invention, is a method for selectively preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: the method comprising: reducing a compound having the following general formula: with a non-chelating, bulky reducing agent to form the R,S-HMA compound. In the above formulae, R 1 is an amino acid side chain ( e.g., a benzyl group, an S-phenyl group, an alkyl group and a para-nitrobenzene group, etc.); R 2 is a blocking or protecting group ( e.g., Boc, Cbz, Moc, etc .); and X 1 is a leaving group ( e.g., a halo group, such as chloro). In a preferred embodiment, the non-chelating, bulky reducing agent is a member selected from the group consisting of LATBH and STBH. In another preferred embodiment, the reduction is carried out in a solvent such as diethyl ether. Once formed, the R,S-HMA can be reacted with an alkali metal base to form an R,S-epoxide. The present invention provides a method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: the method comprising: reducing a halomethyl ketone (HMK) compound having the following general formula: with a reducing agent selected from the group consisting of sodium cyanoborohydride, cerium chloride/sodium borohydride, K-Selectride®, KS-Seletride® and (+)-Dip Chloride™ to form the R,S-HMA compound. In this method, R 1 is an amino acid side chain; R 2 is a blocking group; and X 1 is a leaving group. Again, once formed, the R,S-HMA can be reacted with an alkali metal base to form an R,S-epoxide. Other features, objects and advantages of the invention and its preferred embodiments will become apparent from the detailed description which follows. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 illustrates various routes that can be used to prepare an R,S-epoxide. Figure 1(A) illustrates a method described by Ng, et al., Org. Proc. Res. Dev. 1997, 1, 46; and Beaulieu, et al., J. Org. Chem. 1997, 62, 3441. Figure 1(B) illustrates a method described by Parkes, et al. J. Org. Chem. 1994, 59, 3656. Figure 2 illustrates examples of HIV protease inhibitors where the central linking group can be synthesized by commercial use of diazomethane. Figure 3 illustrates a general reaction scheme that can be used to prepare the epoxide compound. Figure 4 illustrates the two diastereomers that can be formed from the common chloroketone starting material, i.e. , S,S-epoxide and R,S-epoxide. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS The present invention provides compounds and methods that can be used to prepare both reliable and in high yields either diastereomer, i.e. , the S,S- or the R,S-, from the common halomethylketone ( e.g. , chloromethyl ketone) starting material. More particularly, as explained herein in greater detail, the present invention provides reduction methods. A variety of reducing agents can be used to reduce a halomethyl ketone (HMK) to a halomethyl alcohol (HMA) ( see, Table I). However, under most conditions, the predominate diastereomer is the 2S,3S-HMA. For instance, reduction of HMK with sodium borohydride in ethanol (Chen, et al., J. Med Chem. 1996, 39, 1991) produces a 1:4 mixture of R,S:S,S HMA in near quantitative yield. Moreover, the reduction of HMK with aluminium isopropoxide in isopropanol can give ratios as high as 1:18 in favor of the S,S-isomer (see, U.S. Patent Nos. 5,684,176 and 5,847,144, both of which issued to Hilpert). Thus, commercial routes to S,S-HMA are easily achieved. In contrast, the preparation of the R,S-isomer is much more difficult. A slight increase in the R,S-HMA:S,S-HMA ratio is achieved when the reaction solvent, ethanol, is replaced with THF, Further enhancement in the R,S-HMA:S,S-HMA ratio is obtained when the reduction is carried out in the presence of CeCl 3 (Barluenga, J. Org. Chem 1997 , 62,5974); but even then the ratio of R,S-HMA:S,S-HMA is <1:1. Other reducing agents, such as LiAlH4, sodium cyanoborohydride, potassium borohydride, etc., under a variety of reaction conditions, also fail to provide >1:1 R,S-HMA:S,S-HMA. In fact, a perusal of the literature supports the observation that S,S-HMA is the preferred isomer using coordinating reducing reagents, such as borohydrides or aluminium hydrides ( see, U.S. Patent Nos. 5,684,176 and 5,847,144, both of which issued to Hilpert). However, the reduction of HMK proceeds with high R,S diastereoselectivity when lithium aluminum t -butoxyhydride (LATBH) is used as the reducing agent (Raddatz, et al., J. Med. Chem. 1991 , 34, 3267). Quite surprisingly, it has been found that the reduction of HMK with LATBH in, for example, diethylether provides a 8:1 mixture of R,S-HMA:S,S-HMA in 97% yield. This high diastereofacial selectivity of the LATBH reducing agent is unusual since reduction of HMK with similar reducing agents, such as lithium aluminum hydride or sodium borohydride, do not favor R,S diastereoselectivity ( see, U.S. Patent Nos. 5,684,176 and 5,847,144, both of which issued to Hilpert). HMK Reductions: Reagent(s) Solven(s) Temp Time R,S:S,S Li(OtBu)3A1H Et2O 0C 3Hrs 8:1 (+)-Dip Chloride™ (1.4eq) THF 5C-RT 12Hrs 5:1 K-Selectride® THF Reflux 2 Hrs 2:1 K-Selectride®/Ti(OiPr)4 THF 25 C 30Min 2:1 KS-Selectride® THF RT 2 Hrs 2:1 K-Select./MgBr2*OEt2 THF RT 30Min 2.6:1 R-Alpine Borane(Conc.) THF Reflux 9Dys 1:1 L-Selectride® THF R.T. 1 Hr 0.9:1 NaBH4/CeCl3(anh.) THF RT 2 Hrs 0.8:1 N-Selectride® EtOH/THF R.T. 2 Hrs 0.7:1 NaBH4/CeCl3*7H2O THF 25 C 18 Hrs 0.7:1 NaBH4/EDTA(Na2*2H2O) THF RT 30Min 0.7:1 NaCNBH3 THF RT 36Hrs 0.7:1 (+)-2-Butanol/NaBH4 THF RT 1 Hr 0.6:1 Cp2TiBH4 Glyme R.T. 30Min 0.6:1 NaBH4 THF 25 C 2 Hrs 0.6:1 NaBH4/(-)-2-Butanol THF RT 30Min 0.6:1 NaBH4lAt(OiPr)4 THF Reflux 2 Hrs 0.6:1 NaBH4/DiacetoneDglucose THF RT 12Hrs 0.6:1 NaBH4/EDTA THF RT 12Hrs 0.6:1 Na8H4/L-Tartaric Acid THF 5 C 1 Hr 0.6:1 NaBH4/MgBr2*OEt2 THF RT 1 Hr 0.6:1 BH3-t-butylamine THF R.T. 1 Hr 0.5:1 LAH THF 25 C 1 Hr 0.5:1 LS-Selectride® THF RT 1 Hr 0.5:1 NaBH4/D-Tartaric Acid THF RT 30Min 0.5:1 (+)-2-Butanol * BH3 THF RT 1 Hr 0.4:1 NaBH4/CaCl2 MeOH R.T. 1 Hr 0.4:1 AminoAlcohol Borane THF 25 C 12 Hrs 0.3:1 Na(PEG)2BH2 THF RT 30Min 0.3:1 THF*BH3 EtOH/THF R.T. 2 Hrs 0.2:1 Al(iOPr)3 IPA 50C 3Dys 0.05:1 Na HB(OCH3)3 MeOH RT 1 Hr 1:1 Described below, not part of the present invention, is a method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: the method comprising: reducing a compound having the following general formula: with a non-chelating, bulky reducing agent to form the R,S-HMA compound. In the above formulae, R 1 is an amino acid side chain. More particularly, in the above formulae, R 1 is a side chain from any of the naturally occurring amino acids or amino acid mimetics. In a preferred embodiment, R 1 is a benzyl group, a substituted benzyl group, an S-phenyl group, an alkyl group or a para-nitrobenzene group. In an even more preferred embodiment, R 1 is a benzyl group. R 2 , in the above formulae, is a blocking or protecting group. It will be readily apparent to those of skill in the art that suitable -amino blocking groups include, for example, those known to be useful in the art of stepwise synthesis of peptides. Included are acyl type protecting groups ( e.g. , formyl, trifluoroacetyl, acetyl, etc .), aromatic urethane type protecting groups ( e.g ., benzyloxycarboyl (Cbz), substituted Cbz, etc.), aliphaxic urethane type protecting groups ( e.g ., t -butyloxycarbonyl (Boc), isopropylcarbonyl, cyclohexyloxycarbonyl, etc. ) and alkyl type protecting groups (e.g., benzyl, triphenylmethyl, etc .). In a preferred embodiment, the blocking group is selected from the group consisting of Boc, Cbz and Moc. In the above formulae, X 1 is a leaving group. Suitable leaving groups will be readily apparent to those of skill in the art. In a preferred embodiment, the leaving group is a halo group ( e.g., Cl, Br, F or 1). In an even more preferred embodiment, X 1 is a chloro or bromo group. Although many of the compounds disclosed herein contain the exemplar designation "halo," such as halomethyl ketone (HMK) or halomethyl alcohol (HMA), it will be readily apparent to those of skill in the art that other leading groups can be used in place of the halo group. The reduction is carried out using a non-chelating, bulky reducing agent. It has been discovered that non-chelating, bulky reducing agents favor the S,R-diastereomer. Examples of non-chelating, bulky reducing agents suitable for use in the above methods include lithium aluminum t -butoxyhydride (LATBH), sodium tris- t -butoxyborohydride (STBH). In a preferred embodiment, the non-chelating, bulky reducing agent is LATBH. Once formed, the R,S-HMA can be reacted with an alkali metal base to form an R,S-epoxide. An exemplar embodiment of the above method is illustrated by the following reaction scheme: Synthesis of R,S-Boc-Epoxide by LATBH Reduction In this method, the reduction is preferably carried out in a solvent. It will be readily apparent to those of skill in the art that numerous solvents can be used. Exemplar solvents include the following: diethyl ether, THF, MTBE and mixtures thereof. Quite surprisingly, it has been found that the reduction of LATBH is dependent on the solvent employed. For instance, when diethyl ether is used as the solvent, a 8:1 mixture of R,S-HMA:S,S-HMA is obtained. However, when THF or MTBE is used as the solvent the ratio of R,S-HMA:S,S-HMA is less than or equal to about 2:1. Based on these result, it is thought that a variety of factors, such as steric, solvation and chelation, are responsible for the high R,S diastereoselectivity observed in LATBH reduction of HMK. Thus, when LATBH is used as the reducing agent, diethyl ether is preferably used as the solvent. LATBH is commercially available as a white powder and is used as a suspension in diethyl ether. Alternately, LATBH can be prepared in situ by the reaction of LAH with 3 equivalents of t -butylalcohol in diethylether and then reacted with HMK. The best solvent, as judged on basis of R,S-diastereoselectivity, is diethyl ether. However, the solubility of HMK in diethyl ether is relatively low and a large amount of diethyl ether is needed to dissolve CMK, thereby reducing reactor efficiency to some extent. The reactor efficiency can be improved by either adding HMK as a solid or, alternatively, as a solution in a secondary solvent ( e.g. , THF, toluene, ethyl acetate, etc .) to a suspension of LATBH in diethyl ether. The reaction rate is not affected, but the diastereoselectivity can be reduced from 8:1 in pure diethyl ether to about 5:1 with the above modifications. In this method the reduction can be carried out at a temperature ranging from about -30°C to about 25°C. In a preferred embodiment, the reduction is carried out at a temperature ranging from about -5°C to about 5°C. At lower temperatures, larger amounts of solvent are needed to maintain homogeneity; whereas at high temperatures, formation of the epoxide, resulting from intramolecular cyclization, is observed. At 0°C, the reduction reaction is rapid and is complete in less than about 30 minutes. It will be readily apparent to those of skill in the art that the progress of the reduction reaction can be monitored by, for example, HPLC, and the reaction is deemed complete when the amount of unreacted HMK is less than about 1%. Actually, the present invention provides a method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: the method comprising: reducing a halomethyl ketone (HMK) compound having the following general formula: with a reducing agent selected from the group consisting of sodium cyanoborohydride, cerium chloride/sodium borohydride, K-Selectride®, KS-Selectride® and (+)-Dip Chloride™ to form the R,S-HMA compound. In this method, R 1 is an amino acid side chain; R 2 is a blocking group; and X 1 is a leaving group. It will be readily apparent to those of skill in the art that the foregoing discussions relating to R 1 , R 2 and X 1 and their preferred embodiments are fully applicable to this method and, thus, will not be repeated. As with the previously described method, the reduction is preferably carried out in a solvent. It will be readily apparent to those of skill in the art that numerous solvents can be used. Exemplar solvents include, but are not limited, to the following: diethyl ether, THF, MTBE and mixtures thereof. In a preferred embodiment, diethyl ether or THF is employed as the solvent. Moreover, as with the previously described method, the reduction can be carried out at a temperature ranging from about -30°C to about 25°C. In a presently preferred embodiment, the reduction is carried out at a temperature ranging from about -5°C to about 5°C. The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of noncritical parameters that can be changed or modified to yield essentially the same results. EXAMPLES These examples illustrate the preparation of S,S-CMA and R,S-CMA using reduction methods. 1. Preparation of S,S-CMA by Reduction A 500 mL , 3-necked round bottom flask was fitted with a condenser, thermocouple temperature probe, dry nitrogen inlet, and magnetic stirring. A stirred solution of chloromethylketone (CMK) (19.22 g, 0.0645 mol) and Isopropanol (200 mL) was heated to 50°C and aluminum isopropoxide (6.87g, 0.0337 mol, 1.5 eq) was charged to the reactor. The reaction mixture was heated at 50°C for three hours at which point HPLC analysis indicated 0.4% CMK remained. After heating for 1 additional hour and cooling to room temperature, the reaction was quenched with water (200 mL) and glacial acetic acid (∼50 mL) to adjust the pH to 4. The reaction was transferred to a separatory funnel and the organic solids were extracted into ethyl acetate, resulting in two clear phases. The phases were split and the organic phase was evaporated to 18.63 g (97% yield) off-white solid. S,S Chloromethylalcohol (S,S-CMA) : 1 H NMR (CDCl 3 ): δ 1.37 (s, 9 H), 2.97 (m, 2 H, J = 5.1Hz), 3.20 (br d, 1H), 3.55-3.69 (m, 2 H), 3.83-3.93 (m, 2H), 4.59 (br d, 1H, J= 6.6 Hz), 7.21-7.34 (m, 5H); HPLC (Short) t R 3.84 min =99.51%, 4.66 min = 0.49%; HPLC (long) t R 13.26 min = 99.50%, 17.42 min = 0.50%. Proton NMR analysis of final product indicated ∼37:1 ratio of S,S:R,S Boc-phenylalanine Chloromethyalcohol (CMA), and traces of acetic acid. HPLC analysis indicated ∼32:1 ratio of S,S:R,S CMA (95.1% S,S CMA, 3.0% R,S CMA, 0.6% CMK, and 1.3% impurities from the starting material e.g. methyl ester, boc-phenylalanine). Further purification was accomplished by recrystallization from heptane. 2. Sodium Cyanoborohydride Reduction of CMK To a solution of sodium cyanaoborohydride (5.28 g, 84.0 mmol, 1.0 eq) in THF (25 mL) was added a solution of CMK (25.0 g, 84.0 mmol) in THF (100 mL), followed by addition of AcOH (10 mL) over 0.5 h at RT. During this addition, internal temperature was never allowed to rise above 42°C. After 1.5 h, TLC analysis of an aliquot indicated total consumption of CMK signaling reaction completion. The reaction mixture was quenched with H 2 O (250 mL) and the resulting white slurry was stirred at ambient temperature for 1h. The mixture was extracted with ethyl acetate (500 mL) and then concentrated on a rotary evaporator to a volume of ca. 300 mL. Water (100 mL) and the remaining ethyl acetate was removed under reduced pressure at 45°C. The precipitated product was filtered, washed with water (200 mL), and dried in a vacuum oven at 45°C/28 inch-Hg for 15 h to give 23.8 g (95% yield) of a white solid. HPLC analysis revealed that the solid contained a mixture of 41% R,S-CMA and 59% S,S-CMA. 3. Preparation of R,S-CMA by Reduction with Cerium chloride / sodium borohydride. A 5000 mL , 3-necked round bottom flask was fitted with mechanical stirring, Claisen head adapter, condenser, dry nitrogen inlet, glass enclosed thermocouple temperature probe, and solids addition funnel, all oven dried at 120°C and cooled under dry nitrogen. To a stirred slurry of CMK (200g, 0.672 mol, 1.0 eq), cerium chloride heptahydrate (250g, 0.672 mol, 1.0 eq), and THF (716g) was added sodium borohydride (25.5g, 0.673 mol, 1.0 eq) portionwise over 70 minutes during which time a 4.5°C exotherm was observed. The reaction mixture was stirred for an additional 5 hours at room temperature, at which time HPLC analysis indicated that starting material had been consumed. The reaction was cooled to 2°C and ethyl acetate (500 mL) was added. The reaction was quenched with water (1000 mL) at a rate to control the production of hydrogen gas and maintain at a temperature of less than 20°C. The pH of the reaction was adjusted to approximately 6 with glacial acetic acid (18 mL) and additional ethyl acetate (2500 mL) was added to dissolve the solids. The reaction was warmed to room temperature and transferred to a 6000 mL separatory funnel. The organic phase was separated, washed with water and evaporated in vacuo to give 175 g (96% yield) of a white solid. HPLC analysis of the solid indicated 36% R,S boc-phenylalanine chloromethylalcohol (CMA) and 60% S,S CMA; 1 H NMR analysis confirmed a 0.6:1 R,S:S,S CMA ratio. 4. Preparation of R,S-CMA by Reduction with LATBH. Lithium tri-t-butoxyaluminohydride (LATBH) (93.87 g, 0.369 mol, 1.1 eq) and anhydrous diethyl ether (500 mL) were placed in a reactor and cooled to 2°C. A solution of CMK (99.84 g, 0.355 mol) and anhydrous diethyl ether (2000 mL) was added over 90 min maintaining an internal temperature of less than 5°C. After the addition was complete, the mixture was stirred for 30 min at which point HPLC analysis indicated no starting material remaining. The reaction was slowly quenched water (1500 mL) and then acetified with glacial acetic acid (1000 mL) at a rate such the temperature was below 10°C. The reaction was warmed to ambient and the organic phase was separated, washed with water and was evaporated in vacuo to give an orange oil (100.12 g). Hexanes (500 mL) was added to the flask and evaporated on the rotary evaporator to remove residual t-butanol and isobutanol; the evaporation yielded an orange oil/solid (97.34 g, 97% yield). HPLC and 1 H NMR analysis indicated an approximately 6.5:1 ratio of R,S:S,S CMA. The R,S-isomers was purified by extraction into refluxing hexanes (300 mL), filtration while hot to remove the less soluble S,S-isomer, and slow cooling overnight. After filtration and drying, 74.5 g (82.3% yield) of a product that was 92.1% R,S CMA and 5.4% S,S CMA by HPLC and 1 H NMR analysis. 5. Purification of mixtures of S,S- and R,S,-CMA CMA (170 g af a mixure of 0.6 to 1 isomers) and hexanes (800 g) were charged to the flask and heated to reflux for 1 hour. The less soluble isomer mix (90% S,S CMA, 9% R,S CMA) (99.6 g, 58% yield) was removed by filtration of the hot mixture. The filtrate was evaporated to 75% volume, cooled and filtered to give the more soluble isomer mix (94% R,S CMA, 3% S,S CMA) 36.7 g (22% yield) were removed by cold filtration through a 600 mL coarse, sintered glass funnel, The residual filtrate was dryed in vacuo to give a yellow oil (18.6 g, 11% yield) containing a mixture of isomers. A mixture of 32 g of the crude solid (93% R,S-CMA and 6% S,S-CMA) from the hot hexane recrystallization and hexanes (600 mL) was heated to 60°C. The resulting solution was slowly allowed to cool to 53°C and seeded with R,S-CMA crystals. Further crystallization was observed at 37°C at which point significant amount of white needles had formed in solution. The internal temperature was maintained between 35-40°C for 1.5 h, at which point the mixture was hot filtered to provide 25.7 g (80% recovery) of R,S-CMA as white needles. HPLC analyses revealed that R,S-CMA was 99.8% pure and contained ca. 0.2% S,S-CMA. Concentration of hexane filtrate on a rotary evaporator afforded 6.1 g of a white solid which based on HPLC analysis was found to be consist of 91.9% R,S-CMA and 6.4% S,S-CMA. R,S-Chloromethylalcohol (R,S-CMA) : 1 H NMR (CDCl 3 ): δ 1.36 (s, 9 H), 2.94 (m, 2H, J = 7.3 Hz), 3.54 (d, 2H, J = 4.6 Hz), 3.77 (m, 1H, J= 2.1 Hz), 3.94 (m, 1H, J= 7.3 Hz), 4.99 (d, 1H, J= 8.8 Hz), 7.24 (br m, 5H); HPLC (Short) t R 3.87 min = 0.21%, 4.69 min =99.79%. 6. Preparation of R,S-Epoxide A 500 mL flask fitted with a magnetic stir bar, addition funnel, temperature probe, and a nitrogen inlet was charged with R,S-CMA (30.1 g, 100.4 mmol), THF (90 mL) and ethanol (50 mL). The mixture was cooled to 0-3°C and a 40% aq. KOH solution (7.86 g of 86% potassium hydroxide dissolved in 9 mL of water) was added dropwise to the reaction mixture so as to maintain an internal temperature of <3 C. The reaction mixture was stirred at 0-3°C for 3.5 h and then quenched with 29% aq. sodium biphosphate solution (29 mL); the reaction temperature was maintained below 10 °C during quench. Diethyl ether (150 mL) was added, the organic layer was separated, and the aqueous layer was extracted with an additional portion of ether (100 mL). After splitting the phases, the ether layers were combined, dried (Na 2 SO 4 ), filtered, and stripped of solvent under reduced pressure to give an opaque white oil. Hexane (220 mL) was added and the resulting mixture was concentrated on a rotary evaporator until <10% hexane remained and the oily residue was stirred at ambient temperature until crystallization was complete. The precipitated solid was dried and collected to provide 25.9 g (98%) of the title compound, a white solid: mp (DSC): 51.56°C; 1 H NMR (CDCl 3 ): δ 1.39 (s, 9H), 2.59 (s, 1H), 2.70 (dd, 1H, J = 3:9Hz), 2.91 (m, 2H, J = 6.6Hz), 3.01 (m, 1H, J = 3.6Hz), 4.13 (d,1H, J = 7.8Hz), 4.49 (d, 1H, J = 7.2Hz), 7.27 (br m, 5H). The purity, as determined by HPLC analysis, was 99.7% (area%).

Claims: A method for preparing an R,S-halomethyl alcohol (R,S-HMA) compound having the following general formula: said method comprising: reducing a halomethyl ketone (HMK) compound having the following general formula: with a reducing agent selected from the group consisting of sodium cyanoborohydride, cerium chloride/sodium borohydride, K-Selectride®, KS-Selectride® and (+)-Dip Chloride™ to form said R,S-HMA compound; wherein: R 1 is an amino acid side chain; R 2 is a blocking group; and X 1 is a leaving group.

Inventors: CLEMENT TODD E, MALIK ASLAM A, PALANDOKEN HASAN, ROBINSON JAMES III, STRINGER JOY A, CLEMENT, TODD E., MALIK, ASLAM A., PALANDOKEN, HASAN, ROBINSON, JAMES III, STRINGER, JOY A.
Applicants: AEROJET FINE CHEMICALS LLC
Application year: 2000
Main classification: C07C213
IPC codes: C07D263, C07D303, C07C215, C07C213, C07D301