content_image/922975.jpg content_image/922976.jpg
In Reaction Scheme II, the compound of formula (V), a 3: 1 mixture of 3R- and 3S-enantiomers, may be prepared by mixing an aldehyde ketonide of formula (VII) with a difluoro compound of formula (VI), and allowing the mixture to undergo Reformatsky reaction using zinc. 

Further, a 3R-carboxylate of formula (III) can be prepared from the compound of formula (V), as shown in Reaction Scheme III. 

<img src='content_image/922975.jpg'>

wherein, R, R1, R 2 and M have the same meanings as defined above. 

In Reaction Scheme III, the 3R-carboxylate of formula (III) can be obtained as a solid by; (i) protecting the 3-hydroxy group of the compound of formula (V) with a biphenylcar› bonyl protecting group to obtain the compound of formula (IV); and (ii) hydrolyzing the compound of formula (IV) with a base. 

In the inventive method, the protecting group used in step (i) may be a biphenylcarbonyl group which is a benzoyl group substituted with benzene ring optionally the benzene ring is substituted with one or more substituents selected from the group consisting ofhydrogen, cyano, halo, carboalkoxy, tolu› oyl, nitro, alkoxy, alkyl and dialkylamino. Representative examples ofbiphenylcarbonyl include such as 2-phenylben› zoyl (2-biphenylcarbonyl), 4-phenylbenzoyl ( 4-biphenylcar› bonyl) and substituted 2-(or 4-) phenylbenzoyl, preferably 2-phenylbenzoyl and 4-phenylbenzoyl. 

Increased hydrophobicity due to the two benzene ring of biphenylcarbonyl group makes it possible to separate 3R-car› boxylate of formula (III) as a solid even in the water or water containing mixed solvent. 

On the other hand, in case of using a conventional benzoyl group as a hydroxy protecting group, it is impossible to get a 3R-carboxylate salt as a solid in the water or water containing mixed solvent. 

In contrast, in case of introducing a conventional hydroxy 60 protecting group such as 1-naphtoyl, 2-naphtoyl, pivaloyl or acetyl for the 3-hydroxy group of the compound of formula (V), it is very difficult to selectively isolate the 3R-carboxy› late of formula (III) as a solid from the resulting reaction mixture. 65 

The biphenylcarbonyl-based compound used in step (i) may be selected from the group consisting ofbiphenylcarbo- 

nyl ( or substituted biphenylcarbonyl) chloride, bromide, cya› nide or azide, which may be commercially obtained or chemi› cally synthesized in accordance with conventional methods. 

Also, the base used in the neutralization process of step (i) may be selected from the group consisting of pyridine, tri› ethylamine, tributylamine, diisopropylethylamine and meth› ylpiperidine, preferably triethylamine; a catalyst used in the acylation may be 4-dimethylaminopyridine or 4-pyrolidi› nopyridine; and the acylationmay be conducted at -25 to 50° C. 

In the hydrolysis of step (ii), the base may be selected from the group consisting of gaseous ammonia, aqueous ammonia, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and a mixture thereof, preferably potassium bicar› bonate, which may be employed in an amount of 1 equivalent or more, preferably ranging from 1.5 to 5 equivalents based on the compound of formula (IV). 

Also, the mixed solvent essentially comprising water may be a mixture of water and an organic solvent selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, acetone, methylisobutylketone, methylethylketone, metha› nol, ethanol, propanol, isopropanol, dimethylacetamide, dim› ethylformamide, dimethylsulfoxide, ethyl acetate and a mix- ture thereof, preferably a mixture of tetrahydrofuran and methanol; and the water may be employed in an amount ranging from 3 to 15 ml, preferably from 5 to 11 ml, and the organic solvent, from 3 to 30 ml, preferably from 6 to 18 ml, based on 1.0 g of the compound of formula (IV). Thehydroly- sis may be conducted at 5 to 50° C., preferably 10 to 30° C. for 30 min to 2 hours. 

The compound of formula (III) may be isolated easily from the reaction mixture obtained in step (ii), by removing the organic solvent under a reduced pressure, and filtering the resulting mixture; or by extracting the reaction mixture with an organic solvent, and recrystallizing the product in a mixed solvent essentially comprising water. 

In the inventive method, the 3R-carboxylate of formula (III) may be obtained from the compound of formula (V) in a high yield of 60 to 70% via a potassium or sodium salt, or about 40% when an ammonium salt is used as a base in step (ii). Further, the compound of formula (III) obtained in the inventive method has a 3R-carboxylate content of more than 99.7% while the 3S-carboxylate content is less than 0.3% (consequently, e.e value over 99.4%). 

The compound of formula (I) having the erythro structure may be obtained from the compound of formula (III) in a highly enantioselective manner, as shown in Reaction Scheme IV. 

<img src='content_image/922976.jpg'>

