Patent RU-2414459-C2 (RU)
Inventor: SALAN JA KRISTOF
IPC: C07C13/18
Filed: 2005-08-23
Granted: 2011-03-20
Abstract: FIELD: chemistry. ^ SUBSTANCE: invention relates to a method of producing a compound of general formula (I), involving steps in accordance with the following scheme: ^ ^ ^ ^ , where at separate steps: a) a compound of formula (IX) is converted to a compound of formula (V) in the presence of an enzyme selected from lipase B from Candida antarctica, b) the compound of formula (V), in the presence of an acid catalyst through effect of a compound which can form a protective group Z3 which is stable in alkaline medium and labile in acidic medium, is converted to a compound of formula (VIII) and c) the compound of formula (VIII) is converted to a compound of formula (II) in the presence of a nucleophilic agent; d) in the presence of a base B1, the compound of formula (II) is converted through effect of a compound of formula (VI) to a compound of formula (IIIa); e) the compound of formula (IIIa) is converted to a compound of formula (IVa), where the corresponding conversion is carried out through effect of an alcohol in the presence of an acid catalyst; f) through the effect of the compound (VII), the compound (IVa) is converted to a compound of formula (Ia) in the presence of a base B1 and g) if needed, the compound (Ia) is hydrolysed or hydrogenolysed to a compound of formula (I), if R3 denotes H; wherein the compound (IX) is a pure cis-isomer or a mixture of cis/trans-isomers, respectively; variables and substitutes assume the following values, respectively: ring A is C3-C8cycloalkyl, R1, R2, R4 and R5 independently denote , F, CI, Br, C1-C6alkyl or -O-(C1-C6alkyl); R3 denotes H, C1-C6alkyl; R6 denotes C1-C6alkyl or benzyl; X denotes C1-C6alkyl; Y denotes C1-C6alkyl; Z1 denotes a protective group which is stable in acidic medium; Z2 denotes a protective group which is stable in acidic medium; Z3 denotes a protective group which is stable in alkaline medium and labile in acidic medium; Z4 denotes a leaving group; Z5 denotes a leaving group; B1 denotes a tertiary alcoholate of an alkali-earth metal, a tertiary alcoholate of an alkali metal, an amide of an alkali-earth metal, an amide of an alkali metal, a silazide of an alkali-earth metal, a silazide of an alkali metal or a hydride of an alkali metal. The invention also relates to a method of producing a compound of general formula (I), involving steps in accordance with the following scheme: ^ ^ ^ , where at separate steps: a2) through at least one acyl group donor and in the presence of an enzyme selected from lipase B from Candida antarctica, the compound of formula (X) is converted to a compound of formula (V); steps b) - g) are described above, wherein the compound (X) is a pure cis-isomer or a mixture of cis/trans-isomers respectively. The invention also relates to a compound of general formula (IIIa), where ring A is cyclohexyl, where the X-containing and Z3-containing substitutes are in the cis-1,3-position of the cyclohexyl fragment; R1, R2 and R4 independently denote H, F, Cl, C1-C3alkyl or -C(O)-(C1-C6alkyl); Z3 denotes tetrahydropyranyl; X denotes methyl, and to a compound of general formula (VIII), where ring A is cyclohexyl, wherein the Z1-containing and Z3-containing substitutes are in the cis-1,3-position of the cyclohexyl fragment; Z1 denotes -C(O)CH3; Z3 denotes tetrahydropyranyl. ^ EFFECT: efficient method of obtaining the said compound. ^ 14 cl, 5 dwg, 2 tbl, 27 ex