| 主权项 |
1. A process for preparation of prostaglandin F2α analogues bearing a 13,14-en-15-ol ω-chain having on a 15R or 15S optical configuration, represented by the general formula (I), wherein:
X represents —O— or —NH—;R1 is H or C1-3-alkyl;Y represents —O—;R2 is H or phenyl group unsubstituted or substituted by trifluoromethyl group;n represents an integer 0 or 1;p represents an integer 0 or 1, the process comprising the steps of:
(a) treatment of a phenylsulfone of the formula (II): wherein:
R3 and R4 independently represent hydroxyl protecting group —Si(R9)(R10)(R11), where and R9-R11 are the same or different and are C1-6-alkyl or phenyl;R6 is an orthoester group, represented by the general formula (III), wherein R8 is H or C1-C6-alkyl,orR6 represents —C(OR12)3 orthoester group, wherein R12 is C1-C6-alkyl; with a strong organometallic base to yield an α-sulfonyl carbanion of the phenylsulfone of the formula (II),
(b) addition of the α-sulfonyl carbanion in situ to an aldehyde having an optical configuration at a stereogenic center corresponding to 15R or 15S optical configuration of the target prostaglandin, respectively, the aldehyde being represented by the formula (IV), wherein:
R5 represents hydroxyl protecting group —Si(R9)(R10)(R11), wherein R9-R11 are the same or different and represent C1-6-alkyl or phenyl; andY, R2, n and p have the same meaning as defined for the formula (I), to yield a mixture of diastereoisomers of β-hydroxysulfones of the general formula (V): wherein R2-R6, Y, n and p have the same meaning as defined for the formula (I),
(c) reductive desulfonation of the mixture of β-hydroxysulfones of the general formula (V), to yield a compound having the 15R or 15S optical configuration and being represented by the formula (VI): wherein R2-R6, Y, n and p have the same meaning as defined for the formula (I),
(d) removing R3, R4, R5 hydroxyl protecting groups to yield a compound having the 15R or 15S optical configuration and being represented by the formula (VII): wherein
R2, R6, Y, n and p have the same meaning as defined for the formula (I),(e) hydrolysis of the compound of formula (VII) under acidic conditions, to yield a compound having the 15R or 15S optical configuration and being represented by the formula (VIII): wherein:
X represents —O—;R7 represents —CH2—C(CH2OH)2—R8 or R12 respectively; wherein R8 is H or C1-C6-alkyl and R12 is C1-C6-alkyl; andR2, Y, n and p have the same meaning as defined for the formula (I),(f) hydrolysis of the compound of formula (VIII) under basic conditions, to yield a compound having the 15R or 15S optical configuration and being represented by the formula (IA): wherein:
X represents —O—;R1 is H; andR2, Y, n and p have the same meaning as defined for the formula (I), and then alkylating the compound of formula (IA) with C1-3-alkyl halogen in the presence of a strong base, to obtain a compound having the 15R or 15S optical configuration and being represented by the formula (IB): wherein:
X represents —O—;R1 is C1-3-alkyl; andR2, Y, n and p have the same meaning as defined for the formula (I), and, optionally, reacting the compound of formula (IB) with an amine of the formula (IX):
R1NH2 (IX) wherein R1 is C1-3-alkyl, to obtain a prostamid having the 15R or 15S optical configuration and being represented by the formula (IC): wherein:
X represents —NH—,R1 is C1-3-alkyl; andR2, Y, n and p have the same meaning as defined for the formula (I); or, optionally, reacting the compound of formula (VIII) with the amine of the formula (IX):
R1NH2 (IX) wherein R1 is C1-3-alkyl, to obtain a prostamid having the 15R or 15S optical configuration and being represented by the formula (IC); wherein:
X represents —NH—,R1 is C1-3-alkyl; andR2, Y, n and p have the same meaning as defined for the formula (I). |
