Process for preparation of prostaglandin f2 alpha analogues

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,
• or
• R6 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;
• and
• Y, 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;
• and
• R2, 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;
• and
• R2, 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;
• and
• R2, 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;
• and
• R2, 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;
• and
• R2, Y, n and p have the same meaning as defined for the formula (I).