US 2004/0171873 A1Published application

Process for the preparation of 17-phenyl-18,19,20-thinor-pgf 2a and its derivatives

AssigneeFinetech Laboratories Ltd.

InventorsArie Gutman, Gennady Nisnevich, Marina Etinger, Igor Zaltzman, Lev Yudovitch, Boris Pertsikov

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Abstract

The present invention provides a new and effective process for the synthesis of 17-phenyl-18,19,20-trinor-PGF2α and its derivatives, including the anti-glaucoma drugs Bimatoprost and Latanoprost. The benefit of the present invention rises inter alia from the fact that a major intermediate involved in the synthesis of the above compounds may be isolated from a mixture containing also an undesired isomer, by crystallization. In addition, the undesired isomer may be oxidized to give the starting compound, which is then recycled.

Claims22

Dependent claims

A process for the preparation of 17-phenyl-18,19,20-trinor-PGF2α and its derivatives of Formula [1b]

37
wherein
the bond between carbons 1 and 2 is either a single bond (C1—C2) or a double bond (C1═C2), and
R6 is selected from the group consisting of alkoxy and alkylamino;
such process comprising:
(a) stereoselective reduction of the carbonyl group of the compound [4]
38
to yield a mixture of compounds of formulae [5a] and [6a],
39
where [5a] is the predominant isomer, which are subsequently converted into a mixture of compounds of formulae [5] (C1═C2) and [6]:
40
followed by isolation of the compound [5] (C1═C2) from the mixture and, if desired, hydrogenation of the double bond C1═C2 between carbons 1 and 2 of the compound [5] (C1═C2) in the presence of a catalyst to give the compound [5] (C1—C2) where the bond between carbons 1 and 2 is a single bond;
where one of R1 and R2 is an arylcarbonyl group and the other one is selected from the group consisting of arylcarbonyl, acyl, trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl;
(b) converting compound [6] from the mother liquor of step (a) into compound [6a], oxidizing the hydroxyl group of the compound [6a] to yield the compound [4] and recycling the compound [4] to step (a);
(c) reducing the compound [5] with diisobutylaluminum hydride at a temperature range from −20 to +20° C. followed by hydrolysis of the obtained reaction mixture under basic conditions to give the compound [11],
41
wherein the bond between carbons 1 and 2 is either a single bond (C1—C2) or a double bond (C1═C2);
R3 is hydrogen when R1 is acyl and is equal to R1 when it is trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted or alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl;
R4 is hydrogen when R2 is acyl and is equal to R2 when it is trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted or alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl and
(d) reacting compound [11] with a metal salt of 5-(triphenylphosphoranylidene)pentanoic acid, to obtain the compound of formula [1a]
42
and
(e) deriving the carboxyl group of the compound [1a], optionally, after deprotecting the hydroxyl groups, to give the desired compound [1b].

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Dependencies are inferred from the claim text.

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Abstract

A process for the preparation of 17-phenyl-18,19,20-trinor-PGF2α and its derivatives of Formula [1b]

37
wherein
the bond between carbons 1 and 2 is either a single bond (C1—C2) or a double bond (C1═C2), and
R6 is selected from the group consisting of alkoxy and alkylamino;
such process comprising:
(a) stereoselective reduction of the carbonyl group of the compound [4]
38
to yield a mixture of compounds of formulae [5a] and [6a],
39
where [5a] is the predominant isomer, which are subsequently converted into a mixture of compounds of formulae [5] (C1═C2) and [6]:
40
followed by isolation of the compound [5] (C1═C2) from the mixture and, if desired, hydrogenation of the double bond C1═C2 between carbons 1 and 2 of the compound [5] (C1═C2) in the presence of a catalyst to give the compound [5] (C1—C2) where the bond between carbons 1 and 2 is a single bond;
where one of R1 and R2 is an arylcarbonyl group and the other one is selected from the group consisting of arylcarbonyl, acyl, trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted and alkyl-substituted tetrahydro-2H-pyran-2-yl and tetrahydrofuran-2-yl;
(b) converting compound [6] from the mother liquor of step (a) into compound [6a], oxidizing the hydroxyl group of the compound [6a] to yield the compound [4] and recycling the compound [4] to step (a);
(c) reducing the compound [5] with diisobutylaluminum hydride at a temperature range from −20 to +20° C. followed by hydrolysis of the obtained reaction mixture under basic conditions to give the compound [11],
41
wherein the bond between carbons 1 and 2 is either a single bond (C1—C2) or a double bond (C1═C2);
R3 is hydrogen when R1 is acyl and is equal to R1 when it is trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted or alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl;
R4 is hydrogen when R2 is acyl and is equal to R2 when it is trialkylsilyl, dialkylarylsilyl, 1-alkoxyalkyl, unsubstituted or alkyl-substituted tetrahydro-2H-pyran-2-yl or tetrahydrofuran-2-yl and
(d) reacting compound [11] with a metal salt of 5-(triphenylphosphoranylidene)pentanoic acid, to obtain the compound of formula [1a]
42
and
(e) deriving the carboxyl group of the compound [1a], optionally, after deprotecting the hydroxyl groups, to give the desired compound [1b].

20 more elements