Enzymatic processes for producing intermediates useful in...

Details Enzymatic processes for producing intermediates useful in... Enzymatic processes for producing intermediates useful in...

2001-09-06

2002-06-11

Barts, Samuel (Department: 1621)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing oxygen-containing organic compound

C560S129000, C560S226000, C560S227000, C560S231000, C560S228000, C568S376000, C568S388000, C568S389000, C435S135000, C435S131000, C435S136000, C435S147000, C435S148000

Reexamination Certificate

active

06403346

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field
The invention relates to a new process for the preparation of retiferol derivatives of the formula:
wherein
A is —C≡C— or —CH═CH—, and
R
1
and R
2
are independently of each other lower alkyl or lower perfluoroalkyl.
2. Description
Compounds of formula I can be utilized to treat or prevent hyperproliferative skin diseases such as psoriasis, basal cell carcinomas, disorders of keratinization and keratosis neoplastic diseases and disorders of the sebaceous glands such as acne and seborrhoic dermatitis. The compounds of formula I can also be utilized in reversing the conditions associated with photodamage, particularly for the oral or topical treatment of the skin damaged through sun exposure, the effects of wrinkling, elastosis and premature aging, especially for the treatment of psoriasis. Such compounds are known and disclosed in WO 99/43646.
SUMMARY OF THE INVENTION
The subject invention provides a process for preparing a compound of the formula:
wherein A is —C≡C— or —CH═CH— and R
1
and R
2
each independently are lower alkyl or lower perfluoroalkyl. This process comprises coupling a compound of the formula:
wherein X
1
and X
2
are hydroxy protecting groups, with a compound of the formula:
wherein A, R
1
, R
2
are as above and Y is a hydroxy protecting group, to produce the compound of formula I. Preferred hydroxy protecting groups, X
1
and X
2
, are Si(C
1
-C
4
-alkyl)Me
2
or a group R
3
CO— where R
3
is lower alkyl or mono-chlorinated lower alkyl and Y is Si(C
1
-C
4
-alkyl)
3
. It is also preferred where A is —CH═CH—.
The subject invention also provides a process for preparing a compound of the formula:
wherein A is —C≡C— or —CH═CH— and R
1
and R
2
each independently are lower alkyl or lower perfluoroalkyl. The process comprises coupling a compound of formula:
wherein X
1
and X
2
are hydroxy protecting groups, with a compound of formula:
wherein A, R
1
, R
2
are as above and Y is a hydroxy protecting group to produce the compound of formula I. Favorably, X
1
and X
2
are each independently Si(C
1
-C
4
-alkyl)Me
2
or a group R
3
CO— where R
3
is lower alkyl or mono-chlorinated lower alkyl and Y is Si(C
1
-C
4
-alkyl)
3
. It is also preferred that A is —CH═CH—.
Another process provided by the subject invention is for preparing a compound of the formula:
wherein R
1
and R
2
are each independently lower alkyl or lower perfluoroalkyl. This process comprises coupling a compound of formula:
wherein R
3
is lower alkyl or mono-chlorinated lower alkyl, with a compound of formula:
wherein R
1
, R
2
are as above and Y is a Si(C
1-4
-alkyl)
3
. The protected hydroxy groups are then deprotected to obtain a compound of formula Ia.
Yet another inventive process is for preparing a compound of the formula:
wherein R
3
is lower alkyl or mono-chlorinated lower alkyl. This process involves protecting the hydroxy groups of the trans/cis/trans compound of the formula:
or protecting the hydroxy groups of the all cis 1,3,5-trihydroxycyclohexane, to obtain the compound of the formula:
wherein R
3
is lower alkyl or mono-chlorinated lower alkyl). In the case of the all cis 1,3,5-trihydroxycyclohexane, this involves obtaining the protected all cis 1,3,5-trihydroxycyclohexane wherein the hydrogen atoms of the hydroxy groups have been replaced by R
3
as above. The R
3
CO-group is then hydrolyzed in the 5-position in a biphasic water/organic solvent system in an enzymatic reaction to obtain a product of the formula:
wherein R
3
is as above. The hydroxy group o this compound is then oxidized to obtain a compound of formula IIa. The process beneficially uses enzymatic reaction lipases of the EC-class 3.1.1.3 or 3.1.1.34.
A further inventive process prepares a compound of the formula:
wherein X
1
is Si(C
1-4
-alkyl)Me
2
or R
3
CO— where R
3
is lower alkyl or mono-chlorinated lower alkyl. This process comprises protecting one hydroxy group of a compound of the formula:
to obtain a compound of the formula:
wherein X
1
is as above. This compound is then acylated via an enzyme at a further hydroxy group of a compound of the formula (3) in a non-aqueous acylation solvent to obtain a compound of the formula:
wherein X
1
is as above and R
3′
is methyl. The configuration of the carbon atom which carries the remaining unprotected hydroxy group in compound of formula (4) is then inverted and the R
3′
OC— group is cleaved to form a hydroxy derivative. The hydroxy group is then oxidized to obtain a compound of formula IIb. A preferred enzyme is a lipase of the EC-class 3.1.1.3 or lipoprotein lipases of the EC-class 3.1.1.34.
Another inventive process is for preparing a compound of the formula:
wherein R
1
, R
2
are each independently lower alkyl or lower perfluoroalkyl and Y is Si(C
1-4
-alkyl)
3
. This process comprises reacting a compound of the formula:
wherein R
1
, R
2
and Y are as above, with Me
3
SiCH
2
CO
2
R
5
, Ph
3
P═CH—CO
2
R
5
or (EtO)
2
P(O)CH
2
CO
2
R
5
, wherein R
5
is lower alkyl; to obtain the compound of the formula:
wherein R
1
, R
2
, R
5
and Y are as above. The ester group is then reduced to obtain the hydroxy derivative of the compound of formula (10). This is coupled with 5-mercapto-1-phenyltetrazole or 2-mercapto-benzothiazole to obtain the compound of the formula:
wherein R
1
, R
2
and Y are as above, The sulfanyl group of the compound of the formula 11 to then oxidized to obtain the compound of formula IIIa.
The subject invention provides a compound of the formula:
wherein R
1
and R
2
are each independently lower alkyl or lower perfluoroalkyl, Y is Si(C
1-4
-alkyl)
3
and R
5
is a lower alkyl.
In addition, the invention provides a compound of the formula:
wherein R
1
and R
2
are each independently lower alkyl or lower perfluoroalkyl and Y is a Si(C
1-4
-alkyl)
3
.
Also provided is a compound of the formula:
wherein R
1
and R
2
are each independently lower alkyl or lower perfluoroalkyl and Y is Si(C
1-4
-alkyl)
3
.
Another inventive process is for preparing a compound of the formula:
wherein R
1
and R
2
are each independently lower alkyl or lower perfluoroalkyl. This process comprises coupling a compound of the formula:
wherein R
4
is a Si(C
1-4
-alkyl)Me
2
with compound of the formula:
wherein R
1
and R
2
are each independently lower alkyl or lower perfluoroalkyl. The protected hydroxy group is then deprotected to obtain a compound of the formula Ia.
It is preferred when the subject process forms the compound (1R,3R)-5-[(2E,9Z)-12,12,12-trifluoro-11-hydroxy-7,7-dimethyl-11-trifluoromethyl-dodeca-2,9-dienylidene)-cyclohexane-1,3-diol.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid and understand the invention but are not to be construed as limiting.
In general the invention relates to a new process for preparing retiferol derivatives of the formula
wherein
A is —C≡C— or —CH═CH—, and
R
1
and R
2
are independently of each other lower alkyl or lower perfluoroalkyl.
The term “lower alkyl” as used herein denotes straight chain or branched alkyl residues containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl.
The term “lower perfluoroalkyl” denotes lower alkyl groups as defined above wherein the hydrogen atoms are substituted by fluorine, such as in trifluoromethyl, pentafluoroethyl, perfluoropropy, and the like.
In the structural formulas presented herein, a broken bond (
) denotes that the substituent is below the plane of the paper and a wedged bond (
) denotes that the substituent is above the plane of the paper.
Although compounds of formula I can be prepared as described in WO 99/43646, these compounds can be prepared more efficiently in a lower number of reaction steps and in a higher yield by the inventive processes depicted in scheme A, namely by
method A which comprises the coupling of ketones of formula II with compounds of fo

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