Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
1999-04-22
2001-02-06
Lilling, Herbert J. (Department: 1609)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S125000, C435S280000
Reexamination Certificate
active
06184005
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a new process for the preparation of (−)-3,4-trans-compounds involving an enzymatic hydrolysis.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,280,040 discloses a class of 3,4-diarylchromans and their salts useful in the treatment of bone loss. Furthermore, PCT/DK96/00014 discloses that these compounds are useful in the treatment of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment. PCT/DK96/00015 discloses that these compounds are useful in the treatment of gynaecological disorders, such as endometriosis, dysfunctional bleedings, endometrial cancer, polycystic ovarian syndrome and anovulatoric bleeding and for the induction of endometrial thinning. The compounds are also known to have useful effects on gynaecomastia, obesity, vasodilation (respectively from PCT/DK96/00012, PCT/DK96/00011, and PCT/DK96/00013) and furthermore on e.g. Alzheimers disease (PCT/DK96/00010).
A process for the preparation of (+,−)-3,4-trans diarylchromanes is described in U.S. Pat. No. 3,822,287 and by Suprabhat Ray et al. in J.Med.Chem.19,276 (1976). The (+,−)-3,4-trans-isomer is obtained by conversion of the (+,−)-3,4-cis-isomer by means of an organometallic base-catalyzed rearrangement as described in U.S. Pat. No. 3,822,287.
The resolvation of (+,−)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622. According to this process the (+,−)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane is reacted with di-p-toluoyl-l-tartaric acid monohydrate in a protic solvent, the reaction mixture is subjected to fractional crystallization and the crystalline salt is subjected to alkaline hydrolysis to produce the desired enantiomer.
Example 1 of U.S. Pat. No. 4,447,622 describes the preparation of the (−)-3,4-trans enantiomer, shown by the following formula:
When using the process disclosed in U.S. Pat. No. 4,447,622 the desired (−)-3,4-trans enantiomer is only obtained with a low chiral purity, less than 80% ee (enantiomeric excess) after the first crystallization. In order to improve the chiral purity the enantiomer has to be crystallized several times.
One object of the present invention is therefore to provide a new process involving an enzymatic resolution step for the preparation of (−)-3,4-trans enantiomers of compounds of formula I which process is adaptable to large scale manufacture, provide good yields and high purity and reduce the cost of manufacture.
DESCRIPTION OF THIS INVENTION
The present invention concerns a process for the preparation of (−)-3,4-trans-compounds of the formula I
wherein R
1
and R
4
are individually hydrogen, C
1-6
alkyl or C
1-6
alkoxy, R
5
is —O—(CH
2
)
n
—NR
6
R
7
wherein n is an integer in the range of 1 to 6 and R
6
and R
7
independently are C
1-6
alkyl or R
6
and R
7
together with the N atom is a saturated or unsaturated 5- or 6-membered heterocyclic group containing one or two heteroatom(s) which heterocyclic group is optionally substituted with C
1-6
alkyl; and R
2
and R
3
are individually hydrogen or C
1-6
alkyl; or a salt thereof, which comprises
a) treating a cis-racemate of a compound of formula V
or a salt thereof, wherein R
1
, R
2
, R
3
and R
4
are as defined above with an agent of formula R—CO—X, wherein R is C
1-12
alkyl, optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, hetaryl or aryl or C
1-12
alkoxy, optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a cis-racemate of a compound of formula VI
or a salt thereof, wherein R, R
1
, R
2
, R
3
and R
4
are as defined above,
b) treating said cis-racemate of formula VI with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula VIa
or a salt thereof, and a compound of formula VII
or a salt thereof;
or a mixture comprising a compound of formula VIb
or a salt thereof, and a compound of formula VIIa
or a salt thereof,
c) separating said mixture of compound Via and VII or said mixture of compound VIb and VIIa, thereby obtaining a compound of formula VII or a compound of formula VIb, which compound VIb is then hydrolyzed to said compound of formula VII,
d) treating said compound of formula VII or a salt thereof, with an agent of formula Y-R
5
wherein Y is a leaving group, thereby providing a compound of formula VIII
or a salt thereof,
e) treating said compound of formula VIII or a salt thereof with a strong base in an aprotic solvent, thereby obtaining said compound of formula I or a salt thereof.
The above process may also be carried out by starting with a trans-racemate in step a), thus the process comprises
a) treating a trans-racemate of a compound of formula II
or a salt thereof, wherein R
1
, R
2
, R
3
and R
4
are as defined above with an agent of formula R—CO—X, wherein R is C
1-12
alkyl, optionally substituted with C
16
-alkyl, C
1-6
alkoxy, hetaryl or aryl or C
1-12
alkoxy, optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, hetaryl or aryl, and X is a leaving group, thereby providing a trans-racemate of a compound of formula III
or a salt thereof, wherein R
1
, R
2
, R
3
and R
4
are as defined above,
b) treating said trans-racemate of formula III with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula IIIa
or a salt thereof, and a compound of formula IV
or a salt thereof;
or a mixture comprising a compound of formula IIIb
or a salt thereof, and a compound of formula IVa
or a salt thereof,
c) separating said mixture of compound IIIa and IV or said mixture of compound IIIb and IVa, thereby obtaining a compound of formula IV or a compound of formula IIIb, which compound IIIb is then hydrolyzed to said compound of formula IV,
d) treating said compound of formula IV with an agent of formula Y-R
5
wherein Y is a leaving group, thereby obtaining the compound of formula I or a salt thereof.
In another aspect the invention concerns a process for the preparation of (3R,4S)-cis-compounds of the formula VII
wherein R
1
and R
4
are individually hydrogen, C
1-6
alkyl or C
1-6
alkoxy, and R
2
and R
3
are individually hydrogen or C
1-6
alkyl; or a salt thereof, which comprises
a) treating a cis-racemate of formula VI
or a salt thereof, wherein R is C
1-12
alkyl, optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, hetaryl or aryl or C
1-12
alkoxy, optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, hetaryl or aryl, and R
1
, R
2
, R
3
and R
4
are as defined above, with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula VIa
or a salt thereof, and a compound of formula VII
or a salt thereof
or a mixture comprising a compound of formula VIb
or a salt thereof, and a compound of formula VIIa
or a salt thereof,
b) separating said mixture of compound VIa and VII or said mixture of compound VIb and VIIa, thereby obtaining a compound of formula VII or a compound of formula VIb, which compound VIb is then hydrolyzed to said compound of formula VII.
In a further aspect the invention concerns a process for the preparation of (3R,4R)-trans-compounds of the formula IV
wherein R
1
and R
4
are individually hydrogen, C
1-6
alkyl or C
1-6
alkoxy, and R
2
and R
3
are individually hydrogen or C
1-6
alkyl; or a salt thereof, which comprises
a) treating a trans-racemate of formula Ill
or a salt thereof, wherein R is C
1-12
alkyl, optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, hetaryl or aryl or C
1-12
alkoxy, optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, hetaryl or aryl, and R
1
, R
2
R
3
and R
4
are as defined above, with an enzyme having lipase activity, thereby providing a mixture comprising a compound of formula IIIa
or a salt thereof, and a compound of formula IV
or
Gregg Valeta
Lilling Herbert J.
Novo Nordisk A S
Zelson Steve T.
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