Process for the preparation of prostaglandin precursors

Details Process for the preparation of prostaglandin precursors Process for the preparation of prostaglandin precursors

2000-04-12

2001-04-10

Lilling, Herbert J. (Department: 1651)

Chemistry: molecular biology and microbiology

Process of utilizing an enzyme or micro-organism to destroy...

Resolution of optical isomers or purification of organic...

C435S135000, C435S196000, C435S197000, C435S156000

Reexamination Certificate

active

06214611

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to the preparation of prostaglandin omega side chains in optically enriched form.
BACKGROUND OF THE INVENTION
Synthetic prostaglandins with a 4-aryloxy-3-hydroxy-1-(E)-butenyl omega chain, in particular 16-[3-(trifluoromethyl)phenoxy]-17, 18, 19, 20-tetranor-PGF
2a
and its esters, more particularly the isopropyl ester, are potent drugs for the treatment of glaucoma and ocular hypertension. The use of 11-oxaprostaglandins with 4-aryloxy-3-hydroxyl-1-(E)-butenyl side chains for this purpose is disclosed in WO-A-97/23223. The desired activity resides in the dextrorotary 15 R isomeric form. The structure of (+)-16-[3-(trifluoromethyl)phenoxy]-17, 18, 19, 20-tetranor-PGF
2a,
, isopropyl ester, is shown below.
U.S. Pat. No. 4,321,275 discloses a synthesis of the corresponding racemic free acid fluoprostenol, for use as a luteolytic agent and stimulant of uterine smooth muscle contraction in vertinary medicine. This compound is prepared from the Corey lactone aldehyde 4&bgr;-formyl-2,3,3a&bgr;,6a&bgr;-tetrahydro-2-oxo-5&agr;-(4-phenylbenzoyloxy)-cyclopenteno[b]furan, by reaction with dimethyl 2-oxo-3-[3-(trifluoromethyl)phenoxy]-oxypropylphosphonate, thus introducing C14-16 of the omega chain. The resulting enone is transformed to fluoprostenol by non-stereoselective reduction of the keto function to the corresponding alcohol, removal of the 4-phenylbenzoyl group, protection of the two hydroxy groups with tetrahydropyranyl, reduction to the lactol, Wittig olefination with the ylide prepared from (4-carboxybutyl)triphenylphosphonium bromide and removal of the tetrahydropyranyl groups. The active 15 R diastereoisomer is obtained by chromatographic separation.
EP-A-0639563 discloses the preparation of enantiomerically enriched 16-[3-(trifluoromethyl)phenoxy]-17,18,19,20-tetrano-PGF
2∞
isopropyl ester. The active 15 R diastereoisomer of the analogue, 16-(3-chlorophenoxy)-17,18,19,20-tetranor-PGF
2∞
isopropyl ester was formed stereoselectively by reduction of the keto function of the corresponding Corey lactone enone with (−)-B-chlorodiisopinocampheylborane.
The omega chain of prostaglandins may also be introduced in its entirety by means of a coupling reaction between an organocuprate reagent and an electrophilic cyclopentane core synthon. This has the advantage of being a more convergent strategy, whereby the omega chain can be introduced already containing the requisite chirality.
Danilova et al,
DOKL Chem. USSR
(
Engl. Transl.
), 1983 273, 375-377, disclose an organocuprate coupling reaction of an alkenylcuprate formed from racemic 4-(3-trifuloromethylphenoxy)-3-(1-ethoxyethoxy)-1-iodo-1E-butene and a 2-cyclopentenone, to prepare an 11-deoxy analogue of fluoprostenol.
Tolstikov et al,
J. Org. Chem. USSR
(
Engl. Transl
), 1983, 19, 1624-1631 also disclose the racemic precursors to this 1-ethoxyethoxy ether, which are 4-[(3-trifluoromethyl)phenoxy]-1-butyn-3-ol, 4-(3-trifluoromethylphenoxy)-1-iodo-1E-buten-3-ol and their corresponding trimethylsilyl ethers.
The use of an enantiomerically enriched omega chain precursor for the preparation of PGF
2a,
in which the key step is the coupling of an alkenylcuprate reagent to a tricycloheptanone, is disclosed by Davies et al,
J. Chem. Soc., Perkin Trans
1, 1981, 1317).
WO-A-95/33845 discloses the preparation of an enantiomerically enriched propargyl alcohol of the formula
wherein R
1
and R
2
are each H or alkyl, and R
3
is optionally substituted phenyl, alkyl or cycloalkyl, by enantioselective enzyme-mediated bioresolution of the corresponding racemate. In the Examples, racemic 3-hydroxy-4-phenoxy-1-butyne was treated with isopropenyl acetate and lipase PS; the (S)-alcohol was obtained in 98% ee. The (R)-alcohol was obtained in 96% ee by non-enzymatic hydrolysis of the (R)-ester formed in the bioresolution step.
SUMMARY OF THE INVENTION
This invention is based on the discovery that, in order to obtain the single enantiomer of a 4-aryloxy-3-hydroxy-1-(E)-butene, for the ultimate provision of a prostaglandin omega side chain, the procedure of WO-A-95/33845 is not invariably satisfactory. In particular, relatively low ee's are obtained when the aryl group is meta-substituted, e.g. with a key CF
3
of Cl group. An effective synthesis of prostaglandin agents with these omega side chains, in particular for 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor PGF
2a
and its ester derivatives has been found.
According to the present invention, a process for the preparation of a propargylic alcohol, enriched in the (R)-enantiomer, of the formula
wherein R is C
1-4
alkoxy, halogen, or C
1-4
alkyl optionally substituted by OH or halogen, comprises the steps of:
(a) enantioselective (R)-esterification of the racemic alcohol using an acyl donor and a first enzyme,
(b) removal of the unreacted (S)-alcohol; and
(c) enantioselective hydrolysis of the (R)-ester, using a second enzyme.
The propargylic alcohol may then be converted to a protected allylic alcohol of the formula
wherein R is as defined above, R
1
is a blocking group, and X is a metal or a metal-containing group such that the compound is an organometallic reagent or X is a group convertible thereto, which comprises the above steps and, additionally,
(d) introducing the blocking group;
(e) converting the C≡C group to the (E)—CH═CH—X group.
The allylic alcohol may then be converted to a prostaglandin having a &ohgr;-side chain including the group
wherein R is a defined above, which comprises the above steps; if X is the convertible group, converting it to a metal or metal-containing group; and converting the organometallic allylic alcohol to the prostaglandin. This conversion can be done by known means; see references cited above. This conversion is facilitated by the discovery that 8-anti{4-[3-(trifluoromethyl)phenoxy]-3-R-dimethyl-tert-butylsilyloxy-1E-butenyl}-6-endo-dimethyl-tert-butylsilyloxy-2-oxabicyclo[3.2.1]octan-3-one can be isolated in crystalline form, as described and claimed in the copending Patent Application, filed on the same date, entitled “Novel Intermediate for the Synthesis of Prostaglandins”, and claiming priority from British Patent Application No. 9908326.3.
The process of the invention can provide novel prostaglandin &ohgr;-side chain precursors having good ee values, in excess of 80%, preferably at least 97% and most preferably at least 99%. In particular, the present invention provides the (R)-propargylic alcohol in at least 97%, preferably at least 99% ee.
DESCRIPTION OF THE INVENTION
As indicated above, the process of the invention gives a propargylic alcohol that can be readily converted to a trans-alkenylcuprate reagent used to join the omega chain to a synthon for the cyclopentane or other prostaglandin core component. This alkenylcuprate reagent may be prepared from a corresponding simple trans-alkenylmetal derivative, e.g. the trans-alkenyllithium, in which the hydroxy group is protected with a base stable group, e.g. tert-butyldimethylsilyl. The preparation of this trans-alkenylmetal derivative may be either by metallation of the corresponding halide (X=halide, preferably iodide), e.g. by formation of the alkenyllithium with tert-butyllithium, or by hydrometallation of the corresponding alkyne, e.g. with the reagent formed from zirconocene dichloride and tert-butylmagnesium chloride. The trans-alkenyl iodide may be prepared by reaction of a trans-alkenylmetal derivative which may formed by hydrometallation of the alkyne, e.g. the trans-alkenylzirconocene chloride with an electrophilic iodine source, e.g. iodine. The alkyne may be prepared from the corresponding propargylic alcohol by reaction with a protecting group donor, e.g. tert-butyldimethychlorosilane.
A key aspect of the present invention relates to the preparation of the enantionmerically enriched (R)-propargylic alcohol, from the corresponding racemic propargylic alcohol. This involves two enzymatic reactions, u

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