Process for the preparation of PGD2 antagonist

Details Process for the preparation of PGD2 antagonist Process for the preparation of PGD2 antagonist

2003-06-06

2004-02-17

Owens, Amelia (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06693203

ABSTRACT:

BACKGROUND OF THE INVENTION
The benzothiophenecarboxamide derivative S-5751 (8) is a PGD
2
receptor antaongist potentially useful for the treatment of allergic rhinitis (including relieve of nasal congestion), asthma, allergic conjunctivitis, urticaria, ischemic reperfusion injury, inflammation, and atopic dermatitis. The compound is disclosed in PCT Published Application WO98/25919, which also describes its synthesis as shown below:
The preparation of the starting material aminoalkene ester is referenced to U.S. Pat. No. 4,904,819, which describes the synthesis as shown below:
Another process for the preparation of S-5751 is disclosed in WO99/50261 as shown below:
The reported synthesis of S-5751 are not modular or convergent, include superfluous oxidation/reduction steps at the ester group, or require specilized equipment, and therefore are not suitable for scale-up production and are uneconomical to run.
SUMMARY OF THE INVENTION
The present application relates to an efficient process for the preparation of the PGD2 antagonist S-5751
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is schematically shown below:
wherein X is a leaving group and R is a C
1-5
alkyl or a benzyl group.
The present process starts with the commercially available (1R)-(+)-nopinone 1. In the first step, the 5-heptynoate side chain 2a is attached to the (1R)-(+)-nopinone via alkylation of the enolate generated by treating the nopinone with a strong base to form the keto alkyne ester 3a. The preferred base for the reaction is lithium diisopropylamide. The leaving group of the heptynoate side chain 2a may be a halide such as chloride, bromide or iodide, or a sulfonate such as tosylate, mesylate or triflate, and the ester group may be a straight or branched alkyl group or a benzyl group; preferably the heptynoate side chain is ethyl 7-iodo-5-heptynoate. The reaction is conducted in an aprotic organic solvent such as tetrahydrofuran or other ethers such as methyl t-butyl ether or ethyl ether, and preferably in the presence of an amine base such as triethylamine. The reaction temperature is from about −50 to about −10° C., preferabably at about −50 to about −45° C. Reaction generally complete within about one to two hours. Acid, such as trifluoroacetic acid is added to the reaction mixture to quench base that can cause epimerization upon warming the reaction mixture to room temperature. The reaction product contains predominantly the desired diastereomer with a diastereomeric excess (d.e.) of 98% or greater.
In the second step, the keto alkyne ester 3a is converted to the corresponding oxime 4a using conventional methodologies. The keto alkyne ester 3a is treated with hydroxylamine hydrochloride in the presence of sodium acetate which acts as a base and buffer to neutralize HCl salt of hydroxylamine, and the reaction is carried out in a protic solvent such as an alcohol or water or a mixture thereof, and at elevated temperature preferably at about 50° C., and is complete within about 5 hours
In the third step, the oxime 4a is reduced to the corresponding primary amine alkyne ester 5a. The oxime is first treated with titanium (III) chloride at temperature below about 10° C. to give the corresponding imine intermediate. The conversion to the imine is complete in about one hour, after which time a reducing agent such as borane is added and the reaction temperature is maintained at below about 10° C. until the imine to amine conversion is complete.
In the fourth step, the amine alkyne ester 5a is reduced to the corresponding amine alkene ester 6a. Thus hydrogenation of the triple bond to the double bond in the presence of a suitable catalyst, preferably Lindlar's catalyst, is carried out in an organic solvent such as dimethylformamide, and in the presence of ethylenediamine. The reaction is complete within 6 hours. The amino alkene ester is treated with HCl to provide the HCl salt.
In the last step, the amino alkene ester 6a is coupled with the benzothiophenecarboxylic acid 7 using conventional amide formation reaction. The acylation may be accomplished using the acid or an acylating equivalent thereof, such as the acid chloride or the acid anhydride. Preferably, the acid is used in conjunction with one or more coupling agent such as dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and hydroxybenzotriazole. The coupling reaction is carried out in the presence of a base such as diisopropylethylamine (DIPEA or Hunig's base) and in an organic solvent such as tetrahydrofuran. The ester is then converted to the acid by base-catalyzed hydrolysis, which is carried out at elevated temperature, e.g. about 40° C.


REFERENCES:
patent: 6083974 (2000-07-01), Honma et al.
patent: 6217642 (2001-04-01), Kunisch et al.

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