Process for the synthesis of azetidinones

Details Process for the synthesis of azetidinones Process for the synthesis of azetidinones

1999-12-05

2001-03-27

Shah, Mukund J. (Department: 1611)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S230000

Reexamination Certificate

active

06207822

ABSTRACT:

BACKGROUND
This invention relates to an enantioselective process for producing hydroxy-alkyl substituted azetidinones useful as hypocholesterolemic agents, in particular for preparing 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone, claimed in U.S. Pat. No. 5,767,115.
Processes for preparing the corresponding azetidinone without the 3-hydroxy substitutent are claimed in U.S. Pat. Nos. 5,728,827 and 5,561,227. Other processes for preparing 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)-propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone are disclosed in U.S. Pat. Nos. 5,631,365 and 5,739,321.
SUMMARY OF THE INVENTION
This invention provides an improved simple, high-yielding process using neutral conditions for producing the hypocholesterolemic azetidinone having the formula I
comprising:
(a) reacting p-fluorobenzoylbutyric acid of formula II with pivaloyl chloride and acylating the product with a chiral auxiliary of formula III to obtain a ketone of formula IV:
wherein X is —O—, —S— or —N(C
1
-C
6
alkyl); Y is ═O or ═S; and R
1
is C
1
-C
6
alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, C
1
-C
6
alkoxycarbonyl or benzyl, wherein the substituents on phenyl and naphthyl are 1-3 substituents selected from the group consisting of C
1
-C
6
alkyl, phenyl and benzyl;
(b) reducing the ketone of formula IV in the presence of a chiral catalyst to an alcohol of formula V:
(c) reacting the chiral alcohol of formula V, an imine of formula VI and a silyl protecting agent, then condensing the silyl-protected compounds to obtain a &bgr;-(substituted-amino)amide of formula VII, wherein Prot is a silyl protecting group:
(d) cyclizing the &bgr;-(substituted-amino)amide of formula VII with
(i) a silylatinrg agent and a fluoride ion catalyst cyclizing agent;
(ii) a silylating agent and a quaternary ammonium salt of a chiral auxiliary of formula III; or
(iii) a strong non-nucleophlic base;
to obtain the compound of formula VIII:
(e) removing the silyl protecting groups.
Also claimed are the process comprising steps (c), (d) and (e); the process of steps (d) and (e); the process of step (c); and the process of step (d), particularly the cyclization described in step (d)(i).
In still another aspect, the intermediates of formula VII and VIII are claimed.
The process described above is directed to the preparation of the 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone enantiomer, but it will be recognized that by substitution of the appropriate starting materials, other enantiomers can be prepared.


REFERENCES:
patent: 5561227 (1996-10-01), Thiruvengadam et al.
patent: 5631365 (1997-05-01), Rosenblum
patent: 5728827 (1998-03-01), Thiruvengadam et al.
patent: 5739321 (1998-04-01), Wu et al.
patent: 5767115 (1998-06-01), Rosenblum et al.
patent: 5856473 (1999-01-01), Shankar
“Kirk-Othmer Concise Encyclopedia of Chemical Technology”, Grayson, Martin Ed., 1985, John Wiley, New York, p. 1065-1066
Greene, T. W. and Wuts, P.G.M., “Protecting Groups in Organic Synthesis, 3rd Edition”, 1995, John Wiley, New York, p. 113-121.

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