Process for the synthesis of azetidinones

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

1996-01-04

1998-03-17

Berch, Mark L.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540357, 540358, 540360, 540361, 540362, 540363, 540364, 540203, C07D20508, C07D205085, C07D20512

Patent

active

057288275

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND

This invention relates to a process for producing azetidinones useful as hypocholesterolemic agents and as intermediates for the synthesis of penems.
WO 93/02048 discloses stereoselective processes for producing azetidinones. One process for preparing azetidinones wherein the substituents at the C-3 and C-4 positions have trans relative stereochemistry comprises cyclizing a hydroxyamide prepared from a carboxylic acid, an aidehyde and an amine in a process using an oxazolidinone as a chiral auxiliary, The disclosed process comprises the following steps: R-(+)-4-benzyloxazolidinone, with a strong base or a tertiary amine base and treating the resulting anion with the product of step (a); TMEDA and triethylamine, dehydrative coupling agent, optionally adding an activating agent; and with: a phase transfer catalyst, then treating the resulting di- or tri-chlorobenzoate with an aqueous solution of a base and a phase transfer catalyst; or transfer catalyst; or
In another process of WO 93/02048, an azetidinone having trans relative stereochemistry as described above is prepared by cyclizing a .beta.-aminoamide derivative prepared from a carboxylic acid and an imine in a process using an oxazolidinone, preferably S-phenyl-oxazolidinone, as a chiral auxiliary. This process comprises the steps: S-phenyl-oxazolidinone, with a strong base or a tertiary amine base and treating the resulting anion with the product of step (a); tetramethyl-ethylenediamine (TMEDA), then condensing with an imine; and non-nucleophilic base, preferably an alkali metal bistrimethylsilylamide.


SUMMARY OF THE INVENTION

This invention provides a simple, high-yielding process for producing azetidinones under neutral conditions. Azetidinones are useful as hypocholesterolemic agents, as disclosed in WO 93/02048 and PCT International Application No. PCT/US94/00421, and are also useful as intermediates in the synthesis of penems, a known group of antibacterials. This process is applicable for preparing azetidinones which are optionally mono-, di- or unsubstituted at each of the C-3 and C-4 positions and substituted at the ring nitrogen. The stereochemistry of C-3, C-4-disubstituted azetidinones prepared by this process is dependent on the starting material: racemic, stereospecific or enantiomeric compounds can be obtained when the corresponding starting materials are used. In particular, this process is useful for the stereospecific preparation of azetidinones substituted in the C-3 and C-4 positions, and optionally substituted at the ring nitrogen.
In its broadest aspect, this invention relates to a process for preparing an azetidinone comprising reacting a .beta.-(substituted-amino)-amide, a .beta.-(substituted-amino)acid ester, or a .beta.-(substituted-amino)-thiolcarbonic acid ester with a silylating agent and a cyclizing agent.
More particularly, this invention relates to a process for preparing an azetidinone comprising reacting a silylating agent and a fluoride ion catalyst cyclizing agent with a suitably protected compound selected from the group consisting of B--C(O)--, wherein B is a deprotonated chiral auxiliary selected from the group consisting of ##STR1## wherein X is --O--, --S-- or --N(C.sub.1 -C.sub.6 alkyl)-; Y is .dbd.O or .dbd.S; and R.sup.12 and R.sup.13 are independently selected from the group consisting of C.sub.1 -C.sub.6 alkyl, phenyl, naphthyl, substituted phenyl, substituted naphthyl, lower alkoxy-carbonyl and benzyl, wherein the substituents on the phenyl and naphthyl are 1-3 substituents selected from the group consisting of lower alkyl, phenyl and benzyl, or wherein one of R.sup.12 or R.sup.13 is as defined above and the other is hydrogen; or B is (R.sup.14)(R.sup.15)N--, wherein R.sup.14 and R.sup.15 are independently selected from the group consisting of lower alkyl, aryl and benzyl; ester portion is R.sup.14 --S--C(O)--, wherein R.sup.14 is lower alkyl, aryl or benzyl; and thiolcarbonic acid ester portion is R.sup.14 --S--C(O)--, wherein R.sup.14 is lower alkyl, aryl or benzyl.
Alternatively, when B i

REFERENCES:
patent: 4876365 (1989-10-01), Kirkup et al.
Aldrich Chemical Catalog, p. 191 (1994).
Ho, J. Am. Chem. Soc., 106 (1984), pp. 4819-4825.
Calvin J. Chem. Soc., Chem. Commun., (1985), pp. 539-540.
Bringman Synthesis, (Oct., 1991), pp. 829-831.
Corriu, et al., Tetrahedron, 39, No. 6 (1983), pp. 999-1009.
Bouzard, et al, Tetrahedron Let., 29,No. 16 (1988), pp. 1931-1934 (1985), pp. 539-540.
Salzmann, et al, J.Am. Chem. Soc., 102 (1980), pp. 6161-6163.
Condensed Chemical Dictionary, 10th Edition (1980) p. 48.

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