US 4,283,333 A · .alpha.-[4-Oxoazetidin-1-yl]-acetic acid compounds useful as intermediates in preparing 1-oxadethiacephalosporins

Abstract

Azetidine derivatives of the formula: ##STR1## wherein A is amino or substituted amino; COB is carboxy or protected carboxy; R.sup.1 is .dbd.C(CH.sub.3).sub.2, ##STR2## (R.sup.4 is alkyl, aryl or aralkyl); OR.sup.2 and OR.sup.3 independently or taken together with each other represent a ketal; Y is hydrogen or methoxy; Z is hydrogen or halogen, and a process for preparation thereof. Used as intermediates in the preparation of potent antimicrobials 1-oxadethiacephalosporins.

A compound of the formula:

##STR14## wherein A is amino, acrylamino selected from the group consisting of
(1) C.sub.1 -C.sub.10 alkanoylamino,
(2) C.sub.1 -C.sub.5 haloalkanoylamino,
(3) azidoacetamido,
(4) cyanoacetamido,
(5) acylamino of the formula Ar--CQQ'--CONH--, wherein Q and Q' each are hydrogen or methyl, Ar is phenyl or dihydrophenyl, which phenyl and dihydrophenyl may be monosubstituted by C.sub.1 -C.sub.5 alkyl, trifluoromethyl, cyano, aminomethyl, protected carboxymethylthio, hydroxy, C.sub.1 -C.sub.3 alkoxy, C.sub.1 -C.sub.10 alkanoyloxy, chlorine, bromine, iodine, fluorine, or nitro,
(6) 2-sydnon-3-acetamido,
(7) (4-pyridon-1-yl)-acetamido,
(8) acylamino of the formula Ar--G--CQQ'--CONH--, wherein Ar, Q, and Q' are the same as defined above and G is oxygen or sulfur,
(9) acylamino of the formula ##STR15## wherein Ar is the same as defined above and T is hydroxy, carboxy, C.sub.2 -C.sub.7 alkoxycarbonyl, C.sub.8 -C.sub.15 aralkoxycarbonyl, C.sub.7 -C.sub.12 aryloxycarbonyl, C.sub.1 -C.sub.7 alkanoyloxy, C.sub.1 -C.sub.3 alkoxy, cyano, carbamoyl, sulfo or C.sub.1 -C.sub.7 alkoxysulfonyl,
(10) acylamino of the formula ##STR16## wherein Ar is the same as defined above and W and W' are, respectively, (i) hydrogen, (ii) C.sub.2 -C.sub.7 alkoxycarbonyl, (iii) C.sub.3 -C.sub.10 cycloalkyl-(C.sub.2 -C.sub.3)alkoxycarbonyl, (iv) C.sub.5 -C.sub.8 cycloalkoxycarbonyl, (v) C.sub.1 -C.sub.4 alkylsulfonyl-(C.sub.1 -C.sub.4)alkoxycarbonyl, (vi) halo(C.sub.1 -C.sub.3)alkoxycarbonyl, (vii) C.sub.8 -C.sub.15 aralkoxycarbonyl, (viii) C.sub.1 -C.sub.10 alkanoyl or (ix) C.sub.7 -C.sub.15 aroyl, which groups (ii) through (ix) are unsubstituted or monosubstituted by hydroxy, C.sub.1 -C.sub.10 alkanoyloxy, halogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.3 hydroxyalkyl or trifluoromethyl, (x) pyronecarbonyl, (xi) thiopyronecarbonyl, (xii) pyridonecarbonyl, (xiii) carbamoyl, (xiv) guanidinocarbonyl, (xv) 3-methyl-2-oxoimidazolidin-1-ylcarbonyl, (xvi) 3-methanesulfonyl-2-oxoimidazolidin-1-ylcarbonyl, (xvii) 4-methyl-2,3-dioxopiperazin-1-ylcarbonyl or (xviii) 4-ethyl-2,3-dioxopiperazin-1-ylcarbonyl, or W and W', together with the nitrogen atom to which they are attached, represent phthalimido, maleimido or an enamino of the formula ##STR17## (11) acylamino of the formula ##STR18## wherein Ar is the same as defined above and E is hydrogen or C.sub.1 -C.sub.5 alkyl,
(12) 5-aminoadipoylamino,
(13) N-protected 5-aminoadipoylamino,
(14) carboxy-protected 5-aminoadipoylamino, and
(15) acylamino of the formula L--O--CONH--, wherein L is t-butyl, 1,1-dimethylpropyl, cyclopropylmethyl, 1-methylcyclohexyl, isobutyl, 2-alkoxy-t-butyl, 2,2,2-trichloroethyl, benzyl, naphthyl, p-methoxybenzyl, pyridylmethyl or diphenylmethyl,
diacylamino of the formula ##STR19## wherein R is a noncyclic C.sub.2 -C.sub.8 hydrocarbon radical, amino substituted by t-butyl, trityl, methylidene, benzylidene, 1-halo-2-phenylethylidene, 1-alkoxy-2-phenylethylidene, 3,5-di-t-butyl-4-hydroxybenzylidene, o-hydroxybenzylidene or trimethylsilyl, or
a group selected from azido, isocyanato and isocyano;
COB is carboxy or protected carboxy;
R.sup.1 is .dbd.C(CH.sub.3).sub.2, ##STR20## .dbd.PR.sup.4.sub.3 or ##STR21## wherein R.sup.4 is alkyl, monocyclic aryl or monocyclic aralkyl;
OR.sup.2 and OR.sup.3, independently of each other, represent methoxy, ethoxy, propoxy, isobutoxy, pentyloxy, cyclohexyloxy, octyloxy, benzyloxy, phenethyloxy or pyridylmethoxy, or OR.sup.2 and OR.sup.3, taken together, represent ethylenedioxy, propylenedioxy, trimethylenedioxy, phenylethylenedioxy, phenyltrimethylenedioxy or diphenylpropylenedioxy;
Y is hydrogen or methoxy;
and
Z is hydrogen or halogen.

20 more elements

Description3,855 words

Summary2,198 words

#This invention relates to (1) compounds represented by the formula: ##STR3## wherein A is amino or substituted amino; COB is carboxy or protected carboxy; R.sup.1 is .dbd.C(CH.sub.3).sub.2, ##STR4## (R.sup.4 is alkyl, aryl or aralkyl); OR.sup.2 and OR.sup.3 independently or taken together represent a ketal; Y is hydrogen or methoxy; Z is hydrogen or halogen, and (2) a process for preparing compounds represented by the formula: ##STR5## by halogenating compounds represented by the formula: ##STR6## wherein A, COB, R.sup.1 and Y are the same as mentioned above; Hal is halogen; X is oxo or ##STR7## (OR.sup.2 and OR.sup.3 are the same as mentioned above).

#More particularly, it relates to reactions (2), (3) and (4) and compounds (III) and (IV) illustrated in the following reaction sequence. ##STR8## wherein A, COB, Hal, R.sup.1, OR.sup.2, OR.sup.3 and Y are the same as mentioned above.

#In other words, this invention relates to intermediates in the preparation of 1-oxadethiacephalosporins and processes for preparing them, which comprise (1) ketals (III) of methyl ketones (I) and ketals (IV) of halomethyl ketones (II); (2) a process for preparing halomethyl ketones (II) or their ketals (IV) on halogenation of methyl ketones (I) on their ketals (III); (3) a process for preparing ketals (III) on ketalization of methyl ketones (I); (4) a process for preparing halomethyl ketones (II) on deketalization of ketals (IV); and (5) a process for preparing halomethyl ketones (II) from methyl ketones (I) by carrying out the aforementioned processes (3), (2) and (4) successively.

Detailed description1,657 words

#The following examples are provided to further illustrate the products and processes of this invention.

#(1) To a solution of 214 mg of benzyl .alpha.-(2.beta.-acetonyloxy-3.beta.-phenylacetamido-4-oxoazetidin-1-yl)-. alpha.-isopropylideneacetate in 5 ml of dry methanol is added 203 mg of cupric bromide, and the mixture allowed to stand at room temperature for 6 hours, poured into an aqeous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to yield 236 mg of benzyl .alpha.-[2.beta.-(2,2-dimethoxypropoxy)-3.beta.-phenylacetamido 4-oxoazetidin-1-yl]-.alpha.-isopropylidenacetate (100% yield).

#IR: .nu..sub.max.sup.CHCl.sub.3 3470, 1790, 1740, 1695 cm.sup.-1.

Facts

Application

06/019,895Filed 12 Mar 1979 · division

Priority

JP 51-9069028 Jul 1976

Granted

11 Aug 1981

Term ended

11 Aug 1998

Estimated · how

Pre-1995 term; greater of 17 years from grant or 20 years from filing when eligible. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification5 codes

C07D 505/00
Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a
C07D 205/085
With one oxygen atom directly attached in position 2, e.g. beta-lactams: with a nitrogen atom directly attached in position 3
C07F 9/568
Having one nitrogen atom as the only ring hetero atom: four-membered rings
C07D
Heterocyclic compounds

.alpha.-[4-Oxoazetidin-1-yl]-acetic acid compounds useful as intermediates in preparing 1-oxadethiacephalosporins

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.alpha.-[4-Oxoazetidin-1-yl]-acetic acid compounds useful as intermediates in preparing 1-oxadethiacephalosporins

Life of this patent

Life of this patent

Abstract

Drawings

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Claims23

Description3,855 words

Drawings

Classification5 codes

Life of this patent

Description3,855 words