GB1592245A - Intermediates for cephalosporin analogues - Google Patents

Intermediates for cephalosporin analogues Download PDF

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GB1592245A
GB1592245A GB33109/76A GB3310976A GB1592245A GB 1592245 A GB1592245 A GB 1592245A GB 33109/76 A GB33109/76 A GB 33109/76A GB 3310976 A GB3310976 A GB 3310976A GB 1592245 A GB1592245 A GB 1592245A
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to GB33109/76A priority Critical patent/GB1592245A/en
Priority to IL52685A priority patent/IL52685A/en
Priority to IE1653/77A priority patent/IE45650B1/en
Priority to CA284,398A priority patent/CA1076125A/en
Priority to NLAANVRAGE7708790,A priority patent/NL190374C/en
Priority to DE19772735854 priority patent/DE2735854A1/en
Priority to JP52095878A priority patent/JPS6041669B2/en
Priority to FR7724548A priority patent/FR2361365A1/en
Priority to CH973977A priority patent/CH641183A5/en
Priority to BE180027A priority patent/BE857622A/en
Priority to FR7804158A priority patent/FR2370729A1/en
Priority to FR7804159A priority patent/FR2370730A1/en
Publication of GB1592245A publication Critical patent/GB1592245A/en
Priority to US06/589,670 priority patent/US4592865A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings

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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

ERRATUM SPECIFICATTON NO 1592245 Page 1, line 1 after We, insert SHIONOGI SEIYAKU KABUSHIKI KAISHA known as THE PATENT OFFICE 9 May 1983 Bas 25110312 IMisinventionrelatesroiniermeuiaesiurmeyumcataui)-ptt < noptit.u.j-. from penicillins, which intermediates are represented by the following formula :
wherein A is amino or substituted amino ; B is hydroxy or a carboxy-protecting group ; X is a group OR in which R is a group represented by the formula :
in which Nu is a nucleophilic group ; R1 is a group represented by the formula: (54) INTERMEDIATES FOR CEPHALOSPORIN ANALOGUES (71) We, SHIONOGI & CO. LTD., a Japanese Body Corporate, of 12, 3-chome, Dosho-machi, Higashi-ku, Osaka, Japan, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement :- This invention relates to intermediates for the synthesis of cephalosporin analogues from penicillins, which intermediates are represented by the following formula:
wherein A is amino or subsrituted amino ; B is hydroxy or a carboxy-protecting group ; X is a group OR in whicZ a group represented by the formula :
in which Nu is a nucleophilic group ; R'is a group represented by the formula:
in which Ms is methylsulfonyl, Hal is halogen and R2 is optionally substituted alkyl or aryl ; and Y is hydrogen or methoxy; provided that (a) when R is
A is in the 3a position and Y is in the 3ss position or A is in the 3, position and Y is 3a-methoxy ; and (b) when R is-CH2COCH2Nu and R1 is =PR23, A is in the 3e position and Y is in the 3ss position or A is in the 3, B position and Y is 3 -methoxy.
The invention also includes compounds as defined above except that R'is any alkylidene group other than isopropylidene. This class of compounds is not preparable from penicillins, unlike the above-defined intermediates.
The amino substituent (s) in the substituted amino group which may be represented by A at position 3 can be selected from known side chains of natural or synthetic penicillins or cephalosporins, or their equivalents (e. g. acyl, hydrocarbyl, hydrocarbylidene, organic silyl or sulfenyl groups, or like amino substituents which are conventional in the field of cephalosporin or penicillin chemistry). There is a wide variety of possible groups A since they generally have little direct relationship with modification of the substituents at positions 1 or 2.
Representative acyl groups as amino substituents in groups A include the following groups :- 1) (C, to C,,,) alkanoyl ; 2) (C2 to C,) haloalkanoyl ; 3) azidoacetyl or cyanoacetyl ; f) acyl groups represented by the following formula: Ar-CQQ'-CO- in which Q and O'are each hydrogen or methyl and Ar is phenyl, dihydrophenyl, or a monocyclic heterocyclic aromatic group containing from 1 to 4 hetero atoms selected from nitrogen, oxygen, and/or sulfur atoms, and each is optionally substituted by an inert group (e. g. Cl to C3)-alkyl, trifluoromethyl, cyano, aminomethyl, optionally protected carboxymethylthio, hydroxy, (C1 to C3) alkoxy, (Cl to Cijacytoxy, chlorine, bromine, iodine, fluorine, or nitro); 5) 2-sydnon-3-acetyl or (4-pyridon-1-yl) acetyl; 6) acyl groups represented by the following formula: Ar-G-CQQ'-CO- in which G is oxygen or sulfur and Ar, Q, and Q'are as defined above ; 7) acyl groups represented by the following formula :
in which Ar is as defined above and T is i) hydroxy or (Cl to C,,,) acyloxy; ii) carboxy, (C to C78alkoxycarbonyl, mono-or di-cyclic carbo-or hetero-cyclic aralkoxycarbonyl including indanvloxycarbonyl, mono-or di-cyclic carbo-or heterocyclic aryloxycarbonyl, (C1 to C, lalkanovloxy (C, to C3) alkoxycarbonyl, cyano, or carbamoyl ; or iii) sulfo or (C1 to C Dalkoxysulfonyl : 8) acyl groups represented by the following formula :
in which W and W'are each hydrogen or an amino substituent re. g. (C. to C, alkoxy- carbonyl, (C3 to C@) cycloalkyl (C@ to C@0alkoxycarbonyl, (C5 to C4)cycloalkoxy- carbonyl, (C, to C.,)-alkylsulfonyl (C, to C) alkoxycarbonyl, halo (C, to C :) alkoxy- carbonyl, mono-or di-cyclic carbo-or heterocvclic aralkyloxycarbonyl inchiding carbo- benzoxy and diphenylmethocarbonyl, (C, to Cl") alkanoyl, mono-or di-cyclic carboor heterocyclic aromatic acyl optionally substituted by an inert group (e. g. hydroxy, (Ct to C10) alkanoyloxy, halogen, (C, to CBalkvl. (Cl to C) hydroxyalkyl or trifluoro methyl), pyronecarbonyl, thiopyronecarboyl, pyridonecarbonyl, carbamoyl, guanidino carbonyl, optionally substituted ureidocarbonyl (e. g. 3-methyl-2-oxo-imidazolidin-1 ylcarbonyl or 3-methanesulfonyl-2-oxo-imidazolidin-1-ylcarbonyl), optionally substituted aminoxalylcarbamoyl (e. g. 4-methyl-23-dioxopiperazin-1-ylcarbonyl or 4-ethyl2,3-dioxopiperazin-1-ylcarbonyl), or optionally substituted thioureidocarbonyl equivalents of the above-listed ureidocarbonyl groups]; or W-N-W' combined together represent phthalimido, maleimido, or enamino derived from an enolizable carbonyl compound (e. g. C5 to C10) acetoacetates, (C4 to C10) acetacetamides, acetylacetone, acetoacetonitrile or 1,3-cyclopentanedione), and Ar is as defined above ; 9) acyl groups represented by the following formula:
in which E is hydrogen or (C1 to C,) alkyl and Ar is as defined above; 10) 5-aminoadipoyl ; 5-aminoadipoyl protected at the amino group (e. g. with (Cl to C,") alkanoyl, mono-or di-cyclic carbo-or heterocyclic aroyl or aralkanoyl, (C, to C5)haloalkanoyl, or (C2 to C", Zalkoxycarbonyl) ; or 5-aminoadipoyl protected at the carboxy group (e. g. with (Cl to C5) alkyl or mono-or di-cyclic carbo-or heterocyclic aryl or aralkyl) ; each being optionally substituted by (C1 to Cl) a ! kyl, (Ci to C5) alkoxy, halogen, or nitro ; and 11) acyl groups represented by the following formula: L-O-COin which L is an easily removable optionally substituted (Cl to Cl,,) hydrocarbyl group (e. g. t-butyl, 1,1-dimethylpropyl, cyclopropylmethyl, I-methylcyclohexyl, isobornyl, 2-alkoxy-t-butyl, 2,2,2-trichloroethyl, benzyl, naphthyl, p-methoxybenzyl or pyridylmethyl).
ALternatively, the amino substituent in the group A can be a diacyl group derived from a (C, to Cl0) polybasic carboxyNc acid.
Other possible amino substituents in the substituted amino group which may be represented by A include (C, to C. ; J optionally substituted hydrocarbyl (e. g. methyl, ethyl, propyl, tertiary butyl, trityl, methylidene, benzyidene, 1-halo-2-phenylethylidene, 1-alkoxy-2-phenylethylidene, 3,5-di-t-butyl-4-hydroxybenzylidene or o-hydroxybenzylidene), and (C2 to C10)organic silyl (e. g. trimethylsilyl).
Groups convertible into amino or amido (e. g. azido, isocyanato or isocyano) are also included in the scope of group A.
Two amino group substituents (when group A is substituted amino) can be com bined to form a ring structure.
More preferred acyl moieties in the group A when this represents acylamino include: phenylacetyl, phenoxyacetyl, 2-thienylacetyl, 3-thienylacetyl, O-formylmandeloyl, N-t-butoxycarbonyle-phenylglycyl, N-2,2,2-trichloroethoxycarbonyl-&alpha;-phenylglycyl, N-diphenylmethoxycarbonyl-&alpha;-phydroxyphenylglycyl, N-t-butoxycarbonyl-&alpha;-p-(p-methoxybenzyloxy)phenylglycyl, a-phenylmalonyl, a-t-butoxycarbonyl-a-phenyracetyl, a- (5-indanyl) oxycarbonyl-a-phenylacetyl, &alpha;-benzyloxycarbonyl-&alpha;-phenylacetyl, a-p-methoxybenzyloxyor-phenylacetyl, &alpha;-diphenylmethoxycarbonyl-&alpha;-phenylacetyl, q-diphenylmethoxycarbonyl-a-p-hydroxyphenylacetyl, &alpha;-diphenylmethoxycarbonyl-&alpha;-(3,4-dihydroxyphenyl)acetyl, a-t-butoxycarbonyl-a-p-acetoxyphenylacetyl, a-acetoxymethoxycarbonyl < -p-propionyloxyphenylacetyl, &alpha;-diphenylmethoxycarbonyl-&alpha;-p-butyryloxyphenylacetyl, &alpha;-t-butuoxycarbonyl-&alpha;-(p-methoxybenzyloxyphenylacetyl, tr-benzyloxycarbonyl-a- (p- (p-nitrobenzyloxy) phenylacetyl, er-diphenylmethoxycarbonyls-p- (p-methoxybenzyloxy) phenylacetyl, a- (p-methoxybenzyloxy) carbonyl--,-,-p (p-methoxybenzyloxy) phenylacetyl, a-t-butoxycarbonyl-a-p-benzyloxyphenylacetyl, &alpha;-t-butoxycarbonyl-&alpha;-(2-thienyl)acetyl, a-phenoxycarbonyl-a- (2-thienyl) acetyl, a-diphenylmethoxycarbonyl-a- (2-thienyl) acetyl, &alpha;-t-butoxycarbonyl-&alpha;-(3-thienyl)acetyl, a- (5-indanyl) oxycarbonyl < - (3-thienyl) acetyl, &alpha;-benzyloxycarbonyl-&alpha;-(3-thienyl)acetyl, &alpha;-p-methoxybenzyloxycarbonyl-&alpha;-(3-thienyl) acetyl, a-diphenylmethoxycarbonyls- (3-thienyl) acetyl, N- (4-oxothiopyrane-3-carbonyl)-&alpha;-hydroxyphenylglycyl, N- (4-ethyl-2, 3-dioxopiperazin-1-yl) carbonyl- -phenylglycyl, N- (3-methanesulfonyl-2-oxoimidazolidin-1-yI) carbonyl-a-phenylglycyl, N-amidinoaminocarbamoyl-a-phenylglycyl, t-butoxycarbonyl, cyclohexyloxycarbonyl, cyclopropylmethoxycarbonyl, methanesulfonylethoxycarbonyl, isobornyloxycarbonyl, and carbobenzoxy.
In one preferred class of compounds of the invention, A is selected from amino, phenylacetamido, phenoxyacetamido, 2-thienylacetamido, 3-thienylacetamido, O-formylmandelamido, N-protected a-phenylglycinamido, carboxy-protected a-phenylmalonamido, carboxy-protected &alpha;-(p-hydroxyphenyl)malonamido, carboxy-and hydroxyprotected &alpha;- (p-hydroxyphenyl) malonamido, carboxy-protected er- (2-thienyl) malonamido, carboxy-protected (3-thienyl) malonamido, N- (4-oxothiopyrane-3-carboxyl)- a-phenylglycinamido, N- (4-ethyl-2, 3-dioxopiperazin-1-yl)-carbonyltphenylglycin- amido, N- (3-metbanesulfonyl-2-oxo-imidazolidin-1-yl)-carbonyl-a-phenylglycylamido, &alpha;-guanidino-carbonyl-&alpha;-phenylglycinamido, and carboxylic acylamino.
The group B is hydroxy when the group COB is a carboxy group.
The group B can alternatively represent a carboxy-protecting group. Thus, group B can, for example be an oxygen function (for example Cl to Ct0) alkoxy e. g. methoxy, ethoxy or t-butoxy ; mono-or di-cyclic carbo-or heterocyclic aralkoxy (e. g. benzyloxy, methoxybenzyloxy, nitrobenzyloxy, diphenyl methoxy or trityloxy) ; mono-or di-cyclic carbo-or hetero-cyclic aryloxy (e. g. phenoxy or naphthyloxy) ; (Cl to C10) organometalloxv (e. g. trimethylstannyloxy, dimethylchlorosilyloxy or trimethylsilyloxy) ; (C, to C,,,) organic or inorganic acyloxy; metaloxy or a group I, II or III metal (e. g. sodiooxy, potassiooxy or magnesiooxy) ; or (Cl to C, 2) ammonium oxy], a sulfur function for example, forming a Cl to Cul) thiol ester or thiocarboxy], a nitrogen function f forming e. g. amides (e. g. N- (C, to C ;) alkylamides ; N, N-di- (C@ to C5) alkylamides or amides with imidazole or phthalimide) ; hydrazides or azide], or may be selected from other carboxy-protecting groups.
Such groups may, where possible, possess a hetero atom selected from oxygen, sulfur, and/or nitrogen in their carbon skeleton, or may be unsaturated or substituted (e. g. by nitrogen-, oxygen-, sulfur-, carbon-or phosphorus functions or by halogens.
Among carboxy-protecting groups, typica) exampies are those forming (C1 to C5)haloalkyl esters, (C to C,,) acylalkyl esters, (C. to C,.,) alkoxyalkyl esters, (C, to C,") aminoalkyl esters, phenyl ester, carbo-or betero-cyclic mono-or di-cyclic aralkyl esters, esters with a (C, to C10) oxim. (C, to C gN-alkoxyamides, imides with a dibasic acid. N, N'-diisobutylhydrazide, alkali metal or alkaline earth metat satts, (C, to C,) alkylamine salts, or groups equivalent in effect to these groups.
It should be noted that in the above three paragraphs, specified numbers of carbon atoms with respect to pariciilar groups are for the overall group B.
Antibacterially preferred carboxy-protecting groups B include those which form acyloxymethyl esters, phenacyl esters, benzaldoxime ester, N, N-dimethylaminoethyl ester, methanesulfonylethyl ester, alkali metal salts, alkaline earth metal salts, and other groups equivalent in effect to these groups.
Preferred carboxy-protecting groups B include methoxy-t-butoxy, 2,2,2-trichloroethoxy, methanesulfonylethoxy, pivaloyloxymethoxy, phenylacyloxy, benzyloxy, pmethoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, indanyloxy, and alkali or alkaline earth metal oxy.
The halogen represented by Hal can be chlorine, bromine, or iodine, chlorine and bromine being preferered.
The group R2 can vary widely as the group is eliminated from the molecule after the reaction to form the bicyclic final products. The aryl groups which may be represented by R2 include carb-or hetero-cyclic mono-or di-cyclic aromatic groups (e. g. phenyl) optionally substituted by an inert group selected from, for example, halogen, (C, to C) alkyl, (C, t C5) alkoxy or nitro. The alkyl groups which may be represented by R2 include (C, to C10) alkyl optionally substituted by an inert group (e. g. halogen, (Cl to C,) alkoxy or cyano) The nucleophilic groups which may be represented by Nu include oxygen functions [e. g. hydroxy, acyloxy derived from C, to C10) organic acids or inorganic acids (e. g. carboxylic, sulfonic, phosphonic acids or mineral acids), C1 to C10) alkoxy, mono, or di-cyclic carbo-or hetero-cyclic aralkoxy, and monocyclic carbo-or hetero-cyclic aryloxy ; each optionally being substituted (e. g. by (C1 to CsDalkyl, (Cl to Cs) alkoxy, halogen, nitro, (Cl to C, acyloxy, (C2 to C5)alkoxycarbonyl, (C, to C5) acylamino, amino, hydroxy or carboxy (Cl to C3) alkyl optionally protected at the carboxy group)] ; sulfur functions [e. g. mercapto, acylthio derived from (C1 to C, 0) organic acids or inorganic acids (e. g. carboxylic, sulfonic, phosphonic, carbamic or mineral acids), (C, to C10)alkylthio mono-or di-cyclic carbo-or hetero-cyclic aralkylthio, and, and mono or dicyclic carbo-or hetero-cyclic arylthio ; each being optionally substituted (e. g. by (C1 to Cs) alkyl, mono-cyclic carbo-or hetero-cyclic aryl, (C1 to Cs) alkoxy, halogen, nitro, (Cl to C5) acyloxy, (C2 to Cs) alkoxycarbonyl, optionally substituted carboxy- (C, to C3)alkyl, (C1 to C1o7 alkoxycarbonyl- (C1 to C5) alkyl, mono-or dicyclic carbo-or heterocyclic aralkoxy carbonyl- (C to Ca) alkyl, (C1 to C,) acylamino, amino or hydroxy) ; nitrogen functions [e. g. amino, azido, hydrazo, acylamino derived from (Ci to C12) organic or inorganic acids, (C1 to C5)-alkylamin, mono-or di-cyclic carbo-or hetero-cyclic alkylamino or arylamino ; each being optionally substituted (e. g. by hydroxy, (C, to Cs) a ! kyl, : to C5) alkoxy, halogen, nitro, (C2 to C5) alkoxycarbonyl, (Cl to C) acylamino o amino) ; and halogens (e. g. chlorine, bromine and iodine).
Preferred oxygen functions are hydroxy, (C1 to C8)-organic acyloxy, and (Cl t C alkoxy. Preferred sulfur functions are (C 1to C,) organic acylthio, (C1 to Cs- alkylthio, benzylthio, phenylthio, and heterocyclic arylthio containing 1 to 4 hetero atcms selected frcm oxygen, nitrogen, and/or sulfur, each being optionally substituted by (C1 to Ces) alkyl, mono-cyclic carbo-or hetero-cyclic aryl, (C, to C,) alkoxy- carbonyl (Cl to C) alkyl, mono-or di-cyclic carbo-or heterocyclic aralkoxycarbonyl (Cl to C3) alkyl, or halogen. Preferred nitrogen functions are azido and pyridinium.
Preferred halogens are chlorine and bromine.
More specific preferred nucleophilic groups represented by Nu include hydroxy, acetoxy, acetyloxy, prcpionyloxy, methoxy, ethoxy, butoxy, mercapto, acetylthio, propionylthio, amidinothio, methylthio, benzylthio, phenylthio, tetrazolylthio, methyl tetrazolylthio, butyltetrazolylthio, pentyltetrazolylthio, phenyltetrazolylthio, optionally protected carboxymethyltetrazolylthio (e. g. t-butcxycarbonylmethylenetetrazolylthio and diphenylmethoxycarbonylmethyltetrazolylthio, thiadiazolylthio, methylthiadiazolyl- thio, diphenylmethoxycarbonylmethylthiadiazoylthio, triazolylthio, alkyl-dihydroxytriazinlylthio, azido, chloro, and bromo.
When one or more of the groups A, B, Z and Nu has/have reactive functional groups, such, reactive groups can be protected for and during the reactions involved in making the cephalosporin analogues which may be made from the present compounds. Afterwards, the protecting groups can be removed by conventional deprotection procedures.
Some representative specific compounds according to the present invention include the compounds represented by the following formulae:
wherein A is phenylacetamido, phenoxyacetamido, or benzyloxy carbonamido; B is diphenylmethoxy or benzyloxy; Hal is a halogen (e. g. chlorine or bromine) ; Nu is tetrazol-5-ylthio, 1-methyltetrazol-5-ylthio, 2-methyltetrazol-5-ylthio, 1-isobutyltetrazol-5-ylthio, 1-phenyltetrazol-5-ylthio, 1-carboxymethyltetrazol-5-ylthio, 1-t butoxycarbonylmethyltetrazol-5-ylthio, 2-t-butoxycarbonylmethyltetrazol-5-ylthio, 1, 3, 4-thiadiazol-5-ylthio, 2-methyl-1-, 3,4-thiadiazol-5-ylthio, 1-diphenylmethoxycarbonyl methyl-tetrazol-5-ylthio, 1, 2,3-triazol-4-yl-thio, hydroxy, methoxy, acetoxy, chloro or bromo; and Y is hydrogen or methoxy.
Other typical examples of compounds according to the present invention include the compounds represented by the following formulae:
wherein A is a phenylacetamido, phenoxyacetamido, or benzyloxycarbonamido ; B is diphenylmethoxy or benzyloxy ; Hal is halogen (e. g. chlorine or bromine) ; and Y is hydrogen or methoxy.
Other preferred compounds in accordance with the invention are referred to in the specific Examples (see below).
The following specific terms used herein have the meanings specified below unless otherwise stated: alkyl : Straight, branched or cyclic (C, to C, O) alkyl, ptionally being a substituent as defined below; for example"alkyl"includes methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, t-butyl, cyclopropylmethyl, pentyl, isoamyl, cyclopentylmethyl, hexyl, 2-methylpentyl, cyclohexyl, heptyl, isoyoctl, nonyl, decyl, cyclohexylbutvl, ethylcyclo- pentylpropyl and cycloheptyl. This definition is applicable to alkoxy, alkylthio, alkyl- amino, including dialkylamino), aralkyl, and other groups containing an alkyl moiety. acyl : An acyl group derived from a (C, to Cz") organic acid or inorganic acid including aliphatic, araliphatic, aromatic and mineral acids (e. g. carboxylic, sulfonic, sulfinic, phosphonic, carbonic, carbamic, nitric, sulfuric, phosphoric, halogenic and hydrohalogenic acids). This definition is applicable to acyloxy, acylthio, acylamino, (including diacylamino), and other groups containing an acyl moiety. aryl : A monocyclic or dicyclic carbocyclic or heterocyclic aromatic group containing up to 10 carbon atoms in the skeleton and optionally having a substituent. Hetero cyclic aromatic groups can have a hetero atom selected from oxygen, sulfur, and/or nitrogen; for example,"aryl"includes monocyclic furyl, thienyl, pyrryl, oxazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyt, thiazolyl, isothiazolyl, thiodiazolyl, thiatriazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl and phenyl, and dicyclic naphthyl, quinotyl, isoquinolyl, benzo pyrimidyl, benzothienyl, benzothiazolyl, benzoisoxazolyl, benzotriazolyl, indenyl, pyrimidopyrimidyl and pyridopyridyl. This definition is applicable to aryloxy, arylthio, arylamino (including diarylamino), aralkyl, aroyl, aralkanoyl, and other groups con taining an aryl ~~ substituent : A substituent is a group or atom which links through carbon, nitrogen, sulfur, oxygen or halogen, including alkyl, aralkyl, aryl, acyl, carboxy, carboxyalkyl, acyloxyalkyl, hydroxyalkyl, mecaptoalkyl, aminoalkyl, acylaminoalkyl, cyano, hydroxy, alkoxy, acyloxy, aryloxy, aralkyloxy, oxo ; mercapto, sulfo, sulfonyl, sulfinyl, akylthio, aralkylthio, arylthio, acylthio; amino, alklamino, acylamino, aralkylamino, arylamino, nitro, hydrazo; and halogen. amino-or hydroxy-protecting group : a protecting group as already explained with respect to group A. carboxy-protecting group : A protecting group as already explained with respect to group B. protection of functional groups : When the groups A, B and Nu include other reacting functional groups, such reactive groups can be protected permanently or tem porarily for the purposes of use of the compounds in chemical reactions or for their utilization as drugs. Suitable groups can be introduced or removed by conventional protection or deprotection procedures using metbods well known in the art.
Many of the compounds represented by formula I can be prepared by a series of chemical processes which may be represented, for example, by the following reaction scheme :
A40CH2COCH2Nu ac AhOCH2COCH2Nu J Compound(E3 t- C p HOH (9) OD (10) OB y Y Y L A O CH2 CO CH 2Nu M A j zOC1I 2CO CH2Nu JL') < : H j 2 > IIal-oJ NC-. PR23 (11) COB (12) y lez CL CHZCfi-Cliz K A. OCHZCH-CHz Compouxld (2 0- > ANCHOH (13) H (1) CoB Y Y OH i A ; gOC1S2CIIC1I2Hal A4CI2lwUCH2Hal 1 L Or JCOnBal (16) ? PR23- > Compound 2 OB COB Y Compound P A''- Q IIZN,"O (17) COB (18) COB (17) COB (18) COB ? OCH A8moOIlR AwOR =R1 "1 p p R (19) (20) (20) wherein A, B, Hal, Nu, R, Rt, R2 and Y are as hereinbefore defined.
It will be appreciated that the first compound of formula I which would be produced by following the above scheme in sequence is the product of step A.
Each individual reaction from the above scheme or overall synthesis is described in the following sections A to R (excluding 0). The sections comprise general explanation, examples, a list of reaction conditions, as appropriate, and tables showing the physical constants of the products or compounds of this invention. It will be appreciated by the skilled man that other combinations of the individual reactions can be used to synthesize a compound (17) or a compound (18). In such cases, protective groups can be introduced and reaction conditions changed, as appropriate, for better protection of sensitive groups and for subsequent deprotection.
Compounds (18) can be reacylated in a conventional manner to gave compounds (17) wherein A is acylamino (which cephalosporin analogues are strongly antibacterial against gram positive and gram negative bacteria). For this purpose, A is preferably in the, S-position and Y is in the n-position and, more preferably, COB is a carboxyl group. Other stereoisomers at the 3-position are useful as intermediates for preparing such antibacterial compounds.
A. ETHERIFICATION.
This process comprises treatment of 4-halo-3-acylamino-2-oxoazetidin-1-acetic acids with propargyl alcohol, optionally substituted by halogen at the terminal acetylenic carbon, in the presence of a hydrogen halide acceptor (e. g. silver chlorate or silver tetrafluoroborate) in the presence of an inert solvent and preferably at from -30 C to 30 C for from 0.5 to 5 hours.
Example A.
To a solution of 537 mg of diphenylmethyl - B-chloro-3e-phenylacetamido-2- oxoazetidin-1-yl) sisopropylideneacetate in 3 mi of propargyl alcohol is added 500 mg of silver tetrafluoroborate at-23 C with stirring. After 1 hour, benzene and aqueous sodium bicarbonate are added thereto, and the mixture is stirred for a while and then filtered. The benzene layer is worked up in a conventional manner to yield diphenylmethyl a- (, 3-propargyloxy-3 -phenylacetamido-2-oxoazetidin-1- yl) - &alpha; - isopropylideneacetate.
25 mg of Benzyl &alpha; - (4ss - propargyloxy - 3&alpha; - phthalimido - 2 - oxoazetidin- 1-yl)-sr-isopropylideneacetate (NMR: # CDCl3 5. 38d (4Hz) lH, 5. 56d (4Hz) lH may be similarly prepared from 35 mg of benzyl - (43-chloro-3 (r phthalimido- 2 - oxoazetidin -1 -yl - &alpha; - iopropylideneacetate, 60 mg of zinc chloride, 0.2 ml of propargyl alcohol and 16 @l of N-methyl-morpholine at room temperature for 2 hours; and diphenylmethyl &alpha; - (4ss - propargyloxy - 3ss - phenylacetamido - 3&alpha;- methoxy-2-oxoazetidin-1-yl)-n-isopropylideneacetate (NMR: CDCI, 1.98s3H, 2.16s3H, 3.44s2H, 3.63brs3H, 4. Old (2Hz) 2H, 5. 33slH, 6.83brslH, 6.98slH, 7.32ml5H may also be similarly prepared from the corresponding 4ss - chlorocompound, zinc chloride, propargyl alcohol, and N-methylmorpholine.
B. LINDLAR HYDROGENATION.
This reduction is a conventional selective reduction of a triple bond to a double bond. Thus, for example, hydrogenation may be carried out under a hydrogen atmo sphere in a suitable solvent (e. g. an alcohol, an ester or an aqueous solvent) under atmospheric or elevated pressure and with a catalyst for selective hydrogenation (e. g. palladium on various carriers or a nickel catalyst, each being optionally deactivated with a heavy metal salt e. g. the acetate of nitrate of lead, bismuth or copper, or deactivated with acetone, pyridine, quinoline, or a mercaptan) until about 1 mole of hydrogen is consumed. Other types of reduction (e. g. electro-reduction, diazine or metal-proton reduction) can also be used to effect this selective reduction.
Example B.
A solution of 1.0 g of diphenylmethyl a- [4ss - (2-propynyl) oxy-3 -phenyl- acetamido-2-oxoaxetidin-1-yl]-a-ispropylideneacetate in 10 ml of methanol is catalytically hydrogenated in a hydrogen atmosphere with 0.25 g of 5% palladium calcium carbonate catalyst. The product is worked up in a conventional manner to yield 0.88 g. of diphenylmethyl (4ss-allylox-3a-phenylacetamido-2-oxo- azetidin - 1 - yl] - &alpha; - isopropylideneacetate (88% yield0. m. p. 110-112 C.
11.8 g of diphenylmethyl &alpha; - (4&num;-allytoxy-3,-phenylacetamido-2-oxo- azetidin-1-yl)-a-isopropylideneacetate (IR: v maxCHCL. 3430, 1776,1720,1679, 1632,1504 cm-1) are similarly prepared from 12.1 g of diphenylmethyl tz- (4ss- propargyloxy-3 l3-phenylacetamido-2-oxazetidin-1-yl)-a-isopropylidene- acetate in 50 ml of methanol and 500 ml of hydrogen in the presence of 5% palladium on calcium carbonate at room temperature for 1 hour ; diphenylmethyl a- (4ss-ally- oxy-3ss carbobenzoxyamino-2-oxoazetidin-1-yl)-a-isopropylideneacetate may also be similarly prepared from 26.5 g of diphenylmethyl a- (4ss-propargyloxy- 3ss &alpha; carbobenzoxyamino - 2 - oxoazetidin - 1 - yl) - &alpha; isopropylideneacetate (IR: &gamma;maxCHCl@ 3440, 1772,1720,1628,1505 cm-') in 100 ml of methanol and 1180 ml of hydrogen in the presence of 6.6 g of 5% palladium on calcium carbonate at room temperature for 50 minutes ; and diphenylmethyl &alpha; - (rss - allyloxy - 3ss- phenylacetamido-3a methoxy-2-oxoazetidin-1 yl)-a-isopropylideneacetate (IR: &gamma;maxCHCl. 1780, 1725, 1700,1495, cm') melting at 76-77 C may also be maux similarly prepared from the corresponding 4, 8 propargylazetidinone compound, hydrogen, and palladium on calcium carbonate in methanol.
C.
This oxidation may be effected by the action of oxidizing reagents capable of forming expoxides from ethylene compounds. Suitable oxidizing reagents for this process include organic or inorganic oxidizing reagents having oxido-reduction poten tials of at least + 1. 5 volt. Thus, for example, suitable reagents are organic or inorganic peracids, salts of otganic or inorgantc peracids, hydrogen peroxide, metal peroxides, and mixtures of hydrogen peroxide and acids having dissociation constants of at least 10-5 (e. g. acetic acid, formic acid, perchloric acid, trifluoroacetic acid and wolf rumates). Preferred organic peracids include percarboxylic acids and persulfonic acids (e. g. performic acid, peracetic acid, perpropionic acid, monopersuccinic acid, per camphoric acid, mcnoperphthalic acid, trifluoroperacetic acid, perbenzoic acid, m chtcro-perbenzoic acid, ~ m-nitroperbenzoic acid, and toluene-p-persulfonic acid); which acids are preferably used in an inert solvent at from 0 C to 40 C fcr from 1 to 10 hcurs. Preferable inorganic peracids include periodic acid and persulfuric acid. Alternatively, the epoxidation can be carried out by treating a halohydrin with a base. A halohydrin, e. g. as produced in accordance with the section hereinbelow headed HALOHYDRIN FORMATION, may be treated with a base (e. g. organic base or inorganic base) preferably at 0 C to 30 C for 10 to 60 minutes to form the epoxide.
Example C.
(1) Direct epoxidation.
To a solution of 0.88 g of diphenylmethyl a- (4ss allyloxy-3e-phenylacet- amido-2-ozoazetidin-1-yl) isopropylideneacetate in 9 ml of chloroform is added 0. 54 g of m-chloroperbenzoic acid and the mixture is allowed to stand at room temperature overnight. The reaction mixture is washed with an aqueous hydrogen sulfite solution, an aqueous sodium bicarbonate solution, and then water, dried, and concentrated. The residue is chromatographed on 20 parts by volume of silica gel and eluted with a mixture of benzene and ethyl acetate (4: 1) to yield 475 mg of diphenylmethyl a- [ (2, 3-epoxypropoxy)-3 < -phenylacetamido-2-oxoazetidin-1-yl]- a-isopropylideneacetate (51.7% yield). Crude starting material (147 mg ; ca. 17%), m. p. 110-112 C, is recovered.
(2) Via bromohydrin.
To a solution of 148 mg diphenylmethyl a- (3a-phenylacetamido-4ss- allyloxy-2-oxoazetidin-1-yl)-a isopropylideneacetate in 2.0 ml of dimethyl sulfoxide and 0.1 ml of water is added 60 mg of N-bromo-acetamide with ice cooling, and the mixture is stirred at room temperature for 1.5 hours and then ice cooled to. To this mixture is added 80 mg of potassium t-butoxide, and the mixture is stirred at the same temperature for 20 minutes, mixed with water, and extracted with ethyl acetate. The extract is worked up in a conventional manner to yield 120 mg of diphenylmethyl sr- [33r-phenylacetamido-4, Q- (2,3-epoxypropoxy)-2-oxo azetidin-1-yl]-a-isopropylideneacetate. IR : y CHC ; 3410, 1775, 1720,1680 cm-'. m. p. 114-115 (C. max Examples of other such reactions are given in Table D below.
D. EPOXIDE FISSION.
This fission comprises reaction of an epoxide with a nucleophilic reagent of the formula HNu (wherein Nu is a nucleophilic group), or with a reactive derivative thereof, to give a secondary alcohol substituted by Nu at the adjacent position.
The nucleophilic reagents which can be used include hydrogen azide, thioureas, thioamides, alcools (e. g. methanol, ethanol, isopropanol, butanol, or benzyl alcohol), carboxylic acids (e. g. acetic acid, propionic acid, phenylacetic acid, or benzoic acid), thiols (e. g. methanethiol, ethanethiol. dimethylaminoethanethiol, thiophenol, dinitro thiophenol, phenyfmethanethiol, methylimidazolethiol, dihydroimidazoiethiol, pyridinethiol, tetrazolethiol, methyltetrazolethiol, butyltetrazolethiol, phenyltetrazolethiol, triazolethiol, thiadiazolethiol, methylthiadiazoledithiol, indolethio, thiazolethiox benzo thiazolethiol, thienylthiol, oxadiazolethiol, carboxymethylthiadiazothiol, aminomethyl- thiadiazclethiGl, aminothiadiazolethiol, carbalkoxymethyltetrazolethiol ; t-butoxy- carbonylmethyltetrazolethiol, diphenylmethoxycarbonylmethyltetrazolethiol, or nitrophenyltetrazolethiol), amines (e. g. dimethylamine, aniline, or nitrotoluidine), aromatic compounds containing nitrogen (e. g. triazole, pyridine or pyridazine), and water. Suitable reactive derivatives of nucleophilic reagents include alkali metal salts or alkaline earth metal salts (e. g. lithium, sodium, potassium, calcium or magnesium salts, organic base salts (e. g. trimethylamine, N-methylmorpholine or tetramethylammonium hydroxide.
These reagents may be brought into contact with the epoxide preferably at about -10 C to 100 C for from 10 minutes to 2 hours in a solvent to give the objective compound according to conventional procedures. The reaction can be effected in the presence of a base or the ionic species Nu-and an acid.
Example D.
To a solution of 3.7 g of diphenylmethyl a- [4ss- (2,3-epoxvpropoxy)-3a phenylacetamido-2-oxoazetidin-'1-yll-a-isopropylideneacetate in 100 ml of chloroform is added 10 mI of hydrogen bromide and the mixture is stirred for 15 minutes. The reaction mixture is washed with water, dried, and concentrated to yield 4.9 g of crude diphenylmethyl a- [4ss- (3-bromo-2-hydroxypropoxy)- 3a phenylacetamido-2-oxoazetidin-1-yl]-a-isopropylideneacetate. IR : &gamma;maxCHCl3 3400, 1760,1720,1670 cm- max Examples of other such reactions are given in Table E below.
E. HALOHYDRIN FORMATION.
The e : bylene group can be converted to give the corresponding halohydrin by the action of a hypohalogenous acid scurce (e. g. N-halosuccinimide, N-haloacetamide, or hypophalites) in the presence of water, preferably from 10 C to 40 C for from 20 minutes to 3 hours and, if required, in the presence of an inert solvent.
Example E.
To a solution of 688 mg of diphenylmethyl-a- (3 -methoxy-3R-phenyl- acetamido - 4ss - allyloxy - 2 - oxoazetidin - 1 - yl) - &alpha; - isopropylideneacetate in 7 ml of dry dimethylsulfoxide, to which 55 ul of water is added, is added 336 mg of N-bromosuccinimide in small portions at from 15 C to 20 C, and the mixture is stirred at the same temperature for 1 hour. Ice water is added, and the mixture is extracted with a large amount of ethyl acetate. The extract is washed well with water, dried, and evaporated to yield 740 mg of diphenylmethyl ct (3a-methoxy-3, B- phenylacetamido - 4 - (2 - hydroxy - 3 - bromopropyl)oxy - oxoazetidin - 1 - yl] isopropylideneacetate as a colorless foamy material. IR: &gamma;maxChcl3 3600-3200, 1775, 1720,1690,1060 cm-1.
116 mg of Diphenylmethyl a- [4/ ?- (3-chloro-2-hydroxypropyxy)-3a- phenylacetamido-2-oxcazetidin-1-yl]-er-isopropylideneacetate (IR : y mas 3400,1775,1720,1680 cm-1) may be similarly prepared from 108 mg of the corresponding 4ss-allyloxyazetidinone compound, N-chlorosuccinimide, water and dimethyl sulfoxide for 30 minutes at room temperature; and diphenylmethyl &alpha; - [4ss - (3 bromo-2-hydroxypropoxy)-3 -phenylacetamido-2-oxoazetidin-1 yl]- &alpha; - isopropylideneacetate (IR : &gamma;maxCHCl3 3400, 1760,1720,1670 cm1) may also be similarly prepared from 1.05 g of thë corresponding 4ss-allyloxyazetidinone compound, 10 ml of dimethylsulfoxide, 90 ul of water, and 537 mg of N-bromosuccinimide at room temperature for 1 hour.
F. ACETYLENE HALOGENATION.
This process for attaching a halogen atom to an acetylene carbon can be carried out by treating an acetylene compound with a halogenating reagent (e. g. pyridine halogenium salts) preferably in an inert solvent, e. g. chloroform or methylene chloride, at from 10 C to 70 C for from 1 to 5 hours.
Example F.
To an ice cooled and stirred solution of pyridine iodium nitrate in chloroform is added 2.09 of diphenylmethyl &alpha; - [3&alpha; - phenylacetamido - 4ss - (2 - propynyl) oxy 2-oxoazetidin-1-yl]-a-isopropylidene acetate. After 5 minutes, the mixture is warmed up to room temperature, stirred for 2 hours, and poured into cooled dilute hydrochloric acid. The chloroform layer is worked up in a conventional manner to yield 2.00 g of diphenylmethyl a- [3a-phenylacetamido-4ss- (3-iodo-2 propynyl) oxy-2-oxoazetidin-1-yll-a-isopropylideneacetate, m. p. 134-137 C.
IR : Y max 3 3425, 2187,1777,1726,1686,1631,1094 cm-i.
Diphenylmethyl &alpha; - [3ss - phenylacetamido - 4ss - (3 - bromopropargyl) - oxy- 2 - oxoazetidin - 1 - yl] - &alpha; - isoprepylideneacetate (IR: &gamma;maxCHC1 3410, 2218, 1777,1722,1693,1632,1603,1587 cml) may be similarly prepared. These com pounds can also be produced by effecting reaction A (see above) using bromopropargyl alcohol as the reagent.
G. HYDRATION.
This process is carried out by treating an acetylene compound with water in the presence of a catalyst (e. g. mercuric sulfate, mercuric chloride, or mercuric acetate) in an aqueous solvent (e. g. aqueous diluted sulfuric acid), preferably at from-10 C to 100 C for from 15 minutes to 3 hours.
Example G.
To a solution of 601 mg of dipbenytmethyl - [3 -phenylaceiamido-43- (3- bromo-2-propynyl) oxy-2-oxoazetidin-1-yl]-a isopropylideneacetate in 95% aqueous methanol is added 7.7 ml of a 10% sulfuric acid solution of 0.13 mole of mercury sulfate, and the mixture is refluxed under heating for 1 hour, evaporated under reduced pressure, mixed with ice water and extracted with methylene chloride. The extract is worked up in a conventional manner to yield diphenylmethyl a- [3a-phenylacetamido-4ss- (3-bromo-2-oxopropyl) oxy-2-oxoazetidin yl]--isopropylideneacetate (603 mg). IR: y CDC13 3400, 1770, 1726,1675 cm-'." Examples of other such reactions are given in Table H below.
H. OXIDATION OF SECONDARY ALCOHOL.
This process can be carried out by treating a secondary alcohol with an oxidizing reagent to give the corresponding ketone The e oxidizing reagents which can be used include chromates, manganates, hypo halides, halogens, N-haloamides, N-haloimides, oxygen, dialkyl sulfoxide with an acid anhydride, cobaltic ions, pentavalent vanadium, cerium, aluminum alkoxides, per sulfates, or dinitrogen tetraoxide, and they can be used in various solvents for the oxidation reaction e. g. esters, ethers, ketones, halohydrocarbons, or hydrocarbon solvents or mixtures thereof. Chromium trioxide (especially the so-called"Jones reagent"com prising chromium trioxide in 6 to 1ON sulfuric acid) is one of the most feasible oxidizing reagents for this purpose, and is preferably used at from 0 C to 10 C for from 5 to minutes to 2 hours in a ketone solvent, e. g. acetone, or an ether solvent, e. g. dioxane.
Example H.
To a solution of 4.9 g of diphenylmethyl a- [4ss- (3-bromo-2-hydroxy- propoxy)-3a-phenylacetamido-2-oxoazetidin-1-yl] -isopropylideneacetate in 50 ml of acetone is added 5 ml of Jones reagent with ice cooling, and the mixture is stirred at 0 C for 30 minutes and then at room temperature for 30 minutes. Excess reagent is decomposed by the addition of isopropanol and the insoluble material is removed by filtration. The filtrate is worked up in a conventional manner to yield 4.75 g of crude diphenylmethyl a- [4, (3- (3-promo-2-oxopropoxy)-3a- phenylacetamido-2-oxoazetidin-1-yll-a-isopropylideneacetate. IR : y CHC1 3400,1770,1720,1675 cm-1. max Examples of other such reactions are given in Table I below.
I. OZONE CLEAVAGE.
The process can be carried out by treating an unsaturated compound with a suitable oxidizing reagent to give the corresponding oxo compound. Representative oxidizing reagents include hexavalent chromium oxidizing reagents, and a combination of glycol forming and glycol cleaving reagents. The most convenient reagent is ozone (to form an oxidation product called an ozonide) in combination with a subsequent treatment with a reducing reagent including inorganic reducing salts, hydrogen and catalysts, an amalgam of reducing metals, reducing metals and acids, or reducing organic substances including formaldehyde, alkyl sulfides, phosphines, or phosphites.
The reaction can be carried out in a conventional manner, and preferably by bubbling ozone into a solution of the starting material in an inert solvent (e. g. a haloalkane, an alkanoic acid, or an alkanooate solvent) at from-80 C to-5 C until the blue color of ozone appears or a satisfactory reaction is proved by e. g. thin layer chromatography. Then a reducing reagent (e. g. zinc or tin and acetic acid, or a lower alkyl sulfide) is added for reductively cleavage of the e thus-formed ozonide to give the objective oxo compound.
Example I.
Into a solution of 3.67 g of diphenylmethyl a-44ss- [3 (1-methyltetrazol- 5-yl) thio-2-oxopropyl]-3a-phenylacetamido-2-oxoazetidin-1-yl > isopropylideneacetate in 56.4 ml of methylene chloride is introduced ozone at-60 C until the color of the solution turns blue. The mixture is then mixed with 423 mi of dimethylsulfide at the same temperature, stirred at room temperature for 1 hour, washed with water, dried, and evaporated under reduced pressure to yield 3.45 g of diphenylmeLh. yl a-t4ss- [3- (I-methyltetrazol-5-yl) thio-2-oxopropyl] oxy3-a phenylacetamido-2-oxoazetidin-1-yl -a oxoacetate as a foamy material. IR :&gamma;maxCHCl3 3400, 1823, 1748, 1708 crri 1. protic substance (e. g. a mineral acid, an organic acid including formic acid and acetic acid, an alcohol, or water).
The reaction can be carried out in a conventional manner in a solvent inert to the reaction, preferably with zinc and acetic acid at from-30 C to 100 C for from 15 minutes to 2 hours.
Example J.
To a solution of 3.45-of diphenylmethyl 4fl- (1-methyl tetrazol - 5 - yl)thio - 2-oxopropyl]oxy - 3&alpha; - phenylacetamido - 2 - oxoazetidin- 1-yl > -a-oxoacetate in 15 ml of methylene chloride is added 15 ml of acetic acid.
The mixture is stirred with 5. 4-ouf activated zinc powder with ice cooling for 35 minutes, then stirred with a further 2.0 g of zinc powder at 13 C for 20 minutes. Solid material is filtered off, and the filtrate is washed with water, dried, and evaporated under reduced pressure to give 3.30 g of diphenylmethyl a- 4g- [3- (1-methyl trazol-5-yl) thio-2-oxopropyl ;-oxy-3a-phenylacetamido-2-oxazetidin- @ - yl @ - &alpha; - hydroxyacetate. IR : y maxCHCl3 3550-3200, 1786,1750,1678,1100 cm-1 Examples of other such reactions are given in Table K below.
K. HALOGENATION OR SULFONYLATION.
The halogenation process is carried out by contacting a hydroxy compound with a conventional halogenating reagent capable of substituting a hydroxyl group with halogen (e. g. a phosphorus trihalide, pentahalide, or oxyhalide, a thionyl halide, an oxalyl halide, or a hypohatogenous acid or its salts) preferably in an inert solvent and in the presence of an acid receptor at from -10 C to 40 C for from 15 minutes to 3 hours to give the corresponding halo compound.
Altematively, in the sulfonylation process, the hydroxy compound may be treated with a sulfonic acylating reagent (e. g. an alkyl or an aryl-sulfonic halide) in the presence of an acid receptor at from-20 C to 40 C for from 15 to 3 hours to give the corresponding sulfonyloxy compound.
Example K.
To a solution of 3.30 g of diphenylmethyl a-t4ss- [3- (1-methyltetrazol-5- yl) thio-2-oxopropyl] oxo-3a-phenylacetamido-2-oxoazetidin-1-ylX-a- hydroxyacetate in 35 ml of metbylene chlorine are added 0.48 ml of thionyl chloride and 0.45 ml of pyridine with stirring and ice-cooling, and the mixture is stirred for 30 minutes. The reaction mixture is washed with water, dried and evaporated under reduced pressure to yield 3.37 g of diphenylmethyl a-4ss- [3- (1 methyltetrazol- 5-yl) thio-2-oxopropyl] oxy-3 < r-phenylacetamido-2-oxozetidin-1-yl -a- chloroacetate as a foamy material. IR : y CHC13 3420,1800,1760,1680 cm-1. max Examples of other such reactions are given in Table L below.
L. PHOSPHORANYLIDENE INTRODUCTION.
This process is a part of a Wittig reaction. A halo compound may be treated with a phosphine of the formula (wherein R2 is optionally substituted alkyl or aryl) to give the corresponding phosphoranylidene compound.
The phosphine can, for example, be bis (2-cyanoethyl) phenylphosphine, tri (chlorophenyl) phosphine, tricyclohexyTphosphine, bisdiphenylphosphinylmethane, tri- n-butylphosphine, triethylphosphine, tri-n-octylphosphine, triphenylphosphine, tritolylphosphine, or trimethoxyethylphosphine. Triphenylphosphine is the most useful reagent for this puhpose, as the group thus introduced into the molecule is removed in a later stage of the overall synthesis and no complex structure is essential.
The reaction can be carried out in an inert solvent e. g. toluene, benzene, chloroform, tetrahydrofuran, or dioxane, and preferably at from 30 C to 120 C for from 1 to 10 hours.
Example L.
To a solution of 3.37 g of diphenylmethyl a-44ss- [3- (1-methyltetrazol 5-yl) thio - 2 - oxopropyl]oxy - 3&alpha; - phenylacetoamido - 2 - oxazetidin 1 - yl) - &alpha;- chloroacetate in 35 ml of dry methylene chloride is added 4.41 g of triphenylphosphine, and the mixture is heated under reflux in a nitrogen atmosphere for 4 hours. The reaction mixture is then poured into a mixture of 100 ml of ice-water and 10 ml of 5% aqueous sodium bicarbonate solution, and extracted with methylene chloride. The extract is washed with water, dried, and evaoorated to dryness under reduced pressure.
Examples of other such reactions are given in Table J below.
J. REDUCTION OF OXO GROUP.
This process is a conventional reduction of an oxo group to give the corresponding secondary alcohol. The reduction can be carried out by the action of a reducing reagent capable of reducing an oxo group to a secondary hydroxyl group. The reducing reagent can, for example, be a borohydride reducing agent (e. g. borane, sodium borohydride, potassium borohydride or sodium cyanoborohydride), hydrogen in the presence of a catalyst (e. g. palladium or platinum catalysts), an alkali metal alkylaluminium hydride or, most preferably, a metal (e. g. zinc, tin, iron, aluminum, or magnesium) and a The residue is chromatographed on silica gel to give 2. 09 g of diphenylmethyl a--J4/ ?- [3- (1-methyltetrazol-5-yl) thio-2-oxopropylloxy-3a-phenyl- acetamido-2-oxoazetidin-1-yl > -a-triphenylphosphoranylideneacetate.
Examples of other such reactions are given in Table M below.
M. NUCLEOPHILE EXCHANGE.
This process can be effected by substituting a reactive nucleophile with a more stable nucleophile by treatment with a salt of the more stable nucleophile to give the desired compound. Thus, for example, a compound where Nu is halogen may be treated with an alkali metal heteroaromatic thiolate to give the corresponding compound wherein Nu is a heteroaromatic thio group. The reaction is preferably carried out at from-10 C to 40 C for from 10 minutes to 3 hours.
Example M.
To a solution of 603 mg of diphenylmethyl [3a-phenylacetamido-4fl- (3-bromo-2-oxopropyl) oxy-2-oxoazetidin-I-yl]-a-isopropylidene- acetate and 124 mg of 5 mercapto-1-methyltetrazole in 6 ml of acetone is added 135 1 of triethylamine with ice cooling, and the mixture is stirred for 30 minutes.
The reaction mixture is diluted with ice water and extracted with methylene chloride.
The extract is worked up in a conventional manner to yield 161 mg of diphenylmethyl - [3a-phenylacetamido-4ss-g 3- (I-methyltetrazol-5-yl) thio-2oxopropyl-oxy-2-oxoazetidin-I-yl]-isopropylideneacetate.
Examples of other such reactions are given in Table N below.
N. CYCLIZATION.
This process is another part of intramolecular Wittig reaction.
The reaction can be carried out by warming a phosphoranylidene compound having an oxo group at a suitable position in an inert solvent, e. g. dioxane, tetrahydrofuran, benzene, or dichloromethane at from 50 C to 100 C for from 5 to 20 hours.
Example N.
A solution of 2.09 g of diphenylmethyl a-44ss- [3- (1-methyltetrazol-5- yl) thio-2-oxopropyl] oxy-3er-phenylacetamido-2-oxoazetidin-1-ylt triphenylphosphoranylideneacetate in 20 ml of dioxane is refluxed for 17 hours under nitrogen gas. Solvent is removed by evaporation under reduced pressure, and the residue is purified by silica gel chromatography to yield 0.688 of diphenylmethyl-3- (1- methyltetrazol-5-yl (thiomethyl-7a-phenylacetamido-1-dethia-1-oxo-3- cephem-4-carboxylate as crystals melting at 100 to 105 C. IR: v CHCb 3400, 1790,1718,1685 cm-l. 7 max Examples of other such reactions are given in Table P below.
P. DEACYLATION The acyl group of an acylamino-1-dethia-1-oxa-3-cephem-4- carboxylic acid can be removed conveniently according to conventional methods.
The most preferred method consists of 1) dissolving the starting material in an inert solvent (e. g. methylene chloride or chloroform) and stirring it with an iminohalogenating reagent (e. g. phosphorus pentachloride) in the presence of a base (e. g. pyridine) at low temperature (e. g. 50 C to 0 C) for from 0.5 to 5 hours ; 2) diluting with an excess amount of an alcohol (e. g. methanol, ethanol, or isobutanol) and keeping at a temperature of from 0 C to 40 C for 0.5 to 5 hours; and 3) treating with water for from 5 to 60 minutes at room temperature. The last step can be omitted when the subsequent work-up utilizes water.
Example P.
To a solution of 500 mg of diphenylmethyl-1 dethia-oxo-3- (1-methyl tetrazol-5-yl) thiomethyl-lxr phenylacetamido-3-cephem-4-carboylate in 12 ml of dry methylene chloride are added 0.136 ml of pyridine and 0.349 g of phophorus pentachloride at-20 C, and the mixture is stirred at the same temperature for 30 minutes and then at room temperature for 25 minutes. The reaction mixture is stirred with 6.0 ml of anhydrous methanol at-20 C and at room temperature for 1 hour. Water (2.67 ml) is added, and the mixture is poured into 15 ml. of 5% sodium bicarbonate and 50 ml of ice water, and extracted with methylene chloride. The extract is washed with water, dried, and evaporated to dryness under reduced pressure.
The residue is chromatographed on silica gel to give 333 mg of diphenylmethyl I--oxadiethia-3- (1-methyltetrazol-5-yl) thio-methyl-7a-amino-3- cepbem-4-carboxylate as foamy material. IR :"CHCL3 3380, 1785,1720 cm-1. max Examples of other such reactions are given in Table Q below.
Q. METHOXYLATION.
The methoxylation of an a- (3-acylamino-4-OR-2-oxoazetidin-1- yl)- -substituted acetic acid and its derivatives can be carried out by various methods. The most convenient method is to halogenate at the amido nitrogen with from 1 to 2 mole equivalents of a hypohalogenous halogenating reagent (e. g. t-butyl hypochlorite) at a low temperature (e. g. at-50 C to 0 C), and then treating with from 1 to 2 mole equivalents of an alkali metal methoxide (e. g. lithium methoxide) in methanol at the same temperature to give the desired 3a-methoxy compound in high yield.
Example Q.
To a solution of 139 mg of diphenylmethyl < - (3a-phenylacetamido-4/3- propargyloxy-2-oxoazetidin-1-yl)--isopropylideneacetate in 2.7 ml of methylene chloride cooled to-40 C are added 48 1 of t-butyl hypochlorite and then a solution of lithium methoxide in methanol (2 Mole/I), and the mixture is. stirred for about 40 minutes. The mixture is then slightly acidified with about ZO, ut of acetic acid, diluted with methylene chloride, washed with water, an aqueous solution of sodium bicarbonate, an aqueous sodium sulfite solution, and a saturated saline, dried, and evaporated under reduced pressure to give 144 mg of diphenylmethyl a- (3 -methoxy-3, B-phenylacetamido-4iR-popargyloxy-2-oxoazetidin-1- yi-a isopropylideneacetate. NMR: CDCI 1.98s3H, 2,16s3H, 2,16sH+H, 3,44s3H, 3.63brdZH, 401d (2Hz) 2H, 5. 33slET, 6.83brslH, 6.98slH, 7.32ml5H.
Examples of other such reactions are given in Table R below.
For the preparation of antibacterially active 1-oxadethia-cephalosporins (17), the 4/ ?-OR group in the intermediates is essential. In the primary research, a compound having 3, 8-A, 3cr-hydrogen as Y, and 4-Hal was used as the starting material giving an epimer mixture (up to about 1: 1) at the 4-position. The inventors assumed that the introduction of OR occurs predominantly from the trans side of group A, and succeeded in proving this assumption by showing 43-OR introduction when A is in the 3a-position. The products served as well as the sus-A isomers did at starting materials for a series of processes such as hereinabove described and in much better overall yield from compounds (1) to (17) when com pared with the 3ss-A series. It is to be noted that"inversion"of the substituent at the 3-position can be effected to give tte antibacterially preferred 3fl-A series. These processes in the 3tr-A series are one aspect of this invention. The inventors have also, of course, successfully introduced the group Nu into tne molecule in several ways as described hereinabove to thereby prepare more effective 1-oxadethiacephalosporins (17). This introduction of the group Nu and succeeding steps for preparing compounds (17) are an important aspect of this invention.
The introduction of methoxy as group Y in the 3e-position to give compounds (20) from compounds (19) was found to be attainable as in the case of penicillins and cephalosporins in spite of the absence of the additional five-or six-membered ring present in the case of the antibiotics.
A series of reactions starting from compounds (20) to give compounds (17) is a further aspect of this invention. The skilled man will have no difficult in devising various suitable reaction schemes for the above information.
From the above, it will be apparent that depending upon the starting material chosen the reactions described and exemplified above may be employed in many possible alignments to prepare antibacterially active compounds and the compounds of the invention. In the following pages statements of invention are given for many possible processes using the reactions described. Other possible processes will be apparent to the skilled man in exercising his skill upon the process information already given. The various Tables (D, E, H, I, J, K, L, M, N, P, Q and R) referred to above are given after the following process statements and before the claims.
The invention further provides a process for the preparation of a compound of the formula.
wherein A, B and Y are as defined above, which. process comprises reacting a compound of the formula:
with propargyl alcohol, optionally substituted by halogen at the terminal acetylenic carbon.
Also included in the invention is a process for preparing a compound of the formula:
wherein A, B, Hal and Y are as defined above, which process comprises reacting a compound of the formula :
with a halogenating reagent.
Further provided is a process for preparing a compound of the formula:
wherein A, B, Hal and Y are as defined above, which. process comprises treating a compound of the formula:
with water in the presence of a catalyst.
The invention also includes a process for the preparation of a compound of the formula:
wherein A, B, Y and Nu are as defined above, which process comprises treating a compound of the formula :
with a salt of nucleophile Nu.
The invention further provides a process for preparing a compound represented by the formula:
wherein A, B and Y are as defined above, which process comprises reducing a compound represented by the formula:
Also included in the invention is a process for preparing a compound represented by the formula :
wherein A, B and Y are as defined above, which process comprises epoxidizing a compound represented by the formula :
or treating a compound of the formula:
which is a halohydrin, with a base.
The invention further includes a process for preparing a compound represented by the formula :
wherein A, B, Nu and Y are as defined above, which process comprises either treating a compound represented by the formula:
with a nucleophilic reagent represented by the formula: HNu, or with a reactive derivative thereof, or reacting a hypohalogenous acid with a compound of the formula:
Another embodiment of the invention provides a process for preparing a compound represented by the formula :
wherein A, B, Nu and Y are as defined above, which process comprises oxidizing a compound represented by the formula :
Another embodiment provides a process for preparing a compound represented by the formula:
wherein A, B, Nu and Y are as defined above, which process comprises oxidizing a compound represented by the formula:
In yet another embodiment there is provided a process for preparing a compound represented by the formula
wherein A, B, Nu and Y are as defined above, which process comprises reducing a compound represented by the formula:
Still another embodiment is a process for preparing a compound represented by the formula :
wherein A, B, Nu, Hal and Y are as defined above, which process comprises halogenating a compound represented by the formula:
In another process of the invention, similar to the process mentioned immediately above, sulfonylation may be employed instead of halogenation.
In a further embodiment there is provided a process for preparing a compound represented by the formula :
wherein A, B, Nu, R2 and Y are as defined above, which process comprises treating a compound represented by the formula :
or a similar compound with a sulfonyloxy group instead of halogen, with a phosphine compound represented by the formula: PR2 19 The invention also provides a process for preparing a compound of the formula :
wherein A, B and Y are as defined above, which process comprises oxidizing a compound of the formula :
Further provided is a process for preparing a compound of the formula :
wherein A, B and Y are as defined above, which process comprises reducing a compound of the formula:
The invention additionally includes a process for preparing a compound of the formula :
wherein A, B, Hal and Y are as defined above, which process comprises subjecting a compound of the formula:
to epoxide ring fission and halogenation.
This process may, of course, be applied using sulfonylation instead of halogenation.
Also provided is a process for preparing a compound of the formula:
wherein A, B, R2, Hal and Y are as defined above, which process comprises reacting a compound of the formula :
with a compound of the formula PR23.
The invention further provides a process for preparing a compound of the formula:
wherein A, B, R and Y are as defined above and Nu is halogen, which process comprises oxidizing a compound of the formula :
The invention also provides a process for preparing a compound represented by the formula:
wherein A, B, Nu and Y are as defined above, which process comprises warming a compound of the formula:
RI being as defined above, in an inert solvent, optionally followed, when A is substituted amino, by deacylation.
It will be appreciated that the starting material for this last process may, as with any of the processes of the invention, be obtained by an appropriate alignment of the previouslv mentioned process (es), if any, starting from any desired stage.
Yet a further process provided by the invention is a process for preparing a compound of the formula :
wherein A, R, R'and B are as defined above, which process comprises methoxylating a compound of the formula:
The invention further provides a process for preparing a compound (I) wherein X is OR, R being any hydrocarbyl group included within the definition of R given above, and
which process comprises etherifying a compound (I) wherein X is halogen and
(obtained, for example, by a penam cleavage reaction as discussed above). Such etherification may be achieved by treatment with the alcohol ROH. The product of the etherification may be subjected to methoxylation, e. g. by the use of an alkali metal methoxide, to produce a 3e2-methoxy-3ss-nitrogen product. The etherification product can alternatively, be hydrogenated to reduce or eliminate the degree of unsaturation in the group R. As yet another process covered by the present invention, the product of the etherification can be subjected to"hydration"to result in a compound (I) with group R being
A further process which can utilize the etherification product mentioned above is an "acetylene halogenation"wherein R in the starting material is-CH-C-CH and the starting material is reacted with a halogenating agent to give a compound wherein R is-CH2-C#CHal (i.e. one example of the class wherein R is-CH2-C---CNu).
The product obtainable by the last-mentioned"acetylene halogenation"may be subjected to"hydration"and nucleophilic substitution to produce compounds (I) wherein R is--CH2COCH2Nu. Furthermore, the"acetylene halogenation"product may be methoxylation to give a 3 -methoxy product. Similar methoxylation may be carried out with the product of the hydrcgenation mentioned earlier (i. e. hydrogenation of the etherification product). Alternatively, the hydrogenation product may if unsaturation still exists in the group R, be epoxidized to produce a product wherein R is-. CHZCH-CH,.
0 The epoxidation product may, of course, be methoxylated to produce a 3a-methoxy product.
The above-mentioned epoxidation product may, alternatively, be subjected to epoxide ring fission by the action of a compound HNu (e. g. a hydrogen halide) to give a compound (I) wherein
In appropriate cases the product of such fission may be oxidized to give a compound (I) wherein R is CH, COCH, Nu.
Compound (I) wherein
may be subjected to oxidation (ozonization) to give the corresponding compounds (I) wherein R'is =O. Oxidation (ozonization) of compounds (I) wherein
produces compounds (I) wherein R is-CHz-CO-CHNu. Where ozonization has resulted in compounds (I) wherein R'is =O, subsequent reduction produces compounds (I) wherein
Compounds (I) wherein
may be halogenated or methylsulfonylated to give compounds (I) wherein
respectively.
The action of a phospbine PR2^ on a compound (I) wherein
may be used to produce a compound (I) wherein Rl is = Pur23.
Cyclization of a compound (I) wherein RI is =PR23 and R is-CHzCOCHNu may be employed to produce a cephem ring structure and the product of such cyclization may be deacylated if A is acylamino, a salt formed if A is amino, a free carboxy group-COB protected, a protected carboxy group-COB deprotected or a ring substituent Nu interchanged with an alternative ring substituent Nu. Alternatively, or in addition, methoxylation may produce a 7 < r methoxy cephem structure.
Also included in the present invention is a pharmaceutical or veterinary formulation comprising as the active ingredient a compound in accordance with the invention and having antibacterial activity or a cephalosporin analogue prepared from a compound in accordance with the invention.
The invention also provides a pharmaceutical or veterinary composition comprising a compound in accordance with the invention and having antibacterial activity or a cephalosporin analogue prepared from a compound in accordance with the invention, and a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient. Such compositions or formulations may be in unit dosage form.
The invention further provides a method of inhibiting the growth of bacteria in an environment, which method comprises administering to the environment an effective amount of a compound in accordance with the invention and having anti bacterial activity or a cephalosporin analogue prepared from a compound in accordance with the invention, or of a composition or formulation in accordance with the invention.
Such a method can be used in sterilising an environment, e. g. hospital walls, floors or fittings, in preserving perishables (e. g. foodstuffs) or in treating decay, or in the treatment or prevention of disease caused by bacteria in animals.
The following Tables D, E, H, I, J, K, L, M, N, P, Q and R are given to show variations of the specific Examples of the various reactions discussed above in detail. They demonstrate the general applicability of the various reactions to the e preparation of compounds of this invention.
In the Tables, many abbreviations are used for the sake of simplicity and easy understanding. They are listed below for reference, and they consist mainly of those abbreviations that are traditional with those skilled in the art.
Ac = acetyl An = acetone B = benzamido BH = diphenylmethoxycarbonyl Bu = butyl BZ = benzyloxycarbonyl Cb-benzyloxycarbonylamino m-CPBA = m-chloroperbenzoic acid Di = dioxane DMSO = dimethylsulfoxide Et = ethyl G = phenylacetamido hr hour Me = methyl min. = minute NBS = N-bromosuccinimide Ph = phenyl refl. = fefluxing temperature rt. = room temperature S.M. = starting material TDAZ = 1 , 3,4-thiadiazole ring TE TR TETR = tetrazole ring Temp. = temperature THF = tetrahydrofuran After the Tables there are listed the physical constants of the products (in table form). Some products have no cited constants, but they are identified after the process (es) implying that the correct structure has been assigned. This is a result of mere experimental convenience in the laboratory, and is in accordance with scientific tradition.
TABLE D (Epoxidation)
Ex. S.M. Solvent Reagent Temp. Time Temp. Time Crop No. A Y COB (g) (ml) (g) ( C) (min.) ( C) (hr) (g) (1) Direct epoxidation.
1 #G &alpha;H BH 5.77 CHCl3(60) m-CPBA(2.85) rt 48 4.54 2 #Cbz " " 25.6 @ (260) " (15.3) " 48 21.25 3 &alpha;G #H " 0.88 " (9) " (0.54) " " 13 0.475 (2) through bromohydrin. halohdrin formation epoxidation 4 #G &alpha;MeO " 4.90 DMSO(20) NBS(2.4) H2O(1.0) rt 90 t-BuOK(-) rt 0.3 0.12 5 &alpha;B #H " 14.8 " (13) "(10.4) " (6.5) 20 60 "(5.31) 20 1 13.0 6 &alpha;G " " 0.148 " (2) "(0.06) "(0.1) rt 90 " (0.08) 0 0.3 0.12 TABLE E (Epoxide Fission)
Ex. S.M. Solvent HNu Catalyst Temp. Time Crop No. A Y COB Nu (g) (ml) ( C) (min) (g) 1 &alpha;G #H BH -Cl 0.108 CHC3(3) 35% HCl (0.3 ml) - rt 30 0.116 2 " " " -Br 3.7 "(100) HBr(10 ml) - " 15 4.9 3 " " " -S-5-TETR-1-Me 8.22 THF (40) 1.97 NBuLi (1.54) " - 10.35 4 " " " -OAc 1.08 HOAc (10) BF3Et3O (0.05) " 30 1.38 5 #G &alpha;MeO " -Br 0.688 DMSO (7) NBS (0.336) H2O (0.01) " 60 0.74 6 " " " -S-5-TETR-1-Me 3.287 THF (20) 1.97 NBuLi (0.64) " 180 3.82 7 " &alpha;H " -S-5-TETR 16.22 " (200) 3.63 H2SO4 (0.5) 0 240 21.05 8 " " " -S-5-TETR-1-isoBu 5.40 " (50) 1.74 BuLi (2 mMole) rt 360 7.10 9 " " " -S-5-TETR-1-Ph 5.41 " (80) 2.14 " (7.22) " 150 4.45 10 " " " -S-5-TETR-1-CH2COOH 19.13 " (250) 6.18 H2SO4 (0.2) 0 120 28.97 11 " " " -S-5-TDAZ-2-Me 1.50 " (20) 0.44 BuLi (3.22 mMole) rt 60 1.89 12 " " " -OMe 3.06 MeOH (20) - H2SO4 (0.2) 0 15 2.99 # # rt 60 13 " " " -OAc 2.50 HOAc (17) - NaOAc (1.2 g) 55 60 300 2.61 14 " " " -Cl 0.70 CHCl3 (16) 35% HCl (4 ml) rt 15 0.46 15 " " " -OH 8.87 An (90) 18 30% HClO4 (27) " 150 8.5 16 " " " " 21.25 " (220) 44 " (66) " 180 20.6 17 " " " -S-5-TETR-d-Me 10.8 THF (100) 2.8 1.97 BuLi (2) " 360 13.1 18 #B &alpha;MeO BZ -S-5-TETR-1-Me 10.50 THF (950 3.05 1.6 NBuLi (2.75) 20 240 12.25 TABLE H (Hydration)
Ex. S.M. Solvent Hg-salt Temp. Time Crop No. A Y COB Nu (g) (ml) (ml) ( C) (min.) (g) 1 &alpha;G- #H- BH -H 10.5 H2O (2) HgSO4 (0.52 rt 14 0.176 C5H11N (5) 2 " " " -Br 0.601 95% MeOH 0.1M HgSO4 refl. 60 0.603 3 " " " -I 0.324 90% MeOH 0.13M HgSO4 " 70 0.327 (30) 4 #G- &alpha;MeO " -Br 0.192 97% MeOH 0.13 M HgSO4 " 50 0.176 (20) TABLE I (Oxidation of Secondary alochol)
Ex. S.M. An Jones reagent Temp. Time Crop No. A Y COB Nu (g) (ml) (ml) ( C) (min) (g) 1 &alpha;G #H BH -Cl 0.116 5 0.15 rt 60 0.112 2 " " " -Br 1.274 10 1 0 180 1.226 3 " " " -S-5-TETR-1-Me 9.8 100 13 0 120 9.19 # # rt 120 4 " " " -OAc 1.38 25 1.2 rt 60 0.525 5 " " " -Br* 1.17 20 1.5 " 90 0.95* 6 #G &alpha;MeO " -S-5-TETR-1-Me 3.82 35 5 " 60 2.975 7 " " " -Br* 0.444 4 0.4 0 150 0.434* 8 " &alpha;H " -S-5-TETR 21.05 200 25 rt 90 11.07 9 " " " -S-5-TETR-2-Me 2.03 20 1.8 " 90 2.02 10 " " " -S-5-TETR-1-isoBu 7.10 75 6.5 " 90 6.1 11 " " " -S-5-TETR-1-Ph 4.45 50 4.5 " 90 3.92 12 " " " -S-5-TETR-1-CH2COOH 15.9 190 16 " 180 2.6 13 " " " -S-5-TETR-1-CH2COOt-Bu 5.5 40 5 " 90 0.78 # # # " " " -S-5-TETR-2-CH2COOt-Bu 1.92 14 " " " -S-5-TDAZ-2-Me 1.89 15 1.5 " 180 1.17 15 " " " -OMe 2.98 30 3.0 " 120 2.0 16 " " " -OAc 2.60 50 2.0 " 120 2.0 17 " " " -C1 0.40 7 4 equivalents " 220 0.3 18 " " " -S-5-TETR-1-Me 14.1 150 13 " 90 12.4 19 #B &alpha;MeO BZ " 12.2 210 12.6 20 60 11.24 20 " " " -Br 3.53 141 2.82 0 60 3.24 21 G aH BH -C1* 0.15 3 0.05 rt 60 0.14* @@he reactions are for triphenylphosphoranylidenacetic acids instead of isopropylideneacetic acids.
TABLE J (Ozone cleavage) (Part 1)
Ex. S.M. CH2Cl2 Temp. Time Reducing Temp. Time Crop* No. A Y COB Nu (g) (ml) ( C) (min.) reagent (ml) ( C) (min.) (g) 1 &alpha;G #H BH -OAc 0.60 12 -78 - Me2S(1) -78 30 0.617 ( ) rt 30 2 " " " " 0.380 10 " - " (1.6) rt 45 0.395** 3 " " " -S-5-TETR-1-Me 3.67 56 -60 - "(4.2) " 60 3.45 4 " " " " 1.63 20 -78 30 (Zn (4.8 g)) -15 25 (1.62) HOAc (4) 5 " " " " 1.21 65 " - ((Zn(3.6 g)) -20 35 (1.113)** HOAc(14) 6 #G &alpha;MeO " " 0.397 4 " 30 Zn(1.2 g) -10 30 (0.352) ( ) HoAc(1) 7 " &alpha;H " -S-5-TETR 5.50 50 " 30 Me@S(5) -78 30 5.56 ( ) rt 30 8 " " " -S-5-TETR-2-Me 2.02 50 " 15 " (2.5) -78 30 2.00 ( ) rt 30 9 " " " -S-5-TETR-1-isoBu 5.83 117 " 20 " (6) -78 90 6.60 ( ) rt 60 10 " " " -S-5-TETR-1-Ph 3.92 50 " 25 " (5) -78 30 3.87 ( ) rt 30 11 " " " -S-5-TETR-1-CH2BH 2.60 70 " 15 "(5) rt 20 2.50 12 " " " -S-5-TETR-1-CH2COOt-Bu 0.76 20 " - "(1) -78 30 0.71 ( ) rt 13 " " " -S-5-TETR-2-CH2COOt-Bu 2.11 40 " - "(2) -78 30 1.93 ( ) rt 30 14 " " " S-5-TDAZ-2-Me 1.17 30 " 10 " (2) -78 30 1.10 ( ) rt 30 *) The values in parentheses show crops of glycolates produced by simultaneous reduction (Process K).
**) Starting material has H2C - group in place of oxo in the substituent at the position 4.
***) Starting material has MeOOCCH = group in place of oxo in the subtituent at the position 4.
The reaction is carried out in the presence of 3.5 ml of methanol.
TABLE J (Oz one leavage (Part 2) Ex. S.M. CH2Cl2 Temp. Time Reducing Temp. Time Croup* No. A Y COB Nu (g) (ml) ( C) (min.) reagent (ml) ( C) (min) (g) 15 #G &alpha;H BH -OMe 2.00 40 -78 15 Me2 S(3) -78 30 1.96 ( ) rt 30 16 " " " - OAc 2.00 30 " - " -78 30 1.80 ( ) rt 30 17 " " " -8-5-TETR-1-Me 5.20 80 " - " (6) -78 - 4.99 ( ) rt 18 " " " 4-substituent=2,3-epoxy- 1.50 40 " 17 " (3) -78 30 1.51 ( ) propoxy rt 30 19 #B &alpha;MeO BZ -S-TETR-1-Me 11.2 112 -60 - Zn/HOAc -60 to rt (10.2) 20 " " " 4-substituent=2,3-e poxy- 11.5 160 -70 - Zn/HOAc 0 80 (10.36) propoxy TABLE K (Reduction of oxo group) (Part I)
Ex. S. M. * CHC1, Zn HOAu Temp. Time Crop No. A Y COB R (g) (mi) (9) (mi) (OC) (min.) (g) aG H BH-CH2Ct ; cK2 (0.324) 7.5 1 1.5-15-10.30 0. 306 0 2"""-CH, CCH2S-5-TETR-1-Me (1.21) 65 3.6 14-25N-17 35 1.113** y CHCOOMe 3"""-CHzCOCH, S-5-TETR-1-Me (1.63) 20 4.8 4-15~-10 30 1.62 4""""3. 45 15 7.4 15 0 13 55 3. 30 5"""-CH, COCH2OAc 7.4 80 8 80 0 30 7.9 6 0. 617 6 1. 2 6 0 60 0.576 7 3G aMeO"-CH, COCH, S-5-TETR-1-Me (0.397) 5 1. 2 1-10 30 0. 352 8"aH"-CH2COCH2S-5-TETR 5.56 15 15 15 0 180 5. 16 9"""-CH, COCHzS-5-TETR-2-Me 2.0 7 4 7, 120 1.71 10"""-CHZCOCH2 S-5-TETR-1-isoBu 6.60 24 11.1 24"435 5.3 11 91-CH, COCH, S-5-TETR-1-Ph 3.87 15 7.7 15"120 3.91 12"""-CH2COCH2S-5-TETR-1-CH2COOt-Bu 0.71 3 3 3 180 0.69 13"""-CH, COCH, S-5-TETR-2-CH, COOt-Bu 1.87 8 7 8 0 60 1.75 (rt 7) 1 """-CH, COCH, S-5-TDAZ-2-Me 0.83 3.5 3 3.5 0 20 0.80 rut 30 15"""CH2COCH20Me 1.96 8 3 8 0 3 (l 1.81 (rut 210 *) The values in parentheses are those of isopropylideneacetic acids which is subjected to reaction @ to give the starting material of this reaction, when without isolation, it is treated by a required reagent of this reaction.
**) The product has R being -CH2COCH2S-5-TETR-1-Me, and the =CHCOOMe group is removed during the ozonization leaving an oxo grou-.
TABLE K (Reduction of oxo group) (Part 2)
Ex. S. M. CH2CI2 Zn HOAc Temp. Time Crop No.A Y COB R (g) (ml) (g) (ml) ( C) (min.) (g) 16/3GaHBH-CH, COCH, OAc 1. 8010510rt301. 85 -CH C-CF, 0. 42 1 0. 6 1 0 30 0. 40 rt 60 18"""-CH, COCH2S-5-TETR-1-Me2.05 8 3 8 0 80 2.05 19 B aMeO BZ" (11. 2) 149 33. 6 30 0-10. 2 20"""-CH2Ct1 5H2 (11. 5) 240-160 0 90 10. 36 2 0/2 TABLE L (Halogenation and sulfonylation)
Ex. S. M. CH, CI, SOHal2 Base Temp. Time Crop No A Y COB R H l (g) (ml) (ml) (ml) ( C) (min.) (g) 1aGHBH-CH, COCH, S-5-TETR-l-MeCt3. 30350. 48C, H, N (0. 45) 0 30 3. 37 2"""CH2COCH2OAc"7. 9 80 2. 5"(1.1)"20 8. 3 3""""Sr 0. 5 5 02" (0. 21)"25 0. 54 4"""~CHZCi-CHZ"2. 7 80 1. 2 MeO (1.65)"30 3 0 0 5""""C1 0. 3 5 0. 143 CsH > (0. 091)"15 035* 6 3G aMeO"-CH, COCHzS-5-TETR-1-Me"0. 35 3 0. 073"(0.073)-15 10 0.35 7"aH"CH2COCH2S5TETR"5. 16 30 0. 61" (0. 67) 0 60 5. 14 8"""-CH, COCH, S-5-TETR-2-Me"1. 71 10 0. 24"(0.22)"20 1.66 9"""rCH2COCH2S5TETR1isoBu"5. 30 53 1 25" (0. 86) 0 2405.40 (rt 210) 10"""-CH, COCHZS-5-TETR-1-Ph"3. 91 30 0. 49" (0.45) 0 20 3. 92 11"""-CHzCOCH2S-5-TETR-1-CHzCOO t-Bu"0. 69 6 0. 082"(0.076) 30 0. 70 TABLE L (Continued)
Ex. S. M. CH. Ct, SOHal, Base Temp. Time Crop No. A Y COB R Hal (g) (ml) (ml) (ml) ( C) (min.) (g) 12 zig aH BH-CH, COCHS-5-TETR-2-CH, COO t-Bu Cl 1.75 30 0. 21 CSH, N (0. 22) 0 30 1. 85 13"""CH2COCH2S5TDAZ2Me"0. 90 10 030"(0. 11)"1200.90 14"""CH2COCH2OMe"1. 81 10 0.72" (0. 27)"30 1. 88 15-CH, COCH, OAc 99 0. 90 10 0. 34 (0. 13) 90 0. 85 -CH2CI-CIi2 1. 03 5 0. 43 (0. 48)-30 151 1. 0 \ 0J 0 15 17"""-CH, COCH, S-5-TETR-1-Me"3. 8 35 0.66" (0. 49) 0 45 3. 9 18/3B aMeO BZ-CH, COCH, S-5-TETR-l-Me,, 7. 2575 1J6Et, N (1.34) 25 2519"""~CH2CfoI : 2, Br 7.97 140 2.04 ! To (2. 89) 020 0. 21 01 20 aG H BH-CH, COCH2OAc MeSO, 0.5 5 MeSO2CI EtlN (0. 36)"77 0.54 *) Epoxy ring ruptured during the reaction to give a halohydrin.
TABLE M (Phosphoranilidene introduction)
Ex. S. M. CH2C1, Ph, Y Temp. Time Crop No. A Y COB R Hal (g) (ml) (g) ( C) (min.) (g) 1 aG (3H BH-CH, COCH2S-5-TETR-1-Me CI 3. 37 35 4. 41 refl. 240 2. 09 2"""-CH2COCH2OAc"8. 3 80 9. 0"240 3. 6 3"""""0. 58 6 0. 79"240 0. 257 4"""-CH2Cv SH2"034 4 0. 47"IS0 0201 5""""Br 3. 0 80 3. 9"90 (1.17) * 6GaMeO-CH, COCH, S-5-TETR-l-MeClOJ540. 473000. 768 7"aH"CH2COCH2S5TETR"5. 14 40 S. 00"180 1. 90 8"""-CHCUCHzS-5-TETR-2-Me"1. 66 20 2. 4"180 1. 15 9"""-CH2COOCHS-5-TETR-1-isoBu"5. 40 50 5. 0"280 2. 06 10""-CH2COCH2S-S-TETR-1-h"3. 92 40 2. 5"300 4. 10 11 is-CH, COCH2S-5-TETR-1-CH, COOt-Bu 99 0. 70 10 1. 0 180 0. 62 12"""-CH2COCH2S-S-TETR-2-CH2COOt-'Bu"l. oS 20 1. 6, 240 1. 2U 13"""-CH2COCH2S-S-TDAZ-2-Me"0. 90 10 0. 9"240 0. 32 14",-CH2COCH2OMe"1. 88 10 1. 0"240 1. 77 1S""-CH2COCH2OAc"0. 85 7 0. 9"lS0 0. 65 16"""-CH2CHOH-CH2CI"1. 0 10 1. 0 120 0. 62 17"""-CHzCOCH2S-5-TETR-1-Me"4. 95 40 6. 0"180 5. 03 18 B aN/leO BZ""** 75 9. 97"180 6. 52 19,,-C"2Q2Br-**1405. 05rt60 (8. 91) * *) Epoxy ring ruptured during the reaction. The reaction is carried out in the presence of 1.9 ml of dimetani **) Continuous reaction from reaction L, Ex. No. 18 and 19.
TABLE N (Nucleophile exchange)
Ex: S.M. HNu Catalyst Solvent Temp. Time Crop No. A Y COB Hal Nu (g) (g) (ml) (ml) ( C) (min) (g) 1 &alpha;G #H BH Br -S-5-TETR-1-Me 0.603 0.124 Et3N (0.13) An (6) 0 30 0.161 2 " " " I " 0.327 0.063 " (0.075) " (10) " 35 0.192 3 #G &alpha;MeO " Br " 0.176 0.035 " (0.038) "(1.8) " 45 0.088 4 " &alpha;H BZ " " 0.206 0.080 Na salt " (4) rt 10 0.229 5 " " " " -OAc 3.100 0.730 " HCONMe2(16) " 120 3.40 6 #B &alpha;MeO BZ " -S-5-TETR-1-Me 3.24 0.631 " " (49) 0 70 3.382 7 #G &alpha;H BH Cl -S-5-TDAZ-2-Me 0.14 26 Et3N(0.028) An(1) " 30 0.049 TABLE P (Cyclization)
Ex. S.M. Dioxane Temp. Time Crop No. A Y COB R (g) (ml) ( C) (hr) (g) 1 &alpha;G #H BH -CH2COCH2S-5-TETR-1-Me 2.09 20 refl. 17 0.688 2 " " " -CH2COCH2OAc 3.31 70 " 20 1.79 3 #G &alpha;MeO " -CH2COCH2S-5-TETR-1-Me 0.768 8 " 5.5 0.151 4 " &alpha;H " -CH2COCH2S-5-TETR 1.90 20 " 15 0.33 5 " " " -CH2COCH2S-5-TETR-2-Me 1.12 18 " 18 0.56 6 " " " -CH2COCH2-5-TETR-isoBu 1.31 36 " 15 0.70 7 " " " -CH2COCH2S-5-TETR-1-Ph 4.10 40 " 15 2.31 8 " " " -CH2COCH2S-5-TETR-1-CH2COOt-Bu 0.62 10 " 18 0.30 9 " " " -CH2COCH2S-5-TETR-2-CH2COOt-Bu 1.20 30 " 20 0.47 10 " " " -CH2COCH2S-5-TDAZ-2-Me 0.32 5 " 18 0.14 11 " " " -CH2COCH2OMe 1.77 20 " 40 0.87 12 " " " -CH2COCH2OAc 0.63 9 " 20 0.40 13 " " " -CH2COCH2S-5-TETR-1-Me 5.03 50 " 15.5 2.27 14 #B &alpha;MeO BZ " 9.00 @ " 2.5 344 TABLE Q (Deacyl@tion)
Ex. S.M. CH2Cl2 PCl2 C3H3N Temp. Time CH3OH Temp. Time H2O Time Crop No. A Y COB No (g) (ml) (g) (ml) ( C) (min.) (ml) ( C) (min) (ml) (min) (g) -20 30 1 #G #H BH -S-5-TETR-1-Me 0.50 12 0.394 0.136 ( ) 6 rt 60 2.67 - 0.333 rt 25 20 20 10 0 30 - - 0.772* 2 " " " -OAC 1.224 50 1.26 0.55 ( ) ( ) 0 140 rt 25 3 #g &alpha;MeO " -S-5-TETR-1-Me 0.101 2 0.085 0.05 -20 90 2 rt 30 - - 0.013 4 " af@ " -S-5-5-TETR - - - - - - - - - - - -20 30 5 " " " -S-5-TETR-2-Me 0.564 10 0.393 0.15 ( ) 3 rt 30 2.0 10 0.207 rt 30 -20 90 6 " " " -S-5-TETR-1-isoBu 0.589 - 0.393 0.15 ( ) 4 " 30 2.0 30 0.205 rt 30 -20 30 7 " " " -S-5-TETR-1-Ph 1.575 25 0.996 0.385 ( ) 10 " 30 5.0 30 1.228 rt 30 -20 30 8 " " " -S-5-TETR-1-CH2COO 0.300 10 0.180 0.07 ( ) 4 " 30 2.0 30 0.189 t-Bu rt 30 -20 30 9 " " " -S-5-TETR-2-CH2COO 0.470 10 0.282 0.11 ( ) 10 " 30 4.0 30 0.470 t-Bu rt 40 -20 30 10 " " " -S-5-TDAZ-2-Me 0.382 8 0.259 0.10 ( ) 8 " 30 4.0 30 0.274 rt 30 11 " " " -OMe 0.705 10 0.573 0.22 -20 30 10 " 30 5.0 30 0.416 ( ) rt 30 12 " " " -OAc 0.265 10** 0.180 0.09 0 10 5 " 20 10.0 20 0.250 ( ) rt 60 13 " " " -S-5-TETR-1-Me 0.955 24 0.666 0.26 -20 30 12 " 30 6.0 30 0.661 ( ) rt 30 14 #B &alpha;MeO BZ " 1.07 5 0.834 0.49 25 90 11 10 150 - - 0.365 *) isolated as toluene-p-sulfonate, **) Benzene was used in place of methylene chloride as solvent for the reaction.
TABLE R (Methoxylation)
Ex. S. M. CH. CI, t-BuOCtLiOCH/MeOHTemp. TimeCrop No. A COB R R' (g) (ml) (ml) (ml) ( C) (hr) (g) 1aGBH-CH, C=CH=CMe,0.139 2. 7 0. 048 2M ( 40 40 0.144 2""CH2CHH"0. 265 5 0. 07 2M-30 15 0. 185 3""-H2I-H2'"1. 679 30 0. 56 2M (1. 87)-30 20 1. 796 0 4""-CH2CBr"7. 44 74 1. 7 2M(7.42)-10 6.70 5""""0273 THF (60) 0.06 2M (0. 88) 40~r50 1/6 0195 6, BB BZ CH2ctlCH2"10. 41 146 3. 90 2M (23. 1)-30 40 10. 55
A Y COB =Ra IR: vmaxCHCl3 (cm-1) AG aH BH =C (CH3)2 3433, 1778, 1724, 1680, 1632, 1506.
#Cbz " " " 3445, 1778, 1724, 1632, 1508.
&alpha;G- #H- " " 3410, 1775, 1720, 1680.
" " " =O 3425, 1824, 1752, 1710, 1680.
" " " < HOH 3600 -3200, 1780, 1750, 1670.
" " " < HBr 3425, 1795, 1754,1682,1185,1130.
#G- &alpha;MeO " =C(CH3)2 NMR: #CDCI3 2.07s3H, 2.22s3H, 2.2-3.3m3H, 3.45brs3H, 4.23s2H, 6. 06brslH, 6. 80brslH, 6. 98slH, 7.34m 15 H.
#B- &alpha;MeO BZ " 1780, 1725, 1690.
&alpha;B- #H- " " 1775, 1720, 1665.
< OH 1780, 1750, 1685.
A Y COB Nu In : man aG-3H-BH-S-5-'TETR-I-Me 3400, 1823, 1748, 1708.
"""-OAc 3430, 1830, 1740, 1710, 1680.
AG-ameo-S-5-TETR-1-Me "aH"-S-5-TETR 3415, 1830, 1750, 1718, 1695.
"""-S-5-TETR-2-Me -S-5-TETR-1-isoBu 3413, 1823, 1745, 1708, 1687, 1602.
* -S-5-TETR-l-Ph 3425, 1830, 1750, 1714, 1690.
-S-5-TETR-1-CH2BH 1830, 1755, 1710, 1690sh.
-S-5-TETR-l-CH, COOtBu 3420,1830, 1755, 1715, 1690.
"""-S-5-TETR-2-CH, COOtBu 3430,1830,1755,1715,1690.
-S-5-TDAZ-2-Me 3440, 1832, 1755, 1715, 1690.
"""-OMe 3430, 1830, 1750, 1715, 1690.
-OAc 3430,1830,1750,1715.
(4-subst. =-CH2CvCg2 3425, 1824, 1752, 1710, 1682.
A Y COB Nu IR :VCHCl3 max aG-AH-BH-Cl 3400, 1775, 1720, 1680.
-Br 3400, 1760, 1720, 1670.
-S-5-TETR-I-Me " " " -OAc NMR: 2. 00s3H, 2. 05s3H, 2.25s3H.
#G- &alpha;MeO " -Br 3600-3200, 1775, 1720, 1690, 1060.
" " " -S-5-TETR-1-Me NMR: 1.98s3H, 2.28s3H, 3.47s3H, 3.86s3H. aH--S-5-TETR 3425, 3300, 1781, 1734, 1672.
-S-5-TETR-2-Me -S-5-TETR-isoBu 3423, 1773, 1722, 1677.
" " " -S-5-TETR-1-Ph 3425, 3350, 1777, 1727, 1678.
" " " -S-5-TETR-1-CH2COOH 1780, 1735, 1710sh, 1670.
" " " -S-5-TDAZ-2-Me 3425, 3320, 1774, 1722, 1675.
-OMe 3425,3320,1774,1722,1675.
-OAc 3425, 1780, 1730, 1680.
"""Cl 3440, 1780, 1727, 1682.
-OH 3420, 1774, 1720, 1670, 1504.
-OH 3600, 3445, 1778, 1725, 1632, 1508. pB aMeO BZ-S-5-TETR-1-Me 3430, 1775, 1725, 1680.
-Br NMR: 5CD-'32. 03s3H, 2.25s3H, 3.0-4. 0m6H, 4.93d (6Hz)lH, 5. 20s2H, 7.2-7.9m 11H.
A Y COB Nu IR: vmaxCHCl3 (cm-1) &alpha;G- #H- BH -Cl 3410, 1780, 1725, 1680.
" " " -Br 3400, 1770, 1720, 1675.
" " " -S-5-TETR-1-ME ---- " " " -OAc ---- -Br 1771, 1750, 1720, 1680, 1601, 1181.
#G- &alpha;MeO " -S-5-TETR-1-Me 3410, 1778, 1720, 1695.
"aH-"-S-5-TETR 3425,1780, 1730, 1680.
" " " -S-5-TETR-2-Me ---- """-S-5-TETR-1-isoBu 3423, 1777, 1726, 1680.
-S-5-TETR-l-Ph 3430,1792,1730,1680.
"""-S-5-TETR-1-CH, BH 1780, 1725, 1685.
-S-5-TETR-1-CH2COOtBu 1783, 1755, 1690.
-S-5-TETR-2-CH, COOtB u 1782, 1760, 1730, 1690, -S-5-TDAZ-2-Me 3430,1779,1725,1680.
-OMe NMR: 1.97s3H, 2.23s3H, 3.28s3H.
-OAc 3440,1780,1740.
"""-CI 3430,1780,1722,1680.
BZ-OAc 3430,1780,1745,1725,1690,1640, 1500.
"""-S-5-TETR-1-Me 3420,1780,1725,1680.
#B &alpha;MeO BZ " 1775, 1730, 1680.
A Y COB Nu IR : man'' (cm-') &alpha;G #H BH -S-5-TETR-1-Me 3550, 3200, 1786, 1750, 1678, 1100.
" " " -OAc 3420, 1790, 1745, 1680.
#G &alpha;MeO " -S-5-TETR-1-Me 3600-3200, 1790, 1750, 1696, 1490, 1140.
"aH"-S-5-TETR 3325, 1794, 1750, 1680.
-S-5-TETR-2-Me 3400,3360,1785,1750,1680, 1605.
"""-S-5-TETR-1-isoBu 3411, 3320, 1784, 1743, 1678.
"""-S-5-TETR-1-Ph 3425, 3330, 1790, 1748, 1680.
-S-5-TETR-I-CH2COOt-Bu 1795, 1758, 1685.
" " " -S-5-TETR-2-CH2COOt-Bu3410, 1783, 1754, 1680.
" " " -S-5-TDAZ-2-Me 3400-3300, 1790, 1745, 1678.
"""-OMe 3425, 3350, 1790, 1746, 1680.
-OAc 3430, 1790, 1745, 1680. a NMR: #CDCI3 4.05d (4Hz) 2H, -ep.mer (:0087 AB aMeO BZ-S-5-TETR-I-Me 1785, 1745, 1680.
A Y COB Nu Hal IR : vmax 3 (cm-') cG-H-BH-S-5-TETR-t-Me Ct 3420,1800,1760,1680.
"""-OAc"3420, 1790, 1740, 1675.
Br 3420, 1795, 1745, 1780.
0 o """ (4-subst.-OCH2CH-CH,)"3425, 1795, 1754, 1682, 1185, 1130. """"MsO 3420, t795, 1750, 1680, 1375, I 175. iG-aMeO"-S-5-TETR-I-Me CI 1800, 1760, 1695, 1495, I 170.
"aH-"-S-TETR"1800, 1757, t680.
"""-S-5-TETR-2-Me" """-S-5-TETR-1-isoBu"3386, 1792, 1752, 1670.
"""-S-5-TETR- (-Ph"3430, 1800, 1754, 1682.
..-S-5-TETR-t-CH, COO u -S-5-TETR-2-CH COO t-Bu """-S-5-TDAZ-2-Me"3420, 1792, 1750, 1678.
"""-OMe"3425, 1795, 1750, 1680.
"""-OAc" OH """ (4-subst. OCH2CHCH2CI)"3425, 1790, 1752, 1676.
C : HC : I, m~, A Y COB Nu IR : vmax aG 3H BH-S-5-TETR-l-Me---- -OAc 3410, 1765, 1745, 1675. iG aMeO"-S-5-TETR-I-Me---- "aH"-S-5-TETR-1780, 1680, 1610.
-S-5-TETR-2-Me---- -S-5-TETR-1-isoBu 3410, 1772, 1670, 1626.
"""-S-5-TETR-1-Ph 3430, 1780, 1745, 1680, 1634.
-S-5-TETR-1-CH, COOt-Bu 3430, 1780, 1758, 1680.
-S-5-TETR-2-CH, COOt-Bu---- -S-5-TDAZ-2-Me 3420, 1770, 1740, 1672, 1628.
-OMe 3425, 1770, 1736, 1672, 1628.
-OAc 3420, 1770, 1750, 1670.
"""Cl 1, 72, 1740, 1678, 1628. job aMeO BZ-S-5-TETR-I-Me 3430, t770, 1740, 1680, 1630, 1625. aG AH BH 4-substituent =-OCH, CI 3425, 1778, 1680, 1632, 1 l l8.
OH pG aH""3385, 1768, 1667, 1628.
CHC12 A Y COB Nu IR: vmax (cm-1) &alpha;G- #H- BH -S-5-TETR-1-Me 3400,1790,1718, 1685.
"""-OAc 3420,1790,1740, 1685.
#G- &alpha;Me) " -S-5-TETR-1-Me 3400,1780,1710,1690. aH"-S-5-TETR 3420, 1800, 1722, 1680.
" " " -s-5-TETR-2-Me NMR : 3.58s2H, 3.66s2H, 4. 10s3H.
-S-5-TETR-1-isoBu 3420, 1800, 1715, 1683, 1635.
-S-5-TETR-l-Ph 3425,1797, 1717, 1685.
-S-5-TETR-1-CH, COOtBu 3425, 1800, 1750,1722,1680.
-S-5-TETR-2-CH, COOtBu 3420, 1796, 1725, 1682.
" " " -S-5-TDAZ-2-Me 3430, 1798,1720,1680.
"""-OMe 3430,1798,1723,1680.
-OAc 3440, 1800, 1740, 1680.
/3B aMeO BZ-S-5-TETR-I-Me 3440,1789,1723,1691, (1640, 1603, 1584. mp. 85 C
H2N Y COB Nu IR: vmaxCHCl3 (cm-1) a AH-BH-S-5-TETR-1-Me 3380, 1785, 1720.
"""-OAc 3400, 1800, 1735, 1630.
&alpha;MeO " -S-5-TETR-1-Me 3400,3300,1785, 1720, 1625, 1600.
"""-OAc 1785, 1735, 1680, 1640. aH-S-5-TETR -S-5-TETR-2-Me NMR : 1. 74brs2H, 4.17s3H, 4.60s2H.
-S-5-TETR-1-isoBu 3562, 3412, 1789, 1715, 1630.
-S-5-TETR-1-Ph 3425, 3355, 1793, 1722.
-S-5-TETR-I-CH2COOtBu 1795, 1753, 1722.
-S-5-TETR-2-CH2COOtBu 1793, 1758, 1733, 1633.
-S-5-TDAZ-2-Me 3420, 3350, 1794, 1723.
-OMe 3420, 3350, 1785, 1722.
"""-OAc----- "aMeO BZ-S-5-TETR-1-Me NMR : aCDC13 2. 20brs2H, 3. 45s3H, 3.83s3H, 4.27s2H, 4.63brs2H, 5. 30s2H, 7.23-7. 50m5H, 4. 83s1 H.
S. USE OF COMPOUND (18).
The Compounds (18) can be acylated in accordance with a conventional acylation, if required following by deprotection of attached protective group of 4-carboxy to give an antibacterial Compound (17). Acylation can be effected by the action of a reactive derrivative (e. g. free acid in the presence of condensing reagent (e. g. dicyclohexylcarbodiimide, or 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline), halide in the presence of acid acceptor (e. g. pyridine, quinoline, triethylamine, or N-methylmorpholine), reactive ester or amide) of acids having the desired acyl group, in an inert solvent (e. g. methylene chfforide, chloroform, acetone, ethyl acetate, or water) at generally-20 C to 40 C for 15 minutes to 12 hours. Usually 1 to 1.5 mole equivalents of acylating reagent is used against Compound (18).
Said deprotection of attached protective group of 4-carboxy can be effected by the action of acid, base, hydrogen, or like conventional methods well known to those skilled in the art. The acids include mineral acid, strong organic acid like trifluoro- acetic acid, and base being e. g. hydroxide or carbonate of alkali metal, alkali metal thiophenoxide, etc.
Example S.
To a solution of diphenylmethyl 7 -amino-3- (2-methyltetrazol-5-yl)- thiomethyl-oxadethia-3-cephem-4-carboxylate (105 mg) and a-phenylmalonic acid monobenzhydryl ester (277 mg) in tetrahydrofuran (2 ml) is added N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (163 mg) in five portions, and the mixture is stirred at room temperature for 5 hours. The reaction mixture is diluted with ethyl acetate, washed with IN-hydrochloric acid, 5% aqueous solution of sodium hydrogencarbonate, and water, and dried over magnesium sulfate. The residue obtained by evaporating the solution is chromatographed over silica gel containing 10% water (10 g) to give diphenylmethyl 7 - (er-phenyl-a-diphenylmethoxycarbonylacet- amido)-3- (2-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3-cephem- 4--carboxylate (126 mg) as colorless foam from the fraction eluted with a mixture of ethyl acetate and acetic acid (5 : 1). Yield: 71.2%.
IR : v CHCLs 3366, 3280,1797,1720,1680 cm-1. max NMR: 8 CDC134. 17s3H, ca. 4.2m2H, 4.53s2H, 4.71s0.5H, 4.72sO. 5H, 5.02d (4Hz) 1H, 5. 70dd (10; 4Hz) lH, 6.92slH, 6. 95slH, 7.2-8. 0m20H.
(2) To a solution of diphenylmethyl 7 - (&alpha; - phenyl - &alpha; - diphenylmethoxy- carbonylacetamido-3- (2-methyltetrazol-5-yl) thiomethyl-1-oxadethia-3- cephem-4-carboxylate (126 mg) are added anisole (0.8 ml) and trifluoroacetate acid (0.8 ml) under nitrogen atmosphere, and the mixture is stirred for 3 hours at 0 C. The residue obtained by evaporation of the reaction mixture is dissolve in ethyl acetate, and purified by chromatography over silica gel containing 10% water (3 g) to give 7 - (&alpha; - phenyl - &alpha; - carboxyacetamido) - 3- (2 methyltetrazol - 5- yl) thiomethyl 1-oxadethia-3-cephem-4-carboxylic acid (32 mg) from the fraction eluted with a mixture of ethyl acetate and acetic acid (9: 1). Colorless powder. Yield: 43.2%.
IR: v KBr 3400, 2920,2500,1775,1660 cm 1.
Some of the products made as above from Compounds (18) are listed in Table S with IR spectra. They are active against gram positive and negative bacteria and useful for treating human and veterinary bacterial infection at a daily dose of 0.1 g to 5 g preferably intravenous administration of sodium salts in aqueous solution.
TABLE S Physical Constants of
A'Y Nu m. p. IR : vKBr (cm~1) m . x PhIICONti-a-11-3-5-TETR-l-Lle 157-3420, 2520, 1775, 1674, OOH 159 1G06, 7 529, 1376.
00'"-S-5-TDAZ-2-Me 3410, 1772, 1600.
PhgHCONH-""170 1778,1710,1675.
FI 107-3430, 1799, 1720, 1685.
"-ove 10850 340 (), 1778,1675.
H ! '"" 3410, 3060, 1781, 1685.
H2 COOH195 1767, 1682, 1605.
OOH 1950 PhCH CONH-"-OAc 9 3280,1790,1760,1715. ""181-3380, 1790, 1760, 1715, 'SlCH2CONH-1F3 1665.
PhgliCONH----3370, 1785,1740, 1720, ""1675. rli FICONH Piu 1780, 1720, 1680.
PHIICONII-r,-5-TETR-1-Ph 145-1777, 1. 66 8 1597.
SCH-CONn-"-S-5-TETR-l-isoBu--3400, 1785,1680.
COOH COOHCONII-S5-TETR-1-isol3u---3385, 2G80-2525, 7. 780, ""1715, 1665.
HCONII-"-S-5-TETR-2-CH2COOTI---1783, 1732,1668. cool" PhCHCONH- Ph0HCONII-""---1790, 1730, 1635.
GOOH S HCONH-"-S-5-TETR-2-Me---1783, 1712, 1670. coon Ph HCCNII ""3lOU, 2920,2500,177 5, "1660.
Ph IICO\'EI-atc0-Onc COOCNO'-'--- TAHLE S (Part. 2) Physical Constants of
A Y Nu m. p KBt (cm~l) a-l'hCEl2CONII- H-OAc---3520, 1780,1740,1650, -G"'aH-S-5-TETR-l-Me 3400, 1787, 1740, 1650. oofl 142 C R""15G-3390, 1765,1670,1608, S/ IICONEI-160 1520.
COOSI Pli IICONII-ateo 110-1780, 1717, 1631.
1160 HO--CHCONH-"" 1780, 1719, 1632.
Oh ET'OO FICONH-""123-3385, 1785,1727,1705, C00-5-indanyl 126 lb31, 1G13, 1595.
FtCONH-""110-I780 170 5.
0011 114

Claims (1)

  1. WHAT WE CLAIM IS :- 1. A compound of the formula:
    wherein A is amino or substituted amino; B is hydroxy or a carboxy-protecting group; X is a group OR in which R is a group represented by the formula :
    in which Nu is a nucleophilic group; R'is a group represented by the formula :
    in which Ms is methylsulfonyl, Hal is halogen and R2 is optionally substituted alkyl or aryl ; and Y is hydrogen or methoxy ; provided that (a) when R is
    A is in the 3 position and Y is in the 3f3 position or A is in the 3/ ? position and Y is 3 -methoxy ; and (b) when R is-CH., COCHzNu and R1 is =PR23, A is in the 3 position and Y is in the 38 position or A is in the 3ss position and Y is 3 (Y-methoxy.
    2. A compound as claimed in claim 1 modified in that R'is any alkylidene group other than isopropylidene.
    3. A compound as claimed in claim 1 or claim 2, wherein the amino substituent (s) in the substituted amino group represented by A is/are selected from known side chains of natural or synthetic penicillins or cephalosporins.
    4. A compound as claimed in claim 1 or claim 2, wherein the amino substituent (s) in the substituted amino group represented by A is/are selected from acyl, hydrocarbyl, hydrocarbylidene, organic silyl or sulfenyl groups.
    5. A compound as claimed in claim 1 or claim 2, wherein A is an amino group substituted by one or more substituents as listed hereinbefore in generic or specific exemplification of group A.
    6. A compound as claimed in any one of claims 1 to 5, wherein B is a group as listed hereinbefore in generic or specific exemplification of group B.
    7. A compound as claimed in claim 6, wherein B is methoxy, t-butoxy, 2,2,2 trichloroethoxy, methanesulfonylethoxy, pivalovloxymethoxy, phenacyloxy, benzyloxy, p-methoxybenzyloxy, p-nitrobenzyloxy, benzhydryloxy, indanyloxy, or alkali or alkaline earth metal oxy.
    8. A compound as claimed in any one of claims 1 to 7, wherein R2 is a group as listed hereinbefore in generic or specific exemplification of group R'.
    9. A compound as claimed in any one of claims 1 to 8, wherein Nu is a group as listed hereinbefore in generic or specific exemplification of group Nu.
    10. A compound as claimed in claim 9, wherein Nu is hydroxy, acetoxy, acetyloxy, propionyloxy, methoxy, ethoxy, butoxy, mercapto, acetylthio, propionylthio, amidinothio, methylthio, benzvlthio, phenylthio, tetrazolythio, methyltetrazolylthio, butyltetrazo ylthio, pentyltetrazolvlthio, phenyltetrazolylthio, optionally protected carboxymethyl- tetrazolylthio, thiadiazolylthio, methylthiadiazolylthio, diphenylmethoxycarbonyl- methylthiadiazolylthio, triazolylthio, alkyl-dihydroxytriazinylthio, azido, chloro, or bromo.
    11. A compound represented by any one of the following formulae:
    wherein A is phenylacetamido, nhenoxyacetamido, or benzyloxycarbonamido ; B is diphenvlmethoxy or benzyloxy ; Hal is a halogen; Nu is tetrazol-5-ylthio, 1-methyl tetrazol-5-ylthio, 2-methyltetrazol-5-ylthio, 1-isobutyltetrazol-5-ylthio, 1-phenyl- tetrazol-5-ylthio, 1-carboxymethyltetrazol-5-ylthio, 1-t-butoxycarbonylmethyltetrazol-5ylthio, 2-t-butoxycarbonylmethyltetrazol-5-ykhio, 1, 3,4-thiadiazol-5-ylthio, 2-methyl1,3,4-thiadiazol-5-ylthio, 1-diphenylmethoxycarbonylmethyltetrazol-5-ylthio, 1,2,3triazol-4-yl-thio, hydroxy, methoxy, acetoxy, chloro or bromo ; and Y is hydrogen or methoxy.
    12. A compound represented by any one of the following formulae :
    wherein A is a phenylacetamido, phenoxyacetamido, or benzyloxycarbonamido ; B is diphenyl methoxy or benzyloxy ; Hal is halogen ; and Y is hydrogen or methoxy.
    13. A compound as claimed in claim 1 and as referred to hereinbefore.
    14. A process for the preparation of a compound of the formula :
    wherein A, B and Y are as defined in claim 1, which process comprises reacting a compound of the formula :
    with propargyl alcohol, optionally substituted by halogen at the terminal acetylenic carbon.
    15. A process for preparing a compound of the formula:
    wherein A, B, Hal and Y are as defined in claim 1, which process comprises reacting a compound of the formula:
    with a halogenating reagent.
    16. A process for preparing a compound of the formula:
    wherein A, B, Hal and Y are as defined in claim 1, which process comprises treating a compound of the formula:
    with water in the presence of a catalyst.
    17. A process for the preparation of a compound of the formula :
    wherein A, B. Y and Nu are as defined in claim 1, which process comprises treating a compound of the formula:
    with a salt of nucleophile Nu.
    18. A process for preparing a compound represented by the formula:
    whereinA, B and Y are as defined in claim 1, which process comprises reducing a compound represented by the formula :
    19. A process for preparing a compound represenred by the formula:
    wherein A. B and Y are as defined in claim 1, which process comprises epoxidizing a comnound represented by the formula:
    or treating a compound of the formula:
    which is a halohydrin, with a base.
    20. A process for preparing a compound represented by the formula :
    wherein A, B, Nu and Y are as defined in claim 1, which process comprises either treating a compound represented by the formula:
    with a nucleophilic reagent represented by the formula: HNu, or with a reactive derivative thereof ; or reacting a hypohalogenous acid with a compound of the formula:
    Z1. A process for preparing a compound represented by the formula:
    wherein A, B, Nu and Y are as defined in claim 1, which process comprises oxidizing a compound represented by the formula:
    22. A process for preparing a compound represented by the formula:
    wherein A, B, Nu and Y are as defined in claim 1, which process comprises oxidizing a compound represented by the formula,
    23. A process for preparing a compound represented by the formula :
    wherein A, B, Nu and Y are as defined in claim 1, which process comprises reducing a compound represented by the formula :
    24. A process for prepparing a compound represented by the formula:
    wherein A, B, Nu. Hal and Y are defined in claim 1, which process comprises halogenating a compound represented by the formula:
    25. A process as claimed in claim 24 but modified by the employment of sulfonylation instead of halogenation.
    26. A process for preparing a compound represented by the formula:
    wherein A, B, Nu, R2 and Y are as defined in claim 1 which process comprises creating a compound represented by the formula:
    or a similar compound with a sulfonyloxy group instead of halogen, with a phosphine compound represented by the formula : PR2. s
    27. A process for preparing a compound of the formula :
    wherein A, B and Y are as defined in claim 1, which process comprises oxidizing a compound of the formula :
    28. A process for preparing a compound of the formula:
    wherein A, B and Y are as defined in claim 1, which process comprises reducing a compound of the formula:
    29. A process for preparing a compound of the formula:
    wherein A, B, Hal and Y are as in claim 1, which process comprises subjecting a compound of the formula:
    to epoxide ring fission and halogenation.
    30. A process as claimed in claim 29 but modified by the employment of sulfonylation instead of halogenation.
    31. A process for preparing a compound of the formula:
    wherein A. B. R2 and Hal and Y are as in claim 1, which process comprises reacting a compound of the formula:
    with a compound of the formula PR23.
    32. A process for preparing a compound of the formula:
    wherein As B, R2 and Y are as in claim 1 and Nu is halogen, which process comprises oxidizing a compound of the formula:
    33. A process for preparing a compound represented by the formula:
    wherein A, B, Nu and Y are as in claim 1, which process comprises warming a compound of the formula:
    R2 being as defined above, in an inert solvent, optionally followed, when A is substituted amino, by deacylation.
    34. A process for preparing a compound of the formula:
    wherein A, R, RI and B are as in claim 1, which process comprises methylating a compound of the :
    35. A nrocess for preparing a compound as claimed in claim 1, which process comprises subiecting another compound as claimed in claim 1 to one or more reactions of the tyne outlined and exemplified hereinbefore as processes A to M and Q.
    36. A process as claimed in claim 35, wherein the starting compound as claimed in claim 1 has been prepared from a compound of the formula:
    wherein A, B, Hal and Y are as defined in claim 1 by one or more reactions of the type outlined and exemplified hereinbefore as processes A to M and Q.
    37. A process as claimed in claim 35, wherein the starting compound as claimed in claim 1 is a compound of the formula:
    wherein A, B, Hal and Y are as defined in claim 1.
    38. A process as claimed in claim 36 or claim 37, wherein the 4-halo compound has been prepared from a penicillin by penam cleavage.
    39. A process for preparing a compound as claimed in claim 1 and substantially as hereinbefore described.
    40. A process for preparing a compound as claimed in claim 1 and su6stantially as hereinbefore described in any one of the individual runs of Examples A to M and Q including Tables D, E, H, I, J, K, L, M, N, and R.
    41. A compound as claimed in claim 1 which has been prepared in a process as claimed in any one of claims 14 to 32,34, or 35 to 40.
    42. A process f^s pxparing a l-dethia-l-oxo-cephem compound which comprises at least one reaction of the type outlined and exemplified hereinbefore as reactions N and P.
    43. A process for preparing a l-dethia-l-oxa-cephem compound and substan- tially as hereinbefore described in Examples N and P including Tables P and Q.
    44. A 1-dethia-l-oxa-cephem compound which has been prepared in a process as claimed in any one of claims 33,42 or 43.
    45. A pharmaceutical or veterinary formulation comprising a compound as claimed in claim 1 or claim 41 and having anti-bacterial activity or a 1-dethia-l-oxa- cephem compound as claimed in claim 44, the compound of 1-dethia--oxa-cephem compound as claimed in claim 44, the compound or 1-dethia-l-oxa-cephem compound being formulated for pharmaceutical or veterinary use, respectively.
    46. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1 or claim 41 and having anti-bacterial activity or a 1-dethia-1-oxacephem compound as claimed in claim 44, and a pharmaceutically acceptable or veterinarily acceptable, respectively, diluent, carrier or excipient.
    47. A formulation as claimed in claim 45 or a composition as claimed in claim 46 and in unit dosage form.
    48. A method of inhibiting the growth of bacteria in an environment, which method comprises administering to the environment an effective amount of a compound as claimed in claim 1 or claim 41 and having antibacterial activity, a 1-dethia 1-oxa-cephem compound as claimed in claim 44, a composition as claimed in claim 46 or claim 47, or a formulation as claimed in claim 45 or claim 47.
    49. A method as claimed in claim 48 when used in sterilising an environment, in preserving a perishable substance, article or material, in treating decay, or in the treatment or prevention of disease caused by bacteria in a non-human animal.
GB33109/76A 1976-08-09 1976-08-09 Intermediates for cephalosporin analogues Expired GB1592245A (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
GB33109/76A GB1592245A (en) 1976-08-09 1976-08-09 Intermediates for cephalosporin analogues
IL52685A IL52685A (en) 1976-08-09 1977-08-08 3-amino-2-oxo-azetidinyl acetic acid derivatives,their preparation and a process for the preparation of 1-dethia-1-oxa-cephalosporins
IE1653/77A IE45650B1 (en) 1976-08-09 1977-08-08 Intermediates for cephalosporin analogues
CA284,398A CA1076125A (en) 1976-08-09 1977-08-08 Intermediates for cephalosporin analogues
FR7724548A FR2361365A1 (en) 1976-08-09 1977-08-09 PROCESS FOR PREPARING INTERMEDIATE COMPOUNDS FOR THE SYNTHESIS OF 1-OXACEPHALOSPORINS AND NEW PRODUCTS THUS OBTAINED
DE19772735854 DE2735854A1 (en) 1976-08-09 1977-08-09 2-OXOACETIDINE DERIVATIVES
JP52095878A JPS6041669B2 (en) 1976-08-09 1977-08-09 Intermediate for oxacephalosporin synthesis
NLAANVRAGE7708790,A NL190374C (en) 1976-08-09 1977-08-09 PROCESS FOR PREPARING A 1-OXA-1 DETHIACEPHALOSPORINE DERIVATIVE.
CH973977A CH641183A5 (en) 1976-08-09 1977-08-09 SYNTHESIS OF OXACEPHALOSPORINES.
BE180027A BE857622A (en) 1976-08-09 1977-08-09 INTERMEDIARIES FOR THE SYNTHESIS OF OXACEPHALOSPORINS
FR7804158A FR2370729A1 (en) 1976-08-09 1978-02-14 PROCESS AND PREPARATION OF AZETIDINONES WITH REDUCTION OF AN OXO GROUP AND NEW PRODUCTS THUS OBTAINED
FR7804159A FR2370730A1 (en) 1976-08-09 1978-02-14 PROCESS FOR THE PREPARATION OF AZETIDINONE COMPOUNDS AND NEW PRODUCTS THUS OBTAINED
US06/589,670 US4592865A (en) 1976-08-09 1984-03-13 Azetidinone intermediates for cephalosporin analogs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB33109/76A GB1592245A (en) 1976-08-09 1976-08-09 Intermediates for cephalosporin analogues

Publications (1)

Publication Number Publication Date
GB1592245A true GB1592245A (en) 1981-07-01

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Application Number Title Priority Date Filing Date
GB33109/76A Expired GB1592245A (en) 1976-08-09 1976-08-09 Intermediates for cephalosporin analogues

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BE (1) BE857622A (en)
GB (1) GB1592245A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0081824A1 (en) * 1981-12-11 1983-06-22 Meiji Seika Kaisha Ltd. Processes for the production of antibiotic 1-oxadethiacephalosporins
US4534898A (en) * 1982-07-23 1985-08-13 Merck & Co., Inc. 1-Oxa-1-dethia-cephalosporin derivatives

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0081824A1 (en) * 1981-12-11 1983-06-22 Meiji Seika Kaisha Ltd. Processes for the production of antibiotic 1-oxadethiacephalosporins
US4534898A (en) * 1982-07-23 1985-08-13 Merck & Co., Inc. 1-Oxa-1-dethia-cephalosporin derivatives

Also Published As

Publication number Publication date
BE857622A (en) 1978-02-09

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Effective date: 19961109