IE44133B1 - Process for preparing 2-cephem compounds - Google Patents
Process for preparing 2-cephem compoundsInfo
- Publication number
- IE44133B1 IE44133B1 IE2598/76A IE259876A IE44133B1 IE 44133 B1 IE44133 B1 IE 44133B1 IE 2598/76 A IE2598/76 A IE 2598/76A IE 259876 A IE259876 A IE 259876A IE 44133 B1 IE44133 B1 IE 44133B1
- Authority
- IE
- Ireland
- Prior art keywords
- carboxylate
- formula
- nitrobenzyl
- cephem
- oxide
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
3-Acyloxymethyl-delta<2>-cephem compounds of the formula (I) in which the substituents are defined in Claim 1, are obtained by reacting a 3-exomethylenecepham sulphoxide with a mixture of an acyl compound and of an appropriate anhydride at a temperature from 70 to 140 DEG C. The 3-acyloxymethyl-delta<2>-cephem esters of the formula I are generally valuable intermediates in the preparation of cephalosporins with antibiotic activity.
Description
The present invention relates to a novel process whereby a 3-exomethylenecephain sulfoxide ester is reacted with a mixture of a C^-C^ acyl chloride or carboxylic acid and a corresponding C^-C^ acid anhydride at a tempera5 ture of from 70°C. to 130°C- to produce the 2 corresponding 3-acyloxymethyl-4 -cephem, which is useful as an intermediate in the preparation of antibiotically active cephalosporins.
Cephalosporin antibiotics having an acyloxymethyl 10 group at the C3 carbon atom of the cephem nucleus are well recognized in the cephalosporin art, see, for example, United States Patents Nos. 3,270,009; 3,278,531; 3,532,694; 3,705,897; 3,728,342; and 3,795,672. New methods for preparing these cephalosporins continually are being sought.
This invention is directed to a process for preparing 2
3-acyloxymethyl-& -cephem compounds, which compounds are readily convertible by recognized techniques to the aforementioned 3-acyloxymethyl cephalosporin antibiotics.
Recently, 3-exomethylenecepham esters have been 20 described, for example, in Chauvette et al., J. Org. Chem.,
2994 (1973); and in U,S. Patent No. 3,792,995. These compounds have the general formula
YA
Y/Khb
CO
COORi wherein R is hydrogen or an acyl group and R^ is hydrogen.
-24 413 3 pounds is useful as intermediates in the preparation of the aforementioned 3-acyloxymethyl cephalosporins (3-acyloxy3 methyl-Δ -cephem compounds).
This invention is directed to a novel process for preparing a compound of the formula
which comprises reacting a 3-exomethylenecepham sulfoxide of the formula o
+
-444133
The corresponding sulfoxides of Formula XI below are starting materials employed in the process of this invention and are readily available from the corresponding 3-exomethylenecepham esters by known methods. For example, a 3-exomethyl5 enecepham acid or ester can be reacted with a peracid, for example, m-chloroperbenzoic acid, perbenzoic acid or peracetic acid, to form the corresponding sulfoxide.
The 3-exo double bond of the starting material is inert under these conditions of sulfoxide formation, and, con10 sequently, the sulfoxide is prepared by the selective oxidation of the sulfide.
The sulfoxide ester starting materials alternatively and preferably are prepared by a process described by S. Kukolja in co-pending United States Applications Serial.Itos. 536,273
Specification No. 4,081,440, and 536,280, Specification No. 4,052,387, both filed December 24, 1974. According to these described methods, a penicillanic acid ester sulfoxide is reacted with an N-chloro halogenating agent in a dry, inert organic solvent at a temperature between about 70°C. and about 100°C. to provide an azet20 idinone sulfinyl chloride. The sulfinyl chloride then is reacted with a Lewis acid Friedel-Crafts type catalyst in a dry, inert, organic solvent to effect cyclization and to provide the 3-exomethylenecepham sulfoxide ester.
As indicated, the 3-exomethylenecepham sulfoxide esters represent the starting materials of the process of this invention, and it has now been discovered that it is possible to convert these sulfoxide esters to their corre2 sponding 3-acyloxymethyl-A -cephems, which class of com-344X33 with a mixture of an acyl compound of the formula
R4-C-X III in which X is chloro or hydroxy, and a corresponding anhydride of the formula (R4-C-)2o IV at a temperature of from 70°C. to 130°C., in which, in the above formulae, R4 is C1-C|} alkyl, R^ ig a carboxylic acid protecting group, and R is (1) an imido group of the formula
in which l<2 is C2-C4 alkenylene or 1,2-phenylene;
(2) an amido group of the formula 0
R3-C-NHin which R3 is (a) hydrogen, C^-C3 alkyl, halomethyl, benzyloxy,
4-nitrobenzyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzyloxy,
3-(2-chlorophenyl)-5-methylisoxazol-4-yl or 4-chloroacetoxybenzyl;
(b) the group R' in which R' is phenyl or phenyl substituted with 1 or 2 radicals selected from halogens, nitro, cyano, trifluoromethyl, C-pC^ alkyl, or Cj-C4 alkoxy;
(c) a group of the formula R'-(O) -CHj- in which R' is as defined above and m is 0 or 1;
-544133 (d) a group of the formula R’’-CH- in which
COORjR is R' as defined above, 2-thienyl, or 3-thienyl, and R^ is as defined above; or (e) a group of the formula R,,'-CH2- in which
R'1' is 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-thiazolyl, 5-tetrazolyl, 1-tetrazolyl, or 4-isoxazolyl; or (3) an imidazolidinyl group of the formula
in which R' is as defined above and U is nitroso or acetyl.
Rj in the above formulae I and II denotes a carboxylic acid protecting group, and, preferably, one which is removable by hydrogenation. Preferred carboxylic acid protecting groups include, for example, 2,2,2-trihaloethyl, benzyl, g-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, C2-Cg alkanoyloxymethyl, dimethylallyl, phenacyl, or p-halophenacyl, in any of the above of which halo denotes chlorine, bromine or iodine.
Specific illustrations of the preferred carboxylic acid protecting groups include, for example, 2,2,2-trichloroethyl, 2,2,2-t.ribromoethyl, benzyl, g-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, phenacyl, p-chlorophenacyl and g-bromophenacyl.
Highly preferred carboxylic acid protecting groups are benzyl, g-nitrobenzyl, p-methoxybenzyl, 2,2,2-trichloroethyl, phenacyl, g-chlorophenacyl, and p-bromophenacyl.
-64413
Most preferred carboxylic acid protecting groups are £-nitrobenzyl and 2,2,2-trichloroethyl.
The group R in the 7-position of the 3-exomethylenecepham sulfoxide starting materials of Formula II and the 2
3-acyloxymethyl-A -cephem products of Formula I is, m part, 0 defined as R^-C-NH-.
Specific illustrations of R^ include, for example, hydrogen, methyl, ethyl, n-propyl, isopropyl, chloromethyl, bromomethyl, benzyloxy, 4-nitrobenzyloxy,
2,2,2-trichloroethoxy, 4-methoxybenzyloxy, phenyl, 2chlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-nitrophenyl, 2-cyanophenyl, 4-trifluoromethylphenyl, 3-methylphenyl, 2-ethylphenyl, 4-n-propylphenyl, 4-t-butyl15 phenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 3-isopropyloxyphenyl, 4-isobutyloxyphenyl, benzyl, 3-bromobenzyl, 2,5dichlorobenzyl, 4-chloroacetoxybenzyl, 2-nitrobenzyl,
3- cyanobenzyl, 3-trifluoromethylbenzyl, 3-methylbenzyl,
4- n-butylbenzyl, 2-methoxybenzyl, 3-isopropoxybenzyl, phenoxymethyl, 3-iodophenoxymethyl, 4-fluorophenoxymethyl, 3-chloro-4-fluorophenoxymethyl, 2,5-dichlorophenoxymethyl, 3-isopropoxyphenoxymethyl, 4-ethylphenoxymethyl, 4-chlorophenoxymethyl, 3-nitrophenoxymethyl, 4-cyanophenoxymethyl, 2-trifluoromethylphenoxymethyl, 3-methylphenoxymethyl,
4-n-propylphenoxymethyl, 4-n-butylphenoxymethyl, 3-methoxyphenoxymethyl, 4-ethoxyphenoxymethyl, a-(benzayloxycarbonyl) thien-2-ylmethyl, a-(4-nitrobenzyloxycarbonyl)-thien-2ylmethyl, a-(4-methoxybenzyloxycarbonyl)-thien-2-ylmethyl, a-(phenacyloxycarbonyl)-thien-3-ylmethyl, a-(4-nitrobenzyl30 oxycarbonyl)-thien-3-ylmethyl, a-(benzyloxycarbonyl) -744133 thien-3-yImethyl, a- (acetoxymethoxycarbonyl)-thien-2ylmethyl, a-(benzyloxycarbonyl)benzyl, a-(4-nitrobenzyloxycarbonyl)benzyl, a-(4-methoxybenzyloxycarbonyl) benzyl, a-(2,2,2-trichloroethoxycarbonyl) benzyl, a-(g-chlorophen5 acyloxycarbonyl)-4-bromobenzyl, a-(benzyloxycarbonyl)3-chlorobenzyl, a-(4-nitrobenzyloxycarbonyl)-4-fluorobenzyl, a-(4-nitrobenzyloxycarbonyl)-3-methoxybenzyl, a-(4-methoxybenzyloxycarbonyl) -4-isopropoxybenzyl, a-benzyloxycarbonyl3-nitrobenzyl, a-(4-nitrobenzyloxycarbonyl)-2-cyanobenzyl, a-(g-bromophenacyloxycarbonyl)-4-trifluoromethylbenzyl, a-(4-nitrobenzyloxycarbonyl)-4-methylbenzyl, a-benzyloxycarbonyl-3-n-butylbenzyl, a-(benzyloxycarbonyl)-4-methoxybenzyl, a-(4-nitrobenzyloxycarbonyl)-3-isopropoxybenzyl, thien-2-ylmethyl, thien-3-yImethyl, fur-2-ylmethyl, fur-315 ylmethyl, thiazol-2-ylmethyl, tetrazol-5-yImethyl, tetrazol1-ylmethyl, isoxa2ol-4-yImethyl and 3-(2-chlorophenyl)-5methylisoxazol-4-yl.
In portions of the definition of this invention, the group -COOR^ appears. This represents a protected carboxy group.
The term protected carboxy refers to a carboxy group which has been protected by one of the commonly used carboxylic acid protecting groups employed to block or protect the carboxylic acid functionality of a compound while a reaction or sequence of reactions involving other functional sites of the compound are carried out. Such protected carboxy groups are noted for their ease of cleavage to the corresponding carboxylic acid by hydrogenolytic methods. Examples of carboxylic acid protecting groups
-844133 include benzyl, 4-methoxybenzyl, C2-Cg alkanoyloxymethyl, 4-nitrobenzyl, phenacyl, £-halophenacyl, dimethylallyl,
2,2,2-trichloroethyl and succinimidomethyl. The nature of such ester forming groups is not critical so long as the ester formed therewith is stable under the reaction conditions of the process of this invention. Furthermore, other known carboxy protecting groups such as those described by
E. Haslam in Protective Groups in Organic Chemistry,
Chapter 5, are considered to be within the term protected carboxy as used herein.
Preferred R^ groups which participate in the overall definition of the term protected carboxy are benzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2,2,2-trichloroethyl, phenacyl, and £-halophenacyl.
In the foregoing discussion, carboxy protecting groups, of course, are not exhaustively described. The function of these groups is to protect reactive functional groups during preparation of a desired product. They then can be removed without disruption of the remainder of the molecule. Many such protecting groups are well known in the art, and their use is equally applicable in the process of this invention.
The process of this invention also can be carried out using 3-exomethylenecepham sulfoxides of Formula II in which R is a cyclic imido group of the formula
-944133
This cyclic imido group, defined by R2 taken together with the nitrogen-carbonyl combination to which it is bonded, can be formed by reacting the 7-amino group of a 7-amino-3-exomethylenecepham ester sulphoxide viith a decaxboxylic acid or anhydride or other reactive variant thereof, followed by reacting the resulting derivative with a to alkyl haloformate, for exajnple, ethyl chloroformate, in the presence of an organic base. R2 is Cj-C^ alkenylene or 1,2phenylene and can be considered as being the residue of a dicarboxylic acid, the cyclic imide thus represented being prepared from such dicarboxylic acid, its anhydride, or an appropriate reactive variant thereof. Cyclic imides can be prepared, for example, from acids such as maleic, methylmaleic and phthalic acid, or their respective anhydrides, as well as related compounds and compounds of similar reactivities. Additional examples of cyclic anhydrides of the type defined are found in the prior art, such as in the Journal of Organic Chemistry, Volume 26, pp. 3365-3367 (September,
1961).
In addition, the group R in Formulae I and II can be an imidazolidinyl group of the formula
in which U is nitroso or acetyl and R' is phenyl or phenyl substituted with 1 or 2 radicals selected from halogens, nitro cyano, trifluoromethyl, C^-C^ alkyl, and C^-C^ alkoxy.
-1044133
The group thus represented is a 2,2,2-dimethy13- nitroso-5-oxo-4-(substituted)-imidazolidin-l-yl group or a
2,2-dimethyl-3-acetyl-5-oxo-4-(substituted)-imidazolidin1- yl group, and the 4-substituent (R') in the imidazolidinyl 5 formula typically includes phenyl, 3-bromophenyl, 2chlorophenyl, 4-fluorophenyl, 3-iodophenyl, 3-chloro4- fluorophenyl, 2-chloro-4-bromophenyl, 4-nitrophenyl,
2- cyanophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 3ethylphenyl, 4-isopropylphenyl, 4-t-butylphenyl, 3-methoxy10 phenyl, 2-ethoxyphenyl, 4-n-propoxyphenyl, 3-isopropoxyphenyl or 4-isobutoxyphenyl.
The 3-exomethylenecepham sulfoxide starting materials of Formula II in which R is the aforedescribed imidazolidinyl group can be prepared in accordance with known techniques by reacting an exomethylenecepham of the formula
or its corresponding free acid with acetone under moderately basic conditions to produce the labile intermediate of the formula
ioORi
-1144133
This product then, is converted to the stable N-nitroso or N-acetyl derivative in which R is the aforedescribed imidazolidinyl group by treating the product with sodium nitrite or acetic anhydride under acidic conditions and with cooling. The resulting product then can be oxidized to the corresponding sulfoxide of Formula II by well recognized techniques. These preparations are detailed in Gottstein et al., J. Org. Chem., 37 (1972) 2765; and Heusler, Helvetica Chimica Acta, 55 (1972) 388.
As will be apparent to those of ordinary skill in the penicillin and cephalosporin arts, any of the 3-exomethylenecepham sulfoxide starting materials of Formula II are readily preparable from available penicillin sources, such as naturally occurring Penicillin G and/or Penicillin V.
6-Aminopenicillanic acid (6-APA) can be prepared from either of the above naturally-occurring penicillins by cleavage of the 6-acyl function employing techniques well known in the art.
It is possible to prepare, by widely recognized techniques and from 6-APA, any of the starting materials of Formula II. For example, 6-APA can be converted to the desired ester by esterification of the 3-carboxyl function employing any of several typical esterification techniques.
Furthermore, the amino group of 6-APA can be acylated to produce any of the groups defined herein by the term R. This is achieved by reacting 6-APA with an activated form of the acid of the intended acyl group. Such activated forms include the corresponding acid halides, anhydrides, or activated esters, such as the pentachlorophenyl ester.
-1244133
Likewise, the penicillin can be oxidized to the sulfoxide under any of a wide variety of recognized conditions, including treatment of the penicillin with mchloroperbenzoic acid or sodium periodate.
These conversions, cleavage to 6-APA, esterification, acylation, and oxidation, can be carried out in any sequence consistent with the intended structural modifications. In any event, all such conversions can be accomplished employing techniques, conditions, and reagents readily available to and well recognized by one of ordinary skill in the art.
Once the penicillin sulfoxide ester of the formula +
has been obtained, it can be converted to the corresponding 15 3-exomethylenecepham sulfoxide of Formula II by treatment with an N-chloro halogenating agent, for example, N-chlorosuccinimide or N-chlorophthalimide, in a dry, inert solvent, for example, 1,1,2-trichloroethane or toluene, at a temperature of from about 75°C. to about 135°C. to provide an azetidinone sulfinyl chloride of the formula
loORi
-1344133
The sulfinyl chloride then is reacted with a Lewis acid Friedel-Crafts type catalyst in a dry, inert, organic solvent to effect cyclization and to provide the desired
3-exomethylenecepham sulfoxide ester of Formula XI, a starting material of the process of this invention.
Lewis acid Friedel-Crafts catalysts which are useful in the cyclization of the azetidinone sulfinyl chloride include, for example, stannic chloride, zinc chloride, zinc bromide, titanium tetrachloride, and zir10 conium chloride. Stannic chloride is the preferred catalyst for cyclization. The cyclization is carried out at a temperature of from about 20°C. to about 85°C. and in an inert solvent, preferably an aprotic organic solvent, for example, an aromatic hydrocarbon such as benzene, toluene or xylene; or a halogenated aliphatic hydrocarbon such as methylene chloride, 1,2-dichloroethane or 1,1,2-trichloroethane.
As an example of the foregoing preparation of a starting material useful in this process, a solution of p-nitrobenzyl 6-phenoxyacetamidopenicillanate sulfoxide in dry toluene is treated with 1.1 molar equivalents of Nchlorosuccinimide, and the reaction mixture is refluxed for about 90 minutes. The reaction mixture containing gnitrobenzyl 3-methyl-2-(2-chlorosulfinyl-4-oxo-3-phenoxy25 acetamido-l-azetidinyl)-3-butenoate (the sulfinyl chloride intermediate), is cooled to a temperature of about 50°C., and 1.1 molar equivalents of anhydrous stannic chloride are added. The mixture thus obtained is stirred at room temperature for about 90 minutes. Water and ethyl acetate are
-1444133 added to the reaction mixture, and the organic layer is separated. The organic layer containing the product is washed with dilute acid, dilute sodium bicarbonate solution, and then with brine. The washed organic layer then is dried and evaporated to yield g-nitrobenzyl 7-phenoxyacatamido3~exomethylenecepham-4-earboxylate-l-oxide.
Preferred 3-exomethylenecepham sulfoxide esters of Formula II for use as starting materials in the process of this invention are those having the formula '·--r ll (O)m-CHz-C-NH^ (/ +
loORi in which m is O or 1 and R^ is a carboxylic acid protecting group.
Correspondingly, the preferred 3-acyloxymethyl2
Λ -cephem ester products of Formula I obtained from the process of this invention are those of the formula •err· / \ \ z (/ v \ 0
Π ί
I-ώ «-CHt-O-C-Ri ί
COOR, in which m is 0 or 1, R^ is a carboxylic acid protecting group, and R^ is C^-C4 alkyl, and, more preferably, methyl.
Another class of preferred 3-exomethylenecepham sulfoxide esters of Formula II for use in the process of this invention are those having the formula
-1544133
II
-CHs-C-l
NH^ . /\ i=u \/ CHa
CO
COORi in which R^ is a carboxylic acid protecting group.
The 3-acyloxymethyl-6 -cephem esters of Formula 1 produced from the aforementioned preferred class have the formula
-CHa-C-NHx aa ίο
II
0-C-R.i
COORi in which R1 is a carboxylic acid protecting group and R^ is Ci~C^ alkyl, and, more preferably, methyl.
-1644133
The conversion of the 3-exomethylenecepham sul2 foxide to the corresponding 3-acyIoxymethyl-Δ -cephem may be accomplished by reaction with a mixture of an acyl compound of the formula
R.—C—X III and a corresponding anhydride of the formula (r4-C-)2o IV in which X is chloro or hydroxy, and R^ is C^-C^ alkyl.
Thus, the acyl compounds which can be employed include, for example, acetyl chloride, propionyl chloride, n-butyryl chloride, isobutyryl chloride, valeryl chloride, trimethylacetyl chloride, α-methylbutyryl chloride, B-methyIbutyryl chloride, acetic acid, propionic acid, n-butyric acid, isobutyric acid, valeric acid, trimethylacetic acid, a-methyl15 butyric acid and B-methylbutyric acid. As indicated above, each of these acyl compounds is employed in combination with its corresponding symmetrical acid anhydride. For example, when it is intended that the product be a 3-propionoxy2 methyl-Λ -cephem ester, a mixture of propionyl chloride and propionic anhydride, or of propionic acid and propionic anhydride, is employed. It is highly preferred, in the
174133 process of this invention, that a mixture of acetyl chloride and acetic anhydride, or of acetic acid and acetic anhydride, be employed, thereby producing, as product, a 3-acetoxy2 methyl-Δ -cephem ester.
In carrying out the process of this invention with an acyl compound wherein X represents chloro, the 3-exomethylenecepham sulfoxide of Formula II is mixed with a mixture of the selected acyl chloride of Formula III and its corresponding anhydride of Formula IV. Generally, the molar ratio of acyl chloride to 3-exomethylenecepham sulfoxide is from about 1130 to about 3:2, and, preferably, from about 1:20 to about 1:1. In addition, the corresponding anhydride which is employed generally is present in an amount representing at least a molar equivalent relative to the amount of 3-exomethylenecepham sulfoxide and preferably in an amount representing about a ten-fold molar excess. An even larger excess can be employed without detriment; however, no advantage is apparent from the use of such a vast excess.
In carrying out the process of this invention with an acyl compound wherein X represents hydroxy, the 3-exomethylenecepham sulfoxide is mixed with a mixture of the selected carboxylic acid and its corresponding anhydride. Generally, the molar ratio of carboxylic acid to anhydride is from 1:12 to 35:1, and, preferably, from
-18^4133
2:5 to 7:1. Generally at least one and preferably from 1 to 40 millimoles of anhydride, and from 2 to 65 millimoles of acid, at least, will be used per each millimole of 3-exomethylenecepham sulfoxide. A large excess of the acylating mixture can be employed without detriment; however, no advantage is apparent from the use of a vast excess of the acid-anhydride mixture. Preferably, therefore, the acid-anhydride mixture is present in amounts from 2 to 250 millimoles of anhydride, and from
4 to 400 millimoles of acid, per each millimole of the
3-exomethylenecepham sulfoxide.
1944133
Typically, the 3-exomethylenecepham sulfoxide is added to the prepared mixture of the acyl compound and its corresponding anhydride. The resulting mixture then is heated at a temperature of from about 70°C. to about 130°C.
for a time sufficient to achieve conversion to the desired 2
3-acyloxymethyl-A -cephem compound of Formula I. The time necessary to achieve reaction can vary over a wide range, and, typically, will be from about 2 hours to about 80 hours, and, preferably, from about 4 hours to about 6 hours.
It is possible to employ an inert organic solvent in addition to the acylating mixture, particularly when an acyl chloride is used. However, this is not essential, and it does not in any way contribute to the success of the reaction. Examples of inert organic solvents which can be employed include aromatic hydrocarbons, such as benzene, toluene and ethylbenzene; chlorinated hydrocarbons, such as chlorobenzene, carbon tetrachloride and 1,1,2-trichloroethane; and esters, such as ethyl acetate, butyl acetate and ethyl propionate.
The resulting 3-acyloxymethyl-A -cephem product is readily recovered by evaporation of the excess materials and purification of the resulting residue by employing conventional techniques. Such techniques include, for example, chromatographic separation, filtration, crystallization and recrys25 tallization.
Examples of conversions which are available in accordance with the process of this invention include:
£-nitrobenzyl 7-maleimido-3-methylenecepham-4carboxylate-l-oxide to p-nitrobenzyl 7-maleimido-3-acetoxy30 methyl-2-cephem-4-carboxylate;
-2044133
2,2,2-trichloroethyl 7-phthalimido-3-methylenecepham-4-carboxylate-l-oxide to 2,2,2-trichloroethyl 7phthalimido-3~propionoxymethyl-2-cephem-4-carboxylate;
benzyl 7-formamido-3-methylenecepham-4-carboxylate-l-oxide to benzyl 7-formamido-3-butyroxymethyl-2cephem-4-carboxylate;
2,2,2-trichloroethyl 7-acetamido-3-methylenecepham-4-carboxylate-l-oxide to 2,2,2-trichloroethyl 7acetamido-3-acetoxymethyl-2-cephem-4-earboxylate;
£-nitrobenzyl 7-butyramido-3-methylenecepham4-carboxylate-l-oxide to g-nitrobenzyl 7-butyramido-3acetoxymethyl-2-cephem-4-carboxylate;
jg-methoxybenzyl 7-chloroacetamido-3-methylenecepham-4-carboxylate-l-oxide to jg-methoxybenzyl 7-chloroacetamido-3-propionoxymethyl-2-cephem-4-carboxylate;
g-nitrobenzyl 7-(4'-nitrobenzyloxycarboxamido)3-methylenecepham-4-carboxylate-l-oxide to jg-nitrobenzyl
7-(4’-nitrobenzyloxycarboxamido)-3-isobutyroxymethyl-2cephem-4-carboxylate;
jg-chlorophenacyl 7-benzyloxycarboxamido-3methylenecepham-4-carboxylate-l-oxide to jg-chlorophenacyl 7-benzyioxycarboxamido-3~valeroxymethyl-2-cephe!n~4-carboxylate;
succinimidomethyl 7-(benzyloxycarboxamido)-3methylenecepham-4-carboxylate-l-oxide to succinimidomethyl
7-(benzyloxycarboxamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
-2144133
2,2,2-trichloroethyl 7-(2',2',2'-trichloroethoxycarboxamido)-3-methylenecepham-4-carboxylate-l-oxide to
2,2,2-trichloroethyl 7-(2^2^21 -trichloroethoxycarboxamido) 3-propionoxymethyl-2-cephem-4-carboxylate;
acetoxymethyl 7-(4'-methoxybenzyloxycarboxamido)3- methylenecepham-4-carboxylate-l-oxide to acetoxymethyl 7- (4 ’-methoxybenzyloxycarboxamido)-3-acetoxymethyl-2cephem-4-carboxylate;
benzyl 7-phenoxyacetamido-3-methylenecepham4- carboxylate-l-oxide to benzyl 7~phenoxyacetamido-3acetoxymethyl-2-cephem-4-carboxylate;
phthalimidomethyl 7-benzamido-3-methylenecepham4-carboxylate-l-oxide to phthalimidomethyl 7-benzamido-3a.-methylbutyroxymethyl-2-cephem-4-carboxylate;
phenacyl 7-(4'-chlorobenzamido)-3-methylenecepham4-carboxylate-1-oxide to phenacyl 7-(4’-chlorobenzamido)3-acetoxymethyl-2-cephem-4-carboxylate;
•gpchlorophenacyl 7-(3'-bromobenzamido)-3-methylenecepham-4-carboxylate-l-oxide to p-chlorophenacyl 7—(3*— bromobenzamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
pivaloyloxymethyl 7-(4'-nitrobenzamido)-3methylenecepham-4-carboxylate-l-oxide to pivaloyloxymethyl 7-(4'-nitrobenzamido)-3-propionoxymethyl-2-cephem-4carboxylate;
acetoxymethyl 7-(2'-cyanobenzamido)-3-methylenecepham-4-carboxylate-l-oxide to acetoxymethyl 7-(2'-cyanobenzamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
-224 4 13 3 succinimidomethyl 7-(4'-trifluoromethylbenzamido)-3-methyleneeepham-4-carboxylate-l-oxide to succinimidomethyl 7-(4'-trifluoromethylbenzamido)-3-fS-methylbutyroxymethyl-2-cephem-4-carboxylate;
phthalimidomethyl 7-(3’-methylbenzamido)-3methylenecepham-4-carboxylate-l-oxide to phthalimidomethyl 7-(3'-methylbenzamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
2.2.2- tribromoethyl 7-(2'-methoxybenzamido)-3methylenecepham-4-carboxylate-1-oxide to 2,2,2-tribromoethyl 7- (2'-methoxybenzamido)-3-valeroxymethyl-2-cephem-4carboxylate;
propionoxymethyl 7-phenylacetamido-3-methylenecepham-4-carboxylate-1-oxide to propionoxymethyl 7-phenylacetamido-3-acetoxymethyl-2-cephem-4-carboxylate;
g-nitrobenzyl 7-(2'-thienylacetamido)-3-methylenecepham-4-carboxylate-l-oxide to g-nitrobenzyl 7—(2’— thienylacetamido)-3-propionoxymethyl-2-cephem-4-carboxylate;
p-methoxybenzyl 7-phenylacetamido-3-methylenecepham-4-carboxylate-l-oxide to g-methoxybenzyl 7-phenylacetamido- 3-butyroxymethyl-2-cephem-4-carboxylate;
2.2.2- trichloroethyl 7-phenoxyacetamido-3methylenecepham-4-carboxylate-l-oxide to 2,2,2-trichloroethyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4carboxylate;
g-nitrobenzyl 7-(2',5'-dichlorophenylacetamido)3-methylenecepham-4-carboxylate-l-oxide to g-nitrobenzyl 7-(2',5’-dichlorophenylacetamido)-3-acetoxymethyl-2cephem-4-carboxylate;
-2344133 benzyl 7-(3'-bromophenoxyacetamido)-3-methylenecepham-4-carboxylate-l-oxide to benzyl 7-(3*-bromophenoxyacetamido)-3-isobutyroxymethyl-2-cephem-4-carboxylate;
p-bromophenacyl 7-(4’-chlorophenylacetamido)-3methylenecepham-4-carboxylate-l-oxide to p-bromophenacyl 7-(4'-chlorophenylacetamido)-3-acetoxymethyl-2-cephem-4carboxylate;
pivaloyloxymethyl 7- (3'-chlorophenoxyacetamido) 3- methylenecepham-4-carboxylate-l-oxide to pivaloyloxymethyl 7-(3'-chlorophenoxyacetamido)-3-acetoxymethyl-2-cephem-4carboxylate;
p-nitrobenzyl 7-(4'-nitrophenylacetamido)-3methylenecepham-4-carboxylate-l-oxide to p-nitrobenzyl 7(4'-nitrophenylacetamido)-3-propionoxymethyl-2-cephem4- carboxylate;
p-methoxybenzyl 7-(4'-nitrophenoxyacetamido)-3roethylenecepham-4-carboxylate-l-oxide to p-methoxybenzyl 7-(4'-nitrophenoxyacetamido)-3-acetoxyniethyl-2-cephem4-carboxylate;
p-nitrobenzyl 7-(3'-cyanophenylacetamido)-3methylenecepham-4-carboxylate-l-oxide to p-nitrobenzyl 7-(3'-cyanophenylacetamido)-3-butyroxymethyl-2-cephem-4carboxylate;
p-bromophenacyl 7-(2'-cyanophenoxyacetamido)-3methylenecepham-4-carboxylate-l-oxide to p-bromophenacyl
7—(2'-cyanophenoxyacetamido)-3-acetoxymethyl-2-cephem4-carboxylate;
-2444133 propionoxymethyl 7-(4'-trifluoromethylphenylacetamido) -3-methylenecepham-4-carboxylate-l-oxide to propionoxymethyl 7-(4'-trifluoromethylphenylacetamido)3-acetoxymethyl-2-cephem-4-carboxylate;
2.2.2- tribromomethyl 7-(3'-trifluoromethylphenoxyacetamido)-3-methylenecepham-4-carboxylate-l-oxide to
2,2,2-tribromomethyl 7-(3'-trifluoromethylphenoxy acetamido)3-propionoxymethyl-2-cephem-4-carboxylate;
2.2.2- trichloroethy1 7-(2'-ethylphenylacetamido)3- methylenecepham-4-carboxylate-l-oxide to 2,2,2-trichloroethyl 7-(2'-ethylphenylacetamido)-3-acetoxymethy1-2-cephem4- carboxylate;
acetoxymethyl 7-(4'-isopropylphenoxyacetamido)3-methylenecepham-4-carboxylate-l-oxide to acetoxymethyl 7-(4'-isopropylphenoxyacetamido)-3-butyroxymethyl-2cephem-4-^carboxylate;
benzyl 7-(3'-ethoxyphenyl acetamido)-3-methylenecepham-4-carboxylate-l-oxide to benzyl 7-(3'-ethoxyphenylacetamido)-3-isobutyroxymethyl-2-cephem-4-carboxylate;
g-nitrobenzyl 7-(4'-isopropoxyphenoxyacetamido)3-methylenecepham-4-carboxylate-l-oxide to g-nitrobenzyl 7-(4'-isopropoxyphenoxyacetamido)-3-valeroxymethyl-2cephem-4-carboxylate;
g-nitrobenzyl 7-(a-2,2,2-trichloroethoxycarbonylphenylacetamido)-3-methylenecepham-4-carboxylate-l-oxide to g-nitrobenzyl 7-(a-2,2,2-trichloroethoxycarbonylphenylacetamido) -3-a-methylbutyroxymethyl-2-cephem-4-carboxylate;
-2544.133 p-methoxybenzyl 7-(α-phenacyloxycarbonylphenylacetamido) -3-methylenecepham-4-carboxylate-l-oxide to p-methoxybenzyl 7-(α-phenacyloxycarbonyIphenylacetamido)3-acetoxymethyl-2-cephem-4-carboxylafce;
benzyl 7-(2-thienyl-a-benzyloxycarbonylacetamido)
3-methylenecepham-4-carboxylate-1-oxide to benzyl 7-(2thienyl-a-benzyloxycarbonylacetamido)-3-β-methylbutyroxymethyl-2-cephem-4-carboxylate;
2,2,2-trichloroethyl 7-(a^g-nitrobenzyloxycar10 bonylphenylacetamido)-3-methylenecepham-4-carboxylate-loxide to 2,2,2-trichloroethyl 7-(a-g-nitrobenzyloxycarbonyl phenylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
p-nitrobenzyl 7-(a-benzyloxycarbonylphenylacetamido)-3-methylenecepham-4-carboxylate-l-oxide to ja-nitro15 benzyl 7-(α-benzyloxycarbonylphenylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
p-methoxybenzyl 7-(α-4-methoxybenzyloxycarbonylphenylacetamido)-3-methylenecepham-4-carboxylate-l-oxide to jymethoxybenzyl 7-(α-4-methoxybenzyloxycarbonylphenylacet20 amido)-3-propionoxymethyl-2-cephem-4-carboxylate;
p-nitrobenzyl 7— < 2'-thienyl-a-g^-nitrobenzyloxycarbonylacetamido)-3-methylenecepham-4-carboxylate-l-oxide to p-nitrobenzyl 7-(2'-thienyl-a-£-nitrobenzyloxycarbonylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
p-nitrobenzyl 7-(2'-thienylacetamido)-3-methylene cepham-4-carboxylate-l-oxide to £-nitrobenzyl 7— (2* — thienylacetamido)-3-acetoxymethyl-2-cephem-4-carboxylate;
-2644133 benzyl 7-(31-thienylacetamido)-3-methylenecepham4-carboxylate-l-oxide to benzyl 7-(3'-thienylacetamido)-3acetoxymethyl-2-cephem-4-carboxylate;
p-methoxybenzyl 7-(2'-furylacetamido)-3-methylenecepham-4-carboxylate-l-oxide to g-methoxybenzyl 7-(2'furylacetamido)-3-propionoxymethyl-2-cephem-4-carboxylate;
g-chlorophenacyl 7-(3'-furylacetamido)-3-methylenecepham-4-carboxylate-l-oxide to g-chlorophenacyl 7-(3’~ furylacetamido)-3-butyroxymethyl-2-cephem-4-carboxylate;
succinimidomethyl 7-(2'-thiazolylacetamido)-3methylenecepham-4-carboxylate-l-oxide to succinimidomethyl 7- (2’-thiazolylacetamido)-3-valeroxymethyl-2-cephem-4carboxylate;
g-nitrobenzyl 7-(5'-tetrazolylacetamido)-3methylenecepham-4-carboxylate-l-oxide to g-nitrobenzyl 7-(5'-tetrazolylacetamido)-3-a-methylbutyroxymethyl-2cephem-4~carboxylate;
g-nitrobenzyl 7-(1'-tetrazolylacetamido)-3methylenecepham-4-carboxylate-l-oxide to g-nitrobenzyl 7-(1'-tetrazolylacetamido)-3-acetoxymethyl-2-cephem-4carboxylate;
g-methoxybenzyl 7-(4'-isoxazolylacetamido)-3methylenecepham-4-carboxylate-l-oxide to g-methoxybenzyl 7-(4’-isoxazolylacetamido)-3-acetoxymethyl-2-cephem-4carboxylate;
benzyl 7-[3'- (2-chlorophenyl)-5'-methylisoxazol4'-ylcarboxamido]-3-methylenecepham-4-carboxylate-l-oxide to benzyl 7-[3'-(2-chlorophenyl)-5'-methylisoxazol-4'ylcarboxamido]-3-B-methylbutyroxymethyl-2-cephem-4-carboxylate;
-2744133 £-nitrobenzyl 7—(2',2'-dimethyl-3'-acetyl-5'oxo-41-phenylimidazolidin-1'-yl)-3-methylenecepham-4carboxylate-l-oxide to £-nitrobenzyl 7-(21,2'-dimethyl-3'acetyl-5'-oxo-4'-phenylimidazolidin-1'-yl)-3-acetoxymethyl2- cephem-4-carboxylate;
benzyl 7- [2',2'-dimethyl-3'-nitroso-5'-oxo-41(4-chlorophenyi)imidazolidin-1'-yl]-3-methylenecepham4-carboxylate-l-oxide to benzyl 7-[2',2'-dimethyl-3'nitroso-5’-oxo-4'-(4-chlorophenyi)imidazolidin-1'-yl]3- acetoxymethyl-2-cephem-4-carboxylate.
The 3-acyloxymethyl-A -cephem esters of Formula I are useful as intermediates in the preparation of anti2 biotically active cephalosporins. The Δ -cephem product is treated in accordance with the method described in U.S.
a
Patent No. 3,705,897 to produce the corresponding Δ cephem ester. The described method, although specifically 2 directed to 3-halomethyl-A -cephem compounds, nevertheless, is fully applicable to the 3-acyloxymethyl-A -cephem esters of Formula X. The method which is described in the U.S.
patent involves oxidation of the Λ -cephem compound using an oxidizing agent to produce a cephem sulfoxide. With respect to at least a portion of the oxidized product, isomerization 2 . 3 of the double bond from the Δ position to the Λ position occurs. Isomerization of the double bond of the sulfoxide is completed by treating the product with a tertiary amine.
The resulting Δ -cephem sulfoxide is reduced to the corresponding sulfide by treatment with any of a number of defined reducing agents. When this method is applied to the products of Formula I from the process of this invention, a 3
3-acyloxymethyl-Δ -cephem ester is obtained.
-2844133
At this point, it is noteworthy to recognize that, 2 in addition to the Δ -cephem product of Formula I obtained from the process of this invention, a minor amount of the 3 corresponding Δ -cephem compound generally will be produced. The two products, of course, can be separated using one or more of any of several readily recognized techniques, such as those described above. However, since the customary purpose for generating the Δ -cephem compound will con3 template its ultimate conversion to a Λ -cephem antibiotically active compound, no separation is necessary. The o 3 mixture of the A“-cephem and the Δ -cephem, as obtained from the process of the invention, can be treated, under the conditions described above, to produce the desired Δ'cephem compound. The Δ^-cephem present in the starting material as contaminant will simply be oxidized to the sulfoxide and reduced back to the sulfide, and thus be recovered as the desired product.
The corresponding Δ^-cephem acids exhibit potent antibacterial activity. Such compounds are available by cleavage of the ester function. De-esterification can be achieved, depending upon the nature of the protecting group, by any of several recognized procedures, including (1) treatment with an acid such as trifluoroacetic acid, formic acid or hydrochloric acid; (2) treatment with zinc and an acid such as formic acid, acetic acid, or hydrochloric acid; or (3) hydrogenation in the presence of palladium, platinum, rhodium, or a compound thereof, in suspension, or on a carrier such as barium sulfate, carbon or alumina. Further3 more, the resulting 3-acyloxymethyl-A -cephem acid is
-2944133 convertible to other antibiotically active cephalosporins by cleavage of the amido or imido group in the 7-position to the free 7-amino group with subsequent reacylation to produce any of a number of recognized active cephalosporin antibiotics. Cleavage and reacylation methods are well recognized in the cephalosporin art.
Starting with the process of this invention, therefore, several widely recognized cephalosporin antibiotics are available. These include, for example, the sodium salt of
7- (2-thienylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid (cephalothin); 7-(α-aminophenylacetamido)-3-acetoxymethyl-3-cephem-4-carboxylic acid (cephaloglycin); and the sodium salt of 7-cyanoacetamido-3-acetoxymethyl-3cephem-4-carboxylic acid (cephacetrile).
This invention is further illustrated by the examples which follow. Xt is not intended that this invention be limited in scope by reason of any of the examples provided herein. Preparations showing the use of the compounds of Formula X are also provided.
-304 413 3
Example 1
To 5 ml. of fresh acetic anhydride were added 500 mg. (1 millimole) of g-nitrobenzyl 7-phenoxyacetamido3- methylenecepham-4-carboxylate-l-oxide. To the resulting mixture was added one drop of acetyl chloride. The mixture was refluxed at 130-140°C. for 2.75 hours and then was cooled. Ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate and then with water. The resulting organic layer was separated and evaporated to obtain g-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl2- cephem-4-carboxylate as a foam.
nmr 6 (CDCl^) 2.00 (s, 3H, acetoxy); 4.53 (s,
211, -OCf^NH-); 4.70 (d, III, J = 4.5 Hz, Γθ-Η)? 5.73 (d,
IH, J = 4.5 Hz, C?-H); 5.13 (bs, 111, Cj-H); 6.50 (bs, 1H, C2-H); 5.20, 5.33 (2s, IH + IH, -CHjO-); 6.75-7.30 (m,
5H, phenoxy); 7.50, 8.13 (2d, 2H + 2H, AB, J = 9 Hz, nitrobenzylcarboxylate).
Example 2_
To 10 ml. of benzene were added 500 mg. (1 millimole) of g-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham4- carboxylate-l-oxide. To the resulting slurry were added 2 ml. of acetic anhydride and 2 drops of acetyl chloride. The resulting mixture was refluxed at 85°C. for about 15 hours. The resulting reaction mixture then was treated as in Example 1 to obtain g-nitrobenzyl 7-phenoxyacetamido3- acetoxymethyl-2-cephem-4-carboxylate.
-31Example 3_
To 10 ml. of dry toluene were added 500 mg. (1 millimole) of £-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide. To the resulting slurry were added 2 ml. of acetic anhydride and 2 drops of acetyl chloride. The mixture then was refluxed at 110-112°C. for 18 hours. The resulting reaction mixture then was treated as in Example 1 to obtain p-nitrobenzyl 7-phenoxyacetamido3-acetoxymethyl-2-cephem-4-oarboxylate as well as a minor amount of the corresponding Δ3 isomer.
Example £
To 10 ml. of dry toluene were added 500 mg. (1 millimole) of £-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide. To the resulting mixture then were added 2 ml. of acetic anhydride and 0.071 ml. (1 equivalent based upon the cepham sulfoxide) of acetyl chloride. The resulting mixture was refluxed at 111°C. for 5 hours to obtain almost complete conversion of the methylenecepham sulfoxide to p-nitrobenzyl 7-phenoxyacetamido-3-acetoxy20 methyl-2-cephem-4-carbOxylate as well as a minor amount of 3 the corresponding Δ isomer.
-3244133
Example 5^
To a mixture of 33 ml. of acetic acid and 66 ml. of acetic anhydride were added 6 gms. (12 mmoles) of gnitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. The mixture was maintained under a slow stream of nitrogen and then was brought to reflux (about 126eC.). Progress of the reaction was followed by thinlayer chromatography (TLC) using a 1:1 mixture of benzene and ethyl acetate on silica gel plates. The reaction was complete in about 2.5 hours, after which time the resulting reddish solution was evaporated to a dark tar. The resulting residue was dissolved in 50 ml. of ethyl acetate. The ethyl acetate solution was washed three times with 50 ml. each of saturated sodium bicarbonate solution and once with 50 ml. of saturated sodium chloride solution. The ethyl acetate layer then was dried over magnesium sulfate, treated with activated carbon, and filtered through silica gel. The filtrate was evaporated to obtain 5.8 gms. (89 percent) of a 3:1 mixture of g-nitrobenzyl 7-phenoxyaeetamido-3-acetoxymethyl-2-cephem-4-carboxylate and g-nitrobenzyl 7-phenoxyacetamido- 3-acetoxymethyl-3-cephem-4-carboxy late as a light yellow foam.
2 3 nmr (3:1 mixture of Δ and Δ ) (cdci3) 6.5 (broad s, 0.75, A2-C2); 5.8 (dd, 1, C?-H); 4.6 (s, 2, C„ I 3 methylene); 3.6 (broad s, 0.5, Δ -C^); and 2.1-2.2 (ss, 3, 2 3 Δ and Δ C^, acetoxy).
Examples 6-10
The reaction of Example 5 was repeated under varying conditions as follows:
-334 413 3
4J
Ο · ω vo in rO e . · ·
O & w ci in k
CU in in rd
Cl Cl <1) ifl β k •h x: EH in in ko oo id » rd H kO <-d cu · £ O φ o in co Ο rd rd rd in H στ cj ro ι—ί ι—I ϋ
*rd *>
-Ρ Ό * Φ -d d ϋ 0 £ rf rf kO © rd CJ rd o m O in ci «-d
1)
Q nJ Ή ·Η 4J k · 0 nJ rd ϋ >. £ rf x:
c rf <3« in m ci o tn o in ci
Φ •id
X t|4 «-d w
m vo m
3444133
Example 11
To a mixture of 5 ml. of acetic anhydride and 20 ml. of acetic acid were added 600 mg. of 2,2,2-trichloroethyl 7- (g-nitrobenzyloxycarbonylamino)-3-methylenecepham5 4-carboxylate-l-oxide. The resulting mixture was stirred at 110°C. for six hours. The reaction mixture then was cooled, and the solvent was evaporated. The resulting residue was dissolved in ethyl acetate, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate. The organic layer then was dried over magnesium sulfate, evaporated, and the residue was chromatographed over silica gel to obtain 100 mg. of a 6:1 mixture of 2,2,2-trichloroethyl 7-(g-nitrobenzyloxycarbonyl amino)- 3-acetoxymethyl~2-cephem4-carboxylate and 2,2,2-trichloroethyl 7-(p-nitrobenzyloxyI5 carbonylamino)-3-acetoxymethyl-3-cephem-4-carboxylate.
nmr (6:1 mixture of Δ2 and Δ3) ό (CDCl^) 6.45 2 (broad s, 0.83, Λ -C2); 4.75 (s, 2, trichloroethyl); 4.65 (broad s, 1.66, Λ C3'-methylene); 3.5 (broad s, 0.34,
A3-C2>; and 2.10-2.15 (broad s, 3, Δ2 and Δ3 '-acetoxy).
Example 12
To a mixture of 5 ml. of acetic anhydride and 20 ml. of acetic acid were added 600 mg. of g-nitrobenzyl 7-(2-thienylacetamido)-3-methylenecepham-4-carboxylate1-oxide. The resulting mixture was stirred at 110eC. for four hours. The mixture was cooled, evaporated, and the resulting residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvent was evaporated, and the residue was chromatographed over silica gel
-3544133 to obtain 110 mg. of p-nitrobenzyl 7-(2-thienylacetamido)3- acetoxymethyl-2-cephem-4-carboxylate.
nmr 5 (CDC13> 6.4 (broad s, 1, A2-C2); 5.6 (dd, 1, Cy-H); 4.6 (broad s, 2, C3'-methylene); 3.8 (s, 2, C?5 methylene); and 2.05 (s, 3, C3’-acetoxy).
Example 13
To a mixture of 5 mi. of propionic anhydride and 20 ml. of propionic acid were added 600 mg. of g-nitrobenzyl 7-phenoxyaeetamido-3-methylenecepham-4-carboxylate-l-oxide.
The mixture was stirred at 130°C. for six hours. The resulting mixture was cooled, and the solvent was removed in vacuo. The resulting residue was dissolved i.n 150 ml. of ethyl acetate, and the ethyl acetate solution was washed with saturated aqueous sodium bicarbonate. The ethyl acetate layer was separated and dried over magnesium sulfate. The solvent was evaporated, and the residue was chromatographed on silica gel to obtain 166 mg. of g-nitrobenzyl 7-phenoxyacetamido-3-propionyloxymethyl-2-cephem4- carboxylate.
nmr δ (CDCl3) 6.45 (broad s, 1, A2-C2); 5.7 (dd, 1, C?-H); 2.3 (q, 2, methylene of propionoxy); and
1.1 (t, 3, methyl of propionoxy).
Example 14
To a mixture of acetic anhydride and acetic acid was added a portion of p-nitrobenzyl 7-phenylacetamido-3-364 4 1 3 ό methylenecepham-4-carboxylate-l-oxide. The mixture was heated and stirred for a.time, and was then cooled and evaporated to dryness. The residue was dissolved in ethyl acetate, and the product was purified as described in the examples above to obtain g-nitrobenzyl 7-phenylacetamido-3-acetoxymethyl-2-cephem-4-carboxylate.
-37Preparation 1
To 170 ml. of methylene chloride were added 5.65 gms. of g-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate and 20 ml. of isopropyl alcohol. The mixtute was cooled to about 0°C. A solution of 2.12 gms. of 85 percent technical grade m-chloroperbenzoic acid in 55 ml. of methylene chloride was added dropwise rapidly. The progress of the reaction was followed by TLC. After 45 minutes, the methylene chloride mixture was washed three times with 100 ml. of aqueous sodium chloride solution. The methylene chloride layer then was dried over magnesium sulfate and treated with activated carbon. The methylene chloride solution then was cooled in an ice bath, and petroleum ether was added slowly to obtain, by crystallization, 4.39 gms. (76 percent) of g-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylatel-oxide, m.p. 187-188°C.
Analysis: Calc, for C2gH23N3°10S
Theoretical Found
c 53.86% 53.67% H 4.16 3.89 N 7.54 7.29 0 28.70 28.45 S 5.75 5.38
Preparation 2_
To 75 ml. of N,N-dimethylformamide (DMF) were added 2.70 gms. of the product from Preparation 1. The mixture was cooled to -80°C., and 1.6 ml. of phosphorous trichloride was added in one portion. The resulting mixture
-3844133 was stirred for 10 minutes at -80°C., and then was warmed to about 0°C. using an ice water bath. Stirring of the mixture was continued for about 25 minutes, and the resulting oi'ange solution then was poured onto ice. A precipitate formed and was removed by filtration, washed thoroughly with water, and dried to give 2.35 gms. (89.5 percent) of g-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-3-cephem-4-carboxylate.
nmr δ (CDC13-DMSO 1:1) 2.03 (s, 3H, acetoxy);
3.50 (6s, 2H, -S-CH2~); 4.53 (s, 2H, -O-CHj-NH-); 4.90 (d, IH, J -- 4.5 Hz, Cg-H); 5.90 (d, lH, J = 4.5 Hz), C-,-Η) ;
.20, 5.30 (2s, IH + IH, acetoxymethyl); 5.33 (s, 2H, nitrobenzyl); 6.77-7.40 (m, 5H, phenoxy); 7.53, 8.17 (2d, 2H + 2H, AB, J = 9 Hz, nitrobenzylcarboxylate).
Claims (25)
1. A process for preparing a compound of the formula Y. \ / che-o-c-r4 co COORi 2. ,2,2-trichloroethyl 7-(g-nitrobenzyloxycarbonylamino)-3methylenecepham-4-carboxylate-l-oxide with acetic anhydride and acetic acid.
2. A process according to claim 1 wherein X is chloro. (2) an amido group of the formula 0 r 3 -c-nhin which R 3 is
3. A process according to claim 1 wherein X is hydroxy. 3-(2-chlorophenyl)-5-raethylisoxazol-4-yl or 4-chloroacetoxybenzyl; (b) the group R* in which R' is phenyl or phenyl substituted with 1 or 2 radicals selected from halogens, nitro,
4. . in which R is 4-nitrobenzyloxy, 2,2,2-trichloroethoxy, 4-methoxybenzylOxy,
5. . 5 (a) hydrogen, 0 χ -0 3 alkyl, halomethyl, benzyloxy, 5 which comprises reacting a 3-exomethylenecepham sulfoxide of the formula + YkX, COORi with a mixture of an acyl compound of the formula R 4 -C-X III
6. .
7. .
8. . A process according to any one of claims 1 to 3, a group of the formula tf-(O) -CHj-C-NH-. A process of claim 4., in which R' is phenyl. A process of claim 4 or 5, in which m is 0. A process of claim 4 or 5, in which in is 1. A process according to any one of claims X to 3 Z in which R is a group of the formula R’ -CH 2 -C-1JH-.
9. A process of claim 8, in which R* ” is 2thienyl.
10. A process of any of claims 1-9, in which R^ is 2,2,2-trihaloethyl, benzyl, g-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxybenzyl, C 2 _ Cg alkanoyloxymethyl, dimethylallyl, phenacyl, or p-halophenacyl. 10 in which X is chloro or hydroxy, and a corresponding anhydride of the formula (R 4 -C-) 2 O IV at a temperature of from 70°C. to 130°C., in which, in the above formulae, R 4 is C^-C 4 alkyl, R^ is a
11. A process of claim 10, in which R^ is benzyl, g-nitrobenzyl, g-methoxybenzyl, 2,2,2-trichloroethyl, phenacyl, g-chlorophenacyl, or g-bromophenacyl. «I
12. . A process of any of Claims 1-11, in which R 4 ~C-X is acetyl chloride.
13.. A process of claim 12, in which the reaction is carried out in the presence of an inert organic solvent. II
14. . A process of any of claims 1-11, in which R^-C-X is acetic acid.
15. . A process of any of claims I-14, in which the anhydride is present in an amount representing at least a molar equivalent relative to the 3-exomethylenecepham sulfoxide. -4244133 15 carboxylic acid protecting group, and R is (1) an imido group of the formula ./ N——— ( ι i R s -4044133 in which R 2 is C 2 -C 4 alkenylene or 1,2-phenylene;
16. Λ process of Claim 1 for preparing g-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cepheni-4-carboxylate which comprises reacting g-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate~l-oxide with acetic anhydride and acetyl chloride.
17. A process of Claim 1 for preparing g-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate which comprises reacting g-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide with acetic acid and acetic anhydride.
18. A process of Claim 1 for preparing 2,2,2trichloroethyl 7-(g-nitrobenzyloxycarbonylamino)-3-acetoxymethyl-2-cephem-4-carboxylate which comprises reacting
19. A process of Claim 1 for preparing g-nitrobenzyl 7-(2-thienylacetamido)-3-acetoxymethyl-2-cephem-4earboxylate which comprises reacting g-nitrobenzyl 7-(2thienylacetamido)-3-methylenecepham-4-carboxylate-l-oxide with acetic anhydride and acetic acid.
20. a process of Claim 1 for preparing g-nitrobehzyl 7-phenoxyacetamido-3-propionyloxymethyl-2-cephem4-carboxylate which comprises reacting g-nitrobenzyl 7phenoxyacetamido-3-methylenecepham-4-carboxylate-l-oxide with propionic anhydride and propionic acid. -4344133 20 (3) an imidazolidinyl group of the formula N—CHa in which R' is as defined above and U is nitroso or acetyl.
21. · A process of Claim 1 for preparing g-nitrobenzyl 7-phenylacetamido-3-acetoxymethy1-2-cephem-4-carboxylate which comprises reacting g-nitrobenzyl 7-phenylacetamido-3-methylenecepham-4-carboxylate-l-oxide with acetic anhydride and acetic acid.
22. A process according to Claim 2 substantially as hereinbefore described with reference to any one of Examples
23. hereinbefore to 13. A process according to Claim 3 substantially as described with reference to any one of Examples 5
24. A process according to Claim 3 substantially as hereinbefore described with reference to Example 14.
25. A compound, of formula I whenever prepared by a process according to any of claims 1 to 24.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/650,583 US4029651A (en) | 1976-01-19 | 1976-01-19 | Process for preparing 3-acyloxymethyl-2-cephem compounds |
| US05/650,585 US4031082A (en) | 1976-01-19 | 1976-01-19 | Process for preparing 3-acycloxymethyl-2-cephem compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE44133L IE44133L (en) | 1977-07-19 |
| IE44133B1 true IE44133B1 (en) | 1981-08-26 |
Family
ID=27095900
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE2598/76A IE44133B1 (en) | 1976-01-19 | 1976-11-26 | Process for preparing 2-cephem compounds |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5289698A (en) |
| AR (1) | AR213426A1 (en) |
| AT (1) | AT348121B (en) |
| AU (1) | AU503930B2 (en) |
| BG (1) | BG30473A3 (en) |
| CH (1) | CH628059A5 (en) |
| CS (1) | CS192474B2 (en) |
| DD (1) | DD128734A5 (en) |
| DE (1) | DE2656144C2 (en) |
| DK (1) | DK17977A (en) |
| FR (1) | FR2338280A1 (en) |
| GB (1) | GB1566526A (en) |
| GR (1) | GR65892B (en) |
| HU (1) | HU173592B (en) |
| IE (1) | IE44133B1 (en) |
| IL (1) | IL51021A (en) |
| MX (1) | MX3766E (en) |
| NL (1) | NL7700500A (en) |
| NZ (1) | NZ182737A (en) |
| PL (1) | PL104370B1 (en) |
| PT (1) | PT66007B (en) |
| RO (1) | RO69710A (en) |
| SE (1) | SE433849B (en) |
| SU (1) | SU703023A3 (en) |
| YU (1) | YU8677A (en) |
-
1976
- 1976-11-26 GR GR52271A patent/GR65892B/el unknown
- 1976-11-26 IE IE2598/76A patent/IE44133B1/en unknown
- 1976-11-26 NZ NZ182737A patent/NZ182737A/en unknown
- 1976-11-28 IL IL51021A patent/IL51021A/en unknown
- 1976-12-03 AU AU20238/76A patent/AU503930B2/en not_active Expired
- 1976-12-10 DE DE2656144A patent/DE2656144C2/en not_active Expired
- 1976-12-22 BG BG7634974A patent/BG30473A3/en unknown
- 1976-12-23 PT PT66007A patent/PT66007B/en unknown
-
1977
- 1977-01-04 SE SE7700077A patent/SE433849B/en not_active IP Right Cessation
- 1977-01-10 MX MX775319U patent/MX3766E/en unknown
- 1977-01-10 CH CH24877A patent/CH628059A5/en not_active IP Right Cessation
- 1977-01-12 FR FR7700763A patent/FR2338280A1/en active Granted
- 1977-01-12 JP JP229877A patent/JPS5289698A/en active Granted
- 1977-01-13 YU YU00086/77A patent/YU8677A/en unknown
- 1977-01-13 RO RO7789041A patent/RO69710A/en unknown
- 1977-01-14 GB GB1450/77A patent/GB1566526A/en not_active Expired
- 1977-01-18 HU HU77EI723A patent/HU173592B/en unknown
- 1977-01-18 PL PL1977195386A patent/PL104370B1/en not_active IP Right Cessation
- 1977-01-18 DK DK17977A patent/DK17977A/en not_active Application Discontinuation
- 1977-01-18 NL NL7700500A patent/NL7700500A/en not_active Application Discontinuation
- 1977-01-18 SU SU772439832A patent/SU703023A3/en active
- 1977-01-19 AR AR266243A patent/AR213426A1/en active
- 1977-01-19 AT AT28177A patent/AT348121B/en not_active IP Right Cessation
- 1977-01-19 CS CS77368A patent/CS192474B2/en unknown
- 1977-01-19 DD DD7700197001A patent/DD128734A5/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE433849B (en) | 1984-06-18 |
| AT348121B (en) | 1979-01-25 |
| JPS5289698A (en) | 1977-07-27 |
| NL7700500A (en) | 1977-07-21 |
| NZ182737A (en) | 1978-04-28 |
| DK17977A (en) | 1977-07-20 |
| BG30473A3 (en) | 1981-06-15 |
| AR213426A1 (en) | 1979-01-31 |
| RO69710A (en) | 1980-07-15 |
| PL104370B1 (en) | 1979-08-31 |
| HU173592B (en) | 1979-06-28 |
| MX3766E (en) | 1981-06-25 |
| DE2656144C2 (en) | 1985-08-29 |
| AU2023876A (en) | 1978-06-08 |
| GB1566526A (en) | 1980-04-30 |
| SU703023A3 (en) | 1979-12-05 |
| FR2338280A1 (en) | 1977-08-12 |
| PT66007A (en) | 1977-01-01 |
| JPS6120557B2 (en) | 1986-05-22 |
| PL195386A1 (en) | 1978-02-27 |
| AU503930B2 (en) | 1979-09-27 |
| PT66007B (en) | 1978-06-16 |
| FR2338280B1 (en) | 1979-09-28 |
| CS192474B2 (en) | 1979-08-31 |
| DE2656144A1 (en) | 1977-07-21 |
| ATA28177A (en) | 1978-06-15 |
| IL51021A (en) | 1979-09-30 |
| DD128734A5 (en) | 1977-12-07 |
| IL51021A0 (en) | 1977-01-31 |
| SE7700077L (en) | 1977-07-20 |
| GR65892B (en) | 1980-12-01 |
| YU8677A (en) | 1982-06-30 |
| IE44133L (en) | 1977-07-19 |
| CH628059A5 (en) | 1982-02-15 |
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