CA1113087A - Process for preparing cephalosporanic acid derivatives - Google Patents
Process for preparing cephalosporanic acid derivativesInfo
- Publication number
- CA1113087A CA1113087A CA277,957A CA277957A CA1113087A CA 1113087 A CA1113087 A CA 1113087A CA 277957 A CA277957 A CA 277957A CA 1113087 A CA1113087 A CA 1113087A
- Authority
- CA
- Canada
- Prior art keywords
- group
- acid
- iminohalide
- reaction
- subjecting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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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
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE:
A process for preparing a cephalosporanic acid derivative, or a 7-acylaminocephalosporanic acid derivative which comprises subjecting an esterifying agent to reaction in a liquid sulfur dioxide in the presence of a base with an N-protected-cephalosporin C to obtain a diester, subjecting the diester to reaction in an inert solvent with an iminohalide forming agent to produce an iminohalide, subjecting the iminohalide with a lower alcohol to produce an iminoether, subjecting a product produced, after subjecting the iminoether to reaction with a reactive derivative of an organic acid, to hydrolysis and further eliminating the ester group of the carboxylic acid.
A process for preparing a cephalosporanic acid derivative, or a 7-acylaminocephalosporanic acid derivative which comprises subjecting an esterifying agent to reaction in a liquid sulfur dioxide in the presence of a base with an N-protected-cephalosporin C to obtain a diester, subjecting the diester to reaction in an inert solvent with an iminohalide forming agent to produce an iminohalide, subjecting the iminohalide with a lower alcohol to produce an iminoether, subjecting a product produced, after subjecting the iminoether to reaction with a reactive derivative of an organic acid, to hydrolysis and further eliminating the ester group of the carboxylic acid.
Description
The present invention relates to a process for preparing a cephalosporanic acid derivative possessing an antibacterial activity. More specifically, the present invention relates to a novel and efficient process for preparing a 7-acylaminocephalos-poranic acid.
The present inventors have investigated a novel and efficient process for preparing cephalosporin antibiotics which have conventionally been useful as pharmaceuticals. The conven-tional process for preparing a 7-acylaminocephalosporanic acid is as follows. Namely, it is a process in which cephalosporin C is deacylated to produce 7-aminocephalosporanic acid (abbreviated as 7-ACA hereinafter) and then a reactive derivative of a carboxylic acid is subjected to reaction with 7-ACA. According to the `
process, 7-ACA, an intermediate, must be isolated once and there-fore there exist some defects in that the process becomes compli-cated and the yield decreases.
As a result of various investigations for overcoming these defects, the prevent inventors found out a process which is capable of preparing successively the desired 7-acylaminocephalos-poranic acid in high yield by a simple procedure~without producing 7-ACA as an intermediate and accomplished the present invention~
Namely, an object of the present invention is to provide a process for preparing a cephalosporanic acid derivative being valuable for pharmaceuticals and having the formula (V) :
~' ": . `
R6CONH~/ S ~ , . ( V ) I N ~
~\C I OCOCII
COOH
wherein R6CO represents an acyl group, which comprises producing a cephalosporin C derivative having the following formula (I) in which an amino group on the side chain is protected, ~ ` -'.
, . ,~, .
.
. `. ` :'; .
- . :
.
.
..
; HOOC - fH (cH2)3coNH ~s ~ (I) N / l / ~ N ~ CH2OcOcH3
The present inventors have investigated a novel and efficient process for preparing cephalosporin antibiotics which have conventionally been useful as pharmaceuticals. The conven-tional process for preparing a 7-acylaminocephalosporanic acid is as follows. Namely, it is a process in which cephalosporin C is deacylated to produce 7-aminocephalosporanic acid (abbreviated as 7-ACA hereinafter) and then a reactive derivative of a carboxylic acid is subjected to reaction with 7-ACA. According to the `
process, 7-ACA, an intermediate, must be isolated once and there-fore there exist some defects in that the process becomes compli-cated and the yield decreases.
As a result of various investigations for overcoming these defects, the prevent inventors found out a process which is capable of preparing successively the desired 7-acylaminocephalos-poranic acid in high yield by a simple procedure~without producing 7-ACA as an intermediate and accomplished the present invention~
Namely, an object of the present invention is to provide a process for preparing a cephalosporanic acid derivative being valuable for pharmaceuticals and having the formula (V) :
~' ": . `
R6CONH~/ S ~ , . ( V ) I N ~
~\C I OCOCII
COOH
wherein R6CO represents an acyl group, which comprises producing a cephalosporin C derivative having the following formula (I) in which an amino group on the side chain is protected, ~ ` -'.
, . ,~, .
.
. `. ` :'; .
- . :
.
.
..
; HOOC - fH (cH2)3coNH ~s ~ (I) N / l / ~ N ~ CH2OcOcH3
2 COOH
, wherein Rlrepresents a protective group for an amino . group, and R2 represents a hydrogen atom or a protective group for an amino group, or may for a ring structure together with Rl, by a publicly known method starting from cephalosporin C -obtainable from nature, .~ subjecting the thus produced compound (I) to reaction in a liquid sulfur dioxide in the presence of a base with an ester-ifying agent having the formule (II) :
., R
.~ R4 - IC - X (II~
. wherein R3, R4 and R5 may be the same or different, ~` each represents a hydrogen atom, an alkyl group, a substituted or unsubstituted aryl group, an aralkyloxy group, an aralkylthio ., :
: group, an aroyl group, an alkanoyloxy group, an aroyloxy group and an aroylamino group, and X represents a halogen atom or an ., .
~` organic sulfonyloxy group, to obtain a diester having the . :
:: formula (III) :
, .: ` R
~ - COOCCU ( ~)3CO~1 ~ 12 3 .,. COO -R4 subjecting the diester (III) to reaction in an inert solvent , .
. 2 , :
g~i`'7 with an iminohallde forming agent to produce an iminohalide, subjecting the iminohalide with a lower alcohol to produce .
an iminoether, subjecting the product produced after subjecting the iminoether `.
to reaction with a reactive derivative of an organic acid having ..
; the formule (IV) :
R6 ~ COOH (IV) wherein R6CO represents an acyl group, to hydrolysis, and further eliminating the ester group of the carboxylic acid.
Conventionally, when an amido group in a cephalosporin ~ compound is converted into an iminohalide group or an iminoether group, the carboxylic acid at the 4-position must be protected. ..
For the prupose, silylation and esterification have been known.
Silylating method is not a clesirable method industrially ...
since silylating agents are expensive and conversion reaction of an am.ido group in a silyl derivative of cephalosporin C into an iminohalide group and an iminoether group must be conducted at .
a low temperature of -50~ -40C in orcler to prevent the elimi-nation of the protective silyl group (Japanese Patent Publication Sho- 49-45878/1974).
When an ester which is more stable than a silyl deriva-tive is used, the reaction need not be conducted at such a low temperature. However, when esterification is conducted in the ; presence of a base by using an alkyl halide, etc., a part or th~ ~ .
greater part of a ~3-cephalosporin ester isomelizes into a ~2_ .cephalosporin ester in the course o~ the reaction. In this case, in order to turn back the ~2-ester to ~3-ester, the isomeri.c mixture may be oxidized with a peroxide such as m-chloroperbenzoic ~: acid, etc., and.then reduced with phosphorus trichloride, etc.
.
(Cepharosporins and Penicillins Chemistry and Biology, hy E.H.
. Flynn, pl47 - 151), or separation and purification may necessarily be conducted by column chromatography to isolate the ~ -ester. ~ :
- .
'' ' - ' : ' :' ., Recently has been ]cnown a method in which an equivalent amount of a base is added to an equimolar mixture of cephalospo-rin and halomethyl ester under such a rate as the generation rate of an acid anion becomes equal to that of the ester to prevent the side-reaction producing the ~ -ester (Japanese Provisional Patent Publication, Sho-51-16687/1976). However, all of these methods mentioned above are complicated in their procedures and cause low yields.
As other estrifying methods, there exist a method in which a diazoalkane is used, a method in which a dehydrating agent such as dicyclohexylcarbodiimide, etc., is used, and so on~ These methods, however, can not be applied industrially since the reagents employed are very expensive.
As described above, conven-tional techniques could not prepare industrially and easily a ~ -cephalosporin ester in good yields.
As a result of various investigations concerning esteri-~ying methods which do not cause isomerization o~ a double bond, the present inventors found out an entirely novel process in which esterification is conducted in a liquid sulfur dioxide and accomplished the present invention~
The process of the present invention will be explained below in order of the proyress of work.
The present invention is carried out first by dissolv-ing an N-protected-cephalosporin C having the formula (I) and an ~ esterifying agent having the formula (II) in a liquid sulfur - dioxide and refluxing at a temperature of -10_ -5C for several ; hours in the presence of a base, As Rl, a protective group for an amino group of cephalosporin C, there may be mentioned an alkanoyl group such as an acetyl group, a propionyl group, a propionyl group, a butyryl group, etc.; an aroyl group such as a benzoyl group, a .
æ~
p-chlorobenzoyl group, a p-nitrobenzoyl group, etc., an alkoxy-carbonyl group such as an ethoxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl group, etc., a haloalkoxycarbonyl group such as a 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl group, etc., an alkoxyalkoxycarbonyl group such as a 2-methoxyethoxycarbonyl, 2-(n-butoxy) ethoxycarbonyl group, etc., an aralkoxycarbonyl group such as a benxyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-ethoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl group, etc., -a substituted aryl group such as a 2,4-dinitrophenyl, 2,4,6-trinitrophenyl, 2,4-dinitro-6-methoxyphenyl, 4-cyanophenyl, 4-carbomethoxyphenyl group, etc., an arylsulfonyl group such as a benzenesulfonyl, tosyl group, etc., and an arylsufenyl group such as a o-nitrophenylsulfenyl group, etc.
For the ring structure formed by Rl and R2, there may ' be mentioned a phthaloyl, tetrabromophthaloyl, tetrachlorophthal-oyl group and so on.
As an esterifying agent having the formula (II), any agents for esterifying carboxylic acids may be used if the produc-ed esters suffer elimination under mild conditions. As repre-sentative examples for R~ / C - having such properties, there R
may be mentioned the followings :
a t-butyl, p-nitrophenylmethyl, benzhydryl, di- (p-nitro) benzhy-dryl, di- (p-methoxy) benzhydryl, benzyloxymethyl, benzylthiome-thyl, phenacyl, acetoxymethyl, pivaloyloxymethyl, benzoxymethyl, x-benzoyloxyc~llyl group, ctc. ~s X may be Incn~ionc~ a tlalogcr atom such as a chlorine, bromine, iodine atom, etc., and a ` ~0 sulfonyloxy group such as methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy group, etc.
As bases employed, there may be mentioned a tertiary or _5_` ` "
-- .
~ L3~
secondary amine, for example, triethylamine, tripropylamine, tributylamine, pyridine, picoline, lutidine, collidine, quinoline, isoquinoline, N-methylmorpholine, N-ethylmorpholine, N-methyl-piperidine, N-ethylpiperidine, N-methylpyrrolidine, N-ethyl-pyrrolidine, N,N'-te-tramethylguanidine, diethylamine, monomethyl-aniline, piperidine, pyrrolidine, cyclohexylamine, N,N-dimethyl-aniline, N,N-diethylaniline, etc.
The product thus obtained by the present process does not contain a ~2-cephalosporin ester at all.
Accordingly, the complicated procedures such as turning back of the by-product ~2-ester to the ~3-ester or separation and purification by column chromatography, etc., which are necessary in the conventional methods mentioned above, are not required in the present process. The ~ -ester obtained by the present process is stable and can easily be purified by recrystallization.
The thus purified product can be provided for the subsequent reaction. When the ester of the present invention is used, the subsequently conducted iminohalide and iminoether forming reactions can be carried out under temperature conditions (at a temperature of -10 ~ 0C) which can be kept with ease industrial-ly, while the conventional silyl derivatives necessitate a low temperature of -~0 ~ -50C for the purpose. Hence, the present process does not necessitate a special equipment to maintain a low temperature.
Thus, the present process is suitable for industrial manufacturing since it is not only far superior to conventional processes on the standpoints of yield and procedure, but also a Iiquid sulfur dioxide used as a material in the present process .
` is inexpensive.
Next, the ~ -cephalosporin ester is dissolved in an anhydrous inert solvent such as dichloromethane, chloroform, etc., and converted into a iminohalide by reacting with an iminohalide ' forming agent at -10~ 0C in -the presence of a ter-tiary amine such as pyridine, N,N-dimethylaniline, etc. As the iminohalide forming agents, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphoryl chloride, phosphoryl bromide, etc., may be used. As the lower :~
alcohols, methanol, ethanol, propanol, butanol, etc., may widely be used.
- Then, a reactive derivative o~ a carboxylic acid having the general formula (IV) was submitted to reaction. As the carboxylic acids, there may be exemplified the followings : - -Phenylacetic acid derivatives such as a~chlorophenyl-acetic acid, a-bromophenylacetic acid, a-azidophenylacetic acid, a-acetoxyphenylacetic acid, a-propionyloxyphenylacetic acid, a-benzoyloxy-(2-thienyl) acetic acid, a-t-butyloxy-(--mé-thoxy-phenyl) acetic acid, a-valeryloxy- (p-nitrophenyl) acetic acid, a-t-amyloxycarbonyloxyphenylacetic acid, a-t-butyloxycarbonyl-oxyphenylacetic acid, a-(2', 2', 2'-trichloroacetoxy)-phenylacetic acid, a-(~-halogenoethoxycarboxyloxy)-(2-thienyl) acetic acid, a-~2'-phenylacetoxy)phenylacetic acid, ` 20 a-benzyloxycarbonyloxyphenylacetic acid, a-(p-halogenophenoxyacetoxy)phenylacetic acid, ;~ a-N-(2, 2, 2-trichloroethoxycarbonyl) aminophenylacetic acid, a-N-tbenzyloxycarbonyl)aminophenylacetic acid, à-N-(t-butoxycarbonyl)aminophenylacetic acid, , a-N-(t-amyloxycarbonyl)aminophenylacetic acid, a-N-(o-nitrobenzyloxycarbonyl)aminophenylacetic acid, a-N-tp-nitrobenzyloxycarbonyl)aminophenylacetic acid, a-N-(1-carbamylpropen-2-yl)aminophenylacetic acid, a-methylthiophenylacetic acid and a-ethoxycarbonylphenylacetic acid, 2-thienylacetic acid, a-(p-nitrobenzyloxy)-(2-thienyl)acetic acid, mandelic acid, pyridylmercaptoacetic acid, tetrazolylacetic .' .. ..
: . ~ . : -, acid, l-aminocyclohexanecarboxylic acid; ~-aminocyclohexadi-enylacetic acid, a-aminocyclohexenylacetic acid, cyanoacetic acid, etc.
As the reactive derivatives of a carboxylic acid, an alkali metal salt of a mixed anhydride derived from an organic acid and anhydrous sulfuric acid (sulfur trioxide) Japanese Patent Appln. No. Sho-49-20421/1974 , and known functional derivatives such as acid halide, acid anhydride, mixed acid ; anhydride, ac-tive ester, acid azide, acid cyanide, active acid amide, etc., may be used. At this time, it is preferable to make an organic base exist in the medium. As the organic base to be used then, tertiary amines such as pyridine, N,N-dimethyl-aniline, etc., may preferably be used. The reaction temperature is not critical. However, it is preferable to conduct the reaction between -10C and room temperature. The thus obtained reaction product is poured into water to be submitted to hydrolysis. The reaction proceeds readily between an ice cooled remperature and room temperature so that an acyl group on the 7-amino group is exchanged. The hydrolysis of the produced compound may preferably be conducted by using an acid or a base. When an acid is used, it is preferable to maintain the pH value of the-medium between 1.5 and 2.5. The esterified 7-acylaminocephalosporanic acid thus obtained is isolated and ; purified according to an ordinary method. The ester group is eliminated finally. The elimination of ester group is effected under ordinary mild conditions. In the case of benzhydryl ester for example, -the use of trifluoroacetic acid can give a 7-acyla-`~ minocephalosporanic acid in high yield. For the 7-acylamino-cephalosporanic acid obtained as a desired product according to '~ 30 the present invention and represented by the formula (V), there may be exemplified 7-acylaminocephalosporanic acids which may be ; acylated by using various kinds of carboxylic acids (IV). The - . , ' ~ .,' ' - . . . : . .
representative examples for the 7-acylaminocephalosporanic acids were 7-(2-thienylacetamido) cephalosporànic acids, 7-(~-4-pyridylthioacetamido) cephalosporanic acid, 7-cyanoacetamido-.... . . ..
cephalosporanic acid, 7-(a-aminophenylacetamido) cephalosporanic acid, etc.
As described above in detail, the present invention provides a process for obtaining a desired 7-acylaminocephalos-poranic acid, which process comprises protecting the carboxyl group of an N-protected-cephalosporin C by esterifying said cephalosporin C in a liquid sulfur dioxide without rearrangement of the double bond therein, producing an iminochloride and then an iminoether, and subsequently exchanglng acyl groups by using a reactive derivative of a pertinent organic acid. The present process has advantageous points of extreme industrial excellency as follows :
i) The yield of the present process is higher than that of a conventional method.
ii) The procedures are simple.
iii) The reagents employed are easily available ` 20 economically.
iv) Hence, the desired product can be manufactured in : .
a low cost.
., ~ -The present invention will be explained more in detail :.
~ by the following non-limiting examples.
.~ .
` Example 1 Preparation of dibenzhydrYl ester of N-phthaloyl-cephalosporin C
(A) Preparation of N-phthaloylcephalosporin C
.~
~ ~rO ~30 m of arl aqueous solu~ion containing 4.4 g (10 m . ~ . .
mol) of cephalosporin C was added 3.5 g of sodium bicarbonate to adjust the pH value to 7.0 -7.3. To the solution was added ;
;~ 35 m of acetone and further was added dropwise with stirring 5Q m of an acetone solution containing 3 g of N-carbethoxy-` ' `
- _g_ phthalimide. After the dropwise addition, the mixture was stirred at 20C for 1.5 hours. Then the mixture was diluted with 150 m of water and the thus obtained solution was washed twice with 100 m of ethyl acetate. After ad~usting the pH value of the aqueous solution to 2 by using 2N hydrochloric acid, the solution was extracted three times with 100 m of ethyl acetate. m e extract was dried over magnesium sulfate and the solvent was removed by evaporation to obtain an oil of N-phthaloylcephalos-porln C.
10 (B) Preparation of N-phthaloYlcephalosporin C benzh~dryl ester In 50 m of liquid sulfur dioxide were dissolved 5.78 g of N-phthaloylcephalosporin C obtained in (A) and 6.05 g (30 mmol) of ~-chlorodiphenylmethane. Under gentle reflux at -5C of the mlxture 3.5 m (25 mmol) of triethylamine was added dropwise over ~ 10 minutes. After addition thereof and further reflux for 4.5 ; hours, liquid sulfur dioxide was removed by evaporation to obtain an oily substance. The substance was dissolved in chloroform to obtain 200 m of solution, which was then washed with water under acidic conditions, and successively with a saturated 20 aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The chloroform layer was dried over anhydrous magnesium sulfate and evaporated to dryness by removing chloroform. The solid residue was crystallized from `
ethyl acetate to ob-tain 4.65 g of the diester. Single spot was observed on TLC. NMR showed only the existence of ~3-ester.
Elementary analysis (%) (C50H43N3010S = 873.33) ` C H N S
Calcd. 68.31 4.93 4.90 3.65 Found 68.15 4.99 4.96 3.70 NME spectrum (CDC~3, 100 MHz), ppm (Hz) :
1-66/2-23 (-CH2CH2CH2-,m), 1.93 (CH3C0-, s),
, wherein Rlrepresents a protective group for an amino . group, and R2 represents a hydrogen atom or a protective group for an amino group, or may for a ring structure together with Rl, by a publicly known method starting from cephalosporin C -obtainable from nature, .~ subjecting the thus produced compound (I) to reaction in a liquid sulfur dioxide in the presence of a base with an ester-ifying agent having the formule (II) :
., R
.~ R4 - IC - X (II~
. wherein R3, R4 and R5 may be the same or different, ~` each represents a hydrogen atom, an alkyl group, a substituted or unsubstituted aryl group, an aralkyloxy group, an aralkylthio ., :
: group, an aroyl group, an alkanoyloxy group, an aroyloxy group and an aroylamino group, and X represents a halogen atom or an ., .
~` organic sulfonyloxy group, to obtain a diester having the . :
:: formula (III) :
, .: ` R
~ - COOCCU ( ~)3CO~1 ~ 12 3 .,. COO -R4 subjecting the diester (III) to reaction in an inert solvent , .
. 2 , :
g~i`'7 with an iminohallde forming agent to produce an iminohalide, subjecting the iminohalide with a lower alcohol to produce .
an iminoether, subjecting the product produced after subjecting the iminoether `.
to reaction with a reactive derivative of an organic acid having ..
; the formule (IV) :
R6 ~ COOH (IV) wherein R6CO represents an acyl group, to hydrolysis, and further eliminating the ester group of the carboxylic acid.
Conventionally, when an amido group in a cephalosporin ~ compound is converted into an iminohalide group or an iminoether group, the carboxylic acid at the 4-position must be protected. ..
For the prupose, silylation and esterification have been known.
Silylating method is not a clesirable method industrially ...
since silylating agents are expensive and conversion reaction of an am.ido group in a silyl derivative of cephalosporin C into an iminohalide group and an iminoether group must be conducted at .
a low temperature of -50~ -40C in orcler to prevent the elimi-nation of the protective silyl group (Japanese Patent Publication Sho- 49-45878/1974).
When an ester which is more stable than a silyl deriva-tive is used, the reaction need not be conducted at such a low temperature. However, when esterification is conducted in the ; presence of a base by using an alkyl halide, etc., a part or th~ ~ .
greater part of a ~3-cephalosporin ester isomelizes into a ~2_ .cephalosporin ester in the course o~ the reaction. In this case, in order to turn back the ~2-ester to ~3-ester, the isomeri.c mixture may be oxidized with a peroxide such as m-chloroperbenzoic ~: acid, etc., and.then reduced with phosphorus trichloride, etc.
.
(Cepharosporins and Penicillins Chemistry and Biology, hy E.H.
. Flynn, pl47 - 151), or separation and purification may necessarily be conducted by column chromatography to isolate the ~ -ester. ~ :
- .
'' ' - ' : ' :' ., Recently has been ]cnown a method in which an equivalent amount of a base is added to an equimolar mixture of cephalospo-rin and halomethyl ester under such a rate as the generation rate of an acid anion becomes equal to that of the ester to prevent the side-reaction producing the ~ -ester (Japanese Provisional Patent Publication, Sho-51-16687/1976). However, all of these methods mentioned above are complicated in their procedures and cause low yields.
As other estrifying methods, there exist a method in which a diazoalkane is used, a method in which a dehydrating agent such as dicyclohexylcarbodiimide, etc., is used, and so on~ These methods, however, can not be applied industrially since the reagents employed are very expensive.
As described above, conven-tional techniques could not prepare industrially and easily a ~ -cephalosporin ester in good yields.
As a result of various investigations concerning esteri-~ying methods which do not cause isomerization o~ a double bond, the present inventors found out an entirely novel process in which esterification is conducted in a liquid sulfur dioxide and accomplished the present invention~
The process of the present invention will be explained below in order of the proyress of work.
The present invention is carried out first by dissolv-ing an N-protected-cephalosporin C having the formula (I) and an ~ esterifying agent having the formula (II) in a liquid sulfur - dioxide and refluxing at a temperature of -10_ -5C for several ; hours in the presence of a base, As Rl, a protective group for an amino group of cephalosporin C, there may be mentioned an alkanoyl group such as an acetyl group, a propionyl group, a propionyl group, a butyryl group, etc.; an aroyl group such as a benzoyl group, a .
æ~
p-chlorobenzoyl group, a p-nitrobenzoyl group, etc., an alkoxy-carbonyl group such as an ethoxycarbonyl, t-butoxycarbonyl, t-amyloxycarbonyl group, etc., a haloalkoxycarbonyl group such as a 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl group, etc., an alkoxyalkoxycarbonyl group such as a 2-methoxyethoxycarbonyl, 2-(n-butoxy) ethoxycarbonyl group, etc., an aralkoxycarbonyl group such as a benxyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-ethoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl group, etc., -a substituted aryl group such as a 2,4-dinitrophenyl, 2,4,6-trinitrophenyl, 2,4-dinitro-6-methoxyphenyl, 4-cyanophenyl, 4-carbomethoxyphenyl group, etc., an arylsulfonyl group such as a benzenesulfonyl, tosyl group, etc., and an arylsufenyl group such as a o-nitrophenylsulfenyl group, etc.
For the ring structure formed by Rl and R2, there may ' be mentioned a phthaloyl, tetrabromophthaloyl, tetrachlorophthal-oyl group and so on.
As an esterifying agent having the formula (II), any agents for esterifying carboxylic acids may be used if the produc-ed esters suffer elimination under mild conditions. As repre-sentative examples for R~ / C - having such properties, there R
may be mentioned the followings :
a t-butyl, p-nitrophenylmethyl, benzhydryl, di- (p-nitro) benzhy-dryl, di- (p-methoxy) benzhydryl, benzyloxymethyl, benzylthiome-thyl, phenacyl, acetoxymethyl, pivaloyloxymethyl, benzoxymethyl, x-benzoyloxyc~llyl group, ctc. ~s X may be Incn~ionc~ a tlalogcr atom such as a chlorine, bromine, iodine atom, etc., and a ` ~0 sulfonyloxy group such as methanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy group, etc.
As bases employed, there may be mentioned a tertiary or _5_` ` "
-- .
~ L3~
secondary amine, for example, triethylamine, tripropylamine, tributylamine, pyridine, picoline, lutidine, collidine, quinoline, isoquinoline, N-methylmorpholine, N-ethylmorpholine, N-methyl-piperidine, N-ethylpiperidine, N-methylpyrrolidine, N-ethyl-pyrrolidine, N,N'-te-tramethylguanidine, diethylamine, monomethyl-aniline, piperidine, pyrrolidine, cyclohexylamine, N,N-dimethyl-aniline, N,N-diethylaniline, etc.
The product thus obtained by the present process does not contain a ~2-cephalosporin ester at all.
Accordingly, the complicated procedures such as turning back of the by-product ~2-ester to the ~3-ester or separation and purification by column chromatography, etc., which are necessary in the conventional methods mentioned above, are not required in the present process. The ~ -ester obtained by the present process is stable and can easily be purified by recrystallization.
The thus purified product can be provided for the subsequent reaction. When the ester of the present invention is used, the subsequently conducted iminohalide and iminoether forming reactions can be carried out under temperature conditions (at a temperature of -10 ~ 0C) which can be kept with ease industrial-ly, while the conventional silyl derivatives necessitate a low temperature of -~0 ~ -50C for the purpose. Hence, the present process does not necessitate a special equipment to maintain a low temperature.
Thus, the present process is suitable for industrial manufacturing since it is not only far superior to conventional processes on the standpoints of yield and procedure, but also a Iiquid sulfur dioxide used as a material in the present process .
` is inexpensive.
Next, the ~ -cephalosporin ester is dissolved in an anhydrous inert solvent such as dichloromethane, chloroform, etc., and converted into a iminohalide by reacting with an iminohalide ' forming agent at -10~ 0C in -the presence of a ter-tiary amine such as pyridine, N,N-dimethylaniline, etc. As the iminohalide forming agents, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphoryl chloride, phosphoryl bromide, etc., may be used. As the lower :~
alcohols, methanol, ethanol, propanol, butanol, etc., may widely be used.
- Then, a reactive derivative o~ a carboxylic acid having the general formula (IV) was submitted to reaction. As the carboxylic acids, there may be exemplified the followings : - -Phenylacetic acid derivatives such as a~chlorophenyl-acetic acid, a-bromophenylacetic acid, a-azidophenylacetic acid, a-acetoxyphenylacetic acid, a-propionyloxyphenylacetic acid, a-benzoyloxy-(2-thienyl) acetic acid, a-t-butyloxy-(--mé-thoxy-phenyl) acetic acid, a-valeryloxy- (p-nitrophenyl) acetic acid, a-t-amyloxycarbonyloxyphenylacetic acid, a-t-butyloxycarbonyl-oxyphenylacetic acid, a-(2', 2', 2'-trichloroacetoxy)-phenylacetic acid, a-(~-halogenoethoxycarboxyloxy)-(2-thienyl) acetic acid, a-~2'-phenylacetoxy)phenylacetic acid, ` 20 a-benzyloxycarbonyloxyphenylacetic acid, a-(p-halogenophenoxyacetoxy)phenylacetic acid, ;~ a-N-(2, 2, 2-trichloroethoxycarbonyl) aminophenylacetic acid, a-N-tbenzyloxycarbonyl)aminophenylacetic acid, à-N-(t-butoxycarbonyl)aminophenylacetic acid, , a-N-(t-amyloxycarbonyl)aminophenylacetic acid, a-N-(o-nitrobenzyloxycarbonyl)aminophenylacetic acid, a-N-tp-nitrobenzyloxycarbonyl)aminophenylacetic acid, a-N-(1-carbamylpropen-2-yl)aminophenylacetic acid, a-methylthiophenylacetic acid and a-ethoxycarbonylphenylacetic acid, 2-thienylacetic acid, a-(p-nitrobenzyloxy)-(2-thienyl)acetic acid, mandelic acid, pyridylmercaptoacetic acid, tetrazolylacetic .' .. ..
: . ~ . : -, acid, l-aminocyclohexanecarboxylic acid; ~-aminocyclohexadi-enylacetic acid, a-aminocyclohexenylacetic acid, cyanoacetic acid, etc.
As the reactive derivatives of a carboxylic acid, an alkali metal salt of a mixed anhydride derived from an organic acid and anhydrous sulfuric acid (sulfur trioxide) Japanese Patent Appln. No. Sho-49-20421/1974 , and known functional derivatives such as acid halide, acid anhydride, mixed acid ; anhydride, ac-tive ester, acid azide, acid cyanide, active acid amide, etc., may be used. At this time, it is preferable to make an organic base exist in the medium. As the organic base to be used then, tertiary amines such as pyridine, N,N-dimethyl-aniline, etc., may preferably be used. The reaction temperature is not critical. However, it is preferable to conduct the reaction between -10C and room temperature. The thus obtained reaction product is poured into water to be submitted to hydrolysis. The reaction proceeds readily between an ice cooled remperature and room temperature so that an acyl group on the 7-amino group is exchanged. The hydrolysis of the produced compound may preferably be conducted by using an acid or a base. When an acid is used, it is preferable to maintain the pH value of the-medium between 1.5 and 2.5. The esterified 7-acylaminocephalosporanic acid thus obtained is isolated and ; purified according to an ordinary method. The ester group is eliminated finally. The elimination of ester group is effected under ordinary mild conditions. In the case of benzhydryl ester for example, -the use of trifluoroacetic acid can give a 7-acyla-`~ minocephalosporanic acid in high yield. For the 7-acylamino-cephalosporanic acid obtained as a desired product according to '~ 30 the present invention and represented by the formula (V), there may be exemplified 7-acylaminocephalosporanic acids which may be ; acylated by using various kinds of carboxylic acids (IV). The - . , ' ~ .,' ' - . . . : . .
representative examples for the 7-acylaminocephalosporanic acids were 7-(2-thienylacetamido) cephalosporànic acids, 7-(~-4-pyridylthioacetamido) cephalosporanic acid, 7-cyanoacetamido-.... . . ..
cephalosporanic acid, 7-(a-aminophenylacetamido) cephalosporanic acid, etc.
As described above in detail, the present invention provides a process for obtaining a desired 7-acylaminocephalos-poranic acid, which process comprises protecting the carboxyl group of an N-protected-cephalosporin C by esterifying said cephalosporin C in a liquid sulfur dioxide without rearrangement of the double bond therein, producing an iminochloride and then an iminoether, and subsequently exchanglng acyl groups by using a reactive derivative of a pertinent organic acid. The present process has advantageous points of extreme industrial excellency as follows :
i) The yield of the present process is higher than that of a conventional method.
ii) The procedures are simple.
iii) The reagents employed are easily available ` 20 economically.
iv) Hence, the desired product can be manufactured in : .
a low cost.
., ~ -The present invention will be explained more in detail :.
~ by the following non-limiting examples.
.~ .
` Example 1 Preparation of dibenzhydrYl ester of N-phthaloyl-cephalosporin C
(A) Preparation of N-phthaloylcephalosporin C
.~
~ ~rO ~30 m of arl aqueous solu~ion containing 4.4 g (10 m . ~ . .
mol) of cephalosporin C was added 3.5 g of sodium bicarbonate to adjust the pH value to 7.0 -7.3. To the solution was added ;
;~ 35 m of acetone and further was added dropwise with stirring 5Q m of an acetone solution containing 3 g of N-carbethoxy-` ' `
- _g_ phthalimide. After the dropwise addition, the mixture was stirred at 20C for 1.5 hours. Then the mixture was diluted with 150 m of water and the thus obtained solution was washed twice with 100 m of ethyl acetate. After ad~usting the pH value of the aqueous solution to 2 by using 2N hydrochloric acid, the solution was extracted three times with 100 m of ethyl acetate. m e extract was dried over magnesium sulfate and the solvent was removed by evaporation to obtain an oil of N-phthaloylcephalos-porln C.
10 (B) Preparation of N-phthaloYlcephalosporin C benzh~dryl ester In 50 m of liquid sulfur dioxide were dissolved 5.78 g of N-phthaloylcephalosporin C obtained in (A) and 6.05 g (30 mmol) of ~-chlorodiphenylmethane. Under gentle reflux at -5C of the mlxture 3.5 m (25 mmol) of triethylamine was added dropwise over ~ 10 minutes. After addition thereof and further reflux for 4.5 ; hours, liquid sulfur dioxide was removed by evaporation to obtain an oily substance. The substance was dissolved in chloroform to obtain 200 m of solution, which was then washed with water under acidic conditions, and successively with a saturated 20 aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The chloroform layer was dried over anhydrous magnesium sulfate and evaporated to dryness by removing chloroform. The solid residue was crystallized from `
ethyl acetate to ob-tain 4.65 g of the diester. Single spot was observed on TLC. NMR showed only the existence of ~3-ester.
Elementary analysis (%) (C50H43N3010S = 873.33) ` C H N S
Calcd. 68.31 4.93 4.90 3.65 Found 68.15 4.99 4.96 3.70 NME spectrum (CDC~3, 100 MHz), ppm (Hz) :
1-66/2-23 (-CH2CH2CH2-,m), 1.93 (CH3C0-, s),
3.16/3.36 (-SCH2-, AB, J = 18.5), 4.69/4.95 `~ :
.' :
-- '~ : ' ' : ' - . .
(-CH20-, A/B, J - 14), 4.83 (H-6, d~ J = 5),
.' :
-- '~ : ' ' : ' - . .
(-CH20-, A/B, J - 14), 4.83 (H-6, d~ J = 5),
4.91 (thien CH, t, J = 6.5), 5.73 (H-7, dd, J = - -8.5, 5), 6.58 (-NH-, d, J = 8.5), 6.85 (ester -OCH~
s), 7.15/7.21/7.28 (20 arom H, m), 7.67, 7.33 (4 arom H, m) Example 2 Preparation of N-phthaloylcephalosporin C dibenzhydryl ester - Starting from an aqueous solution containing 4.4 g of cephalosporin C, an oil of N-phthaloylcephalosporin C was obtained according to the procedure (A) in Example 1.
Next, 9.88 g of a-bromodiphenylmethane was reacted as an esterifying agent with the thus obtained oil to obtain 7.1 g of N-phthaloylcephalosporin C dibenzhydryl ester. The substance showed a single spot on TLC.
NMR spectrum thereof showed only the existence of ~ -ester.
Example 3 Preparation of cephalothin dibenzhydryl ester .
In 20 m of anhydrous dichloromethane was dissolved 1.76 g of N-phthaloyl cephalosporin C dibenzhydryl ester.
After cooling the solution to -.0C, 0.500 g of phosphorus pentachloride and then 0.261 g of pyridine were added : : .
and the mixture was stirred at that temperature for 1 hour and then at 0 - -5C for 1 hour. The reaction mixture was cooled to -10C and 3.03 g of N,M-dimethylaniline was added to the mixture.
Next, an N,N-dimethyIformamide solution containing 4 mmol of sodium salt of mixed anhydride between 2-thienylacetic acid and -sulfur trioxide was added and the mixture was stirred for Z hours at 0 ~- -5C. The reaction mixture was poured in an ice water and stirred for 1 hour under ice cooling at a pH value of 1.5 . . .
2Ø The mixture was then extracted with chloroform and washed with water.
After removing the solvent by evaporation in vacuo, diqsolving the residue in 20 m of ethyl acetate and washin~ the !
-11- ~
.
' solution with a saturated aqueous solution of sodium bicarbonate and with water, the thus treated solution was dried over anhydrous magnesium sulfate. The solvent was removed by evapor- `
ation in vacuo and the residue was chromatographed on a column of silica gel to develop and elute a main product with chloroform.
The solvent was removed from the eluate by evaporation to obtain 0.89 g of cephalothin 7-(2-thienylacetamido) cephalos-poranic acid dibenzhydryl ester . The IR and NMR spectra of the product were ldentical entirely with those of an authentic 10 sample, respectively.
Elementary analysis t%) (C29H26N2o6s2 = 562-69) C H N S
Calcd. 69.90 4.66 4.98 11.40 Found 70.05 4.70 4.69 11.42 NMR spectrum (CDC~3, 60 M~Iz), ppm (Hz) :
2.00 (CH3CO-, 9), 3.35/3.40 (-SCH2-, AB, J = 18) 3.82 ( ~ , s), 4.79/5.01 (-CH2O-, AB, J = 15), 4.89 (H-6, d, J = 5), 5.79 (H-7, dd, J = 9.5, 5), 6.77 (NH, d, J = 9.5), 6.91 (ester -OCH C , s) ~ ~-` Example 4 Preparation of cephalothin dibenzhydryl ester In 20 m of anhydrous dichloromethane was dissolved 1.76 g of N-phthaloylcephalosporin C dibenzhydryI ester.
After cooling the solution to -10C, 0.500 g of phosphorus pentàchloride was added thereto. After adding subse~uently 0.261 g of piperidine, the mixture was stirred at that temperature Eor 1 hour and at 0~ -5C for 1 hour. After cooling the reaction mixture -to -10C, 3,03 g of N,N-dimethyl-aniline and then 0.67 g of 2-thienylacetyl chloride were added and the mixture was stirred for 2 hours at 0 ~ -5C.` The reaction mixture was poured into 30 m of an ice water and stirxed at a pH value of 1.5 2.0 under ice-cooling for 1 hour.
` ' . . , ~ '`` ' ".` ' After extraction with chloroform, the extract was washed with water. After removing the solvent by evaporation in vacuo, dissolving the residue in 20 m of ethyl acetate, and washing with a saturated aqueous solution of sodium bicarbonate and with water, the solution was dried over anhydrous magnesium sulfate.
After removing the solvent by evaporation in vacuo, the residue was chromatographed through a column of silica gel to develop and elute the main product. After removing the solvent from the eluate by evaporation, 0.~4 g of cephalothin dibenzhydryl ester was obtained.
IR and NMR spectra of the product were identical - -` entirely with those of an authentic sample, respectively.
Example 5 Preparation of cephalothin .
In 5 m~ of anisole was dissolved 0.563 g of cephalothin benzhydryl ester. After adding 20 m of trifluoroacetic acid ; and stirring the mixture at 5 ~- 15C for 5 minutes, the mixture was concentrated under reduced pressure. The thus produced residue was dissolved in ethyl acetal:e and washed with water.
After drying over anhydrous magnesium sulfate and removing the solvent by evaporation in vacuo, ether was added to the mixture to crystalize and obtain cephalothin.
~; IR and NMR spectra of the product were identical " entirely with those of an authentic sample, respectively.
Example 6 Preparation of N-benzoylcephalosporin C benzhydryl ,: , .
ester (A) Preparatlon of N-benzoylcephalosporin C
~o 100 ml of an aqueous solution containing 4.15 g (40 mmol) was added a saturated aqueous solution of sodium hydrogen carbonate to adjust to pH of from 7.o to 7.3. 100 ml of acetone was added to the mixture and 2.1 g (15 mmol) of benzoylchloride in 21 ml of acetone was added dropwise wlth . ~ .
~ stirring under ice-cooling. After dropping, the reaction ~ '.
' .
mixture was stirred further for one hour at the same temperature.
During the reaction was added an aqueous solution of sodium hydrogen carbonate to keep pH at 7.0 ~ 7.3.
After acetone was distilled off under reduced pressure, the residure was washed twice with 10 ml portions of ethyl acetate. The water layer was adjusted to pH 3.3 and washed twice with 20 ml portions of benzene and, after being adjusted to pH 2.0, was extracted three times with 20 ml portions of benzene. The extract was dried over magnesium sulfate and distilled off to give 4.38 g of N-benzoylcephalosporin C in a yield of 84.3 %.
(B) Preparation of N-benzoylcephalosporin C dibenzhydrYl ester The oil containing 10 mmol of N-benzoylcephalosporin C `
obtained above and 6.05 g (30 mmol) of ~-chlorodiphenylmethane were dissolved in 100 ml of liquid sulfur dioxide and the mixture was gently refluxed at -5C. 3.5 ml (25 mmol) of triethylamine was added drop~ise over 10 minutes under reflux.
~fter the addition, the mixture was refluxed for 5.5 hours and the lic~uid sulfur dioxide was removecl by evaporation to give an oil. This oil was dissolved in 200 ml of ethyl acetate and washed with an acidic water to remove basic compounts and then washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solu~ion of sodium chloride. ;
The ethyl acetate solution was dried over magnesium sulfate and evaporated to dryness to give a solid, which was then washed with ether to obtain 1.11 g of the diester. This solid showed a single spot by thin layer chromatography and NMR
~` spectrum did not shown the presence of ~2-compound.~
~ Preparation of cephalothin benzhydryl ester 1.70 g (2 mmol) of N-benzoylcephalosporin C dibenzhydryl exter obtained in Example 6 was dissolved in 20 ml of anhydrous -. , . : ~ . ~ ' . '. :
dichloromethane and cooled ko -10C. 0.5000 g of phosphorus pentachlor:ide and 0.261 g of pyridine were added to the mixture, which was stirred at the same temperature Eor one hour and at 0 to -5C for one hour. The mixture was again cooled to -10C.
1.98 g of pyridine and 0.67 g of thienylacetyl chloride were added and the mixture was stirred at 0 to -5C for 2 hours.
The reaction mixture was poured to 30 ml of ice-water and stirred at pH 1.5 to 2.0 for one hour under ice-cooling and extracted with chloroform. The extract was washed with water and distilled off under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and washed with a satured sodium hydrogen carbonate and water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The main product was developed and eluted with chloroform, and the eluate was distilled off to obtain 0.82 g of cephalothin benzhydryl ester.
Example 8 Preparation of cephalothin benzhydryl ester 4.25 g (5 mmol) of N-benzoylcephalosporin C dibenzhydryl ester obtained in Example 6 was dissolved in 50 ml of dried ` dichloromethane and 1.56 g of phosphorous pentachloride was added to the mixture at -13C and then 0.711 g of pyridine was added. The mixture was stirred at the same temperature for one hour and at 0 to -5C for one hour. ~len, 30 ml of anhydrous methanol was added thereto at -10C and the mixture was stirred at the same temperature for one hour and at 0 to -5C for one hour. 5.53 g of pyridine was added thereto while ]~eeping the temperature at -lO~C and then a dimethylformamide solution of thienylacetic acid - anhydrous sulfuric acid mixed anhydride sodium salt corresponding to 10 mmol was added thereto and the mixture was stirred at 0 to -5C for two hours.
The reaction mixture was poured into 80 ml of ice-water "~
and stirred at pH l.S to 2.0 for one hour under ice-cooling. The mixture was extracted with chloroform and washed with water. The extract was distilled off under reduced pressure and the residue was dissolved in 60 ml of ethyl acetate and washed twice with water and adjusted to pH 8.0 by adding an aqueous saturated solution of sodium hydrogen carbonate and further washed twice with 20 ml portions of water. The ethyl acetate solution was dried over magnesium sulfate and distilled off under reduced pressure. ~ -The residue was subjected to silica gel column chromatography and the main product was developed and eluted with chloroform.
The eluate was distilled off to give 2.20 g of cephalothin benzhydryl ester.
Referential Example .
An N,N-dimethylformamide solution containing sodium salt of mixed anhydride between 2-thienylacetic acid and sulfur trioxide was prepared according to the following procedure.
Five ml of dimethylformamicle was cooled to 0~ 10C.
While distilling sulfur trioxide, 0.~ g thereof was blown into the solvent with stirring. After stirring the solution for 1.5 hours at that temperature, 0.656 g of sodium salt of 2-thienylacetic acid was added and the mixture was stirred at
s), 7.15/7.21/7.28 (20 arom H, m), 7.67, 7.33 (4 arom H, m) Example 2 Preparation of N-phthaloylcephalosporin C dibenzhydryl ester - Starting from an aqueous solution containing 4.4 g of cephalosporin C, an oil of N-phthaloylcephalosporin C was obtained according to the procedure (A) in Example 1.
Next, 9.88 g of a-bromodiphenylmethane was reacted as an esterifying agent with the thus obtained oil to obtain 7.1 g of N-phthaloylcephalosporin C dibenzhydryl ester. The substance showed a single spot on TLC.
NMR spectrum thereof showed only the existence of ~ -ester.
Example 3 Preparation of cephalothin dibenzhydryl ester .
In 20 m of anhydrous dichloromethane was dissolved 1.76 g of N-phthaloyl cephalosporin C dibenzhydryl ester.
After cooling the solution to -.0C, 0.500 g of phosphorus pentachloride and then 0.261 g of pyridine were added : : .
and the mixture was stirred at that temperature for 1 hour and then at 0 - -5C for 1 hour. The reaction mixture was cooled to -10C and 3.03 g of N,M-dimethylaniline was added to the mixture.
Next, an N,N-dimethyIformamide solution containing 4 mmol of sodium salt of mixed anhydride between 2-thienylacetic acid and -sulfur trioxide was added and the mixture was stirred for Z hours at 0 ~- -5C. The reaction mixture was poured in an ice water and stirred for 1 hour under ice cooling at a pH value of 1.5 . . .
2Ø The mixture was then extracted with chloroform and washed with water.
After removing the solvent by evaporation in vacuo, diqsolving the residue in 20 m of ethyl acetate and washin~ the !
-11- ~
.
' solution with a saturated aqueous solution of sodium bicarbonate and with water, the thus treated solution was dried over anhydrous magnesium sulfate. The solvent was removed by evapor- `
ation in vacuo and the residue was chromatographed on a column of silica gel to develop and elute a main product with chloroform.
The solvent was removed from the eluate by evaporation to obtain 0.89 g of cephalothin 7-(2-thienylacetamido) cephalos-poranic acid dibenzhydryl ester . The IR and NMR spectra of the product were ldentical entirely with those of an authentic 10 sample, respectively.
Elementary analysis t%) (C29H26N2o6s2 = 562-69) C H N S
Calcd. 69.90 4.66 4.98 11.40 Found 70.05 4.70 4.69 11.42 NMR spectrum (CDC~3, 60 M~Iz), ppm (Hz) :
2.00 (CH3CO-, 9), 3.35/3.40 (-SCH2-, AB, J = 18) 3.82 ( ~ , s), 4.79/5.01 (-CH2O-, AB, J = 15), 4.89 (H-6, d, J = 5), 5.79 (H-7, dd, J = 9.5, 5), 6.77 (NH, d, J = 9.5), 6.91 (ester -OCH C , s) ~ ~-` Example 4 Preparation of cephalothin dibenzhydryl ester In 20 m of anhydrous dichloromethane was dissolved 1.76 g of N-phthaloylcephalosporin C dibenzhydryI ester.
After cooling the solution to -10C, 0.500 g of phosphorus pentàchloride was added thereto. After adding subse~uently 0.261 g of piperidine, the mixture was stirred at that temperature Eor 1 hour and at 0~ -5C for 1 hour. After cooling the reaction mixture -to -10C, 3,03 g of N,N-dimethyl-aniline and then 0.67 g of 2-thienylacetyl chloride were added and the mixture was stirred for 2 hours at 0 ~ -5C.` The reaction mixture was poured into 30 m of an ice water and stirxed at a pH value of 1.5 2.0 under ice-cooling for 1 hour.
` ' . . , ~ '`` ' ".` ' After extraction with chloroform, the extract was washed with water. After removing the solvent by evaporation in vacuo, dissolving the residue in 20 m of ethyl acetate, and washing with a saturated aqueous solution of sodium bicarbonate and with water, the solution was dried over anhydrous magnesium sulfate.
After removing the solvent by evaporation in vacuo, the residue was chromatographed through a column of silica gel to develop and elute the main product. After removing the solvent from the eluate by evaporation, 0.~4 g of cephalothin dibenzhydryl ester was obtained.
IR and NMR spectra of the product were identical - -` entirely with those of an authentic sample, respectively.
Example 5 Preparation of cephalothin .
In 5 m~ of anisole was dissolved 0.563 g of cephalothin benzhydryl ester. After adding 20 m of trifluoroacetic acid ; and stirring the mixture at 5 ~- 15C for 5 minutes, the mixture was concentrated under reduced pressure. The thus produced residue was dissolved in ethyl acetal:e and washed with water.
After drying over anhydrous magnesium sulfate and removing the solvent by evaporation in vacuo, ether was added to the mixture to crystalize and obtain cephalothin.
~; IR and NMR spectra of the product were identical " entirely with those of an authentic sample, respectively.
Example 6 Preparation of N-benzoylcephalosporin C benzhydryl ,: , .
ester (A) Preparatlon of N-benzoylcephalosporin C
~o 100 ml of an aqueous solution containing 4.15 g (40 mmol) was added a saturated aqueous solution of sodium hydrogen carbonate to adjust to pH of from 7.o to 7.3. 100 ml of acetone was added to the mixture and 2.1 g (15 mmol) of benzoylchloride in 21 ml of acetone was added dropwise wlth . ~ .
~ stirring under ice-cooling. After dropping, the reaction ~ '.
' .
mixture was stirred further for one hour at the same temperature.
During the reaction was added an aqueous solution of sodium hydrogen carbonate to keep pH at 7.0 ~ 7.3.
After acetone was distilled off under reduced pressure, the residure was washed twice with 10 ml portions of ethyl acetate. The water layer was adjusted to pH 3.3 and washed twice with 20 ml portions of benzene and, after being adjusted to pH 2.0, was extracted three times with 20 ml portions of benzene. The extract was dried over magnesium sulfate and distilled off to give 4.38 g of N-benzoylcephalosporin C in a yield of 84.3 %.
(B) Preparation of N-benzoylcephalosporin C dibenzhydrYl ester The oil containing 10 mmol of N-benzoylcephalosporin C `
obtained above and 6.05 g (30 mmol) of ~-chlorodiphenylmethane were dissolved in 100 ml of liquid sulfur dioxide and the mixture was gently refluxed at -5C. 3.5 ml (25 mmol) of triethylamine was added drop~ise over 10 minutes under reflux.
~fter the addition, the mixture was refluxed for 5.5 hours and the lic~uid sulfur dioxide was removecl by evaporation to give an oil. This oil was dissolved in 200 ml of ethyl acetate and washed with an acidic water to remove basic compounts and then washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solu~ion of sodium chloride. ;
The ethyl acetate solution was dried over magnesium sulfate and evaporated to dryness to give a solid, which was then washed with ether to obtain 1.11 g of the diester. This solid showed a single spot by thin layer chromatography and NMR
~` spectrum did not shown the presence of ~2-compound.~
~ Preparation of cephalothin benzhydryl ester 1.70 g (2 mmol) of N-benzoylcephalosporin C dibenzhydryl exter obtained in Example 6 was dissolved in 20 ml of anhydrous -. , . : ~ . ~ ' . '. :
dichloromethane and cooled ko -10C. 0.5000 g of phosphorus pentachlor:ide and 0.261 g of pyridine were added to the mixture, which was stirred at the same temperature Eor one hour and at 0 to -5C for one hour. The mixture was again cooled to -10C.
1.98 g of pyridine and 0.67 g of thienylacetyl chloride were added and the mixture was stirred at 0 to -5C for 2 hours.
The reaction mixture was poured to 30 ml of ice-water and stirred at pH 1.5 to 2.0 for one hour under ice-cooling and extracted with chloroform. The extract was washed with water and distilled off under reduced pressure. The residue was dissolved in 20 ml of ethyl acetate and washed with a satured sodium hydrogen carbonate and water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The main product was developed and eluted with chloroform, and the eluate was distilled off to obtain 0.82 g of cephalothin benzhydryl ester.
Example 8 Preparation of cephalothin benzhydryl ester 4.25 g (5 mmol) of N-benzoylcephalosporin C dibenzhydryl ester obtained in Example 6 was dissolved in 50 ml of dried ` dichloromethane and 1.56 g of phosphorous pentachloride was added to the mixture at -13C and then 0.711 g of pyridine was added. The mixture was stirred at the same temperature for one hour and at 0 to -5C for one hour. ~len, 30 ml of anhydrous methanol was added thereto at -10C and the mixture was stirred at the same temperature for one hour and at 0 to -5C for one hour. 5.53 g of pyridine was added thereto while ]~eeping the temperature at -lO~C and then a dimethylformamide solution of thienylacetic acid - anhydrous sulfuric acid mixed anhydride sodium salt corresponding to 10 mmol was added thereto and the mixture was stirred at 0 to -5C for two hours.
The reaction mixture was poured into 80 ml of ice-water "~
and stirred at pH l.S to 2.0 for one hour under ice-cooling. The mixture was extracted with chloroform and washed with water. The extract was distilled off under reduced pressure and the residue was dissolved in 60 ml of ethyl acetate and washed twice with water and adjusted to pH 8.0 by adding an aqueous saturated solution of sodium hydrogen carbonate and further washed twice with 20 ml portions of water. The ethyl acetate solution was dried over magnesium sulfate and distilled off under reduced pressure. ~ -The residue was subjected to silica gel column chromatography and the main product was developed and eluted with chloroform.
The eluate was distilled off to give 2.20 g of cephalothin benzhydryl ester.
Referential Example .
An N,N-dimethylformamide solution containing sodium salt of mixed anhydride between 2-thienylacetic acid and sulfur trioxide was prepared according to the following procedure.
Five ml of dimethylformamicle was cooled to 0~ 10C.
While distilling sulfur trioxide, 0.~ g thereof was blown into the solvent with stirring. After stirring the solution for 1.5 hours at that temperature, 0.656 g of sodium salt of 2-thienylacetic acid was added and the mixture was stirred at
5 ~ 15C for 1.5 hours to give an entirely transparent solution, thus yielding an N,N-dimethylformamide solution of sodium salt of mixed anhydride between 2-thienylacetic acid and sulfur trioxide.
' ' . "'.' . - ' .
` ' - .
-
' ' . "'.' . - ' .
` ' - .
-
Claims (27)
1. A process for preparing a cephalosporanic acid derivative having the formula (V) :
(V) wherein R6CO represents an acyl group, which comprises subjecting an esterifying agent having the formula (II) :
(II) wherein R3, R4 and R5 may be the same or different, each represents a hydrogen atom, an alkyl group, a substituted or unsubstituted aryl group, an aralkyloxy group, an aralkylthio group, an aroyl group, and X represents a halogen atom or an organic sulfonyloxy group, to reaction in a liquid sulfur dioxide in the presence of a base with an N-protected-cephalosporin C
having the formula (I) :
(I) wherein R1 represents a protective group for an amino group, and R2 represents a hydrogen atom or forms a ring structure together with R1, to obtain a diester having the formula (III) :
( I I I ) wherein R1, R2, R3, R4 and R5 have the same meanings as mentioned above, subjecting the diester (III) to reaction in an inert solvent with an iminohalide forming agent to produce an iminohalide, subjecting the iminohalide with a lower alcohol to produce an iminoether, subjecting a product produced after subjecting the iminoether to reaction with a reactive derivative of an organic acid having the formula (IV) :
R6 - COOH (IV) wherein R6CO represents an acyl group, to hydrolysis and further eliminating the ester group of the carboxylic acid.
(V) wherein R6CO represents an acyl group, which comprises subjecting an esterifying agent having the formula (II) :
(II) wherein R3, R4 and R5 may be the same or different, each represents a hydrogen atom, an alkyl group, a substituted or unsubstituted aryl group, an aralkyloxy group, an aralkylthio group, an aroyl group, and X represents a halogen atom or an organic sulfonyloxy group, to reaction in a liquid sulfur dioxide in the presence of a base with an N-protected-cephalosporin C
having the formula (I) :
(I) wherein R1 represents a protective group for an amino group, and R2 represents a hydrogen atom or forms a ring structure together with R1, to obtain a diester having the formula (III) :
( I I I ) wherein R1, R2, R3, R4 and R5 have the same meanings as mentioned above, subjecting the diester (III) to reaction in an inert solvent with an iminohalide forming agent to produce an iminohalide, subjecting the iminohalide with a lower alcohol to produce an iminoether, subjecting a product produced after subjecting the iminoether to reaction with a reactive derivative of an organic acid having the formula (IV) :
R6 - COOH (IV) wherein R6CO represents an acyl group, to hydrolysis and further eliminating the ester group of the carboxylic acid.
2. The process of Claim 1 in which the group - of said esterifying agent represents a t-butyl group, a p-nitrophenylmethyl group, a benzhydryl group, di-(p-nitro) benzhydryl group, a di-(p-methoxy)benzhydryl group, a benzyloxy-methyl group, a benzylthiomethyl group, a phenacyl group, an acetoxymethyl group, a pivaloyloxymethyl group, a benzoxymethyl group or a .alpha.-benzoyloxyethyl group.
3. The process of Claim 1 in which said base is a tertiary or secondary amine.
4. The process of claim 1 in which said protective group for an amino group is an alkanoyl group, an aroyl group, an alkoxycarbonyl group, a haloalkoxycarbonyl group, an alkoxyalko-xycarbonyl group, an aralkoxycarbonyl group, a substituted aryl group, an arylsulfonyl group or an arylsulfenyl group.
5. The process of Claim 1 in which said ring structure formed by R1 and R2 is a phthaloyl group, a tetrachlorophthaloyl group or a tetrabromophthaloyl group.
6. The process of Claim 1 in which said iminohalide forming agent is phosphorus halide or phosphoryl halide.
7. The process of Claim 1 in which said lower alcohol is methanol, ethanol, propanol or butanol.
8. The process of Claim 1 in which said reactive derivative of an organic acid is an alkali metal salt of a mixed anhydride derived from an organic acid and anhydrous sulfuric acid (sulfur trioxide).
9. The process of Claim 1 in which said organic acid is a phenylacetic acid derivative, thienylacetic acid or its derivative, mandelic acid, pyridylmercaptoacetic acid,tetra-zoylacetic acid, 1-aminocyclohexanecarboxylic acid, a-aminocyclo-hexadienylacetic acid, a-amino-cyclohexenylacetic acid or cyanoacetic acid.
10. The process of Claim 1 in which said reaction with esterifying agent is conducted at -10 - 5°C.
11. The process of Claim 1 in which said reaction with an iminohalide forming agent is conducted at -10 - 0°C in the presence of a tertiary amine.
12. A process for preparing a cephalosporanic acid derivative having the formula (V) :
(V) wherein R6CO represents an acyl group, which comprises subjecting an N-protected-cephalosporin C diethyl ester having the formule (III) :
wherein R1 represents a protective group for an amino group, R2 represents a hydrogen atom, a protective group for an amino group or may form a ring structure together with R1, R3, R4 and R5 may be the same or different, each represents a hydrogen atom, an alkyl, substituted or unsubstituted aryl, aralkyloxy, aralkylthiom aroyl, alkanoyloxy, aroyloxy or aroylamino group, to reaction in an inert solvent with an iminohalide forming agent to produce an iminohalide, subjecting the iminohalide to reaction with a lower alcohol to produce an iminoether, subjecting a product produced after subjecting the iminoether with a reactive derivative of an organic acid having the formula (IV) :
R6 - COOH (IV) wherein R6CO has the same meanings as mentioned above, to hydrolysis, and further eliminating the ester group of the carboxylic acid.
(V) wherein R6CO represents an acyl group, which comprises subjecting an N-protected-cephalosporin C diethyl ester having the formule (III) :
wherein R1 represents a protective group for an amino group, R2 represents a hydrogen atom, a protective group for an amino group or may form a ring structure together with R1, R3, R4 and R5 may be the same or different, each represents a hydrogen atom, an alkyl, substituted or unsubstituted aryl, aralkyloxy, aralkylthiom aroyl, alkanoyloxy, aroyloxy or aroylamino group, to reaction in an inert solvent with an iminohalide forming agent to produce an iminohalide, subjecting the iminohalide to reaction with a lower alcohol to produce an iminoether, subjecting a product produced after subjecting the iminoether with a reactive derivative of an organic acid having the formula (IV) :
R6 - COOH (IV) wherein R6CO has the same meanings as mentioned above, to hydrolysis, and further eliminating the ester group of the carboxylic acid.
13. The process of Claim 12 in which the group - of said diethyl ester (III) represents a t-butyl group, p-nitrophenylmethyl group, a benzhydryl group, di-(p-nitro) benzhydryl group, di-(p-methoxy)benzhydryl group, a benzyloxymethyl group, a benzylthiomethyl group, a phenacyl group, an acetoxyme-thyl group, a pivaloyloxymethyl group, a benzoxymethyl group or a .alpha.-benzoyloxyethyl group.
14. The process of Claim 12 in which said base is a tertiary or secondary amine.
15. The process of Claim l2 in which said protective group for an amino group is an alkanoyl group, an aroyl group, an alkoxycarbonyl group, a haloalkoxycarbonyl group, an alkoxyal-koxycarbonyl group, an aralkoxycarbonyl group, a substituted aryl group, an arylsulfonyl group or an arylsulfenyl group.
16. The process of C]aim 12 in which said ring struct-ure formed by R1 and R2 is a phthaloyl group, a tetrachlorophtha-loyl group or a tetrabromophthaloyl group.
17. rrhe process of Claim 12 in which said iminohalide forming agent is phosphorus halide or phosphoryl halide.
18. The process of Claim 12 in which said lower alcohol is methanol, ethanol, propanol or butanol.
19. The process of Claim 12 in which said reactive derivative of an organic acid is an alkali metal salt of a mixed anhydride derived from an organic acid and anhydrous sulfuric acid (sulfur trioxide).
20. The process of Claim 12 in which said organic acid is a phenylacetic acid derivative, thienylacetic acid or its derivative, mandelic acid, pyridylmercaptoacetic acid, tetrazoylacetic acid, 1-aminocyclohexanecarboxylic acid, .alpha.-amino-cyclohexadienylacetic acid, .alpha.-aminocyclohexenylacetic acid or cyanoacetic acid.
21. The process of Claim 12 in which said reaction with an iminohalide forming agent is conducted at -10 - 0°C in the presence of a tertiary amine.
22. A process for preparing an N-protected-cephalos-porin C diester having the formula (III) :
wherein R1 represents a protective group for an amino group; R2 represents a hydrogen atom, a protective group for an amino group or may form a ring structure together with R1; and R3, R4 and R5 may be the same or different, each represents a hydrogen atom, an alkyl group, or a substituted or unsubstituted aryl, aralkyloxy, aralkylthio, aroyl, alkanoyloxy, aroyloxy or arylamido group, which comprises subjecting an N-protected-cephalosporin C having the formula (I) :
(I) wherein R1 and R2 have the same meanings as mentioned above, to reaction in a liquid sulfur dioxide in the presence of a base with an esterifying agent having the formula (II) :
(II) wherein R3, R4 and R5 have the same meanings as mentioned above, and X represents a halogen atom or an organic sulfonyloxy group.
wherein R1 represents a protective group for an amino group; R2 represents a hydrogen atom, a protective group for an amino group or may form a ring structure together with R1; and R3, R4 and R5 may be the same or different, each represents a hydrogen atom, an alkyl group, or a substituted or unsubstituted aryl, aralkyloxy, aralkylthio, aroyl, alkanoyloxy, aroyloxy or arylamido group, which comprises subjecting an N-protected-cephalosporin C having the formula (I) :
(I) wherein R1 and R2 have the same meanings as mentioned above, to reaction in a liquid sulfur dioxide in the presence of a base with an esterifying agent having the formula (II) :
(II) wherein R3, R4 and R5 have the same meanings as mentioned above, and X represents a halogen atom or an organic sulfonyloxy group.
23. The process of Claim 22 in which the group R4 C - of said diester (III) represents a t-butyl group, a p-nitrophenylmethyl group, a benzhydryl group, di- (p-nitro) benzhydryl group, a di-(p-methoxy)benzhydryl group, a benzyloxy-methyl group, a benzylthiomethyl group, a phenacyl group, a acetoxymethyl group, a pivaloyloxymethyl group, a benzoxymethyl group or a .alpha.-benzoyloxyethyl group.
24. The process of Claim 22 in which said protective group for an amino group is an alkanoyl group, an aroyl group, an alkoxycarbonyl group, a haloalkoxycarbonyl group, an alkoxy-alkoxycarbonyl group, an aralkoxycarbonyl group, a substituted aryl group, an arylsulfonyl group or an arylsulfenyl group.
25. The process of Claim 22 in which said ring structure formed by R1 and R2 is a phthaloyl group, a tetrachloro-phthaloyl group or a tetrabromophthaloyl group or a tetrabromo-phthaloyl group.
26. The process of Claim 22 in which said base is a tertiary or secondary amine.
27. The process of Claim 22 in which said reaction with an iminohalide forming agent is conducted at -10 0°C in the presence of a tertiary amine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP56645/76 | 1976-05-19 | ||
| JP5664576A JPS52142089A (en) | 1976-05-19 | 1976-05-19 | Preparation of cephalosporanic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1113087A true CA1113087A (en) | 1981-11-24 |
Family
ID=13033070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA277,957A Expired CA1113087A (en) | 1976-05-19 | 1977-05-09 | Process for preparing cephalosporanic acid derivatives |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS52142089A (en) |
| CA (1) | CA1113087A (en) |
| DE (1) | DE2721731C2 (en) |
| FR (1) | FR2351983A1 (en) |
| GB (2) | GB1551551A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53112890A (en) * | 1977-03-14 | 1978-10-02 | Meiji Seika Kaisha Ltd | Preparation of cephalosporin ester |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE793191A (en) * | 1971-12-28 | 1973-06-22 | Toyama Chemical Co Ltd | PROCESS FOR PRODUCING 7-ACYLAMIDO-3-CEPHEM-4- CARBOXYLIC ACIDS |
| GB1430238A (en) * | 1972-07-10 | 1976-03-31 | Glaxo Lab Ltd | Esters |
-
1976
- 1976-05-19 JP JP5664576A patent/JPS52142089A/en active Granted
-
1977
- 1977-05-09 CA CA277,957A patent/CA1113087A/en not_active Expired
- 1977-05-13 DE DE19772721731 patent/DE2721731C2/en not_active Expired
- 1977-05-16 GB GB2040777A patent/GB1551551A/en not_active Expired
- 1977-05-16 GB GB3233178A patent/GB1551552A/en not_active Expired
- 1977-05-18 FR FR7715386A patent/FR2351983A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| GB1551552A (en) | 1979-08-30 |
| GB1551551A (en) | 1979-08-30 |
| DE2721731A1 (en) | 1977-12-08 |
| JPS52142089A (en) | 1977-11-26 |
| DE2721731C2 (en) | 1982-12-23 |
| FR2351983A1 (en) | 1977-12-16 |
| FR2351983B1 (en) | 1985-03-15 |
| JPS6133837B2 (en) | 1986-08-04 |
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