CA1102791A - Method for producing cephem compounds - Google Patents
Method for producing cephem compoundsInfo
- Publication number
- CA1102791A CA1102791A CA302,003A CA302003A CA1102791A CA 1102791 A CA1102791 A CA 1102791A CA 302003 A CA302003 A CA 302003A CA 1102791 A CA1102791 A CA 1102791A
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- CA
- Canada
- Prior art keywords
- compound
- mixture
- added
- group
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- 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
- C07D501/02—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D499/42—Compounds with a free primary amino radical attached in position 6
Abstract
Abstract of disclosure Cephem compounds of the formula:
, wherein R2 is hydrogen or an ester residue, or salts thereof are produced in low production cost and excellent yields by a method comprising silylating a compound of the formula:
, wherein R2 is hydrogen or an ester residue, or salts thereof are produced in low production cost and excellent yields by a method comprising silylating a compound of the formula:
Description
11~3*~91 The present invention relates to a method for producing cephem compound. More particularly, the present invention relates to a new and unobvious process for preparing cephem compounds of the formula (I):
S ~
S ~
2 ~ 1 o N ~ CH2OCNH2 (I) COOR
wherein R is hydrogen or an ester residue, and salts thereof.
The above compounds, particularly 7-amino-3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid (i.e. the compound (I) wherein R2 is hydrogen; hereinafter sometimes referred to briefly as 7-ACC) are important intermediates for the production of cephalospor-in antibiotics having a carbamoyloxymethyl group in the 3-position. `
7-ACC is a known compound and various processes for preparing it have been reported. For example, published Japanese Patent Application No. 32829/1973 teaches a method for producing 7-ACC
using 7-aminocephalosporanic acid (hereinafter referred to briefly as 7-ACA) as the starting material. This method, however, is not commercially advantageous in that it involves a large number of steps, employs a costly starting material (7-ACA) and involves a step of esterase hydrolysis.
A possible starting material for producing 7-ACC
appeared to be 7-(D-5-amino-5-carboxyvaleramido)-3-hydroxymethyl-
wherein R is hydrogen or an ester residue, and salts thereof.
The above compounds, particularly 7-amino-3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid (i.e. the compound (I) wherein R2 is hydrogen; hereinafter sometimes referred to briefly as 7-ACC) are important intermediates for the production of cephalospor-in antibiotics having a carbamoyloxymethyl group in the 3-position. `
7-ACC is a known compound and various processes for preparing it have been reported. For example, published Japanese Patent Application No. 32829/1973 teaches a method for producing 7-ACC
using 7-aminocephalosporanic acid (hereinafter referred to briefly as 7-ACA) as the starting material. This method, however, is not commercially advantageous in that it involves a large number of steps, employs a costly starting material (7-ACA) and involves a step of esterase hydrolysis.
A possible starting material for producing 7-ACC
appeared to be 7-(D-5-amino-5-carboxyvaleramido)-3-hydroxymethyl-
3-cephem-4-carboxylic acid (deacetyl-cephalosporin C; hereinafter sometimes referred to briefly as DCPC), which is produced directly by fermentation in high yield and at low-production cost, (Nature New Biology) 246, 154 (1973), published Japanese Patent Application No. 491/1974). But this route is still not satisfactory. Thus, in this method, the 3-hydroxymethyl group is firstccnverted to a carbamoyloxymethyl group and the 7-acylamide group must then be cleaved to obtain 7-ACC. However, in the latter reaction, the carbamoyl group reacts with the phosphorus pentachloride used as . '~': - 1 - ~ ' iiQ;~
cleavage agent, as shown below, making it impossible to achieve satisfactory results (Tetrahedron Letters 1976, 2401):
- la --a~S
OCH
1 3 S~
RCONH t ~ 0 " PC15/Py ~ / \ O
,I N ~ - CH20CNH > ~ ¦ l / 1 2 ~_ N ~ - CH20CNHPC14 COOcH~2 l COOCH~2 ' ~ ~ Methanol C ~ 2~ - N ~ CH20H ~ CH20CNHP(OC1~2 COOCH~
2 COOCH~2 _ COOCH~2 ~RCO=acyl; ~-phenyl; and Py=pyridine~
It has now been discovered, by means of N.M.R. spectrometry that the carbamoyl group in the 3-position of the cephalosporin nucleus is readily silylated and that the silylated carbamoyl group resis~s attack by the halo-genating agent e.g. phosphorus pentachloride.
Accordingly, the present invention provides a process for produc-ing a cephem compound of the formula:
H2N~ ~
0 N ~ CH20CNH2 (I) COOR
wherein R is hydrogen or an ester residue, or a salt thereofJ which com-prises silylating a compound of the formula:
RlCONH~ o N ~ CH20CNH2 (II) COOR
wherein RlCO is an acyl group and R2 has the same meaning as defined above, or a salt thereof to produce a compound silylated at the carbamoyl group of the 3-position, halogenating the silylated compound to produce the correspond-ing iminohalide, reacting the iminohalide with a lower aliphatic alcohol ~o - . : . -9~
produce the corresponding iminoether compound and subjecting the iminoether compound to solvolysis.
ReferringJ now, to the above general formulae~ the acyl group RlCO may be any of the acyl groups thus far known in the art of penicillins and cephalosporins. Preferred, for example, are 5-amino-5-carboxyvaleryl, phenylacetyl, phenoxyacetyl, etc. The most desirable are acyl groups of the formula:
HooccH(cH2)3co-(wherein R3 is a protected amino group).
In the above formulae, the protecting group of the protected amino R3 may be any of the protective groups ~ se known in the art of cephalosporins, for example, phthaloyl, naphthoyl, benzoyl, benzoyl -substituted by nitro, halogen or lower alkyl (Cl 4) (e.g. chlorobenzoyl, p-nitrobenzoyl, toluoyl, p tert-benzoyl, etcO), benzenesulfonyl, benzene--~ sulfonyl substituted by lower alkyl (Cl 4) (e.g. p-tert-butylbenzenesulfonyl, ph~h~ ~y_ toluenesulfonyl, etc.), aryl-substituted acyl (e.g. phenylacetyl, ~h~n~
acetyl, etc.), camphorsulfonyl, alkyl-substituted sulfonyl (e.g. methane-sulfonyl, etc.), aliphatic or halo-aliphatic carboxylic acid-derived acyl groups (e.g. acetyl, valeryl, capryl, n-decanoyl, acryloyl, pivaloyl, chloro-acetyl~ etc.), esterified carboxyl (e.gO tert-butoxycarbonyl, ethoxycarbonyl, isobornyloxycarbonyl, phen~loxycarbonyl, trichloroethoxycarbonyl, benzyloxy-carbonyl, ~methylsulfon~lethoxycarbonyl, ~-methylsulfonylethoxycarbonyl, etc.~, carbamoyl groups ~e.g. methylcarbamoyl, phenylcarbamoyl, naphthyl-carbamoyl, etc.), the corresponding thiocarbamoyl groups and so forth.
The group R2 is hydrogen or an ester residue. The ester residue may in particular be one that is conventionally employed in the cephalosporin -art. Thus, R2 may for example be benzhydryl, tert-butyl, 2,2,2-trichloro-ethyl, p-nitrobenzyl, cyanomethyl, methylthiomethyl, methoxymethyl, pivaloyl-oxymethyl or the like. In view of its ready availability, it is particularly desirable to employ the compound wherein R2 is hydrogen.
_ 3 _ 9~
The compound of general formula (I) forms salts with respect to its amino or carboxyl functions. Thus, it forms salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, etc.; salts with organic acids such as p-toluenesulfonic acid, oxalic acid, etc.; salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium, magnesium, etcO, salts with organic bases such as triethylamine, trimethyl-amine, triethanolamine, etc.
The compound (II) or salt thereof employed as starting material in the process of the present invention is prepared by carbamoylating a corresponding compound of formula (III):
RlcoNH / ~
N ~ --CH2OH (III) COOR
or salt thereof.
This reaction may be conducted by the known procedures, for example by the method described in published Japanese Patent ApplicationsNoO
16494/1972, NoO 81887/1973, No. 67222/1973, No. 67290/1973, No. 32829/1973 and No. 52083/1975. Thus, to effect the carbamoylation, normally a compound of general formula ~III) is reacted with an isocyanate of general formula (IV):
R5NCo (IV) - Cwherein R5 is a group substitutable by hydrogen) to produce a compound of formula (V):
R CONH -rl~ S ~
~N~ L CH20CoNHR5 (V) COOR
~wherein RlCO, R2 and R5 are as hereinbefore defined) and then, R5 in this compound (V) is substituted by a hydrogen atom to obtain a compound of general formula (II). The selection of a compound of general formula (V) and of reaction conditions may be made in accordance with the teachings of the afore-mentioned prior patent literature references. Among the isocyanates ~R5NCo)mentioned in the above patent literature, compounds in which R5 is chloro-sulfonyl, monohalogenoacetyl, dihalogenoacetyl or trihalogenoacetyl are preferred. As compound (IV), chlorosulfonyl isocyanate is particularly de-sirable, Thus, this compound may be reacted with a compound of general formula (III) to obtain the corresponding compound of formula ~V). Then, by contacting it with water under acidic conditions, ~V) can be easily converted to a compound of general formula (II).
A large number of compounds of general formula ~III) are known compounds. Any new compounds of formula ~III) may also be easily produced by procedures analogous to these employed for making the known compounds.
The resultant compound of general formula ~II) is then silylated.
A suitable silylating agent is a compound of the formula: plp P3Si Hal, wherein each of pl, p2 and P3 is a hydrocarbon residue such as a lower alkyl of 1 to 4 carbon atoms (e.gO methyl, ethyl, n-propyl, i-propyl, n-butyl, etc.), an aryl group Ce.g. phenyl, tolyl, etc.) or the like, and Hal is halogen, preferabl~ chlorine or bromine, and one or two of pl, p2 and P3 may be halo-gen, pre~erably chlorine or bromine, and one of pl, p2 and P3 may be hydrogen.
Furthermore, hexa-alkyl(Cl-C4) cyclotrisilazane, octaalkyl ~Cl-C4)cyclotetra-silazane, trialkylCCl-C4)silylacetamide, bis-tri-alkyl~Cl-C4)silylacetamide may be used as the silylating agent in the method of the present invention.
The preferred silylating agents are alkyl~Cl-C4)trihalogenosilane ~e.g.
trimethylsilylchloride), di-alkyl~Cl-C4)dihalogenosilane (e.g. dimethyl-dichlorosilane~, di-alkoxy~Cl-C4)dihalogenosilane ~e.g. dimethoxydichloro-silane, diethoxydichlorosilane), etc. This reaction is preferably conducted in the presence of a base ~e.g. triethylamine, pyridine, picoline, N,N-dimethylaniline, etc.). While the reaction proceeds in the absence of a solvent, it is preferably conducted in an inert solvent such as dichloromethane, dichloroethaneJ chloroform, benzene, toluene, tetrahydrofuran, etc. With res-pect to 1 mol of compound ~II), the silylating agent is employed normally in 2~9~
excess, preferably in an amount of 1.2 to 2 times mols relative to the theoretical amount. The base is desirably used in a proportion of about 1 to 5 mols per compound (II). The reaction temperature is normally about -20C to -40C and the reaction normally goes to completion within about one hour. After the reaction has been com-pleted, the reaction mixture either as it is or after having been concentrated to a suitable concentration is subjected to the next reaction. By this silylation reaction, a silyl group is intro-duced into the carbamoyl group. Where the acyl group (RlCO) has a free carboxyl group and where R2 in COOR2 is hydrogen, silyl groups are also introduced into those carboxyl groups, producing silyl esters. It is disclosed in published Japanese Patent Application No. 40899/1970 that a silyl ester is an excellent protective group for carboxy group when removing an acyl group.
The silylated compound thus obtained is then subjected to cleavage of the amide linkage. The various techniques es-tablished in the art of cephalosporins for such amide-cleavage reactions may be utilized for this purpose. For example, the procedures taught by Japanese Patent Publication No. 13862/1966 and published Japanese Patent Applications No. 95292/1975 and No.
96591/1975 may be followed, for instance. The procedure according to the present invention comprises converting the silylated com-pound to an iminohalide and, then, the latter to an iminoether compound and, finally, subjecting the latter to solvolysis to obtain the compound of general formula (I).
Thus, in the first place, the silylated compound is halogenated, for instance with a halogenating agent such as phosphorus pentachloride, to produce the iminohalide. With respect to each mol of silylated compound, about 1 to 4 mols of phosphorus pentachloride is normally employed. The reaction temperature is usually about ~50 to about 45C. The reaction may , - 6 -ll~Z791 be conducted in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, benzene or toluene. Following this reaction for the production of said iminohalide, the reaction mixture is normally contacted with a lower aliphatic alcohol to convert the iminohalide to the iminoether compound, ~he alcohol may for example be methanol, ethanol, n-butanol or the like. ~his reaction is normally carried out in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran or the like aDd at a temperature in the range of about -50C and +45C, ~he reaction normally goes to completion within about 10 minutes to one hour. ~he resultant iminoether compound is subjected to solvolysis, ~he solvolysis is usually carried out by contacting the iminoether compound with an alcohol, e,g. said lower aliphatic alcohol solvent, or water or the lower aliphalic alcohol and ~ater.
~he amide linkage is cleaved by the solvolysis, ~he silyl group or groups are also removed by the action of the lower aliphatic alcohol or water, ~hus, the compound (I~ or its salt is produced in excellent yield in accordance with the present invention, This solvolysis is normally conducted under acid conditions, The solvent is used in excess, ~he reaction temperature may be within the range of about -50C to about 45C, the reaction being completed in about 10 minutes to 1 hour, The acid condition may be attained by the presence of an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc, in the reaction mixture. ~he pH value of the mixture is 11~*791 usually not higher ~han 1.
The amide-cleavage reaction may also be accomplished by reacting said iminohalide with hydrogen sulfide or thioacetamide to obtain the thioamide derivative, then activating this thioamide and subjecting this activated compound to solvolysis (e.g. the specification of published Japanese Patent Application No. 96591/1975). ~he conditions of reaction (reaction temperature, solvent, etc.) between the iminohalide and hydrogen sulfide or thioacetamide may be similar to the conditions used for the aforesaid reactions for the production of iminohalide and iminoether compounds. The thioamide compound may be acti~ated, for example by reacting it with trichloromethanesulfenyl chloride or sulfur monochloride. The solvolysis of the thus activated compound is effected by exactly the same procedure as the solvolysis of said iminoether compound and gives rise to the compound of formula (I).
Where ~2 in the resultant compound of formula (I) is an ester residue, the compound in which R2 is hydrogen may be produced if desired, by removing the ester residue in a routine manner, e g. by hydrolysis, acid decomposition, reduction or the like in accordance with the per se known procedures ~ he solution containing compound (I) may be directly subjected to the next reaction, or compound ~I) may be isolated beforehand. ~he isolation of compound ~I) may be conducted in a routine manner. ~or example, when the reaction mixture is allowed to cool in the neighborhood , . . - , , .: ~ - . . . . .
,, . . ~ -1~791 of its isoelectric point, 7-ACC separates out from the mixture, ~his precipitate is recovered by filtration, washed with an organic solvent and water and dried. If desired, the compound may be further purified by a procedure well known per se, A good embodiment of the present invention may be shown by the following reaction scheme, HooccH(cH2)3coNH
R' O F~ cH2ocoNH2 COOH
~ silylating agent Y OOCCH(CH2)3CONH F S~ 2 R3N ~ CH20Y
COOY
Xl ~ halogenating agent Y OOCICH(CH2)3C=N F S~ 2 R3 N ~ CH20Y
cooyl an aliphatic alcohol (ROH) OR
YlOOCpH(C~2 )3b'-N ~ 1'$~
R3 ~ N ~ CH20Y2 COOY
I the aliphatic alcohol ~ or/and water (solvolysis) H2N I ~ S~ o N ~ CH20CNH2 (7-ACC) COOH
, ~Z791 In the above schcme, R3 is a protected amino; yl is a silyl group; y2 is a silylated carbamoyl group; Xl is halogen; and ROH is an aliphatic alcohol.
~ he end-products of the present invention are useful as the starting materials for the production of various cephem compounds having excellent antibacterial properties.
Particularly~ 7-ACC and its salts are of value as the starting materials for the production of antibiotics having the formula ~VI) H2-n HnN CCONH ~ ~S
N ~ CH20CONH2 ~VI~
oR4 0 COOR2 , wherein n is a number of a range O' n '1, and R4 is hydrogen or a lower alkyl, and phamaceutically acceptable salts thereof, ~he compounds of the formula ~VI) may form pharmaceutical acceptable salts with respect to the carboxyl function or with respect to the group represented by the formula:
H2-n HnN
, and the pharmaceutical acceptable salts may be salts with the acids or bases above-mentioned regardin~ the compound ~
~ he compound of formula ~VI~ in which R2 is hydrogen and R4 is hydrogen may be produced, for example by the following reaction steps.
.. . . . - .
- - ~
. . . ~ ,., . , . :. :
~l~Z79~
7-ACC or its salt XCH2COCH2COX ~ CH2 r 2 0--~
XCH2COCH2CONH ~ S~ o O ~ CH20CNH2 (VII) I COOH
I Nitrosating Agent XCH2COCCONH 1~ S~
N ~ N ~ CH20CN~2 ~VIII) OH COOH
,l H2NCSNH2 H2 nN ~ S
HnN ~ CCO~H ~ S~
N N ~ -CH OCONH (IX) ~whereln n has the meaning defined hereinbefore; X is chlorine or bromine) In the step of producing a compound (VII~ from 7-ACC, the latter is acylated with 1 to 1 5 molar equivalents of a 4-halogeno-3-oxobutyryl halogenide to give (VII). This acylation re~ction is conducted in a solvent, such as dimethylformamide, dlchloromethane, dimethylacetamide, dimethylsulfoxide, chloroform, acetonitrile or the like, or a mixture of such solvents, and in the presence of 1 to 3 molar equivalents of an organic base such as triethylamine7 N,N-dimethylaniline, pyridine or the like.
~his reaction is conductad at a temperature between -40C
, ~l~Z~l and 40C, preferably lmder cooiing at a temperature from _~ to oC. ~he compound LVIl~ obtain?d is isola~ed as crystals by extraction and concentration, etcO
The compound ~VII) is then nitrosated to (VIII).
~pecifically, compound ~VII) is p~viously dissolved in a solvent, e.g. acetic acid or aqueous acetic acid, and 1 to 2 molar equivalents of a nitrosating agent such as sodium nitrite is added The reaction is conducted at -40C to ~20C. ~he resultant (VIII) is isolated as powders by extraction and phasic transfer operations.
~ hen, (VIII) is reacted with 1 to 2 molar equivalents of thiourea to produce (IX). ~his reac-tion is conducted at O to 20C in a solvent, e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, ace-tonitrile or the like, or a mixture o~ solvents ~he resultant ~IX) is isolated and purified by such procedures as extraction, phasic transfer, pH adjustment, crystallization, column chromatography, etc.
Among compounds of formula ~VI), a compound ~X), i.e. the compound ~VI~ wherein ~2 is hydrogen and R4 is a lower alkyl group such as methyl, ethyl, n-propyl or i-propyl:
H2_nN ~
HnN CCO~-H I ~S~ o ~X) o~N~ CH20C~TH2 OY COOH
(wherein Y is the lower alkyl mentioned above~ n has the meaning defined hereinbefore) .. . .
'. . : ' , : . : ~
, .
- . . ', ~ ' : . -- \
11~2 791 may be produced by reacting a carboxylic acid of formula ~XI~:
(XI) N
OY
~wherein Y and n are as defined hereinbefore 9 Z iS hydrogen or a protective group) or a reactive derivative thereof with 7-~C. In the above compound (XI~, the protective group Z is exemplified by aromatic acyl groups such as benzoyl, benzoyl substituted by halogen, nitro or lower alkyl (Cl 4) (e.g. chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, toluoyl, etc.), naphthoyl, phenylacetyl, phenoxyacetyl, benzenesulfonyl, benzenesulfonyl substituted by lower alkyl (Cl_4) (e.g. p-tert-butylbenzenesul~onyl, toluenesulfonyl, etc ), camphorsulfonyl, methanesulfonyl, aliphatic or halo-aliphatic carboxylic acid-derived acyl groups (e.g. acetyl, valeryl, caprilyl, n-decanoyl, acryloyl, pivaloyl, halogenoacetyl(e.g. monochloroacetyl, monobromoacetyl, dichloroacetyl, trichloroacetyl, etc.), etc. ~7 esterified carboxyl groups (e.g. ethoxycarbonyl, tert-butyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxy-carbonyl, benzyloxycarbonyl, etc.), carbamoyl groups (e.g.
methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl, etc.) and the corresponding thiocarbamoyl groups. The carboxylic acid thus protected or unprotected may be used, either as ,, .. . : . - . . .:
.
.
, . :
ll~Z7~
it is or as a reactive derivative thereof, as an acylating agent for acylating the 7-amino group of compound (I).
~hus, the free acid ~XI), a salt thereof with an alkali metal or alkaline earth metal ~e.g. sodium, potassium, calcium, etc.) or with an organic amine (e.g. trimethyl-amine, p~ridine, etc.) or a reactive derivative thereof, such as the acid halide (e.g. acid chloride, acid bromide, etc.), acid anhydride, mixed acid anhydride, active amide, activated ester or the like may be employed for the purpose of the above-mentioned acylation. As examples of said activated ester may be mentioned the p-nitrophenyl ester, 2~4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester and N-hydroxyphthalimide ester.
~he mixed acid anhydride is exemplified by mixed anhydrides with carbonic acid monoesters (e.g. monome-thyl carbonate, monoisobutyl carbonate, etc.) and mixed anhydrides with lower alkanoic acids which may optionally be substituted by halogen (e.g. pivalic acid~ trichloroacetic acid, etc.).
Where the protected or unprotected carboxylic acid ~XI~
is employed as it is or in the form of a salt, a suitable condensing agent is employed As examples of th6 condensing agent may be mentioned N,N'-di-substituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, etc.; azolides such &s N,N'-carbonylimidazole, N,N'-thionyldiimidazole, etc.; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, etc.; 2-halogenopyridinium salts (e.g.
2-chloropyridinium methyl iodide, 2-fluoropyridinium .. . : , :. . - . - --'' ~' "' '. , , ' ' . ~ ;
- -- . , .
Z79~
methyl iodide, etc.) and so forth. Where such condensing agents are employed, the reaction seems to proceed via a reactive derivative of carboxylic acid ~XI). The reaction is generally conducted in a suitable solvent As examples of said solvent may be mentioned halogenated hydrocarbons such as chloroform, methylene chloride, etc ;
ethers such as tetrahydrofuran, dioxane, etc ; dimethyl-formamide, dimethylacetamide, acetone, water and mixtures thereof. The proportion of carboxylic acid (XI) or a reactive derivative thereof is normally about l to a few molar e~uivalents per mol of compound ~I)o This reaction is generally carried out at a temperature in the range of -50 to ~40C. After the acylation reaction, the pro-tective group may be removed. Removal of an amino-protecting group may be accomplished by procedures known per se, for example, the procedures described in Japanese Patent Application Laid-open No 520~3/1975, ~ure and Applied Chemistry 7, ~35 (196~)) or by procedures analogous thereto. Where, for example, the protective group Z is a monohalogenoacetyl group (e.g. monochloroacetyl), removal of the monohalogeno-acety] from the amino group may be accomplished by reacting the acylated compound with its amino group thus protected with thiourea and a basic reagent ~his reaction is normally conducted in a solvent in the neighborhood of room temper-ature and, in many instances, goes to completion in one to ten and odd hours. The solvent may be any solvent that will not interfere with the reaction. ~hus, for example, ethers (e g. ethyl ether, tetrahydrofuran, dioxane, ll~Z791 etc ), lower alcohols (e.g. methanol, ethanol, etc.), halogenated hydrocarbons (e.g. chlorofor~, methylene dichloride, etc ), esters (e.g. ethyl aceta-te, butyl~
acetate, etc.), ~etones (e,g. acetone, methyl ethyl ketone, etc.), water and mixtures thereof may be mentioned.
~ eacting the protected compound ~X) with thiourea and a basic reagent results in a selective and smooth progress of the reaction for the desired removal of the monohalogeno-acetyl group and~ hence, in the formation of compound ~X).
The basic reagent useful for this reaetion is exemplified by the alkali metal or alkaline earth metal salts of lower aliphatic carboxylic acids and inorganic or organie bases with pKa values not less than 9 5, preferably pK values in the range of 9 8 to 12 0. As examples of the salts of lower aliphatic earboxylic aeids may be mentioned the salts of lower aliphatie earboY.ylie aeid (Cl_6) ~e.g sodium aeetate, potassium acetate, calcium acetate, barium aeetate, sodium formate, sodium propionate, potassium hexanoate, ete.) As examples of said inorganic bases may be mentioned the alkali metal salts of carbonic acid (e,g. sodium carbonate, potassium carbonate, ete,). As said organic bases, there may be mentioned amines mono-, di- or tri-substituted by lower alkyl (C1~4)(e.g. trimethylamine, triethylamine, ethylamine, methylamine, diethylamine, dimethylamine, tri-butylamine, dibutylamine, butylamine, ete.) and 5 to 6-membered cyclic amines N-substituted by lower alkyl (~1-2) (e.g, N-methylpyrrolidine, N-ethylpyrrolidine, N-methyl-piperazine, N-ethylpiperazine, etc ) While, as aforesaid, ' l~Z79~
thiourea is employed in this reaction, it is also possible to employ ~- or N,N-substituted thiourea (e.g. methyl-thiourea, N,N-diethylthiourea, N,N-hexamethylenethiourea, etc.) in place of thiourea.
The starting material ~XI), e.g. 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (s~n-isomer) may ~e produced, for example by the process described hereinafter in detail First, a 4-halogeno-3-oxo-2-hydrox~iminobutyric acid derivative of ~eneral formula ~XII):
(~ X2CH CoC-CooR7 ., SN 4l (XII) OR
~wherein x2 is halogen (e.g chlorine or bromine); R4 is lower alkyl (e g. methyl~; R7 is lower alkyl (C1_3)(e.g.
ethyl)) is reacted with thiourea to obtain an 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid derivative of general formu}a (XIII):
H2-nN ~ 7 HnN C-COOR
(XIII~
SR4l (wherein P4 and ~7 are as respectively defined above).
In this case, the compound ~XIII) is obtained as a mixture of s~n- and anti-isomers. ~his reaction is normally conducted by permitting thiourea to act upon compound (XII) in an organic solvent such as ethanol, methanol, tetra-hydrofuran or the like at room temperature or elevated `\
temperature. The amount of thiourea may be about one to three mols per mol of the compound (XII).
From the resultant mixture of said syn-and anti-forms of compound (XIII), the desired syn-isomer may be separated and recovered by the per se known procedure or by the procedure disclosed in Canadian Patent Application No. 276,067 filed April 13, 1977. The resultant compound (XI) wherein Z is hy-drogen, if desired after the introduction of a protective group Z by a procedure known per se, may be converted to a reactive derivative thereof by a procedure which is also well known per se.
It is in order to mention that, in the above formulas, the moieties of H2 nN~L ZHl nN ~5 HnN HnN
are each supposed to assume a tautomeric structure of 2-amino-thiazole and 2-iminothiazoline forms, thus:-H2N ~ S HN ~ SN ~ ~ HN
~ ~ HN
(2-aminothiazole form) (2-iminothiazoline form) The compounds (VI) and their pharmacologically acceptable salts, may be administered as injections just as the known cephalosporin and penicillin drugs. Thus, ., .
f t these compounds are novel compounds having excellent ~ctivity against a broad spectrum of microorganisms including Gram-negative bacteria such as scherichia coli~
Serratia marcescens, Proteus rettgeri, Enterobacter cloacae, Citrobacter freundii etc, and are ~-lactamase-resistant These compounds may be employed, for example, as disin-fectants for removing said microorganisms from sursical instruments or as a therapeutic agent for the management of infectious diseases When a compound ~VI) or a salt thereof is used as a therapeutic for the therapy of infectio~s diseases, such as the intr-aperitoneal, respiratory organ, urinary tract and other infections, it may be safely administered by the parenteral route to mammalian animals including man, mouse and rat at the dose level of 1 to 20 mg daily per kilogram body weight, in 3 to 4 installments a day. ~he dosage forms may be conven-tional Thus, for example, injectable preparations made by se known procedures may be administered either intra-muscularly or intravenously. ~he carrier to be employed in such injectable preparations may for example be distilled water or physiological saline.
Example 1 In dichloromethane (6 m~) is suspended benzhydryl 7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate (427 mg) Following the addition of pyridine (300 mg), dimethyldichlorosilane (150 mg) is further added under ice-cooling. The mixture is stirred at room temperature for one hour, whereby the ester is completely dissolved.
~l~Z791 ~he solution is cooled to -20C and, after phosphorus pentachloride (600 mg) is added, the mixture is stirred ~or 30 minutes. ~uring this period of time, the temperature increases to -10C. The mixture is cooled to -40C and methanol (4 m~) is added. It is then stirred for 15 minutes, after which water (6 m~) and tetrahydrofuran (4 m~) are added. ~he layers are separated and the water layer is taken,while the organic layer is extracted with water The water layers are combined, washed once with dichloromethane and neutralized with sodium hydrogen carbonate It is then extracted with a solvent mixture of dichloromethane-tetra-hydrofuran and the extract is washed with aqueous sodium chloride, dried, filtered and concentrated ~o the residue is added petroleum ether, whereupon crystals separate out.
By the above procedure is obtained benzhydryl 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylate as crystals melting at 120 to 12~C.
IR(KBr, cm l): 1775, 1728 NMR(d6-DMS0): ~ 3,53(2H, ABq, J=20Hz, 2-CH2), 4.66(2E, ABq, J=13Hz, 3-CH2), 4 84(1H, d, J=5Hz, 6-H), 5 03 (lH d J=5Hz 7-H), 6.55(2H, broad-s. -OCNH2)~ 6 9 (lH, s, -CH~2), 7.39(10H, m) Example 2 Dichloromethane (8.6 ~) is cooled to -30C in nitrogen gas streams and 7-(D-5-p-t-butylbenzamido-5-carboxyvaleramido)-3-hydroxymethyl~3-cephem-4-carboxylic acid di-triethylamine salt (1.7 ~g) is added. ~he mixture is s-tirred and anhydrous potassium carbonate (450 g) is then added and suspended.
ll~Z~9:1 At -25C, the coolin~ bath is removed. Then, dichloromethane (lR) containin~; chlorosulfonyl isocyanate (450 g) is added over a period of about 5 minutes and the mixture is stirred at -10C for 40 minutes. The mixture is ad~usted to pH 0.1 to 0.2 by the addition of 3N-hydrochloric acid and stirred at room temperature for 30 minutes. Then~ it is adjusted to pH 2.7 with potassium carbonate and extracted with tetrahydrofuran (12 ~). After the addition of triethylamine (580 g), the extract is concentrated, dissolved in dichloro-methane (15 ~) 7 dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a syrupy substance.
Upon addition of ether (5 ~), the syrup becomes powders.
The powders are recovered by filtration and dried. By the above procedure is obtained 7-(r-C-p-t-butylbenzamido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid di-triethylamine salt as crude powders (1.7 kg). While this product includes the lactone, it is fully useful for the next deacylation reaction. The above crude powders (3 g) are taken, purified by column chromatography on ~mberlite XAD-2 and Sephadex LH-20, and lyophilized. The above procedure gives a high purity grade of 7-(~-5-p-t-butylbenzamido-5-carboxyvaleramido)-3-carbamoyloxymethyl -3-cephem-4-carboxyllc acid di-triethylamine salt (1.12 ~;).
Il~(KBr, cm 1): 1770, 1330 N~(d6-rMS0): ~ 1.13 (18H, t, J=6Hz, Et3Nx2), 1 31~9H, s,t-Bu), 1.4-2.0(4H, m- -CH(CH2)2-CH2-), 2.20(2H, t,J=6Hz, -CH(CH2)2CH2-), 2.91(12H, q, J=6Hz, Et3Nx2), 3.17 ~ 3.48(2H, ABq, J=18Hz, 2-CH2), 4.24(1H, m~
* ~ra~
- . : - . - . . .
. - ' ''. . . ' , . :
-,'. . ~
. -. - ~
~91 -CF[(CH2)3-), 4.66 & 4.87(2H~ ABq, J=13Hz, 3-CH2),
cleavage agent, as shown below, making it impossible to achieve satisfactory results (Tetrahedron Letters 1976, 2401):
- la --a~S
OCH
1 3 S~
RCONH t ~ 0 " PC15/Py ~ / \ O
,I N ~ - CH20CNH > ~ ¦ l / 1 2 ~_ N ~ - CH20CNHPC14 COOcH~2 l COOCH~2 ' ~ ~ Methanol C ~ 2~ - N ~ CH20H ~ CH20CNHP(OC1~2 COOCH~
2 COOCH~2 _ COOCH~2 ~RCO=acyl; ~-phenyl; and Py=pyridine~
It has now been discovered, by means of N.M.R. spectrometry that the carbamoyl group in the 3-position of the cephalosporin nucleus is readily silylated and that the silylated carbamoyl group resis~s attack by the halo-genating agent e.g. phosphorus pentachloride.
Accordingly, the present invention provides a process for produc-ing a cephem compound of the formula:
H2N~ ~
0 N ~ CH20CNH2 (I) COOR
wherein R is hydrogen or an ester residue, or a salt thereofJ which com-prises silylating a compound of the formula:
RlCONH~ o N ~ CH20CNH2 (II) COOR
wherein RlCO is an acyl group and R2 has the same meaning as defined above, or a salt thereof to produce a compound silylated at the carbamoyl group of the 3-position, halogenating the silylated compound to produce the correspond-ing iminohalide, reacting the iminohalide with a lower aliphatic alcohol ~o - . : . -9~
produce the corresponding iminoether compound and subjecting the iminoether compound to solvolysis.
ReferringJ now, to the above general formulae~ the acyl group RlCO may be any of the acyl groups thus far known in the art of penicillins and cephalosporins. Preferred, for example, are 5-amino-5-carboxyvaleryl, phenylacetyl, phenoxyacetyl, etc. The most desirable are acyl groups of the formula:
HooccH(cH2)3co-(wherein R3 is a protected amino group).
In the above formulae, the protecting group of the protected amino R3 may be any of the protective groups ~ se known in the art of cephalosporins, for example, phthaloyl, naphthoyl, benzoyl, benzoyl -substituted by nitro, halogen or lower alkyl (Cl 4) (e.g. chlorobenzoyl, p-nitrobenzoyl, toluoyl, p tert-benzoyl, etcO), benzenesulfonyl, benzene--~ sulfonyl substituted by lower alkyl (Cl 4) (e.g. p-tert-butylbenzenesulfonyl, ph~h~ ~y_ toluenesulfonyl, etc.), aryl-substituted acyl (e.g. phenylacetyl, ~h~n~
acetyl, etc.), camphorsulfonyl, alkyl-substituted sulfonyl (e.g. methane-sulfonyl, etc.), aliphatic or halo-aliphatic carboxylic acid-derived acyl groups (e.g. acetyl, valeryl, capryl, n-decanoyl, acryloyl, pivaloyl, chloro-acetyl~ etc.), esterified carboxyl (e.gO tert-butoxycarbonyl, ethoxycarbonyl, isobornyloxycarbonyl, phen~loxycarbonyl, trichloroethoxycarbonyl, benzyloxy-carbonyl, ~methylsulfon~lethoxycarbonyl, ~-methylsulfonylethoxycarbonyl, etc.~, carbamoyl groups ~e.g. methylcarbamoyl, phenylcarbamoyl, naphthyl-carbamoyl, etc.), the corresponding thiocarbamoyl groups and so forth.
The group R2 is hydrogen or an ester residue. The ester residue may in particular be one that is conventionally employed in the cephalosporin -art. Thus, R2 may for example be benzhydryl, tert-butyl, 2,2,2-trichloro-ethyl, p-nitrobenzyl, cyanomethyl, methylthiomethyl, methoxymethyl, pivaloyl-oxymethyl or the like. In view of its ready availability, it is particularly desirable to employ the compound wherein R2 is hydrogen.
_ 3 _ 9~
The compound of general formula (I) forms salts with respect to its amino or carboxyl functions. Thus, it forms salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, etc.; salts with organic acids such as p-toluenesulfonic acid, oxalic acid, etc.; salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium, magnesium, etcO, salts with organic bases such as triethylamine, trimethyl-amine, triethanolamine, etc.
The compound (II) or salt thereof employed as starting material in the process of the present invention is prepared by carbamoylating a corresponding compound of formula (III):
RlcoNH / ~
N ~ --CH2OH (III) COOR
or salt thereof.
This reaction may be conducted by the known procedures, for example by the method described in published Japanese Patent ApplicationsNoO
16494/1972, NoO 81887/1973, No. 67222/1973, No. 67290/1973, No. 32829/1973 and No. 52083/1975. Thus, to effect the carbamoylation, normally a compound of general formula ~III) is reacted with an isocyanate of general formula (IV):
R5NCo (IV) - Cwherein R5 is a group substitutable by hydrogen) to produce a compound of formula (V):
R CONH -rl~ S ~
~N~ L CH20CoNHR5 (V) COOR
~wherein RlCO, R2 and R5 are as hereinbefore defined) and then, R5 in this compound (V) is substituted by a hydrogen atom to obtain a compound of general formula (II). The selection of a compound of general formula (V) and of reaction conditions may be made in accordance with the teachings of the afore-mentioned prior patent literature references. Among the isocyanates ~R5NCo)mentioned in the above patent literature, compounds in which R5 is chloro-sulfonyl, monohalogenoacetyl, dihalogenoacetyl or trihalogenoacetyl are preferred. As compound (IV), chlorosulfonyl isocyanate is particularly de-sirable, Thus, this compound may be reacted with a compound of general formula (III) to obtain the corresponding compound of formula ~V). Then, by contacting it with water under acidic conditions, ~V) can be easily converted to a compound of general formula (II).
A large number of compounds of general formula ~III) are known compounds. Any new compounds of formula ~III) may also be easily produced by procedures analogous to these employed for making the known compounds.
The resultant compound of general formula ~II) is then silylated.
A suitable silylating agent is a compound of the formula: plp P3Si Hal, wherein each of pl, p2 and P3 is a hydrocarbon residue such as a lower alkyl of 1 to 4 carbon atoms (e.gO methyl, ethyl, n-propyl, i-propyl, n-butyl, etc.), an aryl group Ce.g. phenyl, tolyl, etc.) or the like, and Hal is halogen, preferabl~ chlorine or bromine, and one or two of pl, p2 and P3 may be halo-gen, pre~erably chlorine or bromine, and one of pl, p2 and P3 may be hydrogen.
Furthermore, hexa-alkyl(Cl-C4) cyclotrisilazane, octaalkyl ~Cl-C4)cyclotetra-silazane, trialkylCCl-C4)silylacetamide, bis-tri-alkyl~Cl-C4)silylacetamide may be used as the silylating agent in the method of the present invention.
The preferred silylating agents are alkyl~Cl-C4)trihalogenosilane ~e.g.
trimethylsilylchloride), di-alkyl~Cl-C4)dihalogenosilane (e.g. dimethyl-dichlorosilane~, di-alkoxy~Cl-C4)dihalogenosilane ~e.g. dimethoxydichloro-silane, diethoxydichlorosilane), etc. This reaction is preferably conducted in the presence of a base ~e.g. triethylamine, pyridine, picoline, N,N-dimethylaniline, etc.). While the reaction proceeds in the absence of a solvent, it is preferably conducted in an inert solvent such as dichloromethane, dichloroethaneJ chloroform, benzene, toluene, tetrahydrofuran, etc. With res-pect to 1 mol of compound ~II), the silylating agent is employed normally in 2~9~
excess, preferably in an amount of 1.2 to 2 times mols relative to the theoretical amount. The base is desirably used in a proportion of about 1 to 5 mols per compound (II). The reaction temperature is normally about -20C to -40C and the reaction normally goes to completion within about one hour. After the reaction has been com-pleted, the reaction mixture either as it is or after having been concentrated to a suitable concentration is subjected to the next reaction. By this silylation reaction, a silyl group is intro-duced into the carbamoyl group. Where the acyl group (RlCO) has a free carboxyl group and where R2 in COOR2 is hydrogen, silyl groups are also introduced into those carboxyl groups, producing silyl esters. It is disclosed in published Japanese Patent Application No. 40899/1970 that a silyl ester is an excellent protective group for carboxy group when removing an acyl group.
The silylated compound thus obtained is then subjected to cleavage of the amide linkage. The various techniques es-tablished in the art of cephalosporins for such amide-cleavage reactions may be utilized for this purpose. For example, the procedures taught by Japanese Patent Publication No. 13862/1966 and published Japanese Patent Applications No. 95292/1975 and No.
96591/1975 may be followed, for instance. The procedure according to the present invention comprises converting the silylated com-pound to an iminohalide and, then, the latter to an iminoether compound and, finally, subjecting the latter to solvolysis to obtain the compound of general formula (I).
Thus, in the first place, the silylated compound is halogenated, for instance with a halogenating agent such as phosphorus pentachloride, to produce the iminohalide. With respect to each mol of silylated compound, about 1 to 4 mols of phosphorus pentachloride is normally employed. The reaction temperature is usually about ~50 to about 45C. The reaction may , - 6 -ll~Z791 be conducted in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, benzene or toluene. Following this reaction for the production of said iminohalide, the reaction mixture is normally contacted with a lower aliphatic alcohol to convert the iminohalide to the iminoether compound, ~he alcohol may for example be methanol, ethanol, n-butanol or the like. ~his reaction is normally carried out in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran or the like aDd at a temperature in the range of about -50C and +45C, ~he reaction normally goes to completion within about 10 minutes to one hour. ~he resultant iminoether compound is subjected to solvolysis, ~he solvolysis is usually carried out by contacting the iminoether compound with an alcohol, e,g. said lower aliphatic alcohol solvent, or water or the lower aliphalic alcohol and ~ater.
~he amide linkage is cleaved by the solvolysis, ~he silyl group or groups are also removed by the action of the lower aliphatic alcohol or water, ~hus, the compound (I~ or its salt is produced in excellent yield in accordance with the present invention, This solvolysis is normally conducted under acid conditions, The solvent is used in excess, ~he reaction temperature may be within the range of about -50C to about 45C, the reaction being completed in about 10 minutes to 1 hour, The acid condition may be attained by the presence of an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, etc, in the reaction mixture. ~he pH value of the mixture is 11~*791 usually not higher ~han 1.
The amide-cleavage reaction may also be accomplished by reacting said iminohalide with hydrogen sulfide or thioacetamide to obtain the thioamide derivative, then activating this thioamide and subjecting this activated compound to solvolysis (e.g. the specification of published Japanese Patent Application No. 96591/1975). ~he conditions of reaction (reaction temperature, solvent, etc.) between the iminohalide and hydrogen sulfide or thioacetamide may be similar to the conditions used for the aforesaid reactions for the production of iminohalide and iminoether compounds. The thioamide compound may be acti~ated, for example by reacting it with trichloromethanesulfenyl chloride or sulfur monochloride. The solvolysis of the thus activated compound is effected by exactly the same procedure as the solvolysis of said iminoether compound and gives rise to the compound of formula (I).
Where ~2 in the resultant compound of formula (I) is an ester residue, the compound in which R2 is hydrogen may be produced if desired, by removing the ester residue in a routine manner, e g. by hydrolysis, acid decomposition, reduction or the like in accordance with the per se known procedures ~ he solution containing compound (I) may be directly subjected to the next reaction, or compound ~I) may be isolated beforehand. ~he isolation of compound ~I) may be conducted in a routine manner. ~or example, when the reaction mixture is allowed to cool in the neighborhood , . . - , , .: ~ - . . . . .
,, . . ~ -1~791 of its isoelectric point, 7-ACC separates out from the mixture, ~his precipitate is recovered by filtration, washed with an organic solvent and water and dried. If desired, the compound may be further purified by a procedure well known per se, A good embodiment of the present invention may be shown by the following reaction scheme, HooccH(cH2)3coNH
R' O F~ cH2ocoNH2 COOH
~ silylating agent Y OOCCH(CH2)3CONH F S~ 2 R3N ~ CH20Y
COOY
Xl ~ halogenating agent Y OOCICH(CH2)3C=N F S~ 2 R3 N ~ CH20Y
cooyl an aliphatic alcohol (ROH) OR
YlOOCpH(C~2 )3b'-N ~ 1'$~
R3 ~ N ~ CH20Y2 COOY
I the aliphatic alcohol ~ or/and water (solvolysis) H2N I ~ S~ o N ~ CH20CNH2 (7-ACC) COOH
, ~Z791 In the above schcme, R3 is a protected amino; yl is a silyl group; y2 is a silylated carbamoyl group; Xl is halogen; and ROH is an aliphatic alcohol.
~ he end-products of the present invention are useful as the starting materials for the production of various cephem compounds having excellent antibacterial properties.
Particularly~ 7-ACC and its salts are of value as the starting materials for the production of antibiotics having the formula ~VI) H2-n HnN CCONH ~ ~S
N ~ CH20CONH2 ~VI~
oR4 0 COOR2 , wherein n is a number of a range O' n '1, and R4 is hydrogen or a lower alkyl, and phamaceutically acceptable salts thereof, ~he compounds of the formula ~VI) may form pharmaceutical acceptable salts with respect to the carboxyl function or with respect to the group represented by the formula:
H2-n HnN
, and the pharmaceutical acceptable salts may be salts with the acids or bases above-mentioned regardin~ the compound ~
~ he compound of formula ~VI~ in which R2 is hydrogen and R4 is hydrogen may be produced, for example by the following reaction steps.
.. . . . - .
- - ~
. . . ~ ,., . , . :. :
~l~Z79~
7-ACC or its salt XCH2COCH2COX ~ CH2 r 2 0--~
XCH2COCH2CONH ~ S~ o O ~ CH20CNH2 (VII) I COOH
I Nitrosating Agent XCH2COCCONH 1~ S~
N ~ N ~ CH20CN~2 ~VIII) OH COOH
,l H2NCSNH2 H2 nN ~ S
HnN ~ CCO~H ~ S~
N N ~ -CH OCONH (IX) ~whereln n has the meaning defined hereinbefore; X is chlorine or bromine) In the step of producing a compound (VII~ from 7-ACC, the latter is acylated with 1 to 1 5 molar equivalents of a 4-halogeno-3-oxobutyryl halogenide to give (VII). This acylation re~ction is conducted in a solvent, such as dimethylformamide, dlchloromethane, dimethylacetamide, dimethylsulfoxide, chloroform, acetonitrile or the like, or a mixture of such solvents, and in the presence of 1 to 3 molar equivalents of an organic base such as triethylamine7 N,N-dimethylaniline, pyridine or the like.
~his reaction is conductad at a temperature between -40C
, ~l~Z~l and 40C, preferably lmder cooiing at a temperature from _~ to oC. ~he compound LVIl~ obtain?d is isola~ed as crystals by extraction and concentration, etcO
The compound ~VII) is then nitrosated to (VIII).
~pecifically, compound ~VII) is p~viously dissolved in a solvent, e.g. acetic acid or aqueous acetic acid, and 1 to 2 molar equivalents of a nitrosating agent such as sodium nitrite is added The reaction is conducted at -40C to ~20C. ~he resultant (VIII) is isolated as powders by extraction and phasic transfer operations.
~ hen, (VIII) is reacted with 1 to 2 molar equivalents of thiourea to produce (IX). ~his reac-tion is conducted at O to 20C in a solvent, e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, ace-tonitrile or the like, or a mixture o~ solvents ~he resultant ~IX) is isolated and purified by such procedures as extraction, phasic transfer, pH adjustment, crystallization, column chromatography, etc.
Among compounds of formula ~VI), a compound ~X), i.e. the compound ~VI~ wherein ~2 is hydrogen and R4 is a lower alkyl group such as methyl, ethyl, n-propyl or i-propyl:
H2_nN ~
HnN CCO~-H I ~S~ o ~X) o~N~ CH20C~TH2 OY COOH
(wherein Y is the lower alkyl mentioned above~ n has the meaning defined hereinbefore) .. . .
'. . : ' , : . : ~
, .
- . . ', ~ ' : . -- \
11~2 791 may be produced by reacting a carboxylic acid of formula ~XI~:
(XI) N
OY
~wherein Y and n are as defined hereinbefore 9 Z iS hydrogen or a protective group) or a reactive derivative thereof with 7-~C. In the above compound (XI~, the protective group Z is exemplified by aromatic acyl groups such as benzoyl, benzoyl substituted by halogen, nitro or lower alkyl (Cl 4) (e.g. chlorobenzoyl, p-nitrobenzoyl, p-tert-butylbenzoyl, toluoyl, etc.), naphthoyl, phenylacetyl, phenoxyacetyl, benzenesulfonyl, benzenesulfonyl substituted by lower alkyl (Cl_4) (e.g. p-tert-butylbenzenesul~onyl, toluenesulfonyl, etc ), camphorsulfonyl, methanesulfonyl, aliphatic or halo-aliphatic carboxylic acid-derived acyl groups (e.g. acetyl, valeryl, caprilyl, n-decanoyl, acryloyl, pivaloyl, halogenoacetyl(e.g. monochloroacetyl, monobromoacetyl, dichloroacetyl, trichloroacetyl, etc.), etc. ~7 esterified carboxyl groups (e.g. ethoxycarbonyl, tert-butyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxy-carbonyl, benzyloxycarbonyl, etc.), carbamoyl groups (e.g.
methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl, etc.) and the corresponding thiocarbamoyl groups. The carboxylic acid thus protected or unprotected may be used, either as ,, .. . : . - . . .:
.
.
, . :
ll~Z7~
it is or as a reactive derivative thereof, as an acylating agent for acylating the 7-amino group of compound (I).
~hus, the free acid ~XI), a salt thereof with an alkali metal or alkaline earth metal ~e.g. sodium, potassium, calcium, etc.) or with an organic amine (e.g. trimethyl-amine, p~ridine, etc.) or a reactive derivative thereof, such as the acid halide (e.g. acid chloride, acid bromide, etc.), acid anhydride, mixed acid anhydride, active amide, activated ester or the like may be employed for the purpose of the above-mentioned acylation. As examples of said activated ester may be mentioned the p-nitrophenyl ester, 2~4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester and N-hydroxyphthalimide ester.
~he mixed acid anhydride is exemplified by mixed anhydrides with carbonic acid monoesters (e.g. monome-thyl carbonate, monoisobutyl carbonate, etc.) and mixed anhydrides with lower alkanoic acids which may optionally be substituted by halogen (e.g. pivalic acid~ trichloroacetic acid, etc.).
Where the protected or unprotected carboxylic acid ~XI~
is employed as it is or in the form of a salt, a suitable condensing agent is employed As examples of th6 condensing agent may be mentioned N,N'-di-substituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, etc.; azolides such &s N,N'-carbonylimidazole, N,N'-thionyldiimidazole, etc.; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, alkoxyacetylene, etc.; 2-halogenopyridinium salts (e.g.
2-chloropyridinium methyl iodide, 2-fluoropyridinium .. . : , :. . - . - --'' ~' "' '. , , ' ' . ~ ;
- -- . , .
Z79~
methyl iodide, etc.) and so forth. Where such condensing agents are employed, the reaction seems to proceed via a reactive derivative of carboxylic acid ~XI). The reaction is generally conducted in a suitable solvent As examples of said solvent may be mentioned halogenated hydrocarbons such as chloroform, methylene chloride, etc ;
ethers such as tetrahydrofuran, dioxane, etc ; dimethyl-formamide, dimethylacetamide, acetone, water and mixtures thereof. The proportion of carboxylic acid (XI) or a reactive derivative thereof is normally about l to a few molar e~uivalents per mol of compound ~I)o This reaction is generally carried out at a temperature in the range of -50 to ~40C. After the acylation reaction, the pro-tective group may be removed. Removal of an amino-protecting group may be accomplished by procedures known per se, for example, the procedures described in Japanese Patent Application Laid-open No 520~3/1975, ~ure and Applied Chemistry 7, ~35 (196~)) or by procedures analogous thereto. Where, for example, the protective group Z is a monohalogenoacetyl group (e.g. monochloroacetyl), removal of the monohalogeno-acety] from the amino group may be accomplished by reacting the acylated compound with its amino group thus protected with thiourea and a basic reagent ~his reaction is normally conducted in a solvent in the neighborhood of room temper-ature and, in many instances, goes to completion in one to ten and odd hours. The solvent may be any solvent that will not interfere with the reaction. ~hus, for example, ethers (e g. ethyl ether, tetrahydrofuran, dioxane, ll~Z791 etc ), lower alcohols (e.g. methanol, ethanol, etc.), halogenated hydrocarbons (e.g. chlorofor~, methylene dichloride, etc ), esters (e.g. ethyl aceta-te, butyl~
acetate, etc.), ~etones (e,g. acetone, methyl ethyl ketone, etc.), water and mixtures thereof may be mentioned.
~ eacting the protected compound ~X) with thiourea and a basic reagent results in a selective and smooth progress of the reaction for the desired removal of the monohalogeno-acetyl group and~ hence, in the formation of compound ~X).
The basic reagent useful for this reaetion is exemplified by the alkali metal or alkaline earth metal salts of lower aliphatic carboxylic acids and inorganic or organie bases with pKa values not less than 9 5, preferably pK values in the range of 9 8 to 12 0. As examples of the salts of lower aliphatic earboxylic aeids may be mentioned the salts of lower aliphatie earboY.ylie aeid (Cl_6) ~e.g sodium aeetate, potassium acetate, calcium acetate, barium aeetate, sodium formate, sodium propionate, potassium hexanoate, ete.) As examples of said inorganic bases may be mentioned the alkali metal salts of carbonic acid (e,g. sodium carbonate, potassium carbonate, ete,). As said organic bases, there may be mentioned amines mono-, di- or tri-substituted by lower alkyl (C1~4)(e.g. trimethylamine, triethylamine, ethylamine, methylamine, diethylamine, dimethylamine, tri-butylamine, dibutylamine, butylamine, ete.) and 5 to 6-membered cyclic amines N-substituted by lower alkyl (~1-2) (e.g, N-methylpyrrolidine, N-ethylpyrrolidine, N-methyl-piperazine, N-ethylpiperazine, etc ) While, as aforesaid, ' l~Z79~
thiourea is employed in this reaction, it is also possible to employ ~- or N,N-substituted thiourea (e.g. methyl-thiourea, N,N-diethylthiourea, N,N-hexamethylenethiourea, etc.) in place of thiourea.
The starting material ~XI), e.g. 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid (s~n-isomer) may ~e produced, for example by the process described hereinafter in detail First, a 4-halogeno-3-oxo-2-hydrox~iminobutyric acid derivative of ~eneral formula ~XII):
(~ X2CH CoC-CooR7 ., SN 4l (XII) OR
~wherein x2 is halogen (e.g chlorine or bromine); R4 is lower alkyl (e g. methyl~; R7 is lower alkyl (C1_3)(e.g.
ethyl)) is reacted with thiourea to obtain an 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid derivative of general formu}a (XIII):
H2-nN ~ 7 HnN C-COOR
(XIII~
SR4l (wherein P4 and ~7 are as respectively defined above).
In this case, the compound ~XIII) is obtained as a mixture of s~n- and anti-isomers. ~his reaction is normally conducted by permitting thiourea to act upon compound (XII) in an organic solvent such as ethanol, methanol, tetra-hydrofuran or the like at room temperature or elevated `\
temperature. The amount of thiourea may be about one to three mols per mol of the compound (XII).
From the resultant mixture of said syn-and anti-forms of compound (XIII), the desired syn-isomer may be separated and recovered by the per se known procedure or by the procedure disclosed in Canadian Patent Application No. 276,067 filed April 13, 1977. The resultant compound (XI) wherein Z is hy-drogen, if desired after the introduction of a protective group Z by a procedure known per se, may be converted to a reactive derivative thereof by a procedure which is also well known per se.
It is in order to mention that, in the above formulas, the moieties of H2 nN~L ZHl nN ~5 HnN HnN
are each supposed to assume a tautomeric structure of 2-amino-thiazole and 2-iminothiazoline forms, thus:-H2N ~ S HN ~ SN ~ ~ HN
~ ~ HN
(2-aminothiazole form) (2-iminothiazoline form) The compounds (VI) and their pharmacologically acceptable salts, may be administered as injections just as the known cephalosporin and penicillin drugs. Thus, ., .
f t these compounds are novel compounds having excellent ~ctivity against a broad spectrum of microorganisms including Gram-negative bacteria such as scherichia coli~
Serratia marcescens, Proteus rettgeri, Enterobacter cloacae, Citrobacter freundii etc, and are ~-lactamase-resistant These compounds may be employed, for example, as disin-fectants for removing said microorganisms from sursical instruments or as a therapeutic agent for the management of infectious diseases When a compound ~VI) or a salt thereof is used as a therapeutic for the therapy of infectio~s diseases, such as the intr-aperitoneal, respiratory organ, urinary tract and other infections, it may be safely administered by the parenteral route to mammalian animals including man, mouse and rat at the dose level of 1 to 20 mg daily per kilogram body weight, in 3 to 4 installments a day. ~he dosage forms may be conven-tional Thus, for example, injectable preparations made by se known procedures may be administered either intra-muscularly or intravenously. ~he carrier to be employed in such injectable preparations may for example be distilled water or physiological saline.
Example 1 In dichloromethane (6 m~) is suspended benzhydryl 7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate (427 mg) Following the addition of pyridine (300 mg), dimethyldichlorosilane (150 mg) is further added under ice-cooling. The mixture is stirred at room temperature for one hour, whereby the ester is completely dissolved.
~l~Z791 ~he solution is cooled to -20C and, after phosphorus pentachloride (600 mg) is added, the mixture is stirred ~or 30 minutes. ~uring this period of time, the temperature increases to -10C. The mixture is cooled to -40C and methanol (4 m~) is added. It is then stirred for 15 minutes, after which water (6 m~) and tetrahydrofuran (4 m~) are added. ~he layers are separated and the water layer is taken,while the organic layer is extracted with water The water layers are combined, washed once with dichloromethane and neutralized with sodium hydrogen carbonate It is then extracted with a solvent mixture of dichloromethane-tetra-hydrofuran and the extract is washed with aqueous sodium chloride, dried, filtered and concentrated ~o the residue is added petroleum ether, whereupon crystals separate out.
By the above procedure is obtained benzhydryl 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylate as crystals melting at 120 to 12~C.
IR(KBr, cm l): 1775, 1728 NMR(d6-DMS0): ~ 3,53(2H, ABq, J=20Hz, 2-CH2), 4.66(2E, ABq, J=13Hz, 3-CH2), 4 84(1H, d, J=5Hz, 6-H), 5 03 (lH d J=5Hz 7-H), 6.55(2H, broad-s. -OCNH2)~ 6 9 (lH, s, -CH~2), 7.39(10H, m) Example 2 Dichloromethane (8.6 ~) is cooled to -30C in nitrogen gas streams and 7-(D-5-p-t-butylbenzamido-5-carboxyvaleramido)-3-hydroxymethyl~3-cephem-4-carboxylic acid di-triethylamine salt (1.7 ~g) is added. ~he mixture is s-tirred and anhydrous potassium carbonate (450 g) is then added and suspended.
ll~Z~9:1 At -25C, the coolin~ bath is removed. Then, dichloromethane (lR) containin~; chlorosulfonyl isocyanate (450 g) is added over a period of about 5 minutes and the mixture is stirred at -10C for 40 minutes. The mixture is ad~usted to pH 0.1 to 0.2 by the addition of 3N-hydrochloric acid and stirred at room temperature for 30 minutes. Then~ it is adjusted to pH 2.7 with potassium carbonate and extracted with tetrahydrofuran (12 ~). After the addition of triethylamine (580 g), the extract is concentrated, dissolved in dichloro-methane (15 ~) 7 dried over anhydrous magnesium sulfate, filtered and concentrated to obtain a syrupy substance.
Upon addition of ether (5 ~), the syrup becomes powders.
The powders are recovered by filtration and dried. By the above procedure is obtained 7-(r-C-p-t-butylbenzamido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid di-triethylamine salt as crude powders (1.7 kg). While this product includes the lactone, it is fully useful for the next deacylation reaction. The above crude powders (3 g) are taken, purified by column chromatography on ~mberlite XAD-2 and Sephadex LH-20, and lyophilized. The above procedure gives a high purity grade of 7-(~-5-p-t-butylbenzamido-5-carboxyvaleramido)-3-carbamoyloxymethyl -3-cephem-4-carboxyllc acid di-triethylamine salt (1.12 ~;).
Il~(KBr, cm 1): 1770, 1330 N~(d6-rMS0): ~ 1.13 (18H, t, J=6Hz, Et3Nx2), 1 31~9H, s,t-Bu), 1.4-2.0(4H, m- -CH(CH2)2-CH2-), 2.20(2H, t,J=6Hz, -CH(CH2)2CH2-), 2.91(12H, q, J=6Hz, Et3Nx2), 3.17 ~ 3.48(2H, ABq, J=18Hz, 2-CH2), 4.24(1H, m~
* ~ra~
- . : - . - . . .
. - ' ''. . . ' , . :
-,'. . ~
. -. - ~
~91 -CF[(CH2)3-), 4.66 & 4.87(2H~ ABq, J=13Hz, 3-CH2),
4.94(1H, d, J=5Hz, 6-H), 5.50(1H, dd, J=5 & 8Hz, 7-H), 6.44(2H, broad-s, -OCONH2), 7.46(2H, d, J=8Hz, Arom-H), 7.79(2H, d, J=8Hz, Arom-H), 8.03(1H, d, J=8Hz, -CONH-), 8.64(1H, d, J=8Hz, -CO~I-) ~lemental analysis, for C381:I62N609~H2o Calcd. C, 57.26; H, 8.09; N, 10~54 ~ound C, 57 17, H, 8.41j N, 10.38 In nitrogen gas streams, 7-(D-5-p-t-butylbenzamido-
5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem~-carboxylic acid di-triethylamine salt (1.7 kg) is dissolved in dichloromethane (7.3 R) and, then, N,~-dimethylaniline (2.6 ~) and dimeth~ldichlorosilane (970 mR) are added. The mixture is stirred at 20 to 30C for 40 minutes. Then, after cooling to -35C, phosphorus pentachloride (1.25 kg) is added in a single dose and the mixture is stirred at -20C
for 15 minutes. ~hen, methanol (5.0 ~) is added dropwise at -30 to -25C, after which it is stirred at -20C for 20 minutes Followin~ the addition of water (4.0 R), the mixture is further stirred at 10 to 13C for 30 minutes.
~he mixture is adjusted to pH 3.5 with 20 O/G sodium carbonate and the resultant precipitate is recovered by filtration and washed with dichloromethane (5 ~) and methanol (5 R).
By the above procedure is obtained 7-amino-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid as crude powders (600 g).
The powders are added to 4N-hydrochloric acid (2 R) and after 15 minutes' stirring at room temperature, the insolubles are filtered off. To the filtrate is added , ' ,: ' . ': ' l~Z791 ethyl acetate (~00 m~) and the mixture is adjusted to pH 3 5 with 20 ~ sodium carbonate. After the addition of methanol (2 ~), the mixture is stirred under ice-cooling for 30 minutesG The resultant cxystals are collected by filtration, washed 3 times with water (300 m~) and 3 times ~ith acetone (400 m~). B~ this procedure is obtained 7-amino-3-carbamoy-oxymethyl-3-cephem-4-carboxylic acid (175 g) of high purity.
UV~max (pH 6.5, phosphate) 265 nm( s7885) I~(KBr, cm 1): 1800, 1710, 1333 NM~(d6-D~MS0): ~ 3,34 & 3.57(2H, ABq, J=18Hz, 2-CH2), 4.58 & 4.87(2H, ABg, J=13Hz, 3-CH2), 4.76(1H, d, J=5Hz,
for 15 minutes. ~hen, methanol (5.0 ~) is added dropwise at -30 to -25C, after which it is stirred at -20C for 20 minutes Followin~ the addition of water (4.0 R), the mixture is further stirred at 10 to 13C for 30 minutes.
~he mixture is adjusted to pH 3.5 with 20 O/G sodium carbonate and the resultant precipitate is recovered by filtration and washed with dichloromethane (5 ~) and methanol (5 R).
By the above procedure is obtained 7-amino-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid as crude powders (600 g).
The powders are added to 4N-hydrochloric acid (2 R) and after 15 minutes' stirring at room temperature, the insolubles are filtered off. To the filtrate is added , ' ,: ' . ': ' l~Z791 ethyl acetate (~00 m~) and the mixture is adjusted to pH 3 5 with 20 ~ sodium carbonate. After the addition of methanol (2 ~), the mixture is stirred under ice-cooling for 30 minutesG The resultant cxystals are collected by filtration, washed 3 times with water (300 m~) and 3 times ~ith acetone (400 m~). B~ this procedure is obtained 7-amino-3-carbamoy-oxymethyl-3-cephem-4-carboxylic acid (175 g) of high purity.
UV~max (pH 6.5, phosphate) 265 nm( s7885) I~(KBr, cm 1): 1800, 1710, 1333 NM~(d6-D~MS0): ~ 3,34 & 3.57(2H, ABq, J=18Hz, 2-CH2), 4.58 & 4.87(2H, ABg, J=13Hz, 3-CH2), 4.76(1H, d, J=5Hz,
6-H), 4.96(1H, d1 J=5Hz, 7-H), 6 50(2H, broad-s, -OCONH2) Elemental analysis, for C9H11~305S-0 5H20 Calcd. C, 38.29; H, 4 29; ~, 14.89 ~ound C, 38.~4; H, 4.25; ~, 14.12 Example 3
7-(D-5-phthalimido-5-carbox~valeramido)-3-hydroxymethyl-3-cephem-4-carboxylic acid (5.21 ~) is dissolved in a mixture (1:1 volume/volume) of tetrahydrofuran and dichloromethane, and the solution is cooled to -35C. ~hen, under stirring, a mixture of chlorosulfonyl isocyanate (2 m~) and dichloro-methane (2 m~) is added over a period of 10 minutes.
During this period of time, the temperature is held at -35to -30C. ~he temperature is then increased to 13C and, following the addition of 3N-hydrochloric acid (10 m~), the mixture is stirxed for 20 minutes. A saturated aqueous solution of sodium chloride (30 m~) is added and the organic " ~ - ~ ' " . ' ': :
1~2791 layer is separated. ~o this organic layer is added a saturated aqueous solution of sodium chloride (10 m~) and water (10 m~) and, with stirring, the mixture is adjusted to pH 4 0 by t~e addition OI aqueous sodium carbonate.
~he water layer is separated and washed with a mixture of tetrahyclrofuran (20 m~) and dichloromethane (20 m~ he mixture (50 m~) of tetrahydrofuran and dichloromethane (1:1 volume/volume) is freshly added and under stirring, hydrochloric acid is added to bring the pH to 2~5. The organic layer is separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous mag~esium sulfate and concentrated under reduced pressure. The concentration residue is dissolved in tetrah~rdrofuran (20 mk), and ethyl acetate (100 m~) is added. ~he mixture is concentrated to about 60 m~ and the precipitate is filtered off. To the filtrate is added ether (200 m~) and the precipitate is recovered by Iiltration, washed with ether and dried over phosphorus pentoxide. By the above procedure is obtained 7-(D-5-phthalimido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (4.6 g).
IR(KBr, cm 1): 1789, 1330 ~MR(d6-~MS0) o 1.26-2.36(6H, m, -(CH2)3-), 3.45(2~1, ABq, J=18Hz, 2-CH2), 4.74(1H, t, J=7Hz, -CH-), 4.77(2H, ABq, J=13Hz, 3-CH2), 5.06(1H, d, J=5Hz, 6-H), 5.62 (lH, dd, J=5 & 8Hz, 7-H), 6.56(2H, s, CO~H2), 7 92 (4H, s, arom-H), 8.74(1H, d, J=8Hz, -CO~H--) 7-(I)-5-phthalimido-5-carboxyvaleramido)-3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid (4,6 g) is dissolved in a mixture of dichloromethane (30 m~), triethylamine (1.8 m~) and l~,N-dimethylaniline (6.~ m~). Then, dimethyl-dichlorosilane (3 0 m~) is added and the mixture is stirred at room temperature for one hour, after which it is cooled to -3~C and phosphorus pentachloride (2.75 g) is added.
~he mixture is stirred at -30 to -2~C for 15 minutes, after which time it is cooled to -40C and methanol (15 m~) is gradually added. During this time, the temperature of the solution is maintained between -30 and -20 ~.
~ hen, the mixture is stirred at -20 to -17C for 20 minutes, at the end of which time water (15 m~) is added ~he mixture is adjusted to pH 3.7 by the addition of aqueous sodium car~onate and stirred under ice-cooling for one hour.
~he resultant precipitate is recovered b~ filtration, washed with dichloromethane, methanol and water in the order mentioned and dried over phosphorus pentoxide. By the above procedure is obtained 7-amino-3-carbamoyloxy~ethyl-3-cephem-4-carboxylic acid (1.70 g) In IR spectrum this product agrees with the product obtained in Example 2.
Example 4 In water (19 m~) is dissolved deacetyl-cephalosporin C sodium monohydrate (7.0 g), followed by addition of tetra-hydrofuran (9 m~) and N-carboethoxyphthalimide (6.8 g).
Under stirring, an aqueous solution of potassium carbonate is added so as to maintain the p~ value of the mixture at 9.1 to 9.3 for 30 minutes and at 9.7 to 9 8 for a succeeding one hour. Thereafter, tetrahydrofuran (26 m~) and dichloro-methane (32 m~) are added and under ice-cooling and stirring, ~ 25 11~Z79~
3N-hydrochloric acid is added to bring the pH to 2.5. The organic layer is separated. The water layer is extracted with a mixture of tetrahydrofuran (18 m~) and dichloro-methane (18 m~) and the organic layers are combined, washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate ~he solvent is then distilled off, whereby a syrupy product is obtained as the residue. This residue is dissolved in tetrahydrofuran (25 ~) and dichloro methane (25 m~) is added. The mixture is cooled to -35C
and, under stirring, a mixture of chlorosulfonyl isocyanate (2 m~) and dichloromethane (2 m~) is added over a period of 10 minutes During this time, the temperature of the solution is maintained at -35 to -30C. The temperature is increased to 13C over a period of 30 minutes and, after the addition of 3N-hydrochloric acid (10 m~), the mixture is stirred for 30 minutes ~ollowing the addition of aqueous sodium chloride (30 m~), the organic layer is separated, washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. Following the addition of triethylamine (6.3 m~), the solvent is distilled off to recover a syrupy residue. This residue is dissolved in dichloromethane (50 m~), followed by the addition of N,N-dimethylaniline (13 m~) and, then, of dimethyldichlorosilane (6 m~). The mixture is stirred at room temperature for one hour Then, the mixture is cooled to -40C and, under stirring, phosphorus pentachloride (5.5 g) is added. The mixture is held at -30 to -25C for 15 minutes and, then, cooled to -40C. Methanol (30 m~) is gradually added at this temperature 7gl ~uring this time, the temperature of the solution is maintained at -30 to -17C ~he temperature is then maintained at -17C
for 20 minutes, at the end of which time the mixture is adjusted to pH 3 7 with aqueous sodium carbonate and stirred under ice-cooling for one hour. The precipitate is recovered by filtration, washed with dichloromethane, methanol, water and acetone in the order mentioned and dried over phosphorus pentoxide By the above procedure is obtained 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (2 32 g).
In IR spectrum, this product is found to agree with the product obtained in Example 2.
Reference Example 1 In dichloromethane ~2 mR) is suspended benzhydryl 7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate (139 mg) and, after the addition of pyridine (100 mg), dimethyldichlorosilane (50 mg) is added under ice-cooling.
~he mixture is stirred for about 50 minutes to obtain a homogeneous solution. An additional amount of pyridine (50 mg) is added and the mixture is cooled to -20C, and phosphorus pentachloride (200 mg) is added. Then, under ice-cooling, the mixture is stirred for 30 minutes, after which it is cooled to -10C and water (2 mR) and tetrahydro~uran (2 mR) are added. The mixture is separated into phases and the organic layer is taken and assayed by thin layer chromatography ~he chromatogram shows only a spot at the same Rf value as that of the starting compound The above mixture is dried, concentrated and the residue is treated with ether ~he resultant crystals are recovered - :
ll~Z791 by filtration. ~he I~ spectrum of this product is in complete agreement with that of benzhydryl 7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate The same reaction as above is carried out without the use of dimethyldichlorosilane ~he thin layer chromatography of this re~ction product mixture revealed no spot of the starting compound, with the spot of no migration being evidenced (developer solvent;ethyl acetate:dichloromethane=
During this period of time, the temperature is held at -35to -30C. ~he temperature is then increased to 13C and, following the addition of 3N-hydrochloric acid (10 m~), the mixture is stirxed for 20 minutes. A saturated aqueous solution of sodium chloride (30 m~) is added and the organic " ~ - ~ ' " . ' ': :
1~2791 layer is separated. ~o this organic layer is added a saturated aqueous solution of sodium chloride (10 m~) and water (10 m~) and, with stirring, the mixture is adjusted to pH 4 0 by t~e addition OI aqueous sodium carbonate.
~he water layer is separated and washed with a mixture of tetrahyclrofuran (20 m~) and dichloromethane (20 m~ he mixture (50 m~) of tetrahydrofuran and dichloromethane (1:1 volume/volume) is freshly added and under stirring, hydrochloric acid is added to bring the pH to 2~5. The organic layer is separated, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous mag~esium sulfate and concentrated under reduced pressure. The concentration residue is dissolved in tetrah~rdrofuran (20 mk), and ethyl acetate (100 m~) is added. ~he mixture is concentrated to about 60 m~ and the precipitate is filtered off. To the filtrate is added ether (200 m~) and the precipitate is recovered by Iiltration, washed with ether and dried over phosphorus pentoxide. By the above procedure is obtained 7-(D-5-phthalimido-5-carboxyvaleramido)-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (4.6 g).
IR(KBr, cm 1): 1789, 1330 ~MR(d6-~MS0) o 1.26-2.36(6H, m, -(CH2)3-), 3.45(2~1, ABq, J=18Hz, 2-CH2), 4.74(1H, t, J=7Hz, -CH-), 4.77(2H, ABq, J=13Hz, 3-CH2), 5.06(1H, d, J=5Hz, 6-H), 5.62 (lH, dd, J=5 & 8Hz, 7-H), 6.56(2H, s, CO~H2), 7 92 (4H, s, arom-H), 8.74(1H, d, J=8Hz, -CO~H--) 7-(I)-5-phthalimido-5-carboxyvaleramido)-3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid (4,6 g) is dissolved in a mixture of dichloromethane (30 m~), triethylamine (1.8 m~) and l~,N-dimethylaniline (6.~ m~). Then, dimethyl-dichlorosilane (3 0 m~) is added and the mixture is stirred at room temperature for one hour, after which it is cooled to -3~C and phosphorus pentachloride (2.75 g) is added.
~he mixture is stirred at -30 to -2~C for 15 minutes, after which time it is cooled to -40C and methanol (15 m~) is gradually added. During this time, the temperature of the solution is maintained between -30 and -20 ~.
~ hen, the mixture is stirred at -20 to -17C for 20 minutes, at the end of which time water (15 m~) is added ~he mixture is adjusted to pH 3.7 by the addition of aqueous sodium car~onate and stirred under ice-cooling for one hour.
~he resultant precipitate is recovered b~ filtration, washed with dichloromethane, methanol and water in the order mentioned and dried over phosphorus pentoxide. By the above procedure is obtained 7-amino-3-carbamoyloxy~ethyl-3-cephem-4-carboxylic acid (1.70 g) In IR spectrum this product agrees with the product obtained in Example 2.
Example 4 In water (19 m~) is dissolved deacetyl-cephalosporin C sodium monohydrate (7.0 g), followed by addition of tetra-hydrofuran (9 m~) and N-carboethoxyphthalimide (6.8 g).
Under stirring, an aqueous solution of potassium carbonate is added so as to maintain the p~ value of the mixture at 9.1 to 9.3 for 30 minutes and at 9.7 to 9 8 for a succeeding one hour. Thereafter, tetrahydrofuran (26 m~) and dichloro-methane (32 m~) are added and under ice-cooling and stirring, ~ 25 11~Z79~
3N-hydrochloric acid is added to bring the pH to 2.5. The organic layer is separated. The water layer is extracted with a mixture of tetrahydrofuran (18 m~) and dichloro-methane (18 m~) and the organic layers are combined, washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate ~he solvent is then distilled off, whereby a syrupy product is obtained as the residue. This residue is dissolved in tetrahydrofuran (25 ~) and dichloro methane (25 m~) is added. The mixture is cooled to -35C
and, under stirring, a mixture of chlorosulfonyl isocyanate (2 m~) and dichloromethane (2 m~) is added over a period of 10 minutes During this time, the temperature of the solution is maintained at -35 to -30C. The temperature is increased to 13C over a period of 30 minutes and, after the addition of 3N-hydrochloric acid (10 m~), the mixture is stirred for 30 minutes ~ollowing the addition of aqueous sodium chloride (30 m~), the organic layer is separated, washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. Following the addition of triethylamine (6.3 m~), the solvent is distilled off to recover a syrupy residue. This residue is dissolved in dichloromethane (50 m~), followed by the addition of N,N-dimethylaniline (13 m~) and, then, of dimethyldichlorosilane (6 m~). The mixture is stirred at room temperature for one hour Then, the mixture is cooled to -40C and, under stirring, phosphorus pentachloride (5.5 g) is added. The mixture is held at -30 to -25C for 15 minutes and, then, cooled to -40C. Methanol (30 m~) is gradually added at this temperature 7gl ~uring this time, the temperature of the solution is maintained at -30 to -17C ~he temperature is then maintained at -17C
for 20 minutes, at the end of which time the mixture is adjusted to pH 3 7 with aqueous sodium carbonate and stirred under ice-cooling for one hour. The precipitate is recovered by filtration, washed with dichloromethane, methanol, water and acetone in the order mentioned and dried over phosphorus pentoxide By the above procedure is obtained 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (2 32 g).
In IR spectrum, this product is found to agree with the product obtained in Example 2.
Reference Example 1 In dichloromethane ~2 mR) is suspended benzhydryl 7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate (139 mg) and, after the addition of pyridine (100 mg), dimethyldichlorosilane (50 mg) is added under ice-cooling.
~he mixture is stirred for about 50 minutes to obtain a homogeneous solution. An additional amount of pyridine (50 mg) is added and the mixture is cooled to -20C, and phosphorus pentachloride (200 mg) is added. Then, under ice-cooling, the mixture is stirred for 30 minutes, after which it is cooled to -10C and water (2 mR) and tetrahydro~uran (2 mR) are added. The mixture is separated into phases and the organic layer is taken and assayed by thin layer chromatography ~he chromatogram shows only a spot at the same Rf value as that of the starting compound The above mixture is dried, concentrated and the residue is treated with ether ~he resultant crystals are recovered - :
ll~Z791 by filtration. ~he I~ spectrum of this product is in complete agreement with that of benzhydryl 7-phenylacetamido-3-carbamoyloxymethyl-3-cephem-4-carboxylate The same reaction as above is carried out without the use of dimethyldichlorosilane ~he thin layer chromatography of this re~ction product mixture revealed no spot of the starting compound, with the spot of no migration being evidenced (developer solvent;ethyl acetate:dichloromethane=
8:2) Reference Example ?
(1) Di~etene (189 g) is dissolved in dichloromethane (~45 m~) and, under cooling at -50~, chlorine (159 g) is introduced. Separately, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (410 g) and triethylamine (334 g) are dissolved in a mixture of dimethylformamide (1.5 ~) and dichloromethane (1 5 ~) After the solution is cooled to -25C, the above reaction mixture is added dropwise at a temperature not exceeding -18C, at which temperature the mixture is stirred for 30 minutes. ~hen~
phosphoric acid (1 kg), water (3 75 ~), methyl ethyl ketone (8.5 ~) and ethyl acetate (3 ~) are added to the above reaction mixture and, under stirring, sodium chloride is added to saturation. The organic layer is taken and the water layer is extracted with methyl ethyl ketone (4.2 ~) and ethyl acetate (1.5 ~) The organic layers are combined, washed 3 times with a saturated aqueous solution of sodium chloride (1 5 ~3 and dehydrated over anhydrous magnesium sulfate.
The solvent is then distilled off and ethyl acetate (500 m~) - 2~ -.
.. . .' ~ .
11~Z79i.
is added to the residue. The resultant crystals are collected by filtration and dried By the above procedure is obtained 7-(3-oxo-4-chlorobutyrylamino)-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid (463 g).
IR(KBr, cm 1): 1773, 1745(sh.), 1720, 1660, 1540, 1~35 NMR(d6-~M~0): ~ 3.42 ~ ~.66(2H, ABq, J=18Hz, 2-CH2), 3.60(2H, s, ~COCH2CO-), 4.~6(2H, s, C~CH2), 4 64 ~
4.94(2H, ABq, J=13Hz, 3-CH2), 5.12(1~, d, J=5Hz, 6-H), 5.68(1H, dd, J=5 ~ 8Hz, 7-H), 6 52(2H, broad-s, CONH2), 9 02(1H, d, J=8Hz, -CO~H-).
(2) In a mixture of acetic acid (2.8 ~) and water (0.7 ~) is suspended 7-(3-oxo~-chlorobutyrylamino)-3-carbamoyloxy-methyl-3-cephem Jl-carboxylic acid (463 g), and sodium nitrite (81.5 g) is added over a period of about 10 minutes, the temperature being maintained at 0 to 3C
After the addition has been completed, the mixture is stirred at the same temperature for 30 minutes, after which time phosphoric acid (500 m~), ethyl acetate (15 ~) and water (4.5 ~) are added. Then, sodium chloride is added to saturation ~he organic Iayer is taken and the water layer is extracted with ethyl acetate (5 ~ he organic layers are combined, washed twice with a saturated aqueous solution of sodium chloride (3.5 ~) and dried over anhydrous magnesium sulfate ~he solvent is distilled off and dichloromethane (500 m~) and petroleum ether (2 ~) are added. ~he resultant precipitate is recovered by filtration and dried. By this procedure is obtained 7-(2-hydroxyimino-3-oxo-4~chlorobutyrylamino)-3-carbamoyloxymethyl-3-cephem-4-- .,. - ~ .
. . , . ~ . -, carboxylic acid (~n-isomer)(4~3 g) IR(KBr, cm 1): 1785, 1730(sh), 1715, 1660, 1545, 1330 ~MR(d6-rMS0): ~3 42 & 3A64(2H, ABq, J=18Hz, 2-CH2), 4 62 &
4 92(2H, ABq, J=13Hz, ~-CH2), 4 81~2H, s, C~CH2-), 5 15(1H, d, J=5Hz, 6-H), 5 78(1H, dd, J=5 & 8Hz, 7-H), 6 52(2H, broad-s, CONH2), 9 26(1H, d, J=8Hz, -CO~H-), 13 12(lH, s, =N-OH).
(Z) In dimethylacetamide(600 m~) is suspended 7-(2-hydroxyimino-3-oxo-4-chlorobutrylamino)-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid (~-isomer)(400 g) together with thiourea (76.1 g) ~he suspension is stirred at room temperature for 6 hours, at the end of which time ether (3 ~) is added. After stirring, the supernatant is discarded Methanol (2 ~) is added to the residual mixture~.
The resultant mi~ture is added dropwi~e to ethyl ac~ta~e (24 1).
~he resultant precipitate is recovered by filtration, dissolved in methanol (1 ~) and added dropwise to ethyl acetate (20 ~) ~he precipitate is recovered by filtration and dried This precipitate is dissolved in an aqueous solution of sodium hydrogen carbonate (160 g) and chromato-graphed on a column of Amberlite XAD-2. Development is carried out with water and the active fractions are pooled, concentrated and lyophilized. The lyophilizate is purified by column chromatography on Sephadex ~H-20. ~he active fractions are concentrated and lyophilized By the above procedure is obtained sodium 7-~2-(2-imino~-thiazolin-4-yl)-2-hydroxyiminoacetamido)-3-carbamoylo~ymethyl-3-cephem-.
--ll~Z79~
4-carboxylate (syn-isomer)(118.5g) IR(KBr, cm 1): 17701 17107 1670, 1610, 1540, 1330 NM~(r20): ~ 3.39 & 3.70(2~, ABq, J=18Hz, 2-CH2), 4.70 4.92(2H, ABq, J=13~z, 3-CH2), 5.24(1~, d, J=5Hz, 6-H), 5.86(1H, d, J=5Hz, 7-H), 6 98(1H, s, thiazoline 5-H) W ~ H20 nm (~): 225(19700), 258(15000) max Reference ~xample 3 (1) Ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate (121 g) and thiourea (47.6 g) are added to ethanol (600 m~) and the mixture is stirred at room temperature for 3 hours.
~he ethanol is distilled off under reduced pressure, and water (350 m~) is added to the residue. ~he water layer is washed with ether, neutralized (pH 7.5) with sodium hydrogen carbonate and extracted with a 1:1 (volume/volume) mixture of ethyl acetate and tetrahydrofuran. The organic layer is washed with water and dried. ~herea~ter, the solvent is distilled off to obtain a crystalline product (45 g).
This product is purified by chromatography on silica gel (developer system=ethyl acetate-n-hexane) and the anti-form of ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate is obtained from a leading portion of the eluate while the syn-form of the same compound is obtained from a trailing portion of the eluate.
s~_-Isomer: White crystals with a tingle of pale yellow;
m~p.185.5C
, ~
. : . . , . . , ~ ~- .
ll~Z79~
Elemental analysis, for C7HgN303$
Calcd. C, 39.06; H, 4 21; N, 19 52 Found C, 39.28; H, 4.10; N, 19.63 z :7/~
~MR(d6-~MSO): ~ 6 80(1H, s, thi~ol 5-H~, 7.12(2H, broad, s., NH2), 11.6(1H, s, OH) (2) Sodium carbonate (10.6 g) is dissolved in water (150 m~) and a solution of ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (s~n-isomer)(10.7 g) in a mixture of tetrahydrofuran (150 m~) and methanol (50 m~) is added.
Under ice-cooling~ dimethyl sulfate (12.6 g) is added dropwise over a period of 5 minutes. After the dropwise addition has been completed, the ice bath is removed and the mixture is stirred at room temperature. In this stage, a white crystalline substance begins to separate out.
After 3 hours, a major part of the organic solvent is distilled off and the residue is cooled with ice. The precipitate is recovered by filtration, rinsed with water and dried.
By the above procedure is obtained ethyl 2-(2-amino-thiazol-4-yl)-2-methoxyiminoacetate(syn-isomer) as white crystals melting at 163 to 164CC.
~lemental analysis, for C8Hl1N303S
Calcd. C, 41.91j H, 4.84; N, 18.33 ~ ound C, 41.57; H, 4.76; N, 18.07 ~MR(crcQ3) ~: 4.0 ~ OCH3), 5 80(2H, broad s., ~H2), 6.74(1H, s, 5H) (3) In N,N-dimethylformamide (10 m~) is dissolved ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetabe~s;gn-isomer, - , .................... ~ ., ' : ;' ' ' '' ''' ' ' , :
11~Z791 m.p. 163 to 164C) (2.15 g) and, under ice-cooling7 chloro-acetyl chloride (1.27 g) is added dropwise. ~he mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for 30 minutes, at the end of which time water (50 m~) is added. ~he mixture is extracted twice with ethyl acetate (100 m~ each) The extracts are combined, washed with 5 ~ aqueous sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in the order mentioned and dried. The solvent is distilled off, whereupon ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino-acetate (syn-isomer) is obtained as crystals melting at 111 to 112C
Elemental analysis, for CloH12N304SC~
Calcd. C, 39.29~ H, 3.96; N, 13.74 ~ ound C, 39.15) H, 3.91; N, 13.69 NMR(CDC~3): ~ 4.00( H, s~ =NOCH3), 4.24(2H, s, C~CH2CO), C 7.15(lH, s, thi~ol 5-H) (4) ~thyl 2-(2-chloroacetamidothiazol-/l-yl)-2-methoxy-iminoacetate(s~n-isomer) (9.62 g) is dissolved in a solution containing water (85 ml), ethanol (452 ml) and p~tassium hydroxide (9 g). ~he mixture is stirred at room temperature for 2 hours. ~he ethanol is distilled off under reduced pressure and water (85 m~) is added to the residue. The mixture is washed with ethyl acetate (100 m~) and the water layer is adjusted to pH 2 with 10 /c hydrochloric acid and extracted twice with 200 m~ portions of ethyl acetate. ~he extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried.
.
. .
7~1 The solvent is then distilled off, whereupon 2-(2-chloro-acetamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn-isomer) is obtained as crys-tals melting at 170 to 171C.
Elemental analysis C8H8N804SC e Calcd. C, 34 60; H, 2.90; ~, 15,13 ~ lound C, 34.97; H, 3.03; ~, ~4.74 NMR~d6-DMSO). ~ 3.95(3H, s, =NOCH~), 4.40(2H, s, C~CH2CO), 7.57(1H, s, thiazole 5-H) (5) In dry tetrahydrofuran (60 mR) is dissolved 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid (s~n-isomer)(1.5 g) and, under stirring, triethylamine (0 55 g) is added The mixture is cooled to -10C and isobutyl chloroformate (0.74 g) is added dropwise The mixture is stirred at that temperature for 2 hours. ~o the resultant mixed acid anhydride solution is added a solution (ice-cooled) of triethylamine (0.55 g) and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (].5 g) in 50 /c aqueous tetrahydrofuran (60 me). The mixture is stirred under ice-cooling for one hour and, then, at room temperature for 2 hours. After a major part of the tetrahydrofuran is distilled off under reduced pressure, water (600 me) and, then, ethyl acetate (120 m~) are added. The mixture is adjusted to pH about 2 with 1~-hydrochloric acid and separated into two phases The water layer is extracted 3 times with ethyl acetate (150 me each). ~he ethyl acetate layers are combined, washed with water, dried and concentrated to recover 1.75 g of 7-~2-(2-chloroacetamidothiazol~4-yl)-2-methoxyiminoacetamido)-~-.. .
llGZ79~.
carbamoyloxymethyl-3-cephem-4-carboxylic acid.
The entire amount of this product is dissolved in tetrahydrofuran (45 m~), and after the addition of thiourea (0 6 g) and sodium acetate trihydrate (1 g), the mixture is stirred at room temperature for 4 hours. ~he precipitate is recovered by filtration, dissolved in water (30 m~) and adjusted to pH about 7.0 with sodium hydrogen carbonate.
It is then purified by passage through a column of Amberlite XAD~-2. By the above procedure is obtained sodium 7-(2-(2-aminothiazol 4-yl)-2-methoxyiminoacetamido)-3-carbamoyloxy-methyl-3-cephe~-4-carboxylate (syn-isomer) as white powders 100 mg.
NMR spectrum (D20): ~ 3.48(2H, q, 2-CH2), 3.92(3H, s, OCH3), 4.16(2H, q, 3-CH2); 5.27(1H d, 6-H), 5 70(1H, d, 7-H), 6.95(1H, s, thiazole ~
-
(1) Di~etene (189 g) is dissolved in dichloromethane (~45 m~) and, under cooling at -50~, chlorine (159 g) is introduced. Separately, 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (410 g) and triethylamine (334 g) are dissolved in a mixture of dimethylformamide (1.5 ~) and dichloromethane (1 5 ~) After the solution is cooled to -25C, the above reaction mixture is added dropwise at a temperature not exceeding -18C, at which temperature the mixture is stirred for 30 minutes. ~hen~
phosphoric acid (1 kg), water (3 75 ~), methyl ethyl ketone (8.5 ~) and ethyl acetate (3 ~) are added to the above reaction mixture and, under stirring, sodium chloride is added to saturation. The organic layer is taken and the water layer is extracted with methyl ethyl ketone (4.2 ~) and ethyl acetate (1.5 ~) The organic layers are combined, washed 3 times with a saturated aqueous solution of sodium chloride (1 5 ~3 and dehydrated over anhydrous magnesium sulfate.
The solvent is then distilled off and ethyl acetate (500 m~) - 2~ -.
.. . .' ~ .
11~Z79i.
is added to the residue. The resultant crystals are collected by filtration and dried By the above procedure is obtained 7-(3-oxo-4-chlorobutyrylamino)-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid (463 g).
IR(KBr, cm 1): 1773, 1745(sh.), 1720, 1660, 1540, 1~35 NMR(d6-~M~0): ~ 3.42 ~ ~.66(2H, ABq, J=18Hz, 2-CH2), 3.60(2H, s, ~COCH2CO-), 4.~6(2H, s, C~CH2), 4 64 ~
4.94(2H, ABq, J=13Hz, 3-CH2), 5.12(1~, d, J=5Hz, 6-H), 5.68(1H, dd, J=5 ~ 8Hz, 7-H), 6 52(2H, broad-s, CONH2), 9 02(1H, d, J=8Hz, -CO~H-).
(2) In a mixture of acetic acid (2.8 ~) and water (0.7 ~) is suspended 7-(3-oxo~-chlorobutyrylamino)-3-carbamoyloxy-methyl-3-cephem Jl-carboxylic acid (463 g), and sodium nitrite (81.5 g) is added over a period of about 10 minutes, the temperature being maintained at 0 to 3C
After the addition has been completed, the mixture is stirred at the same temperature for 30 minutes, after which time phosphoric acid (500 m~), ethyl acetate (15 ~) and water (4.5 ~) are added. Then, sodium chloride is added to saturation ~he organic Iayer is taken and the water layer is extracted with ethyl acetate (5 ~ he organic layers are combined, washed twice with a saturated aqueous solution of sodium chloride (3.5 ~) and dried over anhydrous magnesium sulfate ~he solvent is distilled off and dichloromethane (500 m~) and petroleum ether (2 ~) are added. ~he resultant precipitate is recovered by filtration and dried. By this procedure is obtained 7-(2-hydroxyimino-3-oxo-4~chlorobutyrylamino)-3-carbamoyloxymethyl-3-cephem-4-- .,. - ~ .
. . , . ~ . -, carboxylic acid (~n-isomer)(4~3 g) IR(KBr, cm 1): 1785, 1730(sh), 1715, 1660, 1545, 1330 ~MR(d6-rMS0): ~3 42 & 3A64(2H, ABq, J=18Hz, 2-CH2), 4 62 &
4 92(2H, ABq, J=13Hz, ~-CH2), 4 81~2H, s, C~CH2-), 5 15(1H, d, J=5Hz, 6-H), 5 78(1H, dd, J=5 & 8Hz, 7-H), 6 52(2H, broad-s, CONH2), 9 26(1H, d, J=8Hz, -CO~H-), 13 12(lH, s, =N-OH).
(Z) In dimethylacetamide(600 m~) is suspended 7-(2-hydroxyimino-3-oxo-4-chlorobutrylamino)-3-carbamoyloxy-methyl-3-cephem-4-carboxylic acid (~-isomer)(400 g) together with thiourea (76.1 g) ~he suspension is stirred at room temperature for 6 hours, at the end of which time ether (3 ~) is added. After stirring, the supernatant is discarded Methanol (2 ~) is added to the residual mixture~.
The resultant mi~ture is added dropwi~e to ethyl ac~ta~e (24 1).
~he resultant precipitate is recovered by filtration, dissolved in methanol (1 ~) and added dropwise to ethyl acetate (20 ~) ~he precipitate is recovered by filtration and dried This precipitate is dissolved in an aqueous solution of sodium hydrogen carbonate (160 g) and chromato-graphed on a column of Amberlite XAD-2. Development is carried out with water and the active fractions are pooled, concentrated and lyophilized. The lyophilizate is purified by column chromatography on Sephadex ~H-20. ~he active fractions are concentrated and lyophilized By the above procedure is obtained sodium 7-~2-(2-imino~-thiazolin-4-yl)-2-hydroxyiminoacetamido)-3-carbamoylo~ymethyl-3-cephem-.
--ll~Z79~
4-carboxylate (syn-isomer)(118.5g) IR(KBr, cm 1): 17701 17107 1670, 1610, 1540, 1330 NM~(r20): ~ 3.39 & 3.70(2~, ABq, J=18Hz, 2-CH2), 4.70 4.92(2H, ABq, J=13~z, 3-CH2), 5.24(1~, d, J=5Hz, 6-H), 5.86(1H, d, J=5Hz, 7-H), 6 98(1H, s, thiazoline 5-H) W ~ H20 nm (~): 225(19700), 258(15000) max Reference ~xample 3 (1) Ethyl 4-chloro-3-oxo-2-hydroxyiminoacetate (121 g) and thiourea (47.6 g) are added to ethanol (600 m~) and the mixture is stirred at room temperature for 3 hours.
~he ethanol is distilled off under reduced pressure, and water (350 m~) is added to the residue. ~he water layer is washed with ether, neutralized (pH 7.5) with sodium hydrogen carbonate and extracted with a 1:1 (volume/volume) mixture of ethyl acetate and tetrahydrofuran. The organic layer is washed with water and dried. ~herea~ter, the solvent is distilled off to obtain a crystalline product (45 g).
This product is purified by chromatography on silica gel (developer system=ethyl acetate-n-hexane) and the anti-form of ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate is obtained from a leading portion of the eluate while the syn-form of the same compound is obtained from a trailing portion of the eluate.
s~_-Isomer: White crystals with a tingle of pale yellow;
m~p.185.5C
, ~
. : . . , . . , ~ ~- .
ll~Z79~
Elemental analysis, for C7HgN303$
Calcd. C, 39.06; H, 4 21; N, 19 52 Found C, 39.28; H, 4.10; N, 19.63 z :7/~
~MR(d6-~MSO): ~ 6 80(1H, s, thi~ol 5-H~, 7.12(2H, broad, s., NH2), 11.6(1H, s, OH) (2) Sodium carbonate (10.6 g) is dissolved in water (150 m~) and a solution of ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (s~n-isomer)(10.7 g) in a mixture of tetrahydrofuran (150 m~) and methanol (50 m~) is added.
Under ice-cooling~ dimethyl sulfate (12.6 g) is added dropwise over a period of 5 minutes. After the dropwise addition has been completed, the ice bath is removed and the mixture is stirred at room temperature. In this stage, a white crystalline substance begins to separate out.
After 3 hours, a major part of the organic solvent is distilled off and the residue is cooled with ice. The precipitate is recovered by filtration, rinsed with water and dried.
By the above procedure is obtained ethyl 2-(2-amino-thiazol-4-yl)-2-methoxyiminoacetate(syn-isomer) as white crystals melting at 163 to 164CC.
~lemental analysis, for C8Hl1N303S
Calcd. C, 41.91j H, 4.84; N, 18.33 ~ ound C, 41.57; H, 4.76; N, 18.07 ~MR(crcQ3) ~: 4.0 ~ OCH3), 5 80(2H, broad s., ~H2), 6.74(1H, s, 5H) (3) In N,N-dimethylformamide (10 m~) is dissolved ethyl 2-(2-aminothiazol-4-yl)-2-methoxyiminoacetabe~s;gn-isomer, - , .................... ~ ., ' : ;' ' ' '' ''' ' ' , :
11~Z791 m.p. 163 to 164C) (2.15 g) and, under ice-cooling7 chloro-acetyl chloride (1.27 g) is added dropwise. ~he mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for 30 minutes, at the end of which time water (50 m~) is added. ~he mixture is extracted twice with ethyl acetate (100 m~ each) The extracts are combined, washed with 5 ~ aqueous sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride in the order mentioned and dried. The solvent is distilled off, whereupon ethyl 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyimino-acetate (syn-isomer) is obtained as crystals melting at 111 to 112C
Elemental analysis, for CloH12N304SC~
Calcd. C, 39.29~ H, 3.96; N, 13.74 ~ ound C, 39.15) H, 3.91; N, 13.69 NMR(CDC~3): ~ 4.00( H, s~ =NOCH3), 4.24(2H, s, C~CH2CO), C 7.15(lH, s, thi~ol 5-H) (4) ~thyl 2-(2-chloroacetamidothiazol-/l-yl)-2-methoxy-iminoacetate(s~n-isomer) (9.62 g) is dissolved in a solution containing water (85 ml), ethanol (452 ml) and p~tassium hydroxide (9 g). ~he mixture is stirred at room temperature for 2 hours. ~he ethanol is distilled off under reduced pressure and water (85 m~) is added to the residue. The mixture is washed with ethyl acetate (100 m~) and the water layer is adjusted to pH 2 with 10 /c hydrochloric acid and extracted twice with 200 m~ portions of ethyl acetate. ~he extracts are combined, washed with a saturated aqueous solution of sodium chloride and dried.
.
. .
7~1 The solvent is then distilled off, whereupon 2-(2-chloro-acetamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn-isomer) is obtained as crys-tals melting at 170 to 171C.
Elemental analysis C8H8N804SC e Calcd. C, 34 60; H, 2.90; ~, 15,13 ~ lound C, 34.97; H, 3.03; ~, ~4.74 NMR~d6-DMSO). ~ 3.95(3H, s, =NOCH~), 4.40(2H, s, C~CH2CO), 7.57(1H, s, thiazole 5-H) (5) In dry tetrahydrofuran (60 mR) is dissolved 2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetic acid (s~n-isomer)(1.5 g) and, under stirring, triethylamine (0 55 g) is added The mixture is cooled to -10C and isobutyl chloroformate (0.74 g) is added dropwise The mixture is stirred at that temperature for 2 hours. ~o the resultant mixed acid anhydride solution is added a solution (ice-cooled) of triethylamine (0.55 g) and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (].5 g) in 50 /c aqueous tetrahydrofuran (60 me). The mixture is stirred under ice-cooling for one hour and, then, at room temperature for 2 hours. After a major part of the tetrahydrofuran is distilled off under reduced pressure, water (600 me) and, then, ethyl acetate (120 m~) are added. The mixture is adjusted to pH about 2 with 1~-hydrochloric acid and separated into two phases The water layer is extracted 3 times with ethyl acetate (150 me each). ~he ethyl acetate layers are combined, washed with water, dried and concentrated to recover 1.75 g of 7-~2-(2-chloroacetamidothiazol~4-yl)-2-methoxyiminoacetamido)-~-.. .
llGZ79~.
carbamoyloxymethyl-3-cephem-4-carboxylic acid.
The entire amount of this product is dissolved in tetrahydrofuran (45 m~), and after the addition of thiourea (0 6 g) and sodium acetate trihydrate (1 g), the mixture is stirred at room temperature for 4 hours. ~he precipitate is recovered by filtration, dissolved in water (30 m~) and adjusted to pH about 7.0 with sodium hydrogen carbonate.
It is then purified by passage through a column of Amberlite XAD~-2. By the above procedure is obtained sodium 7-(2-(2-aminothiazol 4-yl)-2-methoxyiminoacetamido)-3-carbamoyloxy-methyl-3-cephe~-4-carboxylate (syn-isomer) as white powders 100 mg.
NMR spectrum (D20): ~ 3.48(2H, q, 2-CH2), 3.92(3H, s, OCH3), 4.16(2H, q, 3-CH2); 5.27(1H d, 6-H), 5 70(1H, d, 7-H), 6.95(1H, s, thiazole ~
-
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing a cephem compound of the formula:
(I) wherein R2 is hydrogen or an ester residue, or a salt thereof, which comprises silylating a compound of the formula:
(II) wherein R1CO is an acyl group and R2 has the same meaning as defined above, or a salt thereof to produce a compound silylated at the carbamoyl group of the 3-position, halogenating the silylated compound to produce the correspond-ing iminohalide, reacting the iminohalide with a lower aliphatic alcohol to produce the corresponding iminoether compound and subjecting the iminoether compound to solvolysis.
(I) wherein R2 is hydrogen or an ester residue, or a salt thereof, which comprises silylating a compound of the formula:
(II) wherein R1CO is an acyl group and R2 has the same meaning as defined above, or a salt thereof to produce a compound silylated at the carbamoyl group of the 3-position, halogenating the silylated compound to produce the correspond-ing iminohalide, reacting the iminohalide with a lower aliphatic alcohol to produce the corresponding iminoether compound and subjecting the iminoether compound to solvolysis.
2. A method as claimed in Claim 1, wherein R2 is hydrogen and the acyl group is a group of the formula:
wherein R3 is a protected amino group.
wherein R3 is a protected amino group.
3. A method as claimed in Claim 2, wherein the acyl group is 5-p-t butylbenzamido-5-carboxyvaleryl.
4. A method as claimed in Claim 2, wherein the acyl group is D-5-p-t-butylbenzamido-5-carboxyvaleryl.
5. A method as claimed in Claim 2, wherein the acyl group is 5-phthalimido-5-carboxyvaleryl.
6. A method as claimed in claim 2, wherein the acyl group is D-5-phthalimido-5-carboxyvaleryl.
7. A method as claimed in claim 1, 2 or 3, wherein the silylation is effected with dimethyldichlorosilane.
8. A method as claimed in claim 4, 5 or 6 wherein the silylation is effected with dimethyldichlorosilane.
9. A method as claimed in claim 1, 2 or 3, wherein the lower aliphatic alcohol is methanol.
10. A method as claimed in claim 4, 5 or 6 wherein the lower aliphatic alcohol is methanol.
11. A method as claimed in claim 1, 2 or 3, wherein the halogenation is effected with phosphorus pentachloride.
12. A method as claimed in claim 4, 5 or 6, wherein the halogenation is effected with phosphorus pentachloride.
13. A method as claimed in claim 1, wherein R1CO- is D-5-p-t-butyl-benzamino-5-carboxyvaleryl or D-5-phthalimido-5-carboxyvaleryl, the silylation is effected with dimethyldichloro-silane, the halogenation is effected with phosphorus pentachloride and the lower alcohol is methanol.
14. A method as claimed in claim 1, 2 or 13 wherein the solvolysis is effected with water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4927677A JPS53135996A (en) | 1977-04-27 | 1977-04-27 | Preparation of cephalosporin compounds |
| JP49276/1977 | 1977-04-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1102791A true CA1102791A (en) | 1981-06-09 |
Family
ID=12826317
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA302,003A Expired CA1102791A (en) | 1977-04-27 | 1978-04-26 | Method for producing cephem compounds |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS53135996A (en) |
| CA (1) | CA1102791A (en) |
| DE (1) | DE2818025A1 (en) |
| ES (1) | ES468942A1 (en) |
| FR (1) | FR2388816A1 (en) |
| GB (1) | GB1602876A (en) |
| NL (1) | NL7804535A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT70205A (en) * | 1979-04-06 | 1979-10-01 | Glaxo Group Ltd | Improvements in or relating to cephalosporin compounds |
| IL63207A (en) * | 1980-07-24 | 1985-09-29 | Lonza Ag | Process for the preparation of 2-(2-aminothiazole-4-yl)-2-(syn)-methoxyiminoacetic acid esters |
| GB8320520D0 (en) * | 1983-07-29 | 1983-09-01 | Glaxo Group Ltd | Chemical process |
| CN114014823B (en) * | 2021-12-15 | 2023-07-07 | 山东金城医药化工有限公司 | Preparation method of trans-northioxomate ethyl ester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7216136A (en) * | 1971-12-14 | 1973-06-18 |
-
1977
- 1977-04-27 JP JP4927677A patent/JPS53135996A/en active Pending
-
1978
- 1978-04-19 ES ES468942A patent/ES468942A1/en not_active Expired
- 1978-04-25 DE DE19782818025 patent/DE2818025A1/en not_active Withdrawn
- 1978-04-26 CA CA302,003A patent/CA1102791A/en not_active Expired
- 1978-04-26 FR FR7812429A patent/FR2388816A1/en active Granted
- 1978-04-27 NL NL7804535A patent/NL7804535A/en not_active Application Discontinuation
- 1978-04-27 GB GB1672178A patent/GB1602876A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| NL7804535A (en) | 1978-10-31 |
| DE2818025A1 (en) | 1978-11-09 |
| FR2388816B1 (en) | 1981-07-24 |
| GB1602876A (en) | 1981-11-18 |
| FR2388816A1 (en) | 1978-11-24 |
| JPS53135996A (en) | 1978-11-28 |
| ES468942A1 (en) | 1978-12-01 |
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