Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
  • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
  • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
  • C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• This invention relates to a process for selectively cleaving an amic acid function from 11-7 5mm acid) cephalosporin. f i i It has been a customary practice for some time in the development of cephalosporin antibiotics to employ an imide substituent in the 7-position when that portion of the molecule was not the point of investigation. The presence of such a protective group, particularly the phthalimido group, tended to render the 7-position chemically quite inert and afforded the possibility to treat other portions of the molecule rather vigorously with the relative assurance that the 7-position would remain intact.
• amic acid function of acep halosp-orin canbe cleaved with outtopening the ,B-lac tam ring.
• This invention comprises such a method.
• the amic acid function 5 will be obtained by partial cleavage of an imide function; however, this is by no means essential.
• This invention relates to a. process for cleaving the amic acid function of a 7-(amic acid) cephalosporin having the formula 2O COOH in which R,, is an alkyl group having from 1 to 4 carbon atoms;
• cleavage cleaving
• cleaving and the like, are intended to refer to the removal of a substituent in the 7-position of a cephalosporin thereby to produce a free 7-amino cephalosporin.
• a first step involves conversion of an amic acid function to produce a corresponding mixed anhydride.
• R and R taken together with the carbon atoms to which they are at-.
• a typical method by which partial cleavage is effected involves an alkaline hydrolysis such as is described in Sheehan et al.. Journal of the Arm'rl'tun C/lt'lllifll/ Sucit'l). 73, 1951 pp. 43674372.
• alkaline hydrolysis which can be employed to accomplish partial cleavage to the amic acid include use of an alkali metal hydroxide or sulfide.
• an alkali metal hydroxide or sulfide such as sodium hydroxide, potassium hydroxide. lithium hydroxide. sodium sulfide. potassium sulfide, lithium sulfide. and the like.
• alkali metal hydroxide or sulfide such as sodium hydroxide, potassium hydroxide. lithium hydroxide. sodium sulfide. potassium sulfide, lithium sulfide. and the like.
• from about 1 to 2 equivalents of the alkali metal hydroxide or sulfide are employed, except in the instance in which the free acid of the cephalosporin is employed. in which case the free carboxyl itself will consume one equivalent of the alkaline reagent. and. therefore. an additional equivalent will be required.
• the pH of the reaction medium ranges from about 9 to about 1 l.
• the hydrolysis is achieved generally by use of an aqueous medium containing an inert, water-miscible organic solvent. such as. for example. tetrahydrofuran. N.N-dimethylformamide. acetone. dimethylsulfoxidc, dioxanc. and the like.
• the partial cleavage generally is quite rapid. typically being completed in from about 3 to about 30 minutes, and more typically in from about 5 to about 10 minutes.
• the temperature of reaction usually is from about l()C. to about room temperature, and preferably.
• the amic acid can also have the formula COOR
• the above amic acid. as well as phthalamic acid de fined herein. are also available from sources other than their corresponding imide precursors.
• the free amino compound can be reacted with the appropriate anhydride. for example. maleic anhydride. to produce the corresponding amic acid compound, specifically, in this case, the 3-carboxyacrylamido compound.
• One step of the process of this invention comprises the conversion of the amic acid to a mixed anhydride.
• the mixed anhydride is not isolated in accordance with the process of this inventionphowever. it has the for mula R, represents an alkyl group. preferably a lower alkyl group having from 1 to 4 carbon atoms.
• the conversion of the amic acid to the mixed anhydride is accomplished by reacting the amic acid with an alkyl chloroformate.
• an alkyl chloroformate such as ethyl chloroformate. propyl chloroformate. t-butyl chloroformate, isobutyl chloroformate. and the like.
• a lower alkyl chloroformatc is employed. typically one in which the alkyl group has from about l to about 4 carbon atoms.
• This reaction is carried out in the presence of a tertiary amine. such as pyridine. quinoline, triethylamine. N- methylmorpholine. N.N-dimethylaniline. and the like. Additionally.
• this reaction typically is carried out in the presence of an aprotic organic solvent. That is. one which does not offer or accept protons.
• aprotic organic solvent that is. one which does not offer or accept protons.
• solvents are known to those skilled in the art and can be used in accordance with the process of this invention. Included as such solvents are N.N-dimethyl formamide, N,N-dimethylacetamide, tetrahydrofuran, dioxane, aliphatic nitriles, such as acetonitrile, propionitrile, and the like; aromatic hydrocarbons and halogenated derivatives, such as benzene, toluene, dichlorobenzene, and the like; and aliphatic halogenated hydrocarbons, such as methylene chloride, chloroform. bromoform, carbon tetrachloride, carbon tetrabromide', ethylene dichloride. ethylene dibromide, and the like.
• the reaction is carried out for from about 5 to about 40 minutes, preferably from about 20 to about 30 minutes at a temperature of from about -20C. to about +5C., and preferably from about -20C. to about 5C.
• the mixed anhydride is maintained intact by retaining the reaction mixture at approximately the temperature at which the reaction was carried out.
• the aforementioned mixed anhydride cephalosporin can then be selectively cleaved by a step-wise treatment thereof with a hydrazine, typically unsubstituted hydrazine, methyl hydrazine, or N,N'-dimethylhydrazine, followed by product recovery and/or further treatment depending upon the product which is desired and the particular hydrazine which is employed.
• a hydrazine typically unsubstituted hydrazine, methyl hydrazine, or N,N'-dimethylhydrazine
• the hydrazine treatment involves the reaction of the mixed anhydride in an inert organic solvent such. as any of the aprotic solvents mentioned hereinabove with one equivalent of the hydrazine. Care must be taken 'to avoid the presence of any excess hydrazine. Therefore, in order to ensure the avoidance of such excess, up to one equivalent of the hydrazine per equivalent of the original amic acid is employed, and, typically, a slight deficiency of hydrazine is employed.
• the reaction' is carried out at relatively cold temperatures ranging from about -l0C. to about room temperature and preferably at about ice temperature (0C.).
• the hydrazine typically-is added to the mixed anhydride mixture while the mixture is at the relatively cold reaction temperature.
• the mixture of the mixed anhydride in the organic solvent is maintained at the temperature of reaction while the' hydrazine, previously cooled, is added.
• the reaction is rather rapid, generally being completed within from about 1 to about minutes, and the reaction generally is permitted to proceed for about an additional 5 minutes.
• the particular treatment which the hydrazine reaction mixture then receives depends upon the structure of the hydrazine which is employed and the ultimate product which is desired.
• the hydrazines which are used have the structure R HNNHR,
• R; and R independently are hydrogen or methyl.
• R and R independently are hydrogen or methyl.
• R5; and R in the hydrazine which is employed are both hydrogen, a complex of the free 7-amino cephalosporin and the by-product, diketophthalazine, forms, and this complex must be broken. This can be accomplished by heating the mixture or by treating the mixture with acid or, more'readily, by a combination of both heat and acid treatment.
• the complex typically can be broken by'subjecting the reaction mixture to a temperature of from about 50C. to about C. for from about 5 to about 20 minutes, and the free amino compound recovered by recognized techniques.
• the diketophthalazine complex can also be broken by treating th e reaction mixture with an acid.
• an acid Virtually any acid, organic or inorganic, can be used. Typical such acids include, for example, hydrochloric acid, hy-. drobromic acid, phosphoric acid, p-toluenesulfonic acid, sulfuric acid, methanesulfonic acid, and the like.
• An equivalent or a moderate excess of the acid typically up to about two equivalents of the acid, based upon the amic acid, is employed.
• acid is employed in conjunction with heat. and, therefore, the resulting reaction mixture is heated to a temperature of from about 50C. to about l()0C., and the decomposition of the complex is permitted or proceed. Depending upon the relative temperature which is employed, the reaction typically will be completed within from about 5 to about l0 minutes.
• an acid is employed. the free 7-amino cephalosporin in the form of its acid addition salt is thereby produced and is recovered in accordance with known techniques.
• any of the typical acyl fune' tions can be thereby introduced into the 7-position of the cephalosporin molecule simply by selection of the appropriate acyl halide, preferably the corresponding acyl chloride.
• the resulting 7-acylamido cephalosporin can be readily recovered by techniques well recognized in the art.
• Typical acyl halides are those of the formula in which Y is a halogen, such as chlorine, bromine, or iodine, and R, is 7 C to C -alkanoyl;
• each Q is hydrogen or methyl.
• Ar is 2- thienyl. "3-thienyl. 2-furyl. 3-furyl; 2-pyrrolyl, 3-.
• cephalosporin used as starting material in the process-of this invention has the following fomiula:
• R in the above formula as well as in the various products of the process of this invention denotes a carboxy protecting groupl'lhe nature of the carbosy protecting group is not important. and any of those recognized in the art can he used. Preferably. however. this group is the residue of an ester function which is removable by acid treatment or by hydrogenation. Preferred carbosy pivaloyloxymethyl, 'propionoxymethyl, phenacyl, pchlorophenacyl. p-bromop'henacyl, and the like.
• ester residues are t-butyl. benzyl, p-nitrobenzyl. I p-methoxybenzyl, benzhydryl. and 2.2.2-trichloroethyl; most preferably. the ester residue is' p -nitrobenzyl.
• the 7-position of the cephalosp'orin contains'a 2-carboxybenzamido group (typically derived from a phthalimido'group) or a maleamido P- i I
• the process of this invention proceeds stepwise from a '7-( 2 carboxybenzamido)- to an unisolated mixed anhydride to a 7-aminoor 7-acylamidocephalosporin.
• This step-wise sequence includes conversion of 7-maleamidoto an unisolated' mixed anhydride to a 7-aminoor 7- position will contain one of the following: methyl. ace-
• the following are representative of the product conversions which are available in accordance with the process ofv this invention. it will be understood. however. that the ratio of products may vary depending upon the particular reactants which are employed. the relative quantities of reactants. and the conditions of reaction.
• 0,000 nmr.(CDCl,,) a 1.55 (s, 9. t-Bu); 2.l (s, 3. CH 3.5 (s. 2. CH 4.9 and 5.3 (ABq. 2. .l l4 Hz); 5.1 (d. l, .l Hz); 5.82 (d. I.
• the pH of the aqueous layer from above was lowered to pH 2.5 with 1N HCl and then was extracted with ethyl acetate (2 X 30 ml.). The ethyl acetate extracts were combined. washed with brine (30 ml.) and dried over MgSO The ethyl acetate was evaporated in vacuo during which time a colorless crystalline product crystallized. when the volume had been reduced to ca. 10 mL. the solution was filtered giving 190 mg. (6.571 of 7( 2-ca rboxybenzamido )-3-methyl-2-cephem-4- carboxylic acid; m.p. 196-198 (dec.); ir (KBr) 1773. 1700.
• the identical (nmr. ir. m.p.) substance also can be obtained in 94% yield from phthalic anhydride and the t-butyl ester of 7-ADCA.
• aqueous layer was acidified to pH 4.3 with lN H 50 and extracted twice with ethyl acetate.
• the ethyl acctate extract was washed. dried. and evaporated to give 660 mg. 68% of the phthalamic acid as an amorphous solidsldln 85.6'(MeCN); ir (CHCl l78l. 1740 and 1710 cm"; nmr (CDCl;,) 8 2.08 (x. 3. CH 3.] and 3.43 (ABq. 2. .l 17 Hz). 3.79 (s. 3. CH 5.0 (d.
• EXAMPLE 8 p-Methoxybenzyl 7-amino-3-methyl-3-cephem-4-carboxylate. p-toluene sulfonic acid salt ln accordance with the procedure of Example 2. pmethosyhenzyl 7-( 2-carboxybenzmido )-3-methyl-3- cephcm-4-carboxylate' is converted to p- 7-amino-3-methyl-3-cephem-4- carboxylatc, p-toluenesulfonic acid salt.- using p-toluenc'sullonic acid monohydrate. instead of hydrochloric acid as in Example 2. This material is identical with the salt described by C hauvette et. al.. J. Org.
• ethyl chloroforrnate (0.l ml.. 2 mmol.) is added. and then after 0.5 hourat 0C.. anhydrous hydrazine (0.03 ml.. l mmol.) is added to the reaction mixture. After 15 minutes. the mixture is filtered. and the filtrate is evaporated to dryness in vacuo. The residue is taken up in acetone ml.) and tetrahydrofuran (15 ml.), and phenylacetyl chloride (0.l3 ml., 1 mmol.) is added.
• R and R are hydrogen, or R and R taken together with the carbon atoms to which they are attached represent an orthophenylene ring;
• R is a carboxy protecting group; and
• R is hydrogen, acetoxy, methoxy, methylthio, (5- methyl-l,3,4-thiadiazol-2-yl)thio, or l-methyllH-tetrazol-S-yUthio; which comprises the steps of l. reacting said 7-(amic acid) cephalosporin with an alkyl chloroformate in the presence of a tertiary amine to form the corresponding mixed anhydride having the formula in which R,, is an alkyl group having from 1 to 4 carbon atoms;
• R is C,-C alkyl, 2,2.2-trichloroethyl, benzyl, p-nitrobenzyl, pmethoxybenzyl, benzhydryl, C C alkanoyloxymethyl. phenacyl, or p-halophenacyl.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Cephalosporin Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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Citations (3)

• 1973
  • 1973-06-18 US US371011A patent/US3905966A/en not_active Expired - Lifetime
• 1974
  • 1974-05-07 IE IE963/74A patent/IE39253B1/xx unknown
  • 1974-05-09 IL IL44791A patent/IL44791A/en unknown
  • 1974-05-15 CA CA199,956A patent/CA1018155A/fr not_active Expired
  • 1974-06-12 GB GB2683874A patent/GB1474544A/en not_active Expired
  • 1974-06-17 BE BE1006024A patent/BE816408A/fr unknown
  • 1974-06-18 JP JP49070086A patent/JPS61352B2/ja not_active Expired
  • 1974-06-18 ES ES427388A patent/ES427388A1/es not_active Expired
  • 1974-06-18 NL NL7408170A patent/NL7408170A/xx not_active Application Discontinuation
  • 1974-06-18 DE DE2429166A patent/DE2429166A1/de not_active Withdrawn
  • 1974-06-18 CH CH831974A patent/CH601313A5/xx not_active IP Right Cessation
  • 1974-06-18 FR FR7421140A patent/FR2233328B1/fr not_active Expired
• 1976
  • 1976-05-17 ES ES448016A patent/ES448016A1/es not_active Expired

Patent Citations (3)

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