IL29948A - Process for converting a penicillin sulfoxide ester to a cephalosprin antibiotic - Google Patents
Process for converting a penicillin sulfoxide ester to a cephalosprin antibioticInfo
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- IL29948A IL29948A IL29948A IL2994868A IL29948A IL 29948 A IL29948 A IL 29948A IL 29948 A IL29948 A IL 29948A IL 2994868 A IL2994868 A IL 2994868A IL 29948 A IL29948 A IL 29948A
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- Prior art keywords
- ester
- sulfoxide
- acid
- penicillin
- alkyl
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- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
PROCESS FOR CONVERTING A PENICILLIN SULFOXIDE ESTER TO A CEPHALOSPORIN ANTIBIOTIC »DDiss iD 'x'as a? TOOK na'an'? v^nn 1 ' n sol axn iioa 'oi Ό »D as ηιαιπ , This invention relates to a process for improving the yield and quality of cephalosporin antibiotics produced by heating analogous penicillin sulfoxide esters using tertiary sulfonamides to direct the conversion of penicillin sulfoxide esters to cephalosporin antibiotics.
More particularly, the present Invention provides a process for converting a penicillin sulfoxide ester to a cephalosporin antibiotic by heating the penicillin sulfoxide ester under acid conditions for a time sufficient to effect conversion thereof, which comprises heating the penicillin sulfoxide ester dissolved in a tertiary sulfonamide at a temperature of from about 80°C. to about 175°C, which tertiary sulfonamide is represented by the formula: 0 it R-, -S-N-F x II I f- 0 R3 wherein (a) each of R1, R2, and R^ is C to C1Q alkyl, phenyl, tolyl, pr xylyl, at least one of R^ , R2,. and R^ is to C10 alkyl, and R^, R2, and R^ together contain not more than 18 carbon atoms; (b) R^ is a to C10 alkyl, phenyl, tolyl, or xylyl, and R2 and R^ are taken together with the nitrogen atom to which they are bonded to complete a mpnocyclic ring radical bonded to the sulfur atom, which radical contains' rom to 6 saturated carbon atoms, and which radical can contain a ring member oxygen atom gamma to the ring nitrogen, such that R-^ R2, and R^ together contain up tp about 12 carbon atoms; (c) Ri and R2 are taken tpgether with the sulfon-amide grouping to which they are bonded to form a sulfur oxide and mononitrogen monocyclic ring having from 3 to 5 saturated ring carbon atoms therein,, and R^ is alkyl, phenyl, tblyl, or xylyl such that R-^> R2> and R^ together contain up to about 12 carbon atoms, and/or (d) ¾ Is -^NR^R^ and each R2, R3, R , and R^ is alkyl such that the sulfondlamlde formed thereby contains up to about 12 carbon atoms.
United States Patent No. 3, 275, 626 discloses and claims a method for preparing antibiotic substances by heating a penicillin sulfoxide ester under acid conditions to effect conversion thereof to a variety of products, including des- · acetoxycephalosporin-type antibiotics , The foregoing patent discloses that the characteristic thlazolidine ring of a penicillin can be converted to the characteristic thiazine ring of the cephalosporins by heating a penicillin sulfoxide ester at a temperature of from about 100° C. to about 175° C. in the presence of an acid.
The process of the present invention is broadly applicable to the conversion of the prior-art penicillins, so long as they are not otherwise converted under the conditions of acidity and elevated temperature employed. In all cases they must be esterified and must be converted into the corre-r sponding sulfoxide prior to treatment. A wide range of penicillins can be effectively treated in accordance with the invention, including benzyl penicillin, n-heptyl penicillin, phenylmercaptomethyl penicillin, and the like. The preferred . penicillin is phenoxymethyl penicillin ( "penicillin-V") .
Penicillin nucleus (6-aminopenicillanic acid, "6-APA") can also be treated successfully, but the 6-amino group should first be protected with an easily removable group, such as carboallyloxy, tert-butoxycarbonyloxy or the like. The product obtained b the treatment of the N- rotected 6-APA is the corresponding N-protected 7-amlnodesacetoxycephalosporanic acid ("7-ADCA") ester, which after cleavage of the N-protect-ing group, can be acylated in a known manner to produce the desired desacetoxycephalosporin in the form of the ester.
Examples of sulfonamides which may be used in. the process of this invention include: (1) N,N-dimethylmethahesulfonamide, Ν,Ν^-diethyl-methanesulfonamide, N,Nr-di-tert-bu'tylmethanesulfonamide, N,N-dioctylmethanesulfonamide, Ν,Ν-dimethylethanesulfonamide, N-phenyl -N-rethylmethanesulfonamide, N,N-bis ( -methylphenyl) utane-sulfonamide, N- (p-tolyl) -N-propylmethanesulfonamide, N-methyl-N- (3>5-dlmethylphenyl)ethanesulfonamide, N-etnyl-N-methylben-zenesulfonamide, Ν,Ν-dlmethyloctanesulfonamide, Ν,Ν-diethyl-octanesulfonamide, N, N-dimethyl-4-ethylbenzenesulfonamidej (2) N- (methyIsulfonyl) pyrrolidine, N-(et ylsulfonyl) -pyrrolidine, N- (phenylsulfonyl) pyrrolidine, N- (propylsulfonyl) -pyrrolidine, N- (hexylsulfonyl) pyrrolidine, N- (propylsulfohyl) -piperidine, N- (methylsulfonyl)mprpholine, N- (phenylsuifonyl) -morpholine, N- (heptylsulfonyl) piperidine; (3) 2-phenylisothiazolidine-l,l-dloxlde, 2-methyl-isothiazolidine-l,l-dioxide, 2-hexylisothlazqlidlne-l,1-di-oxide, 2-phenyltetrahydro-2H-l,2-thiazine-l,l-dioxlde, 2-ethyl-tetrahydro-2H-l,2-thiazine-l,l-dioxide ; and (4) tetramethylsulfondlamide, Ν,Ν' -tetrapropylsulfon-dlamide, and the like.
In conducting the process of this invention, the penicillin sulfoxide ester is dissolved in the tertiary sulfonamide solvent system, either as the only solvent, or mixed with an optimum proportion of another tertiary sulfonamide or an in-ert organic liquid diluent or both with the aid of heat, if necessary as defined above, and with the acid substance used to promote the rearrangement. Use of the tertiary sulfonamide as the only solvent except; for the acid substance is preferred for highest yields of desacetoxycephalosporin products. For best results, the penicillin sulfoxide ester concentration in the selected tertiary sulfonamide medium, that is, the total solvent, is maintained below about 15 percent, by weight, preferably below 10 percent by weight.
The acid substance can be commingled or mixed with the tertiary sulfpnamide medium before, simultaneously with, or after the penicillin sulfoxide ester starting material is dissolved therein. The acid substance should be a nonoxidiz-lng protic acid or Lewis acid capable of accepting electrons from the oxygen of . the thlazolldlne sulfoxide bond in the terr-tiary sulfonamide/penicillin sulfoxide ester/acid medium.
Preferred aqid substances for use in the improved process of this invention in lude the alkanoic acid anhydrides having from 2-6 carbon atoms in each acid moiety, such as acetic anhydride, propionic anhydride, n-butanolc anhydride, pentanoic anhydride, hexanoic anhydrides, and mixed anhydrides of Cg-Cg alkanoic acids, cyclic saturated dibasic acid anhydrides such as succinic anhydride, glutarlc anhydride, strong Lewis acids such as aluminum chloride, boron trifluoride, hydrogen fluoride, ferric chloride, and strong nonoxidizing mineral acids such as p-toluenesul pnic, benzenesulfonlc, methanesulfonlc, naphthalenesulfonic, and other sulfonic acids or various phosphorus acids such as orthophosphoric acid, methylphosphonic, and the like, hydrochloric acid, as well as other acidic substances such as thlonyl chloride, cyanogen bromide, and the like. For reasons of availability, cost, and generally better results, acetic anhydride and aluminum chloride are especially preferred acid substances.
In general, amounts of acid substance ranging from about 1 percent to about 20 percent by volume of total solvent medium can be used. With lower amounts of acid, the rate of reaction is undesirably slow for practical use. Larger amounts of acid may be used but are not necessary. For best practice it is preferred that the acid substance be present in amounts at least equimolar to the molar concentration of the penicillin sulfoxide esters, and in most cases the higher yields are obtained in the shortest times when from about 2 to about 5 molar equivalents of the acid substance per molar equivalent of the penicillin sulfoxide ester are used at the optimum temperature.
The penicillin sulfoxide ester in the acidified tertiary sulfonamide solvent is heated to from about 80° C. to about 175° C. to direct the rearrangement of the penicillin sulfoxide ester to the corresponding desacetoxycephalosporln ester. The preferred temperature range is from about 90°C. to about 150°C, and the preferred reaction time is from about 1 to about 15 hours. Lower temperatures require more time, while at higher temperatures the reaction mixture tends to discolor and produce a more complex rearrangement product.
In preparing the penicillin sulfoxide esters for use as starting materials in the process of this invention, the penicillin sulfoxide may be prepared prior to esterlfying the penicillanic acid carboxyl group, or alternatively the selected penicillin may be esterified first and then the resulting penicillin ester may. be sulfoxylated according to conventional methods. Reference is made to the Morin and Jackson patent, U.S. 3 , 275, 626.
By way of example and for completeness, the following summarizes the steps that can be taken to prepare a desired ester. A typical example Involves the preparation . of a 7-(D-a-phenylglycylamido)desacetoxycephalosporanic acid, an orally active .cephalosporin-type antibiotic,, from the corresponding 6-(D-a-phenylglycylamido)penicillanic acid sulfoxide ester. (a) The penicillin sulfoxide ester is dissolved in a tertiary sulfonamide solvent medium together with acetic anhydride or other equivalent acid substance to obtain an acidified liquid solution of the penicillin sulfoxide ester. (b) The penicillin sulfoxide ester solution is heated to between from about 80°C. to about 175° C. to form the corresponding desacetoxycephalosporin ester. (c) The desacetoxycephalosporanic acid is recovered from the reaction product obtained in step (b), e.g., by treating the product with 90 percent acetic acid and zinc dust for 1 to 3 hours at -5°C. to 20°C. to obtain the 7T (D-a-phenylgly-cylamldo) -3-methyl-3-cephem- -carboxylic acid / - (D-a-phenyl-glycylamido)desacetpxycephalosporanic acid^ (generic name -cephalexin) which is useful as" an antibiotic in combating diseases caused by penicillin-resistant strains of Staphylo-coccus aureus.
The prior art describes literally thousands of penicillin compounds almost all of which can be converted to desacetoxycephalosporin compounds by the improved process of this invention. The only limitation on the penicillin compounds which can be employed in the process of this invention is that they must not undergo other undesirable conversions under the reaction conditions of the process. A few typical examples will illustrate/ to those familiar with the art, penicillins which may be used as starting materials, and the desacetoxy-cephalosporins obtained therefrom. The desacetoxycephalosporin compounds produced by the process of this Invention from the corresponding penicillin sulfoxide esters are useful, after ester group removal > as bacteriostatic and bactericidal antibiotics in the therapy of diseases caused by various Gram- positive and Gram^negatlve microorganisms. 7-Aminodesacetoxy- cephalosporanip acid, produced from a corresponding 6-amino- peniqillanate sulfoxide ester by this invention is useful as an intermediate to prepare desacetoxycephalosporln antibiotic substances.
The esterlfied penicillin sulfoxides listed below yield the indicated corresponding desacetoxycephalosporins after heat rearrangement of the penicillin sulfoxide esters according to the method of this Invention and removal of the ester group by conventional methods. 6-^/21 -Methoxy-2 » - (2!'-thienyl ) acetamido7-2, 2-dimethyl -penam-3rparboxylic acid yields l-£∑ -methoxy-21 - (2"-thienyl) -. acetamido7^3-methyl-3-cephem- -carboxylic acid. 6-.(Phenylacetamido) -2, 2-dimethylpenam-3-carboxylic acid yields 7- (phenylacetamido) -3"methyl-3-cephem-4-carboxylic acid. 6- (Thiophene-2-acetamido) -2, 2-dimethylpenam-3-car-boxylic acid yields 7- (thiophene-2-acetamido) -3-methyl-3-r cephemr-4-carboxylic acid. 6- -2,2-dlmethylpenam-3-carboxylic aqid yields 7- (phenylmercaptoacetamido) -3-methyl-3-cephem-4-rcarboxyllc acldt 6- (2* -Furylacetamido) -2, 2-dimethylpenam-3-carboxylic acid yield 7- (21 -furylacetamido) -3-methyl-3-cephem-4-carboxylic acid. 6- (21 -protected amino-2 ' -phenylacetamido) -r2, 2-di-methylpenam-3-carboxylic acid yields 7- (21 -protected amino-2 '-phenylacetamido) -3^methy1 τ3-cephem-4-carboxy1ic acid . 6-Benzoyl-2, 2-dimethylpenam-3 -carboxylic acid yields 7-benzoyl-3-methyl-3-cephem- -carboxylic acid.
This Invention is further illustrated by the following detailed examples.
EXAMPLE 1 2, 2., 2-Trichloroethyl 6 - (phenylacetamido) enicilla-nate sulfoxide was prepared by reacting penicillin G potassium salt /benzylpenicillin, potassium salt/ with 2, 2, 2-trichloro-ethanol in methylene chloride in the presence of pyridine hy-drochlorlde and dicyclohexylcarbodiimide and then reacting the resulting 2, 2, 2-triehloroethyl 6- (phenylacetamido) penlcillanate ester intermediate with 85 percent m-chloroperbenzoic acid in chloroform in an ice bath medium to form the 2, 2, 2-trichloro-ethyl 6- (phenylacetamido) penlcillanate sulfoxide.
A solution of 1 gram of 2, 2, 2-trichloroethyl 6- (phenylacetamido) penlcillanate sulfoxide and 1.2 g. o acetic anhydride in 50 ml. of N- (propylsul onyl ) piperidine is warmed to 130°C. in an oil' bath for about 5 hours to insure complete reaction. The N- (propylsulfonyl) piperidine solvent is removed and the crude product which remains as residue is dissolved in 25 ml, of 90 percent acetic acid and then 5 g. of zinc dust is added to the solution. The resulting mixture is stirred and cooled in an ice bath for three hours to remove the triqhlbro-ethyl ester group and to form the corresponding 7- (phenylaeet-amido)desacetoxycephalosporanic acid / - (phenylacetamido) ^3 -methyl -3 -cephem- -carboxylic acid_7.
EXAMPLE 2 2, 2, 2-Trichloroethyl 6- (thiophenacetamido)penicilia-nate sulfoxide was prepared from 6- (thlophene-2-acetamido) -peniclllanic acid potassium salt following the procedure set forth in Example 1.
A mixture of 1 g. of 2, 2, 2-trichloroethyl 6-(thio-phene-2-acetamido)penicillanate sulfoxide, 1.2 g. of propionic anhydride and sufficient 2-methylisothiazolidine -1 , 1 -dioxide to make, 0 ml. of solution upon warming is heated to 139°C. for effect solution and stirred at that temperature for 4 to 5 hours to insure complete reaction. of the penicillin sulfoxide esters. The 2-methyllsothlazolidine-l,l-dioxide is removed and the crude product which remains as residue is taken up in 25 ml. of 90 percent acetic acid solution and then grams of zinc dust is added. The resulting mixture is stirred at ice bath temperature to remove the ester group and to form the 7- (thiophene-2-acetamido)desacetoxycephalosporanic acid phene-2-acetamido) -3-methyl-3-cephem- -carboxylic acid/.
EXAMPLE 3 Phenoxyisopropylpenicillin sulfoxide 2, 2, 2-trichloro-ethyl ester was prepared by reacting phenoxyisopropylpenicillin potassium salt with sodium metaperiodate in acidified water solution to form the sulfoxide and reacting the resulting phenoxyisopropylpenicillin sulfoxide as the sodium salt with 2, 2, 2-trichloroethanol in methylene chloride containing a small amount of pyridine and N,N-dicyclohexylcarbodiimlde in an amount equivalent to the penicillin to form the 2, 2, 2-trichloroethyl phenoxyisopropylpenicillin sulfoxide 2, 2, 2-trichloroethyl 6^·(α,α-dimethyl-a-phenoxyacetamido) r2, 2-dimethylpenam-3-carboxylate sulfoxide/.
A 3.0 g. (5.7 mmoles) portion of the 2 , 2, 2-trichloro- ethyl phenoxyisopropyl penicillin sulfoxide ester, described above, Is dissolved In 120 ml. of warmed tetramethylsulfondi-amlde containing 2.9 g, (28.5 mmoles) of acetic anhydride. The mixture is heated in an oil bath for about 5 hours to insure complete reaction. The tetramethylsulfondlamide is removed under high vacuum. The crude 2,2,2-trichloroethyl 7-(a,a-di-methyl-a-phenoxyacetamido) -3-methyl -3-cephem-4-carboxylate product is dissolved in 90 percent acetic acid and zinc dust as described in Example 1, to obtain the free 7- (α,a-dimethyl~ a-phenoxyacetamido) -3-methyl-3-cephem-4-carboxyllc acid.
EXAMPLES 4, 5 and 6 α,α-Dimethyl.-a-phenoxymethylpeniclllin sulfoxide p-methoxy- phenyl ester (4) The p-methox phenyl 6-(a,a-dimethyl-a-phenoxyacet-amldo) -2,2-dimethylpenam-3-earboxylate sulfoxide was prepared using p-methoxyphenol in place of 2,2,2-trichloroethanol, as described in Example 3. Recrystallization of this ester from chloroform-petroleum ether afforded an analytical sample; m.p. 159°C. to l6l°C; IR and NMR analyses were satisfactory for this penicillin sulfoxide aromatic ester; thin-layer chromatography showed single-spot material.
, -Dimethyl-a-phenoxymethylpenicillin sulfoxide p-methoxy- benzyl ester (5) The p-methoxybenzyl 6- (α,α-dimethyl-a-phenoxyacet-amido) -2, 2-dimethylpenam-3-carboxylate sulfoxide was prepared using p-methoxybenzyl alcohol in place of 2,2,2-trlchloro-ethanol, as described in Example 3. This ester purified from ethyl acetate-petroleum ether has a m.p. of l63-l65°C. IR and NMR analyses were consistent with this penicillin sulfoxide aromatic ester; thin-layer chromatography showed single^spot material. α,α-Dimethyl-a-phenoxypenicillin sulfoxide 2,2-dichloroethyl ester (6) The 2,2-dichloroethyl 6- (α,α-dimethyl-a-phenoxyacet- amldo) -2, 2r-dimethylpenam-3-carboxylate sulfoxide was prepared as described in Example 3 by using 2,2-dichloroethanpl in place of 2,2,2-trichloroethanol . This ester, purified from ethyl acetate-petroleum ether, gave a m.p. 113°C. to H5°C, IR and NMR analyses were consistent with this penicillin sulfoxide ester; thin-layer chromatography showed single-spot material. 7- ( ,α-Dimethyl-q-phenoxyacetamido) τ3-desacetoxycephaloBporanic acid p-methoxyphenyl. ester. (4), p-^methoxybenzyl ester (5), 2,2-dlchloromethyl ester (6) The p-methoxyphenyl, p-methox benzyl, and 2,2-di-. chloroethyl esters of 7- (α,α-dimethyl-a-phenoxyacetamido) -3-methyl-3-cephem-4-carboxylic acid, are prepared by dissolving the above respective penam sulfoxide esters in N,N-dimethyl-p-tolylsulfonamide, together with from 2 to 5 molar equivalents of acetic anhydride, relative to the respective penam sulfoxide esters therein, and heating the resulting solutions to about 130°C. to l40°C. for about 1 hour.
EXAMPLE 7 2,2,2-Trichloroethyl chloroformate To a solution of phosgene, 40 g. (400 moles), in 200 ml. of dry benzene there were added dropwise 2,2,2-trichloro-ethanol, 15.8 g. (100 moles), and pyridine, 12 g. (152 moles) in a mixture of 200 ml. of dry benzene and 400 ml. of anhydrous ethyl ether with occasional cooling to keep the temperature slightly below 20° C. The addition required two hours. The precipitated pyridine hydrochloride was filtered off. The filtrate was cooled, poured into 1 liter of ice water and . shaken in a separatory funnel. The organic layer was separated, dried over MgSCty, and evaporated in vacuo. Distillation of the residue from over CaCO^ gave a 15 g. (67 percent) yield of the 2,2, 2-trichloroethyl chloroformate; b.p. 43°C/10.5 mm.; ~n_7 = I. 698; X max. 5.62/*; the NMR analysis was satisfactory.
Anal, calcd. for C^HgCl^Og: CI, 66.94. Found: CI, 66.74.
N-(2,2,2-Trichloroeth ffoxycarbonyl) -D-phenylgl clne (I) A solution of D-phenylglycine, 22.7 g. (150 mmoles), in 300 ml. of water, l60 ml. of 1 N NaOH and 150 ml. of ether was cooled in an ice-alcohol bath. While stirring, simultaneous dropwise additions of 2, 2, 2-trichloroethyl chloroformate, 42.5 g. (200 mmoles) in 200 ml. of dry dioxane and 200 ml. of 1 N NaOH were made. The additions required about one hour.
The reaction mixture was maintained near 0°C. for another hour, washed with a large volume of cold ether, and then acidified to pH 2.5 in the presence of cold ethyl acetate. The organic layer was separated, washed with cold water, dried (MgSO^), and evaporated in vacuo. The crystalline solid ree^ ldue weighed 45 g. and was recrystallized by dissolving in 150 ml. of benzene, filtering, and diluting with 40 ml. of petroleum ether. The yield of pure N- (2,2,2Ttrichloroethyloxy-carbonyl)phenylglycine product was 30.2 g. (62 percent); m.p. l42-l44°C; electrometric titration in 66 percent aqueous di-methylformamide showed a pK'a = 5.55 and an apparent molecular weight = 332 (calcd. 327); the NMR analysis was satisfactory.
Anal. Calcd. for C1;LH10C13N0 : C, 40.45; H, 3.09; N, 4.29. Found: C, 4θ.6θ; H, 3.24; N, 4.55. 6- N- (2,2,2-Trlchloroethylcarbonyl) -D-phenylglycyl7amino- penlcillanic acid (II) 2 2 2-Trichloroeth l chloroformate 11.6 . 8 .0 mmoles), was dissolved in 420 ml. of analytical grade acetone containing a. few drops of dimeth lbenzylamine and cooled in an ice-alcohol bath. While stirring, N- (2, 2, 2-trichloroethoxy- earbonyl) -D-phenylgl cine, 28.0 g. (85.0 mmoles), and triethyl-amine, 8.7 g. (86.0 mmoles) in 420 ml. of acetone were added dropwise over a period of thirty minutes to form the N- (2, 2, 2-trichloroethoxycarbonyl) -D-phenylglycyl 2, 2, 2-trichloroethyl carbonate. The mixture was stirred in the cold an additional fifteen minutes. 6-Aminopenicillanic acid (6-APA), 18.6 g. (85.Ο mmoles), in 70 ml. of cold water containing triethyl-amine, 8.7 g. (86.0 mmoles), was added in one portion to the reaction. The mixture was stirred in the cold for two hours, concentrated in vacuo to remove the acetone and diluted with a volume of water. The aqueous solution was layered with ethyl acetate, cooled, and acidified to pH 2.5 with 1 N HCi The ethy^L acetate was separated, washed with cold water, and back-titrated into water to pH 6'.7 with 1 N NaOH to form the sodium salt. The aqueous salt-containing layer; was separated, filtered and evaporated to dryness In vacuo. The residue, after trituration with dry acetone, was a white amorphous powder, weighing 24.6 g. (53 percent yield); eleetrometric titration in 66 percent aqueous dimethylformamide showed a pK'a = 5.25 and an apparent molecular weight = 539 (calcd. 47) ; IR and NMR were as expected for the desired product. 6 - H- (2,2,2-Trichloroethoxycarbonyl) -Drphenylglycy!L amino- penicillanic acid sulfoxide (III) An 18 g. portion of 6- T - (2, 2, 2-trichlorethoxy-carbonyl) -D-phenylglycyl/aminopenicillanic acid sodium salt was dissolved in 300 ml. of water. The pH of the solution was adjusted to 5.4 with 1 N HCI. Sodium metaperlodate, 7.1 g. 33 mmoles was added portionwise and the mixture was stirred at room temperature for two hours, acidified to pH 2.5 in the cold and in the presence of ethyl acetate. The organic layer containing the penicillin sulfoxide was separated, washed with cold water, dried over M SO^ and evaporated in vacuo. The crude penicillin sulfoxide residue weighed 16 g. Crystallize τ tion was effected by dissolving the product in 64 ml. of N,N- dlmethylacetamide and diluting with 640 ml. of anhydrous ether, filtering, and diluting slowly with 40 ml. of petroleum ether. The yield of pure 6- α-/ - (2,2,2vtrichloroethoxycar- bonyl)amino7-a-phenylacetamldo -2, 2-dimethylpenam-3-carboxylic acid sulfoxide product was 11.6 g. (56 percent); m.p. 153- . 155°C. As evidenced by NMR and IR analysis, this product was solvated with one mole of dimethylacetamide .
Anal. Calcd. for C19H2ocl3N3°7sc H9NO: c> ^3.99; H, 4.65; N, 8.92. Pound: C, 44.26; H, 5.02; N, 8.65. 6-/ - (2, 2,2-Trichloroethoxycarbonyl ) -D-phenylglycyl7sniino- peniclllanic acid sulfoxide 2,2,2-trichloroethyl ester (IV) A 7 g. (11.2 mmoles) -portion of 6-^/T- (2,2,2-tri-chloroethoxycarbonyl) -D-phenylglycylamido7-2,2-dlmethylpenam-3-carboxylic acid sulfoxide was dissolved in 85 ml. of dry tetrahydrofuran (THF) containing pyridine, 1.77 g. (22.3 mmoles ). The solution was cooled in an ice-alcohol bath and stirred while adding 2, 2,2-trichloroethyl chloroformate, 3.6 g. (16.7V mmoles), in 20 ml. of THF. The mixture was stirred in the cold for two hours, at room temperature for three hours, and heated to gentle reflux for fifteen minutes. The solvent was removed in vacuo. The amlner-protected-D-phenylglycylpeni-cillin sulfoxide ester residue was taken up in cold ethyl acetate for successive washes with water, 5 percent aHC03 solution, and water. The ethyl acetate solution was dried (MgSO^) and evaporated in vacuo, giving 5.2 g. of an amorphous solid.
Crystallization from 7 ml. of ethanol gave a 4.5 g. (59 percent) yield of 2,2,2-trichloroethyl 6-/ Ττ (2,2,2-trichloro- ethoxycarbonyl) -D-phenylglycylamldo7r2,2rdimethylpenam-3- carboxylate sulfoxide ester product; m.p. l80-l82°C. A 1-rgram sample of this product was recrystallized from ethanol -water for analysis; m.p. l85r 86°C.
Anal† Caled. for C, 37.51; H, 3,14; N, 6.25. Found: C, 37.96; H, 3.39; N, 6.02. 7- (q-Aminophenylacetamido) -3-desacetoxycephalosporanic acid (V) A 3.2 g. (4.5 mmoles) portion of the 2, 2,2-trichloro-ethyl 6- n-(2J2,2-trichlor9ethpxycarbonyl)-D-phenylglycylamido7-2,2-dimethylpenam^3-carboxylate sulfoxide ester is dissolved in 120 ml. of Ν,Ν-dimethylmethanesulfonamide solvent containing acetic anhydride, 2.3 g. (22.5 mmoles) , and heated in an oil bath at 135°C. for one hour to effect rearrangement. The solvent and excess acid reagent are removed under high vacuum.
The residual oil is taken up in 50 ml. of 95 percent acetic acid and cooled in ice. Zinc dust, 10 g, (153 mmoles) is added and the mixture is stirred in the cold for three hours to remove the blocking group from the glycyl amino nitrogen. The reaction mixture was filtered. The zinc is washed with two volumes of acetic acid. The wash and filtrate are combined and concentrated to dryness in vacuo. The crude desacetoxycephalo-sporin residue is taken up in 100 ml. water, cppled, and acidified to pH 1 with trifluoroacetic acid, and the desQcetoxy-r cephalogjycin trlfluoroacetic acid salt is extracted with methylisobutyl ketone. The organic solvent is dried (MgSOij) and evaporated in vacuo, and the residue triturated with an-hydrous ethyl ether, giving the trifluoroacetic acid salt of desaeetox ce halo l cin as a ink ' amor hous owder. A bl - autograph of this product (against a Bacillus subtllls seeded agar plate). of a paper chromatogram developed with butanol, acetic acid, water (3:lil) shows a single biologically-active spot corresponding exactly in Rf value with that of desacetoxy- cephaloglycin - (D-phenylglycylamido) -3-methyl -3-cephem -4 - carboxylic acid_7 prepared by an alternate synthesis. The NMR analysis showed the C-3-methyl absorption band characteristic of desacetoxycephalosporins as a singlet at τ 7.90.
EXAMPLE 8 thio ' A 1-gram portion of 2, 2, 2-trichloroethylheptyl#ij-i - £ p/t#methylpenicillin sulfoxide ester, obtained by reacting heptylmereaptomethylpenicillin potassium salt with 2, 2, 2-tri- chloroethanol in methylene dichloride, and then treating the resulting ester with sodium metaperlodate at ice bath tempera- tures to form the 2, 2, 2-triehloroethyl heptylm^ ¾¾¾ethyl- penicillin sulfoxide, is dissolved in 50 ml. of warmed N,N- diethylbenzenesulfonamide with I.5 grams of aluminum chloride.
The resulting mixture is warmed to 95°C. for 1 hour to form thio the 2, 2, 2-trichloroethyl J- ( eptyllii itttt>a cetam±do) -3-methyl- 3-cephem- -carboxylate ester. Most of the Ν,Ν-diethylbenzene- sulfonamide is removed under vacuum and the crude cephem ester product is taken up in 90 percent acetic acid and treated with zinc dust at 0°C. to 20°C. to remove the ester group and to form the 7- (heptylir/e'r^'^ti^cetamido) -3-methy 1 -3-cephem -4- carboxylic acid antibiotic.
Claims (7)
1. A process for converting a penicillin sulfoxide ester to a cephalosporin antibiotic by heating the penicillin sulfoxide ester under acid conditions for a time sufficient to effect conversion thereof, which comprises heating the Penicuik lin sulfoxide ester dissolved in a tertiary sulfonamide at a temperature of from about 80°0. to about 175°C, which tertiary sulfonamide is represented by the formula: 0 H R-.-3-N-R2 M l wherein (a) each of R- R2 » and alkyl, phenyl, tolyl, or xylyl, at least one of R^ R2, and Rj is to C^Q alkyl, and R-^, R2» and R^ together contain not more than l8 carbon atoms; (b) R]_ is a C to G10 alkyl, phenyl, tolyl, or xylyl, and R2 and Rj are taken together with the nitrogen atom to which they are bonded to oomplete a monocyclic ring radical bonded to the sulfur atom, which radical contains from 4 to 6 saturated carbon atoms, and which radical can contain a ring member oxygen atom gamma to the ring nitrogen, such that Ri,- R2, and R^ together contain up to about 12 oarbon atoms; (0) R^ and R2 are taken together with the sulfonamide grouping to which they are bonded to form a sulfur oxide and mononitrogen monocyclic ring having from 5 to 5 saturated ring carbon atoms therein, and Rj is alkyl, phenyl, tolyl, or xylyl such that R^, R2» and together contain up to about 12 carbon atoms, and/or (d) R la alkyl such that ns up to about 12 carbon atoms.
2. The prooese of olalra 1 wherein the tertiary sul- fonamlde la one in whioh each of R^, R2> and Rj la Οχ to O^Q alkyl, phenyl, tolyl, or xylyl, at least one of R^, R2, and Rj la to OTLO alkyl and R^, R2 and Rj together contain not more than ΐθ oarbon atoms. 5.
3. The prooesa of olaim 2 wherein the tertiary aul-^ fonamlde la , N-dime th lmethane sulfonamide .
4. The process of (a) dissolving in a 6- ■ . . (^,o(-dimethyl-c -phenoxyaoetamldo)-2<2-!dlrmethylpenam'-5-oar--boxylic acid sulfoxide ester, the ester group being a 2,2,2-trlchloroethyl, 2,2-dlohloroethyl, p-methoxyphenyl or p-methoxy benzyl group, with aoetlo anhydride in molar excess relative to said ester, (b) heating the reeulting solution from step (a) to from about 90°0. to about 150°0. to form the corresponding 7-r(?(,o<-dimethyl-fC^-phe1noxyaoetamido)-3-methyl-3-cephem-4-car-boxylate eater, and (0) recovering 7-(
5. The process of claim 1 which oomprises (a) dissolving in N-(propylsulfonyl)piperldlne a phenoxy methyl peniol^lin sulfoxide ester, the ester gro p being a 2,2,2-trlchloroethyl, 2,2-dichloroethyl, p-methoxyphenyl or p-methoxybenzyl group, with aoetlo anhydride in molar excess relative to said ester, (b) heating the re au It ing solution from step (a) to from about 90°C. to about 150°C. to form the 7-(phenoxy-acetamldp)-3-methyl-3-oephem-4-oarbox late ester, and (c) recovering 7-(phenoxyaoetamldo)-3-'-methyl-3-cephem-4-carboxyllc acid from the respective ester obtained in step (b) .
6. The process of claim 1 which comprises (a) dissolving in , N-^dime thy lmethane sulfonamide a 2,2,2-trichloroethyl 6- !?-(proteoted amino) -D-c phenylgly^ cylamldo7-2,2-dlmethylpenam-5-carboxylate sulfoxide ester, and acetic anhydride in molar expess relative to said ester, (b) heating the solution resulting from step (a) to from about 90°C . to about ¾50°0. to form 2,2,2-trichloroethyl 7 - IT- (protected amino) -D^-phenylglyoy lamldoy-J-me thy 1-3-cephem-4-carbox late ester, and (c) recovering 7-(D--e-phenylglycylacetamldo)-3-methyl-3-cephera-4-carboxyllc acid from the ester obtained in step (b) .
7. , A prooese for ponverting a penicillin sulfoxide ester to a cephalosporin antibiotic by heating the penicillin sulfoxide ester under acid conditions for a time sufficient to effect conversion thereof substantially as hereinbefore described with particular reference to the examples.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63662967A | 1967-05-08 | 1967-05-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
IL29948A0 IL29948A0 (en) | 1968-07-25 |
IL29948A true IL29948A (en) | 1971-08-25 |
Family
ID=24552693
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL29948A IL29948A (en) | 1967-05-08 | 1968-05-07 | Process for converting a penicillin sulfoxide ester to a cephalosprin antibiotic |
Country Status (12)
Country | Link |
---|---|
JP (1) | JPS4920318B1 (en) |
BE (1) | BE714747A (en) |
CH (1) | CH540292A (en) |
CY (1) | CY705A (en) |
DE (1) | DE1770360C3 (en) |
DK (1) | DK140101B (en) |
FR (1) | FR1561048A (en) |
GB (1) | GB1204394A (en) |
IL (1) | IL29948A (en) |
MY (1) | MY7300489A (en) |
NL (1) | NL6806533A (en) |
SE (1) | SE357750B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4767851A (en) * | 1984-07-16 | 1988-08-30 | Gema, S.A. | Process for the preparation of 7-amino and 7-substituted amino-desacetoxycephalosporins |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3275626A (en) * | 1962-07-31 | 1966-09-27 | Lilly Co Eli | Penicillin conversion via sulfoxide |
-
1968
- 1968-05-07 IL IL29948A patent/IL29948A/en unknown
- 1968-05-07 SE SE06143/68A patent/SE357750B/xx unknown
- 1968-05-07 DK DK210468AA patent/DK140101B/en not_active IP Right Cessation
- 1968-05-07 FR FR1561048D patent/FR1561048A/fr not_active Expired
- 1968-05-07 BE BE714747D patent/BE714747A/xx not_active IP Right Cessation
- 1968-05-08 CH CH683968A patent/CH540292A/en not_active IP Right Cessation
- 1968-05-08 JP JP43030825A patent/JPS4920318B1/ja active Pending
- 1968-05-08 GB GB21833/68A patent/GB1204394A/en not_active Expired
- 1968-05-08 NL NL6806533A patent/NL6806533A/xx unknown
- 1968-05-08 DE DE1770360A patent/DE1770360C3/en not_active Expired
-
1973
- 1973-10-01 CY CY70573A patent/CY705A/en unknown
- 1973-12-30 MY MY489/73A patent/MY7300489A/en unknown
Also Published As
Publication number | Publication date |
---|---|
CY705A (en) | 1973-10-01 |
DK140101B (en) | 1979-06-18 |
IL29948A0 (en) | 1968-07-25 |
NL6806533A (en) | 1968-11-11 |
DE1770360B2 (en) | 1974-10-24 |
SE357750B (en) | 1973-07-09 |
CH540292A (en) | 1973-08-15 |
GB1204394A (en) | 1970-09-09 |
DK140101C (en) | 1979-11-12 |
BE714747A (en) | 1968-11-07 |
DE1770360A1 (en) | 1971-10-21 |
JPS4920318B1 (en) | 1974-05-23 |
DE1770360C3 (en) | 1975-06-12 |
MY7300489A (en) | 1973-12-31 |
FR1561048A (en) | 1969-03-21 |
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