Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.


  1. Advanced Patent Search
Publication numberUS3592751 A
Publication typeGrant
Publication dateJul 13, 1971
Filing dateApr 14, 1969
Priority dateApr 14, 1969
Publication numberUS 3592751 A, US 3592751A, US-A-3592751, US3592751 A, US3592751A
InventorsRobert A Archer, Douglas O Spry
Original AssigneeLilly Co Eli
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Penicillin sulfoxide conversion process
US 3592751 A
Abstract  available in
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

United States Patent Oflice 3,592,751 Patented July 13, 1971 U.S. Cl. 204-158 Claims ABSTRACT OF THE DISCLOSURE Converting 2-(C to C -a1kanoyloxy)methy1 penicillin sulfoxides to a mixture of l-S:2-S, l-Sz2-R, 1-R:2-S and l-Rz2-R isomers by exposing such penicillin sulfoxides to ultraviolet light in the presence of acetone, the products from which treatment are useful for the production of 3- alkanoyloxymethylcephalosporin antibiotically active compounds, e.g., cephalothin, a commerical antibiotic.

CROSS REFERENCE This application is a continuation-in-part of our prior application, Ser. No. 806,211, filed Mar. 11, 1969.

INTRODUCTION This invention relates to the production of cephalosp orin compounds from penicillin sulfoxides. More particularly, this invention provdes a process for convertng 2 -(C to C alkanoyloxy)methyl-Z-methyl penicillin sulfoxides, either as the acid or in ester form to a steric configuraton containing the sulfoxde oxygen and the free Z-methyl group of the penicillin from which configuration the 2-(C to C alkanoyloxy)methyl-Z-methyl penicillin sulfoxide can be converted to a 3-alkanoyloxymethyl cephalosporin compound by known methods. The 3-alkanoyloxymethylcephalosporin compounds can be converted by known methods to any of a variety of known cephalosporin C type antibiotics.

BACKGROUND OF THE INVENTION The semi-synthetic production of 7-acylamidodesacetoxycephalosporin antibiotics from penicillin starting materials has become of importance recently due to the proccess invention of Morin and Jackson (U.S. Pat. 3,275,626) who describe and claim a process for converting penicillin sulfoxide esters to desacetoxycephalosporanic acid esters. Various process improvements have been made on the process for improving the yield and ease of operation in manufacturing deacetoxycephalosporin antibiotics from penicillin starting materials. An important antibiotic resulting from those developments is cephalexin, which also can be named as 7-(D-ot-amino-a-phenylacetamido)desacetoxycephalosporanic acid and which is normally used for antibiotic administration purposes as the zwitterion of that acid, although cationic salts such as the sodium and potassium salts and anionic salts such as the hydrochloride can also be used.

However, prior attempts to convert a penicillin sulfoxide to cephalosporin C type antibiotic compounds, e.g., those described in Flynn U.S. Pat. 3,218,318 have been limitedv to conversion of the penicillin sulfoxide ester to the desacetoxycephalosporin ester by the Morin-Jackson process, as improved by subsequent workers in the art and then finding a means for functionalizing the 3-methyl group of the desacetoxycephalosporin ester product. Such functionalization of desacetoxycephalosporin esters has been accomplished according to the invention of Webber and Van Heyningen, described in their applications, Ser. No. 790,866 and Ser. No. 790,842, both filed Jan. 13, 1969, and

in the application parent thereto (Ser. No. 703,523, filed Feb. 7, 1968, now abandoned).

However, to our knowledge, no one has been able to convert a penicillin sulfoxide directly to a cephalosporin C type of compound, such as those described in the Flynn patent above, without the necessity of functionalizing a 3-methyl group of a desacetoxycephalosporin. Those in the cephalosoprin antibiotic art are searching for ways of making 3-alkanoyloxymethylcephalosporin compounds directly from Z-alkanoylated penicillin sulfoxides in order to avoid the necessity of functionalizing the 3-rnethyl group of a desacetoxycephalosporin. Such a process route would permit the ready preparation of commercially available cephalosporin C type antibiotics such as sodium cepha1othin, and cephalosporin C antibiotics such as sodium cephaloridine, without the necessity of fermentation derived cephalosporin C and the 7-aminocephalosporanic acid (7-ACA) therefrom from which chemicals such antibiotics are presently commercially prepared and without the necessity of functionalizing a 3-methyl group of a desaceatoxycephalosporin ester.

Those closely related to the penicillin sulfoxide art have been unable to date to find the chemical and physical conditions which permit the direct conversion of a 2- alkanoylated penicillin sulfoxide to a 2-alkanoyloxymethyl-A -cephalosporin compound. Persons skilled in the art, familiar with the possibilities of this conversion, realize that if such conversion could be accomplished, there would be no need to functionalize the 3-rnethyl group of a desacetoxycephalosporin ester as described above. There is a need in the antibiotic art for simplified methods or processes for converting penicillins to cephalosporin compounds which can be converted to known and new cephalosporin antibiotics.

It is an object of this invention to provide a key step in an overall process for converting a penicillin to a 3- alkanoyloxymethylcephalosporin compound.

It is a more specific object of this invention to provide process conditions for obtaining the required steric configuration of 2-(alkanoyloxymethyl)penicillin sulfoxide which configuration is required for the direct conversion thereof to a 3-alkanoyloxymethyl cephalosporin compound, which can be converted by known means to a cephalosporin antibiotic.

SUMMARY OF THE INVENTION Briefly, this invention provides a process which comprises treating a 2-(C to C -alkanoyloxy)methyl-Z-methyl penicillin sulfoxide acid, or an ester of such acid which is not affected by ultraviolet light, dissolved in an acetone containing medium or an equivalent light energy transfer compound, with ultraviolet light for a time suificient to form a mixture of l-S-2S, l-S-2-R, 1-R-2-S, and 1-R-2-R isomers of Z-(C to C -alkanoyloxy)methyl-Z-methyl penicillin sulfoxide acid or ester.

It has been found according to this invention that the above process conditions will correctly orient both the sulfoxide oxygen and the free methyl group to the alpha or beta cis steric plane. This cis steric plane relationship has been found to be necessary for the successful conversion of such Z-(alkanoyloxy)methyl-Z-methyl penicillin sulfoxide acid or ester to the desired 3-alkanoyloxymethylcephalosporin compound.

DETAILED DESCRIPTION OF THE INVENTION In general, by this invention we have discovered that if one of the two methyl groups bonded to the carbon atom in the 2-position of penicillin sulfoxide obtained from the penicillin is first converted to a 2-(alkanoyloxy) methyl group by methods now known, e.g., by treating the penicillin sulfoxide in ester form with an alkanolic acid anhydride followed by reoxidation to the sulfoxide, the

resulting 2-(alkanoyloxy)methyl-2-methyl penicillin sulfoxide compound can be dissolved in acetone, or an acetone-containing organic solvent, and subjected to the action of light, preferably ultraviolet light for a time sulficient to convert the 2-(alkanoyloxy)methyl-Z-methyl penicillin compound to a mixture of steric configurations. In such steric forms the 2-(alkanoyloxy)methyl-2-methyl penicillin sulfoxide can be converted by known rearrangement procedures directly to a 3-alkanoyloxymethyl cephalosporin compound, which are useful for making cephalosporin antibiotics by procedures now known.

The 2 (alkanoyloxy)methyl 2 methyl penicillin sulfoxide acid or ester starting material has the steric structure wherein R and R are as defined hereinbelow. A specific example of such a starting material is tert-butyl 2-(acetoxymethyl)-2-methyl 6 phenoxyacetamido-penam-3- carboxylate. This steric configuration is not amenable to rearrangement to the corresponding 3 acetoxymethyl cephalosporin ester.

We have discovered that this configuration must be changed to a steric form which will rearrange. This invention provides a process for effecting that steric change.

The steric isomerization of this step of the process of this invention is illustrated by the following general chemical equation:

COOR R or alpha configuration 1-R-2-R Cahn, Ingold, Prelog steric nomenclature system S or beta configuration In the above structural formula denotes a general sulfoxide bond with no limitation on its alpha or beta steric configuration.

refers to the alpha or R configuration of the sulfoxide,

wherein the oxygen angles down from the plane of the penicillin. The sulfoxide configuration refers to the beta of S configuration of the sulfoxide, wherein the oxygen angles up from the plane of the penicillin. The steric relationships of the alkanoyloxymethyl and methyl groups in the four possible epimers are denoted with the same method of writing the bonds.

Isomer II, being a trans isomer, will not rearrange to a cephalosporin. Isomer IV will rearrange to a cephalosporin. Isomer III would rearrange to a cis isomer and convert to a cephalosporin in the rearrangement step which follows the photochemical process of this invention. Isomer I is a cis isomer which should convert to a cephalosporin but has a tendency to re-isomerize to isomer II, which does not rearrange to a cephalosporin.

The process of this invention can be applied to the 2-alkanoyloxymethyl-2-methyl derivatives of a wide variety of penicillin sulfoxides which are readily prepared from prior art penicillins. The 2-alkanoyloxymethyl-2- methyl penicillins must be converted to the sulfoxides prior to treatment in accordance with this invention and preferably are esterified with an ester group which is not affected by ultraviolet light, that is, one that does not undergo a photochemical reaction. The ester group is not required for the ultraviolet light treatment step, but it is desired to protect the carboxyl group in the heat rearrangement step which follows. Alternatively, the penicillin sulfoxide acid can be subjected to the light treatment step, under the conditions described above, and then the product thereof can be esterified by conventional proceduresprior to the heat rearrangement step. This is the preferred method when the desired ester group is sensitive to ultraviolet light. The 2-(alkanoyloxy)methyl-2-methyl penicillin sulfoxide derivatives from a wide variety of penicillins can be effectively treated in accordance with this invention, including benzyl penicillin, n-heptyl penicillin, phenylmercaptomethyl penicillin, and other penicillins readily obtained by known precursor-fermentation methods, described, for example, in Behrens et al. US. Pats. 2,479,- 295 to 2,479,297 and 2,562,407 to 2,562,411 and 2,623,- 876. For economic reasons the preferred penicillins are phenoxymethyl penicillin (penicillin V), phenylacetyl penicillin (penicillin G), and 2-thienylmethyl penicillin. Penicillin nucleus (6-aminopenicillanic acid), 6-APA can also be used successfully, but the 6-amino group should first be protected with an easily removable group, such as carboallyloxy, tert-butoxycarbonyl, benzyloxycarbonyl, triphenylmethyl (trityl), trimethylsilyl, or the like.

5 Preferred 2-(alkanoyloxy)methyl 2 methyl penicillin sulfoxide compounds which can be used in the process of this invention are exemplified by the following structure:

Y a r; s cm o RC o-Nrr-io-o 0101120 d-alk i O=CN'C---CO O R wherein R is C to C -alkyl, benzyl, phenoxymethyl, phenylmercaptomethyl, C to C -alkyloxymethyl, thienylmethyl, furylmethyl, and N-protected-a-aminobenzyl;

-Alkyl has from 1 to 3 carbon atoms; and R is hydrogen, C to C -tert-alkyl, benzyl, benzhydryl, C to C -tertalkenyl or C to C -tert-alkynyl.

It is preferred to apply the process improvement of this invention to the direct conversion of a 2-(C to C -alkanoyloxy)methyl-Z-methyl penicillin sulfoxide ester to the desired corresponding 3-(C to C -alkanoyloxy)methyl cephalosporin ester. In this preferred procedure, a penicillin which has desired acylamido group in the 6-position of the penicillin nucleus is treated with a peracid or other suitable oxidizing agent to convert the penicillin thiazolidine sulfur to the sulfoxide oxidation state, and with an esterifying agent to protect the penicillin carboxyl group with an ester group which can be cleaved after the reaction by treatment with an acid such as hydrochloric acid, trifluoroacetic acid, or by hydrogenolysis in the presence of a hydrogenation catalyst such as palladium or rhodium on a carbon, barium sulfate, or alumina carrier, or by suspending a compound of palladium in the liquid hydrogenation reaction mixture. Examples of easily cleaved ester groups defining R which can be used in the Z-(C to C -alkanoyloxy)methyl-2-methyl penicillin sulfoxide ester starting material include benzyl, benzhydryl, tert-butyl, tert-pentyl, 1,1-dimethyl-2-butenyl, 1,l-dimethyl-2-pentenyl, 1,1-dimethyl 2 propynyl, 1,1-dimethyl-2- butynyl, 1,1-dimethyl-2-pentynyl, and the like.

The 2-(C to C -alkanoyloxy)methyl-Z-methyl penicillin sulfoxide acid or ester is dissolved in acetone, an acetone mixture with tetrahydrofuran, tert-butanol, or a mixture of water and tetrahydrofuran or tert-butanol. Equivalent light energy transfer agents such as methyl ethyl ketone, diethyl ketone, or the like, may be used in place of acetone, but acetone is preferred. The solution is exposed to ultraviolet light for from about 1 to about 24 hours, preferably 5 to 10 hours, depending upon the intensity and distance of the ultraviolet light source.

The light source can be any lamp or light generating device which produces ultraviolet light in the middle ultraviolet (U.V.) range, which is light having wave lengths having from about 2,750 to about 3,800 angstrom units. The light is filtered by conventional methods to remove light wave lengths below about 2,700 angstrom units. Examples of lamps which may be used as light sources for this invention are the medium pressure mercury arc lamps available commercially. The utraviolet light output and operating conditions for several of such lamps are set forth in Photochemistry, by Jack C. Calvert and James N. Pitts, Jr., published by John Wiley and Sons, Inc., New York (1966), Library of Congress Catalog Card Number 65-2428 8, page 691. Suitable glass filtering devices, e.g., in the form of a glass tube or sleeve, can be inserted between the lamp and the reaction mixture vessel to filter light of unwanted wave length. Examples include those glass tubes or sleeves sold under the Pyrez and Corex labels. The reaction vessel can be one which circumscribes the light source. Apparatus for this purpose is commonly available, some examples of which are depicted in the above-cited Photochemistry text.

For efficient operation of the process, oxygen and air are preferably excluded from the reaction mixture during the irradiation thereof. Air exclusion can be maintained by a number of known procedures, e.g., by use of a nitrogen atmosphere or preferably by the passing of an inert Preparation of starting material To a stirred, cooled (0) solution of the methyl 2- (acetoxymethyD-Z-methyl 6 acetamido-penam-3-carboxylate sulfide (6 .0 g., 1.82 10 m.) in ml. CHCl was added dropwise 3.60 g. (1.82 10 m.) m-chloroperbenzoic acid dissolved in 60 ml. CHCl The reaction was allowed to go 18 hours at 40 C. It was then washed with saturated NaHCO NaCl, and dried (Na SO and evaporated under reduced pressure. Crystallization from acetone/hexanes gave 1.84 g. of white crystals M1. 1685-1690 C.

Analysis.Calcd. for C H N O- S (percent): C, 44.07; H, 5.24; O, 32.34. Found (percent): C, 44.91; H, 4.99; O, 32.20.

a 1 percent dioxane=+166.4. IR(CHC13) 1800 cm.- (B-lactam C=O), 1750, 1682, 1450, 1050 (sulfoxide) NMR (CDCI 61.24 (s.3H,CH 2.02 (s.,3H,-O Ac), 2.11

sulfoxide configuration determined from the NMR shielding of the Z-wmethyl relative to the sulfide (16 eps); configuration of the 2-methyl determined by N.O.E. (Nuclear Overmauser Efiects)14 percent N.O.E. between 2,0t Me and H A mixture (490 mg., 1.41 mmole) of methyl 2-acet0xymethyl-Z-methyl 6 acetamido-penam-3-carboxylate-1- oxide in ml. of acetone was placed in a wheel shaped (hollow in the center) reaction vessel fitted with a quartz immersion well in which was placed a 450 watt medium pressure mercury-arc lamp which was surrounded by a Pyrex brand of glass filter sleeve. Helium gas was bubbled through the reaction mixture while irradiation continued for 6 hours. After the photolysis (irradiation) the reaction mixture was evaporated under reduced pressure to remove the acetone. The residue was taken up in benzene and chromatographed on silica gel (Brinkman No. 7729, particle size less than 0.08 mm. diameter, compound/ silica gel ratio 1/ 15 using a gradient system of 1.5 liters of benzene and 1.5 liters of ethyl acetate. The products isolated consisted of (1) 190 mg. of a mixture of in a ratio of 65 percent by weight of isomer (c) to 35 percent by weight of isomer (d). About 415 mg. of the starting material weight was recovered in the above four products. These isomeric fractions Were rechromatographed to isolate the pure epimers. In the above Formulas (b), (c), and (d), the left hand portion of the methyl methyl penicillin sulfoxide ester is omitted to pinpoint the steric configurations involved in this invention and because those portions of the structures are not essential to this invention.

A mixture of mg. of methyl 2-acetoxymethyl-2- methyl-6-phenoxyacetamido-penam 3 canboxylate-loxide having the steric configuration as indicated in column 3, in 190 ml. of acetone was photolyzed as in Example 1 to give a mixture of isomers of the same penicillin sulfoxide ester but having the above-indicated steric isomer variation, namely (a) l-S, 2-S, (b) l-S, 2-R, (c) l-R, 2-8, and (d) l-R, 2-R. The isomer mixture was separated from the photochemical reaction mixture as described in Example 1 and then separated one from the other by silica gel thin layer chromatography using a 3:1 v./v. ethyl acetatezbenzene mixture as the eluting solvent.

The steric isomers of the ultraviolet light treated penicillin sulfoxide product can be used in the corresponding 3-(C to C -alkanoyloxymethyl)-A -cephalosporanic acid compounds by known penicillin sulfoxide ester rearrangement procedures. For example, if the steric isomer penicillin sulfoxide product is in acid form, it can be converted to an ester form with an easily removable ester-forming alcohol, such as alcohols of the radicals defining R above, the 6-acylarnido group can be removed by known procedures, and replaced with an imide forming group by N-alkylation procedures, e.g., as described in US. Pat. No. 3,311,621, or by Schitfs base formation, and then rearranged in the presence of a catalyst, as described, for example, in US. Pat. 3,275,626. Preferred conditions for this penicillin sulfoxide ester rearrangement now contemplated are to dissolve the product containing the cis oriented 2-(C to C -alkanoyloxymethyl)-2-methyl penicillin sulfoxide ester in a tertiary carboxamide containing solvent system, using a sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid as the acid medium, and providing a means, either chemical or physical, or both, for removing water from the reaction mixture during the rearrangement operation. A Water-azeotrope-forming liquid such as benzene, dichloroethane, or the like, which can be part of the solvent system provides a good means for removing Water in the proper equipment such as a Dean-Stark or Barret type of water trap or the like to separate the water layer from the azeotropic liquid. The reaction mixture is usually heated to from 80 C. to C. for from 1 to about 24 hours. When the rearrangement has been completed, the ester group can then be removed by treatment with an acid such as hydrochloric acid or trifluoroacetic acid, or as in the case of some such compounds, by hydrogenation of the re-acylated product in the presence of palladium or rhodium on a carrier such as carbon, barium sulfate, alumina, or the like, to form antibiotic compounds. An example of a known Cephalosporin C type antibiotic which can be prepared from the cis oriented 2-(C to 4-alkanoyloxymethyl)-2-methylpenicillin sulfoxide acid or ester is cephaloglycin [3-acetoxymethyl 7 (D-a-amino a phenylacetamido)-A cephem-4-carboxylic acid] which is normally used in the zwitterionic or inner salt form. Other antibiotically active compounds which can be prepared include:

3 propionoxymethyl 7 phenoxyacetamido A cephem-4-carboxylic acid from the 2-(propionoxymethyl)- 2-methyl-penam-3-carboxylic acid, or an ester thereof, and 3-butanoyloxymethyl-7-(D-a-amino-u-phenylacetamido) -A -cephem-4 carboxylic acid in the zwitterionic form from a 2-(butanoyloxymethyl)-2-methyl-penam-3-carboxylic acid, or ester variant.

Specific penicillin, penicillin sulfoxide, and penicillin sulfoxide ester starting materials and products have sometimes been named herein using the penam nomenclature for the penicillins as described by Sheehan, Henery-Logan, and Johnson in the I. Am. Chem. Soc., 75, p. 3293, footnote 2 (1953). In accordance with these systems of nomenclature, penam refers to the following saturated ring structures:

1 6 S 2 P t E 1 O=CNCHZ Penam By this nomenclature system, one of the sources of starting materials for this invention, penicillin V, is named 2,2- dimethyl-6-phenoxyacetamido-penam 3 carboxylic acid. The 2-(C to C -alkanoyloxymethyl)-2-methyl penicillin starting materials can be prepared, e.g., by reacting the penicillin sulfoxide acid or ester with the C to C -alkanoic acid anhydride as described, for example, in U.S. Pat. 3,275,626 and allowed application, Ser. No. 491,832 filed Sept. 30*, 1965, now U.S. Pat. 3,466,275.

We claim:

1. A process which comprises treating with ultraviolet light in an acetone-containing medium a 2-C to Ca -alkanoyloxy)methyl-2-methyl penicillin sulfoxide acid or an ester thereof which ester group is not afiected by ultra violet light for a time sufficient to form a mixture of 1-8 2-S, l-S 2-R, l-R 2-S, l-R 2-R isomers of 2-(C to C -alkanoyloxy)methyl penicillin acid or ester.

2. A process as defined in claim 1 wherein the 2-(C to C -alkanoyloxy)-2-methyl penicillin sulfoxide compound has the formula wherein R is C to C -alkyl, benzyl, phenoxymethyl, phenylmercaptomethyl, C to C -alkyloxymethyl, thienylmethyl, furylmethyl, an N-protected-a-aminobenzyl, alkyl has from 1 to 3 carbon atoms, and R is hydrogen, C to C -tert-alkyl, benzyl, benzhydryl, or C to C -tert-alkynyl.

3. A process as defined in claim 2 wherein the 2-(C to C -alkanoyloxymethyl)-2-methyl penicillin sulfoxide compound is methyl 2-acetoxymethyl-2-methyl-6-acetamido-penam-3-carboxylate-l-oxide so that after the ultraviolet light treatment in the acetone medium, there is formed a mixture of isomers of methyl 2-acetoxymethyl- 2-methyl-6-acetamido-penam-3-carboxylate-l-oxide having the l-R, 2-R, l-R, 2-S, l-S, 2-R, and 1-8, 2-S orientations.

4. A process as defined in claim 2 wherein the 2-(C to C -alkanoyloxymethyl)penicillin sulfoxide compound is methyl 2 acetoxymethyl 2 methyl 6 phenoxyacetamido penam 3 carboxylate 1 oxide so that after the ultraviolet light treatment in the acetone me dium, there is formed a mixture of isomers of methyl 2 acetoxymethyl 2 methyl 6 phenoxyacetamidopenam 3 carboxylate 1 oxide having the l-R, 2-R, l-R, 2-S, 1-S, 2-R, and 1-5, 2-S orientations.

5. In a process for converting a penicillin sulfoxide ester to a cephalosporin ester, the improvement which comprises l) exposing to ultraviolet light in the presence of acetone a 2-(C to C -alkanoxymethyl)-2-methyl penicillin sulfoxide acid or an ester thereof which ester group is not affected by ultraviolet light for a time sufficient to form a mixture of 1-5, 2-S 1-S, 2-R, l-R, 2-S, l-R, 2-R isomers of the methyl penicillin sulfoxide acid or ester.

References Cited UNITED STATES PATENTS 3,275,626 9/1966 Morin et a1. 260243 HOWARD S. WILLIAMS, Primary Examiner

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4348264 *Feb 9, 1981Sep 7, 1982Pfizer Inc.Photocatalyzed process for producing carbapenams and carbapen-2-ems
U.S. Classification204/157.7, 204/912, 204/900
International ClassificationC07D499/44, B01J19/12, C07D499/00
Cooperative ClassificationC07D499/00, B01J19/123, Y10S204/912, Y10S204/90
European ClassificationC07D499/00, B01J19/12D2