SU703023A3 - Method of preparing 3-acyloxymethyl-delta-2-cephems - Google Patents

Description

(54) METHOD FOR OBTAINING 3-ACYLOXIMETHYL-D-CETHEMES

.. I

The invention relates to a new (method for the preparation of 3-acyloxymethyl-D-cephems, is an intermediate product in the production of antibiotics of the cephalosporin series.

A method of producing 3 .- (functionally substituted methyl) -D-cephemes is known, which consists in the fact that 3-bromomethyl-d2-cephemes are reacted with an appropriate nucleophilic agent, in particular, to obtain 3-acyloxymethylpolymers with an acylurulent agent.

The original 3-bromomethyl proeideas obtainment by bromination of the corresponding 3-methyl-D-cefems, and the latter, in turn, are obtained by isomerization of 3-methyl-D-cephems 1.

The 7-acyl amide dodecetoxycephalosporins themselves are obtained from penidillins in two stages: oxidation of penicillins to the corresponding sulfoxides and subsequent transformation of penicillin sulfoxide.

The disadvantage of this method is the complexity and multistage of the process, since the starting products are obtained from the most abundant raw material - penicillins in five stages.

The aim of the invention is the simplification of the process and the recovery of the raw material base of the starting materials for the synthesis of 3-acyloxymethyl-cephemes.

This goal is achieved by the method of obtaining 3-acyloxymethyl-D-cephems of the general Aormula

rt

Rj-CONft-if n

(H2-0-C-R2;

COORi

where r | - p-nitrobenzyl or 2,2,2-trichloroethyl;

Rg -, -alkyl and

R, is benzyl, p-nitrobenzyloxy, phenoxymethyl. or 2-t.iylmathyl, which is that the sulfoxide of the 3-exomethylenecepham of the general formula

Bj-cotjh

CHj COORi

where R ,, and Rj have the above

30 values, is reacted with a mixture of an acyl compound of the general formula. . : R, where R, j has the indicated value and X is xjfop or hydroxy group, and the corresponding anhydride of the general formula (R;, 0) 0, where Rjj is the same as the molar ratio between sulfide oxide 3-exomethyleneceram and anhydride 1 ; 1-10 at a temperature of 8–5–140 ° C. The starting sulfoxide 3-indomethylene of tsofam is obtained from the sulfoxide of the corresponding penicillin by treating N-haloI 151M with a medium, for example, s-54 chlorosuccinimide or N-chloroftapimide, in a medium of dry inert solvent. for example, 1,1,2-trichloroethane or toluene, at 75-135 ° C, followed by treatment of the resulting azetidin sulfonyl chloride with a catalyst such as Lewis acid or Friedel Crafts in a dry, inert organic solvent. Example 1. To 5 ml of fresh acetic anhydride, 500 m (1 mmol) of p-nitrobenzyl-7-phenoxy-acetamido-3-methylene cepha-4-carboxylate-1-oxide and then 1 drop of acetic chloride are added. The mixture is heated under reflux at 130-140 ° C for 2.75 hours, cooled, ethyl acetate is added and the mixture is washed with an aqueous solution of sodium bicarbonate, then with water. The organic layer is separated and evaporated to give p-nitrobene.-7-phenoxyacetamido -3-acetoxymethyl-2-cephem-4-carboxylate as a spongy mass, NMR spectrum (CDCCi), 2.00 (S, 3N, acetoxy); 4.53 (s, 2H, -OCHJ.NH-); 4.70 {d, 1H, P 4.5 Hz, Ce-H); 5.73 (d, 1H, 3 4.5 Hz, Cr-H); 5.13 (bS, 1H, C4.-H); 6.50 (bS, 1H,); 5.20, 5.33 {2S, 1H + 1H,); 6.75-7.30 (t, 5H, phenoxy) f 7.50; 8.13 (2d, 2H + 2H, B, D - 9 Hz, nitrobenzylcarboxylate). Example 2. To 10 ml of benzene, 500 mg (1 mmol) of p-nitroben zil-7 -phene siachtamido-3-methylene cepam-4-carboxylate-1-oxide was added, then 2 ml of acetic anhydride and 2 drops of acetyl chloride, Heat at reflux at about 15 h. The mixture is treated as in Example I obtained half p-nitrobenzyl-7-phenoxy-acetamido-3-acetoxymethyl-2-cephem-4-carboxylate. Example 3. To 10 ml of dry toluene was added 500 mg (1 mmol) of p-nitrobenzyl-7-phenoxyacetamido-3-. -methylphenyl-4-carboxylate-1-oxide, then 2 ml of acetic anhydride and 2 drops of acetyl chloride, heated for 18 hours under reflux at 110-112 ° C, the mixture is treated as in example 1, and get p-nitrobenzyl-7- phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate, along with a minor amount of the corresponding d-isomer. Example 4. K10 ml of dry toluene was added 500 mg (1 mmol) of p-nitrobenzyl-7-phenoxyacetamido-3-methylene cepha-4-carboxylate-1-oxide, 2 ml of acetic anhydride and 0.071 ml (1.equivalent, calculated as cefamsulfoxide) acetyl chloride. Heated for 5 hours with i (reflux condenser at 111 ° C. P-nitrobenzyl-7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate is obtained together with a small amount of the corresponding d-isomer. Example b, cjjie sy 33 ml 8 g (12 mmol) p-nitrobenzyl-7-phenoxyacetamido-3-methylene cepha-4-carboxylate-1-oxide are added with acetic anhydride and 66 ml of acetic anhydride, kept under a slow pass of a stream of nitrogen and heated under reflux (about) , The progress of the reaction is controlled according to thin-layer chromatography (those) on silica gel in system b nzol-ethyl acetate (1: 1), the reaction ends after about 2.5 hours. The resulting reddish solution is evaporated to a dark resinous mass, which is dissolved in 50 ml of ethyl acetate. The solution is washed with 3x50 ml of sodium bicarbonate solution and 50 ml of saturated solution sodium chloride, dried over magnesium sulfate, treated with activated carbon and filtered through silica gel. The filtrate is evaporated to give 5.8 g (89%) of a mixture (3: 1) of p-nitrobenzyl-7-phenoxy-edetamido-3-acetoxymethyl-2-cephem- 4-carboxylate and p-nitrobenzyl-7-phenoxy; Etamido-3-acetoxymethyl-3-cephem-4-carboxylate as a light yellow spongy mass,. . ., NMR spectrum of a mixture (CDCfj) / o-6.5 (wide S, 0.75, A-C); 5.8 (dd, 1, Su-H); 4.6 (s, 2, cy, methylene); 3, e (wide S, 0.5,); 2.12, 2 (SS, 3, D and A-C3-acetoxy).; Examples 6-10, Repeat. Example 5, using different amounts of reagents. The results are shown in the table. Example 11. To a mixture of 5 ml of acetic anhydride and 20 ml of acetic acid are added 600 mg of 2,2,2-trichloroethyl-7- (p-nitrobenzyloxycar6-nylamino) -3-methylene cephamide-4-carboxylate 1-oxide, stirred bh at , cooled and the solvent is evaporated. The residue is dissolved in ethyl acetate, the solution is washed with a saturated aqueous solution of bicarbonate on ry, dried over silica gel, and 100 mg of a mixture (6: 1) of 2,2,2-trichloroethyl-7- (p-nitrobenzyloxy-bonylamino) -3-acetoxymethyl- is obtained. 2-cephem, -4-carboxylate and 2,2,2-trichloroethyl-7- (p-nitrbbeneyloxycarbonylamino-3-a-methoxymethyl-3-cephem-4-carboxylate lat. NMR spectrum (s: b, 45 (shee rock S, 0.83,); 4.75 (S, 2, trichloroethyl); 4.65 (wide S, 1.66 D -C methylene); 3.5 (wide S, 0.34,); 2, 10-2.15 (broad S 3, D-and A-c, - acetone si),; P and me r 12. To a mixture of 5 ml of acetic anhydride and 20 ml of acetic; Acids 600 mg of p-nitrobenzyl-7- (2-thienylacetamido) -3-methylene cepha-4-carboxylate-1-oxide are added, the mixture is stirred for 4 hours at 110 ° C, cooled, evaporated and the resulting residue is dissolved in ethyl acetate. washed with an aqueous solution of sodium bicarbonate, suspended over magnesium sulfate, evaporated and the residue chromatographed on silica gel to obtain 110 g of p-nitrobenyl-7- (2-thienylacetamido) -3-acetoxymethyl-2-cephem-4-carboxylate. NMR spectrum () / o: 6, 4 (wide S, 1,); 5.6 (dd, 1, Cr-H 4.6 (broad S, 2, Cj-methylene); 3.8 (S, 2, St-methylene) 2.05 (S, 3, € 3-acetoxy) Example 13. To a mixture of 5 ml of propionic anhydride and 20 ml of pro: tiHOHOBoft acid is added 600 mg of p nitrobenzyl-7-phenoxyacetamido-3-methylene cephamic-4-carboxylate-1-oxide is stirred for 6 hours at 130 s, cooled and the solvent is removed The residue is dissolved in 150 ml of ethyl acetate, the solution is washed with saturated aqueous sodium bicarbonate solution, dried over silica gel. And 166 mg of p-nitrobenzyl-7-phenoxy-acetamido-3-propionyl-kaimethyl-2-cef (and, 4-carboxylate are obtained. NMR -spectrum (ATP h), - 6.45 (shiR01 a S, 1, D-Cd); 5.7 (dd, 1, Cf-K); 2.3 (q, 2, methylene, propionyloxy groups); and 1.1 ( t, 3, methyl propionyloxy groups) f Example 14. To a mixture of acetic anhydride and acetic acid, p-nitrobenzyl-7-f8Nylaceta mido-3-methylene cephamic-4. -carboxylate | -1-oxide is added, heated and mixed for some time, then eatembhlouyot and evaporated to dryness. The residue is: in ethyl acetate and the product is purified as indicated in the preceding; P-nitrobenzyl-7-phenylacetamido-3-acetoxymethyl-2-cefam-4-carboxylate is obtained. ; Example 15. Obtaining sulfoxide D -isomer from d-isomer. To 170 ml of methylene chloride was added .5.65 g of p-nitrobenzyl-7-phenoxy-acetamidO-3-acetoxymethyl-2-cephem-4-carboxyllate silate and 20 ml of isopropyl alcohol, | cooled to, quickly, dropwise, added a solution of 2.12 g of 85% technical m-chloroperbenzoic acid in 55 ml of methylene chloride. The course of the reaction is controlled according to those. After 45 minutes, the methylene chloride layer is washed with 3x100 ml of an aqueous solution of sodium chloride, lined up with magnesium sulphate, treated with activated carbon, cooled in an ice bath, and petroleum ether is gradually added. 4.39 g (76%) of p-nitrobenzyl-7-phenoxy-acetamido-3-acetoxymethyl-3-cephem-4-carboxylate-1-oxide are obtained, m.p. 187-188 ° C. Calculated,%: C 53.86; H 4.16; N 7.54; O 28.70; S 5.75. SL5 23 NjOjo S. Found,%: C 53.67; H 3.89; N 7.29; O 28.45; S 5.38. 15. Getting D Isoprimer. 2.70 g of sulfoxide from the previous example is added to 75 ml of M, M-dimethylformamide, cooled to

(-80) C and immediately add 1.6 ml of phosphorus trichloride. The mixture is stirred at -80 ° C for 10 minutes, heated to 0 ° C using an ice bath, stirred for 25 minutes, and the resulting orange solution is poured onto ice. The precipitate was filtered off, washed thoroughly with water and dried to give 2.35 g (89.5%) of p-nitrobenzyl-7-phenoxy-Cetamido-3-acetoxy Methyl-3-cephem-4-carboxylate,

NMR spectrum (CDC-Ej-d 1-methyl sulfoxide, 131), (: 2.03 (S, 3N, acetoxy) 3.50 (6S, 2H, - S -) 4.53 (S, 2H O-SND, - KH-); 4.90 (d, 1H, J 4.5 Hz, Cg-H); 5.90 (d, IH, and 4.5 Hz); 5.20, 5.30 J2S, 1H + 1H, acetoxymethyl): 5.33 (S, 2H, nitrobenzyl) J 6.77-7.40 (t, 5H, fenxy); 7.53; 8.17 (2d, 2H + 2H, AB, 9 Hz, nitrobenzyl);

Claims (1)

1. US patent No. 3637678, cl. 260-243 C, published, 1972.