WO2009129662A1

WO2009129662A1 - Process for preparation of 7-phenylacetamido-3-chloromethyl-3-cephem-4- carboxylic acid p-methoxybenzyl ester

Info

Publication number: WO2009129662A1
Application number: PCT/CN2008/001019
Authority: WO
Inventors: 莫章桦; 张世喜; 潘向东; 刘和平; 谢维礼; 雷良平; 陶小玲; 刘超; 李涛
Original assignee: 湖南有色凯铂生物药业有限公司
Priority date: 2008-04-21
Filing date: 2008-05-26
Publication date: 2009-10-29
Also published as: CN101260116A

Abstract

A process for the preparation of 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester(GCLE), comprises the steps of: reacting penicillin G potassium salt with 4-methoxybenzyl chloride to obtain penicillin G 4-methoxybenzyl ester; oxidizing with peracetic acid to obtain penicillin G sulfoxide p-methoxybenzyl ester; treating with 2-mercaptobenzothiazole, followed by phenylsulfinic acid, to obtain a ring-opening intermediate; further treating with chlorine gas to obtain a chlorinated product; and ring-closing in the presence of ammonia gas to obtain 7-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (GCLE).

Description

Method for synthesizing 7-phenylacetamide-3-chloromethyl-4-ceporanoic acid p-oxyl benzyl ester

The invention relates to a method for synthesizing a cephalosporin antibiotic intermediate 7-phenylacetamide-3-chloromethyl-4-cephalosporanic acid p-oxyl benzyl ester (GCLE), belonging to the technical field of drug production. Background technique

The cephalosporin intermediate represented by the following formula is an important compound for synthesizing various cephalosporins, and is mainly used for preparing synthetic raw materials of cephalosporin drugs having different 7-position side chains and 3-position different substituted sulfhydryl groups. .

Production of semi-synthetic cephalosporins by GCLE, such as: cefaclor, cefazolin, cefmendo, ceftazidime, cefotidin, cefepime, cefpirome, etc., with high yield and simple process, The advantages of low cost, etc., therefore greatly replace the 7-ACA trend.

The synthesis of GCLE is mainly based on penicillin and is synthesized by two methods: (1) halogenation after ring expansion; (2) chlorination before ring expansion. There are many reports on the (1) method in the domestic and foreign literatures, and few studies on the (2) method. The synthesis technology of GCLE is very difficult. Although there are some progress in the research of synthetic technology in China, the cost is still high and the quality is not good. Therefore, research and development techniques that are simple, low-cost, high-quality, and suitable for large-scale industrial production have become a top priority.

Summary of the invention

The technical problem to be solved by the present invention is to solve the above problems in the prior art and provide a 7-phenylacetamide-3- which is more suitable for large-scale industrial production and higher product quality. A method for the synthesis of p-chlorobenzyl ester (GCLE) of chloromethyl-4-cefradanoic acid.

The technical scheme of the present invention is: using penicillin G potassium salt as a starting material, firstly reacting with p-methoxybenzyl chloride to obtain p-methoxybenzyl ester; and then using peroxyacetic acid to oxidize to obtain penicillin sulfoxide; The penicillin sulfoxide ester first reacts with 2-mercaptobenzothiazole and then with benzenesulfinic acid to obtain a ring-opening product; the ring-opening product and chlorine gas act to obtain a chlorination product; the chlorination product is closed under the action of ammonia gas. 7-Phenylacetamide-3-chloroindolyl-4-cephalosporin p-oxobenzyl ester (GCLE) was obtained. It includes the following steps:

(1) The penicillin G potassium salt and p-methoxybenzyl chloride are placed in a mixed solvent of an organic solvent and water, and the organic solvent used is N,N-dimercaptocarboxamide (DMF), N, N-di a mixture of one or more of mercaptoacetamide (DMAC), acetonitrile, tetrahydrofuran, dissolved and esterified, and esterification is carried out at -10 ° C - 100 ° C to obtain an esterified product (11) .

(2) The esterification product (Π) is dissolved in an organic solvent, and the organic solvent used is a mixture of one or more of ethanol, decyl alcohol, terpene benzene, diphenylbenzene, DMF and DMAC, dissolved and used with peracetic acid Oxidation gives the oxidation product (Ι Π). The peracetic acid used was at a concentration of 8% to 40%.

(3) The oxidation product (III) is dissolved in an organic solvent, and the organic solvent used is a mixture of one or more of ethanol, decyl alcohol, terpene benzene, diphenylbenzene, acetonitrile, tetrahydrofuran, acetone, DMF and DMAC. Dissolving and adding 2-mercaptobenzothiazole followed by benzenesulfinic acid gave the ring-opened product (IV). The concentration of benzenesulfinic acid used is from 10% to 50%.

(4) The ring-opening product (IV) is dissolved in an organic solvent, and the organic solvents used are carbon tetrachloride, dioxane, ethanol, decyl alcohol, toluene, diphenylbenzene, acetonitrile, tetrahydrofuran, DMF and DMAC. Mixing one or more of them, dissolving and introducing chlorine gas to obtain a chlorinated intermediate, distilling off the solvent, then adding DMF or DMAC to dissolve, and then adding a saturated DMF solution of ammonia to obtain ⁷ -phenylacetamide- 3-Chloromethyl-4-cephalosporanic acid p-oxybenzyl ester (GCLE).

The synthetic route of the present invention is shown in Figure 1. The penicillin sulfoxide ester is prepared from penicillin potassium salt. Different reaction sequences can be used for esterification and oxidation reaction. Since the stability of penicillin ester is stronger than that of penicillin acid, it is preferred to oxidize after esterification. In the present invention, The esterification of step (1) is carried out first, followed by the oxidation of step (2).

In the step (1) of the present invention, after the esterification of the penicillin G potassium salt and the p-methoxybenzyl chloride, it is necessary to extract the hydrazine with a suitable organic solvent, and on the one hand, the penicillin G potassium salt which is not completely reacted can be removed. The inorganic salt to be produced, on the other hand, can also remove the organic solvent used in the step (1), and the organic solvent used can be recovered and reused by distillation.

For the esterification product (II), 30% -35 % H ₂ O ₂ can be used as an oxidizing agent; it can also be oxidized with an inorganic oxidizing agent and an organic peroxide such as manganese dioxide, sodium periodate, peracetic acid, m-chloro The corresponding penicillin sulfoxide carboxylate is obtained by oxidation of benzoic acid or the like. In the present invention, in the step (2), the peroxidic acetic acid oxidation method is employed, and the operation is convenient and the conversion is complete.

In the conventional method, the commonly used ring opening reagents are NBS, NCS and N-halogen reagents, and the present invention uses 2-mercaptobenzothiazole to open a ring and then convert to a benzenesulfinic acid intermediate.

The invention adopts direct chlorination of chlorine gas, which not only makes the reaction yield higher, but also facilitates the operation and control of the reaction.

Compared with the prior art, the invention has the advantages of short synthetic route, low cost, high product yield, stable product quality, convenient operation and convenient industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1 is a synthetic route diagram of the present invention (GCLE)

2 is a high pressure liquid chromatogram of a product (GCLE) of Example 1 of the present invention;

Figure 3 is a high pressure liquid chromatogram of the product of Example 2 of the present invention (GCLE)

detailed description:

The content of the present invention will be further explained below in conjunction with specific embodiments.

Example 1 (1) Synthesis of penicillin versus benzyloxybenzyl ester (π)

Weigh 100g of penicillin industrial salt, add 200mL of DMF and 200mL of purified water to dissolve, add 60g of p-methoxybenzyl chloride and 4g of tetrabutyl bromide, heat to reflux, then react at this temperature for 4 hours, cool to room temperature, use The indole Benzene 3 χ 150 mL was extracted, and the combined extracts were added and dried for 2 hours, and the obtained product was used for the oxidation reaction without isolation, yield 97%.

(2) Synthesis of penicillin G sulfoxide versus benzyloxybenzyl ester (III)

The obtained esterified solution was poured into a three-necked flask, and 100 mL of anhydrous decyl alcohol was added thereto. The temperature was controlled at 10-15 ° C, 150 mL of 15% peroxyacetic acid was added dropwise, and the reaction was kept for 20 hours. After the reaction was completed, the temperature was lowered to 0 ° C. First, wash twice with 200 mL of purified water, then wash twice with 200 mL of 10% sodium hydrogen citrate solution, then dry with anhydrous magnesium sulfate for 2 hours, then distill off the solvent under reduced pressure, and add the residue to anhydrous decyl alcohol. After lOOmL, a large amount of solid was precipitated, and the mixture was stirred under TC overnight, and crystals were filtered, washed with a small amount of cold methanol to give 118 g of white crystals, yield 93%. mp150-151 ° C _o IR (KBr) υ (cm" ¹ ) : 3359 (-NH-), 1796 (β-lactam C=0), 1745 (ester 00), 1687 and 1515 (amide C= 0), 1035 (-SO-).

(3) Synthesis of ring-opening product azabutanone sulfinic acid intermediate (IV)

Weigh the compound (ΙΠ) 4 Og, add 1500 mL of decene and 20 g of 2-mercaptobenzothiazole, heat to reflux, then react at this temperature for 10 hours, cool to room temperature, concentrate the solvent to dryness, then add 1500 mL of acetone to dissolve, then 60 g of 20% benzenesulfinic acid was added, and the mixture was reacted at room temperature for 6 hours, and then cooled to room temperature. The solvent was evaporated under reduced pressure to give a solid, which was washed with 100 mL of cold anhydrous methanol to give 40 g of white crystals, yield 78%. m. p. 115-117 ° C.

(4) Synthesis of GCLE

20 g of the compound (IV) was weighed, dissolved in 500 mL of dioxane, and the temperature was controlled at 10 to 15 ° C, 12 g of chlorine gas was introduced, and the reaction was carried out at this temperature for 1 hour. Concentrated to dryness under reduced pressure, the obtained chloro intermediate was dissolved in 200 mL of DMF, then cooled to -10 ° C, and DMF saturated with ammonia was added dropwise with stirring. The solution was 300 mL. After the addition, the reaction was carried out at -10-15 ° C for 1 hour. Then, the temperature was raised to 0 ° C, the activated carbon was decolorized for 30 minutes, and the activated carbon was removed by filtration. The mother liquid was added dropwise with 100 mL of purified water under stirring, and the white crystals were precipitated, and the mixture was kept for 2 hours, and filtered to obtain a solid vacuum dried for 6 hours to obtain a GCLE crystal llg, purity 96.8. % (HPLC, Figure 2) yield 70%. Mp160 °C.

Example 2

(1) Synthesis of penicillin versus benzyloxybenzyl ester (Π)

Penicillin industrial salt weighed 150g, 300mL of purified water and added 30QmLDMF dissolved, ⁹ 0g of Yue-chlorobenzyl group and 6g tetrabutyl press, heated to reflux, and reacted for 4 hours at this temperature, cooled to room temperature, The mixture was extracted with terpene benzene 3 x 230 mL, and the combined extracts were dried for 2 hours to give a yield of 96.5%.

(2) Synthesis of penicillin G sulfoxide versus benzyloxybenzyl ester (ΠΙ)

The obtained esterified solution was poured into a three-necked flask, 150 mL of anhydrous decyl alcohol was added, the temperature was controlled at 10-15 ° C, 230 mL of 15% peroxyacetic acid was added dropwise, and the reaction was kept for 20 hours. After the reaction was completed, the temperature was lowered to 0 ° C. First, wash twice with 300 mL of purified water, and then use 300 mL of 10 °/. The sodium hydrogen sulfite solution was washed twice, and then dried over anhydrous magnesium sulfate for 2 hours. The solvent was evaporated under reduced pressure, and the residue was evaporated to ethyl alcohol (150 mL) to give a solid solid, which was stirred at 0 ° C overnight and filtered. Crystallization, washing with a small amount of cold methanol afforded 175 g of white crystals. Mp150-151°C _o IR(Br) υ (cm ^-1 ): 3359 (-NH-), 1796 (β -lactam C=0) , 1745 (ester C=0) , 1687 and 1515 (amide C= 0 ), 1035 (-SO-).

60 g of the compound (III) was weighed, 2250 mL of terpene and 30 g of 2-mercaptobenzothiazole were added, and the mixture was heated to reflux, and then reacted at this temperature for 10 hours, cooled to room temperature, and the solvent was concentrated to dryness, then dissolved in 2250 mL of acetone, and then added. 90 g of 20% benzenesulfinic acid, reacted at room temperature for 6 hours, then cooled to room temperature, and the solvent was distilled off under reduced pressure to give a solid which was washed with 150 mL of cold anhydrous methanol. Polyester, 61 g of white crystals were obtained in a yield of 79.3%. m. ρ· 115- 117 ° C. (4) Synthesis of GCLE

24 g of the compound (IV) was weighed, dissolved in 600 mL of dioxane, and the temperature was controlled at 10 - ¹⁵ ° C, 15 g of chlorine gas was introduced, and the reaction was carried out at this temperature for 1 hour. The organic intermediate was dissolved in 240 mL of DMF, then cooled to <RTI ID=0.0>> After the addition, the reaction was carried out at -10 - 15 ° C for 1 hour. Then, the temperature was raised to (TC, activated carbon for 30 minutes, and the activated carbon was removed by filtration. The mother liquor was added dropwise 120 mL of purified water under stirring, and white crystals were precipitated, and the mixture was kept for 2 hours, and filtered to obtain a solid vacuum-dried for 6 hours to obtain 13.3 g of GCLE crystals, and the purity was 96.2. % (HPLC, Figure 3) Yield 70.5 ° / mp l 60 ° C.

Claims

Rights request

A method for synthesizing 7-phenylacetamide-3-chloromethyl-4-cephalosporanic acid p-oxyl benzyl ester, characterized in that it comprises the following steps:

(1) The penicillin G potassium salt and the p-methoxybenzyl chloride are placed in a mixed solvent of an organic solvent and water, and the organic solvent used is hydrazine, hydrazine-dimethylformamide (DMF), hydrazine, hydrazine-II. a mixture of one or more of mercaptoacetamide (DMAC), acetonitrile, tetrahydrofuran, dissolved and esterified, and the esterification reaction is carried out at -10 ° C - 10 (TC) to obtain an esterified product (Π) ;

(2) The esterification product (Π) is dissolved in an organic solvent, and the organic solvent used is a mixture of one or more of ethanol, decyl alcohol, terpene benzene, diphenylbenzene, DMF and DMAC, dissolved and used with peracetic acid Oxidation, the oxidation product (III) is obtained; the peroxyacetic acid concentration used is 8% to 40%;

(3) The oxidation product (Ι Π) is dissolved in an organic solvent, and the organic solvent used is a mixture of one or more of ethanol, methanol, toluene, diphenylbenzene, acetonitrile, tetrahydrofuran, acetone, DMF and DMAC, dissolved Further, 2-sulfenylbenzothiazole is added, followed by the addition of phenylsulfinic acid to obtain a ring-opening product (IV). The concentration of benzenesulfinic acid used is from 10% to 50%;

(4) The ring-opening product (IV) is dissolved in an organic solvent, and the organic solvent used is carbon tetrachloride, dioxane, ethanol, decyl alcohol, toluene, diphenylbenzene, acetonitrile, tetrahydrofuran, DMF and DMAC. One or several kinds of mixtures, dissolved and passed into chlorine gas to obtain a chlorinated intermediate, distilled off the solvent, then dissolved in DMF or DMAC, and then added with ammonia-saturated DMF solution to obtain 7-phenylacetamide-3 _Chloromethyl-4-cephalosporanic acid p-oxybenzyl ester (GCLE).