CN108588164A - The preparation method of cefozopran hydrochloride - Google Patents

Abstract

The invention discloses a kind of synthetic methods of cefozopran hydrochloride; using GCLE as starting material; GIMPE intermediates are condensed to yield with Imidazopyridazine under iodide; it hydrolyzes to obtain 7 ACP through phenol hydrolysis and immobilized penicillin acylated enzyme, 7 ACP are condensed to yield azoles orchid alkali crude product with azoles orchid active ester, and crude product obtains cefozopran hydrochloride with hydrochloric acid after DMF is recrystallized at salt; this method is easy to operate; condition is easily-controllable, is easy to industrialized production, is with a wide range of applications.

Description

The preparation method of cefozopran hydrochloride

Technical field

The present invention relates to a kind of synthetic methods of cefozopran hydrochloride.

Background technology

Cefozopran hydrochloride is the forth generation cephalosporin researched and developed at first by Japanese Wu Tian companies.Nineteen ninety-five with The trade name of Firstcin is listed in Japan for the first time.The route of compound patent US4864022 be using 7-ACP as starting material, It is condensed with 2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- methoxyimino acetic acid under phosphorus pentachloride effect and generates azoles orchid Then alkali obtains cefozopran hydrochloride with hydrochloric acid at salt, route is as follows：

Starting material 7-ACP quality differences are larger in the route, domestic large-scale production not yet, with 2- (5- amino -1,2, 4- thiadiazoles -3- bases) -2- methoxyimino acetic acid condensation reactions are due to 2- (5- amino -1,2,4- thiadiazoles -3- bases) -2- first Oxyimino group acetic acid activity is low, and reaction selectivity is poor, generates a large amount of impurity, and finished product quality is difficult to ensure.

A kind of method of synthetic hydrochloric acid Cefozopran intermediate 7-ACP is described in patent CN102336772, this method is Using GCLE as starting material, is reacted with Imidazopyridazine under sodium iodide effect and generate GIMPE, GIMPE water under phenol effect Solution sloughs C4 protecting groups, under phosphorus pentachloride effect hydrolysis slough C7 protecting groups and obtain 7-ACP, this method intermediate treatment ratio Cumbersome, reaction process uses phosphorus pentachloride, and reaction selectivity is low, to equipment requirement height, is unfavorable for industrialized production, route It is as follows：.

Patent CN102040616 describes a kind of synthetic method of cefozopran hydrochloride, and it is starting that this method, which is with GCLE, Then raw material is condensed to yield GIMPE through 3 iodine substitutions with Imidazopyridazine, GIMPE is obtained after phenol deprotection and enzyme hydrolysis 7-ACP, 7-ACP are passed through is condensed to yield azoles orchid alkali with azoles orchid active ester, then obtains cefozopran hydrochloride, this method at salt with hydrochloric acid It post-processes cumbersome, is unfavorable for industrialized production, route is as follows：

Invention content

It is an object of the invention to overcome disadvantage and deficiency present in existing cefozopran hydrochloride synthetic method, to A kind of new synthetic method is provided.

With compound 2 (GCLE) for starting material, through being condensed into compound 3 (GIMPE) with imidazoles pyridazine, then again through benzene Phenol sloughs C4 protecting groups, and the chosen higher acylase of property takes off C7 protecting groups and synthesizes to obtain compound 4 (7-ACP), Compound 4 and compound 7 (Cefozopran active ester) are condensed to yield Cefozopran alkali crude product, after Cefozopran alkali crude product refining with Hydrochloric acid obtains compound 1 (cefozopran hydrochloride) at salt, and reaction equation is as follows：

Specific reaction step is as follows：

The synthetic method of the cefozopran hydrochloride (1) of the present invention, includes the following steps：

A) it is starting material with compound 2, under iodide effect, chemical combination is condensed to obtain with compound 6 (Imidazopyridazine) Object 3 (GIMPE).

B) compound 3 obtains 4 (7- of compound after immobilized penicillin acylated enzyme hydrolyzes again after phenol is deprotected ACP)；

C) compound 4 (7-ACP) obtains compound 5 (azoles orchid alkali) crude product with compound 7 (azoles orchid active ester) condensation reaction

D) compound 5 (azoles orchid alkali) crude product obtains compound 1 (cefozopran hydrochloride) with hydrochloric acid after DMF is recrystallized at salt

Advantageous effect

A) implement according to case study on implementation in the present invention, its HPLC purity of obtained cefozopran hydrochloride finished product can reach 99.5%, maximum single miscellaneous respectively less than 0.1%, reach standards of pharmacopoeia.

B) step a is committed step, and GCLE need not be post-processed after being reacted with iodide directly to react with Imidazopyridazine, The direct crystallization filtering of solvent is added after reaction, post-processing is simple, is very suitable for industrialized production.

C) step b is committed step, and the direct crystallization filtering of solvent is added after GIMPE and phenol deprotection, and post-processing is simple, Phenol is filtered out, the enzymatic hydrolysis reaction of lower step is conducive to, yield is improved and product quality, the HPLC purity of 7-ACP crude products reaches To 95.0%.

D) step c is committed step, is distilled after adjusting pH value after reaction, and solvent crystallization filtering is added, rear to locate Reason is simple, is suitble to industrialized production.

E) step d azoles orchid alkali refining is committed step, and after DMF solvent recrystallizes, HPLC purity reaches azoles orchid alkali crude product 98.5%.

F) technological parameter is optimized in the present invention, and further investigation industrialization makes entire process industry level improve, It can mass produce.

Illustrate the high-efficient liquid phase chromatogram that Fig. 1 is the embodiment of the present invention 5.

Specific implementation mode

Below in conjunction with specific embodiment, the present invention will be further described, and the total synthetic route of the present invention is as follows：

The synthesis of embodiment 1, intermediate GIMPE (formula 3)

Acetone 1125g is added in clean 5L reactors, is added with stirring GCLE (formula 2) 250g, anhydrous sodium iodide 92.5g, 30 ± 2 DEG C of interior temperature insulation reaction 1.5~2 hours put into Imidazopyridazine (formula 6) 104.0g, add 125g acetone and wash Charge door, 35~45 DEG C of interior temperature insulation reaction 5 hours, stream plus isopropanol 1975g are washed, charging in about 30 minutes is completed, cooling 10~ 15 DEG C are stirred 30 minutes, are continued to be cooled to 0~5 DEG C and are stirred 1~1.5 hour, and filtering is washed with 770g isopropanols/470g acetone Filter cake, 40 ± 2 DEG C are dried in vacuum overnight to obtain greenish yellow solid GIMPE (formula 3), molar yield 90.0~95.0%, HPLC purity More than 90.0%, moisture is less than 1.0%.

The synthesis of embodiment 2, intermediate 7-ACP (formula 4).

In the 5L reactors of dried and clean, GIMPE (formula 3) 360g, phenol (preheating) 1.5kg is added, in water-bath temperature control 50~55 DEG C of temperature is stirred to react 11~12 hours, is cooled to 35~40 DEG C after reaction, fast drop 580g isopropyl ethers and The mixed liquor of 320g isopropanols is added dropwise to complete for 10~15 minutes, and 35~40 DEG C of temperature control stirs 30 minutes.35~40 DEG C 30 points of temperature control By fast drop methylisobutylketone 2325g in clock, rear insulated and stirred is added 1~1.5 hour, filter, washed with methylisobutylketone.

It is added water 2.25kg and 72g sodium bicarbonate in 5L beakers, acetone 480g, after mixing, the solid that will obtain rapidly It is transferred to and stirring and dissolving, addition 435g isopropyl ethers stirs 20 minutes, water layer is collected in liquid separation, and activated carbon 30g decolorations are added in water layer It filters after 30 minutes, is washed with the mixed liquor of 600g purified waters and 97.5g acetone, 25~35 DEG C of temperature control is added in advance with purifying The immobilized penicillin acylated enzyme 90g that water washing is crossed, reaction process sodium bicarbonate keeps system PH7.3~7.8, and (PH stops becoming Hour do not add sodium bicarbonate), insulation reaction 4 hours filters after reaction, purify water washing with 450g, collection filtrate, Activated carbon 30g and sodium pyrosulfite 15g is added, decolourizes 30 minutes, filtering, purified water 450g washings are collected filtrate and are transferred to In 5L reactors, 10~15 DEG C of temperature control slowly adjusts PH to 1.9~2.0 (dropwise addition process prevents slug), stirring 30 with concentrated hydrochloric acid Minute, it is cooled to 0~5 DEG C of insulated and stirred 1~1.5 hour, filters by several times, washed with 0~5 DEG C of 200g of cold water, use cold methanol 150g is washed, and yellow solid 7-ACP (formula 4) is dried in vacuum overnight to obtain in 40 DEG C, and purity is more than 95.0%, and moisture is less than 5.0%, Molar yield 45~55%.

The synthesis of embodiment 3, Cefozopran alkali crude product (formula 5).

33g triethylamines and first is added dropwise in the addition methanol 600g in the there-necked flask of 1500ml, 7-ACP90g, 5~10 DEG C of temperature control The mixed liquor of alcohol 68g stirs to clarify after being added dropwise to complete, and active ester 122g is added, and 15~25 DEG C of temperature control reacts 8~10 hours, After reaction with glacial acetic acid tune PH6.7~7.0,30~35 DEG C of vacuum distillations of water-bath to sticky, addition acetone 3360g, stirring 1 It~1.5 hours, filters by several times, washs filter cake twice with acetone, 40 DEG C are dried in vacuo to obtain Cefozopran alkali crude product (formula 5), purity More than 95%, molar yield 60.0~70.0%.

The purifying of embodiment 4, Cefozopran alkali crude product (formula 5).

In 1000ml there-necked flasks, DMF 420g, water 84g, concentrated hydrochloric acid 30g is added, is cooled to 10~15 DEG C, cephalo is added Azoles orchid alkali crude product 150g, stirs to clarify, and activated carbon 15g is added, and stirs 30 minutes, filtering, with 10~15 DEG C 80% of DMF water Crystallization is precipitated in solution 140g washing, 10~15 DEG C of temperature control triethylamine tune PH4.5, stirring, and low speed growing the grain 2 hours continues with three Ethamine is adjusted to PH6.8~7.6, is cooled to 0~5 DEG C and keeps the temperature 2 hours, and filtering is washed twice, 45 DEG C are dried in vacuo in vain with acetone Color solid, yield 85.0~95.0%.Purity is more than 98.5%.

The synthesis of embodiment 5, cefozopran hydrochloride (formula 1).

Acetone 186g, purified water 150.4g, absolute ethyl alcohol 22g, concentrated hydrochloric acid 80g, cooling are added in 1000ml there-necked flasks To 10 DEG C hereinafter, input refines rear azoles orchid alkali 140g, it stirs to clarify, is warming up to 20~30 DEG C of addition activated carbon 8.4g, decoloration 30~40 minutes, filtering was washed with the mixed liquor of acetone 46g purified waters 56g, and 20~30 DEG C of filtrate temperature control added third with 40 minutes stream Ketone 560g, stirring to crystal are precipitated (stirring sees whether crystallization in 10 minutes, if crystal seed is not added in crystallization), growing the grain 3h, with 40~ It slowly flows within 50 minutes and adds acetone 400g (being uniformly slowly added dropwise, abundant crystallization, otherwise product is more sticky and yield is relatively low), add Insulated and stirred 12~16 hours afterwards, filtering, are first washed with the mixed liquor of acetone 200g purified waters 40g, then washed with 200g acetone, 35 DEG C of filter cake is dried in vacuo to obtain dry product, and purity is more than 99.5%, molar yield 65~75%.H-NMR：δ 3.39 (1H, s), δ 3.56 (1H, d), δ 3.56 (3H, s), δ 5.18 (1H, d), δ 5.49 (2H, d), δ 5.87 (1H, dd), δ 8.05 (1H, dd), δ 8.21 (2H, s), δ 8.40 (1H, d), δ 8.87 (1H, d), δ 8.95 (1H, d), δ 9.13 (1H, d), δ 9.60 (1H, d)；Efficient liquid Phase chromatogram is shown in attached drawing 1, and wherein data are shown in Table 1 in high-efficient liquid phase chromatogram

Table 1 is high-efficient liquid phase color modal data

Claims (8)

1. the method for preparing a kind of compound 1：

The method step includes：

A) it is starting material with compound 2, under iodide effect, compound 3 is condensed to yield with compound 6

B) compound 3 obtains compound 4 after immobilized penicillin acylated enzyme hydrolyzes again after phenol is deprotected

C) compound 4 obtains 5 crude product of compound with 7 condensation reaction of compound

D) 5 crude product of compound obtains compound 1 with hydrochloric acid after DMF is recrystallized at salt.

2. according to the method described in claim 1, it is characterized in that iodide described in step (a) are sodium iodide or iodate Potassium；Iodination reaction temperature is 0~50 DEG C, and the reaction time is 30~180 minutes；Compound 2 is not required to after being reacted with iodide with elder generation It post-processes and is directly added into 6 condensation reaction of compound generation compound 3；With the reaction temperature of 6 condensation reaction of compound be 10~ 55 DEG C, the reaction time is 3~8 hours；The mass ratio of compound 2 and compound 6 is 1:1~1:3.

3. the method according to claim 2, it is characterised in that 3 post-processing approach of compound is direct crystallization method, used Solvent be methanol, ethyl alcohol, propyl alcohol, isopropanol, several alcohols of butanol or more mixed solvent.

4. according to the method described in claim 1, it is characterized in that compound 4 described in step (b) is with compound 3 and phenol Enzyme hydrolysis is acylated after deprotection reaction with penicillin immobilization to be made, compound 3：The mass ratio of phenol is 1：3 to 1：6, reaction 45~65 DEG C of temperature, reaction time are 5~15 hours.

5. according to the method described in claim 2, it is characterized in that the compound 4 is anti-with compound 3 and phenol deprotection The post-processing approach answered be direct crystallization method, solvent used be methanol, ethyl alcohol, propyl alcohol, isopropanol, butanol, methyl ether, ether, The mixture of isopropyl ether or above-mentioned several solvents, above-mentioned solvent is added dropwise in reaction solution, and solvent acetone, methyl are then added dropwise again The mixture of isobutyl ketone, butanone or above-mentioned several solvents filters after direct crystallization, filter cake is dissolved to the acetone water of sodium bicarbonate In solution, enzymatic hydrolysis reaction is directly used in after extraction is decolourized.

6. according to the method described in claim 5, it is characterized in that the enzymatic hydrolysis reaction described in the step (b) is fixed Change PA ase reaction, reaction temperature is 0~50 DEG C；Reaction time is 2~6 hours；The pH value of reaction process is 7.2 ~8.6, reaction process uses sodium bicarbonate adjusting control system pH value；The processing step of the enzymatic hydrolysis reaction：Enzyme hydrolysis After filter, in filtrate be added sodium pyrosulfite as stabilizer, then through concentrated hydrochloric acid adjusting pH value to 1.0~4.0, tied Crystalline substance, crystallization temperature are -5~25 DEG C.

7. according to the method described in claim 1, it is characterized in that with compound 7 ester occurs for compound 4 in the step (c) Change reaction, reaction temperature is 0~35 DEG C；Reaction time is 4~14 hours；React molar ratio 1:1~1:3；Reaction dissolvent is The mixture of methanol, ethyl alcohol, propyl alcohol, isopropanol or above-mentioned solvent；Catalysts are triethylamine；The post-processing of ester reaction is to use Hydrochloric acid, sulfuric acid, glacial acetic acid adjust pH value to 6.5~7.5；Its vapo(u)rizing temperature is no more than 35 DEG C；Crystallization solvent is acetone, methyl is different The mixture of butanone, butanone either above-mentioned several solvents, recrystallization temperature are 0~30 DEG C.

8. according to the method described in claim 1, it is characterized in that the recrystallization of step (d) compound 5 is with DMF, water, dense salt Acid is mixed solvent, and quality proportioning is concentrated hydrochloric acid：Water：DMF is 1:2.8:14, azoles orchid alkali crude product：The mass ratio of mixed solvent is 1:2 to 1:8；Crystallization is precipitated crystal with triethylamine regulation system terminal pH value, and terminal pH value is 4.5~7.5.