CN101225069A - Method for synthesizing meropenem intermediate - Google Patents

Abstract

The invention provides a synthesis method of a side chain H of a meropenem, which is characterized in that a new radical is introduced respectively for three functional groups of 4R hydroxy L hydroxyproline and a certain spatial configuration is kept. The synthesis method for the side chain H of a meropenem has the advantages of moderate process conditions, stable product quality, and high yield, which is applicable to the industrial production on a large scale.

Description

A kind of synthetic method of meropenem intermediate

(1) technical field:

The present invention relates to a kind of synthetic method of meropenem intermediate, the synthetic method of especially a kind of meropenem side chain H.

(2) background technology:

Meropenem (meropenem) is that first is applied to clinical 1-β methyl carbon cyanogen enzyme carbapenem antibiotic, has good chemical stability, stable to β-Nei Xiananmei and kidney dehydrogenation peptide-I enzyme (DHP-I enzyme), has a broad antifungal spectrum, Gram-positive and negative bacterium are all had the obvious suppression effect, are one of choice drugs for the treatment of at present severe and multi-drug resistant bacteria infection.In industrial production now, meropenem is by parent nucleus MAP and side chain H two portions synthetic, though the route of synthetic side chain H is a lot, but exist man-hour longer mostly, energy consumption is higher, a series of problems such as poor stability and yield are low, therefore producing the meropenem side chain H that synthesizes steady quality, high yield is a problem that needs to be resolved hurrily present stage.

(3) summary of the invention:

The object of the present invention is to provide the synthetic method of a kind of meropenem side chain H; this method is introduced new group respectively in 3 functional groups of 4R-hydroxyl-L-proline; also to keep certain steric configuration; used processing condition gentleness; constant product quality and yield height are fit to large-scale industrial production.

Technical scheme of the present invention: the synthetic method of a kind of meropenem side chain H; meropenem side chain H chemical name is (2s; 4s)-1-(to the nitro carbobenzoxy-(Cbz))-2-dimethylformamide base-4-mercapto pyrrolidine; it is characterized in that with 4R-hydroxyl-L-proline (1) be raw material; under alkaline condition, react with nitrobenzyl chloroformate ester; obtain the 4R-hydroxyl-L-proline compd A (2) of amido protecting; aminolysis gained intermediate (3) behind the carboxylic hydroxyl of isopropyl chlorocarbonate activating compounds A (2); again intermediate (3) is obtained compd B (4) with the Methanesulfonyl chloride acidylate; compd B (4) is replaced the Compound C (5) that obtains 4-hydroxyl configuration inversion with thioacetic acid potassium, and Compound C (5) obtains meropenem side chain H (6) through alkaline hydrolysis.

The synthetic method of a kind of meropenem side chain H is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 4R-hydroxyl-L-proline (1), the 2mol/L aqueous sodium hydroxide solution, drip 20%-25% nitrobenzyl chloroformate ester dichloromethane solution at 0 ℃～5 ℃, its weight quota is than being 4R-hydroxyl-L-proline (1) 12-15,2mol/L aqueous sodium hydroxide solution 120-140,20%-25% nitrobenzyl chloroformate ester dichloromethane solution 117, dropwised the back insulation reaction 1.0～1.5 hours, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals, 0 ℃～5 ℃ growing the grains 1.0～1.5 hours, put down material and get rid of material with whizzer, constant pressure and dry, get compd A (2), with the weight quota of the material that synthetic reaction process is thrown of described compd A (2) than 33.7, yield 95%, 132 ℃～134 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add methylene dichloride, compd A (2), triethylamine, its weight quota is than being methylene dichloride 200, compd A (2) 31, triethylamine 15-17, stir down and reaction mixture is cooled to-12 ℃～-15 ℃, drip weight quota than being the isopropyl chlorocarbonate of 18-20, control reaction temperature is between-10 ℃～-12 ℃, dropwised afterreaction 5～10 minutes, add the dimethylammonium hydrochloride, drip triethylamine, its weight quota is than being dimethylammonium hydrochloride 16-18, triethylamine 28-30 dropwises, the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1.0～1.5 hours, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, add weight quota than being the triethylamine of 28-30, stir, be cooled to-10 ℃～-13 ℃, drip weight quota than being the Methanesulfonyl chloride of 16-17, control reaction temperature is between-10 ℃～-15 ℃, dropwised the back insulation reaction 5～10 minutes, the TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid, tell methylene dichloride and used anhydrous sodium sulfate drying mutually 1.0～1.5 hours, activated carbon decolorizing 0.5～1.0 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip 30/50 methyl alcohol/sherwood oil crystallization, 0 ℃～-5 ℃ growing the grains 1.0～1.5 hours, centrifuge dripping gets white solid compd B (4), with the weight quota ratio of the material of throwing in the synthetic reaction process of described compd B (4) be 28, yield 67% (in compd A (2)), fusing point: 116 ℃～120 ℃;

3) meropenem side chain H's (6) is synthetic:

In reactor, drop into compd B (4), N, N-dimethylformamide (DMF), its weight quota is than being compd B (4) 25, N, N-dimethylformamide (DMF) 118, after the stirring and dissolving, add weight quota than being the thioacetic acid potassium of 11.5-12.5, stirring was warming up to 35 ℃～40 ℃, 35 ℃～40 ℃ insulation reaction 14～15 hours; Pour reaction solution in frozen water hydrolysis,-5 ℃～0 ℃ stirring reaction 1.0～1.5 hours, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, added weight quota and make its whole dissolvings than the methylene dichloride that is 80～100; Static 15～20 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, add weight quota than being the methyl alcohol of 4X, stirring is cooled to-15 ℃～-18 ℃, the sodium hydroxide solution that adds 4mol/L fast, react the hydrochloric acid that adds 2mol/L after 10～15 minutes fast, control PH=1～3, after the TLC monitoring reaction finishes, washing, the combined dichloromethane phase, drying, decolouring is filtered, be distilled to weight quota than being 2X, add weight quota than for adding weight quota behind the dissolve with methanol of 4X, lower the temperature, drip weight quota than being the sherwood oil of 2X than being the three normal-butyl phosphorus of 0.1X, stirring and crystallizing, the cooling growing the grain, filter white powder, i.e. meropenem side chain H (6), with the weight quota ratio of the material of throwing in the synthetic reaction process of described meropenem side chain H (6) be 13, yield 61.2% (in compd B (4)) is 32.2% in 4R-hydroxyl-L-proline ultimate yield, fusing point 119 ℃～120.

The method of calculation of above-claimed cpd C (5) can adopt the known heavy method of giving money as a gift, and the wet weight that is about to Compound C (5) is converted into the crude product weight of Compound C (5) by calculating.

Beneficial effect of the present invention is analyzed:

The present invention is directed to the synthetic method of existing meropenem side chain, compare big technological improvement, mainly show:

(1) former technology is when synthetic compound C (5), and getting rid of needs behind the material carry out next step reaction again after dry, and man-hour is longer, and energy consumption is higher, and when dry to the stability of material, quality product also has bigger influence; The present invention makes solvent with methylene dichloride, and weight in wet base material Compound C (5) all is dissolved in the methylene dichloride, divides aquifer yield, adopts the heavy method of giving money as a gift, and directly carries out next step reaction, has therefore saved man-hour, has reduced energy consumption, and quality product has also had large increase.

(2) when synthetic meropenem side chain H (6), former technology is dissolved with the methyl alcohol single solvent after selecting for use Compound C (5) dry, because material solubleness in methyl alcohol is less, cause reaction not exclusively, and raw material and finished product are not easily separated, must adopt silica gel column chromatography to separate, need with a large amount of silica gel and inflammable and explosive organic solvent ethyl acetate, sherwood oil, potential safety hazard is very big, and man-hour is long, yield is low, the cost height; The present invention selects for use Compound C (5) moist, the method of giving money as a gift counting, with double solvents methylene dichloride, methyl alcohol material is all dissolved, therefore effectively improved reaction conditions, with positive tributyl phosphorus reduction, do not need the method for silica gel column chromatography, product separation is opened, and quality product, yield all are significantly improved, and have increased the safety in production coefficient.

Facts have proved former technology meropenem side chain H (6) content 95-97%, yield 23.5% (in 4R-hydroxyl-L-proline); After improving technology, meropenem side chain H (6) content 96-97%, yield 32.2% (in 4R-hydroxyl-L-proline), raw material consumption has reduced by 1000 yuan/kilogram, and has shortened 50% man-hour.As seen, the present invention shortens in nearly one times the whole reflection cycle, makes yield be increased to 32.2% by 23.5%, and yield obviously improves.

Superiority of the present invention: the synthetic method that (1) this patent adopts has overcome a series of problems of the synthetic meropenem side chain H of former technology, by meticulous screening reaction solvent, make product meropenem side chain H on quality, stability and yield, all be improved significantly; (2) the more former technology of used synthetic method shortening in man-hour, energy consumption reduces, and the processing condition gentleness is fit to large-scale industrial production.

(4) Figure of description:

Fig. 1: the chemical reaction whole process of synthetic meropenem side chain H (6).

Fig. 2: the chemical reaction process of synthetic mesophase product compd A (2).

Fig. 3: the chemical reaction process of synthetic mesophase product compd B (4).

Fig. 4: by the chemical reaction process of the synthetic meropenem side chain H (6) of compd B (4).

(5) embodiment:

Embodiment 1: the synthetic method of a kind of meropenem side chain H; meropenem side chain H chemical name is (2s; 4s)-1-(to the nitro carbobenzoxy-(Cbz))-2-dimethylformamide base-4-mercapto pyrrolidine; it is characterized in that with 4R-hydroxyl-L-proline (1) be raw material; under alkaline condition, react with nitrobenzyl chloroformate ester; obtain the 4R-hydroxyl-L-proline compd A (2) of amido protecting; aminolysis gained intermediate (3) behind the carboxylic hydroxyl of isopropyl chlorocarbonate activating compounds A (2); again intermediate (3) is obtained compd B (4) with the Methanesulfonyl chloride acidylate; compd B (4) is replaced the Compound C (5) that obtains 4-hydroxyl configuration inversion with thioacetic acid potassium, and Compound C (5) obtains meropenem side chain H (6) through alkaline hydrolysis.

The synthetic method of a kind of meropenem side chain H is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 12 kilograms of 4R-hydroxyl-L-prolines (1), 140 kilograms of 2mol/L aqueous sodium hydroxide solutions, drip 117 kilogram of 20% nitrobenzyl chloroformate ester dichloromethane solution at 0 ℃, dropwised the back insulation reaction 1 hour, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals,, put down material and get rid of material with whizzer 5 ℃ of growing the grains 1.5 hours, constant pressure and dry, get (2) 33.7 kilograms of compd As, yield 95%, 132 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add 200 kilograms of methylene dichloride, (2) 31 kilograms of compd As, 15 kilograms of triethylamines, stir down and reaction mixture is cooled to-15 ℃, drip 20 kilograms of isopropyl chlorocarbonates, control reaction temperature is at-12 ℃, dropwise afterreaction 5 minutes, and added 16 kilograms of dimethylammonium hydrochlorides, drip 30 kilograms of triethylamines, dropwise the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1.5 hours, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, adds 28 kilograms of triethylamines, stir, be cooled to-13 ℃, drip 17 kilograms of Methanesulfonyl chlorides, control reaction temperature is at-10 ℃, dropwised the back insulation reaction 5 minutes, TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid is told methylene dichloride and was used anhydrous sodium sulfate drying mutually 1 hour, activated carbon decolorizing 1 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip 30/50 methyl alcohol/sherwood oil crystallization ,-5 ℃ of growing the grains 1 hour, centrifuge dripping gets (4) 28 kilograms of white solid compd Bs, yield 67%, fusing point: 116 ℃;

3) meropenem side chain H's (6) is synthetic:

Drop into (4) 25 kilograms of compd Bs, N in reactor, 118 kilograms of N-dimethylformamides (DMF) after the stirring and dissolving, add 11.5 kilograms of thioacetic acid potassiums, stir and are warming up to 35 ℃, 35 ℃ of insulation reaction 15 hours; Pour reaction solution in frozen water hydrolysis, 0 ℃ of stirring reaction 1 hour, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, the methylene dichloride that adds 80 kilograms makes its whole dissolvings; Static 20 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, adds methyl alcohol 4X kilogram, stirs and is cooled to-18 ℃, add the 4mol/L sodium hydroxide solution fast, react the quick 2mol/L of adding hydrochloric acid after 10 minutes, control PH=1, after the TLC monitoring reaction finishes, washing, combined dichloromethane phase, drying, decolouring, filter, be distilled to the 2X kilogram, add 0.1X kilogram three normal-butyl phosphorus after adding 4X kilogram dissolve with methanol, cooling, drip 2X kilogram sherwood oil, stirring and crystallizing, cooling growing the grain, filter white powder, be (6) 13 kilograms of meropenem side chain H, yield 61.2%, 120 ℃ of fusing points.

Embodiment 2: the synthetic method of a kind of meropenem side chain H; meropenem side chain H chemical name is (2s; 4s)-1-(to the nitro carbobenzoxy-(Cbz))-2-dimethylformamide base-4-mercapto pyrrolidine; it is characterized in that with 4R-hydroxyl-L-proline (1) be raw material; under alkaline condition,, obtain the 4R-hydroxyl-L-proline compd A of amido protecting with the nitrobenzyl chloroformate ester reaction

(2); aminolysis gained intermediate (3) behind the carboxylic hydroxyl of isopropyl chlorocarbonate activating compounds A (2); again intermediate (3) is obtained compd B (4) with the Methanesulfonyl chloride acidylate; compd B (4) is replaced the Compound C (5) that obtains 4-hydroxyl configuration inversion with thioacetic acid potassium, and Compound C (5) obtains meropenem side chain H (6) through alkaline hydrolysis.

The synthetic method of a kind of meropenem side chain H is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 15 kilograms of 4R-hydroxyl-L-prolines (1), 120 kg 2mol/L aqueous sodium hydroxide solution, at 5 ℃ of nitrobenzyl chloroformate ester dichloromethane solutions that drip 117 kilogram 25%, dropwised the back insulation reaction 1.5 hours, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals,, put down material and get rid of material with whizzer 0 ℃ of growing the grain 1 hour, constant pressure and dry, get (2) 33.7 kilograms of compd As, yield 95%, 134 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add 200 kilograms of methylene dichloride, (2) 31 kilograms of compd As, 17 kilograms of triethylamines, stir down and reaction mixture is cooled to-12 ℃, drip 18 kilograms of isopropyl chlorocarbonates, control reaction temperature is at-10 ℃, dropwise afterreaction 10 minutes, and added 18 kilograms of dimethylammonium hydrochlorides, drip 28 kilograms of triethylamines, dropwise the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1 hour, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, adds 30 kilograms of triethylamines, stir, be cooled to-10 ℃, drip 16 kilograms of Methanesulfonyl chlorides, control reaction temperature is at-15 ℃, dropwised the back insulation reaction 10 minutes, TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid is told methylene dichloride and was used anhydrous sodium sulfate drying mutually 1.5 hours, activated carbon decolorizing 0.5 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip methyl alcohol/sherwood oil crystallization of 30/50,0 ℃ of growing the grain 1.5 hours, centrifuge dripping gets (4) 28 kilograms of white solid compd Bs, yield 67%, fusing point: 120 ℃;

3) meropenem side chain H's (6) is synthetic:

In reactor, drop into (4) 25 kilograms of compd Bs, N, after 118 kilograms of stirring and dissolving of N-dimethylformamide (DMF), add 12.5 kilograms of thioacetic acid potassiums, stir and be warming up to 40 ℃, 40 ℃ of insulation reaction 14 hours; Pour reaction solution in frozen water hydrolysis ,-5 ℃ of stirring reactions 1.5 hours, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, the methylene dichloride that adds 100 kilograms makes its whole dissolvings; Static 15 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, adds methyl alcohol 4X kilogram, stirs and is cooled to-15 ℃, add the 4mol/L sodium hydroxide solution fast, react the quick 2mol/L of adding hydrochloric acid after 15 minutes, control PH=3, after the TLC monitoring reaction finishes, washing, combined dichloromethane phase, drying, decolouring, filter, be distilled to the 2X kilogram, add 0.1X kilogram three normal-butyl phosphorus after adding 4X kilogram dissolve with methanol, cooling, drip 2X kilogram sherwood oil, stirring and crystallizing, cooling growing the grain, filter white powder, be (6) 13 kilograms of meropenem side chain H, yield 61.2%, 119 ℃ of fusing points.

Embodiment 3: the synthetic method of a kind of meropenem side chain H; meropenem side chain H chemical name is (2s; 4s)-1-(to the nitro carbobenzoxy-(Cbz))-2-dimethylformamide base-4-mercapto pyrrolidine; it is characterized in that with 4R-hydroxyl-L-proline (1) be raw material; under alkaline condition, react with nitrobenzyl chloroformate ester; obtain the 4R-hydroxyl-L-proline compd A (2) of amido protecting; aminolysis gained intermediate (3) behind the carboxylic hydroxyl of isopropyl chlorocarbonate activating compounds A (2); again intermediate (3) is obtained compd B (4) with the Methanesulfonyl chloride acidylate; compd B (4) is replaced the Compound C (5) that obtains 4-hydroxyl configuration inversion with thioacetic acid potassium, and Compound C (5) obtains meropenem side chain H (6) through alkaline hydrolysis.

The synthetic method of a kind of meropenem side chain H is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 14 kilograms of 4R-hydroxyl-L-prolines (1), 130 kilograms of 2mol/L aqueous sodium hydroxide solutions, drip 117 kilogram of 23% nitrobenzyl chloroformate ester dichloromethane solution at 3 ℃, dropwised the back insulation reaction 1.3 hours, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals,, put down material and get rid of material with whizzer 3 ℃ of growing the grains 1.2 hours, constant pressure and dry, get (2) 33.7 kilograms of compd As, yield 95%, 133 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add 200 kilograms of methylene dichloride, (2) 31 kilograms of compd As, 16 kilograms of triethylamines, stir down and reaction mixture is cooled to-13 ℃, drip 19 kilograms of isopropyl chlorocarbonates, control reaction temperature is between-11 ℃, dropwise afterreaction 7 minutes, and added 17 kilograms of dimethylammonium hydrochlorides, drip 29 kilograms of triethylamines, dropwise the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1.3 hours, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, adds 29 kilograms of triethylamines, stir, be cooled to-12 ℃, drip 16.5 kilograms of Methanesulfonyl chlorides, control reaction temperature is at-13 ℃, dropwised the back insulation reaction 8 minutes, TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid is told methylene dichloride and was used anhydrous sodium sulfate drying mutually 1.2 hours, activated carbon decolorizing 0.8 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip methyl alcohol/sherwood oil crystallization of 30/50 ,-3 ℃ of growing the grains 1.2 hours, centrifuge dripping gets (4) 28 kilograms of white solid compd Bs, yield 67%, fusing point: 118 ℃;

3) meropenem side chain H's (6) is synthetic:

Drop into (4) 25 kilograms of compd Bs, N in reactor, 118 kilograms of N-dimethylformamides (DMF) after the stirring and dissolving, add 12.0 kilograms of thioacetic acid potassiums, stir and are warming up to 38 ℃, 38 ℃ of insulation reaction 14.5 hours; Pour reaction solution in frozen water hydrolysis ,-3 ℃ of stirring reactions 1.2 hours, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, the methylene dichloride that adds 90 kilograms makes its whole dissolvings; Static 17 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, adds methyl alcohol 4X kilogram, stirs and is cooled to-17 ℃, add the 4mol/L sodium hydroxide solution fast, react the quick 2mol/L of adding hydrochloric acid after 13 minutes, control PH=2, after the TLC monitoring reaction finishes, washing, combined dichloromethane phase, drying, decolouring, filter, be distilled to the 2X kilogram, add 0.1X kilogram three normal-butyl phosphorus after adding 4X kilogram dissolve with methanol, cooling, drip 2X kilogram sherwood oil, stirring and crystallizing, cooling growing the grain, filter white powder, be (6) 13 kilograms of meropenem side chain H, yield 61.2%, 119.5 ℃ of fusing points.

Claims (5)

1. the synthetic method of a meropenem side chain H; it is characterized in that with 4R-hydroxyl-L-proline (1) be raw material; under alkaline condition, react with nitrobenzyl chloroformate ester; obtain the 4R-hydroxyl-L-proline compd A (2) of amido protecting; aminolysis gained intermediate (3) behind the carboxylic hydroxyl of isopropyl chlorocarbonate activating compounds A (2); again intermediate (3) is obtained compd B (4) with the Methanesulfonyl chloride acidylate; compd B (4) is replaced the Compound C (5) that obtains 4-hydroxyl configuration inversion with thioacetic acid potassium, and Compound C (5) obtains meropenem side chain H (6) through alkaline hydrolysis.

2. the synthetic method of a kind of meropenem side chain H according to claim 1 is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 4R-hydroxyl-L-proline (1), the 2mol/L aqueous sodium hydroxide solution, drip 20%-25% nitrobenzyl chloroformate ester dichloromethane solution at 0 ℃～5 ℃, its weight quota is than being 4R-hydroxyl-L-proline (1) 12-15,2mol/L aqueous sodium hydroxide solution 120-140,20%-25% nitrobenzyl chloroformate ester dichloromethane solution 117, dropwised the back insulation reaction 1.0～1.5 hours, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals, 0 ℃～5 ℃ growing the grains 1.0～1.5 hours, put down material and get rid of material with whizzer, constant pressure and dry, get compd A (2), with the weight quota of the material that synthetic reaction process is thrown of described compd A (2) than 33.7, yield 95%, 132 ℃～134 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add methylene dichloride, compd A (2), triethylamine, its weight quota is than being methylene dichloride 200, compd A (2) 31, triethylamine 15-17, stir down and reaction mixture is cooled to-12 ℃～-15 ℃, drip weight quota than being the isopropyl chlorocarbonate of 18-20, control reaction temperature is between-10 ℃～-12 ℃, dropwised afterreaction 5～10 minutes, add the dimethylammonium hydrochloride, drip triethylamine, its weight quota is than being dimethylammonium hydrochloride 16-18, triethylamine 28-30 dropwises, the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1.0～1.5 hours, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, add weight quota than being the triethylamine of 28-30, stir, be cooled to-10 ℃～-13 ℃, drip weight quota than being the Methanesulfonyl chloride of 16-17, control reaction temperature is between-10 ℃～-15 ℃, dropwised the back insulation reaction 5～10 minutes, the TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid, tell methylene dichloride and used anhydrous sodium sulfate drying mutually 1.0～1.5 hours, activated carbon decolorizing 0.5～1.0 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip 30/50 methyl alcohol/sherwood oil crystallization, 0 ℃～-5 ℃ growing the grains 1.0～1.5 hours, centrifuge dripping gets white solid compd B (4), with the weight quota ratio of the material of throwing in the synthetic reaction process of described compd B (4) be 28, yield 67% (in compd A (2)), fusing point: 116 ℃～120 ℃;

3) meropenem side chain H's (6) is synthetic:

In reactor, drop into compd B (4), N, N-dimethylformamide (DMF), its weight quota is than being compd B (4) 25, N, N-dimethylformamide (DMF) 118, after the stirring and dissolving, add weight quota than being the thioacetic acid potassium of 11.5-12.5, stirring was warming up to 35 ℃～40 ℃, 35 ℃～40 ℃ insulation reaction 14～15 hours; Pour reaction solution in frozen water hydrolysis,-5 ℃～0 ℃ stirring reaction 1.0～1.5 hours, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, added weight quota and make its whole dissolvings than the methylene dichloride that is 80～100; Static 15～20 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, add weight quota than being the methyl alcohol of 4X, stirring is cooled to-15 ℃～-18 ℃, the sodium hydroxide solution that adds 4mol/L fast, react the hydrochloric acid that adds 2mol/L after 10～15 minutes fast, control PH=1～3, after the TLC monitoring reaction finishes, washing, the combined dichloromethane phase, drying, decolouring is filtered, be distilled to weight quota than being 2X, add weight quota than for adding weight quota behind the dissolve with methanol of 4X, lower the temperature, drip weight quota than being the sherwood oil of 2X than being the three normal-butyl phosphorus of 0.1X, stirring and crystallizing, the cooling growing the grain, filter white powder, i.e. meropenem side chain H (6), with the weight quota ratio of the material of throwing in the synthetic reaction process of described meropenem side chain H (6) be 13, yield 61.2% (in compd B (4)) is 32.2% in 4R-hydroxyl-L-proline ultimate yield, 119 ℃～120 ℃ of fusing points.

3. the synthetic method of a kind of meropenem side chain H according to claim 1 and 2 is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 12 kilograms of 4R-hydroxyl-L-prolines (1), 140 kilograms of 2mol/L aqueous sodium hydroxide solutions, drip 117 kilogram of 20% nitrobenzyl chloroformate ester dichloromethane solution at 0 ℃, dropwised the back insulation reaction 1 hour, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals,, put down material and get rid of material with whizzer 5 ℃ of growing the grains 1.5 hours, constant pressure and dry, get (2) 33.7 kilograms of compd As, yield 95%, 132 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add 200 kilograms of methylene dichloride, (2) 31 kilograms of compd As, 15 kilograms of triethylamines, stir down and reaction mixture is cooled to-15 ℃, drip 20 kilograms of isopropyl chlorocarbonates, control reaction temperature is at-12 ℃, dropwise afterreaction 5 minutes, and added 16 kilograms of dimethylammonium hydrochlorides, drip 30 kilograms of triethylamines, dropwise the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1.5 hours, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, adds 28 kilograms of triethylamines, stir, be cooled to-13 ℃, drip 17 kilograms of Methanesulfonyl chlorides, control reaction temperature is at-10 ℃, dropwised the back insulation reaction 5 minutes, TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid is told methylene dichloride and was used anhydrous sodium sulfate drying mutually 1 hour, activated carbon decolorizing 1 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip 30/50 methyl alcohol/sherwood oil crystallization ,-5 ℃ of growing the grains 1 hour, centrifuge dripping gets (4) 28 kilograms of white solid compd Bs, yield 67%, fusing point: 116 ℃;

3) meropenem side chain H's (6) is synthetic:

Drop into (4) 25 kilograms of compd Bs, N in reactor, 118 kilograms of N-dimethylformamides (DMF) after the stirring and dissolving, add 11.5 kilograms of thioacetic acid potassiums, stir and are warming up to 35 ℃, 35 ℃ of insulation reaction 15 hours; Pour reaction solution in frozen water hydrolysis, 0 ℃ of stirring reaction 1 hour, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, the methylene dichloride that adds 80 kilograms makes its whole dissolvings; Static 20 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, adds methyl alcohol 4X kilogram, stirs and is cooled to-18 ℃, add the 4mol/L sodium hydroxide solution fast, react the quick 2mol/L of adding hydrochloric acid after 10 minutes, control PH=1, after the TLC monitoring reaction finishes, washing, combined dichloromethane phase, drying, decolouring, filter, be distilled to the 2X kilogram, add 0.1X kilogram three normal-butyl phosphorus after adding 4X kilogram dissolve with methanol, cooling, drip 2X kilogram sherwood oil, stirring and crystallizing, cooling growing the grain, filter white powder, be (6) 13 kilograms of meropenem side chain H, yield 61.2%, 120 ℃ of fusing points.

4. the synthetic method of a kind of meropenem side chain H according to claim 1 and 2 is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 15 kilograms of 4R-hydroxyl-L-prolines (1), 120 kg 2mol/L aqueous sodium hydroxide solution, at 5 ℃ of nitrobenzyl chloroformate ester dichloromethane solutions that drip 117 kilogram 25%, dropwised the back insulation reaction 1.5 hours, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals,, put down material and get rid of material with whizzer 0 ℃ of growing the grain 1 hour, constant pressure and dry, get (2) 33.7 kilograms of compd As, yield 95%, 134 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add 200 kilograms of methylene dichloride, (2) 31 kilograms of compd As, 17 kilograms of triethylamines, stir down and reaction mixture is cooled to-12 ℃, drip 18 kilograms of isopropyl chlorocarbonates, control reaction temperature is at-10 ℃, dropwise afterreaction 10 minutes, and added 18 kilograms of dimethylammonium hydrochlorides, drip 28 kilograms of triethylamines, dropwise the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1 hour, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, adds 30 kilograms of triethylamines, stir, be cooled to-10 ℃, drip 16 kilograms of Methanesulfonyl chlorides, control reaction temperature is at-15 ℃, dropwised the back insulation reaction 10 minutes, TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid is told methylene dichloride and was used anhydrous sodium sulfate drying mutually 1.5 hours, activated carbon decolorizing 0.5 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip methyl alcohol/sherwood oil crystallization of 30/50,0 ℃ of growing the grain 1.5 hours, centrifuge dripping gets (4) 28 kilograms of white solid compd Bs, yield 67%, fusing point: 120 ℃;

3) meropenem side chain H's (6) is synthetic:

In reactor, drop into (4) 25 kilograms of compd Bs, N, after 118 kilograms of stirring and dissolving of N-dimethylformamide (DMF), add 12.5 kilograms of thioacetic acid potassiums, stir and be warming up to 40 ℃, 40 ℃ of insulation reaction 14 hours; Pour reaction solution in frozen water hydrolysis ,-5 ℃ of stirring reactions 1.5 hours, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, the methylene dichloride that adds 100 kilograms makes its whole dissolvings; Static 15 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, adds methyl alcohol 4X kilogram, stirs and is cooled to-15 ℃, add the 4mol/L sodium hydroxide solution fast, react the quick 2mol/L of adding hydrochloric acid after 15 minutes, control PH=3, after the TLC monitoring reaction finishes, washing, combined dichloromethane phase, drying, decolouring, filter, be distilled to the 2X kilogram, add 0.1X kilogram three normal-butyl phosphorus after adding 4X kilogram dissolve with methanol, cooling, drip 2X kilogram sherwood oil, stirring and crystallizing, cooling growing the grain, filter white powder, be (6) 13 kilograms of meropenem side chain H, yield 61.2%, 119 ℃ of fusing points.

5. the synthetic method of a kind of meropenem side chain H according to claim 1 and 2 is characterized in that concrete steps are as follows:

1) compd A (2) is synthetic:

In reactor, add 14 kilograms of 4R-hydroxyl-L-prolines (1), 130 kilograms of 2mol/L aqueous sodium hydroxide solutions, drip 117 kilogram of 23% nitrobenzyl chloroformate ester dichloromethane solution at 3 ℃, dropwised the back insulation reaction 1.3 hours, the static methylene dichloride phase of telling, water dichloromethane extraction 3 times, methylene dichloride phase aqueous phase discarded is filtered, water uses the 6mol/L sulfuric acid acidation to PH=2, separate out a large amount of white crystals,, put down material and get rid of material with whizzer 3 ℃ of growing the grains 1.2 hours, constant pressure and dry, get (2) 33.7 kilograms of compd As, yield 95%, 133 ℃ of fusing points;

2) compd B (4) is synthetic:

In reactor, add 200 kilograms of methylene dichloride, (2) 31 kilograms of compd As, 16 kilograms of triethylamines, stir down and reaction mixture is cooled to-13 ℃, drip 19 kilograms of isopropyl chlorocarbonates, control reaction temperature is between-11 ℃, dropwise afterreaction 7 minutes, and added 17 kilograms of dimethylammonium hydrochlorides, drip 29 kilograms of triethylamines, dropwise the TLC monitoring; Water successively after reaction finishes, 2mol/L hydrochloric acid, water, 5% sodium hydrogen carbonate solution, saturated sodium-chloride washing reaction liquid, wash the back organic phase and use anhydrous sodium sulfate drying 1.3 hours, added activated carbon decolorizing 2 hours, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate gets in intermediate (3) the suction reactor, adds 29 kilograms of triethylamines, stir, be cooled to-12 ℃, drip 16.5 kilograms of Methanesulfonyl chlorides, control reaction temperature is at-13 ℃, dropwised the back insulation reaction 8 minutes, TLC monitoring, water successively after reaction finishes, 1mol/L hydrochloric acid, 5% Sodium phosphate dibasic and SODIUM PHOSPHATE, MONOBASIC mixing solutions, saturated sodium-chloride washing reaction liquid is told methylene dichloride and was used anhydrous sodium sulfate drying mutually 1.2 hours, activated carbon decolorizing 0.8 hour, filter, with a small amount of washed with dichloromethane filter cake, merging filtrate, concentrating under reduced pressure, drip methyl alcohol/sherwood oil crystallization of 30/50 ,-3 ℃ of growing the grains 1.2 hours, centrifuge dripping gets (4) 28 kilograms of white solid compd Bs, yield 67%, fusing point: 118 ℃;

3) meropenem side chain H's (6) is synthetic:

Drop into (4) 25 kilograms of compd Bs, N in reactor, 118 kilograms of N-dimethylformamides (DMF) after the stirring and dissolving, add 12.0 kilograms of thioacetic acid potassiums, stir and are warming up to 38 ℃, 38 ℃ of insulation reaction 14.5 hours; Pour reaction solution in frozen water hydrolysis ,-3 ℃ of stirring reactions 1.2 hours, light yellow solid Compound C (5), dry, yellow solid Compound C (5) is all put in the reactor, the methylene dichloride that adds 90 kilograms makes its whole dissolvings; Static 17 minutes, tell methylene dichloride phase and water, the weight that calculates Compound C (5) is designated as X, is the radix that feeds intake with X, calculates the amount of unclassified stores; The methylene dichloride that will contain Compound C (5) is pumped in the reactor, adds methyl alcohol 4X kilogram, stirs and is cooled to-17 ℃, add the 4mol/L sodium hydroxide solution fast, react the quick 2mol/L of adding hydrochloric acid after 13 minutes, control PH=2, after the TLC monitoring reaction finishes, washing, combined dichloromethane phase, drying, decolouring, filter, be distilled to the 2X kilogram, add 0.1X kilogram three normal-butyl phosphorus after adding 4X kilogram dissolve with methanol, cooling, drip 2X kilogram sherwood oil, stirring and crystallizing, cooling growing the grain, filter white powder, be (6) 13 kilograms of meropenem side chain H, yield 61.2%, 119.5 ℃ of fusing points.

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