Method for recovering 4-BMA from 4-BMA mother liquor reclaimed material by using chiral amine

Abstract

A method for recovering 4-BMA from a 4-BMA mother liquor reclaimed material belongs to the field of synthesis of medical intermediates, and comprises the following steps: 1) adding the 4-BMA mother liquor reclaimed material into a solvent, heating and dissolving; 2) adding a chiral amine reagent to precipitate 4-BMA in the recycled material, and filtering to obtain 4-BMA salt; 3) adding alkali into the 4-BMA salt for dissociation, and extracting the dissociated chiral amine reagent; and 4) adding acid to separate out 4-BMA, filtering and drying to obtain qualified 4-BMA. According to the method, the chiral amine reagent and 4-BMA are used for selective salification and crystallization, and isomer impurities are not salified and are continuously dissolved in the solvent, so that the product is purified, and the method has the characteristics of high recovery rate, good product quality and simple method, is obvious in reliability and economical efficiency, has obvious cost advantage and is suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of chemical intermediate synthesis, and in particular to a method for recovering 4-BMA from 4-BMA mother liquor recovery material by utilizing chiral amine. Background Art

[0002] Carbapenem antibiotics are atypical β-lactam antibiotics with the broadest antibacterial spectrum and the strongest antibacterial activity. They have become one of the most important antibacterial drugs for combating severe bacterial infections because of their stability to β-lactamases and low toxicity. Meropenem, as a member of the carbapenem antibiotics, is widely used because of its unique advantages in treating multidrug-resistant bacterial infections. 4-BMA (Formula I), as the mother nucleus of meropenem, is an important intermediate for the synthesis of meropenem. Its chemical name is (3S, 4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(R)-1-carbonylethyl]-2-azetidinone, and its structural formula is as follows: (I) The current industrial synthesis route of 4-BMA is shown below: Using 4-AA as the starting material, a Reformatsky reaction is carried out with a chlorospiro ring or a bromospiro ring under the action of zinc powder to obtain a condensation product intermediate, and a new chiral center is constructed in the process. The condensation product is then hydrolyzed under the action of hydrogen peroxide and a base to generate 4-BMA. In the process of constructing the chiral center, the isomeric impurity (3S, 4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(S)-1-carbonylethyl]-2-azetidinone (Formula II) is inevitably produced, and its structure is as follows: (II) During the post-treatment process, the 4-BMA product precipitates in the system, but a small amount of the product remains in the mother liquor. After the mother liquor is recovered, the recovered product is obtained. The purity of 4-BMA is only about 40-70%, and the main impurities are isomers of the above formula II. The use of traditional recrystallization means for recovery not only has a low yield, but also the product quality cannot reach the takeaway standard at one time. In addition, the mixed solvent used has the problem of difficult recovery and is not suitable for industrial production. At present, there are many reports on the optimization of 4-BMA process, but there are no relevant patent reports on obtaining qualified products from recovered products containing a large amount of impurities. Summary of the invention

[0003] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a method for recovering 4-BMA from 4-BMA mother liquor recovery material by using chiral amines, which has high product purity and less isomer impurities.

[0004] The technical solution adopted by the present invention to solve the technical problem is: a method for recovering 4-BMA from 4-BMA mother liquor recovery material, comprising the following steps: 1) Add the recovered 4-BMA mother liquor into the solvent and heat it to dissolve; 2) Add a chiral amine reagent to precipitate 4-BMA in the recovered material, cool it down and filter it to obtain 4-BMA salt; 3) 4-BMA salt is freed by adjusting the base in water, and the freed chiral amine reagent is extracted with a solvent; 4) In a water and organic solvent system, add hydrochloric acid to acidify to precipitate 4-BMA, filter and dry to obtain qualified 4-BMA.

[0005] The invention provides a method for recovering 4-BMA from a 4-BMA mother liquor recovery material. A chiral amine reagent is used to selectively form salts and crystallize 4-BMA, and isomer impurities are retained in the mother liquor, so that the product is purified. This not only improves the recovery rate of 4-BMA, but also ensures the high purity of the product. The purity of the obtained 4-BMA product is more than 95%, and the isomer impurities of formula II are less than 2.5%, which meets the use requirements of downstream.

[0006] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the solvent in step 1) is one or a combination of the following: toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, acetone, tetrahydrofuran, methanol, ethanol, isopropanol, water. The present invention selects an appropriate solvent to ensure that the 4-BMA mother liquor recovery material can be fully dissolved, and at the same time, the chiral amine reagent 4-BMA salt can be fully crystallized, thereby improving the recovery rate of 4-BMA.

[0007] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the mass ratio of the solvent to the 4-BMA mother liquor recovery material in step 1) is 2 to 30: 1. An appropriate solvent mass ratio helps to improve the recovery rate of 4-BMA, so that more 4-BMA can be recovered and reused from the mother liquor recovery material.

[0008] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the heating temperature of step 1) for heating and dissolving is 30° C. to 80° C. Within this temperature range, the solvent can more effectively dissolve 4-BMA in the 4-BMA mother liquor recovery material and avoid thermal decomposition or deterioration at too high a temperature.

[0009] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the chiral amine reagent described in step 2) is one of R(+)-α-methylbenzylamine, R(+)-α-ethylbenzylamine, (R)-(+)-1-(4-chlorophenyl)ethylamine, (1S,2R)-2-amino-1,2-diphenylethanol, (R)-(+)-α-1-naphthylethylamine, D-phenylalaninol, D-phenylglycinol, and (R)-(-)-1-cyclohexylethylamine.

[0010] The preferred chiral amine reagent can highly selectively form a salt with 4-BMA, thereby effectively promoting the precipitation and purification process of 4-BMA, reducing the precipitation of isomeric impurities, and improving the purity and quality of the product. The formed 4-BMA salt has good crystallization characteristics and is easy to separate from the solution by filtration.

[0011] More preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the chiral amine reagent in step 2) is R(+)-α-methylbenzylamine or R(+)-α-ethylbenzylamine. Selecting R(+)-α-methylbenzylamine or R(+)-α-ethylbenzylamine as the chiral amine reagent can not only maintain higher product purity and reaction effect, but also improve economic and environmental benefits.

[0012] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the molar ratio of the chiral amine reagent to 4-BMA in step 2) is 1 to 4: 1. Within this molar ratio range, the chiral amine reagent can fully form a salt with 4-BMA, thereby improving the recovery rate of 4-BMA, while avoiding excessive chiral amine reagent from precipitating with the product, affecting the purity of the final product, and reducing costs.

[0013] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the crystallization temperature during the precipitation of 4-BMA in step 2) is 30°C to 80°C, and the filtration temperature during the cooling filtration is -20 to 40°C. Crystallization in the range of 30°C to 80°C can control the precipitation rate of 4-BMA salt and avoid impurity inclusion caused by too fast precipitation. Filtration in the range of -20 to 40°C can ensure that most of the 4-BMA salt is precipitated, improve the yield, and avoid the precipitation of isomers, which affects the purity of the product.

[0014] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the extraction solvent in step 3) is one of the following: toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, and the mass ratio of the extraction solvent in step 3) to the 4-BMA mother liquor recovery material in step 1) is 0.5 to 10: 1. Within this mass ratio range, it can be ensured that the extraction solvent is fully in contact with the 4-BMA mother liquor recovery material, thereby effectively extracting the chiral amine reagent and improving the extraction efficiency.

[0015] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the pH after alkali adjustment and freeing in step 3) is 9 to 14, and the alkali adjustment temperature during alkali adjustment and freeing is -5°C to 40°C; the extraction temperature during solvent extraction is -5°C to 40°C. Within this pH range, 4-BMA is more completely freed, which is beneficial to improving the extraction efficiency. Controlling the alkali adjustment temperature and the extraction temperature at -5°C to 40°C helps to improve the extraction efficiency. Lower temperatures can reduce the occurrence of side reactions and maintain the stability and purity of the product.

[0016] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the organic solvent described in step 4) is one of the following: toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, acetone; the mass ratio of water described in step 4) to the 4-BMA mother liquor recovery material described in step 1) is 2 to 15:1, and the mass ratio of the organic solvent to the 4-BMA mother liquor recovery material described in step 1) is 0.5 to 5:1. By using these organic solvents, the chiral amine reagent can be effectively extracted, the recovery rate of the chiral amine can be improved, and 4-BMA can be prevented from being extracted and affecting the product yield.

[0017] Preferably, in the above method for recovering 4-BMA from 4-BMA mother liquor recovery material, the pH after hydrochloric acid acidification in step (4) is 0.5-2; the temperature during hydrochloric acid acidification is -5°C-40°C; and the filtration temperature is -5°C-40°C. By accurately controlling the pH and temperature after hydrochloric acid acidification, the product purity and yield of 4-BMA can be improved.

[0018] Compared with the prior art, the method for recovering 4-BMA from 4-BMA mother liquor recovery material by using chiral amines has the following beneficial effects: compared with the prior art, the method adopts a chiral amine reagent and 4-BMA to form salt to obtain purified 4-BMA salt, and further obtains qualified 4-BMA, and isomer impurities are retained in the salt-forming mother liquor. The method can convert most of the recovered 4-BMA into qualified products, has high yield, is simple to operate, and has obvious economic benefits. DETAILED DESCRIPTION

[0019] The present invention is described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited to these embodiments. Any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0020] Example 1 1) Detect the content of 4-BMA in the 4-BMA mother liquor recovery material, add the 4-BMA mother liquor recovery material into ethyl acetate and heat it to 60°C to dissolve it, and the mass ratio of the solvent to the 4-BMA mother liquor recovery material is 15:1.

[0021] 2) Add R(+)-α-methylbenzylamine to cause 4-BMA in the recovered material to precipitate and crystallize at 50°C, with the molar ratio of the chiral amine reagent to 4-BMA being 2:1; cool to -5°C and filter to obtain 4-BMA salt.

[0022] 3) 4-BMA salt is freed by adjusting the base in water, and the base is adjusted to a pH of 12 at 5° C., wherein the mass ratio of water to the recovered 4-BMA mother liquor in step 1) is 6:1, and the freed chiral amine reagent is extracted with ethyl acetate; the mass ratio of the extraction solvent to the recovered 4-BMA mother liquor in step 1) is 5:1, and the extraction temperature is 0° C.

[0023] 4) Prepare a water and ethyl acetate system, wherein the mass ratio of water, ethyl acetate and 4-BMA mother liquor recovered in step 1) is 7:3:1, then add hydrochloric acid to acidify to pH 1 at 5°C to precipitate 4-BMA, filter at 5°C and dry to obtain qualified 4-BMA. The calculated recovery yield is 75.6%, the detected product purity is 98.76%, and the isomer impurity is 0.43%.

[0024] Example 2 1) Detect the content of 4-BMA in the 4-BMA mother liquor recovery material, add the 4-BMA mother liquor recovery material into ethyl acetate and heat it to 60°C to dissolve it, and the mass ratio of the solvent to the 4-BMA mother liquor recovery material is 15:1.

[0025] 2) Add D-phenylalaninol to make 4-BMA in the recovered material precipitate and crystallize at 50°C, and the molar ratio of the chiral amine reagent to 4-BMA is 2:1; cool to -5°C and filter to obtain 4-BMA salt.

[0026] 3) 4-BMA salt is freed by adjusting the base in water, and the base is adjusted to a pH of 12 at 5° C., wherein the mass ratio of water to the recovered 4-BMA mother liquor in step 1) is 6:1, and the freed chiral amine reagent is extracted with ethyl acetate; the mass ratio of the extraction solvent to the recovered 4-BMA mother liquor in step 1) is 5:1, and the extraction temperature is 0° C.

[0027] 4) Prepare a water and ethyl acetate system, wherein the mass ratio of water, ethyl acetate and 4-BMA mother liquor recovered in step 1) is 7:3:1, then add hydrochloric acid to acidify to pH 1 at 5°C to precipitate 4-BMA, filter at 5°C and dry to obtain qualified 4-BMA. The calculated recovery yield is 72.9%, the detected product purity is 98.29%, and the isomeric impurity is 0.76%.

[0028] Example 3 1) Detect the content of 4-BMA in the 4-BMA mother liquor recovery material, add the 4-BMA mother liquor recovery material into dichloromethane and heat it to 50°C to dissolve it, and the mass ratio of the solvent to the 4-BMA mother liquor recovery material is 10:1.

[0029] 2) Add R(+)-α-ethylbenzylamine to cause 4-BMA in the recovered material to precipitate and crystallize at 50°C, and the molar ratio of the chiral amine reagent to 4-BMA is 1.5:1; cool to -5°C and filter to obtain 4-BMA salt.

[0030] 3) 4-BMA salt is freed by adjusting the base in water, and the base is adjusted to a pH of 13 at 10° C., wherein the mass ratio of water to the recovered 4-BMA mother liquor in step 1) is 5:1, and the freed chiral amine reagent is extracted with dichloroethane; the mass ratio of the extraction solvent to the recovered 4-BMA mother liquor in step 1) is 3:1, and the extraction temperature is 10° C.

[0031] 4) Prepare a water and dichloromethane system, wherein the mass ratio of water, dichloromethane and 4-BMA mother liquor recovered in step 1) is 10:2:1, then add hydrochloric acid to acidify to pH 1.5 at 10°C to precipitate 4-BMA, filter at 10°C and dry to obtain qualified 4-BMA. The calculated recovery yield is 74.5%, the detected product purity is 98.67%, and the isomeric impurity is 0.47%.

[0032] Example 4 1) Detect the content of 4-BMA in the 4-BMA mother liquor recovery material, add the 4-BMA mother liquor recovery material into tetrahydrofuran and heat it to 60°C to dissolve it, and the mass ratio of the solvent to the 4-BMA mother liquor recovery material is 20:1.

[0033] 2) Add (R)-(+)-α-1-naphthylethylamine to cause 4-BMA in the recovered material to precipitate and crystallize at 60°C, with the molar ratio of the chiral amine reagent to 4-BMA being 3:1; cool to 10°C and filter to obtain 4-BMA salt.

[0034] 3) adjusting the base to free the 4-BMA salt in water, adjusting the base to free the 4-BMA salt at 15° C. to a pH of 11, wherein the mass ratio of water to the 4-BMA mother liquor recovered in step 1) is 12:1, and extracting the free chiral amine reagent with tetrahydrofuran; the mass ratio of the extraction solvent to the 4-BMA mother liquor recovered in step 1) is 7:1, and the extraction temperature is 15° C.

[0035] 4) Prepare a water and tetrahydrofuran system, wherein the mass ratio of water, tetrahydrofuran and 4-BMA mother liquor recovered in step 1) is 5:4:1, then add hydrochloric acid to acidify to pH 1 at -1°C to precipitate 4-BMA, filter at -1°C and dry to obtain qualified 4-BMA. The calculated recovery yield is 72.2%, the detected product purity is 98.22%, and the isomeric impurity is 0.79%.

[0036] Example 5 1) Detect the content of 4-BMA in the 4-BMA mother liquor recovery material, add the 4-BMA mother liquor recovery material into toluene and heat it to 80°C to dissolve it, and the mass ratio of the solvent to the 4-BMA mother liquor recovery material is 2:1.

[0037] 2) Add R(+)-α-methylbenzylamine to cause 4-BMA in the recovered material to precipitate and crystallize at 80°C, and the molar ratio of the chiral amine reagent to 4-BMA is 0.5:1; cool to 40°C and filter to obtain 4-BMA salt.

[0038] 3) 4-BMA salt is freed by adjusting the base in water, and the base is adjusted to pH 9 at 40° C., wherein the mass ratio of water to the 4-BMA mother liquor recovered in step 1) is 2:1, and the freed chiral amine reagent is extracted with toluene; the mass ratio of the extraction solvent to the 4-BMA mother liquor recovered in step 1) is 0.5:1, and the extraction temperature is 40° C.

[0039] 4) Prepare a water and toluene system, wherein the mass ratio of water, toluene and 4-BMA mother liquor recovered in step 1) is 15:0.5:1, then add hydrochloric acid to acidify to pH 0.5 at 40°C to precipitate 4-BMA, filter at 40°C and dry to obtain qualified 4-BMA. The calculated recovery yield is 70.9%, the detected product purity is 98.36%, and the isomer impurity is 0.51%.

[0040] Example 6 1) Detect the content of 4-BMA in the 4-BMA mother liquor recovery material, add the 4-BMA mother liquor recovery material into ethyl acetate and heat it to 30°C to dissolve it, and the mass ratio of the solvent to the 4-BMA mother liquor recovery material is 30:1.

[0041] 2) Add D-phenylalaninol to make 4-BMA in the recovered material precipitate and crystallize at 30°C, and the molar ratio of the chiral amine reagent to 4-BMA is 4:1; cool to -20°C and filter to obtain 4-BMA salt.

[0042] 3) 4-BMA salt is freed by adjusting the base in water, and the base is adjusted to a pH of 14 at -5°C, wherein the mass ratio of water to the 4-BMA mother liquor recovered in step 1) is 15:1, and the freed chiral amine reagent is extracted with ethyl acetate; the mass ratio of the extraction solvent to the 4-BMA mother liquor recovered in step 1) is 10:1, and the extraction temperature is -5°C.

[0043] 4) Prepare a water and ethyl acetate system, wherein the mass ratio of water, ethyl acetate and 4-BMA mother liquor recovered in step 1) is 2:5:1, then add hydrochloric acid to acidify to pH 2 at -5°C to precipitate 4-BMA, filter at -5°C and dry to obtain qualified 4-BMA. The calculated recovery yield is 71.6%, the detected product purity is 98.21%, and the isomer impurity is 0.83%.

[0044] The above is only a preferred embodiment of the present invention, and does not limit the present invention in other forms. Any technician familiar with the profession may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still belongs to the protection scope of the technical solution of the present invention.

Claims

1. A method for recovering 4-BMA from 4-BMA mother liquor recovery material, comprising the following steps: 1) Add the recovered 4-BMA mother liquor into the solvent and heat it to dissolve; 2) Add a chiral amine reagent to precipitate the 4-BMA in the recovered material into salt, cool it down and filter it to obtain the 4-BMA salt; 3) dissolving the obtained 4-BMA salt in water, freeing it by adjusting the base, and extracting the freed chiral amine reagent with an extraction solvent; 4) Add an organic solvent to the aqueous phase after separation of the chiral amine, add hydrochloric acid dropwise to acidify, precipitate 4-BMA, filter and dry to obtain qualified 4-BMA.

2. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The solvent described in step 1) is one of the following or a combination thereof: toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, acetone, tetrahydrofuran, methanol, ethanol, isopropanol, water, and the mass ratio of the solvent to the 4-BMA mother liquor recovery material is 2-30:

1.

3. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The heating temperature for the step 1) is 30°C to 80°C.

4. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The chiral amine reagent described in step 2) is one of R(+)-α-methylbenzylamine, R(+)-α-ethylbenzylamine, (R)-(+)-1-(4-chlorophenyl)ethylamine, (1S,2R)-2-amino-1,2-diphenylethanol, (R)-(+)-α-1-naphthylethylamine, D-phenylalaninol, D-phenylglycinol, and (R)-(-)-1-cyclohexylethylamine.

5. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The molar ratio of the chiral amine reagent to 4-BMA in step 2) is 1-4:

1.

6. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The crystallization temperature of 4-BMA during precipitation in step 2) is 30°C to 80°C, and the filtration temperature during the cooling filtration is -20°C to 40°C.

7. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The extraction solvent described in step 3) is one of the following: toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, and the mass ratio of the extraction solvent described in step 3) to the 4-BMA mother liquor recovery material described in step 1) is 0.5~10:

1.

8. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The pH after alkali adjustment and extraction in step 3) is 9-14, and the temperature during alkali adjustment and extraction is -5°C-40°C.

9. A method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The organic solvent described in step 4) is one of the following: toluene, xylene, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, acetone; the mass ratio of the organic solvent to the 4-BMA mother liquor recovery material described in step 1) is 0.5~5:

1.

10. The method for recovering 4-BMA from 4-BMA mother liquor recovery material according to claim 1, characterized in that: The pH after hydrochloric acid acidification in step 4) is 0.5-2; the temperature during hydrochloric acid acidification is -5°C-40°C.

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