CN104803868B - Method for recovering 3-isobutyl glutaric acid monoamide - Google Patents
Method for recovering 3-isobutyl glutaric acid monoamide Download PDFInfo
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Abstract
The invention discloses a method for recovering 3-isobutyl glutaric acid monoamide from pregabalin intermediate 3-isobutyl glutaric acid monoamide mother liquor containing more than 20 percent, which comprises the following steps: a) concentrating the mother liquor to dryness, and then adding water into the system; b) heating, and adding liquid alkali into the system to adjust the pH value; c) cooling, and adding hydrochloric acid into the system to adjust the pH value; d) continuously cooling, preserving heat, filtering and drying the system with the adjusted pH value; e) and adding a solvent into the dried sample, pulping, filtering, and drying to obtain a final product. The invention provides a method for recovering 3-isobutyl glutaric acid monoamide, which is green, environment-friendly, simple and convenient and has little pollution.
Description
Technical Field
The invention provides a method for recovering 3-isobutyl glutaric acid monoamide from pregabalin intermediate mother liquor, belonging to the field of pharmaceutical chemicals.
Background
Pregabalin, the english name Pregabalin, is a novel gamma-aminobutyric acid (GABA) receptor antagonist developed by Pfizer corporation. The pharmaceutical composition is approved for adjuvant therapy of adult partial seizure epilepsy in 6 months in 2005, is the most promising drug in developed epilepsy therapeutic drugs, has strong anticonvulsant effect, small side effect, small dose, small administration frequency, and has the advantages of anxiolytic effect and the like compared with gabapentin, does not interact with the existing antiepileptic drugs, and is convenient to be used together with other antiepileptic drugs for synergistic antiepileptic effect. Indications are increased in 2006 for 3 months, generalized anxiety disorder and social anxiety disorder are treated, and treatment of spinal cord injury, trauma, multiple sclerosis, diabetic neuropathic pain and herpes zoster neuropathic pain is approved again in 2009, so that clinical application of the traditional Chinese medicine is further expanded. Because pregabalin has better effects of resisting epilepsy and anxiety, treating neuropathic pain and the like, pregabalin is widely applied in clinic at present.
At present, a plurality of synthesis lines are adopted, a compound 1 is resolved to obtain a resolved salt and an isomer 2 of the compound 1, a compound 3 is dissociated to obtain a compound 5, and the compound 5 is degraded by hoffmann to obtain pregabalin.
The invention is carried out during the whole process of obtaining compound 1 by further processing after racemization of compound 2 to obtain intermediate 4. At present, the yield of a compound 3 obtained by resolving a compound 1 by a resolving agent is generally 33-35%, the yield of a process of obtaining 1 by racemizing an isomer 2 is generally 40-45%, namely more than 20% of the compound 1 is not further treated to directly form solid waste and liquid waste, which has great influence on environmental protection and cost.
Disclosure of Invention
The invention aims to provide a method for recovering 3-isobutyl glutaric acid monoamide from a mother liquor containing more than 20% of pregabalin intermediate 3-isobutyl glutaric acid monoamide, which comprises the following steps:
1. a process for recovering 3-isobutylglutaric acid monoamide from a mother liquor containing more than 20% of pregabalin intermediate 3-isobutylglutaric acid monoamide, characterized by comprising the steps of:
1) concentrating the mother liquor to dryness, and then adding water into the system;
2) heating, and adding liquid alkali into the system to adjust the pH value;
3) cooling, and adding hydrochloric acid into the system to adjust the pH value;
4) continuously cooling the system with the adjusted pH value, preserving heat, filtering and drying;
5) and adding a solvent into the dried sample, pulping, filtering, and drying to obtain a final product.
The mother liquor refers to ethyl acetate filtrate which is obtained by adding ammonia water dropwise into 3-isobutyl glutaric anhydride for reaction, then extracting with ethyl acetate, concentrating, cooling and carrying out suction filtration.
The weight of the water added in the step 1) is 1-4 times of the weight of the concentrate.
And 2) heating to 30-50 ℃, and adjusting the pH to be more than or equal to 13.
And 3) cooling to 20-30 ℃.
And 3) adjusting the pH value to 2-4.
And 4) cooling in the step 4 to 0-10 ℃.
The solvent used in the step 5) is ethyl acetate, dichloromethane or toluene.
The invention has very obvious advantages under the current environment-friendly pressure form: by recycling, the total organic carbon content in the wastewater can be reduced, the atom utilization rate is improved, and the direct discharge of materials in the mother liquor is avoided to pollute the environment; no special equipment and instruments are required; has the characteristic of green chemistry. In conclusion, the invention provides a method for recovering 3-isobutyl glutaric acid monoamide, which is green, environment-friendly, simple and convenient and has less pollution.
Detailed Description
The invention is further illustrated with reference to the following examples, which, however, do not constitute any limitation of the invention.
Preparation example Ethyl acetate mother liquor example
Preparation of 3-isobutylglutaric acid monoamide ethyl acetate mother liquor: weighing 500g of concentrated and dried raceme, adding 2000mL of toluene, heating to 110-120 ℃, stirring, and simultaneously dividing water. After water separation, cooling to 40-50 ℃, dropwise adding 1500g of water and 500g of 30% NaOH aqueous solution, keeping the temperature and stirring for 3-4 hours after adding, cooling to 20-30 ℃, standing for layering, after separating out the aqueous phase, adding 1000.0g of water into the organic phase, stirring, standing for layering, and mixing after separating out the aqueous phase. Dropwise adding concentrated hydrochloric acid into the water phase within the temperature range of 0-10 ℃ to adjust the pH value to 1.5-4, and finishing the adjustment. Adding 1000 mL and 600mL ethyl acetate respectively, stirring, standing for layering, combining organic phases, distilling under reduced pressure to 800mL, slowly cooling to 0 +/-5 ℃, and filtering to obtain filtrate, namely the ethyl acetate mother liquor of the 3-isobutylglutaric acid.
Example 1:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 300g of water into the evaporated system, heating to 40 ℃, adding 100g of 30% liquid alkali into the system, adjusting the pH to 14, cooling the system with the adjusted pH to 20 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 2, adjusting the pH to 0, keeping the temperature, stirring for 3 hours, and filtering and drying to obtain a filter cake. Adding 350ml of toluene into the dried filter cake, pulping for 1h, and performing suction filtration and drying to obtain 75g of 3-isobutylglutaric acid monoamide, wherein the yield is 15.0 percent and the purity is 99.73 percent.
Example 2:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 200g of water into the evaporated system, heating to 45 ℃, adding 100g of 30% liquid alkali into the system to adjust the pH to 14, cooling the system with the adjusted pH to 30 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 2, adjusting the pH to 5 ℃, keeping the temperature, stirring for 2h, and filtering and drying to obtain a filter cake. Adding 300ml of toluene into the dried filter cake, pulping for 2 hours, and performing suction filtration and drying to obtain 78.3g of 3-isobutylglutaric acid monoamide, wherein the yield is 15.6 percent and the purity is 99.64 percent.
Example 3:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 400g of water into the evaporated system, heating to 30 ℃, adding 90g of 30% liquid alkali into the system to adjust the pH to 13, cooling the system with the adjusted pH to 20 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 3, adjusting the pH to 10 ℃, keeping the temperature, stirring for 2 hours, and filtering and drying to obtain a filter cake. Adding 400ml of toluene into the dried filter cake, pulping for 1.5h, and performing suction filtration and drying to obtain 73.8g of 3-isobutyl glutaric acid monoamide, wherein the yield is 14.8 percent, and the purity is 99.85 percent.
Example 4:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 250g of water into the evaporated system, heating to 50 ℃, adding 100g of 30% liquid alkali into the system to adjust the pH to 14, cooling the system with the adjusted pH to 30 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 2.5, adjusting the pH until the pH is reduced to 8 ℃, keeping the temperature, stirring for 2.5h, and filtering and drying to obtain a filter cake. Adding 250ml of toluene into the dried filter cake, pulping for 1h, and performing suction filtration and drying to obtain 84.7g of 3-isobutylglutaric acid monoamide, wherein the yield is 16.9 percent and the purity is 99.85 percent.
Example 5:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 180g of water into the evaporated system, heating to 45 ℃, adding 95g of 30% liquid alkali into the system to adjust the pH to 14, cooling the system with the adjusted pH to 30 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 3, adjusting the pH to 5 ℃, keeping the temperature, stirring for 3 hours, and filtering and drying to obtain a filter cake. Adding 350ml ethyl acetate into the dried filter cake, pulping for 1h, filtering and drying to obtain 81.1g of 3-isobutyl glutaric acid monoamide, wherein the yield is 16.2 percent and the purity is 99.90 percent.
Example 6:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 250g of water into the evaporated system, heating to 40 ℃, adding 100g of 30% liquid alkali into the system to adjust the pH to 14, cooling the system with the adjusted pH to 20 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 2, adjusting the pH to be 3 ℃, keeping the temperature, stirring for 2h, and filtering and drying to obtain a filter cake. Adding 350ml of ethyl acetate into the dried filter cake, pulping for 2 hours, and performing suction filtration and drying to obtain 80.7g of 3-isobutyl glutaric acid monoamide, wherein the yield is 16.1 percent, and the purity is 99.93 percent.
Example 7:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 320g of water into the evaporated system, heating to 48 ℃, adding 97g of 30% liquid alkali into the system to adjust the pH to 14, cooling the system with the adjusted pH to 28 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 4, adjusting the pH to 0, keeping the temperature, stirring for 3 hours, and filtering and drying to obtain a filter cake. Adding 400ml ethyl acetate into the dried filter cake, pulping for 1.5h, filtering and drying to obtain 75.5g of 3-isobutyl glutaric acid monoamide, wherein the yield is 15.1 percent, and the purity is 99.73 percent.
Example 8:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 400g of water into the evaporated system, heating to 42 ℃, adding 100g of 30% liquid alkali into the system, adjusting the pH to 14, cooling the system with the adjusted pH to 20 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 1, adjusting the pH to 0, keeping the temperature, stirring for 2 hours, and filtering and drying to obtain a filter cake. And adding 360ml of ethyl acetate into the dried filter cake, pulping for 1h, and performing suction filtration and drying to obtain 87.5g of 3-isobutylglutaric acid monoamide, wherein the yield is 17.5 percent and the purity is 99.69 percent.
Example 9:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 390g of water into the evaporated system, heating to 35 ℃, adding 100g of 30% liquid caustic soda into the system to adjust the pH to 14, cooling the system with the adjusted pH to 20 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 3, adjusting the pH until the pH is reduced to 8 ℃, keeping the temperature and stirring for 2.5h, and carrying out suction filtration and drying to obtain a filter cake. Adding 350ml of dichloromethane into the dried filter cake, pulping for 1h, filtering and drying to obtain 79g of 3-isobutyl glutaric acid monoamide, wherein the yield is 15.8 percent, and the purity is 99.85 percent.
Example 10:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 450g of water into the evaporated system, heating to 48 ℃, adding 100g of 30% liquid alkali into the system to adjust the pH to 14, cooling the system with the adjusted pH to 20 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 3.5, adjusting the pH to 0, then cooling to 0 ℃, keeping the temperature and stirring for 2.5h, and carrying out suction filtration and drying to obtain a filter cake. Adding 380ml of dichloromethane into the dried filter cake, pulping for 2 hours, filtering and drying to obtain 86g of 3-isobutylglutaric acid monoamide, wherein the yield is 17.2 percent and the purity is 99.91 percent.
Example 11:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 300g of water into the evaporated system, heating to 40 ℃, adding 100g of 30% liquid alkali into the system, adjusting the pH to 14, cooling the system with the adjusted pH to 25 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 2, adjusting the pH to 0, keeping the temperature, stirring for 2h, and filtering and drying to obtain a filter cake. Adding 300ml of dichloromethane into the dried filter cake, pulping for 1h, filtering and drying to obtain 90.5g of 3-isobutyl glutaric acid monoamide, wherein the yield is 18.1 percent, and the purity is 99.63 percent.
Example 12:
750ml of ethyl acetate mother liquor which is filtered and filtered is taken, concentrated to dryness and weighed to obtain 155 g. Adding 400g of water into the evaporated system, heating to 45 ℃, adding 100g of 30% liquid alkali into the system to adjust the pH to 14, cooling the system with the adjusted pH to 20 ℃, then dropwise adding concentrated hydrochloric acid until the pH is equal to 1.5, adjusting the pH to 0, then cooling to 0 ℃, keeping the temperature and stirring for 2.5h, and carrying out suction filtration and drying to obtain a filter cake. Adding 350ml of dichloromethane into the dried filter cake, pulping for 1.5h, filtering and drying to obtain 84g of 3-isobutyl glutaric acid monoamide, wherein the yield is 16.8 percent, and the purity is 99.79 percent.
Claims (8)
1. A process for recovering 3-isobutylglutaric acid monoamide from a mother liquor containing more than 20% of pregabalin intermediate 3-isobutylglutaric acid monoamide, characterized by comprising the steps of:
1) concentrating the mother liquor to dryness, and then adding water into the system;
2) heating, and adding liquid alkali into the system to adjust the pH value;
3) cooling, and adding hydrochloric acid into the system to adjust the pH value;
4) continuously cooling the system with the adjusted pH value, preserving heat, filtering and drying;
5) adding a solvent into the dried sample, pulping, filtering and drying to obtain a final product;
the mother liquor refers to ethyl acetate filtrate which is obtained by adding ammonia water dropwise into 3-isobutyl glutaric anhydride for reaction, then extracting with ethyl acetate, concentrating, cooling and carrying out suction filtration.
2. The method of claim 1, wherein the water added in step 1) is 1 to 4 times the weight of the concentrate.
3. The method according to claim 1, wherein the temperature in the step 2) is raised to 30-50 ℃.
4. The method according to claim 1, wherein the pH in step 2) is adjusted to 13 or more.
5. The method according to claim 1, wherein the temperature in step 3) is reduced to 20-30 ℃.
6. The method according to claim 1, wherein the pH in step 3) is adjusted to 2 to 4.
7. The method according to claim 1, wherein the temperature reduction in the step 4) is to be 0-10 ℃.
8. The method according to claim 1, wherein the solvent used in step 5) is ethyl acetate, dichloromethane, toluene.
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| CN111747862A (en) * | 2020-06-22 | 2020-10-09 | 浙江华海药业股份有限公司 | Method for recovering pregabalin intermediate 3-isobutyl glutaric acid monoamide |
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