CN105481712A - Racemization recycling method of Pregabalin intermediate mother liquor from resolution - Google Patents
Racemization recycling method of Pregabalin intermediate mother liquor from resolution Download PDFInfo
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- CN105481712A CN105481712A CN201510850853.9A CN201510850853A CN105481712A CN 105481712 A CN105481712 A CN 105481712A CN 201510850853 A CN201510850853 A CN 201510850853A CN 105481712 A CN105481712 A CN 105481712A
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- mother liquor
- carbamoylmethyl
- methylhexanoic acid
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- 238000000034 method Methods 0.000 title claims abstract description 27
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 20
- 239000012452 mother liquor Substances 0.000 title claims abstract description 17
- 229960001233 pregabalin Drugs 0.000 title claims abstract description 14
- 230000006340 racemization Effects 0.000 title claims abstract description 14
- 238000004064 recycling Methods 0.000 title abstract 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 18
- FNAQPQLVCOZGRH-UHFFFAOYSA-N 4-(2-methylpropyl)piperidine-2,6-dione Chemical compound CC(C)CC1CC(=O)NC(=O)C1 FNAQPQLVCOZGRH-UHFFFAOYSA-N 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000018044 dehydration Effects 0.000 claims abstract description 10
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- 238000001816 cooling Methods 0.000 claims abstract description 5
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims abstract description 3
- 238000011084 recovery Methods 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 12
- NPDKTSLVWGFPQG-UHFFFAOYSA-N 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)CC(CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-UHFFFAOYSA-N 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- NPDKTSLVWGFPQG-ZETCQYMHSA-N (3s)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@@H](CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-ZETCQYMHSA-N 0.000 claims description 7
- 238000009833 condensation Methods 0.000 claims description 7
- 230000005494 condensation Effects 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 238000013517 stratification Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract 2
- 239000008096 xylene Substances 0.000 abstract 2
- 238000009776 industrial production Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 8
- 229940009697 lyrica Drugs 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 3
- UATSLDZQNXAKMA-UHFFFAOYSA-N 3-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(CC(O)=O)CC(O)=O UATSLDZQNXAKMA-UHFFFAOYSA-N 0.000 description 2
- HYHLWVJLJXARGY-UHFFFAOYSA-N 3-(aminomethyl)benzamide Chemical compound NCC1=CC=CC(C(N)=O)=C1 HYHLWVJLJXARGY-UHFFFAOYSA-N 0.000 description 2
- YGHRJJRRZDOVPD-UHFFFAOYSA-N 3-methylbutanal Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- DTGKSKDOIYIVQL-NQMVMOMDSA-N (+)-Borneol Natural products C1C[C@]2(C)[C@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-NQMVMOMDSA-N 0.000 description 1
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- LHSAKGVBHJUEOV-UHFFFAOYSA-N 2-(2-methylpropyl)pentanedioic acid Chemical compound CC(C)CC(C(O)=O)CCC(O)=O LHSAKGVBHJUEOV-UHFFFAOYSA-N 0.000 description 1
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 240000005636 Dryobalanops aromatica Species 0.000 description 1
- 208000011688 Generalised anxiety disease Diseases 0.000 description 1
- 238000006845 Michael addition reaction Methods 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 208000029364 generalized anxiety disease Diseases 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- -1 triethylamine Chemical compound 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/20—Preparation of optical isomers by separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/86—Oxygen atoms
- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a racemization recycling method of Pregabalin intermediate mother liquor from resolution. The method comprises the following steps: (1) after resolution of 3-(carbamoymethyl)-5-methylhexanoic acid racemate is carried out by using (R)-phenylethylamine, mother liquor is condensed and dissolved in water, concentrated hydrochloric acid is used for adjusting pH value to 1-3, cooling is carried out for crystallization, and (S)-3-(carbamoymethyl)-5-methylhexanoic acid is obtained; (2) (S)-3-(carbamoymethyl)-5-methylhexanoic acid is added into xylene, after dissolving, temperature is raised to 80-150 DEG C for dehydration and cyclization, and 3-isobutylglutarimid is obtained; (3) under an alkaline condition, 3-isobutylglutarimid is hydrolyzed, and 3-(carbamoymethyl)-5-methylhexanoic acid racemate is obtained. Xylene is selected as a solvent for the dehydration and cyclization reaction, so that recycling yield is high, reaction time is short, expensive reagents are not needed and cost is low; the method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to the racemization recovery method that a kind of pregabalin intermediate (R)-3-(carbamoylmethyl)-5-methylhexanoic acid splits mother liquor.
Background technology
The chemical name of lyrica (Pregabalin) is (S)-3-aminomethyl-5-methylhexanoic acid, is novel γ-aminobutyric acid (GABA) receptor antagonist developed by Pfizer.Be used for the treatment of the partial seizure of adult patients in July, 2004 first through European Union's approval, commodity are called Lyrica.In June, 2005, in March, 2006 increased indication through FDA Food and Drug Administration (FDA) approval in U.S.'s listing, treatment generalized anxiety disorder and sociability anxiety disorder.Within 2009, get permission again to treat spinal cord injury, wound, multiple sclerosis, diabetic neuropathy pain and belt-shaped blister neuralgia, make its clinical application be further expanded.The structural formula of lyrica is as follows:
。
At present, the method preparing lyrica is all adopt methyl cyanoacetate and isovaleric aldehyde to be raw material mostly, first carries out the condensation of Borneo camphor Culture Revolution that, then with diethyl malonate generation Michael addition, then through intermediate 3-isobutylglutaric acid that hydrochloric acid hydrolysis decarboxylation obtains; Intermediate 3-isobutylglutaric acid is dehydrated into acid anhydride under aceticanhydride, and ammonia solution obtains key intermediate 3-(carbamoylmethyl)-5-methylhexanoic acid raceme.Prepare lyrica by key intermediate 3-(carbamoylmethyl)-5-methylhexanoic acid raceme and then there are following two kinds of methods:
Method 1: first 3-(carbamoylmethyl)-5-methylhexanoic acid raceme is obtained 3-aminomethyl-5-methylhexanoic acid raceme through Hofmann degradation, then splits with (S)-MA and obtains (S)-lyrica (as world patent document WO2008138874A).
Method 2: first the mesotomy of 3-(carbamoylmethyl)-5-methylhexanoic acid is obtained intermediate (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, then obtain (S)-lyrica (as american documentation literature US5616793A) through Hofmann degradation.
By product (R)-lyrica after method 1 splits due to cannot recycle, thus adds production cost and the pollution to environment.
By product (S)-3-(carbamoylmethyl)-5-methylhexanoic acid after method 2 splits then can be recycled after racemization, thus greatly reduces costs.
For the racemization recovery method of (S)-3-(carbamoylmethyl)-5-methylhexanoic acid, existing document discloses following several:
(1) world patent document WO9638405A is disclosed obtains 2-isobutylglutaric acid raceme by (S)-3-(carbamoylmethyl)-5-methylhexanoic acid after concentrated hydrochloric acid hydrolysis, then obtains 3-(carbamoylmethyl)-5-methylhexanoic acid raceme through condensation, ammonia solution.The deficiency of the method is: yield is lower, only has about 60%, and processing step is more, and aftertreatment spent acid waste liquid is more, improper suitability for industrialized production.
(2) Chinese patent literature CN104030936A is disclosed is condensed into 3-isobutyl-glutarimide with condensing agent by (S)-3-(carbamoylmethyl)-5-methylhexanoic acid, then hydrolysis obtains 3-(carbamoylmethyl)-5-methylhexanoic acid raceme in the basic conditions.The deficiency of the method is: condensing agent price is higher, causes production cost higher, is not suitable for suitability for industrialized production.
(3) disclosed first the reaction in a solvent with alkali reagent DMAP of Chinese patent literature CN104140375A generates 4-isobutyl basic ring-2,4-dioxopiperidine, then be hydrolyzed in ethanol with sodium hydroxide, potassium hydroxide or lithium hydroxide etc. and generate 3-carbamoylmethyl-5-methylhexanoic acid.This recovery method deficiency is: yield only has about 60% equally, lower equally, and alkali reagent DMAP price is higher equally, is not suitable for suitability for industrialized production.
(4) indian patent document IN2009MU01327 disclosed by (S)-3-(carbamoylmethyl)-5-methylhexanoic acid under the catalysis of the acid reagents such as organic bases or sulfuric acid such as triethylamine, obtain 3-isobutyl-glutarimide with refluxing toluene 10 ~ 24h, then obtain 3-(carbamoylmethyl)-5-methylhexanoic acid raceme through hydrolysis.The method reaction times is still longer, and temperature of reaction is higher, and transformation efficiency is lower, is not suitable for suitability for industrialized production equally.
Summary of the invention
The pregabalin intermediate of suitability for industrialized production of the object of the invention is to solve the problem, provide that a kind of yield is higher, cost is lower, be applicable to splits the recovery method of mother liquor.
The technical scheme realizing the object of the invention is: a kind of pregabalin intermediate splits the racemization recovery method of mother liquor, there are following steps: (R)-phenylethylamine 1. will be adopted to split 3-(carbamoylmethyl) soluble in water after mother liquor concentrations after-5-methylhexanoic acid raceme, pH to 1 ~ 3 are regulated with concentrated hydrochloric acid, cooling crystallization, obtains (S)-3-(carbamoylmethyl)-5-methylhexanoic acid; 2. (the S)-3-(carbamoylmethyl 1. step obtained)-5-methylhexanoic acid joins in dimethylbenzene, and dissolve post-heating to 80 ~ 150 DEG C and carry out dehydration condensation, obtain 3-isobutyl-glutarimide; 3. 3-isobutyl-glutarimide step 2. obtained is hydrolyzed in the basic conditions and obtains 3-(carbamoylmethyl)-5-methylhexanoic acid raceme.
Above-mentioned steps 2. described in (S)-3-(carbamoylmethyl) weight ratio of-5-methylhexanoic acid and dimethylbenzene is 1: 5 ~ 1: 30, preferably 1: 10 ~ 1: 15.
Above-mentioned steps 2. in temperature of reaction be preferably 110 ~ 130 DEG C.
Above-mentioned steps concrete grammar is 3. as follows: in the 3-isobutyl-glutarimide that 2. step obtains, add water and alkaline reagents, stirs the reaction that is hydrolyzed, stratification, and water layer concentrated hydrochloric acid regulates pH to 1 ~ 3, and extraction is concentrated, cooling crystallization, and suction filtration is dry.
Above-mentioned steps 3. described in alkaline reagents be potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood or sodium carbonate.
The positively effect that the present invention has: the solvent that method choice dimethylbenzene of the present invention reacts as dehydration condensation, can obtain higher recovery yield, and the reaction times is shorter, and the reagent without the need to using price higher, thus cost is lower, suitability for industrialized production can be applicable to.
Embodiment
(embodiment 1)
The pregabalin intermediate of the present embodiment splits the racemization recovery method of mother liquor, has following steps:
1. (the S)-3-(carbamoylmethyl will obtained after the mother liquor concentrations after fractionation)-5-methylhexanoic acid-(R)-phenylethylamine salt (65.0g) is dissolved in the water of 325g, pH to 1 ~ 3 are regulated with concentrated hydrochloric acid, be cooled to 5 DEG C, insulated and stirred 1h, suction filtration, once, suction filtration, obtains (S)-3-(carbamoylmethyl of 39.5g to the making beating of filter cake use water)-5-methylhexanoic acid.
(S)-3-(carbamoylmethyl of the 39.5g 2. 1. step obtained)-5-methylhexanoic acid joins in the dimethylbenzene of 460g, and be warming up to 120 DEG C after stirring and dissolving and carry out reflux water-dividing reaction 8h, obtain the reaction mass containing 3-isobutyl-glutarimide.
3. the reaction mass containing 3-isobutyl-glutarimide step 2. obtained is cooled to 30 DEG C, add the water of 610g and the salt of wormwood of 150g, stirring reaction 1h, stratification, water layer concentrated hydrochloric acid regulates pH to 1 ~ 3, with toluene (250g × 3) extraction three times, concentrated after merging organic phase, be cooled to less than 10 DEG C, insulation crystallization 1h, suction filtration, dries the 3-(carbamoylmethyl obtaining 34.0g)-5-methylhexanoic acid raceme, yield is 86.1%.
(embodiment 2 ~ embodiment 5)
Each embodiment is substantially the same manner as Example 1, and difference is in table 1.
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| Dimethylbenzene | 460g | 460g | 460g | 395g | 600g |
| Dehydration condensation temperature of reaction | 120℃ | 130℃ | 110℃ | 120℃ | 120℃ |
| The dehydration condensation reaction times | 8h | 7h | 9h | 8h | 8h |
| Raceme | 34.0g | 34.1g | 33.7g | 33.8g | 34.2g |
| Yield | 86.1% | 86.3% | 85.3% | 85.6% | 86.6% |
(comparative example 1 ~ comparative example 5)
Each comparative example is substantially the same manner as Example 1, and difference is in table 2.
Table 2
| Embodiment 1 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | |
| Dehydration condensation reaction solvent | 460g dimethylbenzene | 460g toluene | 460g toluene | The DMF of 460g | The DMF of 460g | The DMF of 460g |
| Dehydration condensation temperature of reaction | 120℃ | 120℃ | 120℃ | 120℃ | 150℃ | 150℃ |
| The dehydration condensation reaction times | 8h | 8h | 24h | 8h | 8h | 24h |
| Raceme | 34.0g | 17.6g | 24.6g | 14.6g | 16.9g | 22.7g |
| Yield | 86.1% | 44.6% | 62.3% | 37.0% | 42.8% | 57.5% |
Claims (6)
1. pregabalin intermediate splits a racemization recovery method for mother liquor, it is characterized in that having following steps:
1. (R)-phenylethylamine will be adopted to split 3-(carbamoylmethyl) soluble in water after mother liquor concentrations after-5-methylhexanoic acid raceme, regulate pH to 1 ~ 3 with concentrated hydrochloric acid, cooling crystallization, obtains (S)-3-(carbamoylmethyl)-5-methylhexanoic acid;
2. (the S)-3-(carbamoylmethyl 1. step obtained)-5-methylhexanoic acid joins in dimethylbenzene, and dissolve post-heating to 80 ~ 150 DEG C and carry out dehydration condensation, obtain 3-isobutyl-glutarimide;
3. 3-isobutyl-glutarimide step 2. obtained is hydrolyzed in the basic conditions and obtains 3-(carbamoylmethyl)-5-methylhexanoic acid raceme.
2. pregabalin intermediate according to claim 1 splits the racemization recovery method of mother liquor, it is characterized in that: step 2. described in (S)-3-(carbamoylmethyl) weight ratio of-5-methylhexanoic acid and dimethylbenzene is 1: 5 ~ 1: 30.
3. pregabalin intermediate according to claim 1 splits the racemization recovery method of mother liquor, it is characterized in that: step 2. described in (S)-3-(carbamoylmethyl) weight ratio of-5-methylhexanoic acid and dimethylbenzene is 1: 10 ~ 1: 15.
4. pregabalin intermediate according to claim 1 splits the racemization recovery method of mother liquor, it is characterized in that: step 2. in temperature of reaction be 110 ~ 130 DEG C.
5. the racemization recovery method of mother liquor is split according to the pregabalin intermediate one of Claims 1-4 Suo Shu, it is characterized in that step concrete grammar is 3. as follows: in the 3-isobutyl-glutarimide that 2. step obtains, add water and alkaline reagents, stirring is hydrolyzed reaction, stratification, water layer concentrated hydrochloric acid regulates pH to 1 ~ 3, extraction, concentrated, cooling crystallization, suction filtration, dry.
6. pregabalin intermediate according to claim 5 splits the racemization recovery method of mother liquor, it is characterized in that: step 3. described in alkaline reagents be potassium hydroxide, sodium hydroxide, lithium hydroxide, salt of wormwood or sodium carbonate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111747862A (en) * | 2020-06-22 | 2020-10-09 | 浙江华海药业股份有限公司 | A kind of method of reclaiming pregabalin intermediate 3-isobutylglutaric acid monoamide |
| CN112745240A (en) * | 2021-01-19 | 2021-05-04 | 宁波酶赛生物工程有限公司 | Recrystallization method of high-selectivity pregabalin intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996038405A1 (en) * | 1995-06-02 | 1996-12-05 | Warner-Lambert Company | Methods of making (s)-3-(aminomethyl)-5-methylhexanoic acid |
| WO2011077463A1 (en) * | 2009-12-24 | 2011-06-30 | Msn Laboratories Limited | Process for preparing pregabalin and its intermediate |
| CN104140375A (en) * | 2014-05-16 | 2014-11-12 | 南通常佑药业科技有限公司 | Preparation method of pregabalin |
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| CN112745240A (en) * | 2021-01-19 | 2021-05-04 | 宁波酶赛生物工程有限公司 | Recrystallization method of high-selectivity pregabalin intermediate |
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