CN109761838A - A kind of method for preparing pregabalin intermediate and recovering resolving agent - Google Patents
A kind of method for preparing pregabalin intermediate and recovering resolving agent Download PDFInfo
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- CN109761838A CN109761838A CN201910132480.XA CN201910132480A CN109761838A CN 109761838 A CN109761838 A CN 109761838A CN 201910132480 A CN201910132480 A CN 201910132480A CN 109761838 A CN109761838 A CN 109761838A
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- phenyl ethylamine
- isobutylglutaric
- hydrochloric acid
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- 238000000034 method Methods 0.000 title claims abstract description 28
- 229960001233 pregabalin Drugs 0.000 title claims abstract description 17
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 title claims abstract description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000009835 boiling Methods 0.000 claims abstract description 32
- 239000010410 layer Substances 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- NPDKTSLVWGFPQG-SSDOTTSWSA-N (3r)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-SSDOTTSWSA-N 0.000 claims abstract description 16
- 238000002425 crystallisation Methods 0.000 claims abstract description 15
- 230000008025 crystallization Effects 0.000 claims abstract description 15
- 239000012528 membrane Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000012044 organic layer Substances 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000004321 preservation Methods 0.000 claims description 10
- 238000005292 vacuum distillation Methods 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 5
- 238000002791 soaking Methods 0.000 claims description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims 1
- 238000000638 solvent extraction Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 25
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 230000007935 neutral effect Effects 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract 3
- 229940117803 phenethylamine Drugs 0.000 abstract 3
- 238000001914 filtration Methods 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 235000011121 sodium hydroxide Nutrition 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- 239000002351 wastewater Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 238000011084 recovery Methods 0.000 description 10
- 238000000967 suction filtration Methods 0.000 description 9
- 238000005352 clarification Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000010792 warming Methods 0.000 description 8
- 238000004064 recycling Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- -1 3- Butyl glutaryl amine Chemical class 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- AYXYPKUFHZROOJ-UHFFFAOYSA-N 3-(azaniumylmethyl)-5-methylhexanoate Chemical compound CC(C)CC(CN)CC(O)=O AYXYPKUFHZROOJ-UHFFFAOYSA-N 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 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 1
- KPMYVTHJOSXIIF-UHFFFAOYSA-N 4-carbamoyl-6-methylheptanoic acid Chemical class C(C(C)C)C(C(=O)N)CCC(=O)O KPMYVTHJOSXIIF-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241000349750 Baphia nitida Species 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000007925 phenylethylamine derivatives Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种制备普瑞巴林中间体(R)‑3‑异丁基戊二酸单酰胺和回收拆分剂(R)‑苯乙胺的方法，该方法包括以下步骤：1)化合物7溶解于水中；2)加入离子膜液碱，调节pH至11.0～13.0；3)加入盐酸，调节pH至近中性；4)加入有机溶剂萃取分层；5)步骤3)中水层加入盐酸，调节pH至1.0～3.0；6)降温至0～15℃析晶、甩滤、烘干得到(R)‑3‑异丁基戊二酸单酰胺；7)步骤4)中有机层减压蒸馏出前沸和中沸后，收集90～130℃馏分得到回收(R)‑苯乙胺。本发明是在目前安全环保、提质增效和市场激烈竞争形式下，具有比较明显的优势，本发明提供的是一条安全环保、简单方便、收率高的制备普瑞巴林中间体(R)‑3‑异丁基戊二酸单酰胺和回收拆分剂(R)‑苯乙胺的方法。The invention discloses a method for preparing a pregabalin intermediate (R)-3-isobutylglutaric acid monoamide and recovering a resolving agent (R)-phenethylamine. The method comprises the following steps: 1) compound 7. Dissolve in water; 2) Add ionic membrane liquid caustic soda, adjust pH to 11.0-13.0; 3) Add hydrochloric acid, adjust pH to near neutral; 4) Add organic solvent to extract layers; 5) Step 3) Add hydrochloric acid to water layer , adjust the pH to 1.0～3.0; 6) cool down to 0～15 ℃ for crystallization, shake off filtration, and dry to obtain (R)-3-isobutylglutaric acid monoamide; 7) reduce the pressure of the organic layer in step 4). After the pre-boiling and middle-boiling are distilled off, the 90-130° C. fractions are collected to recover (R)-phenethylamine. The present invention has obvious advantages under the current form of safety and environmental protection, quality improvement and efficiency improvement and fierce market competition. -3-Isobutylglutaric acid monoamide and the method for reclaiming resolving agent (R)-phenethylamine.
Description
Technical field
The present invention provide it is a kind of prepare pregabalin intermediate (R) -3- isobutylglutaric acid monoamides and recycling resolving agent
(R)-phenyl ethylamine method, belongs to field of medicine and chemical technology.
Background technique
Pregabalin (Pregabalin, compound 1) is (S)-with pharmacological activity of 3- aminomethyl -5- methylhexanoic acid
Type isomers, clinic are mainly used for treating peripheral neuralgia and auxiliary therapy limitation partial seizure.Pregabalin
It is the revolutionary drug for the treatment of neurogenic pain that Pfizer company, the U.S. takes the lead in succeeding in developing and apply for the registration of.Puri bar
Woods is a kind of analog of neurotransmitter GABA, insane by inhibiting CNS voltage-dependent ca channel α 2- σ protein subunit to resist
Epilepsy effect, while having good liposoluble performance by blood-brain barrier, preferable anti-epileptic treatment is shown in clinical test
Effect, binding force is 6 times high compared with Gabapentin (compound 2), but dosage is smaller, and the duration is longer, and side effect is also more
It is few.The Pregabalin of in September, 2010 is in Discussion on Chinese Listed, and solving shortage in Chinese market, really effectively simultaneously data are adequately neural
The problem of pathological pain therapeutic agent.As novel psychotherapeutic drugs, Pregabalin is rapid-action, and Small side effects have
The wide prospect of marketing.
Currently, there are mainly two types of the industrialized producing technologies of Pregabalin: chemical synthesis and enzyme process.It industrializes more extensive
Using the former.Wherein, it is obtained based on pregabalin in chemical synthesis with reprocessing after being split using resolving agent.Following two
Synthesis technology is used widely in industrialized production.
[technique 1]
[technique 2]
Technique 1 and technique 2 are torn open using R- phenyl ethylamine (compound (1)) and S-MA (compound (2)) respectively
Point, pregabalin is obtained after treated.It can be recycled through racemization in technique 1 through splitting obtained isomers (compound 6)
It is recycled to its raceme (compound 5), compares technique 2 and show apparent cost advantage.
Pregabalin belongs to the S type isomers of 3- aminomethyl -5- methylhexanoic acid, (R) -3- during its chemical synthesis
Isobutylglutaric acid monoamides and R- phenyl ethylamine are its very important intermediate and resolving agent.That reports on document at present should
Intermediate synthesis and resolving agent recycling route 1 can be described as follows (see attached drawing 1): ((the R) -3- isobutyl group penta of compound 7 in technique 1
Diacid monoamides-(R)-phenyl ethylamine salt) adjusted free acid, crystallization, centrifugation to obtain ((the R) -3- isobutylglutaric acid list of compound 8
Amide), the organic solution of R- phenyl ethylamine is obtained by extraction through organic solvent through the free R- phenyl ethylamine out of alkali tune for centrifuge mother liquor, then
Boiling (extractant) and middle boiling before removing by distillation, finally distillation obtains R- phenyl ethylamine.But it is prepared through the process route
(R) -3- isobutylglutaric acid monoamides contain R- phenyl ethylamine residual, lead to have R- in the Pregabalin crude product of subsequent preparation
Phenylethylamine derivative generation leads to its mass deviation, and synthesize (R) -3- isobutylglutaric acid monoamides yield it is relatively low (about 85~
93%) and the R- phenyl ethylamine rate of recovery is relatively low (being lower than 97%).Meanwhile containing higher organic substance residues in waste water 1, lead to height
Dense high-salt wastewater processing difficulty is larger, and energy consumption is higher, and Determination of Total Nitrogen in Waste Water and COD are in 800~1000mg/L and 50k~80k
Mg/L is horizontal.
Summary of the invention
It prepares pregabalin intermediate (R) -3- isobutylglutaric acid monoamides the object of the present invention is to provide a kind of and returns
The method for receiving resolving agent (R)-phenyl ethylamine, comprising the following steps:
1) (R) -3- isobutylglutaric acid monoamides-(R)-phenyl ethylamine salt is dissolved in the water；
2) under the conditions of 15~45 DEG C, Ionic Membrane is added, after adjusting pH to 11.0~13.0, and protects at such a temperature
Temperature；
3) after keeping the temperature, hydrochloric acid is added under the conditions of 15~45 DEG C, adjusts pH to 6.0~8.0；
4) organic solvent extracting and demixing is added；
5) hydrochloric acid is added under the conditions of 15~45 DEG C in water layer in step 4), after adjusting pH to 1.0~3.0, and in the temperature
Lower heat preservation；
6) after keeping the temperature, 0~15 DEG C of crystallization, rejection filter, drying is cooled to and obtains (R) -3- isobutylglutaric acid monoamides；
7) with after middle boiling, 90~130 DEG C of fractions of collection are recycled (R)-for boiling before organic layer is evaporated under reduced pressure out in step 4)
Phenyl ethylamine.
Organic solvent described in step 4) is selected from: toluene, dimethylbenzene, chloroform and methylene chloride；Extraction times are for 2 times or big
In 2 times.
The volumetric usage of the step 1) water is 3~6ml relative to every g compound 7.
The temperature of the step 1) dissolution is 35~70 DEG C.
The soaking time of the step 2) is 0.5~1h.
The total volume dosage of the step 4) organic solvent is 3ml~20ml relative to every g compound 7.
The soaking time of the step 5) is 0.5~4 hour.
The crystallization time of the step 6) is 1~6 hour.
The vacuum degree of the step 7) vacuum distillation is 0.08~0.10MPa.
Route 2 of the present invention is shown in attached drawing 2.
The present invention is under current safety and environmental protection, upgrading synergy and market keen competition form, with obvious excellent
Gesture: firstly, it is preferentially free to the progress alkali tune of compound 7, and extracted free R- phenyl ethylamine out from water phase using organic solvent
Out, the organic impurities such as R- phenyl ethylamine in route 1 be can avoid to be precipitated with compound 8, and bring the derivative other impurities of subsequent handling into
The phenomenon that occur, to promote compound 8 and subsequent step product quality, increase and adjust pH to neutral operation, it is different to reduce 3-
Butyl glutaryl amine, which decomposes, generates 3- isobutylglutaric acid impurity, effective Improving The Quality of Products.Secondly, organic solvent extracts
In the process, organic impurities a large amount of in water phase can be removed, make after 8 crystallization of compound in the filtrate (waste water 2) of rejection filter total nitrogen and
COD sharp fall meets low density wastewater processing standard, three-protection design efficiency and cost is greatly lowered.Third, the route
Obtained compound 8 and recycling R- phenyl ethylamine yield in route 1 compared to being obviously improved.4th, what which obtained
8 purity of compound is up to 99.7% or more, and recycling R- phenyl ethylamine purity is easy to operate up to 99.5% or more, without complicated point
From the compound 8 and recycling R- phenyl ethylamine that can obtain high-purity.To sum up, the present invention is to provide a safety and environmental protection,
It is simple and convenient, high income to prepare pregabalin intermediate (R) -3- isobutylglutaric acid monoamides and recycling resolving agent (R)-benzene
Ethamine.
Detailed description of the invention
Fig. 1 is the schematic diagram of route 1.
Fig. 2 is the schematic diagram of route 2.
Specific embodiment
The present invention is further elaborated below with reference to example, but these examples do not form any restrictions to the present invention.
Embodiment 1:
100g compound 7 is added into four-hole boiling flask, adds water 400mL, is warming up to 35~45 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 15~30 DEG C, adjusts pH=12~13, insulated and stirred 30min.It is dripped under the conditions of 15~30 DEG C
Add hydrochloric acid, adjusts pH=6.0~7.0.Toluene (200mL+100mL) is added to extract 2 times, combining methylbenzene layer is stand-by.Water layer 35~
45 DEG C of dropwise addition hydrochloric acid adjust pH=1.0, insulated and stirred 30min, are cooled to 5 DEG C of heat preservation crystallization 2h, filter drying and obtain (R) -3-
Isobutylglutaric acid monoamides, weigh 58.9g, yield 97.0%, purity 99.7%.Waste water COD is 6075mg/L after suction filtration, always
Nitrogen 220mg/L.Boiling and middle boiling before toluene layer vacuum distillation removal, collect 90~130 DEG C of fractions and are recycled (R)-phenyl ethylamine, claim
Weight 38.2g, (compound 7 is (R) -3- isobutylglutaric acid monoamides-(R)-phenyl ethylamine salt, (R)-benzene to the rate of recovery 97.2%
The ethamine rate of recovery is calculated as in 100g compound 7 containing 39.3g (R)-phenyl ethylamine, similarly hereinafter), purity 99.6%.
Embodiment 2:
100g compound 7 is added into four-hole boiling flask, adds water 600mL, is warming up to 45~60 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 30~45 DEG C, adjusts pH=12~13, insulated and stirred 1h.It is added dropwise under the conditions of 30~45 DEG C
Hydrochloric acid adjusts pH=6.0~7.0.It is extracted 2 times through toluene (400mL+200mL), combining methylbenzene layer is stand-by.Water layer is 15~35
DEG C hydrochloric acid is added dropwise, adjusts pH=2.0, insulated and stirred 30min, be cooled to 10 DEG C of heat preservation crystallization 1h, filters to dry and obtain (R) -3-
Isobutylglutaric acid monoamides, weigh 58.8g, yield 96.9%, purity 99.8%.Waste water COD is 6926mg/L after suction filtration, always
Nitrogen 280mg/L.Boiling and middle boiling before toluene layer vacuum distillation removal, collect 90~130 DEG C of fractions and are recycled (R)-phenyl ethylamine, claim
Weight 38.4g, the rate of recovery 97.7%, purity 99.5%.
Embodiment 3:
100g compound 7 is added into four-hole boiling flask, adds water 300mL, is warming up to 60~70 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 20~30 DEG C, adjusts pH=11~12, insulated and stirred 0.5h.It is dripped under the conditions of 20~30 DEG C
Add hydrochloric acid, adjusts pH=7.0~8.0.It is extracted 2 times through dimethylbenzene (300mL+200mL), it is stand-by to merge diformazan benzene layer.Water layer exists
25~35 DEG C of dropwise addition hydrochloric acid adjust pH=3.0, insulated and stirred 30min, are cooled to 0 DEG C of heat preservation crystallization 0.5h, and suction filtration is dried
To (R) -3- isobutylglutaric acid monoamides, weigh 59.4g, yield 97.8%, purity 99.8%.Waste water COD is after suction filtration
6102mg/L, 214 mg/L of total nitrogen.Boiling and middle boiling before toluene layer vacuum distillation removal, collect 90~130 DEG C of fractions and are recycled
(R)-phenyl ethylamine, weigh 38.4g, the rate of recovery 97.7%, purity 99.7%.
Embodiment 4:
100g compound 7 is added into four-hole boiling flask, adds water 500mL, is warming up to 30~45 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 20~30 DEG C, adjusts pH=12~13, insulated and stirred 1h.It is added dropwise under the conditions of 20~30 DEG C
Hydrochloric acid adjusts pH=7.0~8.0.It is extracted 3 times through methylene chloride (300mL+100mL+100mL), merges dichloromethane layer and wait for
With.Water layer adjusts pH=1.0, insulated and stirred 3h in 25~35 DEG C of dropwise addition hydrochloric acid, is cooled to 15 DEG C of heat preservation crystallization 3h, filters and dries
Dry to obtain (R) -3- isobutylglutaric acid monoamides, weigh 58.6g, yield 96.5%, purity 99.9%.Waste water COD after suction filtration
For 7530mg/L, total nitrogen 240mg/L.Boiling and middle boiling before dichloromethane layer vacuum distillation removal, collect 90~130 DEG C of fractions and obtain
(R)-phenyl ethylamine is recycled, weigh 38.5g, the rate of recovery 98.0%, purity 99.6%.
Embodiment 5:
100g compound 7 is added into four-hole boiling flask, adds water 400mL, is warming up to 30~45 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 20~30 DEG C, adjusts pH=12~13, insulated and stirred 1h.It is added dropwise under the conditions of 20~30 DEG C
Hydrochloric acid adjusts pH=6.0~7.0.It is extracted 2 times through chloroform (300mL+200mL), it is stand-by to merge chloroform layer.Water layer is 20~30
DEG C hydrochloric acid is added dropwise, adjusts pH=1.0, insulated and stirred 1h, be cooled to 5 DEG C of heat preservation crystallization 1h, filters to dry and obtain (R) -3- isobutyl
Base glutaryl amine, weigh 58.8g, yield 96.9%, purity 99.8%.Waste water COD is 6018mg/L, total nitrogen after suction filtration
210mg/L.Boiling and middle boiling before chloroform layer vacuum distillation removal, collect 90~130 DEG C of fractions and are recycled (R)-phenyl ethylamine, weigh
38.3g, the rate of recovery 97.5%, purity 99.8%.
Embodiment 6:
100g compound 7 is added into four-hole boiling flask, adds water 400mL, is warming up to 50~60 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 25~35 DEG C, adjusts pH=11~12, insulated and stirred 0.5h.It is dripped under the conditions of 25~35 DEG C
Add hydrochloric acid, adjusts pH=7.0~8.0.It is extracted 2 times through methylene chloride (400mL+200mL), it is stand-by to merge dichloromethane layer.Water
Layer adjusts pH=2.0, insulated and stirred 1h in 15~25 DEG C of dropwise addition hydrochloric acid, is cooled to 5 DEG C of heat preservation crystallization 2h, filters drying and obtains
(R) -3- isobutylglutaric acid monoamides, weigh 58.9g, yield 97.1%, purity 99.8%.Waste water COD is after suction filtration
6328mg/L, total nitrogen 211mg/L.Boiling and middle boiling before dichloromethane layer vacuum distillation removal, collect 90~130 DEG C of fractions and obtain
(R)-phenyl ethylamine is recycled, weigh 38.3g, the rate of recovery 97.5%, purity 99.6%.
Embodiment 7:
100g compound 7 is added into four-hole boiling flask, adds water 500mL, is warming up to 50~60 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 25~35 DEG C, adjusts pH=12~13, insulated and stirred 0.5h.It is added dropwise under the conditions of 25~35 DEG C
Hydrochloric acid adjusts pH=7.0~8.0.It is extracted 3 times through toluene (300mL+100mL+100mL), combining methylbenzene layer is stand-by.Water layer exists
25~35 DEG C of dropwise addition hydrochloric acid adjust pH=1.0, insulated and stirred 1h, are cooled to 0 DEG C of heat preservation crystallization 1h, filter drying and obtain (R)-
3- isobutylglutaric acid monoamides, weigh 58.4g, yield 96.2%, purity 99.8%.Waste water COD is 6283mg/L after suction filtration,
Total nitrogen 208mg/L.Boiling and middle boiling before toluene layer vacuum distillation removal, collect 90~130 DEG C of fractions and are recycled (R)-phenyl ethylamine,
Weigh 38.4g, the rate of recovery 97.7%, purity 99.7%.
Embodiment 8:
100g compound 7 is added into four-hole boiling flask, adds water 400mL, is warming up to 45~60 DEG C of stirring dissolved clarifications, controls temperature
Ionic Membrane is added dropwise under the conditions of 30~45 DEG C, adjusts pH=11~12, insulated and stirred 1h.It is added dropwise under the conditions of 30~45 DEG C
Hydrochloric acid adjusts pH=6.0~7.0.It is extracted 2 times through toluene (300mL+200mL), combining methylbenzene layer is stand-by.Water layer is 15~25
DEG C hydrochloric acid is added dropwise, adjusts pH=3.0, insulated and stirred 30min, be cooled to 5 DEG C of heat preservation crystallization 3h, filters and dry that obtain (R) -3- different
Butyl glutaryl amine, weigh 58.7g, yield 96.7%, purity 99.9%.Waste water COD is 6018mg/L, total nitrogen after suction filtration
255mg/L.Boiling and middle boiling before toluene layer vacuum distillation removal, collect 90~130 DEG C of fractions and are recycled (R)-phenyl ethylamine, weigh
38.7g, the rate of recovery 98.5%, purity 99.6%.
Claims (10)
1. a kind of prepare pregabalin intermediate (R) -3- isobutylglutaric acid monoamides and recycle resolving agent (R)-phenyl ethylamine
Method, it is characterised in that the following steps are included:
(1) (R) -3- isobutylglutaric acid monoamides-(R)-phenyl ethylamine salt is dissolved in the water；
(2) under the conditions of 15~45 DEG C, Ionic Membrane is added, after adjusting pH to 11.0~13.0, and keeps the temperature at such a temperature；
(3) after step (2) insulation reaction, hydrochloric acid is added under the conditions of 15~45 DEG C, adjusts pH to 6.0~8.0；
(4) organic solvent extraction is added, isolates organic layer and water layer；
(5) hydrochloric acid is added under the conditions of 15~45 DEG C in water layer in step (4), after adjusting pH to 1.0~3.0, and at such a temperature
Heat preservation；
(6) after keeping the temperature, 0~15 DEG C of crystallization, rejection filter, drying is cooled to and obtains (R) -3- isobutylglutaric acid monoamides；
(7) with after middle boiling, 90~130 DEG C of fractions of collection are recycled (R)-benzene for boiling before organic layer is evaporated under reduced pressure out in step (4)
Ethamine.
2. according to the method described in claim 1, it is characterized in that the volumetric usage of step (1) described water is relative to every gram (R)-
3- isobutylglutaric acid monoamides-(R)-phenyl ethylamine salt is 3mL~6mL.
3. according to the method described in claim 1, it is characterized in that the temperature of step (1) described dissolution is 35~70 DEG C.
4. according to the method described in claim 1, it is characterized in that step (2) soaking time is 0.5~1h.
5. according to the method described in claim 1, it is characterized in that organic solvent described in step (4) is selected from: toluene, diformazan
Benzene, chloroform and methylene chloride.
6. according to the method described in claim 1, it is characterized in that step (5) soaking time is 0.5~4h.
7. according to the method described in claim 1, it is characterized in that step (4) extraction times are 2 times or are greater than 2 times.
8. according to the method described in claim 1, it is characterized in that the volumetric usage of organic solvent described in step (4) relative to
Every gram of (R) -3- isobutylglutaric acid monoamides-(R)-phenyl ethylamine salt is 3mL~20mL.
9. according to the method described in claim 1, it is characterized in that the 1.0~6.0h of time of step (6) crystallization.
10. according to the method described in claim 1, it is characterized in that step (7) vacuum distillation vacuum degree be 0.08~
0.10MPa。
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