CN109942516A - Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone - Google Patents
Compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone Download PDFInfo
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- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 150000001875 compounds Chemical class 0.000 title claims abstract description 27
- 229930188620 butyrolactone Natural products 0.000 title claims abstract description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 17
- 235000019441 ethanol Nutrition 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 229960004756 ethanol Drugs 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 5
- 235000010290 biphenyl Nutrition 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 14
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 238000005194 fractionation Methods 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229910000831 Steel Inorganic materials 0.000 description 3
- 229960003965 antiepileptics Drugs 0.000 description 3
- 239000010959 steel Substances 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 230000003556 anti-epileptic effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 1
- 101000584505 Homo sapiens Synaptic vesicle glycoprotein 2A Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 102100030701 Synaptic vesicle glycoprotein 2A Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 229950011546 carabersat Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- -1 dichloromethane Alkane Chemical class 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 208000028326 generalized seizure Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229960004002 levetiracetam Drugs 0.000 description 1
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- RCLXAPJEFHPYEG-ZWKOTPCHSA-N n-[(3r,4s)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydrochromen-4-yl]-4-fluorobenzamide Chemical compound N([C@@H]1[C@@H](O)C(C)(C)OC2=CC=C(C=C21)C(=O)C)C(=O)C1=CC=C(F)C=C1 RCLXAPJEFHPYEG-ZWKOTPCHSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 229940053180 other antiepileptics in atc Drugs 0.000 description 1
- 229960001816 oxcarbazepine Drugs 0.000 description 1
- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940030966 pyrrole Drugs 0.000 description 1
- 229960003312 retigabine Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to compound R A to prepare the purposes in Bu Waxitan intermediate chirality butyrolactone, and compound BW-CX progress chiral resolution is obtained BW-C by compound R A, is shown below,
Description
Technical field
The present invention relates to preparations among a kind of Bu Waxitan, and in particular to a kind of compound R A is in preparation Bu Waxi
Purposes in smooth intermediate chirality butyrolactone.
Background technique
Epilepsy is a kind of long-term chronic brain diseases, is that the unexpected abnormal excessive electric discharge of the brain cell as caused by cerebral lesion is drawn
The brain function imbalance syndrome of hair.Symptom when by breaking-out can be divided mainly into partial seizures and Generalized seizure.Antiepileptic
Object (antiepilepticdrugs, AEDs) can be divided into 3 classes according to the development history of drug: 1st generation is traditional classical AEDs, packet
Include dilantin sodium, carbamazepine and sodium vedproate etc.；2nd generation is modern times AEDs, including Oxcarbazepine, Levetiracetam and Jia Ba
Spray fourth etc..3rd on behalf of new A EDs, including Bu Waxitan, carabersat, retigabine and pyrrole Lun Panai etc..
For Bu Waxitan as the 3rd generation new A EDs, mechanism of action is unique, logical by SV2A high affinity interaction and sodium ion
Road inhibiting effect significantly improves its antiepileptic activity.Its good safety and pharmacokinetics, especially central nervous system
The good tolerability of system is the main reason for it is better than other antiepileptics.
The existing preparation document report of Bu Waxitan mainly has: J.Med.Chem.2004,47 (3), 530-549；
WO2007031263,WO2005026435,US2003120080,US2007100150；The common feature of prior art is desirable
It can be obtained using high performance liquid chromatography by the separation that chiral preparatory column carries out API isomers.Due to not in intermediate rank
The chirality of section building propyl, relevant epimer can only be separated at present using efficient liquid phase, and preparation amount can not expire
Foot production needs.
Summary of the invention
To overcome the shortcomings of the existing technology, the present invention provides a kind of compound R A in preparation Bu Waxitan intermediate chirality fourth
New application in ester improves production efficiency, realizes large-scale production.
In order to achieve the above object, the technical solution adopted by the present invention:
Compound R A is torn open as chirality preparing the purposes in Bu Waxitan intermediate chirality butyrolactone, the compound R A
Divide agent, the structural formula of compound R A are as follows:
Wherein, Q1 is any substituent group；Q2 is any substituent group.
The compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone, and compound R A is by compound
BW-CX carries out chiral resolution and obtains BW-C, is shown below,
Preferably, RA selects the compound of having structure:
The purposes in Bu Waxitan intermediate chirality butyrolactone is being prepared based on above compound RA, in the Bu Waxitan
The synthetic method of mesosome chirality butyrolactone are as follows:
The synthetic method specific steps of above-mentioned Bu Waxitan intermediate chirality butyrolactone are as follows:
(1) BW-A is dissolved in dehydrated alcohol, under cooling circulating water cooling condition, sodium borohydride is slowly added to, to BW-
It after A fully reacting, extracts, BW-B is concentrated under reduced pressure to obtain；
(2) gained BW-B is dissolved in dehydrated alcohol, catalyst is added, hydrogen is passed through, in room temperature, pressure 0.03MPa
Under conditions of react, until BW-B restores completely, filter, filtrate decompression is concentrated to give BW-CX；
(3) gained BW-CX and ethyl alcohol, sodium hydroxide are mixed, stirring at normal temperature 0.5-1.5h is added after concentrated hydrochloric acid is added dropwise
RA, stirring, are recrystallized to give BW-D.RA at centrifugal filtration；
(4) water and concentrated hydrochloric acid is added after reaction 2-4 hours to gained BW-D.RA to be extracted with dichloromethane, by dichloromethane
Alkane extract is concentrated up to BW-C.
Further, the catalyst is palladium carbon.
The beneficial effects of the present invention are:
Compound R A is used to prepare Bu Waxitan intermediate chirality butyrolactone BW-C by the present invention.Using the cloth in the present invention
Wa Xitan intermediate chirality butyrolactone BW-C synthesis material stype Wa Xitan, process flow is simple, splits without chiral column, can
Realize large-scale production.
Specific embodiment
The present invention will be further described with reference to the examples below, and described embodiment is only present invention a part
Embodiment is not whole embodiment.Based on the embodiments of the present invention, those skilled in the art are not making
Other all embodiments obtained, belong to protection scope of the present invention under the premise of creative work.
Embodiment 1:
(1) preparation of BW-B:
It is pumped into 86.6kgBW-A into 1000L glassed steel reaction vessels, then is pumped into 606kg dehydrated alcohol, the logical cooling of kettle collet
Recirculated water, nitrogen are replaced three times, and 25.38kg sodium borohydride is slowly added to.It is reacted 2 hours after charging.Acetic acid aqueous solution is quenched
It goes out reaction.55-60 DEG C of reduced pressure；It is pumped into 200kg water, 350kgDCM extraction.45-50 DEG C of hot water is concentrated under reduced pressure organic phase and obtains
70kgBW-B, yield 90%.
1H NMR (400MHz, DMSO-d6) 0.927 (t, J=4.6,3H, CH3)；1.616~1.522 (m, 2H, CH2)；
2.383 (t, J=7.6,2H, CH2)；4.847(s,2H,CH2)；5.932(s,1H,CH)
(2) preparation of BW-CX:
70kgBW-B is added in 1000L glassed steel reaction vessels, then is pumped into 280kg dehydrated alcohol, and hydrogen is replaced 2 times.It is added
3.1kg10% palladium carbon (dry weight 1.07kg).It is reacted 9 hours in room temperature 0.03-0.05MPa.Filtered under nitrogen, 20kg ethyl alcohol
Washing reaction kettle and filter cake.BW-CX68kg is concentrated under reduced pressure to obtain in 45-55 DEG C of 500L glassed steel reaction vessels in filtrate.Yield 96%.
1H NMR (400 MHz, DMSO-d6) δ 4.406 (t, J=8.8,1H, OCH2)；3.921 (t, J=8.8,2H,
OCH2)；2.641~2.509 (m, 2H, COCH2)；2.255~2.195 (m, 1H, CH)；1.456~1.395 (m, 2H, CH2)；
1.363~1.290 (m, 2H, CH2)；0.925 (t, J=7.6,3H, CH3)
(3) preparation of BW-D.RA:
It is pumped into 165kg ethyl alcohol in 500L reaction kettle, 55kg BW-CX is added.20.6kg sodium hydroxide is added；Stirring at normal temperature 1
Hour.54.4kg concentrated hydrochloric acid (BW-DX being obtained, without separation) is added dropwise.50.9kg (1R, 2S) -2- amino -1,2- diphenyl is added
Alcohol at normal temperature stirs 30 minutes.Centrifugal filtration.Solid is recrystallized to give BW-D.RA 59kg, resolution yield with ethanol water
76%.
(4) preparation of BW-C
It is pumped into 660kg water into 1000L reaction kettle, 35.3kg concentrated hydrochloric acid is added, 59kg BW-D.RA is added, at this time BW-
D.RA is formed free BW-D by salt acid dissociation, and BW-D is not needed to be separated, and 20-60 DEG C is reacted 3 hours.Room temperature is cooled to, is pumped into
The extraction of 371kg methylene chloride.Concentration methylene chloride can obtain BW-C19kg, yield 92%.E.e. >=99.8%.
1H NMR (400 MHz, DMSO-d6) δ 4.411 (t, J=7.6,1H, OCH2)；3.926 (t, J=7.2,1H,
OCH2)；2.650~2.516 (m, 2H, COCH2)；2.265~2.206 (m, H, CH)；1.461~1.401 (m, 2H, CH2)；
1.369~1.288 (m, 2H, CH2)；0.931 (t, J=7.2,3H, CH3)
Embodiment 2:
Preparation process is identical with embodiment 1, and (1R, 2S) -2- amino -1,2- diphenyl ethyl alcohol in step C is replaced with
BW-C is prepared in (1R, 2S) -2- amino -1- phenyl -2- (pyridin-4-yl) ethyl alcohol.Resolution yield 78%, other step yields
It is close with embodiment 1.BW-C e.e. >=99.8%.
Embodiment 3:
Preparation process is identical with embodiment 1, and (1R, 2S) -2- amino -1,2- diphenyl ethyl alcohol in step C is replaced with
BW-C is prepared in (1S, 2S) -2- amino -2- phenyl -1- (pyridine -2- base) ethyl alcohol.Resolution yield 69%, other step yields
It is close with embodiment 1.BW-C e.e. >=99.8%.
Embodiment 4:
Preparation process is identical with embodiment 1, and (1R, 2S) -2- amino -1,2- diphenyl ethyl alcohol in step C is replaced with L-
BW-C is prepared in aniline propyl alcohol.Resolution yield 58%, other step yields are close with embodiment 1.BW-C e.e.≥
99.8%.
Processing step through the invention prepares Bu Waxitan intermediate chirality butyrolactone, and then for synthesizing Bu Waxi
It is smooth, it can be achieved that industrialization large-scale production, meets industrial demand.
Claims (9)
1. compound R A is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone, which is characterized in that the compound R A
As chiral resolving agent, the structural formula of compound R A are as follows:
OrWherein,
Q1 is any substituent group；Q2 is any substituent group.
2. compound R A according to claim 1 is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone, special
Sign is that compound BW-CX progress chiral resolution is obtained BW-C by compound R A, is shown below,
3. compound R A according to claim 1 or 2 is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone,
It is characterized in that, RA is (1R, 2S) -2- amino -1,2- diphenyl ethyl alcohol, structural formula are as follows:
4. compound R A according to claim 1 or 2 is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone,
It is characterized in that, RA is (1R, 2S) -2- amino -1- phenyl -2- (pyridin-4-yl) ethyl alcohol, structural formula are as follows:
5. compound R A according to claim 1 or 2 is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone,
It is characterized in that, RA is (1S, 2S) -2- amino -2- phenyl -1- (pyridine -2- base) ethyl alcohol, structural formula are as follows:
6. compound R A according to claim 1 or 2 is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone,
It is characterized in that, RA is L- aniline propyl alcohol, structural formula are as follows:
7. the synthetic method of Bu Waxitan intermediate chirality butyrolactone, which is characterized in that application is such as any one of claim 1-6 institute
It states compound R A and is preparing the purposes in Bu Waxitan intermediate chirality butyrolactone, synthetic route are as follows:
8. the synthetic method of Bu Waxitan intermediate chirality butyrolactone according to claim 7, which is characterized in that including with
Lower specific steps:
(1) BW-A is dissolved in dehydrated alcohol, under cooling circulating water cooling condition, is slowly added to sodium borohydride, it is anti-to BW-A
After answering completely, extracts, BW-B is concentrated under reduced pressure to obtain；
(2) gained BW-B is dissolved in dehydrated alcohol, catalyst is added, is passed through hydrogen, in room temperature, the item that pressure is 0.03MPa
It reacts, until BW-B is restored completely, filters, filtrate decompression is concentrated to give BW-CX under part；
(3) gained BW-CX and ethyl alcohol, sodium hydroxide are mixed, stirring at normal temperature 0.5-1.5h is added RA after concentrated hydrochloric acid is added dropwise, stirs
It mixes, centrifugal filtration, be recrystallized to give BW-D.RA；
(4) water and concentrated hydrochloric acid is added after reaction 2-4 hours to gained BW-D.RA to be extracted with dichloromethane, methylene chloride is extracted
Liquid is taken to be concentrated up to BW-C.
9. the synthetic method of Bu Waxitan intermediate chirality butyrolactone according to claim 8, which is characterized in that described to urge
Agent is palladium carbon.
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| CN114394921A (en) * | 2022-02-22 | 2022-04-26 | 浙江九洲药业股份有限公司 | Preparation method of high-purity brivaracetam |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018042393A1 (en) * | 2016-09-05 | 2018-03-08 | Micro Labs Limited | Novel process for the preparation of brivaracetam |
| CN108947883A (en) * | 2017-05-25 | 2018-12-07 | 北京万全德众医药生物技术有限公司 | The preparation of Bu Waxitan |
| CN109134406A (en) * | 2018-08-02 | 2019-01-04 | 丽珠集团新北江制药股份有限公司 | A kind of synthetic method of Bu Waxitan intermediate and Bu Waxitan |
| US20220048856A1 (en) * | 2018-12-19 | 2022-02-17 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing brivaracetam and intermediate thereof |
-
2019
- 2019-03-27 CN CN201910239178.4A patent/CN109942516A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018042393A1 (en) * | 2016-09-05 | 2018-03-08 | Micro Labs Limited | Novel process for the preparation of brivaracetam |
| CN108947883A (en) * | 2017-05-25 | 2018-12-07 | 北京万全德众医药生物技术有限公司 | The preparation of Bu Waxitan |
| CN109134406A (en) * | 2018-08-02 | 2019-01-04 | 丽珠集团新北江制药股份有限公司 | A kind of synthetic method of Bu Waxitan intermediate and Bu Waxitan |
| US20220048856A1 (en) * | 2018-12-19 | 2022-02-17 | Zhejiang Huahai Pharmaceutical Co., Ltd | Method for preparing brivaracetam and intermediate thereof |
Non-Patent Citations (2)
| Title |
|---|
| HIROYUKI NOHIRA ，等: "Optical resolution of fragrant lactones", 《HETEROCYCLES》 * |
| 周超，等: "布瓦西坦的不对称合成研究进展", 《中国新药杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114394921A (en) * | 2022-02-22 | 2022-04-26 | 浙江九洲药业股份有限公司 | Preparation method of high-purity brivaracetam |
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