CN118184562A - Preparation method of (R) -4-propyl pyrrolidine-2-ketone - Google Patents
Preparation method of (R) -4-propyl pyrrolidine-2-ketone Download PDFInfo
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- CN118184562A CN118184562A CN202211605450.4A CN202211605450A CN118184562A CN 118184562 A CN118184562 A CN 118184562A CN 202211605450 A CN202211605450 A CN 202211605450A CN 118184562 A CN118184562 A CN 118184562A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims abstract description 7
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 3
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 16
- LJOQGZACKSYWCH-UHFFFAOYSA-N dihydro quinine Natural products C1=C(OC)C=C2C(C(O)C3CC4CCN3CC4CC)=CC=NC2=C1 LJOQGZACKSYWCH-UHFFFAOYSA-N 0.000 claims description 15
- -1 anthraquinone-1, 4-diyl Chemical group 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 claims description 12
- 229960002161 brivaracetam Drugs 0.000 claims description 12
- 101000924984 Salmonella typhimurium (strain LT2 / SGSC1412 / ATCC 700720) 3-dehydroquinate dehydratase Proteins 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 8
- NCBVCRLVTCSQAG-ZCFIWIBFSA-N (4r)-4-propylpyrrolidin-2-one Chemical compound CCC[C@H]1CNC(=O)C1 NCBVCRLVTCSQAG-ZCFIWIBFSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002879 Lewis base Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 150000007527 lewis bases Chemical class 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 6
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 5
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 5
- 229960000948 quinine Drugs 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 claims description 4
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 claims description 3
- 235000019253 formic acid Nutrition 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 compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 230000000911 decarboxylating effect Effects 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 abstract description 5
- 229940126062 Compound A Drugs 0.000 abstract description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 abstract description 2
- 238000006717 asymmetric allylation reaction Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101100234002 Drosophila melanogaster Shal gene Proteins 0.000 description 3
- 235000015076 Shorea robusta Nutrition 0.000 description 3
- 244000166071 Shorea robusta Species 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 231100000025 genetic toxicology Toxicity 0.000 description 3
- 230000001738 genotoxic effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SJRXWMQZUAOMRJ-VOTSOKGWSA-N ethyl (e)-hex-2-enoate Chemical compound CCC\C=C\C(=O)OCC SJRXWMQZUAOMRJ-VOTSOKGWSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000010410 layer Substances 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
- 239000003446 ligand Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 125000003410 quininyl group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a preparation process of (R) -4-propyl pyrrolidine-2-ketone, which comprises the following steps: (1) The compound A is subjected to asymmetric allylation reaction to generate a compound B; (2) preparing a compound C by catalytic hydrogenation of the compound B; (3) The compound C undergoes decarboxylation reaction to prepare (R) -4-propyl pyrrolidine-2-ketone.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a preparation method of a brivaracetam intermediate, in particular to a preparation method of a brivaracetam intermediate (R) -4-propyl pyrrolidine-2-ketone.
Background
Brivaracetam (english name: brivaracetam), chemical name: (S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butyramide is a third generation antiepileptic drug developed by Belgium UCB company, has the advantages of strong binding capacity with ligand, high bioavailability and the like, and the good clinical curative effect shows that the drug is expected to become another heavy-weight drug in the antiepileptic field after levetiracetam. The structural formula of brivaracetam is shown in the following formula 1:
at present, the preparation methods of the brivaracetam are many, and the traditional preparation process needs to prepare the brivaracetam with a target configuration by a resolution method, but increases the production cost of the brivaracetam. With the progress of scientific technology, chiral synthesis methods are increasingly favored by pharmaceutical raw material manufacturers.
In the preparation of brivaracetam, (R) -4-propylpyrrolidin-2-one is an important intermediate in the synthesis process.
WO2016075082A1 discloses that the (R) -4-propyl-pyrrolidin-2-one is obtained by the further cyclization reaction of an amine with a single configuration which is produced by reductive amination of transaminase, but the ee value of the product is 92%, the chiral purity is low and the industrial production is difficult.
WO2020148731A1 discloses that trans-2-hexenoic acid ethyl ester is used as a raw material to prepare (R) -4-propyl pyrrolidine-2-ketone, and the route needs to use nitromethane and other raw materials with genotoxicity, and meanwhile needs to split, so that the synthesis steps are complicated, and the industrial production is not facilitated.
Disclosure of Invention
The invention aims to provide a preparation method of (R) -4-propyl pyrrolidine-2-ketone, which overcomes the defects in the synthetic route and realizes the preparation method which does not involve materials with genotoxicity, has simple preparation process and high product purity and is more beneficial to industrial production. Specifically, the invention adopts the following technical scheme:
A preparation method of a brivaracetam intermediate (R) -4-propyl pyrrolidin-2-one, which comprises the following steps:
(1) The compound 3- (2-acetoxy-3-enamino) -3-oxo-propionic acid ester of the formula A is subjected to asymmetric allyl alkylation reaction to obtain a compound (R) -2-oxo-4- (propyl-1-alkenyl) pyrrolidine-3-carboxylic acid ester of the formula B;
(2) The compound of the formula B is subjected to catalytic hydrogenation to obtain a compound of the formula C (R) -2-oxo-4-propyl pyrrolidine-3-carboxylate;
(3) Decarboxylating the compound of the formula C to obtain a compound (R) -4-propyl pyrrolidin-2-one of the formula D;
Wherein R 1 is methyl, ethyl, isopropyl, tert-butyl, etc.; r 2 is acetyl, tert-butoxycarbonyl or benzyl.
In one embodiment, the asymmetric allylic alkylation reaction of step (1) is performed over a catalyst.
In one embodiment, the catalyst in step (1) is a lewis base.
In one embodiment, the lewis base in the step (1) is one or more of quinine, quinine 1,4- (2, 3-naphthyridine) diether [ (DHQ) 2 shal ], quinine 1,4- (2, 3-naphthyridine) diether [ (DHQD) 2 shal ], quinine (anthraquinone-1, 4-diyl) diether [ (DHQD) 2AQN ] and quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether [ (DHQD) 2PYR ].
Preferably, the lewis base is hydrogenated quinine 1,4- (2, 3-naphthyridine) diether [ (DHQ) 2 shal ], hydrogenated quinine (anthraquinone-1, 4-diyl) diether [ (DHQD) 2AQN ], hydrogenated quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether [ (DHQD) 2PYR ].
In one embodiment, the reaction solvent in the step (1) is one or more of dichloromethane, chloroform and tetrahydrofuran.
In one embodiment, the reaction temperature in step (1) is from-40 to 50 ℃.
In one embodiment, the reducing agent used in the catalytic hydrogenation in the step (2) is one or more of hydrogen, sodium borohydride, sodium cyanoborohydride, potassium borohydride, formic acid and formic acid amine.
In one embodiment, the catalyst used in the catalytic hydrogenation in the step (2) is one or more of palladium carbon, cuprous chloride and nickel chloride.
In one embodiment, the decarboxylation condition in step (3) is heating at a temperature of 120-180 ℃.
The invention has the beneficial effects that: provides a preparation method of a brivaracetam intermediate (R) -4-propyl pyrrolidine-2-ketone, which does not relate to materials with genotoxicity, has simple preparation process and high product purity, and is more beneficial to industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
In the present invention, the term "compound represented by formula X" is sometimes expressed as "compound X"; as will be appreciated by those skilled in the art. For example, both the compounds of formula A and the compound A refer to the same compound.
Example 1
Preparation of Compound B
To a 500mL three-necked flask, 24.3g of methyl (E) -3- ((2-acetoxypent-3-en-1-yl) amino) -3-oxopropionate, 0.78g of (DHQ) 2PHAL and 200mL of dichloromethane were sequentially added at room temperature, after the reaction was stirred at room temperature for 24 hours, TLC was detected to be complete, 150mL of water was added, stirred for 5 minutes, allowed to stand for 5 minutes, the water layer was removed, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography to give 15.7g of methyl (R) -2-oxo-4- ((E) -prop-1-en-1-yl) pyrrolidine-3-carboxylate as a pale yellow oily liquid, molar yield: 85.7%, HPLC purity: 97.6%.
Examples two to seven
With reference to the steps and material amounts of the first embodiment, the reaction solvent, the reaction time, the reaction temperature, the lewis base and the like are adjusted, and the second to seventh embodiments are carried out, and specific reaction conditions, yields and the like are as follows:
Example eight
Preparation of Compound C
At room temperature, 9.2g of (4R) -2-oxo-4- ((E) -prop-1-en-1-yl) pyrrolidine-3-carboxylic acid methyl ester, 0.18g of 10% palladium carbon (2%), 50ml of methanol are added into a hydrogenation kettle, the hydrogen is replaced for 2-3 times, 3.0-3.5kg/cm 2 is controlled to be stirred and hydrogenated for 3 hours, after the reaction, filtration, a small amount of methanol in a filter cake is leached, the filtrate is concentrated to be dry under reduced pressure, 8.2g of light yellow oily liquid is obtained through silica gel column chromatography, namely (R) -2-oxo-4-propyl pyrrolidine-3-carboxylic acid methyl ester, and the yield is: 88.5% and purity 98.0%.
Example nine
Preparation of Compound C
To a 250mL round bottom flask was added 9.2g of (R) -2-oxo-4- ((E) -prop-1-en-1-yl) pyrrolidine-3-carboxylic acid methyl ester, 0.5g of 10% palladium on carbon, 7.8g of ammonium acetate and 50mL of methanol at room temperature for 24h, after the reaction, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure, and 8.6g of a pale yellow oily liquid was obtained by silica gel column chromatography, namely (R) -2-oxo-4-propylpyrrolidine-3-carboxylic acid methyl ester, yield: 92.5%, purity: 96.6%.
Examples ten
Preparation of Compound C
To a 250mL round bottom flask was added 9.2g of methyl (R) -2-oxo-4- ((E) -prop-1-en-1-yl) pyrrolidine-3-carboxylate, 50mL of methanol, and 0.6g of sodium borohydride (0.2 g each) was added in three portions, followed by reaction at room temperature for 10 hours, slowly adding diluted hydrochloric acid after the addition, adjusting the pH of the reaction solution to about 4-5, and then adding 50mL of chloroform for extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and subjected to silica gel column chromatography to give 13.6g of a pale yellow oily liquid, namely (R) -2-oxo-4-propylpyrrolidine-3-carboxylic acid methyl ester, yield: 81.7% of purity: 97.8%.
Example eleven
Preparation of Compound D
To a 250mL round bottom flask were added 18.5g of (R) -2-oxo-4-propylpyrrolidin-3-carboxylic acid methyl ester, 150mL of DMSO and 30mL of water in sequence, the temperature was raised to 150℃and the reaction was carried out for 2 hours, after which the solvent was removed by concentration under reduced pressure, and 10.2g of pale yellow oily liquid was obtained by silica gel column chromatography, namely (R) -4-propylpyrrolidin-2-one, yield 80.3% purity: 99.1%.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (9)
1. A novel process for the preparation of a brivaracetam intermediate, which is a compound of formula D (R) -4-propylpyrrolidin-2-one, characterized in that it comprises the steps of:
(1) The compound 3- (2-acetoxy-3-enamino) -3-oxo-propionic acid ester of the formula A is subjected to asymmetric allyl alkylation reaction to obtain a compound (R) -2-oxo-4- (propyl-1-alkenyl) pyrrolidine-3-carboxylic acid ester of the formula B;
(2) The compound of the formula B is subjected to catalytic hydrogenation reaction to obtain a compound of the formula C (R) -2-oxo-4-propyl pyrrolidine-3-carboxylate;
(3) Decarboxylating the compound of the formula C to obtain a compound (R) -4-propyl pyrrolidin-2-one of the formula D;
Wherein R 1 is methyl, ethyl, isopropyl, tert-butyl, etc.; r 2 is acetyl, tert-butoxycarbonyl or benzyl.
2. The process of claim 1, wherein the asymmetric allylic alkylation reaction of step (1) is performed under the action of a catalyst.
3. The process of claim 2, wherein the catalyst in step (1) is a lewis base.
4. The process according to claim 3, wherein the Lewis base is one or more of quinine, hydrogenated quinine 1,4- (2, 3-naphthyridine) diether [ (DHQ) 2PHAL ], hydrogenated quinine 1,4- (2, 3-naphthyridine) diether [ (DHQD) 2PHAL ], hydrogenated quinine (anthraquinone-1, 4-diyl) diether [ (DHQD) 2AQN ] and hydrogenated quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether [ (DHQD) 2PYR ], preferably hydrogenated quinine 1,4- (2, 3-naphthyridine) diether [ (DHQ) 2PHAL ], hydrogenated quinine (anthraquinone-1, 4-diyl) diether [ (DHQD) 2AQN ], hydrogenated quinine-2, 5-diphenyl-4, 6-pyrimidine dimethyl ether [ (DHQD) 2PYR ].
5. The preparation method according to claim 1, wherein the asymmetric allylic alkylation reaction in the step (1) is performed in an organic solvent, and the organic solvent is one or more of dichloromethane, chloroform and tetrahydrofuran.
6. The process according to claim 1, wherein the reaction temperature in step (1) is-40 to 50 ℃.
7. The method according to claim 1, wherein the reducing agent used in the catalytic hydrogenation in the step (2) is one or more of hydrogen, sodium borohydride, sodium cyanoborohydride, potassium borohydride, formic acid, and amine formate.
8. The preparation method according to claim 1, wherein the catalyst used in the catalytic hydrogenation in the step (2) is one or more of palladium carbon, cuprous chloride and nickel chloride.
9. The process according to claim 1, wherein the decarboxylation condition in step (3) is heating at 120 to 180 ℃.
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