CN114409586A - Preparation method of levetiracetam - Google Patents
Preparation method of levetiracetam Download PDFInfo
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- CN114409586A CN114409586A CN202111594240.5A CN202111594240A CN114409586A CN 114409586 A CN114409586 A CN 114409586A CN 202111594240 A CN202111594240 A CN 202111594240A CN 114409586 A CN114409586 A CN 114409586A
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 48
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 23
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 28
- 239000000047 product Substances 0.000 claims description 22
- 238000001816 cooling Methods 0.000 claims description 20
- 239000012295 chemical reaction liquid Substances 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 18
- 238000004537 pulping Methods 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 16
- AHAQQEGUPULIOZ-WCCKRBBISA-N methyl (2s)-2-aminobutanoate;hydrochloride Chemical compound Cl.CC[C@H](N)C(=O)OC AHAQQEGUPULIOZ-WCCKRBBISA-N 0.000 claims description 16
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 16
- 238000001704 evaporation Methods 0.000 claims description 15
- 239000000706 filtrate Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 238000002386 leaching Methods 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 10
- 238000007363 ring formation reaction Methods 0.000 claims description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 9
- -1 (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyric acid ethyl ester hydrochloride Chemical compound 0.000 claims description 8
- 238000005804 alkylation reaction Methods 0.000 claims description 8
- 238000005915 ammonolysis reaction Methods 0.000 claims description 8
- XBPOBCXHALHJFP-UHFFFAOYSA-N ethyl 4-bromobutanoate Chemical compound CCOC(=O)CCCBr XBPOBCXHALHJFP-UHFFFAOYSA-N 0.000 claims description 8
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 238000005886 esterification reaction Methods 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 6
- 238000010025 steaming Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229910052806 inorganic carbonate Inorganic materials 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- ZZWPOYPWQTUZDY-BYPYZUCNSA-N methyl (2s)-2-aminobutanoate Chemical class CC[C@H](N)C(=O)OC ZZWPOYPWQTUZDY-BYPYZUCNSA-N 0.000 claims description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 24
- 239000002994 raw material Substances 0.000 abstract description 10
- 230000003287 optical effect Effects 0.000 abstract description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 abstract description 3
- 238000006477 desulfuration reaction Methods 0.000 abstract description 2
- 230000023556 desulfurization Effects 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 230000001276 controlling effect Effects 0.000 description 9
- 239000012467 final product Substances 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000007858 starting material Substances 0.000 description 7
- 239000001961 anticonvulsive agent Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- QRQVFVYABBZXFO-ZETCQYMHSA-N methyl (2s)-2-(2-oxopyrrolidin-1-yl)butanoate Chemical compound COC(=O)[C@H](CC)N1CCCC1=O QRQVFVYABBZXFO-ZETCQYMHSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- FFEARJCKVFRZRR-UHFFFAOYSA-N L-Methionine Natural products CSCCC(N)C(O)=O FFEARJCKVFRZRR-UHFFFAOYSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- 229930195722 L-methionine Natural products 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229960004452 methionine Drugs 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010061334 Partial seizures Diseases 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 208000028329 epileptic seizure Diseases 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- CYBOBNODYVJFNM-JEDNCBNOSA-N (2s)-2-amino-2-methylbutanoic acid;hydrochloride Chemical compound Cl.CC[C@](C)(N)C(O)=O CYBOBNODYVJFNM-JEDNCBNOSA-N 0.000 description 1
- HDBMIDJFXOYCGK-DFWYDOINSA-N (2s)-2-aminobutanamide;hydrochloride Chemical compound Cl.CC[C@H](N)C(N)=O HDBMIDJFXOYCGK-DFWYDOINSA-N 0.000 description 1
- AMMBUJFMJOQABC-UHFFFAOYSA-N 1-carboxypropylazanium;chloride Chemical compound Cl.CCC(N)C(O)=O AMMBUJFMJOQABC-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 229940096978 oral tablet Drugs 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a preparation method of levetiracetam, which comprises the following steps: the preparation method of levetiracetam adopts a brand-new synthesis method, directly uses (S) -2-aminobutyric acid as an initial raw material, does not need a complex splitting procedure, avoids the problem of using benzene as a splitting solvent, simplifies the production process, and better meets the production requirements of raw material medicines because benzene is not needed; the preparation method of levetiracetam provided by the invention has the advantages of high total yield, high optical purity of the obtained product, mild reaction conditions and simple reaction process; the preparation method of levetiracetam provided by the invention does not use oxalyl chloride, phosphorus pentoxide and other tube products in documents and does not use a complex desulfurization process, so that the operation is simpler, and the preparation method is more friendly to personnel and environment.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of levetiracetam.
Background
Levetiracetam is a novel antiepileptic drug developed by UCB pharmaceutical company in Belgium, and has the chemical name of (S) -2- (2-oxo-1-pyrrolidine) butanamide and the molecular formula of: c8H14N2O2Molecular weight is 170.21, and the chemical structural formula is:
levetiracetam is an adjunctive treatment for epilepsy or partial seizures in adults and children older than 4 years approved by the State food and drug administration. It was first marketed in europe and the united states in 1999 for adult partial seizures; the oral tablet and injection are approved again for the adjuvant treatment of partial epileptic seizure in children 4 years old or older at 6 months of 2005; the product is marketed in China in 3 months of 2007 with the trade name of Kapura.
Levetiracetam is more ideal than other antiepileptic drugs in pharmacokinetics, and has the advantages of easy absorption by oral administration, high bioavailability, high therapeutic index, no interaction with other antiepileptic drugs, slight side effect, good tolerance and the like. Compared with other antiepileptic drugs, the anti-hypoxia protective activity of the compound is about 10 times higher, and the anti-cerebral ischemia protective activity of the compound is about 4 times higher. Levetiracetam is the only antiepileptic drug with unique property for preventing epileptic seizure at present, and has wide market prospect.
At present, levetiracetam is mainly synthesized by adopting a chemical resolution method, an asymmetric hydrogenation catalysis method or amino acid as a raw material. However, many of these methods have some adverse factors on production or product quality. For example, a method for synthesizing levetiracetam by a chemical resolution method developed by UCB company of Belgian is to use racemic (R, S) -2- (2-oxo-1-pyrrolidine) butyric acid as a starting material, use R- (+) -alpha-methylbenzylamine as a resolving agent, resolve in benzene and treat with strong base to obtain free (S) -2- (2-oxo-1-pyrrolidine) butyric acid. The acid reacts with ethyl chloroformate, and then the acid and ammonia gas are subjected to ammonolysis reaction to obtain the levetiracetam. However, benzene is adopted as a resolution solvent, and is classified as a class of solvents, so that the use of benzene is avoided, and therefore, the method adopts benzene as the resolution solvent, has high hazard and does not meet the requirements of production of bulk drugs.
U.S. Pat. No. US2005/0182262A1 discloses a method for preparing levetiracetam by reacting (S) -2-aminobutyric acid hydrochloride as a starting material with thionyl chloride and methanol to obtain (S) -2-aminobutyric acid methyl ester hydrochloride, reacting with ammonia water to obtain (S) -2-aminobutanamide hydrochloride, reacting with 4-chlorobutyryl chloride, and cyclizing. Phosphorus pentachloride and oxalyl chloride are used in the patent. Phosphorus pentachloride belongs to a third class of monitoring chemicals, and the production and the import and export are regulated by national prohibited chemical offices (national Ministry of industry and communications); oxalyl chloride has high toxicity and corrosivity, reacts violently with water to release toxic gas carbon monoxide, and has low total yield which is only 60-70%.
In the document, research on synthesis of levetiracetam, an antiepileptic therapeutic drug, J fine chemical intermediates, 2005,35(2):27-28), L-methionine is used as an initial raw material to synthesize levetiracetam, and the levetiracetam is synthesized through the steps of sulfomethylation, esterification, ammonolysis, amidation and intramolecular condensation cyclization reaction, wherein the reaction route is as follows:
chinese patent CN1020604C also reports a synthetic route using L-methionine as starting material, except that the method of finally removing thiomethyl is adopted to obtain levetiracetam, and the reaction route is as follows:
the two synthetic methods have convenient sources of the initial raw material L-methionine and lower price, but a large amount of nickel catalyst is needed for removing the methylthio, and the sulfur-containing compound is easy to cause catalyst poisoning, is not easy to recover and has higher production cost, and the demethylthio byproduct is stink, thereby being not beneficial to environmental protection.
The synthetic method for preparing levetiracetam disclosed by the prior art has the defects of inconvenient raw material source, more complex reaction steps, higher catalyst price, unfavorable environmental protection and the like.
Disclosure of Invention
In order to solve the problems of inconvenient raw material sources, complex reaction steps, high catalyst price and environmental friendliness in the prior art, the invention provides the preparation method of the levetiracetam, which does not need to be split, has little environmental pollution and high yield.
The invention adopts the following technical scheme for solving the technical problems: a preparation method of levetiracetam comprises the following steps:
a: esterification reaction: reacting (S) -2-aminobutyric acid with methanol at the temperature of 20-30 ℃ for 16-18 h, then dropwise adding thionyl chloride into the reaction liquid at the temperature of-5-0 ℃, and performing post-treatment to obtain (S) -2-aminobutyric acid methyl ester hydrochloride;
b: alkylation reaction: adding inorganic base and (S) -2-aminobutyric acid methyl ester salt into isopropanol, heating to 40-80 ℃, dropwise adding 4-bromobutanoic acid ethyl ester for alkylation reaction, and performing aftertreatment on reaction liquid to obtain (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyric acid ethyl ester hydrochloride;
c: and (3) cyclization reaction: dissolving (S) -4- [ (1-methoxy-1-oxobutan-2-yl) amino ] butyric acid ethyl ester hydrochloride in a solvent under stirring at room temperature under an alkaline condition; extracting with toluene, adding 2-hydroxypyridine into the organic phase, heating to 95-105 ℃, carrying out cyclization reaction, and carrying out post-treatment on the reaction liquid to obtain (S) -methyl 2- (2-oxopyrrolidine-1-yl) butyrate;
d: ammonolysis reaction: adding (S) -2- (2-oxopyrrolidine-1-yl) methyl butyrate into ammonia water, reacting at-20 ℃, and carrying out post-treatment on the reaction liquid to obtain levetiracetam.
Further, in the step A, the mass ratio of the (S) -2-aminobutyric acid to the methanol to the thionyl chloride is 1: 2-8: 1-2.5.
Further, the post-treatment process in the step A is as follows: evaporating the solvent under reduced pressure, pulping with ethyl acetate for 2 hours, centrifuging, leaching the wet product with ethyl acetate, centrifuging, and drying under reduced pressure.
Further, the mass ratio of the (S) -2-aminobutyric acid methyl ester hydrochloride, the inorganic base, the isopropanol and the 4-bromobutyric acid ethyl ester in the step B is 1: 1-2: 3-4: 1-2.
Further, the inorganic base in the reaction in the step B is one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide.
Further, in the step C, the mass ratio of the (S) -ethyl 4- [ (1-methoxy-1-oxobutan-2-yl) amino ] butyrate hydrochloride to the 2-hydroxypyridine to the solvent to the base is 1: 0.01-1: 2-4: 0.2-0.5.
Further, the solvent in the step C is selected from one or more of purified water, alcohols, esters, ketones or ethers; the alkali is one of inorganic carbonate, bicarbonate or ammonia.
Further, the mass ratio of (S) -methyl 2- (2-oxopyrrolidin-1-yl) butyrate to aqueous ammonia in step D is 1:2 to 10.
Further, the post-treatment process in the step B: cooling the reaction liquid, filtering to remove salt, evaporating to remove the solvent under reduced pressure, and filtering to remove salt again; cooling the filtrate to 0-5 ℃, dropwise adding a hydrogen chloride isopropanol solution to form salt, and controlling the pH to be less than 1; adding isopropyl ether, pulping, centrifuging, leaching the wet product with mixed solution of isopropanol and isopropyl ether, and drying under reduced pressure;
and C, post-treatment process: decompressing the reaction liquid and distilling off the toluene;
and D, post-treatment process: and (3) decompressing and steaming the reaction liquid to remove water, pulping by using ethyl acetate, centrifuging, and decompressing and drying.
Compared with the prior art, the invention has the beneficial effects that:
1. the preparation method of levetiracetam adopts a brand new synthesis method, directly uses (S) -2-aminobutyric acid as an initial raw material, does not need a complex splitting procedure, avoids the problem of using benzene as a splitting solvent, simplifies the production process, and better meets the production requirements of raw material medicines because benzene is not needed.
2. The preparation method of levetiracetam provided by the invention has the advantages of high total yield, high optical purity of the obtained product, mild reaction conditions and simple reaction process.
3. The preparation method of levetiracetam provided by the invention does not use oxalyl chloride, phosphorus pentoxide and other tube products in documents and does not use a complex desulfurization process, so that the operation is simpler, and the preparation method is more friendly to personnel and environment.
4. The preparation method of levetiracetam has the advantages that the yield of the obtained product is high, the molar yield of the cyclization reaction step can reach more than 90%, the total molar yield from the starting materials to the final product can reach more than 50%, and simultaneously the High Performance Liquid Chromatography (HPLC) purity and the optical purity of the obtained levetiracetam are high, the HPLC purity can reach 99.94%, the optical purity can reach 99.95%, and the levetiracetam meets the requirements of the quality standard of the original research of medicines.
Drawings
The invention will be further described with reference to the following drawings and detailed description:
FIG. 1 is a high performance liquid chromatogram of the product levetiracetam of example 1 of the invention.
Detailed Description
In order to make the technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following specific embodiments.
Example 1
A: esterification reaction: adding 62.0kg of methanol and 15.5kg of (S) -2-aminobutyric acid into a reaction kettle, heating to 30 ℃, reacting for 16 hours, cooling to-5-0 ℃, slowly dropwise adding 19.7kg of thionyl chloride, controlling the temperature to-5-0 ℃, removing the solvent by reduced pressure distillation after dropwise adding, pulping for 2 hours by using 69.8kg of ethyl acetate, centrifuging, leaching a wet product by using 20.0kg of ethyl acetate, centrifuging, and drying under reduced pressure to obtain 20.83kg of (S) -2-aminobutyric acid methyl ester hydrochloride, wherein the molar yield is 90.2%, and the liquid phase purity is 99.5%;
b: alkylation reaction: adding 81.86kg of isopropanol, 20.83kg of (S) -2-aminobutyric acid methyl ester hydrochloride and 28.75kg of anhydrous sodium carbonate into a reaction kettle, heating to 40 ℃, refluxing for 2 hours, dropwise adding 34.37kg of 4-bromobutyric acid ethyl ester, and refluxing for 16 hours until the (S) -2-aminobutyric acid methyl ester hydrochloride remains less than or equal to 3.0%; cooling the reaction liquid, filtering to remove salt, evaporating to remove the solvent under reduced pressure, and filtering to remove salt again; cooling the filtrate to 0-5 ℃, dropwise adding 24.79kg of hydrogen chloride isopropanol solution to form salt, and controlling the pH of the filtrate to be less than 1 after dropwise adding; adding isopropyl ether into the filtrate, pulping, centrifuging, leaching the wet product with mixed solution of isopropanol and isopropyl ether, and drying under reduced pressure to obtain 21.78kg of dry product, wherein the molar yield is 60% and the liquid phase purity is 99.7%;
c: and (3) cyclization reaction: 85.38kg of purified water, 9.58kg of anhydrous sodium carbonate, and 21.78kg of ethyl (S) -4- [ (1-methoxy-1-oxobutan-2-yl) amino ] butanoate hydrochloride were added to the reaction vessel at room temperature, and the mixture was dissolved by stirring at room temperature; extracting with toluene 32.67kg once, washing the organic phase with 37.68kg once, adding 2-hydroxypyridine 1.52kg into the organic phase, heating to 95 ℃ for reaction for 20 hours, detecting by TLC until the content of (S) -4- [ (1-methoxy-1-oxobutan-2-yl) amino ] butyric acid ethyl ester hydrochloride is not reduced, evaporating toluene under reduced pressure to obtain oily (S) -2- (2-oxopyrrolidin-1-yl) butyric acid methyl ester 13.79kg with a molar yield of 91.5%, and directly carrying out the next step;
d: ammonolysis reaction: adding 60.81kg of ammonia water into a reaction kettle, cooling to-5-0 ℃, dropwise adding 13.79kg of (S) -methyl 2- (2-oxopyrrolidin-1-yl) butyrate, after dropwise adding, keeping the temperature at-5-0 ℃ for reacting for 8 hours, carrying out reduced pressure evaporation to remove water, adding 62.5kg of ethyl acetate, pulping, centrifuging, and drying under reduced pressure to obtain 12.36kg of final product levetiracetam, wherein the molar yield is 97.5%, the total molar yield is 48.28%, the HPLC purity is 99.90%, and the optical purity is 99.91% from the beginning of the starting raw material (S) -2-aminobutyric acid to the final product levetiracetam.
Example 2
A: esterification reaction: adding 124.0kg of methanol and 15.5kg of (S) -2-aminobutyric acid into a reaction kettle, heating to 20 ℃, reacting for 18 hours, cooling to-5-0 ℃, slowly dropwise adding 15.5kg of thionyl chloride, controlling the temperature to-5-0 ℃, removing the solvent by reduced pressure distillation after dropwise adding, pulping for 2 hours by using 70.0kg of ethyl acetate, centrifuging, leaching a wet product by using 20.0kg of ethyl acetate, centrifuging, drying under reduced pressure to obtain 21.31kg of (S) -2-aminobutyric acid methyl ester hydrochloride, wherein the molar yield is 92.3%, and the liquid phase purity is 99.0%;
b: alkylation reaction: adding 81.86kg of isopropanol, 21.31kg of (S) -2-aminobutyric acid methyl ester hydrochloride and 42.62kg of anhydrous potassium carbonate into a reaction kettle, heating to 80 ℃, refluxing for 2 hours, dropwise adding 34.37kg of 4-bromobutyric acid ethyl ester, and refluxing for 16 hours until the (S) -2-aminobutyric acid methyl ester hydrochloride is less than or equal to 3.0 percent; cooling the reaction liquid, filtering to remove salt, evaporating to remove the solvent under reduced pressure, and filtering to remove salt again; cooling the filtrate to 0-5 ℃, dropwise adding 24.79kg of hydrogen chloride isopropanol solution to form salt, and controlling the pH of the filtrate to be less than 1 after dropwise adding; adding isopropyl ether into the filtrate, pulping, centrifuging, leaching the wet product with mixed solution of isopropanol and isopropyl ether, and drying under reduced pressure to obtain 22.88kg of dry product, wherein the molar yield is 61.6%, and the liquid phase purity is 99.4%;
c: and (3) cyclization reaction: 91.52kg of methanol, 9.58kg of anhydrous sodium carbonate and 22.88kg of ethyl (S) -4- [ (1-methoxy-1-oxobutan-2-yl) amino ] butyrate hydrochloride are added into the reaction kettle at room temperature, and stirred and dissolved at room temperature; extracting with toluene 32.67kg once, washing the organic phase with 37.68kg water once, adding 2-hydroxypyridine 1.52kg into the organic phase, heating to 105 ℃ for reaction for 20 hours, detecting by TLC until the content of (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyric acid ethyl ester hydrochloride is not reduced any more, evaporating toluene under reduced pressure to obtain oily (S) -2- (2-oxopyrrolidin-1-yl) butyric acid methyl ester 14.32kg with a molar yield of 90.5%, and directly carrying out the next step;
d: ammonolysis reaction: adding 28.64kg of ammonia water into a reaction kettle, cooling to-5-0 ℃, dropwise adding 14.32kg of (S) -methyl 2- (2-oxopyrrolidin-1-yl) butyrate, after dropwise adding, keeping the temperature at-5-0 ℃ for reacting for 8 hours, reducing pressure, steaming to remove water, adding 62.5kg of ethyl acetate, pulping, centrifuging, and drying under reduced pressure to obtain 12.92kg of levetiracetam which is a final product, wherein the molar yield is 98.2%. Starting from the starting material (S) -2-aminobutyric acid to the final product levetiracetam, the total molar yield is 50.53%, the HPLC purity is 99.91%, and the optical purity is 99.93%.
Example 3
A: esterification reaction: adding 310.0kg of methanol and 62.00kg of (S) -2-aminobutyric acid into a reaction kettle, heating to 25 ℃, reacting for 17 hours, cooling to-5-0 ℃, slowly dropwise adding 155.0kg of thionyl chloride, controlling the temperature to-5-50 ℃, removing the solvent by reduced pressure evaporation after dropwise adding, pulping for 2 hours by using 280.0kg of ethyl acetate, centrifuging, leaching a wet product by using 80.0kg of ethyl acetate, centrifuging, and drying under reduced pressure to obtain 84.69kg of (S) -2-aminobutyric acid methyl ester hydrochloride, wherein the molar yield is 91.7%, and the liquid phase purity is 89.98%;
b: alkylation reaction: adding 338.76kg of isopropanol, 84.69kg of (S) -2-aminobutyric acid methyl ester hydrochloride and 169.38kg of anhydrous sodium hydroxide into a reaction kettle, heating to 80 ℃, refluxing for 2 hours, dropwise adding 84.69kg of 4-bromobutyric acid ethyl ester, and refluxing for 16 hours until the (S) -2-aminobutyric acid methyl ester hydrochloride remains less than or equal to 3.0%; cooling the reaction liquid, filtering to remove salt, evaporating to remove the solvent under reduced pressure, and filtering to remove salt again; cooling the filtrate to 0-5 ℃, dropwise adding 24.79kg of hydrogen chloride isopropanol solution to form salt, and controlling the pH of the filtrate to be less than 1 after dropwise adding; adding isopropyl ether into the filtrate, pulping, centrifuging, leaching the wet product with mixed solution of isopropanol and isopropyl ether, and drying under reduced pressure to obtain 89.46kg of dry product, wherein the molar yield is 60.6%, and the liquid phase purity is 99.1%;
c: and (3) cyclization reaction: adding 357.84kg of acetone, 17.89kg of anhydrous potassium carbonate and 89.46kg of ethyl (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyrate hydrochloride into a reaction kettle at room temperature, and stirring and dissolving at room temperature; extracting with 132.0kg of toluene once, washing the organic phase with 148.0kg of water once, adding 89.46kg of 2-hydroxypyridine into the organic phase, heating to 100 ℃ for reaction for 20 hours, detecting by TLC until the content of (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyric acid ethyl ester hydrochloride is not reduced any more, and evaporating toluene under reduced pressure to obtain 56.13kg of oily (S) -2- (2-oxopyrrolidin-1-yl) butyric acid methyl ester, wherein the molar yield is 90.7%, and directly carrying out the next step;
d: ammonolysis reaction: adding 112.26kg of ammonia water into a reaction kettle, cooling to-5-0 ℃, dropwise adding 56.13kg of (S) -methyl 2- (2-oxopyrrolidin-1-yl) butyrate, reacting at-5-0 ℃ for 8 hours after dropwise adding, reducing pressure, steaming to remove water, adding 252.0kg of ethyl acetate, pulping, centrifuging, and drying under reduced pressure to obtain 50.45kg of levetiracetam, which is a final product, wherein the molar yield is 97.8%. Starting from the starting material (S) -2-aminobutyric acid to the final product levetiracetam, the total molar yield is 49.29%, the HPLC purity is 99.89%, and the optical purity is 99.92%.
Example 4
A: esterification reaction: adding 310.0kg of methanol and 155kg of (S) -2-aminobutyric acid into a reaction kettle, heating to 30 ℃, reacting for 16 hours, cooling to-5-0 ℃, slowly dropwise adding 387.5kg of thionyl chloride, controlling the temperature to-5-0 ℃, removing the solvent by reduced pressure evaporation after dropwise adding, pulping for 2 hours by using 700.0kg of ethyl acetate, centrifuging, leaching a wet product by using 200.0kg of ethyl acetate, centrifuging, drying under reduced pressure to obtain 208.96kg of (S) -2-methyl aminobutyric acid hydrochloride, wherein the molar yield is 90.5%, and the liquid phase purity is 99.33%;
b: alkylation reaction: adding 626.88kg of isopropanol, 208.96kg of (S) -2-aminobutyric acid methyl ester hydrochloride and 208.96kg of anhydrous sodium carbonate into a reaction kettle, heating to 40 ℃, refluxing for 2h, dropwise adding 323.89kg of 4-bromobutyric acid ethyl ester, and performing reflux reaction for 16 h until the residual (S) -2-aminobutyric acid methyl ester hydrochloride is less than or equal to 3.0%; cooling the reaction liquid, filtering to remove salt, evaporating to remove the solvent under reduced pressure, and filtering to remove salt again; cooling the filtrate to 0-5 ℃, dropwise adding 244.48kg of hydrogen chloride isopropanol solution to form salt, and controlling the pH of the filtrate to be less than 1 after dropwise adding; adding isopropyl ether into the filtrate, pulping, centrifuging, leaching the wet product with mixed solution of isopropanol and isopropyl ether, and drying under reduced pressure to obtain 221.45kg of dry product, wherein the molar yield is 60.8%, and the liquid phase purity is 99.1%;
c: and (3) cyclization reaction: adding 442.9kg of diethyl ether, 110.73kg of anhydrous sodium carbonate and 221.45kg of ethyl (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyrate hydrochloride into a reaction kettle at room temperature, and stirring and dissolving at room temperature; extracting with toluene 330.0kg once, washing the organic phase with 370.0kg water once, adding 2-hydroxypyridine 22.15kg into the organic phase, heating to 105 ℃ for reaction for 20 hours, detecting by TLC until the content of (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyric acid ethyl ester hydrochloride is not reduced, evaporating toluene under reduced pressure to obtain 137.41kg of oily (S) -2- (2-oxopyrrolidine-1-yl) butyric acid methyl ester, wherein the molar yield is 89.7%, and directly carrying out the next step;
d: ammonolysis reaction: adding 1374.1kg of ammonia water into a reaction kettle, cooling to-5-0 ℃, dropwise adding 137.41kg of (S) -methyl 2- (2-oxopyrrolidin-1-yl) butyrate, after dropwise adding, keeping the temperature at-5-0 ℃ for reacting for 8 hours, reducing pressure, steaming to remove water, adding 630.0kg of ethyl acetate, pulping, centrifuging, and drying under reduced pressure to obtain 123.37kg of a final product levetiracetam, wherein the molar yield is 97.7%. Starting from the starting material (S) -2-aminobutyric acid to the final product levetiracetam, the total molar yield is 48.22%, the HPLC purity is 99.94%, and the optical purity is 99.95%.
It should be understood that the detailed description and specific examples, while indicating the invention, are given by way of illustration only, since various other embodiments will become apparent to those skilled in the art upon reference to the following detailed description.
Claims (9)
1. A preparation method of levetiracetam is characterized by comprising the following steps:
a: esterification reaction: reacting (S) -2-aminobutyric acid with methanol at the temperature of 20-30 ℃ for 16-18 h, then dropwise adding thionyl chloride into the reaction liquid at the temperature of-5-0 ℃, and performing post-treatment to obtain (S) -2-aminobutyric acid methyl ester hydrochloride;
b: alkylation reaction: adding inorganic base and (S) -2-aminobutyric acid methyl ester salt into isopropanol, heating to 40-80 ℃, dropwise adding 4-bromobutanoic acid ethyl ester for alkylation reaction, and performing aftertreatment on reaction liquid to obtain (S) -4- [ (1-methoxy-1-oxobutane-2-yl) amino ] butyric acid ethyl ester hydrochloride;
c: and (3) cyclization reaction: dissolving (S) -4- [ (1-methoxy-1-oxobutan-2-yl) amino ] butyric acid ethyl ester hydrochloride in a solvent under stirring at room temperature under an alkaline condition; extracting with toluene, adding 2-hydroxypyridine into the organic phase, heating to 95-105 ℃, carrying out cyclization reaction, and carrying out post-treatment on the reaction liquid to obtain (S) -methyl 2- (2-oxopyrrolidine-1-yl) butyrate;
d: ammonolysis reaction: adding (S) -2- (2-oxopyrrolidine-1-yl) methyl butyrate into ammonia water, reacting at-20 ℃, and carrying out post-treatment on the reaction liquid to obtain levetiracetam.
2. The method for preparing levetiracetam according to claim 1, wherein in the step A, the mass ratio of the (S) -2-aminobutyric acid to the methanol to the thionyl chloride is 1: 2-8: 1-2.5.
3. The process for preparing levetiracetam according to claim 1 or 2, wherein the post-treatment in step A comprises: evaporating the solvent under reduced pressure, pulping with ethyl acetate for 2 hours, centrifuging, leaching the wet product with ethyl acetate, centrifuging, and drying under reduced pressure.
4. The preparation method of levetiracetam according to claim 1, wherein the mass ratio of (S) -methyl 2-aminobutyrate hydrochloride, the inorganic base, the isopropanol and the ethyl 4-bromobutyrate in the step B is 1: 1-2: 3-4: 1-2.
5. The method for preparing levetiracetam according to claim 1 or 4, wherein the inorganic base in the reaction in step B is one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide.
6. The method for preparing levetiracetam according to claim 1, wherein the mass ratio of (S) -ethyl 4- [ (1-methoxy-1-oxobutan-2-yl) amino ] butyrate hydrochloride to 2-hydroxypyridine to solvent to base in step C is 1: 0.01-1: 2-4: 0.2-0.5.
7. The method for preparing levetiracetam according to claim 1, wherein the solvent in step C is selected from one or more of purified water, alcohols, esters, ketones or ethers; the alkali is one of inorganic carbonate, bicarbonate or ammonia.
8. The method for preparing levetiracetam according to claim 1, wherein the mass ratio of (S) -methyl 2- (2-oxopyrrolidin-1-yl) butyrate to ammonia water in step D is 1:2 to 10.
9. The method for preparing levetiracetam according to claim 1, wherein the post-treatment process in step B is as follows: cooling the reaction liquid, filtering to remove salt, evaporating to remove the solvent under reduced pressure, and filtering to remove salt again; cooling the filtrate to 0-5 ℃, dropwise adding a hydrogen chloride isopropanol solution to form salt, and controlling the pH to be less than 1; adding isopropyl ether, pulping, centrifuging, leaching the wet product with mixed solution of isopropanol and isopropyl ether, and drying under reduced pressure;
and C, post-treatment process: decompressing the reaction liquid and distilling off the toluene;
and D, post-treatment process: and (3) decompressing and steaming the reaction liquid to remove water, pulping by using ethyl acetate, centrifuging, and decompressing and drying.
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