CN102816083B - The preparation method of scheme for lacosamide - Google Patents
The preparation method of scheme for lacosamide Download PDFInfo
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- CN102816083B CN102816083B CN201210266258.7A CN201210266258A CN102816083B CN 102816083 B CN102816083 B CN 102816083B CN 201210266258 A CN201210266258 A CN 201210266258A CN 102816083 B CN102816083 B CN 102816083B
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- lacosamide
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- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 title claims abstract description 46
- 229960002623 lacosamide Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title description 15
- 238000000034 method Methods 0.000 claims abstract description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 40
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 30
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 10
- 229940059260 amidate Drugs 0.000 claims description 10
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000005917 acylation reaction Methods 0.000 claims description 9
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 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 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 11
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- -1 carbobenzoxy-(Cbz) Chemical class 0.000 description 7
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 230000006872 improvement Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000006340 racemization Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 206010015037 epilepsy Diseases 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
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- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 208000021722 neuropathic pain Diseases 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052697 platinum Inorganic materials 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011122 softwood Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- FWQHRZXEQNUCSY-UHFFFAOYSA-N tert-butyl N-[2-(ethoxycarbonylamino)-5-[(4-fluorophenyl)methyl-prop-2-ynylamino]phenyl]carbamate Chemical compound CCOC(=O)NC1=C(C=C(C=C1)N(CC#C)CC2=CC=C(C=C2)F)NC(=O)OC(C)(C)C FWQHRZXEQNUCSY-UHFFFAOYSA-N 0.000 description 3
- 235000020985 whole grains Nutrition 0.000 description 3
- 206010010904 Convulsion Diseases 0.000 description 2
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 230000006181 N-acylation Effects 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010931 ester hydrolysis Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLRGEJWRGPHNPU-UHFFFAOYSA-N (2,3-diethoxyphenyl)-diphenylphosphane Chemical compound CCOC1=CC=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1OCC XLRGEJWRGPHNPU-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 1
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
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- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
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- 238000009833 condensation Methods 0.000 description 1
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- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- XNZFUKOVJVOLPE-UHFFFAOYSA-N furan;pyridine Chemical class C=1C=COC=1.C1=CC=NC=C1 XNZFUKOVJVOLPE-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
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- 150000002780 morpholines Chemical class 0.000 description 1
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- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
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- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 229940089285 vimpat Drugs 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
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the method that one prepares (R)-2-Acetamido-N-benzyl-3-methoxypropionamide (scheme for lacosamide).Method of the present invention improves purity and the yield of scheme for lacosamide by the temperature condition of each step of control.Method route of the present invention is reasonable, technological operation simple, condition controls clear and definite.
Description
Technical field
The present invention relates to a kind of preparation method treating the scheme for lacosamide of epilepsy and neuropathic pain, be specifically related to a kind of preparation method that improve the improvement of the scheme for lacosamide of purity and yield.
Background technology
Scheme for lacosamide (lacosamide), chemistry (R)-2-Acetamido-N-benzyl-3-methoxypropionamide by name, be the novel N-methyl-D-aspartate receptor glycine binding site antagonist of Belgian UCB. S.A. (BE) Bruxelles Belgium exploitation, be mainly used in the assisting therapy of diabetic neuralgia and adults with epilepsy partial seizure clinically.This strain new type functional amino acid anticonvulsant drug, has dual anticonvulsant effect, the slow inactivation of alternative promotion sodium-ion channel, the reaction mediating proteins and regulation and control are subsided, thus delays even stop epileptic seizures and alleviate diabetic neuropathic pain.Scheme for lacosamide was successively gone on the market in European Union and U.S.'s approval in August, 2008 and October, trade(brand)name Vimpat.Scheme for lacosamide has two kinds of formulations to get permission listing: diaphragm (50,100,150 and 200mg/ sheet), injection (10mg/ml, 20ml/ props up), clinical study shows, its tolerance compared with other anticonvulsive drug is better, and untoward reaction (as drowsiness and cognitive and behavior disorder) is lighter.
Document discloses the synthetic method of four kinds of scheme for lacosamide: first method to comprise D-Ser through carbobenzoxy-(Cbz) protection, methyl iodide methylates, Ester hydrolysis, amidation, remove protection, obtained (R)-2-Acetamido-N-benzyl-3-methoxypropionamide (scheme for lacosamide) of N-acetylize, total recovery about 46%; Or methylate after first amidation, total recovery about 52%.This method reactions steps is more, enantiomeric purity more than 97%, and reagent cost is high, severe reaction conditions, and by product is more, must through purification by column chromatography, and enantiomeric purity does not reach requirement.Second method comprises N-tertbutyloxycarbonyl-D-Ser after dimethyl sulfate methylation of ester, isobutyl chlorocarbonate activation, generates (R)-2-t-butoxycarbonyl amino-3-methoxyl group-N-benzyl propionic acid amide; scheme for lacosamide is obtained again, total recovery about 5% through deprotection, N-acetylize.This method total recovery is lower, during preparation (R)-2-t-butoxycarbonyl amino-3-methoxyl group-N-benzyl propionic acid amide, by product is many, with chloroform: purity 97.3% after normal hexane (1: 9) recrystallization, but purification yield only 14.4%, is unsuitable for suitability for industrialized production (Ma Yinling, Zhao Feng, Zhang Kai, Liu Leina, Du Yumin. the synthesis of scheme for lacosamide. Chinese Journal of Pharmaceuticals .Chinese Journal of Pharmaceuticals 2009,40 (9); P641-643).The third method comprises D-Ser and acetic anhydride is generated acid amides, then through isobutyl chlorocarbonate activation, with benzylamine condensation under alkaline condition (as N-methylmorpholine), silver suboxide and methyl iodide methylate obtained, total recovery about 20%.This method synthetic route is simple, but expensive reagents, be unsuitable for suitability for industrialized production, and product section racemization (about 25%).4th kind of method comprises the cyclization under the catalysis of diethoxy triphenyl phosphine of D-Ser methyl esters and generates (R)-aziridine-2-methyl-formiate, then through N-acetylize, open loop, Ester hydrolysis, last and benzylamine reacts obtained, and total recovery is lower than 10%.This method complex operation, cost are higher, and total recovery is low.
In sum, the problem existing for existing scheme for lacosamide preparation method mainly scheme for lacosamide optical purity do not reach requirement and yield is low.
Therefore, at present in the urgent need to a kind of preparation method improving the improvement of scheme for lacosamide purity and yield.
Summary of the invention
The object of this invention is to provide a kind of method preparing scheme for lacosamide.
Another object of the present invention is to provide a kind of method preparing the pharmaceutical composition comprising scheme for lacosamide.
The method preparing scheme for lacosamide provided by the present invention comprises the following steps:
A () makes formula I generation amidate action,
Obtain the compound of formula II:
(b) compound of formula II is sloughed compound that R group obtains formula III:
with
C () makes the compound generation acylation reaction of formula III obtain (R)-2-Acetamido-N-benzyl-3-methoxypropionamide (scheme for lacosamide);
Wherein, R is N-protected base, and the described amidate action in step (a) carries out at-20 ~-15 DEG C of temperature; In step (b) to make the compound of formula II slough R group be carry out at 0 ~ 5 DEG C of temperature; Described acylation reaction in step (c) is carried out at 20 ~ 25 DEG C of temperature.
In the embodiment of first aspect, the described amidate action in step (a) uses isobutyl chlorocarbonate as catalyzer.
In the embodiment of first aspect, the solvent that described amidate action in step (a) uses is selected from methylene dichloride (DCM), tetrahydrofuran (THF) (THF), toluene, dimethyl sulfoxide (DMSO) (DMSO), DMF (DMF), methyl alcohol and Virahol; Preferred methylene dichloride.
In the embodiment of first aspect, the described amidate action in step (a) carries out in the presence of a base.Described alkali is selected from N-methylmorpholine and triethylamine, preferred N-methylmorpholine.
In the embodiment of first aspect, described N-protected base is selected from tertbutyloxycarbonyl (Boc), carbobenzoxy-(Cbz) (Cbz) and fluorenylmethyloxycarbonyl (Fmoc).In one embodiment, described N-protected base is carbobenzoxy-(Cbz) (Cbz), and described carbobenzoxy-(Cbz) (Cbz) is removed by the method for hydrogenation under platinum catalysis.In another embodiment, described N-protected base is fluorenylmethyloxycarbonyl (Fmoc), and described fluorenylmethyloxycarbonyl (Fmoc) is removed by silica gel catalyst method.In still another embodiment, described N-protected base is tertbutyloxycarbonyl (Boc), and described tertbutyloxycarbonyl (Boc) is removed by mineral acid hydrolysis method, and wherein said mineral acid is trifluoroacetic acid and hydrochloric acid, preferred hydrochloric acid.And preferred, described hydrochloric acid is concentrated hydrochloric acid.
In the embodiment of first aspect, the acylating reagent of the described acylation reaction in step (c) is selected from diacetyl oxide, oxalyl chloride and Acetyl Chloride 98Min., preferred diacetyl oxide.
In the embodiment of first aspect, isolate scheme for lacosamide by crystallization from final reacting mixture, wherein said crystallization is carried out in mixed solvent, and described mixed solvent is the mixture of ether and normal hexane.Preferably, the volume ratio of ether and normal hexane is 1: 2.
The method that preparation provided by the invention comprises the pharmaceutical composition of scheme for lacosamide comprises the steps:
A () prepares scheme for lacosamide by the embodiment of first aspect, and
B scheme for lacosamide and pharmaceutically acceptable auxiliary material are prepared into tablet or capsule by ().
Method of the present invention is the improvement made on the basis of second method, starting raw material directly using (R)-2-N-Boc-amino-3-methoxypropionic acid as reaction, and selecting response carries out in the basic conditions, by strictly controlling the temperature of reaction process, (temperature often walking reaction in whole reaction process controls necessary strict simultaneously, temperature head is less than 1 DEG C), the product chiral purity finally obtained and ordinary purity and yield all high than additive method.
The scheme for lacosamide preparation method of improvement of the present invention compared with the existing methods, provides following advantage: (1) improves the overall yield of reaction; (2) eliminate the problem of racemization in reaction, chiral purity reaches 99.1%, and ordinary purity reaches 97.8%.
Detailed Description Of The Invention
The present invention relates to a kind of improvement for the treatment of the synthetic method of the scheme for lacosamide of epilepsy and neuropathic pain.
Concrete implementation step is as follows:
Flow process 1
In flow process 1, the feature of reactions steps a is:
1) solvent is selected
Alcohols (Virahol, ethanol, methyl alcohol etc.), halogenated alkane (methylene dichloride, chloroform etc.), pyridine furans (dihydropyridine, tetrahydrofuran (THF) etc.), toluene, dimethyl sulfoxide (DMSO) (DMSO), N, dinethylformamide (DMF) etc. can as reaction solvent, the methylene dichloride of preferred drying is as solvent, through verification experimental verification, methylene dichloride is as solvent, product racemization degree has remarkable reduction, and boiling point is lower, be easy to be removed.
2) selection of temperature
The present invention is from raw material, and intermediate and the end product of each step all exist chirality, so thermal creep stress is the key of this experiment.Through repeatedly validation trial, reactions steps a of the present invention selects to carry out at-20 ~-15 DEG C of temperature.
3) selection of catalyzer
Prioritizing selection isobutyl chlorocarbonate is as catalyzer.
4) selection of alkali
Reaction is carried out in the presence of a base, and alkali is as triethylamine, diisopropyl ethyl amine, 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene, saleratus and morpholine analog derivative (such as, N-methylmorpholine).This experiment prioritizing selection N-methylmorpholine.
In flow process 1, the feature of reactions steps b is:
Slough N-protected base R.The method of sloughing N-protected base R has three classes:
1) hydrogenation method under platinum catalysis
When N-protected base R is carbobenzoxy-(Cbz) (Cbz), described carbobenzoxy-(Cbz) (Cbz) is removed by the method for hydrogenation under platinum catalysis.(under Pt/C exists, the object of de-Cbz can be realized under atmosphere of hydrogen at normal temperature and pressure.
2) mineral acid hydrolysis method
(a) trifluoroacetic acid (TFA) method
TFA can be hydrolyzed some acid nonfast blocking groups, as Boc protecting group, adamantyloxycarbonyl (Adoc) etc.
Concrete reaction mechanism is as follows:
(b) hydrochloric acid method
Hydrochloric acid method uses concentrated hydrochloric acid and organic solvent (as ethyl acetate) with certain proportioning (about 1: 2) wiring solution-forming, then room temperature reaction.
3) silica gel catalyst method
Silica gel catalyst method adds toluene in reactant, after stirring, adds silica gel, reflux, after reaction terminates, is cooled to room temperature, filters, then clean silica gel with different solvents, after filtrate evaporate to dryness, purify further.
Silica gel catalyst method selectivity deprotection
The present invention preferably adopts concentrated hydrochloric acid method to be hydrolyzed N-protected base (at strong acidic condition, reaction yield is high), and temperature controls at 0 ~ 5 DEG C.
In flow process 1, the feature of reactions steps c is:
Reactions steps c is N-acylation reaction, and the acylating reagent of described N-acylation reaction can adopt acid anhydrides, acyl chlorides etc., such as diacetyl oxide, oxalyl chloride and Acetyl Chloride 98Min. etc.; Reaction conditions is gentleer, generally at 20 ~ 25 DEG C of temperature.
The present invention adopts diacetyl oxide, and thermal creep stress is 20 ~ 25 DEG C, acidylate yield 87.9%, than with acyl chlorides and other acylating reagent yields higher.
The purification step of crude product:
The present invention also comprises the purge process of product, because scheme for lacosamide very easily racemization reaction occurs in a solvent, so general recrystallization method can not be adopted to refine, we have passed through groping under different solvents condition in an experiment, finally determine to adopt mixed solvent (ether: normal hexane=1: 2) stirring and crystallizing, compared with other purification process, this method purifying products yield reaches 87.9%, and purity reaches 97.8%.
Embodiment
Embodiment 1
(R) synthesis of-N-benzyl-2-N-Boc-amino-3-methoxypropionamide (formula II compound)
In reaction flask, 10g (R)-2-N-Boc-amino-3-methoxypropionic acid is dissolved in the tetrahydrofuran (THF) of 80ml drying, controls the temperature-15 ~-10 DEG C of reaction solution; 5.6g isobutyl chlorocarbonate, 6.2g N-methylmorpholine is added under-10 ~-5 DEG C of conditions, stir 1.5h, then-15 ~-10 DEG C time, in reaction flask, drip benzylamine (5.89g) solution being dissolved in 20ml tetrahydrofuran (THF), 25 ~ 30 DEG C of reaction 2.0h, HPLC method detection reaction are slowly warming up to whether completely in 0.5h.The hydrochloric acid of 80ml water, 80ml1mol/L, 80ml saturated sodium bicarbonate solution and 80ml water washing reaction solution is used successively after reaction terminates, separating lower floor's organic phase is concentrated into dry, obtain oily matter, then the ether of 80ml is added: normal hexane=1: the mixed solvent of 1, frozen water cooling is stirred, crystallization, suction filtration, obtain 9.2g white powdery solids, yield 86.0%.HPLC ordinary purity 92.3%, chiral purity 81.4%.
Embodiment 2
(R) synthesis of-N-benzyl-2-N-Boc-amino-3-methoxypropionamide (formula II compound)
In reaction flask, 10g (R)-2-N-Boc-amino-3-methoxypropionic acid is dissolved in the methylene dichloride of 80ml drying, controls the temperature-15 ~-10 DEG C of reaction solution; 5.6g isobutyl chlorocarbonate, 6.2g N-methylmorpholine is added under-10 ~-5 DEG C of conditions, stir 1.5h, then-15 ~-10 DEG C time, in reaction flask, drip benzylamine (5.89g) solution being dissolved in 20ml methylene dichloride, 25 ~ 30 DEG C of reaction 2.0h, HPLC method detection reaction are slowly warming up to whether completely in 0.5h.The hydrochloric acid of 80ml water, 80ml1mol/L, 80ml saturated sodium bicarbonate solution and 80ml water washing reaction solution is used successively after reaction terminates, separating lower floor's organic phase is concentrated into dry, obtain oily matter, then the ether of 80ml is added: normal hexane=1: the mixed solvent of 1, frozen water cooling is stirred, crystallization, suction filtration, obtain 8.3g white powdery solids, yield 59.0%.HPLC ordinary purity 95.3%, chiral purity 89.9%.
Embodiment 3
(R) synthesis of-N-benzyl-2-N-Boc-amino-3-methoxypropionamide (formula II compound)
In reaction flask, 10g (R)-2-N-Boc-amino-3-methoxypropionic acid is dissolved in the methylene dichloride of 80ml drying, control the temperature-20 ~-15 DEG C of reaction solution, 5.6g isobutyl chlorocarbonate, 6.2g N-methylmorpholine is added under-20 ~-15 DEG C of conditions, stir 1.5h, then keep dripping benzylamine (5.89g) solution being dissolved in 20ml methylene dichloride in this temperature condition downhill reaction bottle, whether reaction 7.0h, HPLC method detection reaction is complete.The hydrochloric acid of 80ml water, 80ml 1mol/L, 80ml saturated sodium bicarbonate solution and 80ml water washing reaction solution is used successively after reaction terminates, separating lower floor's organic phase is concentrated into dry, obtain oily matter, then 80ml ether is added: normal hexane=1: the mixed solvent of 1, frozen water cooling is stirred, crystallization, suction filtration, obtain 7.4g white powdery solids, yield 52.6%.HPLC ordinary purity 97.9%, chiral purity 99.1%.
Embodiment 4
(R) synthesis of-2-Amino-N-benzyl-3-methoxypropionamide (formula III compound)
In reaction flask, formula II compound 10g is dissolved in the methylene dichloride of 80ml, add 36% concentrated hydrochloric acid of 25.0ml wherein, keep temperature 25 ~ 30 DEG C, stir about 2.0h, TLC thin layer detects (developping agent: ethanol: normal hexane: ammoniacal liquor=1: 1: 0.1) whether reaction completes at this temperature.Reaction adds 80ml water after stopping, divide water-yielding stratum, sodium hydroxide solution with 30% is about 15ml adjust pH to 11 ~ 12, adding after sodium-chlor 30.0g dissolves uses methylene dichloride 60ml × 3 to extract again, separate organic layer, merge organic layer, be concentrated into dry, obtain oily matter 7.1g, yield > 100% (crude product).HPLC ordinary purity 86.3%, chiral purity 78.3%.
Embodiment 5
(R) synthesis of-2-Amino-N-benzyl-3-methoxypropionamide (formula III compound)
In reaction flask, formula II compound 10g is dissolved in the methylene dichloride of 80ml, be cooled to less than 15 DEG C, add 36% concentrated hydrochloric acid 25.0ml wherein, keep temperature 15 ~ 20 DEG C, stir about 3 ~ 4h, TLC thin layer detects (developping agent: ethanol: normal hexane: ammoniacal liquor=1: 1: 0.1) whether reaction completes at this temperature.Reaction adds 80ml water after stopping, divide water-yielding stratum, sodium hydroxide solution with 30% is about 15ml adjust pH to 11 ~ 12, adding after sodium-chlor 30.0g dissolves uses methylene dichloride 60ml × 3 to extract again, separate organic layer, merge organic layer, be concentrated into dry, obtain oily matter 6.9g, yield > 100% (crude product).HPLC ordinary purity 94.3%, chiral purity 85.3%.
Embodiment 6
(R) synthesis of-2-Amino-N-benzyl-3-methoxypropionamide (formula III compound)
In reaction flask, formula II compound 10g is dissolved in the methylene dichloride of 80ml, be cooled to less than 0 DEG C, add 36% concentrated hydrochloric acid 25.0ml wherein, keep temperature 0 ~ 5 DEG C, stir about 5 ~ 6h at this temperature, TLC thin layer detection (developping agent: ethanol: normal hexane: ammoniacal liquor=1: 1: 0.1) whether reaction completes, reaction adds 80ml water after stopping, divide water-yielding stratum, sodium hydroxide solution with 30% is about 15ml adjust pH to 11 ~ 12, adding after sodium-chlor 30.0g dissolves uses methylene dichloride 60ml × 3 to extract again, separate organic layer, merge organic layer, be concentrated into dry, obtain oily matter 5.9g, yield 87.4%.HPLC ordinary purity 99.4%, chiral purity 99.8%.
Embodiment 7
(R) synthesis of-2-Acetamido-N-benzyl-3-methoxypropionamide (scheme for lacosamide)
In reaction flask, modus ponens III compound 5.0g is dissolved in methylene dichloride 50ml, stirring and dissolving, cool to about 0 DEG C, add diacetyl oxide 10.0ml, 20 ~ 25 DEG C are warmed up under stirring, stir 2.0h at this temperature, whether TLC (developping agent: methyl alcohol: methylene dichloride (1: 15)) detection reaction completes, water (20m1 × 3) is used successively after reacting completely, 8% sodium bicarbonate aqueous solution (20m1) and water (20m1 × 3) washing, pressure reducing and steaming solvent, obtain white solid, add mixed solution (ether: normal hexane=1: 2) recrystallization, obtain scheme for lacosamide crude product 5.9g, yield 87.9%.HPLC ordinary purity 97.8%, chiral purity 99.1%.
The scheme for lacosamide that embodiment 7 is obtained
1h nuclear magnetic resonance spectrum (
1h-NMR) determination data is in table 1.
Table 1 scheme for lacosamide sample is in DMSO-d6
1h-NMR data
Embodiment 8
Prepared scheme for lacosamide can be prepared into tablet or capsule by following prescription composition and preparation method.
Prescription forms:
Preparation method:
1. supplementary material is sieved for subsequent use.The hydroxypropylcellulose taking recipe quantity adds appropriate purified water wiring solution-forming, makes tackiness agent, for subsequent use.
2. take the scheme for lacosamide of recipe quantity, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose mix, add tackiness agent softwood, granulate, dry, whole grain, add micropowder silica gel, Magnesium Stearate mix.
3. can be pressed into by equal proportion tablet that specification is 50mg, 100mg, 150mg, 200mg respectively or filling specification is the capsule of 50mg, 100mg, 150mg, 200mg.
4. tablet film coating pre-mix dose can be carried out dressing.
Embodiment 9
Prepared scheme for lacosamide can be prepared into tablet or capsule by following prescription composition and preparation method.
Prescription forms:
Preparation method:
1. supplementary material is sieved for subsequent use.The HPMC taking recipe quantity adds appropriate purified water wiring solution-forming, makes tackiness agent, for subsequent use.
2. take scheme for lacosamide, Microcrystalline Cellulose, lactose, croscarmellose sodium mix, add tackiness agent softwood, granulate, dry, whole grain, add micropowder silica gel, Magnesium Stearate mix.
3. can be pressed into by equal proportion tablet that specification is 50mg, 100mg, 150mg, 200mg respectively or filling specification is the capsule of 50mg, 100mg, 150mg, 200mg.
4. tablet film coating pre-mix dose can be carried out dressing.
Embodiment 10
Prepared scheme for lacosamide can be prepared into tablet or capsule by following prescription composition and preparation method.
Prescription forms:
Preparation method:
1. supplementary material is sieved for subsequent use.The PVP K30 taking recipe quantity adds appropriate purified water wiring solution-forming, makes tackiness agent, for subsequent use.
2. take scheme for lacosamide, Microcrystalline Cellulose, N.F,USP MANNITOL, polyvinylpolypyrrolidone mix, add tackiness agent softwood, granulate, dry, whole grain, add micropowder silica gel, Magnesium Stearate mix.
3. can be pressed into by equal proportion tablet that specification is 50mg, 100mg, 150mg, 200mg respectively or filling specification is the capsule of 50mg, 100mg, 150mg, 200mg.
4. tablet film coating pre-mix dose can be carried out dressing.
Claims (8)
1. prepare a method for scheme for lacosamide, said method comprising the steps of:
A () makes formula I generation amidate action,
Obtain the compound of formula II:
(b) compound of formula II is sloughed compound that R group obtains formula III:
C () makes the compound generation acylation reaction of formula III obtain scheme for lacosamide;
Wherein, R is N-protected base, and described N-protected base is tertbutyloxycarbonyl, and the described amidate action in step (a) carries out in the presence of a base, at-20 ~-15 DEG C of temperature; In step (b) to make the compound of formula II slough R group be carry out at 0 ~ 5 DEG C of temperature with concentrated hydrochloric acid; Described acylation reaction in step (c) is carried out at 20 ~ 25 DEG C of temperature; described method also comprises isolates scheme for lacosamide by crystallization from final reacting mixture; wherein said crystallization is carried out in mixed solvent, described mixed solvent be ether and normal hexane mixture and wherein the volume ratio of ether and normal hexane be 1:2.
2. the method for claim 1, the described amidate action wherein in step (a) uses isobutyl chlorocarbonate as catalyzer.
3. the method for claim 1, the solvent that the described amidate action wherein in step (a) uses is selected from methylene dichloride, tetrahydrofuran (THF), toluene, dimethyl sulfoxide (DMSO), DMF, methyl alcohol and Virahol.
4. method as claimed in claim 3, the solvent that the described amidate action wherein in step (a) uses is methylene dichloride.
5. the method for claim 1, wherein said alkali is selected from N-methylmorpholine and triethylamine.
6. method as claimed in claim 5, wherein said alkali is N-methylmorpholine.
7. the method for claim 1, the acylating reagent of the described acylation reaction wherein in step (c) is selected from diacetyl oxide, acetic acid and Acetyl Chloride 98Min..
8. method as claimed in claim 7, the acylating reagent of the described acylation reaction wherein in step (c) is diacetyl oxide.
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| EP2067765A2 (en) * | 2007-12-04 | 2009-06-10 | Ranbaxy Laboratories Limited | Intermediate compounds and their use in preparation of lacosamide |
| CN1989102B (en) * | 2004-10-02 | 2011-04-20 | Ucb医药有限公司 | Improved synthetic method of lacosamide |
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| EP2067765A2 (en) * | 2007-12-04 | 2009-06-10 | Ranbaxy Laboratories Limited | Intermediate compounds and their use in preparation of lacosamide |
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