WO2007074390A2 - Process for preparing rhodanine-3-acetic acid: a key intermediated of epalrestat - Google Patents
Process for preparing rhodanine-3-acetic acid: a key intermediated of epalrestat Download PDFInfo
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- WO2007074390A2 WO2007074390A2 PCT/IB2006/003790 IB2006003790W WO2007074390A2 WO 2007074390 A2 WO2007074390 A2 WO 2007074390A2 IB 2006003790 W IB2006003790 W IB 2006003790W WO 2007074390 A2 WO2007074390 A2 WO 2007074390A2
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- Prior art keywords
- formula
- compound
- methyl
- acetate
- acetic acid
- Prior art date
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- JGRMXPSUZIYDRR-UHFFFAOYSA-N 2-(4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl)acetic acid Chemical compound OC(=O)CN1C(=O)CSC1=S JGRMXPSUZIYDRR-UHFFFAOYSA-N 0.000 title abstract description 16
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 title description 8
- 229950010170 epalrestat Drugs 0.000 title description 7
- CHNUOJQWGUIOLD-UHFFFAOYSA-N epalrestate Natural products C=1C=CC=CC=1C=C(C)C=C1SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-UHFFFAOYSA-N 0.000 title description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 4
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims abstract description 3
- 229910052744 lithium Inorganic materials 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 3
- 150000004703 alkoxides Chemical class 0.000 claims description 3
- 229940086542 triethylamine Drugs 0.000 claims description 3
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims 1
- ONQBOTKLCMXPOF-UHFFFAOYSA-N 1-ethylpyrrolidine Chemical compound CCN1CCCC1 ONQBOTKLCMXPOF-UHFFFAOYSA-N 0.000 claims 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 11
- 239000002253 acid Substances 0.000 abstract description 2
- 239000012736 aqueous medium Substances 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 229910052500 inorganic mineral Inorganic materials 0.000 abstract 1
- 239000011707 mineral Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 22
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 17
- 239000010410 layer Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 229940093499 ethyl acetate Drugs 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 11
- JIQVZPLTMDPXAE-UHFFFAOYSA-N methyl 2-[(2-ethoxycarbothioylsulfanylacetyl)amino]acetate Chemical compound CCOC(=S)SCC(=O)NCC(=O)OC JIQVZPLTMDPXAE-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229960002449 glycine Drugs 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 6
- FCYYBUGNYDVXCX-UHFFFAOYSA-N methyl 2-[(2-chloroacetyl)amino]acetate Chemical compound COC(=O)CNC(=O)CCl FCYYBUGNYDVXCX-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- -1 Alkali metal ethylxanthate Chemical class 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 238000010960 commercial process Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- 0 *C(C*C(*)=N)=O Chemical compound *C(C*C(*)=N)=O 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 description 1
- CHNUOJQWGUIOLD-SMTGYRLFSA-N 2-[(5e)-5-[(e)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]acetic acid Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1\SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-SMTGYRLFSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 208000032131 Diabetic Neuropathies Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FSIMCBJACONSOW-UHFFFAOYSA-N [(2-chloroacetyl)-methylamino] acetate Chemical compound CC(=O)ON(C)C(=O)CCl FSIMCBJACONSOW-UHFFFAOYSA-N 0.000 description 1
- GFDXUDOOSMBQTF-UHFFFAOYSA-N [(2-ethoxycarbothioylsulfanylacetyl)-methylamino] acetate Chemical compound CCOC(=S)SCC(=O)N(C)OC(C)=O GFDXUDOOSMBQTF-UHFFFAOYSA-N 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- IEMGWBMVQLVHEY-UHFFFAOYSA-N ethyl 2-(3-amino-6,7-dihydro-5h-cyclopenta[b]pyridin-7-yl)acetate Chemical compound NC1=CN=C2C(CC(=O)OCC)CCC2=C1 IEMGWBMVQLVHEY-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- SOOQKEUJVJWXTI-UHFFFAOYSA-N methyl 2-aminoacetate;sulfuric acid Chemical compound OS(O)(=O)=O.COC(=O)CN SOOQKEUJVJWXTI-UHFFFAOYSA-N 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 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 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D277/36—Sulfur atoms
Definitions
- the present invention relates to a novel and improved process for the preparation of rhodanine-3- acetic acid, having CAS No. [ 5718-83-2] -[ compound of formula-II ] which is used for the preparation of (E,E)-5-(2-Methyl-3-phenyl-2-propenylidene)-4-oxo-2-thioxo-3- thiazolidineacetic acid, known as Epalrestat [I] .
- Epalrestat is used in the treatment of diabetic neuropathy.
- Epalrestat has CAS No. [82159-09-9].
- Rhodanine-3- acetic acid of formula-II as shown in scheme-I in which carbon disulphide is added to glycine in NH 4 OH using phase transfer catalyst followed by the reaction with sodium chloroacetate and cyclizing it using concentrated HCl to give Rhodanine-3- acetic acid of formula [H].
- Rhodanine-3- acetic acid of formula-[II] which involves reaction of glycine with carbon disulfide and sodium chloroacetate to give Rhodanine 3 -acetic acid .
- the process of present invention overcomes the disadvantages of prior art processes by avoiding the use of carbon disulfide in preparation of Rhodanine-3- acetic acid.
- the present invention also discloses a novel method for the preparation of Rhodanine-3 -acetic acid which involves formation and use of novel intermediate having a structure of formula-
- Rhodanine-3-acetic acid [II] is prepared as per scheme-II comprising steps:
- Rhodanine 3- acetic acid is the key intermediate in the synthesis of Epalrestat; It is prepared from glycine by following steps which are described in Scheme-II as follows:
- R is C 1-8 alkyl, benzyl,cycloalkyl,alkyleneCl-6, phenyl, substituted phenyl etc
- X is Cl, Br, I, OTs, OMs
- Y is Cl, Br, I, OTs, OMs
- Rl is selected from C1-C4 alkyl, benzyl, aryl etc. and preferably Rl is Ethyl or isopropyl and more preferably ethyl.
- step-1 In step-1
- the solvents in step-1 is selected from alcohol, such as MeOH, EtOH, IPA, BuOH, etc.; aromatic hydrocarbons such as toluene, benzene, Xylene ; Cycloalkanes such as cyclohexane, cyclopentane ; nitrile group of solvents like acetonitrile, propionitrile or mixtures thereof
- step-2 In step-2
- the solvents used in step-2 is selected from
- Ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether,
- Nitriles such as acetonitrile. or mixtures thereof.
- the preferred solvent is water. Temperature of reaction is between O 0 C to 40 0 C
- the base used for the neutralization is selected from inorganic alkalimetal bicarbonate, carbonates and hydroxides such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate etc, preferably sodium bicarbonate, organic tertiary amines such as NEt3, N-Methylmorpholine, N-Methylpyrrolidine, N- Ethylpiperidine, DBU, DBN, diisopropylethyl amine etc.
- inorganic alkalimetal bicarbonate, carbonates and hydroxides such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate etc, preferably sodium bicarbonate, organic tertiary amines such as NEt3, N-Methylmorpholine, N-Methylpyrrolidine, N- Ethylpiperidine, DBU, DBN, diisopropylethyl amine etc.
- Solvent for the reaction is water.
- step-4 Temperature of the reaction is between O to 10O 0 C preferably 30 to 35 0 C.
- the base used for cyclization is selected from:
- tertiary amine like triethyl amine, N-methyl morpholine, N-methyl pyrrolidine, N-ethyl pyi ⁇ olidine,diisopropyl ethyl amine , DBU DBN ; alkoxide group of bases like NaOMe , NaOEt , Sodium or pottasium isopropoxide, Sodium or potassium tert. butoxide.
- the preferred base is NaOMe.
- the solvent for the reaction may be selected from :
- Halogen group of solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and optionally mixtures thereof ,
- Aromatic hydrocarbon group of solvents such as benzene, toluene, xylene and optionally mixtures thereof
- Nitrile group of solvents such as acetonitrile, propionitrile and optionally mixtures thereof.
- step-5 In step-5
- the acid used is selected from aq. hydrochloric acid, aq. sulfuric acid, aq. phosphoric acid, aq. hydrobromic acid etc.
- the temperature of the reaction is from 25-125 0 C , preferably carried out at the reflux temperature (about 100 0 C)
- aminoacetic acid (30Og, 4mol) is stirred with 1.5 L methanol under cooling. Purge dry HCl gas into cooled mass. The reaction mass is refluxed and maintained at reflux temperature for 2 hours. The absence of aminoacetic acid is checked on
- potassium ethyl xanthate (27 Ig, 1.69mol) is stirred with 2.2L of water at 30-35 0 C.
- the solution of methyl[(chloroacetyl)amino]acetate (28Og, 1.69mol), dissolved in 600ml of water is added at 30-35 0 C.
- the reaction mass is stirred for 5 hours.
- the absence of methyl[(chloroacetyl)amino]acetate is checked by TLC.
- the reaction mass is filtered and washed with 1800ml water. The wet cake is unloaded and dried in oven at 55-6O 0 C for 5-6 hours.
- reaction mass is stirred for 4 hours at 5-10 0 C.
- the absence of methyl( ⁇ [(ethoxycarbonothioyl)thio]acetyl ⁇ amino) acetate is checked by TLC.
- the reaction mass is dumped into cooled (0-5 0 C) 70ml 30% Hydrochloric acid. 300ml of water is added at 0-5 0 C and temperature is raised to 25-30 0 C. The organic layer is separated. Aqueous layer is extracted with 500ml ethyl acetate.
- Methyl( ⁇ [(ethoxycarbonothioyl)thiojacetyl ⁇ amino) acetate is checked by TLC.
- the Reaction mass is dumped into chilled 5-10°C phosphoric acid solution (15ml H 3 PO 4 with 40ml water).
- To the reaction mass is charged 100ml of water at 5-1O 0 C.
- the temperature is raised to 25- 3O 0 C.
- the organic layer is separated.
- Aqueous layer is extracted with (75ml) ethyl acetate.
- Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (8g, 0.038mol) is stirred with mixture of 25ml acetic acid and 20ml of 25% sulfuric acid solution at reflux temperature for 2 hours. 20ml 33% aqueous acetic acid solution is added in the reaction mass. Reflux is maintained for 21 hours. The absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin ⁇ 3-yl)acetate is checked by TLC. The reaction mass is dumped into cooled water.
- Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (28g, 0.1364mol) is stirred with 48% aqueous HBr (60ml) at reflux for 4 hours. Absence of methyl(4-oxo-2-thioxo-l,3- thiazolidin-3-yl) acetate is checked with TLC. The reaction mass is dumped into chilled water.
- Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (10 gm, 0.048 mol) is stirred with 30% Aqueous Hydrochloric Acid solution(70 ml) at reflux temperature for 15 hours. Absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate is checked by TLC. The reaction mass is quenched with DM Water. Aqueous layer is extracted with ethyl acetate.
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Abstract
A process for preparation of (4-oxo-2-thioxo-1,3-thiazolidin-3-yl) acetic acid comprising: (a) reaction of compound of formula (VIII) wherein Y is Cl, Br, I, OTs, OMs and R is C1-8 alkyl, benzyl, cycloalkyl, phenyl, substituted phenyl and their like; with a compound of formula (VIIIA) wherein M is K, Na or Li, preferably K; R1 is C1-4 alkyl, benzyl, C1-C8 cycloalkyl, phenyl and their like, in aqueous medium to give a compound of formula (IX) (b) cyclizing a compound of formula (IX) using a base to give a compound of formula (X) in a solvent. (c) hydrolyzing (X) using aqueous mineral acid.
Description
FIELD OF INVENTION
The present invention relates to a novel and improved process for the preparation of rhodanine-3- acetic acid, having CAS No. [ 5718-83-2] -[ compound of formula-II ] which is used for the preparation of (E,E)-5-(2-Methyl-3-phenyl-2-propenylidene)-4-oxo-2-thioxo-3- thiazolidineacetic acid, known as Epalrestat [I] . Epalrestat is used in the treatment of diabetic neuropathy. Epalrestat has CAS No. [82159-09-9].
Toshimasa ISHIDA et al. in Tetrahedron Letters vol30, No. 8, pages 959-962 (1989) published the structure elucidation of of all four geometrical isomers of Epalrestat (ONO- 2235) based on NMR and UV spectroscopic evidences and assigned (Z)-3-carboxymethyl~ [(2E)-methylphenylpropenylidene]-rhodanine as clinically important compound. Epalrestat is marketed as (Z,E) form by Ono Pharmaceuticals Co. Ltd. under the trade name 'Kinedak' since 1992.
BACKGROUND OF INVENTION :
Li, Yuezhen et.al. in Chinese Journal Zhongguo Yaowu Huaxue Zazhi (2001), 11(3), 165- 167 describe synthesis of Rhodanine-3- acetic acid of formula-II as shown in scheme-I in which carbon disulphide is added to glycine in NH4OH using phase transfer catalyst followed by the reaction with sodium chloroacetate and cyclizing it using concentrated HCl to give Rhodanine-3- acetic acid of formula [H]. Scheme-I
ca
aminoacetic acid [IV]
CICH2COONa
(4-oxo-2-thioxo-1 ,3-thiazolidin-3-yl)acetic acid
Li, Duxin et. al. in Chinese Journal Shanxi Daxue Xuebao, Ziran Kexuban (1995), 18(4),
413-16 describe the preparation of II [refer scheme-I], wherein, reaction of compound -[IV] with Chloroacetic acid in aqueous Na2CO3 gives compound of formula [V] . Compound of formula [V] reacts with HCl and gives Rhodanine-3 -acetic acid [II] .
A publication in Journal of Zhejiang University, Medical Science (2003 Aug), 32(4), 356-8
,describes method of synthesis of Rhodanine-3- acetic acid of formula-[II] which involves reaction of glycine with carbon disulfide and sodium chloroacetate to give Rhodanine 3 -acetic acid .
AU processes disclosed in prior art use Carbon disulfide which is hazardous and generally undesirable in large scale commercial processes. It is hence desirable to develop a process for preparing Rhodanine-3 -acetic acid without using carbon disulfide.
SUMMARY
The process of present invention overcomes the disadvantages of prior art processes by avoiding the use of carbon disulfide in preparation of Rhodanine-3- acetic acid.
The present invention also discloses a novel method for the preparation of Rhodanine-3 -acetic acid which involves formation and use of novel intermediate having a structure of formula-
[IX] .
In accordance with the present invention Rhodanine-3-acetic acid [II] is prepared as per scheme-II comprising steps:
1. Aminoacetic acid [VI] is reacted with methanol in HCl to give methyl aminoacetate hydrochloride [VII ; where R is Me]
2. Methyl aminoacetate hydrochloride [VII ; where R is Me] is reacted with chloroacetyl chloride [VIIA ; where X and Y is Cl] to give methyl[(chloroacetyl)amino]acetate [VIII ; where Y is Cl and R is Me ],
3. Methyl[(chloroacetyl)amino]acetate [VIII ; where Y is Cl and R is Me ] is reacted with Alkali metal ethylxanthate [VIIIA ; where M is K] i.e. potassium ethyl xanthate to give methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate [IX ; where R is Me and Rl is Et ],
4. Methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate [IX ; where R is Me and Rl is Et ], is cyclised to give methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate [X ; whereR is methyl],
5. Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate [X ; whereR is methyl] is hydrolysed to give Rhodanine-3-acetic acid [H].
DETAILED DESCRIPTION OF THE INVENTION :
It may be noted that these reactions are earned out without the use of carbon disulfide which is hazardous and undesirable on large scale commercial processes. Rhodanine 3- acetic acid is the key intermediate in the synthesis of Epalrestat; It is prepared from glycine by following steps which are described in Scheme-II as follows:
SCHEME-I
Step-1
.HCI
Vl V)]
Rl is selected from C1-C4 alkyl, benzyl, aryl etc. and preferably Rl is Ethyl or isopropyl and more preferably ethyl.
In step-1
The solvents in step-1 is selected from alcohol, such as MeOH, EtOH, IPA, BuOH, etc.; aromatic hydrocarbons such as toluene, benzene, Xylene ; Cycloalkanes such as cyclohexane, cyclopentane ; nitrile group of solvents like acetonitrile, propionitrile or mixtures thereof
In step-2
The solvents used in step-2 is selected from
(a) Water,
(b) Aromatic hydrocarbons like benzene, toluene, xylene, cyclohexane
(c) Halogenated solvents like dichloromethane, 1,2 dichloroethane, chloroform etc
(d) Ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether,
(e) Nitriles such as acetonitrile. or mixtures thereof.
The preferred solvent is water. Temperature of reaction is between O0C to 400C
The base used for the neutralization is selected from inorganic alkalimetal bicarbonate, carbonates and hydroxides such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate etc, preferably sodium bicarbonate, organic tertiary amines such as NEt3, N-Methylmorpholine, N-Methylpyrrolidine, N- Ethylpiperidine, DBU, DBN, diisopropylethyl amine etc.
In step-3
Solvent for the reaction is water.
Temperature of the reaction is between O to 10O0C preferably 30 to 350C.
In step-4
The base used for cyclization is selected from:
(a) tertiary amine like triethyl amine, N-methyl morpholine, N-methyl pyrrolidine, N-ethyl pyiτolidine,diisopropyl ethyl amine , DBU DBN ; alkoxide group of bases like NaOMe , NaOEt , Sodium or pottasium isopropoxide, Sodium or potassium tert. butoxide. The preferred base is NaOMe.
The solvent for the reaction may be selected from :
(a) Halogen group of solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and optionally mixtures thereof ,
(b) Aromatic hydrocarbon group of solvents such as benzene, toluene, xylene and optionally mixtures thereof
(c) Nitrile group of solvents such as acetonitrile, propionitrile and optionally mixtures thereof.
In step-5
In the hydrolysis reaction, the acid used is selected from aq. hydrochloric acid, aq. sulfuric acid, aq. phosphoric acid, aq. hydrobromic acid etc.
The temperature of the reaction is from 25-1250C , preferably carried out at the reflux temperature (about 1000C)
The present invention is illustrated by the following non-limiting examples.
Example- 1
(a) Preparation ofmethylaminoacetate hydrochloride [VII ; where R is Me]
In 3 lit. multi- necked round bottom flask equipped with stirrer, condenser, thermometer and
HCl gas purging arrangement, aminoacetic acid (30Og, 4mol) is stirred with 1.5 L methanol under cooling. Purge dry HCl gas into cooled mass. The reaction mass is refluxed and maintained at reflux temperature for 2 hours. The absence of aminoacetic acid is checked on
TLC. The reaction mass is cooled to room temperature and maintained for 1 hour. The white crystalline product is filtered and washed with 300ml of methanol and sucked dry. The product is dried at 50-550C for 6 hours.
Yield of methyl aminoacetate hydrochloride = 460gms. M.P. = 175°C.
(b) Preparation ofmethylaminoacetate hydrogen sulfate
In 500 ml three necked round bottom flask equipped with stirrer, condenser, water bath aminoacetic acid (25gm, 0.33mol) is stirred with 125ml of methanol at 100C. Added (34.96g,
0.349mol) sulfuric acid drop wise at 100C during 1 hour. Heated to reflux and maintained it for 2 hours. The absence of amino acetic acid is checked by TLC. Distilled out methanol to get methyl aminoacetate hydrogen sulfate as oil.
Yield = 60 gm.
Example-2
Preparation of methyl(chloroacetylamino) acetate [VIII ; where R is Me and Y is Cl] In 10 L multi-necked round bottom flask equipped with mechanical stirrer, addition funnel, thermometer placed in ice bath , is charged sodium bicarbonate (30 Ig, 3.58mol) and stirred with 4.5L of water and cooled to 0-50C. Methylaminoacetate hydrochloride (45Og, 3.58mol) is added slowly at 0-50C. Chloroacetyl chloride (286ml, 3.58mol) is then added dropwise at 0- 5°C by maintaining pH of 6-7 with sodium bicarbonate (400g, 4.76mol). The mass is stirred at 0-50C for 1 hour and then at 25-300C for 1 hour. The absence of starting material is checked by TLC. After the disappearence of starting material on TLC, reaction mass is extracted with chloroform (4.5L). Chloroform is distilled out completely to give methyl(chloroacetylamino)acetate obtained as as oil. Yield = 46Og (%Yield=77%)
ExampIe-3
Preparation of methyl({[(ethoxycarhonothioyl)thio]acetyl}amino)acetate [ IX ; where R is Me and Rl is Et ]
In 5 Lit. multi-necked round bottom flask equipped with stirrer, thermometer and dropping funnel, potassium ethyl xanthate (27 Ig, 1.69mol) is stirred with 2.2L of water at 30-350C. The solution of methyl[(chloroacetyl)amino]acetate (28Og, 1.69mol), dissolved in 600ml of water is added at 30-350C. The reaction mass is stirred for 5 hours. The absence of
methyl[(chloroacetyl)amino]acetate is checked by TLC. The reaction mass is filtered and washed with 1800ml water. The wet cake is unloaded and dried in oven at 55-6O0C for 5-6 hours.
Yield of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate = 366g
(%Yield=86%)
Example-4
(a) Preparation ofmethyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate [X ; where R is Me ] In 1 Lit multi-necked round bottom flask equipped with mechanical stirrer, water bath thermometer ,condenser, Nitrogen gas purging arrangement, sodium methoxide (32.3g, 0.6mol) is stirred with 150ml methylene dichlori.de at 5-100C under nitrogen atmosphere. The solution of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (5Og, 0.1989mol) dissolved into 150ml of dichloromethane is added at 5-100C during 1 hour. The reaction mass is stirred for 4 hours at 5-100C. The absence of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino) acetate is checked by TLC. The reaction mass is dumped into cooled (0-50C) 70ml 30% Hydrochloric acid. 300ml of water is added at 0-50C and temperature is raised to 25-300C. The organic layer is separated. Aqueous layer is extracted with 500ml ethyl acetate. Organic layer is combined with main organic layer and distilled to give methyl(4-oxo-2-thioxo-l,3-thiazolidine~3-yl)acetate [X ; where R is Me ] as orange-red coloured oil. Yield = 40gm
(%Yield=97%)
(b) Preparation of 'methyl(4-oxo-2-thioxo-l ,3-thiazolidine-S-yl) acetate [X ; where R is Me ] In 100 ml three necked round bottom flask Methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (2g, 0.0079mol) is stirred with toluene(20 ml) at 60-650C. Added triethylamine solution (8ml, 0.0569mol in 10ml of toluene) at 60-650C slowly under nitrogen atmosphere. The reaction mass is stirred and heated to 80-850C for 12 hours. The absence of methyl({[(ethoxycarbonotliioyl)thio] acetyl} amino)acetate is checked by TLC. Reaction mass is dumped into 250ml of ice-water. The toluene layer is separated . Aqueous layer is again extracted with 25ml of toluene. The toluene layer is collected and washed with water (50ml) thrice. The toluene layer is distilled out to
give an orange-red colour oily mass. 95mg of methyl(4-oxo-2~thioxo-l,3-thiazolidme-3- yl)acetate [X ; where R is Me ] is obtained by column chromatography.
(c) Preparation ofmethyl(4-oxo-2~thioxo-l,3-thiazolidine~3-yl)acetate [X ; where R is Me ]
In 100 ml cap. three necked round bottom flask equipped with stirrer, thermometer Potassium tert. Butoxide (10.03g, 0.089mol) is stirred with 20ml of ethylenedichloride at 5-100C under nitrogen atmosphere. Added the solution of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (5g, 0.019mol dissolved into 20ml of ethylenedichloride) at 5-10°C during lhour. Maintained 5-1O0C for 3 hours. The absence of methyl({[(ethoxycarbonothioyl)thio]acetyl} amino)acetate is checked by TLC. Dumped the reaction mass into ice chilled aqueous HCl solution (50ml 30% HCl in 200ml water). Ethylene dichloride layer is separated at 25-300C. The aqueous layer is extracted with 100ml of ethyl acetate. Both the organic layers are combined. The organic layer is distilled to give methyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate [X ; where R is Me ] as orange-red colour oily mass. Yield = 4gm (%Yield= 97%)
(d) Preparation ofmethyl(4-oxo-2-ihioxo-l,3-thiazolidine-3-yl)acetate [X ; where R is Me ] In 250 ml cap. three necked round bottom flask equipped with stirrer, thermometer, ice bath Sodium methoxide (6.5g, 0.12mol) is stirred with 50ml of dichloroethane at 5-100C under nitrogen atmosphere. Added solution of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (1Og, 0.039mol dissolved into 50ml of dichloroethane) to above solution at 5-1O0C during 1 hour. Stir at 5-100C for 3 hours. The absence of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate is checked by TLC. The reaction mass is dumped into chilled (0-50C) 100ml 15% aqueous Hydrochloric acid solution. Temperature of reaction mass is raised to 25-300C. The organic layer is separated . Aqueous layer is extracted with 50ml ethylacetate. Both the organic layers are combined and distilled out to give methyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate[X ; where R is Me ] as orange-red coloured oil. Yield = 8gm
(%Yield = 97%)
(e) Preparation ofmethyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate [X ; where R is Me ]
In 500 ml three necked round bottom flask equipped with stirrer, ice bath ,dropρing funnel, and thermometer Methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (15.0g,
0.059mol) is dissolved in methylenechloride (150ml) and cooled to 10°C. The solution of sodium methoxide (9.68g, 0.179mol dissolved into 30ml of methanol) under nitrogen atmosphere at 8-12°C is added in to the reaction mass during 1 hour. The temperature is maintained at 8-12°C for 1 hour. The absence of
Methyl({[(ethoxycarbonothioyl)thiojacetyl}amino) acetate is checked by TLC. The Reaction mass is dumped into chilled 5-10°C phosphoric acid solution (15ml H3PO4 with 40ml water). To the reaction mass is charged 100ml of water at 5-1O0C. The temperature is raised to 25- 3O0C. The organic layer is separated. Aqueous layer is extracted with (75ml) ethyl acetate. Organic layers are combined and distilled out organic layer to give methyl(4-oxo-2-thioxo- l,3-thiazolidine-3~yl)acetate [X ; where R is Me ] as orange-red coloured oil. Yield = 12g (%Yield = 97%)
Example-5
(a) Preparation of (4-oxo-2-thioxo~l ,3-thiazolidin-3-yl)acetic acid [II]
In 100 ml three necked round bottom flask equipped with stirrer, condenser, thermometer, oil bath, Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (8g, 0.038mol) is stirred with mixture of 25ml acetic acid and 20ml of 25% sulfuric acid solution at reflux temperature for 2 hours. 20ml 33% aqueous acetic acid solution is added in the reaction mass. Reflux is maintained for 21 hours. The absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin~3-yl)acetate is checked by TLC. The reaction mass is dumped into cooled water. Aqueous layer is extracted with ethyl acetate, ethyl acetate layer is distilled out and triturated with 20ml hexane to give (4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetic acid [II] as yellow colored product. Yield = 4gm (%Yield= 53.7%)
(b) Preparation of(4~oxo-2-thioxo-l,3-thiazolidin-3-yl)acetic acid [II]
In 250 ml cap. three necked round bottom flask equipped with stirrer, thermometer condenser, and oil bath , Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (28g, 0.1364mol) is stirred
with 48% aqueous HBr (60ml) at reflux for 4 hours. Absence of methyl(4-oxo-2-thioxo-l,3- thiazolidin-3-yl) acetate is checked with TLC. The reaction mass is dumped into chilled water. Aqueous layer is extracted with ethyl acetate, and ethyl acetate layer is distilled out to give (4- oxo-2~thioxo-l,3-thiazolidin-3-yl)acetic acid [II] as dark red colour product. Yield = 19gm (%Yield = 72.8%)
( c) Preparation of ' (4-oxo-2-thioxo-l , 3 -thiazolidin-3-yl) acetic acid [II] In 100 ml cap. three necked round bottom flask equipped with stirrer, thermometer, condenser, and oil bath, Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (8g, 0.038mol) is stirred with a mixture of (32ml acetic acid and 32ml Hydrochloric acid) at reflux temperature for 40 hours. Absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate is checked by TLC. The reaction mass is dumped into ice-water. Reaction mass is extracted with ethylacetate. The organic phase is distilled out to give oily mass which is triturated with hexane to give (4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetic acid [ II] as yellow solid. Yield = 3.3gm (%Yield = 44%)
(d) Preparation of (4-oxo-2-thioxo-l ,3-thiazolidin-3-yl)acetic acid [ II]
In 250 ml three necked round bottom flask equipped with stirrer, thermometer, condenser, and oil bath Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (10 gm, 0.048 mol) is stirred with 30% Aqueous Hydrochloric Acid solution(70 ml) at reflux temperature for 15 hours. Absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate is checked by TLC. The reaction mass is quenched with DM Water. Aqueous layer is extracted with ethyl acetate. The organic layer is collected and distilled out it to give (4-oxo-2-thioxo-l,3-thiazolidin-3- yl)acetic acid [II] as the oily mass which is triturated with hexane to obtain yellow colour product. Yield = 7 gm
(e) Preparation of (4-oxo-2-thioxo-l ,3-thiazolidin-3-yl)acetic acid [II]
In 100 ml three necked round bottom flask equipped with thermometer, stirrer, oil bath, condenser, Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (12 gm, 0.058 mol) is stirred with mixture of solution of (10 ml 85% H3PO4 and 40 ml water) to reflux temperature for 50 hours. TLC is checked for the completion of starting material, and reaction mass is quenched into ice water. The reaction mass is extracted with ethyl acetate, dried over sodium sulfate and distilled out ethyl acetate and applied high vacuum to get an oily mass, triturated it with hexane to give (4-oxo~2-thioxo-l,3-thiazolidin-3-yl)acetic acid [II] as yellow color product. Yield=4 gm
Claims
[1] A process of preparation of (4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetic acid from a compound of formula
[IX] where Rl is C1-4 alkyl, benzyl, C1-C8 cycloalkyl, phenyl etc. R is as defined above,
Base used is Ci^alkali metal alkoxides or tertiary amine bases , in which a compound of formula IX is prepared by a reaction of compound of formula
Where Y is Cl, Br, I, OTs, OMs and R is as defined above With a compound of formula
M is K, Na or Li preferably K
VIIIA
Where R and Rl are as defined above and Y is Cl9Br9I, OTs, OMs .
[2] The process as per claim 1 where
Y is Cl , R is Me, Rl is Et and M is K
[3] The process as per claim 1 where reaction of VIIIA and VIII is carried out in aq. Medium.
[4] The base used for conversion of compound of formula IX into a compound of formula-X is selected from: (a) tertiary amine like triethyl amine, N-methyl morpholine, N-methyl pyrrolidine, N-ethyl pyrrolidine, diisopropyl ethyl amine , DBU DBN ; alkoxide group of bases like NaOMe , NaOEt , Sodium or pottasium isopropoxide,
Sodium or potassium tert. Butoxide and the preferred base is NaOMe.
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| CN110003028A (en) * | 2019-04-25 | 2019-07-12 | 山东泰和水处理科技股份有限公司 | A kind of preparation method of high-purity glycine ester hydrochloride |
| CN112010770A (en) * | 2020-09-07 | 2020-12-01 | 河北东华舰化工有限公司 | Novel production method of glycine ethyl ester hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5356917A (en) * | 1985-08-09 | 1994-10-18 | Eli Lilly And Company | Aryl-substituted rhodanine derivatives |
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- 2006-12-28 WO PCT/IB2006/003790 patent/WO2007074390A2/en active Application Filing
- 2006-12-28 JP JP2008548043A patent/JP2009528978A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5356917A (en) * | 1985-08-09 | 1994-10-18 | Eli Lilly And Company | Aryl-substituted rhodanine derivatives |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106316870A (en) * | 2016-08-18 | 2017-01-11 | 精晶药业股份有限公司 | Synthesis method of L-glycine methyl ester salt product |
| CN106316869A (en) * | 2016-08-18 | 2017-01-11 | 精晶药业股份有限公司 | Synthesis method of beta-alanine methyl ester salt product |
| CN110003028A (en) * | 2019-04-25 | 2019-07-12 | 山东泰和水处理科技股份有限公司 | A kind of preparation method of high-purity glycine ester hydrochloride |
| CN112010770A (en) * | 2020-09-07 | 2020-12-01 | 河北东华舰化工有限公司 | Novel production method of glycine ethyl ester hydrochloride |
| CN114163396A (en) * | 2021-12-14 | 2022-03-11 | 北京阳光诺和药物研究股份有限公司 | Preparation method of epalrestat intermediate |
| CN114163396B (en) * | 2021-12-14 | 2022-10-04 | 北京阳光诺和药物研究股份有限公司 | Preparation method of epalrestat intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007074390A3 (en) | 2009-04-16 |
| JP2009528978A (en) | 2009-08-13 |
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