CN1646492A - 链状低聚乳酸硫酯 - Google Patents
链状低聚乳酸硫酯 Download PDFInfo
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- CN1646492A CN1646492A CNA038087715A CN03808771A CN1646492A CN 1646492 A CN1646492 A CN 1646492A CN A038087715 A CNA038087715 A CN A038087715A CN 03808771 A CN03808771 A CN 03808771A CN 1646492 A CN1646492 A CN 1646492A
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- Prior art keywords
- compound
- formula
- group
- lactic acid
- aryl
- Prior art date
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- 239000002253 acid Substances 0.000 title abstract description 13
- 150000007970 thio esters Chemical class 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 64
- 125000003118 aryl group Chemical group 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 22
- 125000006239 protecting group Chemical group 0.000 claims abstract description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 2
- 125000000623 heterocyclic group Chemical group 0.000 abstract description 2
- 125000001931 aliphatic group Chemical group 0.000 abstract 1
- -1 lactic acid thioester Chemical class 0.000 description 85
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 31
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 23
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 17
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical compound OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000007789 gas Substances 0.000 description 12
- 239000004310 lactic acid Substances 0.000 description 12
- 235000014655 lactic acid Nutrition 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- MNKRTDOUBUSQHX-UHFFFAOYSA-N 2,4-dihydroxy-2-methyl-3-oxopentanoic acid Chemical compound CC(O)C(=O)C(C)(O)C(O)=O MNKRTDOUBUSQHX-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- GNWXVOQHLPBSSR-UHFFFAOYSA-N oxolane;toluene Chemical compound C1CCOC1.CC1=CC=CC=C1 GNWXVOQHLPBSSR-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- UIOKLEZTPFZUMQ-UHFFFAOYSA-N 2-(1h-imidazol-2-yldisulfanyl)-1h-imidazole Chemical compound N=1C=CNC=1SSC1=NC=CN1 UIOKLEZTPFZUMQ-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 125000006502 nitrobenzyl group Chemical group 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical group C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- MNCMBBIFTVWHIP-UHFFFAOYSA-N 1-anthracen-9-yl-2,2,2-trifluoroethanone Chemical group C1=CC=C2C(C(=O)C(F)(F)F)=C(C=CC=C3)C3=CC2=C1 MNCMBBIFTVWHIP-UHFFFAOYSA-N 0.000 description 1
- ATPQHBQUXWELOE-UHFFFAOYSA-N 1-hydroxysulfanyl-2,4-dinitrobenzene Chemical compound OSC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O ATPQHBQUXWELOE-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229930182843 D-Lactic acid Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- YKFRUJSEPGHZFJ-UHFFFAOYSA-N N-trimethylsilylimidazole Chemical compound C[Si](C)(C)N1C=CN=C1 YKFRUJSEPGHZFJ-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical compound CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 125000005422 alkyl sulfonamido group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N beta-phenylpropanoic acid Natural products OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- LKLDFYPLBLUBDL-UHFFFAOYSA-N bis(dimethylamino)phosphinous acid Chemical compound CN(C)P(O)N(C)C LKLDFYPLBLUBDL-UHFFFAOYSA-N 0.000 description 1
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229940022769 d- lactic acid Drugs 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IDNUEBSJWINEMI-UHFFFAOYSA-N ethyl nitrate Chemical compound CCO[N+]([O-])=O IDNUEBSJWINEMI-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- FCJSHPDYVMKCHI-UHFFFAOYSA-N phenyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OC1=CC=CC=C1 FCJSHPDYVMKCHI-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920001432 poly(L-lactide) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- A61K31/4164—1,3-Diazoles
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Abstract
本发明的目的是制备且分离作为单一化合物的末端具有硫酯基的链状低聚乳酸硫酯。本发明提供通式(1)表示的化合物或其盐:(式中,X表示氢原子或羟基的保护基;Y表示脂肪族基、芳基或杂环基;n为0~19的整数)。
Description
技术领域
本发明涉及链状低聚乳酸硫酯及其制备方法。更详细地说,本发明涉及末端具有硫酯基的链状低聚乳酸硫酯及其制备方法。
背景技术
已有报道指出,缩合度3~19的环状和/或链状的聚L-乳酸混合物作为抗恶性肿瘤药有用(特开平9-227388号公报和特开平10-130153号公报),另外,作为癌症患者的QOL改善剂有用(特愿平11-39894号说明书;日本癌治疗学会志第33卷第3号第493页)。另外也判断出,缩合度3~19的环状和/或链状的聚乳酸混合物具有降血糖作用,作为用于预防和/或治疗糖尿病或糖尿病并发症的药物有用(特愿平11-224883号),而且也判断出对于抑制过剩的食欲、增进基础代谢以及改善和/或预防肥胖有用。
事实不断证明,上述的缩合度3~19的环状和/或链状的低聚乳酸混合物显示出多种多样的药效,人们期待着今后能够作为药品开发。为了将低聚乳酸作为药品开发,希望将具有特定链长的聚乳酸作为单一的化合物分离,而不是由不同链长的聚乳酸构成的混合物。为了将具有特定链长的聚乳酸作为单一化合物分离,人们尝试着合成了一种将末端羧基酯化的、缩合度3~20的链状低聚乳酸酯(特愿2001-69766)。但是,目前尚没有关于合成出低聚乳酸酯的末端具有硫酯基的化合物的报告。
发明内容
本发明的课题是要解决制备且分离作为单一化合物的末端具有硫酯基的链状低聚乳酸硫酯。本发明的另一个课题是要提供该化合物的制备方法。
本发明者们为了解决上述课题进行了悉心研究,结果发现,通过将乳酸用作起始原料,使其与二硫化物反应,由此成功地合成出末端具有硫酯基的链状低聚乳酸硫酯。本发明就是基于这些见解完成的。即,本发明提供一种式(1)表示的化合物或其盐:
(式中,X表示氢原子或羟基的保护基;Y表示脂肪族基、芳基或杂环基;n为0~19的整数)。
优选地,n为0~5的整数,特别优选n为0或2。
优选地,Y为杂环基,更优选Y为含有1或2个杂原子的5~10元的芳香族杂环基,特别优选Y为吡啶基、或(4-叔丁基-N-异丙基)咪唑基。
根据本发明的另一侧面,提供一种式CH3CH(OX)CO-S-Y表示的化合物的制备方法,其中包括使式CH3CH(OX)COOH(式中,X表示氢原子或羟基的保护基)表示的化合物与式Y-S-S-Y(式中,Y表示脂肪族基、芳基或杂环基)表示的化合物反应。
根据本发明的其他侧面,提供一种式CH3CH(OX)COOCH(CH3)COOCH(CH3)CO-S-Y(式中,X表示氢原子或羟基的保护基;Y表示脂肪族基、芳基或杂环基)表示的化合物的制备方法,其中包括使式CH3CH(OX)COOCH(CH3)COOH(式中,X表示氢原子或羟基的保护基)表示的化合物与式CH3CH(OH)CO-S-Y(式中,Y表示脂肪族基、芳基或杂环基)表示的化合物反应。
实施发明的最佳方案
以下,详细说明本发明的实施方案和实施方法。
本发明涉及下述式(1)表示的化合物或其盐:
(式中,X表示氢原子或羟基的保护基;Y表示脂肪族基、芳基或杂环基;n为0~19的整数)。
X所表示的羟基的保护基的种类没有特别的限定,本领域技术人员可以适宜选择。作为羟基的保护基的具体例,可以列举以下的基团。
(醚型)
甲基、甲氧基甲基、甲硫基甲基、苄氧基甲基、叔丁氧基甲基、2-甲氧基乙氧基甲基、2,2,2-三氯乙氧基甲基、二(2-氯乙氧基)甲基、2-(三甲基甲硅烷基)乙氧基甲基、四氢吡喃基、3-溴四氢吡喃基、四氢噻喃基、4-甲氧基四氢吡喃基、4-甲氧基四氢噻喃基、4-甲氧基四氢噻喃基S,S-二氧化物基、四氢呋喃基、四氢噻吩基;
1-乙氧基乙基、1-甲基-1-甲氧基乙基、1-(异丙氧基)乙基、2,2,2-三氯乙基、2-(苯基氢硒基)乙基、叔丁基、烯丙基、肉桂基、对氯苯基、苄基、对甲氧基苄基、邻硝基苄基、对硝基苄基、对卤苄基、对氰基苄基、3-甲基-2-吡啶甲基N-氧化物基、二苯甲基、5-二苯并环庚基、三苯甲基、α-萘基二苯甲基、对甲氧基苯基二苯甲基、对-(p′-溴苯甲酰甲氧基)苯基二苯甲基、9-蒽基、9-(9-苯基)呫吨基、9-(9-苯基-10-氧代)蒽基、苯并异噻唑基S,S-二氧化物基;
三甲基甲硅烷基、三乙基甲硅烷基、异丙基二甲基甲硅烷基、叔丁基二甲基甲硅烷基(TBDMS基)、(三苯甲基)二甲基甲硅烷基、叔丁基二苯基甲硅烷基、甲基二异丙基甲硅烷基、甲基二叔丁基甲硅烷基、三苄基甲硅烷基、三(对二甲苯基)甲硅烷基、三异丙基甲硅烷基、三苯基甲硅烷基;
(酯型)
甲酸酯、苯甲酰基甲酸酯、乙酸酯、氯乙酸酯、二氯乙酸酯、三氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、苯氧基乙酸酯、对氯苯氧基乙酸酯、2,6-二氯-4-甲基苯氧基乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯、2,4-二(1,1-二甲基丙基)苯氧基乙酸酯、氯二苯基乙酸酯、p-P-苯基乙酸酯、3-苯基丙酸酯、3-苯甲酰基丙酸酯、异丁酸酯、单琥珀酸酯、4-氧代戊酸酯、新戊酸酯、金刚烷二甲酸酯、巴豆酸酯、4-甲氧基巴豆酸酯、(E)-2-甲基-2-丁烯酸酯、苯甲酸酯、邻(二溴甲基)苯甲酸酯、邻(甲氧羰基)苯甲酸酯、对苯基苯甲酸酯、2,4,6-三甲基苯甲酸酯、p-P-苯甲酸酯、α-萘甲酸酯;
(碳酸酯型)
甲基碳酸酯、乙基碳酸酯、2,2,2-三氯乙基碳酸酯、异丁基碳酸酯、乙烯基碳酸酯、烯丙基碳酸酯、肉桂基碳酸酯、对硝基苯基碳酸酯、苄基碳酸酯、对甲氧基苄基碳酸酯、3,4-二甲氧基苄基碳酸酯、邻硝基苄基碳酸酯、对硝基苄基碳酸酯、S-苄基硫代碳酸酯;
(其他)
N-苯基氨基甲酸酯、N-咪唑基氨基甲酸酯、硼酸酯、硝酸酯、N,N,N’,N’-四甲基二氨基磷酸酯、2,4-二硝基苯基次磺酸酯。
应予说明,上述的保护基的引入方法和脱保护方法是本领域技术人员公知的,例如记载于Teodora,W.Green,Protective Groups inOrganic Synthesis,John & Wiley & Sons Inc.(1981)等中。
本发明中,Y所表示的脂肪族基、芳基或杂环基的种类没有特别的限定。
作为本发明中的脂肪族基,可以列举低级烷基、低级链烯基或低级炔基等。脂肪族基的碳原子数没有特别的限定,一般为1~10个,优选为1~6个,更优选为1~4个。脂肪族基的链型没有特别的限定,可以是直链、支链、环状链或其组合。
作为本发明中的脂肪族基,特别优选低级烷基。作为低级烷基的具体例,可以列举甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、仲丁基、叔丁基、环丙基甲基、环丁基、戊基、己基等。
作为本发明中的芳基,为碳原子数6~24、优选6~12的芳基,该芳基也可以具有1个以上的取代基。作为芳基的具体例,可以列举例如苯基、萘基、对甲氧基苯基等。
作为本发明中的杂环基,为含有1个以上氧原子、氮原子或硫原子的5~10元环的饱和或不饱和的单环或稠环。作为杂环基的具体例,可以列举例如吡啶基、咪唑基、喹啉基、异喹啉基、嘧啶基、吡嗪基、哒嗪基、酞嗪基、三嗪基、呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、噻二唑基、三唑基、苯并咪唑基、吡咯烷基(ピロリジノ)、吗啉代基等。另外,这些杂环也可以具有1个以上的取代基。
作为芳基或杂环基可以具有的取代基,可以列举卤素原子(氟、氯、溴或碘)、烷基、芳基、碳酰胺基、烷基磺酰胺基、芳基磺酰胺基、烷氧基、芳氧基、烷硫基、芳硫基、氨基甲酰基、氨磺酰基、氰基、烷基磺酰基、芳基磺酰基、烷氧基羰基、芳氧基羰基、以及酰基等。
本发明中,优选地,Y为芳香族基,特别优选Y为含有1或2个杂原子的5~10元的芳香族杂环基。最优选Y为吡啶基、或(4-叔丁基-N-异丙基)咪唑基。
n为0~19的整数。n为0的场合,形成乳酸的1倍体,n为1的场合,形成乳酸的2倍体,n为2的场合,形成乳酸的3倍体,n为3的场合,形成乳酸的4倍体,以下同样,n为19的场合,形成乳酸的20倍体。
本发明中,优选地,n为0~5的整数,特别优选n为0或2。
通式(1)中X为氢原子的场合,本发明的化合物也可以作为金属盐存在,作为这种金属盐,可以列举钠盐、钾盐等碱金属盐;镁盐、钙盐等碱土金属盐;铝盐或锌盐等。
进而,本发明的化合物的各种水合物、溶剂合物或多晶形的物质也包括在本发明的范围内。
由于本发明的化合物中含有不对称碳原子,因此存在立体异构体,所有可能的异构体、以及以任意比例含有2种以上该异构体的混合物也包括在本发明的范围内。即,本发明的化合物包括光学活性体、消旋体、非对映异构体等的各种光学异构体的混合物以及其分离得到的物质。
本发明的化合物的立体构型依赖于用作原料的化合物中的乳酸单元的立体构型。也就是说,根据用作原料的化合物中的乳酸单元使用的是L型、D型还是其混合物,本发明化合物的立体构型也呈现出多样性。在本发明中,作为乳酸单元的立体构型,优选使用L型。
以下说明本发明化合物或其盐的制备方法。
通式(1)中相当于n为0的化合物的CH3CH(OX)CO-S-Y表示的化合物,可以通过使CH3CH(OX)COOH(式中,X表示氢原子或羟基的保护基)与通式Y-S-S-Y(式中,Y表示脂肪族基、芳基或杂环基)表示的化合物反应来制备。
作为起始物质使用的CH3CH(OX)COOH,可以使用L-乳酸、D-乳酸或其混合物。乳酸中的羟基也可以被保护起来。
在使式CH3CH(OX)COOH表示的化合物与式Y-S-S-Y表示的化合物反应的场合,首先,向含有式CH3CH(OX)COOH表示的化合物的溶液中加入三苯基膦溶液。向得到的混合物中添加含有式Y-S-S-Y表示的化合物的溶液,搅拌一定时间,使其反应。
式CH3CH(OX)COOH表示的化合物与式Y-S-S-Y表示的化合物的用量可以适宜选择,优选CH3CH(OX)COOH∶Y-S-S-Y=1∶0.5~1∶2,更优选为1∶0.7~1∶1.5。
反应温度只要能使反应进行就没有特别的限定,优选为-100℃~室温。
反应优选在反应溶剂的存在下实施。反应溶剂只要是对反应为惰性的溶剂就没有特别的限制,优选使用苯、甲苯、二甲苯、乙苯等的芳香族烃溶剂以及四氢呋喃(THF)、乙醚、二甲氧基乙烷等。
另外,作为反应氛围气,可以使用氮气和氩气等惰性气体氛围气。
以下具体地说明一例本发明方法的优选实施方案。
在氩气氛围气下,在室温下,向L-乳酸的甲苯溶液中加入三苯基膦的甲苯溶液,进而加入式Y-S-S-Y表示的化合物(例如,吡啶基二硫化物或者2,2-双(4-叔丁基-N-异丙基)咪唑基二硫化物等)的甲苯溶液,搅拌15小时。减压浓缩后,加入水,用氯仿萃取数次。盐析后,用硫酸钠干燥,减压浓缩,用硅胶柱色谱(展开溶剂乙醚/CHCl3=1/1)进行分离精制,得到L-乳酸吡啶基硫醇酯。
通式(1)中相当于n为1的化合物的CH3CH(OX)COOCH(CH3)CO-S-Y表示的化合物,可以通过作为起始物质使用CH3CH(OX)COOCH(CH3)COOH代替CH3CH(OX)COOH,与上述同样的与式Y-S-S-Y表示的化合物反应来制备。
通式(1)中相当于n为2的化合物的CH3CH(OX)COOCH(CH3)COOCH(CH3)CO-S-Y(式中,X表示氢原子或羟基的保护基;Y表示脂肪族基、芳基或杂环基)表示的化合物,可以通过使式CH3CH(OX)COOCH(CH3)COOH(式中,X表示氢原子或羟基的保护基)表示的化合物与式CH3CH(OH)CO-S-Y(式中,Y表示脂肪族基、芳基或杂环基)表示的化合物反应来制备。
式CH3CH(OH)CO-S-Y表示的化合物的制备方法如本说明书中的上文所示。
式CH3CH(OX)COOCH(CH3)COOH(式中,X表示氢原子或羟基的保护基)表示的化合物,是根据希望将羟基保护起来的乳酰乳酸。在本发明中,优选使用将羟基保护起来的乳酰乳酸(即,X为羟基的保护基的场合)。
式CH3CH(OX)COOCH(CH3)COOH(式中,X表示羟基的保护基)与式CH3CH(OH)CO-S-Y(式中,Y表示脂肪族基、芳基或杂环基)表示的化合物的反应,是通常的酯化反应。
该酯化反应通过例如向含有式CH3CH(OX)COOCH(CH3)COOH表示的化合物的溶液中,加入二环己基碳化二亚胺溶液,搅拌后,添加式CH3CH(OH)CO-S-Y表示的化合物的溶液、以及二甲氨基吡啶溶液,搅拌一定时间来进行。
式CH3CH(OX)COOCH(CH3)COOH表示的化合物与式CH3CH(OH)CO-S-Y表示的化合物的用量可以适宜选择,优选为式CH3CH(OX)COOCH(CH3)COOH∶式CH3CH(OH)CO-S-Y=1∶0.3~1∶2,更优选为1∶0.4~1∶1.5。
反应温度只要能使反应进行就没有特别的限定,优选为-100℃~室温。
另外,反应优选在反应溶剂的存在下实施。反应溶剂只要是对反应为惰性的溶剂就没有特别的限制,优选使用甲苯、苯、二甲苯、烷基苯、四氢呋喃(THF)、乙醚、二甲氧基乙烷等。
另外,作为反应氛围气,可以使用氮气和氩气等惰性气体氛围气。
如上所述,可以制备通式(1)中n为0、1或2的化合物。对于n为3的化合物,与上述同样,可以使用仅仅含有所希望数目的乳酸单元的硫酯化合物作为起始物质,使其与式CH3CH(OX)COOCH(CH3)COOH(式中,X表示羟基的保护基)表示的化合物反应来合成。
以下用实施例更具体地说明本发明,但本发明不受这些实施例的限定。
实施例
实施例1:L-乳酸吡啶基硫醇酯的合成
在氩气氛围气下,在室温下,向L-乳酸(化合物12)0.0901g(1mmol)的10ml甲苯溶液中,加入三苯基膦0.289g(1.1mmol)的5ml甲苯溶液,再加入吡啶基二硫化物(化合物13)0242g(1.1mmol)的5ml甲苯溶液,搅拌15小时。减压浓缩后,加入30ml水,用氯仿进行萃取(分3次,各15ml)。盐析后,用硫酸钠干燥后,减压浓缩,用硅胶柱色谱(展开溶剂 乙醚/CHCl3=1/1)进行分离精制,得到L-乳酸吡啶基硫醇酯(化合物14)0.0556g,收率30%([α]20 D=-24.55°(C=0.11(CHCl3)))。
L-乳酸吡啶基硫醇酯(化合物14)
IR(cm-1):1737(C=O),3438(-OH)
1H-NMR(300MHz,CDCl3)
δ(ppm)=1.59(3H,d,J=7.2Hz)
4.06(1H,q,J=7.2Hz)
7.23(1H,ddd,J=0.9Hz,5.1Hz,7.2Hz)
7.41(1H,d,J=7.8Hz)
7.70(1H,ddd,J=1.8Hz,7.5Hz,8.1Hz)
8.43(1H,d,J=5.7Hz)
实施例2:L-乳酸(4-叔丁基-N-异丙基)咪唑基硫醇酯的合成
(实施例2之1)
在氩气氛围气下,在室温下,向L-乳酸(化合物12)0.450g(5mmol)的50ml THF-甲苯(1∶1)混合溶液中,加入三苯基膦1.44g(5.5mmol)的25ml THF-甲苯(1∶1)混合溶液,再加入2,2-双(4-叔丁基-N-异丙基)咪唑基二硫化物(化合物16)2.17g(5.5mmol)的25ml THF-甲苯(1∶1)混合溶液,搅拌7小时。减压浓缩后,加入30ml水,用氯仿进行萃取(分3次,各15ml)。盐析后,用硫酸钠干燥后,减压浓缩,用硅胶柱色谱(展开溶剂乙醚/CHCl3=1/1)进行分离精制,得到L-乳酸(4-叔丁基-N-异丙基)咪唑基硫醇酯(化合物17)0.308g,收率23%([α]20 D=-80.82°(C=2.0(CHCl3)))。
L-乳酸(4-叔丁基-N-异丙基)咪唑基硫醇酯(化合物17)
IR(cm-1):1718(C=O),3440(-OH)
1H-NMR(300MHz,CDCl3)
δ(ppm)=1.26(9H,s)
1.40(3H,d,J=7.2Hz)
1.45(3H,d,J=6.6Hz)
1.55(3H,d,J=7.2Hz)
3.93(1H,q,J=7.2Hz)
4.34(1H,sept,J=6.6Hz)
6.65(1H,s)
(实施例2之2)
在氩气氛围气下,在0℃下,向L-乳酸(化合物12)0.901g(10mmol)的100ml THF-甲苯(1∶1)混合溶液中,加入三苯基膦2.89g(11mmol)的50ml THF-甲苯(1∶1)混合溶液,再加入2,2-双(4-叔丁基-N-异丙基)咪唑基二硫化物(化合物16)4.34g(11mmol)的50ml THF-甲苯(1∶1)混合溶液,搅拌5小时,进而在室温下搅拌10小时。减压浓缩后,加入30ml水,用氯仿进行萃取(分3次,各15ml)。盐析后,用硫酸钠干燥后,减压浓缩,用硅胶柱色谱(展开溶剂乙醚/CHCl3=1/1)进行分离精制,得到L-乳酸(4-叔丁基-N-异丙基)咪唑基硫醇酯(化合物)0.463g,收率17%。生成物的仪器测试数据与上述一致。
实施例3:O-(叔丁基二甲基甲硅烷基)乳酰乳酸的合成
在氩气氛围气下,在室温下,向咪唑2.04g(30mmol)的30ml二氯甲烷溶液中,滴入叔丁基二甲基甲硅烷基氯化物2.06g(15mmol)的10ml二氯甲烷溶液,搅拌30分钟后,加入乳酰乳酸(化合物19)0.486g(3mmol)的10ml二氯甲烷溶液,搅拌18小时。加入200ml水,用乙醚进行萃取(分3次,各200ml)。盐析后,用硫酸钠干燥后,减压浓缩,得到生成物1.15g。得到的生成物直接用于以后的反应。
在室温下,向得到的生成物1.15g的30ml甲醇溶液中加入THF10ml,进而加入碳酸钾1.00g(7.2mmol)的10ml水溶液,搅拌1小时。将溶液减压浓缩至体积的1/4后,用饱和食盐水30ml稀释,将溶液冷却至0℃,用1M硫酸氢钾溶液12.5ml调整至pH=4~5。然后,用乙醚进行萃取(分3次,各50ml)。盐析后,用硫酸钠干燥后,减压浓缩,得到O-(叔丁基二甲基甲硅烷基)乳酰乳酸(化合物20)0.591g,收率71%([α]20 D=-36.91°(C=2.0(CHCl3)))。
O-(叔丁基二甲基甲硅烷基)乳酰乳酸(化合物20)
IR(cm-1):1733(C=O),3185(-OH)
1H-NMR(300MHz,CDCl3)
δ(ppm)=0.10(6H,d,J=7.5Hz)
0.91(9H,s)
1.45(3H,d,J=6.6Hz)
1.56(3H,d,J=7.2Hz)
4.40(1H,q,J=6.6Hz)
5.12(1H,q,J=7.2Hz)
实施例4:3倍体(4-叔丁基-N-异丙基)咪唑基硫醇酯的合成
在氩气氛围气下,在室温下,向O-(叔丁基二甲基甲硅烷基)乳酰乳酸(化合物20)0.276g(1mmol)的10ml甲苯溶液中,加入二环己基碳化二亚胺0.206g(1mmol)的5ml甲苯溶液,搅拌15分钟后,加入L-乳酸(4-叔丁基-N-异丙基)咪唑基硫醇酯(化合物17)0.135g(0.5mmol)的5ml甲苯溶液、二甲氨基吡啶0.0661g(0.5mmol)的5ml甲苯溶液,搅拌2小时。用饱和氯化铵溶液进行处理,用乙醚进行萃取(分3次,各30ml)。盐析后,用硫酸钠干燥后,当用硅胶柱色谱(乙醚/己烷=1/1)进行柱过滤时,得到3倍体(4-叔丁基-N-异丙基)咪唑基硫醇酯TBDMS体(化合物21)0.138g,粗收率52%。
1H-NMR(300MHz,CDCl3)
δ(ppm)=0.09(6H,d,J=5.1Hz)
0.90(9H,s)
1.23(9H,s)
1.29(3H,d,J=6.6Hz)
1.34(3H,d,J=7.2Hz)
1.38(3H,d,J=6.6Hz)
1.42(3H,d,J=6.9Hz)
1.45(3H,d,J=6.96Hz)
4.36(1H,q,J=6.6Hz)
4.56(1H,sept,J=6.6Hz)
5.25(1H,q,J=6.9Hz)
5.39(1H,q,J=6.9Hz)
6.67(1H,s)
工业实用性
按照本发明,可以提供作为单一化合物的末端具有硫酯基的链状低聚乳酸硫酯。通过利用本发明提供的的低聚乳酸硫酯的单一化合物,能够将低聚乳酸硫酯作为药品、药品原料、食品添加剂、化妆品原料、制剂原料、制剂添加剂进行开发。
Claims (8)
2.权利要求1中所述的化合物或其盐,其中,n为0~5的整数。
3.权利要求1中所述的化合物或其盐,其中,n为0或2。
4.权利要求1~3任一项中所述的化合物或其盐,其中,Y为杂环基。
5.权利要求1~4任一项中所述的化合物或其盐,其中,Y为含有1或2个杂原子的5~10元的芳香族杂环基。
6.权利要求1~5任一项中所述的化合物或其盐,其中,Y为吡啶基、或(4-叔丁基-N-异丙基)咪唑基。
7.一种式CH3CH(OX)CO-S-Y表示的化合物的制备方法,其中包括使式CH3CH(OX)COOH(式中,X表示氢原子或羟基的保护基)表示的化合物与式Y-S-S-Y(式中,Y表示脂肪族基、芳基或杂环基)表示的化合物反应。
8.一种式CH3CH(OX)COOCH(CH3)COOCH(CH3)CO-S-Y(式中,X表示氢原子或羟基的保护基;Y表示脂肪族基、芳基或杂环基)表示的化合物的制备方法,其中包括使式CH3CH(OX)COOCH(CH3)COOH(式中,X表示氢原子或羟基的保护基)表示的化合物与式CH3CH(OH)CO-S-Y(式中,Y表示脂肪族基、芳基或杂环基)表示的化合物反应。
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JPS552264B2 (zh) * | 1973-12-24 | 1980-01-19 | ||
JPS585163B2 (ja) * | 1975-02-25 | 1983-01-29 | 三井東圧化学株式会社 | サツソウザイ |
CH618322A5 (zh) * | 1975-08-25 | 1980-07-31 | Ciba Geigy Ag | |
CH620339A5 (zh) * | 1976-03-05 | 1980-11-28 | Ciba Geigy Ag | |
GB1588731A (en) * | 1977-03-09 | 1981-04-29 | Ici Ltd | Cotton desiccation with phenoxyalkanoic acids |
JPS60149554A (ja) * | 1984-01-13 | 1985-08-07 | Hokko Chem Ind Co Ltd | 3,4−ジクロルベンジルチオ−ルエステル誘導体および土壌殺菌剤 |
AU779592B2 (en) * | 1999-08-09 | 2005-02-03 | Amato Pharmaceutical Products, Ltd. | Therapeutic agent for diabetes |
EP1219616A4 (en) * | 1999-09-20 | 2002-11-06 | Amato Pharm Prod Ltd | PROCESS FOR THE PREPARATION OF CYCLIC LACTIC ACID OLIGOMERS |
CA2385321A1 (en) * | 1999-09-20 | 2001-03-29 | Mikio Watanabe | Method for producing cyclic lactic acid oligomer |
CA2383152A1 (en) * | 1999-09-20 | 2001-03-29 | Tamotsu Terao | Agent for enhancing stamina and agent for promoting glycogen accumulation |
WO2001039782A1 (fr) * | 1999-12-03 | 2001-06-07 | Amato Pharmaceutical Products, Ltd. | Agent de radioprotection |
WO2001054705A1 (fr) * | 2000-01-26 | 2001-08-02 | Amato Pharmaceutical Products, Ltd. | Inhibiteurs d'implantation de cellules cancereuses |
US20040110834A1 (en) * | 2001-01-12 | 2004-06-10 | Masahiro Murakami | Preventives for microbial infections |
EP1358885A1 (en) * | 2001-01-12 | 2003-11-05 | Amato Pharmaceutical Products, Ltd. | Antiallergic agents |
EP1362594A1 (en) * | 2001-01-24 | 2003-11-19 | Amato Pharmaceutical Products, Ltd. | Anti-stress agents |
JP2002265420A (ja) * | 2001-03-13 | 2002-09-18 | Tendou Seiyaku Kk | 鎖状オリゴ乳酸エステル |
JP2002275256A (ja) * | 2001-03-19 | 2002-09-25 | Tendou Seiyaku Kk | 乳酸オリゴマーの製造方法 |
-
2003
- 2003-02-18 CA CA002480001A patent/CA2480001A1/en not_active Abandoned
- 2003-02-18 TW TW092103323A patent/TW200303299A/zh unknown
- 2003-02-18 WO PCT/JP2003/001696 patent/WO2003076404A1/ja not_active Application Discontinuation
- 2003-02-18 AU AU2003211386A patent/AU2003211386A1/en not_active Abandoned
- 2003-02-18 RU RU2004127918/04A patent/RU2004127918A/ru not_active Application Discontinuation
- 2003-02-18 KR KR10-2004-7012861A patent/KR20040085202A/ko not_active Application Discontinuation
- 2003-02-18 EP EP03705267A patent/EP1484319A4/en not_active Withdrawn
- 2003-02-18 CN CNA038087715A patent/CN1646492A/zh active Pending
- 2003-02-18 JP JP2003574625A patent/JPWO2003076404A1/ja active Pending
- 2003-02-18 US US10/503,582 patent/US20050222420A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
US20050222420A1 (en) | 2005-10-06 |
KR20040085202A (ko) | 2004-10-07 |
EP1484319A4 (en) | 2007-01-24 |
CA2480001A1 (en) | 2003-09-18 |
EP1484319A1 (en) | 2004-12-08 |
JPWO2003076404A1 (ja) | 2005-07-07 |
RU2004127918A (ru) | 2005-04-10 |
WO2003076404A1 (fr) | 2003-09-18 |
TW200303299A (en) | 2003-09-01 |
AU2003211386A1 (en) | 2003-09-22 |
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