RU2609006C2 - Способ получения пеметрекседа и его лизиновой соли - Google Patents
Способ получения пеметрекседа и его лизиновой соли Download PDFInfo
- Publication number
- RU2609006C2 RU2609006C2 RU2015108042A RU2015108042A RU2609006C2 RU 2609006 C2 RU2609006 C2 RU 2609006C2 RU 2015108042 A RU2015108042 A RU 2015108042A RU 2015108042 A RU2015108042 A RU 2015108042A RU 2609006 C2 RU2609006 C2 RU 2609006C2
- Authority
- RU
- Russia
- Prior art keywords
- pemetrexed
- salt
- acid
- lysine
- water
- Prior art date
Links
- 229960005079 pemetrexed Drugs 0.000 title claims abstract description 69
- 238000000034 method Methods 0.000 title claims abstract description 38
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 title claims abstract description 35
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 title claims abstract 9
- 238000002360 preparation method Methods 0.000 title description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 118
- DEJAOZLLEHXUBF-KRWDZBQOSA-N diethyl (2s)-2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound C1=CC(C(=O)N[C@@H](CCC(=O)OCC)C(=O)OCC)=CC=C1CCC1=CNC2=C1C(=O)N=C(N)N2 DEJAOZLLEHXUBF-KRWDZBQOSA-N 0.000 claims abstract description 62
- 239000000203 mixture Substances 0.000 claims abstract description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 51
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 49
- -1 sodium carboxylate Chemical class 0.000 claims abstract description 41
- AIZPFZIKHIJCQX-UHFFFAOYSA-N 4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(O)=O)C=C1 AIZPFZIKHIJCQX-UHFFFAOYSA-N 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 239000002253 acid Substances 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 239000011541 reaction mixture Substances 0.000 claims abstract description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000004472 Lysine Substances 0.000 claims abstract description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 239000011734 sodium Substances 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 4
- 229960002989 glutamic acid Drugs 0.000 claims abstract description 4
- STUHQDIOZQUPGP-UHFFFAOYSA-N morpholin-4-ium-4-carboxylate Chemical compound OC(=O)N1CCOCC1 STUHQDIOZQUPGP-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000001093 anti-cancer Effects 0.000 claims abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 51
- 235000019441 ethanol Nutrition 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 33
- 230000015572 biosynthetic process Effects 0.000 claims description 29
- 238000003786 synthesis reaction Methods 0.000 claims description 18
- 238000002441 X-ray diffraction Methods 0.000 claims description 17
- 238000001228 spectrum Methods 0.000 claims description 17
- NYDXNILOWQXUOF-UHFFFAOYSA-L disodium;2-[[4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino]pentanedioate Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)NC(CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-UHFFFAOYSA-L 0.000 claims description 13
- GPIQOFWTZXXOOV-UHFFFAOYSA-N 2-chloro-4,6-dimethoxy-1,3,5-triazine Chemical compound COC1=NC(Cl)=NC(OC)=N1 GPIQOFWTZXXOOV-UHFFFAOYSA-N 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000009739 binding Methods 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000002955 isolation Methods 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 230000003993 interaction Effects 0.000 claims description 4
- HZRUTVAFDWTKGD-JEDNCBNOSA-N (2s)-2,6-diaminohexanoic acid;hydrate Chemical compound O.NCCCC[C@H](N)C(O)=O HZRUTVAFDWTKGD-JEDNCBNOSA-N 0.000 claims description 3
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 150000005690 diesters Chemical class 0.000 claims description 2
- 229960003349 pemetrexed disodium Drugs 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 5
- WSEQLMQNPBNMSL-FJXQXJEOSA-N diethyl (2s)-2-aminopentanedioate;hydron;chloride Chemical compound Cl.CCOC(=O)CC[C@H](N)C(=O)OCC WSEQLMQNPBNMSL-FJXQXJEOSA-N 0.000 abstract description 4
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 239000002244 precipitate Substances 0.000 abstract description 2
- 239000011230 binding agent Substances 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 51
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 32
- 239000000725 suspension Substances 0.000 description 23
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 150000001299 aldehydes Chemical class 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 239000012265 solid product Substances 0.000 description 11
- 238000000113 differential scanning calorimetry Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- GDEKSBCRJKAARB-UHFFFAOYSA-N methyl 4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1CCC1=CNC2=C1C(=O)N=C(N)N2 GDEKSBCRJKAARB-UHFFFAOYSA-N 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000002243 precursor Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 229930195725 Mannitol Natural products 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 231100000024 genotoxic Toxicity 0.000 description 3
- 230000001738 genotoxic effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- 239000011877 solvent mixture Substances 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 229940110282 alimta Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 238000004320 controlled atmosphere Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- PKKOQVAJFXOJOA-UHFFFAOYSA-N methyl 4-(4-oxobutyl)benzoate Chemical compound COC(=O)C1=CC=C(CCCC=O)C=C1 PKKOQVAJFXOJOA-UHFFFAOYSA-N 0.000 description 2
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 229950010474 pemetrexed disodium hemipentahydrate Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- DAAXYQZSKBPJOX-FQEVSTJZSA-N (2S)-2-amino-3-[4-[5-[3-(4-hydroxyphenyl)-4-methoxyphenyl]-1,2,4-oxadiazol-3-yl]phenyl]propanoic acid Chemical compound COC1=C(C=C(C=C1)C2=NC(=NO2)C3=CC=C(C=C3)C[C@@H](C(=O)O)N)C4=CC=C(C=C4)O DAAXYQZSKBPJOX-FQEVSTJZSA-N 0.000 description 1
- NELIUNLOEKDZCC-HVDRVSQOSA-N (2s)-2-aminopentanedioic acid;4-methylbenzenesulfonic acid Chemical class OC(=O)[C@@H](N)CCC(O)=O.CC1=CC=C(S(O)(=O)=O)C=C1 NELIUNLOEKDZCC-HVDRVSQOSA-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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- GNENVASJJIUNER-UHFFFAOYSA-N 2,4,6-tricyclohexyloxy-1,3,5,2,4,6-trioxatriborinane Chemical compound C1CCCCC1OB1OB(OC2CCCCC2)OB(OC2CCCCC2)O1 GNENVASJJIUNER-UHFFFAOYSA-N 0.000 description 1
- SWELIMKTDYHAOY-UHFFFAOYSA-N 2,4-diamino-6-hydroxypyrimidine Chemical compound NC1=CC(=O)N=C(N)N1 SWELIMKTDYHAOY-UHFFFAOYSA-N 0.000 description 1
- ZSPTYLOMNJNZNG-UHFFFAOYSA-N 3-Buten-1-ol Chemical compound OCCC=C ZSPTYLOMNJNZNG-UHFFFAOYSA-N 0.000 description 1
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OLAFFPNXVJANFR-UHFFFAOYSA-N DG Chemical compound N1C(N)=NC(=O)C2=C1NC=C2 OLAFFPNXVJANFR-UHFFFAOYSA-N 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- IACAQNVRIWVYNQ-DFWYDOINSA-N N[C@@H](CCC(=O)O)C(=O)O.C(C)[ClH]CC Chemical compound N[C@@H](CCC(=O)O)C(=O)O.C(C)[ClH]CC IACAQNVRIWVYNQ-DFWYDOINSA-N 0.000 description 1
- JACXUEYJJKTYSW-UHFFFAOYSA-N O.O.O.O.O.O.O.[Na] Chemical compound O.O.O.O.O.O.O.[Na] JACXUEYJJKTYSW-UHFFFAOYSA-N 0.000 description 1
- YLUGBQJQQLZZNL-UHFFFAOYSA-N O.O.O.O.O.O.O.[Na].[Na] Chemical compound O.O.O.O.O.O.O.[Na].[Na] YLUGBQJQQLZZNL-UHFFFAOYSA-N 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- OZZWQNVSVKLLBK-UHFFFAOYSA-N [Na].[Na].O.O.O.O.O.[Na].[Na] Chemical compound [Na].[Na].O.O.O.O.O.[Na].[Na] OZZWQNVSVKLLBK-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- HERPVHLYIHBEFW-ZETCQYMHSA-N diethyl (2s)-2-aminopentanedioate Chemical compound CCOC(=O)CC[C@H](N)C(=O)OCC HERPVHLYIHBEFW-ZETCQYMHSA-N 0.000 description 1
- LLIOKEUXNHKVHC-ZDUSSCGKSA-N dimethyl (2s)-2-[(4-ethynylbenzoyl)amino]pentanedioate Chemical compound COC(=O)CC[C@@H](C(=O)OC)NC(=O)C1=CC=C(C#C)C=C1 LLIOKEUXNHKVHC-ZDUSSCGKSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- XIXADJRWDQXREU-UHFFFAOYSA-M lithium acetate Chemical compound [Li+].CC([O-])=O XIXADJRWDQXREU-UHFFFAOYSA-M 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- IHYNKGRWCDKNEG-UHFFFAOYSA-N n-(4-bromophenyl)-2,6-dihydroxybenzamide Chemical compound OC1=CC=CC(O)=C1C(=O)NC1=CC=C(Br)C=C1 IHYNKGRWCDKNEG-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- CSMWJXBSXGUPGY-UHFFFAOYSA-L sodium dithionate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)S([O-])(=O)=O CSMWJXBSXGUPGY-UHFFFAOYSA-L 0.000 description 1
- KBCAPKSCEJANTH-UHFFFAOYSA-M sodium;4-[2-(2-amino-4-oxo-1,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate Chemical compound [Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C([O-])=O)C=C1 KBCAPKSCEJANTH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM2012A000398 | 2012-08-08 | ||
| IT000398A ITRM20120398A1 (it) | 2012-08-08 | 2012-08-08 | Procedimento di sintesi pemetrexed e suo sale di lisina. |
| PCT/IB2013/056497 WO2014024164A1 (en) | 2012-08-08 | 2013-08-08 | Process for the preparation of pemetrexed and lysin salt thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2015108042A RU2015108042A (ru) | 2016-09-27 |
| RU2609006C2 true RU2609006C2 (ru) | 2017-01-30 |
Family
ID=47018368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2015108042A RU2609006C2 (ru) | 2012-08-08 | 2013-08-08 | Способ получения пеметрекседа и его лизиновой соли |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP2882753B1 (forum.php) |
| KR (1) | KR102288417B1 (forum.php) |
| CN (1) | CN104736540B (forum.php) |
| AU (1) | AU2013301156B2 (forum.php) |
| BR (1) | BR112015002429A8 (forum.php) |
| CY (1) | CY1118514T1 (forum.php) |
| DK (1) | DK2882753T3 (forum.php) |
| ES (1) | ES2607890T3 (forum.php) |
| HR (1) | HRP20170011T1 (forum.php) |
| HU (1) | HUE032304T2 (forum.php) |
| IN (1) | IN2015DN00833A (forum.php) |
| IT (1) | ITRM20120398A1 (forum.php) |
| LT (1) | LT2882753T (forum.php) |
| MX (1) | MX362858B (forum.php) |
| PL (1) | PL2882753T3 (forum.php) |
| PT (1) | PT2882753T (forum.php) |
| RS (1) | RS55515B1 (forum.php) |
| RU (1) | RU2609006C2 (forum.php) |
| SI (1) | SI2882753T1 (forum.php) |
| SM (2) | SMT201600474T1 (forum.php) |
| TW (1) | TWI609017B (forum.php) |
| WO (1) | WO2014024164A1 (forum.php) |
| ZA (1) | ZA201501549B (forum.php) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107641124A (zh) * | 2016-07-22 | 2018-01-30 | 上海创诺制药有限公司 | 一种培美曲塞二酸新晶型及其制备方法 |
| CN109836425B (zh) * | 2017-11-24 | 2023-01-24 | 江苏创诺制药有限公司 | 一种合成培美酸的制备工艺 |
| CA3090494A1 (en) | 2018-02-07 | 2019-08-15 | L.E.A.F. Holdings Group Llc | Alpha polyglutamated pemetrexed and uses thereof |
| CN110128428A (zh) * | 2018-02-09 | 2019-08-16 | 鲁南制药集团股份有限公司 | 培美曲塞丙氨酸盐 |
| CN110128426B (zh) * | 2018-02-09 | 2021-12-14 | 鲁南制药集团股份有限公司 | 培美曲塞谷氨酸盐 |
| CN110128427A (zh) * | 2018-02-09 | 2019-08-16 | 鲁南制药集团股份有限公司 | 培美曲塞缬氨酸盐 |
| CN111333658A (zh) * | 2020-05-06 | 2020-06-26 | 贵州联科中贝制药科技有限公司 | 一种培美曲塞二钠水合物的制备方法 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2127274C1 (ru) * | 1992-09-25 | 1999-03-10 | Эли Лилли Энд Компани | СПОСОБ ПОЛУЧЕНИЯ 5-ЗАМЕЩЕННЫХ ПИРРОЛО (2,3-α)ПИРИМИДИНОВ |
| EP2301909A1 (en) * | 2008-05-30 | 2011-03-30 | Shanghai Cdymax Pharmaceuticals Co., Ltd | Processes for preparing pemetrexed disodium and its intermediate,4-(4-carbomethoxyphenyl)butanal |
| EP2409978A2 (en) * | 2010-07-22 | 2012-01-25 | Chemi SPA | A novel process for the synthesis of pemetrexed disodium salt |
| WO2012056285A1 (en) * | 2010-10-25 | 2012-05-03 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of pemetrexed |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0440795B1 (en) | 1988-10-31 | 1994-10-19 | MITSUI TOATSU CHEMICALS, Inc. | Process for preparing organic group-substituted sodium aluminum hydride |
| IL96531A (en) | 1989-12-11 | 1995-08-31 | Univ Princeton | History of Acid N- (Diomeric-H1-Pyrolo] D-2,3 [Pyrimidine-3-Ilacyl (-glutamic, preparation and pharmaceutical preparations containing them) |
| KR0162654B1 (ko) | 1989-12-11 | 1998-11-16 | 알렌 제이. 시니스갤리 | N-(피롤로[2,3-d]피리미딘-3-일아크릴)-글루타민산 유도체 |
| US5416211A (en) * | 1992-09-25 | 1995-05-16 | Eli Lilly And Company | Process for preparing 5-substituted pyrrolo-[2,3-d]pyrimidines |
| DE19725647A1 (de) | 1997-06-18 | 1998-12-24 | Basf Ag | Cyclopenta[I]phenanthren-Metallkomplex-Katalysatorsysteme |
| ZA987550B (en) | 1997-09-26 | 2000-02-21 | Lilly Co Eli | Processes and intermediates useful to make antifolates. |
| US7138521B2 (en) | 2000-02-25 | 2006-11-21 | Eli Lilly And Company | Crystalline of N-[4-[2-(2-Amino-4,7-dihydro-4oxo-3H-pyrrolo[2,3-D]pyrimidin-5-YL)ethyl]benzoyl]-L-glutamic acid and process therefor |
| EP1957497B1 (en) | 2006-08-14 | 2015-09-30 | Sicor, Inc. | Processes for preparing intermediates of pemetrexed |
| WO2008021410A2 (en) * | 2006-08-14 | 2008-02-21 | Sicor Inc. | Highly pure pemetrexed diacid and processes for the preparation thereof |
| CA2804855A1 (en) | 2010-07-28 | 2012-02-02 | Eagle Pharmaceuticals, Inc. | Pharmaceutical compositions containing pemetrexed having extended storage stability |
-
2012
- 2012-08-08 IT IT000398A patent/ITRM20120398A1/it unknown
-
2013
- 2013-08-06 TW TW102128058A patent/TWI609017B/zh active
- 2013-08-08 HU HUE13777144A patent/HUE032304T2/en unknown
- 2013-08-08 RU RU2015108042A patent/RU2609006C2/ru active
- 2013-08-08 AU AU2013301156A patent/AU2013301156B2/en active Active
- 2013-08-08 MX MX2015001712A patent/MX362858B/es active IP Right Grant
- 2013-08-08 PL PL13777144T patent/PL2882753T3/pl unknown
- 2013-08-08 PT PT137771440T patent/PT2882753T/pt unknown
- 2013-08-08 DK DK13777144.0T patent/DK2882753T3/en active
- 2013-08-08 HR HRP20170011TT patent/HRP20170011T1/hr unknown
- 2013-08-08 CN CN201380041935.8A patent/CN104736540B/zh active Active
- 2013-08-08 EP EP13777144.0A patent/EP2882753B1/en active Active
- 2013-08-08 SI SI201330427A patent/SI2882753T1/sl unknown
- 2013-08-08 KR KR1020157005932A patent/KR102288417B1/ko active Active
- 2013-08-08 LT LTEP13777144.0T patent/LT2882753T/lt unknown
- 2013-08-08 BR BR112015002429A patent/BR112015002429A8/pt not_active Application Discontinuation
- 2013-08-08 ES ES13777144.0T patent/ES2607890T3/es active Active
- 2013-08-08 IN IN833DEN2015 patent/IN2015DN00833A/en unknown
- 2013-08-08 SM SM20160474T patent/SMT201600474T1/it unknown
- 2013-08-08 RS RS20161202A patent/RS55515B1/sr unknown
- 2013-08-08 WO PCT/IB2013/056497 patent/WO2014024164A1/en active Application Filing
-
2015
- 2015-03-06 ZA ZA2015/01549A patent/ZA201501549B/en unknown
-
2016
- 2016-12-28 CY CY20161101351T patent/CY1118514T1/el unknown
- 2016-12-28 SM SM201600474T patent/SMT201600474B/it unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2127274C1 (ru) * | 1992-09-25 | 1999-03-10 | Эли Лилли Энд Компани | СПОСОБ ПОЛУЧЕНИЯ 5-ЗАМЕЩЕННЫХ ПИРРОЛО (2,3-α)ПИРИМИДИНОВ |
| EP2301909A1 (en) * | 2008-05-30 | 2011-03-30 | Shanghai Cdymax Pharmaceuticals Co., Ltd | Processes for preparing pemetrexed disodium and its intermediate,4-(4-carbomethoxyphenyl)butanal |
| EP2409978A2 (en) * | 2010-07-22 | 2012-01-25 | Chemi SPA | A novel process for the synthesis of pemetrexed disodium salt |
| WO2012056285A1 (en) * | 2010-10-25 | 2012-05-03 | Fresenius Kabi Oncology Ltd. | An improved process for the preparation of pemetrexed |
Also Published As
| Publication number | Publication date |
|---|---|
| IN2015DN00833A (forum.php) | 2015-06-12 |
| LT2882753T (lt) | 2016-12-12 |
| EP2882753B1 (en) | 2016-10-05 |
| TWI609017B (zh) | 2017-12-21 |
| HRP20170011T1 (hr) | 2017-03-10 |
| HUE032304T2 (en) | 2017-09-28 |
| DK2882753T3 (en) | 2017-01-16 |
| PT2882753T (pt) | 2016-12-27 |
| MX2015001712A (es) | 2015-08-14 |
| EP2882753A1 (en) | 2015-06-17 |
| BR112015002429A2 (pt) | 2017-07-04 |
| SMT201600474T1 (it) | 2017-03-08 |
| CY1118514T1 (el) | 2017-07-12 |
| SMT201600474B (it) | 2017-03-08 |
| BR112015002429A8 (pt) | 2019-07-30 |
| AU2013301156A1 (en) | 2015-02-05 |
| ITRM20120398A1 (it) | 2014-02-09 |
| PL2882753T3 (pl) | 2017-04-28 |
| ZA201501549B (en) | 2016-01-27 |
| MX362858B (es) | 2019-02-20 |
| KR102288417B1 (ko) | 2021-08-11 |
| WO2014024164A1 (en) | 2014-02-13 |
| RS55515B1 (sr) | 2017-05-31 |
| KR20150045458A (ko) | 2015-04-28 |
| RU2015108042A (ru) | 2016-09-27 |
| TW201412741A (zh) | 2014-04-01 |
| SI2882753T1 (sl) | 2017-02-28 |
| CN104736540B (zh) | 2017-08-25 |
| CN104736540A (zh) | 2015-06-24 |
| ES2607890T3 (es) | 2017-04-04 |
| AU2013301156B2 (en) | 2017-08-31 |
| HK1209426A1 (en) | 2016-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2609006C2 (ru) | Способ получения пеметрекседа и его лизиновой соли | |
| JP5161764B2 (ja) | 場合により２−置換されていてもよい１，６−ジヒドロ−６−オキソ−４−ピリミジンカルボン酸の製造方法 | |
| TWI555751B (zh) | Condensed heterocyclic derivatives of the salt and its crystallization | |
| CA2412368A1 (fr) | Derives de benzimidazole, leur preparation et leur application en therapeutique | |
| JP2008543975A (ja) | 高度に純粋なペメトレキセド二酸およびその調製方法 | |
| US9073899B2 (en) | Solid forms of dabigatran etexilate mesylate and processes for their preparation | |
| JP7283832B2 (ja) | ピリジンスルホンアミドリン酸エステル系化合物又はその医薬上許容される塩、その製造方法、その用途及び薬物組成物 | |
| KR20090106633A (ko) | ＰＤＥ5 억제제로서 유용한 6-벤질-2,3,4,7-테트라히드로-인돌로[2,3-ｃ]퀴놀린 화합물 | |
| CN110092740A (zh) | 一种稠环化合物及其应用 | |
| KR0165894B1 (ko) | 3-[(5-메틸-2-푸라닐)메틸]-N-(4-피페리디닐)-3H-이미다조[4,5-b]-피리딘-2-아민 2-하이드록시-1,2,3-프로판트리카르복실레이트 | |
| FR2883285A1 (fr) | Sel besylate de la 7-(2-(4-(3-trifluoromethyl-phenyl) -1,2,3,6-tetrahudro-pyrid-1-yl)ethyl) isoquinoleine, sa preparation et son utilisation en therapeutique | |
| JP2008174551A (ja) | ラベプラゾールナトリウムの結晶形態 | |
| DK152501B (da) | Fremgangsmaade til fremstilling af pyrrolooe1,2-aaapyrimidiner eller salte deraf | |
| JP7493835B2 (ja) | 小分子プロスタグラジン輸送阻害剤 | |
| US20240092780A1 (en) | Adducts and dimer compounds synthesized using gk method | |
| HK1209426B (en) | Process for the preparation of pemetrexed and lysin salt thereof | |
| CZ2017762A3 (cs) | Soli a krystalické formy venetoclaxu | |
| CS199258B2 (en) | Process for preparing new antibiotic compounds of rifamycine-s,substituted in 3 position by aliphatic substituted aminogroup | |
| JP2002512232A (ja) | 新規ジフェニル置換６員環複素環化合物、それらの製造方法及び薬物としてのそれらの使用 | |
| JPH01156942A (ja) | ４−オキソ−４−（置換フェニル）ブテノイル−サリシレート | |
| CN114085214A (zh) | 索凡替尼杂质及其制备方法和用途 | |
| EP0983270B1 (en) | Process for preparing 6-o-monoesters of castanospermine | |
| CN120774918A (en) | Protein degradation agent compound and preparation method, pharmaceutical composition and application thereof | |
| CZ2013866A3 (cs) | Způsob výroby a nová krystalická forma intermediátu syntézy ticagreloru | |
| JPS60255778A (ja) | ２位置換ジヒドロピリミジン誘導体およびその製造法 |