CN109153660A - 用于制备具有增强稳定性的依前列醇钠的方法 - Google Patents
用于制备具有增强稳定性的依前列醇钠的方法 Download PDFInfo
- Publication number
- CN109153660A CN109153660A CN201780031475.9A CN201780031475A CN109153660A CN 109153660 A CN109153660 A CN 109153660A CN 201780031475 A CN201780031475 A CN 201780031475A CN 109153660 A CN109153660 A CN 109153660A
- Authority
- CN
- China
- Prior art keywords
- sodium
- mass
- drug
- epoprostenol
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 28
- LMHIPJMTZHDKEW-XQYLJSSYSA-M Epoprostenol sodium Chemical compound [Na+].O1\C(=C/CCCC([O-])=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 LMHIPJMTZHDKEW-XQYLJSSYSA-M 0.000 title claims description 57
- 230000002708 enhancing effect Effects 0.000 title description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 76
- 239000000243 solution Substances 0.000 claims description 55
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- 230000007062 hydrolysis Effects 0.000 claims description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims description 18
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- -1 sodium alkoxide Chemical class 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 13
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims description 13
- 150000007529 inorganic bases Chemical class 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 12
- 238000004108 freeze drying Methods 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- 238000005057 refrigeration Methods 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 230000008030 elimination Effects 0.000 claims description 8
- 238000003379 elimination reaction Methods 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- 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 7
- UOZDOLIXBYLRAC-UHFFFAOYSA-L [2-hydroxy-3-(trimethylazaniumyl)propyl]-trimethylazanium;diiodide Chemical compound [I-].[I-].C[N+](C)(C)CC(O)C[N+](C)(C)C UOZDOLIXBYLRAC-UHFFFAOYSA-L 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- 239000011697 sodium iodate Substances 0.000 claims description 6
- 235000009518 sodium iodide Nutrition 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 229940032753 sodium iodate Drugs 0.000 claims description 5
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 4
- NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000015281 sodium iodate Nutrition 0.000 claims description 4
- PXGPLTODNUVGFL-BRIYLRKRSA-N (E,Z)-(1R,2R,3R,5S)-7-(3,5-Dihydroxy-2-((3S)-(3-hydroxy-1-octenyl))cyclopentyl)-5-heptenoic acid Chemical compound CCCCC[C@H](O)C=C[C@H]1[C@H](O)C[C@H](O)[C@@H]1CC=CCCCC(O)=O PXGPLTODNUVGFL-BRIYLRKRSA-N 0.000 claims description 3
- CWLQVJJNUZJEBW-UHFFFAOYSA-L disodium iodate iodide Chemical compound [Na+].I(=O)(=O)[O-].[I-].[Na+] CWLQVJJNUZJEBW-UHFFFAOYSA-L 0.000 claims description 3
- 229960003013 epoprostenol sodium Drugs 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims 1
- 239000008186 active pharmaceutical agent Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 18
- 229960001123 epoprostenol Drugs 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 159000000000 sodium salts Chemical class 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 125000002346 iodo group Chemical group I* 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 229930184489 Iodoether Natural products 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- VSHDHKDWBUMJIJ-UHFFFAOYSA-N iodo hypoiodite Chemical compound IOI VSHDHKDWBUMJIJ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000004702 methyl esters Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000004471 Glycine Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 150000002084 enol ethers Chemical class 0.000 description 3
- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- DZUXGQBLFALXCR-UHFFFAOYSA-N (+)-(9alpha,11alpha,13E,15S)-9,11,15-trihydroxyprost-13-en-1-oic acid Natural products CCCCCC(O)C=CC1C(O)CC(O)C1CCCCCCC(O)=O DZUXGQBLFALXCR-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000004593 Epoxy Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- YWOITFUKFOYODT-UHFFFAOYSA-N methanol;sodium Chemical compound [Na].OC YWOITFUKFOYODT-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- XXQBEVHPUKOQEO-UHFFFAOYSA-N potassium superoxide Chemical compound [K+].[K+].[O-][O-] XXQBEVHPUKOQEO-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 208000002815 pulmonary hypertension Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 2
- 229940001584 sodium metabisulfite Drugs 0.000 description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- JCZPMGDSEAFWDY-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanamide Chemical compound NC(=O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO JCZPMGDSEAFWDY-SQOUGZDYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229930188012 Bromoether Natural products 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- UEJQQMLXZQUJHF-UHFFFAOYSA-L [K+].[I+].[I-].[I-] Chemical compound [K+].[I+].[I-].[I-] UEJQQMLXZQUJHF-UHFFFAOYSA-L 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004982 aromatic amines Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 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
- HJCMMOODWZOXML-UHFFFAOYSA-N bromo hypobromite Chemical compound BrOBr HJCMMOODWZOXML-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical class C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
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- 229940072033 potash Drugs 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(O)=O DZUXGQBLFALXCR-CDIPTNKSSA-N 0.000 description 1
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- 229920005989 resin Polymers 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
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- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Abstract
本发明提供了稳定的依前列醇钠和用于制备该药物活性成分的方法。
Description
本发明的主题是可在深度冷冻室(-20℃±5℃)中储存至少3年的稳定的依前列醇钠及其制备方法。
具有式I的依前列醇钠是具有式IV的天然前列环素的经合成产生的钠盐。名称前列环素钠和依前列醇钠是等同的。
依前列醇钠的主要治疗领域是对肺动脉高压(PAH)的治疗(European Heart J.,2004,25,2243-2278)。
自1976年分离以来(Nature,1976,263,663-665),已知前列环素是花生四烯酸的代谢产物并且它具有强血管舒张作用和血小板聚集抑制作用。
还很快变得清楚的是,该分子在化学上是高度不稳定的,在中性或酸性水性溶液中它转化为生物学无活性的具有式V的6-氧代-PGF1α(方案1)。
方案1.
其极快降解(在生理pH下其在水性溶液中的半衰期为3-4分钟)的原因是:除了烯醇-醚结构外,链端羧基加速其质子化和离子化形式两者的分解(J.C.S.Chem.Comm.,1979,129-130)。首次合成并且也是证明结构的合成是由Corey及其小组从THP2-PGF2α开始进行的(J.A.Chem.Soc.,1977,99,2006-2008)。该方法示出在方案2中。
方案2.
在该方法中,使具有式VI的的THP2-PGF2α与N-溴代琥珀酰亚胺反应,以获得具有式VII和VIII的溴代醚非对映异构体。除去THP基团(四氢吡喃基)后,通过色谱法分离具有式IX和X的非对映异构体。在空间位阻较小(外型)位置含有溴取代基的具有式IX的异构体,用在叔丁醇中的叔丁醇钾处理时,在溴化氢消除下在1.5小时内转变为具有式IV的烯醇-醚。通过快速醚萃取将烯醇-醚从温和酸性水性溶液分离,然后用重氮甲烷转化为具有式XI的甲酯。
在空间位阻(内型)位置含有溴取代基的具有式X的异构体在上述条件下仅很小程度地反应。
具有式XI的甲酯在酸性介质中转化为具有式XII的6-氧代-PGF1α甲酯,然而,这种转化比前列环素的水解更缓慢(方案3)。
方案3.
首次合成之后几乎同时进行许多其他制备。合成的关键步骤是PGF2α或其衍生物的卤代环化,然后在碱的作用下进行卤化氢消除。由于游离酸的化学不稳定性,产物总是以其盐的形式分离和储存。
及其同事首先证明(Tetrahedron Letters,1977,30,2627-2628)
-溴代-和碘代-环化反应也可以从未受保护的PGF2α及其甲酯实现,
-两种卤代醚非对映异构体在碱的作用下转化为顺式-乙烯基醚衍生物(前列环素),
-在碘代衍生物的情况下,卤化氢消除更快,甚至在碳酸钾的作用下,碘化氢也从碘代衍生物中消除。
在卤代环化反应中
-使用在乙酸-水混合物(作为溶剂)中的KIO3+KI、或在吡啶中的I2、或在乙腈中的ICl作为碘源,
-使用在二氯甲烷中的N-溴代琥珀酰亚胺、或在二氯甲烷和乙腈中的二溴二甲基乙内酰脲、或在二氯甲烷中的N-溴代樟脑酰亚胺作为溴源。
用在适当的醇中的乙醇钾或叔丁醇钾碱进行卤化氢消除。在碘代取代基的情况下,甚至在碳酸钾的作用下也发生消除。
Johnson及其同事(J.Am.Chem.Soc.,1977,99,4182-4184)通过以下方式首次制备了冻干的前列环素钠盐:用在甲醇:水=1:1混合物中的等量氢氧化钠水解具有式XI的甲酯,然后将所获得的含有依前列醇钠盐的反应混合物冷冻干燥。冻干物即白色粉末在-30℃下保持稳定至少两个月。
使用在水或二氯甲烷溶剂中的KI-I2试剂作为碘源,在碳酸钠的存在下从PGF2α甲酯制备该甲酯。
碘化氢消除的反应条件:
-在痕量的高氯酸的存在下,用在四氢呋喃中的碳酸银
-用在苯中的1,5-二氮杂双环[4.3.0]壬-5-烯(DBN)碱
-在18-冠醚存在下,用在二甲基甲酰胺中的超氧化钾(KO2)。
Whittaker(Tetrahedron Letters,1977,32,2805-2808)从PGF2α甲酯制备了具有式XIV的碘代醚非对映异构体。将碘源即水性KI-I2试剂滴加到PGF2α甲酯的醚溶液,该醚先前用水性碳酸氢钠溶液饱和。当将碘溶解于醚或二氯甲烷中时,达到了更好的结果。
将碘代醚非对映异构体在甲醇中用10当量甲醇钠处理。消除碘化氢后,用1N氢氧化钠溶液水解酯基。依前列醇钠盐从浓缩的水性反应混合物中以细针的形式结晶。
将盐滤出,用1N氢氧化钠洗涤并在空气中干燥,同时约3.5%的晶体表面被碳酸钠覆盖,这保护了烯醇-醚结构产物。将钠盐储存在密封管中。
该方法展示在方案4中。
方案4.
Nicolau及其同事(J.C.S.Chem.Comm.,1977,630-631)在碳酸钾的存在下使具有式XIII的PGF2α甲酯与碘在二氯甲烷中反应。从具有式XIV的非对映异构体中消除碘化氢是在甲苯中,在110℃下,用1,5-二氮杂双环[5.4.0]十一碳-5-烯(DBU)碱,或更优选在甲醇中,在甲醇钠的存在下进行。
如果具有式XIV的碘代醚非对映异构体用在含5%水的甲醇中的甲醇钠处理,则除了碘化氢消除之外,还发生酯基的水解(方案5),并且所产生的依前列醇钠盐在溶液中保持稳定。前列环素钠储备溶液在进一步稀释后用于生物学研究。
方案5.
Johnson及其同事在其1978的出版物(J.Am.Chem.Soc.,1978,100,7690-7705)中描述了前列环素钠及其异构体杂质的制备。合成的最详细描述公开于1982年(Methods inEnzymology,1982,86,459-446)。它涉及前列环素钠的合成。
起始物质是具有式XIII的PGF2α甲酯,将其溶解于二氯甲烷中,向该溶液中添加饱和碳酸氢钠溶液,并且在0℃剧烈搅拌下向所产生的悬浮液中添加碘于二氯甲烷中的溶液。在反应结束时,分离各相,用二氯甲烷萃取水相,将合并的有机相首先经亚硫酸钠溶液洗涤,然后用饱和盐溶液洗涤,然后经硫酸钠干燥,过滤并真空蒸发。产物是具有式XIV的碘代醚非对映异构体的10:1比率混合物。
将碘代醚非对映异构体溶解于无水乙醚中,并且使用DBN或DBU碱进行碘化氢消除。在反应结束时,真空蒸馏出醚,将产物用醚:己烷:三乙胺=1:1:0.02混合物萃取并且通过色谱法纯化。蒸发的主馏分,即前列环素甲酯可直接进行下一步骤,或从乙醚:己烷:0.01%三乙胺溶剂混合物中结晶。产率:60%,mp:56℃-58℃。
将所获得的前列环素甲酯溶解于无二氧化碳的甲醇中,添加等摩尔量的1N氢氧化钠溶液并且使混合物在惰性气氛中在40℃下反应3小时。在水解结束时,添加甲醇并浓缩反应混合物。将残余物溶于水中并用乙腈结晶。将所产生的蓬松前列环素钠晶体保存在真空除湿器中。
产率:82%。
根据专利说明书GB 1583961中描述的方法,将具有式XIII的PGF2α甲酯溶解于乙醚中,首先向该溶液添加水性碳酸氢钠溶液,然后滴加水性碘化钾-碘溶液。将混合物在室温下搅拌过夜,然后添加醚,将混合物用水性硫代硫酸钠洗涤,然后用水洗涤,干燥并蒸发。使残余物(具有式XIV的碘代醚非对映异构体)与在甲醇中的甲醇钠在惰性气氛中反应,然后真空除去甲醇。将残余物(具有式XI的前列环素甲酯,无定形固体物质)用苯洗涤并用1N氢氧化钠处理,同时将其转化为前列环素钠的无色针状物。
作者通过省略对碘代醚非对映异构体的蒸发简化了该方法,而是将水性1N氢氧化钠溶液添加到在甲醇溶液中的甲醇钠中。在水解结束时,除去甲醇并且前列环素钠从剩余的水溶液中以细针的形式结晶。
从引用的文献中可以看出,就化学过程而言,解决了从PGF2α开始对依前列醇钠(前列环素钠)的制备。
然而,由于依前列醇的化学不稳定性,如何保存药物和药物产品的问题仍然存在。
根据上述方法
-将冻干的钠盐在-30℃下储存两个月,或者
-将其通过结晶分离并且将晶体的表面用碳酸钠覆盖并稳定,然后将其储存在密闭管中,避免空气,或者
-从钠盐制备储备溶液并且将其以溶液形式储存,或者
-将结晶盐储存在真空除湿器中。
改善依前列醇钠药物和成品的稳定性是一个重要的目标,因为预期无菌药物组合物在室温下保持其药物含量12小时,或者如果不能达到,则其必须在4℃下稳定12小时。
含有依前列醇钠药物“配制用于静脉内使用的注射用无菌钠盐”的药物产品(GlaxoSmithKline,1995)的稳定性通过将其pH值设定为大约10.5来确保。
是一种白色或几乎白色的粉末。每个安瓿含有含量相当于0.5mg或1.5mg依前列醇的钠盐、3.76mg甘氨酸、2.93mg氯化钠、50mg甘露醇、以及另外用于pH调节的氢氧化钠。
对于静脉内施用,必须将溶解于特定的溶解混合物(50ml无色缓冲溶液,其由94mg甘氨酸、73.3mg氯化钠、适于注射制剂的水、和氢氧化钠组成)中。
溶液的pH为10.2-10.8。如果不立即使用制备的溶液,可以在避光的同时在2℃-8℃下储存最多2天,并且可不再深度冷冻。
在较低的pH值下,溶液的稳定性显著降低。
专利申请WO 2007/092343中描述的方法的新颖性在于,在高pH值(在pH>11)下,在至少一种碱化剂的存在下,依前列醇溶液的稳定性与的稳定性相比显著增加。
在本说明书中,描述了含有依前列醇或依前列醇盐、一种碱化剂和赋形剂的本体溶液的制备,并且该溶液的pH设定为pH>11,优选设定为12.5-13.5,优选设定为13。然后将由此获得的溶液冻干,冷冻干燥过程的参数也在说明书中给出。
在静脉内施用之前,将冻干物溶解,所获得的(稀释的)溶液的pH也>11。
这种高pH溶液可用于与溶液相同的治疗目的。由于其较高的pH,该溶液在室温下保持其活性成分含量的90%达14-48小时。
由于这种增强的稳定性,不需要用于溶解的特定溶剂,可以使用任何用于静脉内施用的可商购溶液。
该溶液对微生物更有抗性。
根据专利说明书
-依前列醇或依前列醇盐与碱化剂的量的比率可以为1:25-1:200
碱化剂确保碱性介质但不含碱性羟基,它可以为精氨酸、赖氨酸、葡甲胺、N-甲基-葡糖胺、pKa>9.0氨基酸、三磷酸钠、碳酸钠、EDTA四钠盐。
-赋形剂的量为1%-10%
赋形剂可以为羟乙基淀粉、山梨醇、乳糖、葡聚糖、麦芽糖、甘露糖、核糖、蔗糖、甘露醇、海藻糖、环糊精、甘氨酸和聚乙烯吡咯烷酮。
-依前列醇盐优选为钠盐
-溶液的pH用无机碱或有机碱设定
无机碱为氢氧化钠、氢氧化钾、氢氧化镁或氢氧化铵。
有机碱为芳族胺或芳族醇。
-将溶液在无菌小瓶中冻干。
最有利的配制品的组合物包含0.5mg依前列醇(或等量的盐)、50mg精氨酸和50mg甘露醇,然后将溶液的pH设定为13并冻干。
将冻干物溶解于50ml溶剂中,所获得的溶液的pH>11(根据实施例:11.58-11.6)。
由此制备的依前列醇溶液在设定为相似的pH(pH=13)后比溶液更稳定。
根据本发明,在从未受保护的PGF2α(式III)开始的两个反应步骤(方案6)中以最短的方式制备依前列醇钠。
方案6.
与早期方法相比,本方法的优点是它不含卤化的或其他对环境有害的溶剂。
两个反应步骤均在四氢呋喃中进行,因此,在第一步骤后,足以浓缩反应混合物,可能危害具有式II的敏感碘代衍生物的漫长耗时的完全蒸发是不必要的。
用于碘代环化的碘源是在酸性介质中发生的碘化钠-碘酸钠的反应。
在反应过程中,除产物之外形成的碘化钠连续地与碘酸钠反应,并且所产生的碘用于碘代环化。
如果我们选择PGF2α:NaI:NaIO3=3:2:1比率的反应混合物,则碘的利用率接近100%,这意味着我们的方法不会污染环境。
用甲醇钠试剂进行碘化氢消除。在反应结束时,真空蒸馏出四氢呋喃,向残余物中添加氢氧化钠溶液并使依前列醇钠盐结晶。将沉淀的钠盐溶解于水中并冻干。
我们研究了用于盐形成的氢氧化钠量对酸敏性依前列醇钠的稳定性的影响。
为此目的,用强酸性阳离子交换DOWEX树脂除去依前列醇钠盐中可能存在的过量碱,向不含过量碱的盐的水性溶液中添加不同量的氢氧化钠,并将所获得的溶液冻干。
从1%的水性冻干物溶液中,我们测量pH并在室温下在封闭的玻璃容器中开始加速稳定性研究。
在0、24、48和144小时后通过HPLC跟踪稳定性样品的活性成分含量的变化。
从测得的活性成分含量计算出依前列醇钠的分解速率(表1)。
1.表1.
依前列醇钠的分解速率
令我们惊讶的是,发现在添加过量氢氧化钠的影响下,依前列醇钠的稳定性显著增加,直至大约5.5质量%,然后开始降低至较小的程度。
为了达到这种增强的稳定性,不需要氨基酸或其他缓冲效应赋形剂的存在。
基于这些未预期到的实验结果,改进了我们的新技术,我们将漏斗滤湿(funnel-wet)的结晶依前列醇钠盐溶解于水中,向该水溶液添加一个量的2M NaOH溶液,该量使得冷冻干燥后的产物含有4质量%过量的氢氧化钠。
通过这种新方法制备的依前列醇钠的稳定性非常好,可在深度冷冻室(-20℃±5℃)中储存至少3年。表征产物分解的6-氧代-PGF1α杂质的量在储存期间没有显示任何变化(表2.)。
表2.
在深度冷冻室(-20℃±5℃)储存过程中6-氧代-PGF1α含量的变化
通过新方法制备的依前列醇钠可以在冷藏室(5℃±3℃)中储存至少6个月(表3.)。
表3.
在冷藏室(5℃±3℃)储存过程中6-氧代-PGF1α含量的变化
根据我们的新方法,将PGF2α溶解于四氢呋喃中。用于碘代环化的碘源是在酸性介质中进行的碘化钠-碘酸钠反应。在环化反应结束时,将饱和氯化钠溶液添加到反应混合物并且用四氢呋喃-己烷混合物萃取产物。用焦亚硫酸钠溶液除去过量的碘。将产物溶液洗涤、干燥、浓缩至确定的重量,并且无需进一步纯化即可进行接下来的碘化氢消除步骤。
使用甲醇钠碱在四氢呋喃溶液中进行碘化氢消除。在反应结束时,将2M氢氧化钠溶液添加至反应混合物,通过蒸馏除去四氢呋喃并使依前列醇钠产物结晶。滤出晶体,洗涤,并向产物中添加一个量的2M NaOH溶液,该量使得冷冻干燥后的钠盐含有4质量%过量的氢氧化钠。然后将溶液冻干。
冻干物为白色或近白色粉末,可在深度冷冻室(-20℃±5℃)中储存至少3年,在冷藏室(5℃±3℃)中储存至少6个月。
与上述一致,本发明的主题是可在深度冷冻室(-20℃±5℃)中储存至少3年的稳定的依前列醇钠,其特征在于依前列醇钠和相对于依前列醇钠为3质量%-7.5质量%量的无机碱或碱性水解无机盐以冻干形式储存。
本发明的另一主题是用于制备可在深度冷冻室(-20℃±5℃)中储存至少3年的稳定的依前列醇钠的方法,其特征在于依前列醇钠盐的水性溶液是在确保介质pH>11的无机碱或碱性水解无机盐的存在下冻干的。
使用含钠阳离子的碱或盐作为确保介质pH>11的无机碱或碱性水解无机盐。
含钠阳离子的无机碱可以为氢氧化钠或碳酸钠,优选氢氧化钠,碱性水解无机盐可以为磷酸三钠。
根据本发明,依前列醇钠冻干物含有相对于钠盐为3质量%-7.5质量%量的无机碱或碱性水解无机盐。
该方法包括在一个量的添加的氢氧化钠溶液的存在下冻干依前列醇钠盐的水溶液,该量使得冻干物含有3质量%-7.5质量%,优选4质量%-6质量%的过量氢氧化钠。发现优选的4%-5%-6%NaOH过量在储存实践中同样良好。
本发明的另一主题是用于通过碘代环化和碘化氢消除制备稳定的依前列醇钠的方法,其方式如下:
a.)使用未受保护的PGF2α作为起始物质,
b.)使用碘化钠-碘酸钠混合物作为碘源,
c.)环化和碘化氢消除是在相同的溶剂中进行,
d.)在确保介质pH>11的无机碱或碱性水解无机盐的存在下冻干依前列醇钠盐的水溶液。
根据本发明的优选实施方案,使用PGF2α:碘化钠:碘酸钠=3:2:1比率的反应混合物。
使用四氢呋喃作为溶剂。
本发明的进一步细节在实施例中说明,并非将本发明限制于这些实施例。
实施例:
5ξ-碘代-9-脱氧-6ξ,9α-环氧前列腺素F1α(5-I-PGI1)
从3l水、87.7ml浓硫酸和247g硫酸钠制备1M硫酸氢钠溶液。向该溶液中添加1.2l水,然后在搅拌下添加95.1g碘酸钠于1.2l水中的溶液、473.4g前列腺素F2α于1.5l四氢呋喃中的溶液,最后添加148.1g碘化钠于0.44l水中的溶液。在反应结束时,将饱和氯化钠溶液和四氢呋喃:己烷=1:1的混合物倒入反应混合物中。分离各相,用四氢呋喃:己烷=1:1混合物萃取水相。将合并的有机相用5%焦亚硫酸钠溶液洗涤,然后用稀释且饱和的盐溶液洗涤,经硫酸钠干燥并浓缩至大约1kg。
5-I-PGI1中间体无需进一步纯化即可进行下一反应步骤。
(5Z,9α,11α,13E,15S)-6,9-环氧-11,15-二羟基前列-5,13-二烯-1-酸钠盐((5Z,
9α,11α,13E,15S)-6,9-Epoxy-11,15-dihydroxyprosta-5,13-dien-1-acid
sodium salt)
(5-I-PGI1)
向前一步骤中获得的5-I-PGI1中间体(浓缩至大约1kg)中添加12.4l无水四氢呋喃和721g甲醇钠,并且将混合物在室温下搅拌。在反应结束时,将2M氢氧化钠溶液添加到反应混合物并且真空蒸馏出四氢呋喃。将混合物在室温下搅拌直至沉淀出大量晶体,然后将其冷却至0℃以完成晶体沉淀。滤出晶体,用2M洗涤,然后用1M氢氧化钠溶液洗涤。然后将晶体溶解于一个量的2M氢氧化钠溶液中,该量使得产物含有4质量%过量的氢氧化钠。将溶液冻干。
产率:针对PGF2a计算为250g(50%),产物是白色粉末。
Claims (12)
1.一种可在深度冷冻室(-20℃±5℃)中储存至少3年的稳定的依前列醇钠药物,其特征在于所述冻干的药物包含依前列醇钠盐,并且相对于该依前列醇钠盐的量,其包含3质量%-7.5质量%的无机碱或碱性水解无机盐。
2.权利要求1的药物,其特征在于所述冻干的药物包含依前列醇钠盐,并且相对于该依前列醇钠盐的量,其包含4质量%的无机碱或碱性水解无机盐。
3.权利要求1的药物,其特征在于所述冻干的药物包含依前列醇钠盐,并且相对于该依前列醇钠盐的量,其包含5质量%的无机碱或碱性水解无机盐。
4.权利要求1的药物,其特征在于所述冻干的药物包含依前列醇钠盐,并且相对于该依前列醇钠盐的量,其包含6质量%的无机碱或碱性水解无机盐。
5.权利要求1-4的药物,其特征在于其含有氢氧化钠作为无机碱。
6.一种用于制备可在深度冷冻室(-20℃±5℃)中储存至少3年的稳定的依前列醇钠的方法,其特征在于在确保介质pH>11的一个量的无机碱或碱性水解无机盐的存在下冻干该依前列醇钠盐的水溶液,该量使得相对于该依前列醇钠盐的量,所述冻干物包含3质量%-7.5质量%、优选4质量%-6质量%的过量氢氧化钠。
7.权利要求6的方法,其特征在于使用包含钠阳离子的碱或盐作为无机碱或碱性水解无机盐。
8.权利要求6的方法,其特征在于使用氢氧化钠或碳酸钠、优选氢氧化钠作为包含钠阳离子的碱。
9.权利要求6的方法,其特征在于使用磷酸三钠作为含钠阳离子的无机盐。
10.一种通过用碘进行环化并且通过碘化氢消除制备稳定的依前列醇钠的方法,其特征在于
a.)使用未受保护的PGF2α作为起始物质,
b.)使用碘化钠-碘酸钠混合物作为碘源,
c.)该环化和该碘化氢消除是在相同的溶剂中进行,
d.)在确保介质pH>11的无机碱或碱性水解无机盐的存在下冻干该依前列醇钠盐的水溶液。
11.权利要求9的方法,其特征在于使用PGF2α:碘化钠:碘酸钠=3:2:1比率的反应混合物。
12.权利要求9的方法,其特征在于使用四氢呋喃作为溶剂。
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CN103585119A (zh) * | 2013-11-13 | 2014-02-19 | 北京泰德制药股份有限公司 | 一种包含依前列醇及其药用盐的稳定化制剂及其制备方法 |
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