CN116621813A - 一种富马酸伏诺拉生的制备纯化方法 - Google Patents
一种富马酸伏诺拉生的制备纯化方法 Download PDFInfo
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- CN116621813A CN116621813A CN202310590507.6A CN202310590507A CN116621813A CN 116621813 A CN116621813 A CN 116621813A CN 202310590507 A CN202310590507 A CN 202310590507A CN 116621813 A CN116621813 A CN 116621813A
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- voronoi
- fluorophenyl
- fumarate
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- pyrrole
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 42
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000000746 purification Methods 0.000 title claims abstract description 19
- IXCSYEVJOAWXRH-UHFFFAOYSA-N 5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrole-3-carbaldehyde Chemical compound FC1=CC=CC=C1C1=CC(C=O)=CN1S(=O)(=O)C1=CC=CN=C1 IXCSYEVJOAWXRH-UHFFFAOYSA-N 0.000 claims abstract description 18
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000926 separation method Methods 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 14
- 239000001530 fumaric acid Substances 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 230000003472 neutralizing effect Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000010779 crude oil Substances 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 14
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 7
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- 150000004753 Schiff bases Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 6
- ROGSHYHKHPCCJW-WLHGVMLRSA-N (e)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-n-methylmethanamine Chemical compound OC(=O)\C=C\C(O)=O.C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F ROGSHYHKHPCCJW-WLHGVMLRSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
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- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QMATYTFXDIWACW-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1F QMATYTFXDIWACW-UHFFFAOYSA-N 0.000 description 3
- MQULPEUCGKEHEG-UHFFFAOYSA-N 5-(2-fluorophenyl)-1h-pyrrole-3-carbaldehyde Chemical compound FC1=CC=CC=C1C1=CC(C=O)=CN1 MQULPEUCGKEHEG-UHFFFAOYSA-N 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 230000027119 gastric acid secretion Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical group ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 229950003825 vonoprazan Drugs 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- XJZQDVQLOSFFRK-UHFFFAOYSA-N 1-[5-(2-fluorophenyl)-1h-pyrrol-3-yl]-n-methylmethanamine Chemical compound CNCC1=CNC(C=2C(=CC=CC=2)F)=C1 XJZQDVQLOSFFRK-UHFFFAOYSA-N 0.000 description 2
- QDNWNJSLWKHNTM-UHFFFAOYSA-N 2-bromo-1-(2-fluorophenyl)ethanone Chemical compound FC1=CC=CC=C1C(=O)CBr QDNWNJSLWKHNTM-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229940126535 potassium competitive acid blocker Drugs 0.000 description 2
- -1 pyridine-3-sulfonyl Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- NOUFLZSMHQHSHA-UHFFFAOYSA-N 2-[2-(2-fluorophenyl)-2-oxoethyl]propanedinitrile Chemical compound FC1=CC=CC=C1C(=O)CC(C#N)C#N NOUFLZSMHQHSHA-UHFFFAOYSA-N 0.000 description 1
- GDHXJNRAJRCGMX-UHFFFAOYSA-N 2-fluorobenzonitrile Chemical compound FC1=CC=CC=C1C#N GDHXJNRAJRCGMX-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- ZDEFHFJZEDEKJO-UHFFFAOYSA-N 5-(2-fluorophenyl)-1h-pyrrole-3-carbonitrile Chemical compound FC1=CC=CC=C1C1=CC(C#N)=CN1 ZDEFHFJZEDEKJO-UHFFFAOYSA-N 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000019057 Cytochrome P-450 CYP2C19 Human genes 0.000 description 1
- 108010026925 Cytochrome P-450 CYP2C19 Proteins 0.000 description 1
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- 101100189356 Mus musculus Papolb gene Proteins 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- KTNZABADLXDWLM-UHFFFAOYSA-N [5-(2-fluorophenyl)-1h-pyrrol-3-yl]methanol Chemical compound OCC1=CNC(C=2C(=CC=CC=2)F)=C1 KTNZABADLXDWLM-UHFFFAOYSA-N 0.000 description 1
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
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- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
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- BFDBKMOZYNOTPK-UHFFFAOYSA-N vonoprazan Chemical compound C=1C=CN=CC=1S(=O)(=O)N1C=C(CNC)C=C1C1=CC=CC=C1F BFDBKMOZYNOTPK-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- G06V20/00—Scenes; Scene-specific elements
- G06V20/50—Context or environment of the image
- G06V20/52—Surveillance or monitoring of activities, e.g. for recognising suspicious objects
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06V—IMAGE OR VIDEO RECOGNITION OR UNDERSTANDING
- G06V10/00—Arrangements for image or video recognition or understanding
- G06V10/40—Extraction of image or video features
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
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- Chemical & Material Sciences (AREA)
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- Physics & Mathematics (AREA)
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- Plural Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种富马酸伏诺拉生的制备纯化方法,属于原料药制备技术领域。该方法首先将5‑(2‑氟苯基)‑1‑(吡啶‑3‑磺酰基)‑1H‑吡咯‑3‑甲醛与甲胺形成schiff base后还原成伏诺拉生粗品,伏诺拉生粗品成对甲苯磺酸盐过程中降低杂质A、杂质B的含量,分离伏诺拉生对甲苯磺酸盐过程中将杂质C基本完全留在母液中,然后中和、再成伏诺拉生富马酸盐,从而得到高纯度富马酸伏诺拉生原料药,该方法提高了原料药纯度,降低了生产成本,适合工业化大生产。
Description
技术领域
本发明属于原料药制备技术领域,具体地说,涉及一种富马酸伏诺拉生的制备纯化方法。
背景技术
富马酸伏诺拉生(Vonoprazan fumarate,TAK-438),化学名为1-[5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-基]-N-甲基甲胺单富马酸盐。是由日本武田制药公司开发的一种新型钾离子竞争性酸阻滞剂(P-CAB)。富马酸伏诺拉生在胃壁细胞胃酸分泌的最后一步发挥作用,它通过抑制K+对H+、K+-ATP酶(质子泵)结合,来抑制并提前终止胃酸的分泌,对人体具有强劲、持久的抑制胃酸分泌作用。与目前的质子泵抑制剂(PPI)相比,不存在CYP2C19代谢,所以在临床试验中表现出较好的疗效。2014年12月PMDA批准其上市,用于治疗糜烂性食管炎、胃溃疡、十二指肠溃疡、幽门螺旋杆菌根除,商品名为Takecab。
富马酸伏诺拉生,其结构式如下式(1):
分子式:C17H16FN3O2S.C4H4O4
分子量:461.46
C AS号:1260141-27-2
文献CN2010800181149,以邻氟苯乙酮为起始原料,与溴素经溴代反应得到2-溴-2'-氟苯乙酮,接着与丙二腈发生取代反应得到2-[2-(2-氟苯基)-2-氧代乙基]丙二腈,再经盐酸关环、钯碳加氢得到中间体5-(2-氟苯基)-1H-吡咯-3-甲腈(QS-A),通过雷尼镍氢化反应得到关键中间体5-(2-氟苯基)-1H-吡咯-3-甲醛(ZJT-A),ZJT-A在DIPEA条件下与吡啶-3-磺酰氯进行取代得到5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛,再与甲胺经还原胺化得到5-(2-氟苯基)-N-甲基-1-(3-吡啶基磺酰基)-1H-吡咯-3-甲胺,最后与富马酸成盐得到目标化合物富马酸伏诺拉生;具体合成工艺如下式(2)所示:
文献CN200680047897,以邻氟苯乙酮为起始原料,以乙酸乙酯为溶剂,与溴化铜发生溴代反应得到得到中间体2-溴-1-(2-氟苯基)-乙酮,接着与氰乙酸乙酯发生取代反应后再以盐酸发生关环反应得到2-氯-5-(2-氟苯基)-1H-吡咯-3-羧酸乙酯。其通过钯碳加氢脱去氯原子后再以DIBAL(二异丁基氢化铝)还原酯基的得到(5-(2-氟苯基)-1H-吡咯-3-基)甲醇,再通过TPAP(四丙基高钌酸铵),NMMO(4-甲基吗啉氮氧化物)发生氧化反应得到关键中间体5-(2-氟苯基)-1H-吡咯-3-甲醛。再与吡啶-3-磺酰氯在氢化钠条件下,以四氢呋喃为溶剂,进行取代反应得到中间体5-(2-氟基)-1-(3-吡啶基磺酰基)-1H-吡咯-3-甲醛,再经甲胺经还原胺化,最后与富马酸成盐得到目标化合物富马酸伏诺拉生。合成路线图如下式(3)所示:
文献CN201610531849以2-氟苯甲氰为起始原料,与盐酸乙醇溶液进行醚化反应得到中间体,在Ag(OTf)2(三氟甲磺酸银)的催化条件下与呋喃发生环加成反应得到重要中间体5-(2-氟苯基)-1H-吡咯-3-甲醛,与吡啶-3-磺酰氯在氢化钠条件下,以四氢呋喃为溶剂,进行取代反应得到中间体5-(2-氟苯基)-1-(3-吡啶基磺酰基)-1H-吡咯-3-甲醛,再与甲胺经还原胺化,最后与富马酸成盐得到目标化合物富马酸伏诺拉生。具体合成工艺如下式(4)所示:
上述方法制备富马酸伏诺拉生原料药均有一个共同的特征,用到硼氢化钠还原,而硼氢化钠均有可能吡啶环被还原,生成杂质A和杂质B,同时也有个顽固性杂质C产生,因而终产品均有三个难以去除的杂质,杂质结构如下式(5)、(6)及(7)所示:
按照现有技术,要得到合格的原料药产品,必须经过多次重结晶方可去除杂质A、杂质B和杂质C。收率大幅度降低,生产成本提高。
本发明为伏诺拉生对甲苯磺酸盐及其成盐过程,结构如下式(8)所示:
本发明利用伏诺拉生产品成对甲苯磺酸盐,在成对甲苯磺酸盐回流过程中可有效地将杂质A和杂质B水解成1-[5-(2-氟苯基)-1H-吡咯-3-基]-N-甲基甲胺(杂质D,式(9)所示),而杂质D很容易留在母液中得到去除,杂质C和对甲苯磺酸难以成盐从而结晶过程可以完全去除。
发明内容
为了克服现有技术中富马酸伏诺拉生的纯化方法繁琐(多次重结晶),制得的产品纯度不高、达不到原料药要求,收率低,生产成本高,不适合工业化生产等缺陷而提供了一种富马酸伏诺拉生纯化及其制备方法。本发明的纯化方法操作简单安全、后处理简单、制得的产品纯度高、能够达到原料药标准、收率高、生产成本低而且适合于工业化生产。
2、技术方案
为实现上述目的,本发明提供如下技术方案:
一种富马酸伏诺拉生的制备纯化方法,
包括以下步骤:
(1)将以5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛制备的伏诺拉生粗品加入到丙酮或丙酮与乙醇的混合溶剂中去,加入对甲苯磺酸一水合物,加热回流后降温析晶,过滤得伏诺拉生对甲苯磺酸盐;
(2)将步骤(1)中伏诺拉生对甲苯磺酸盐在水和二氯甲烷溶液中加碱中和后,分离伏诺拉生油状物,与富马酸成盐反应得到富马酸伏诺拉生。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的对甲苯磺酸一水合物摩尔比为0.9~1.5。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的对甲苯磺酸一水合物摩尔比为0.98~1.05。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的丙酮与乙醇的混合溶剂的质量比如下:
5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛:丙酮:乙醇三者之间的质量比为1:(3~10):(0~4)。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的丙酮与乙醇的混合溶剂的质量比如下:
5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛:丙酮:乙醇三者之间的质量比为1:8:1。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(1)中加热回流时间为0.1~8h。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(1)中加热回流时间为1~3h。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(2)中中和伏诺拉生对甲苯磺酸盐所用碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、氨水、氢氧化钠、氢氧化钾等一种或几种。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(2)中中和伏诺拉生对甲苯磺酸盐所用碱为氢氧化钠。
上述所述的富马酸伏诺拉生的制备纯化方法,
步骤(2)中所述的分离的方法如下:
步骤201、将加碱中和后的溶液在分离容器中静置2h-8h,采用照相机对分离容器侧视和俯视图像进行拍摄提取,获取侧视图和俯视图;
步骤202、将两个图像按照像素点划分,提取两个图像各个像素点的色度值,记为(x1,x2,x3,...,xn1)和(y1,y2,y3,...,yn2),其中n1为侧视图像素点的数量,其中n2为主视图像素点的数量,计算主视图和侧视图各个像素点的平均色度和/>计算整体平均色度/>其中xi为侧视图像素点的第i项色度,yi为主视图像素点的第i项色度;
步骤203、将计算的整体平均色度与设定的色度安全范围进行比较,判断体平均色度是否在设定的色度安全范围内,若是,则进行下一步,若否,则继续静置。
有益效果
本发明的纯化方法操作简单安全、后处理简单、制得的产品纯度高、能够达到原料药标准、收率高、生产成本低而且适合于工业化生产。具体来说,本发明利用伏诺拉生产品成对甲苯磺酸盐,在成对甲苯磺酸盐回流过程中可有效地将杂质A和杂质B水解成1-[5-(2-氟苯基)-1H-吡咯-3-基]-N-甲基甲胺(杂质D),而杂质D很容易留在母液中得到去除,杂质C和对甲苯磺酸难以成盐从而结晶过程可以完全去除。本发明的主要精髓在于将伏诺拉生粗品成对甲苯磺酸盐,在成盐回流过程中可有效地去除杂质A和杂质B,在成盐析晶过程可基本上完全去除杂质C,再通过中和、成富马酸盐,从而得到富马酸伏诺拉生原料,该原料药含量高、杂质低,符合药品生产标准。
附图说明
图1为本发明中伏诺拉生对甲苯磺酸盐1HNMR图谱;
图2为本发明中伏诺拉生粗品HPLC图谱;
图3为本发明中制备伏诺拉生对甲苯酸盐1h反应液HPLC图谱;
图4为本发明中伏诺拉生对甲苯酸盐HPLC图谱;
图5为本发明中富马酸伏诺拉生HPLC图谱。
具体实施方式
下面将对本发明实施例中的技术方案进行详细描述,所描述的实施例仅是本发明的部分实施例。基于本发明中的实施例,本领域普通技术人员所获得的所有其他实施例,都属于本发明保护的范围。下面结合具体实施例对本发明进一步进行描述。
实施例1
1-[5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-基]-N-甲基甲胺对甲苯磺酸盐(伏诺拉生对甲苯磺酸盐)的制备
氮气保护下,在反应瓶中加入甲醇(1000ml),5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛(100.00g,0.30mol),27~35%甲胺甲醇(45.35g,0.39mol),在25±5℃搅拌反应1h。将体系温度冷却至0~15℃,滴加NaBH4(5.21g,0.14mol)的DMA(500ml)溶液,控制体系温度0~15℃,滴加完毕,0~15℃条件下保温反应2~6h,反应完全后,加水(1800ml),用6mol/L盐酸调pH=2~3,控制体系温度10~15℃,搅拌(1~1.5h),控制温度10~15℃,加入(氨水:水=1:1)溶液800ml。DCM萃取体系(500ml×3次),合并有机层,20%食盐水洗涤(500ml×3次),无水硫酸钠(200g)干燥。过滤掉硫酸钠,滤液减压蒸馏至干,得深色油状物。
将油状物加入到反应瓶中,加丙酮(800ml)和乙醇(100ml),分批加入一水合对甲苯磺酸(57.62g,0.30mol),在外温80℃条件下保温反应3h,停止加热,冷却至0~10℃搅拌析晶8h,过滤,滤饼用丙酮洗涤(200ml×3次),真空干燥至不再减重,得类白色固体119.08g,收率76.0%(结合图1-3所示)。
实施例2
1-[5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-基]-N-甲基甲胺单富马酸盐(富马酸伏诺拉生)的制备
称取伏诺拉生对甲苯磺酸盐(23.22g,44.9mmol)加入到1000ml水中和500ml的二氯甲烷,所得悬浊液用20%氢氧化钠溶液调节pH至9,分液,水层用二氯甲烷100ml×2萃取两次,合并有机相,用100ml水洗一次,有机相加入无水硫酸钠干燥;滤去干燥剂,减压浓缩,得到红色油状物;油状物用100ml DMA溶解加入到500ml三口瓶中,加入富马酸5.16g,加完,升温至50℃搅拌1h,加入EA250ml,搅拌降温至10~25℃,维温搅拌1h;过滤,用300ml无水乙醇洗涤;过滤完,收集滤饼,45℃减压干燥至不再减重,得白色固体17.74g,收率85.7%(结合图4与图5所示)。
实施例3
步骤(2)中所述的分离的方法如下:
步骤201、将加碱中和后的溶液在分离容器中静置2h-8h,采用照相机对分离容器侧视和俯视图像进行拍摄提取,获取侧视图和俯视图;
步骤202、将两个图像按照像素点划分,提取两个图像各个像素点的色度值,记为(x1,x2,x3,...,xn1)和(y1,y2,y3,...,yn2),其中n1为侧视图像素点的数量,其中n2为主视图像素点的数量,计算主视图和侧视图各个像素点的平均色度和/>计算整体平均色度/>其中xi为侧视图像素点的第i项色度,yi为主视图像素点的第i项色度;
步骤203、将计算的整体平均色度与设定的色度安全范围进行比较,判断体平均色度是否在设定的色度安全范围内,若是,则进行下一步,若否,则继续静置。
以上示意性的对本发明及其实施方式进行了描述,该描述没有限制性,所示的也只是本发明的实施方式之一,实际的结构并不局限于此。所以,如果本领域的普通技术人员受其启示,在不脱离本发明创造宗旨的情况下,不经创造性的设计出与该技术方案相似的结构方式及实施例,均应属于本发明的保护范围。
Claims (10)
1.一种富马酸伏诺拉生的制备纯化方法,其特征在于:
包括以下步骤:
(1)将以5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛制备的伏诺拉生粗品加入到丙酮或丙酮与乙醇的混合溶剂中去,加入对甲苯磺酸一水合物,加热回流后降温析晶,过滤得伏诺拉生对甲苯磺酸盐;
(2)将步骤(1)中伏诺拉生对甲苯磺酸盐在水和二氯甲烷溶液中加碱中和后,分离伏诺拉生油状物,与富马酸成盐反应得到富马酸伏诺拉生。
2.根据权利要求1所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的对甲苯磺酸一水合物摩尔比为0.9~1.5。
3.根据权利要求2所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的对甲苯磺酸一水合物摩尔比为0.98~1.05。
4.根据权利要求1所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的丙酮与乙醇的混合溶剂的质量比如下:
5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛:丙酮:乙醇三者之间的质量比为1:(3~10):(0~4)。
5.根据权利要求4所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(1)中所述的5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛与所述的丙酮与乙醇的混合溶剂的质量比如下:
5-(2-氟苯基)-1-(吡啶-3-磺酰基)-1H-吡咯-3-甲醛:丙酮:乙醇三者之间的质量比为1:8:1。
6.根据权利要求1所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(1)中加热回流时间为0.1~8h。
7.根据权利要求6所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(1)中加热回流时间为1~3h。
8.根据权利要求1所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(2)中中和伏诺拉生对甲苯磺酸盐所用碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、氨水、氢氧化钠、氢氧化钾等一种或几种。
9.根据权利要求8所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(2)中中和伏诺拉生对甲苯磺酸盐所用碱为氢氧化钠。
10.根据权利要求1所述的富马酸伏诺拉生的制备纯化方法,其特征在于:
步骤(2)中所述的分离的方法如下:
步骤201、将加碱中和后的溶液在分离容器中静置2h-8h,采用照相机对分离容器侧视和俯视图像进行拍摄提取,获取侧视图和俯视图;
步骤202、将两个图像按照像素点划分,提取两个图像各个像素点的色度值,记为(x1,x2,x3,...,xn1)和(y1,y2,y3,…,yn2),其中n1为侧视图像素点的数量,其中n2为主视图像素点的数量,计算主视图和侧视图各个像素点的平均色度和/>计算整体平均色度/>其中xi为侧视图像素点的第i项色度,yi为主视图像素点的第i项色度;
步骤203、将计算的整体平均色度与设定的色度安全范围进行比较,判断体平均色度是否在设定的色度安全范围内,若是,则进行下一步,若否,则继续静置。
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