CN1733714A - 富马酸伊布利特的合成方法 - Google Patents
富马酸伊布利特的合成方法 Download PDFInfo
- Publication number
- CN1733714A CN1733714A CN 200510050686 CN200510050686A CN1733714A CN 1733714 A CN1733714 A CN 1733714A CN 200510050686 CN200510050686 CN 200510050686 CN 200510050686 A CN200510050686 A CN 200510050686A CN 1733714 A CN1733714 A CN 1733714A
- Authority
- CN
- China
- Prior art keywords
- reaction
- ibutilide
- oxo
- product
- fumaric acid
- 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
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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 22
- 229960004053 ibutilide Drugs 0.000 title claims abstract description 21
- ALOBUEHUHMBRLE-UHFFFAOYSA-N Ibutilide Chemical compound CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 ALOBUEHUHMBRLE-UHFFFAOYSA-N 0.000 title claims abstract description 20
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 10
- 239000001530 fumaric acid Substances 0.000 title claims abstract description 9
- 238000001308 synthesis method Methods 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 36
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims abstract description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 15
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 10
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000012280 lithium aluminium hydride Substances 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- PCIOHQNIRPWFMV-WXXKFALUSA-N Ibutilide fumarate Chemical compound OC(=O)\C=C\C(O)=O.CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1.CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 PCIOHQNIRPWFMV-WXXKFALUSA-N 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
- LBTPIFQNEKOAIM-UHFFFAOYSA-N n-phenylmethanesulfonamide Chemical compound CS(=O)(=O)NC1=CC=CC=C1 LBTPIFQNEKOAIM-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 9
- 238000010189 synthetic method Methods 0.000 claims description 9
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000003416 antiarrhythmic agent Substances 0.000 claims description 5
- 239000012024 dehydrating agents Substances 0.000 claims description 5
- 238000003457 Shi epoxidation reaction Methods 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- HOGDNTQCSIKEEV-UHFFFAOYSA-N n'-hydroxybutanediamide Chemical compound NC(=O)CCC(=O)NO HOGDNTQCSIKEEV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 10
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 abstract 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 abstract 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 abstract 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 abstract 1
- IUZZLNVABCISOI-UHFFFAOYSA-N n-ethylheptan-1-amine Chemical compound CCCCCCCNCC IUZZLNVABCISOI-UHFFFAOYSA-N 0.000 abstract 1
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 abstract 1
- 229940014800 succinic anhydride Drugs 0.000 abstract 1
- 238000002604 ultrasonography Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 150000001721 carbon Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000003288 anthiarrhythmic effect Effects 0.000 description 3
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 3
- RCFKEIREOSXLET-UHFFFAOYSA-N disulfamide Chemical compound CC1=CC(Cl)=C(S(N)(=O)=O)C=C1S(N)(=O)=O RCFKEIREOSXLET-UHFFFAOYSA-N 0.000 description 3
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- -1 ibutilide molecular ion Chemical class 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 230000010354 integration Effects 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 206010003662 Atrial flutter Diseases 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- GGFOZRQCNXQCLO-UHFFFAOYSA-N aniline;methanesulfonic acid Chemical compound CS(O)(=O)=O.NC1=CC=CC=C1 GGFOZRQCNXQCLO-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical group [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims (3)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CNB2005100506866A CN1328253C (zh) | 2005-07-12 | 2005-07-12 | 富马酸伊布利特的合成方法 |
Applications Claiming Priority (1)
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CNB2005100506866A CN1328253C (zh) | 2005-07-12 | 2005-07-12 | 富马酸伊布利特的合成方法 |
Publications (2)
Publication Number | Publication Date |
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CN1733714A true CN1733714A (zh) | 2006-02-15 |
CN1328253C CN1328253C (zh) | 2007-07-25 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CNB2005100506866A Active CN1328253C (zh) | 2005-07-12 | 2005-07-12 | 富马酸伊布利特的合成方法 |
Country Status (1)
Country | Link |
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CN (1) | CN1328253C (zh) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101412687B (zh) * | 2008-11-10 | 2012-01-11 | 浙江师范大学 | 旋光纯富马酸伊布利特的制备方法 |
CN101664385B (zh) * | 2009-10-28 | 2013-04-10 | 马鞍山丰原制药有限公司 | 富马酸伊布利特注射液及其制备方法 |
CN104262137A (zh) * | 2014-09-23 | 2015-01-07 | 湖南农业大学 | 碱提酸沉法分离青蒿素生产废料中二氢青蒿酸 |
-
2005
- 2005-07-12 CN CNB2005100506866A patent/CN1328253C/zh active Active
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101412687B (zh) * | 2008-11-10 | 2012-01-11 | 浙江师范大学 | 旋光纯富马酸伊布利特的制备方法 |
CN101664385B (zh) * | 2009-10-28 | 2013-04-10 | 马鞍山丰原制药有限公司 | 富马酸伊布利特注射液及其制备方法 |
CN104262137A (zh) * | 2014-09-23 | 2015-01-07 | 湖南农业大学 | 碱提酸沉法分离青蒿素生产废料中二氢青蒿酸 |
Also Published As
Publication number | Publication date |
---|---|
CN1328253C (zh) | 2007-07-25 |
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