CN102001992A - 一种丁酸氯维地平的制备方法 - Google Patents
一种丁酸氯维地平的制备方法 Download PDFInfo
- Publication number
- CN102001992A CN102001992A CN201010509225.1A CN201010509225A CN102001992A CN 102001992 A CN102001992 A CN 102001992A CN 201010509225 A CN201010509225 A CN 201010509225A CN 102001992 A CN102001992 A CN 102001992A
- Authority
- CN
- China
- Prior art keywords
- ion
- preparation
- dichlorophenyl
- dihydro
- butyrate clevidipine
- 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 abstract description 9
- KPBZROQVTHLCDU-UHFFFAOYSA-N clevidipine Chemical compound CCCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC(Cl)=C1Cl KPBZROQVTHLCDU-UHFFFAOYSA-N 0.000 title abstract description 6
- 229960003621 clevidipine butyrate Drugs 0.000 title abstract description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 claims abstract description 4
- KPBZROQVTHLCDU-GOSISDBHSA-N clevidipine Chemical compound CCCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@H]1C1=CC=CC(Cl)=C1Cl KPBZROQVTHLCDU-GOSISDBHSA-N 0.000 claims description 24
- 229960003597 clevidipine Drugs 0.000 claims description 24
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 22
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000001953 recrystallisation Methods 0.000 claims description 10
- -1 alkaline earth metal cation Chemical class 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229910052728 basic metal Inorganic materials 0.000 claims description 5
- 150000003818 basic metals Chemical class 0.000 claims description 5
- BDPZFQLKFUONAG-UHFFFAOYSA-N chloromethyl butanoate Chemical compound CCCC(=O)OCCl BDPZFQLKFUONAG-UHFFFAOYSA-N 0.000 claims description 5
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 claims description 4
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 4
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 4
- 229910001416 lithium ion Inorganic materials 0.000 claims description 4
- 229910001414 potassium ion Inorganic materials 0.000 claims description 4
- 229910001415 sodium ion Inorganic materials 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- ZLTFGYXJLXNRIP-UHFFFAOYSA-N 5-(carboxymethyl)pyridine-3-carboxylic acid Chemical compound OC(=O)CC1=CN=CC(C(O)=O)=C1 ZLTFGYXJLXNRIP-UHFFFAOYSA-N 0.000 claims description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- 229910001424 calcium ion Inorganic materials 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910001425 magnesium ion Inorganic materials 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 229960003512 nicotinic acid Drugs 0.000 abstract description 11
- 239000011664 nicotinic acid Substances 0.000 abstract description 11
- 238000004440 column chromatography Methods 0.000 abstract description 2
- LXKYGQCVPGFMOE-UHFFFAOYSA-N butanoic acid carbonochloridic acid Chemical compound C(CCC)(=O)O.ClC(=O)O LXKYGQCVPGFMOE-UHFFFAOYSA-N 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 150000002739 metals Chemical class 0.000 abstract 1
- 0 CC1=C(*)C(c2cccc(Cl)c2Cl)C(C(O)=O)=C(C)N1 Chemical compound CC1=C(*)C(c2cccc(Cl)c2Cl)C(C(O)=O)=C(C)N1 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 210000004204 blood vessel Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000003445 Hantzsch reaction Methods 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- 206010000358 Accelerated hypertension Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940010811 cleviprex Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000013146 percutaneous coronary intervention Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
Description
Claims (6)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN2010105092251A CN102001992B (zh) | 2010-10-14 | 2010-10-14 | 一种丁酸氯维地平的制备方法 |
Applications Claiming Priority (1)
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CN2010105092251A CN102001992B (zh) | 2010-10-14 | 2010-10-14 | 一种丁酸氯维地平的制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN102001992A true CN102001992A (zh) | 2011-04-06 |
CN102001992B CN102001992B (zh) | 2012-05-23 |
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CN2010105092251A Active CN102001992B (zh) | 2010-10-14 | 2010-10-14 | 一种丁酸氯维地平的制备方法 |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103012249A (zh) * | 2013-01-06 | 2013-04-03 | 武汉科福新药有限责任公司 | 丁酸氯维地平的制备方法 |
CN103073485A (zh) * | 2013-01-17 | 2013-05-01 | 北京嘉林药业股份有限公司 | 一种丁酸氯维地平的制备方法 |
CN103382175A (zh) * | 2012-05-04 | 2013-11-06 | 上海医药工业研究院 | 一种丁酸氯维地平晶型ⅱ的制备方法 |
CN103420899A (zh) * | 2012-05-25 | 2013-12-04 | 四川科伦药物研究有限公司 | 一种丁酸氯维地平的纯化方法 |
CN105198797A (zh) * | 2015-11-12 | 2015-12-30 | 华仁药业股份有限公司 | 丁酸氯维地平的纯化方法 |
CN105461619A (zh) * | 2015-12-10 | 2016-04-06 | 合肥久诺医药科技有限公司 | 一种高纯度丁酸氯维地平的制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000031035A1 (en) * | 1998-11-23 | 2000-06-02 | Astrazeneca Ab | New manufacturing process |
-
2010
- 2010-10-14 CN CN2010105092251A patent/CN102001992B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000031035A1 (en) * | 1998-11-23 | 2000-06-02 | Astrazeneca Ab | New manufacturing process |
Non-Patent Citations (2)
Title |
---|
《中国医药工业杂志》 20091031 高辉等 丁酸氯维地平合成路线图解 第77-79页 1-6 , 2 * |
《有机化学》 19930930 王积涛等 羧酸的化学反应 南开大学出版社 第465页第14.3节 1-6 , 1 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103382175A (zh) * | 2012-05-04 | 2013-11-06 | 上海医药工业研究院 | 一种丁酸氯维地平晶型ⅱ的制备方法 |
CN103382175B (zh) * | 2012-05-04 | 2016-02-24 | 上海医药工业研究院 | 一种丁酸氯维地平晶型ⅱ的制备方法 |
CN103420899A (zh) * | 2012-05-25 | 2013-12-04 | 四川科伦药物研究有限公司 | 一种丁酸氯维地平的纯化方法 |
CN103420899B (zh) * | 2012-05-25 | 2016-01-27 | 四川科伦药物研究有限公司 | 一种丁酸氯维地平的纯化方法 |
CN103012249A (zh) * | 2013-01-06 | 2013-04-03 | 武汉科福新药有限责任公司 | 丁酸氯维地平的制备方法 |
CN103073485A (zh) * | 2013-01-17 | 2013-05-01 | 北京嘉林药业股份有限公司 | 一种丁酸氯维地平的制备方法 |
CN105198797A (zh) * | 2015-11-12 | 2015-12-30 | 华仁药业股份有限公司 | 丁酸氯维地平的纯化方法 |
CN105461619A (zh) * | 2015-12-10 | 2016-04-06 | 合肥久诺医药科技有限公司 | 一种高纯度丁酸氯维地平的制备方法 |
CN105461619B (zh) * | 2015-12-10 | 2019-01-25 | 合肥久诺医药科技有限公司 | 一种丁酸氯维地平的制备方法 |
Also Published As
Publication number | Publication date |
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CN102001992B (zh) | 2012-05-23 |
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Owner name: GUANGDONG JIABO PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: QINGYUAN JIABO PHARMACEUTICAL CO., LTD. |
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Address after: 511517 bio tech city, hi tech Zone, Guangdong, Qingyuan Patentee after: GUANGDONG JIABO PHARMACEUTICAL Co.,Ltd. Address before: 511517 bio pharmaceutical City, Qingyuan hi tech Industrial Development Zone, Guangdong Patentee before: QINGYUAN JIABO PHARMACEUTICAL Co.,Ltd. |
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Denomination of invention: A kind of preparation method of clevidipine butyrate Effective date of registration: 20220829 Granted publication date: 20120523 Pledgee: Industrial and Commercial Bank of China Co.,Ltd. Qingyuan Economic Development Zone Sub branch Pledgor: GUANGDONG JIABO PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980013893 |
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PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
PC01 | Cancellation of the registration of the contract for pledge of patent right |
Granted publication date: 20120523 Pledgee: Industrial and Commercial Bank of China Co.,Ltd. Qingyuan Economic Development Zone Sub branch Pledgor: GUANGDONG JIABO PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980013893 |