CN102850296A - 曲美他嗪的制备方法 - Google Patents
曲美他嗪的制备方法 Download PDFInfo
- Publication number
- CN102850296A CN102850296A CN2012103795891A CN201210379589A CN102850296A CN 102850296 A CN102850296 A CN 102850296A CN 2012103795891 A CN2012103795891 A CN 2012103795891A CN 201210379589 A CN201210379589 A CN 201210379589A CN 102850296 A CN102850296 A CN 102850296A
- Authority
- CN
- China
- Prior art keywords
- trimetazidine
- preparation
- reaction
- piperazine
- formic 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
Links
- UHWVSEOVJBQKBE-UHFFFAOYSA-N Trimetazidine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 UHWVSEOVJBQKBE-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229960001177 trimetazidine Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 32
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000019253 formic acid Nutrition 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 11
- 230000002829 reductive effect Effects 0.000 abstract description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract description 4
- 238000006268 reductive amination reaction Methods 0.000 abstract description 4
- 238000010992 reflux Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 238000010025 steaming Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 229910052763 palladium Inorganic materials 0.000 abstract description 2
- 239000010970 precious metal Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- UCTUXUGXIFRVGX-UHFFFAOYSA-N 2,3,4-trimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1OC UCTUXUGXIFRVGX-UHFFFAOYSA-N 0.000 abstract 2
- 229910010084 LiAlH4 Inorganic materials 0.000 abstract 1
- 239000012295 chemical reaction liquid Substances 0.000 abstract 1
- 239000012280 lithium aluminium hydride Substances 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- 239000012279 sodium borohydride Substances 0.000 abstract 1
- 229910000033 sodium borohydride Inorganic materials 0.000 abstract 1
- 238000010792 warming Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 6
- 229910010082 LiAlH Inorganic materials 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- HEAQHTKDZPKODU-UHFFFAOYSA-N 1-(chloromethyl)-2,3,4-trimethoxybenzene Chemical compound COC1=CC=C(CCl)C(OC)=C1OC HEAQHTKDZPKODU-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000004004 anti-anginal agent Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- MSSDTZLYNMFTKN-UHFFFAOYSA-N 1-Piperazinecarboxaldehyde Chemical compound O=CN1CCNCC1 MSSDTZLYNMFTKN-UHFFFAOYSA-N 0.000 description 1
- -1 2,3,4-trimethoxy benzyl diethylenediamine Chemical compound 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000001466 anti-adreneric effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- ZYORFJZPPWUUCE-UHFFFAOYSA-N formaldehyde;piperazine Chemical compound O=C.C1CNCCN1 ZYORFJZPPWUUCE-UHFFFAOYSA-N 0.000 description 1
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (9)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN201210379589.1A CN102850296B (zh) | 2012-09-29 | 2012-09-29 | 曲美他嗪的制备方法 |
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CN201210379589.1A CN102850296B (zh) | 2012-09-29 | 2012-09-29 | 曲美他嗪的制备方法 |
Publications (2)
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CN102850296A true CN102850296A (zh) | 2013-01-02 |
CN102850296B CN102850296B (zh) | 2015-01-07 |
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CN201210379589.1A Active CN102850296B (zh) | 2012-09-29 | 2012-09-29 | 曲美他嗪的制备方法 |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554057A (zh) * | 2013-11-13 | 2014-02-05 | 武汉武药科技有限公司 | 曲美他嗪衍生物及其制备方法 |
CN114213360A (zh) * | 2022-01-11 | 2022-03-22 | 五峰赤诚生物科技股份有限公司 | 一种曲美他嗪的制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4832889A (zh) * | 1971-08-25 | 1973-05-02 | ||
JPH0832889A (ja) * | 1994-07-15 | 1996-02-02 | Sharp Corp | 映像信号処理回路 |
CN1715275A (zh) * | 2004-06-29 | 2006-01-04 | 北京德众万全药物技术开发有限公司 | 一种简单的曲美他嗪及其药用盐的制备方法 |
CN101575321A (zh) * | 2009-06-18 | 2009-11-11 | 绍兴文理学院 | 曲美他嗪及其盐酸盐的生产方法 |
CN102140084A (zh) * | 2010-02-03 | 2011-08-03 | 辽宁本源制药有限公司 | 一种曲美他嗪及其盐酸盐的生产方法 |
-
2012
- 2012-09-29 CN CN201210379589.1A patent/CN102850296B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4832889A (zh) * | 1971-08-25 | 1973-05-02 | ||
JPH0832889A (ja) * | 1994-07-15 | 1996-02-02 | Sharp Corp | 映像信号処理回路 |
CN1715275A (zh) * | 2004-06-29 | 2006-01-04 | 北京德众万全药物技术开发有限公司 | 一种简单的曲美他嗪及其药用盐的制备方法 |
CN101575321A (zh) * | 2009-06-18 | 2009-11-11 | 绍兴文理学院 | 曲美他嗪及其盐酸盐的生产方法 |
CN102140084A (zh) * | 2010-02-03 | 2011-08-03 | 辽宁本源制药有限公司 | 一种曲美他嗪及其盐酸盐的生产方法 |
Non-Patent Citations (1)
Title |
---|
王文浩,等: "曲美他嗪合成方法的改进", 《中国药物化学杂志》, vol. 13, no. 4, 31 August 2003 (2003-08-31), pages 219 - 221 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554057A (zh) * | 2013-11-13 | 2014-02-05 | 武汉武药科技有限公司 | 曲美他嗪衍生物及其制备方法 |
CN103554057B (zh) * | 2013-11-13 | 2016-04-20 | 武汉武药科技有限公司 | 曲美他嗪衍生物及其制备方法 |
CN114213360A (zh) * | 2022-01-11 | 2022-03-22 | 五峰赤诚生物科技股份有限公司 | 一种曲美他嗪的制备方法 |
Also Published As
Publication number | Publication date |
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CN102850296B (zh) | 2015-01-07 |
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Legal Events
Date | Code | Title | Description |
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C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C53 | Correction of patent of invention or patent application | ||
CB03 | Change of inventor or designer information |
Inventor after: He Maoqun Inventor after: Miao Dezu Inventor after: Wang Longke Inventor after: Huang Wentao Inventor after: Gao Feng Inventor after: Cao Guangwei Inventor after: Liu Yang Inventor after: Zhang Peng Inventor before: He Maoqun Inventor before: Miao Dezu Inventor before: Wang Longke Inventor before: Huang Wentao Inventor before: Cao Guangwei Inventor before: Liu Yang Inventor before: Zhang Peng |
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COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: HE MAOQUN MIAO DEZU WANG LONGKE HUANG WENTAO CAO GUANGWEI LIU YANG ZHANG PENG TO: HE MAOQUN MIAO DEZU WANG LONGKE HUANG WENTAO GAO FENG CAO GUANGWEI LIU YANG ZHANG PENG |
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C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of trimetazidine Effective date of registration: 20161027 Granted publication date: 20150107 Pledgee: Agricultural Bank of China, Limited by Share Ltd, Yiyuan county subbranch Pledgor: Reyoung Pharmaceutical Co., Ltd. Registration number: 2016990000912 |
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PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
CP01 | Change in the name or title of a patent holder |
Address after: 256100 No. 6 Erlang Road, Yiyuan County, Zibo, Shandong Patentee after: Ruiyang Pharmaceutical Co., Ltd Address before: 256100 No. 6 Erlang Road, Yiyuan County, Zibo, Shandong Patentee before: REYOUNG PHARMACEUTICAL Co.,Ltd. |
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CP01 | Change in the name or title of a patent holder | ||
PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20201228 Granted publication date: 20150107 Pledgee: Agricultural Bank of China Limited by Share Ltd. Yiyuan county subbranch Pledgor: REYOUNG PHARMACEUTICAL Co.,Ltd. Registration number: 2016990000912 |
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PC01 | Cancellation of the registration of the contract for pledge of patent right |