CN102372642A - (1s)-4,5-二甲氧基-1-[(甲基氨基)甲基]苯并环丁烷的制备方法 - Google Patents
(1s)-4,5-二甲氧基-1-[(甲基氨基)甲基]苯并环丁烷的制备方法 Download PDFInfo
- Publication number
- CN102372642A CN102372642A CN2011101849040A CN201110184904A CN102372642A CN 102372642 A CN102372642 A CN 102372642A CN 2011101849040 A CN2011101849040 A CN 2011101849040A CN 201110184904 A CN201110184904 A CN 201110184904A CN 102372642 A CN102372642 A CN 102372642A
- Authority
- CN
- China
- Prior art keywords
- compound
- dimethoxy
- methyl
- formula
- preparation
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- SAVVFXUMMFHSJC-SECBINFHSA-N 1-[(7s)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]-n-methylmethanamine Chemical compound COC1=C(OC)C=C2[C@@H](CNC)CC2=C1 SAVVFXUMMFHSJC-SECBINFHSA-N 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 239000002904 solvent Substances 0.000 claims abstract description 27
- 230000002829 reductive effect Effects 0.000 claims abstract description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical compound C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- 238000010792 warming Methods 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 13
- 230000001476 alcoholic effect Effects 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 claims description 8
- 238000005266 casting Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 239000005457 ice water Substances 0.000 claims description 8
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical group COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- DIIIHASDQIQOFX-UHFFFAOYSA-N 7-methylbicyclo[4.2.0]octa-1,3,5-triene Chemical compound C1=CC=C2C(C)CC2=C1 DIIIHASDQIQOFX-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- UYDCNAUYWZIXOX-UHFFFAOYSA-N CC1CC2=C1C=CC=C2.C=N Chemical compound CC1CC2=C1C=CC=C2.C=N UYDCNAUYWZIXOX-UHFFFAOYSA-N 0.000 abstract 1
- LKLFKDDNECXUQZ-DDWIOCJRSA-N bicyclo[4.2.0]octa-1,3,5-triene [(7S)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methanamine Chemical compound C1CC2=C1C=CC=C2.O(C)C2=CC1=C([C@H](C1)CN)C=C2OC LKLFKDDNECXUQZ-DDWIOCJRSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- -1 washes 50 mL * 2 Chemical compound 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- JDZSBHBIJDIACW-MRVPVSSYSA-N [(7s)-3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl]methanamine Chemical compound C1=C(OC)C(OC)=CC2=C1[C@@H](CN)C2 JDZSBHBIJDIACW-MRVPVSSYSA-N 0.000 description 6
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 description 6
- 229960003825 ivabradine Drugs 0.000 description 6
- 125000005909 ethyl alcohol group Chemical group 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- ZLWULWWXACZTPR-UHFFFAOYSA-N [ClH]=O Chemical compound [ClH]=O ZLWULWWXACZTPR-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (8)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110184904.0A CN102372642B (zh) | 2011-07-04 | 2011-07-04 | (1s)-4,5-二甲氧基-1-[(甲基氨基)甲基]苯并环丁烷的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201110184904.0A CN102372642B (zh) | 2011-07-04 | 2011-07-04 | (1s)-4,5-二甲氧基-1-[(甲基氨基)甲基]苯并环丁烷的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN102372642A true CN102372642A (zh) | 2012-03-14 |
CN102372642B CN102372642B (zh) | 2014-01-08 |
Family
ID=45791931
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201110184904.0A Active CN102372642B (zh) | 2011-07-04 | 2011-07-04 | (1s)-4,5-二甲氧基-1-[(甲基氨基)甲基]苯并环丁烷的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN102372642B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107056706A (zh) * | 2015-12-21 | 2017-08-18 | 江苏恒瑞医药股份有限公司 | 一种用于制备盐酸伊伐布雷定α晶型的方法 |
US10221141B2 (en) | 2015-06-03 | 2019-03-05 | Urquima, S.A. | Method for the preparation of highly pure ivabradine base and salts thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0043194A2 (en) * | 1980-06-19 | 1982-01-06 | FISONS plc | Bicyclo-octatriene derivatives, pharmaceutical compositions containing them and processes and intermediates for their production |
CN1659142A (zh) * | 2002-04-26 | 2005-08-24 | 石原产业株式会社 | 吡啶化合物或其盐和含有它们的除草剂 |
US20050261376A1 (en) * | 2004-05-19 | 2005-11-24 | Jean-Michel Lerestif | Process for the synthesis of (is)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane and addition salts thereof, and to the application thereof in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
WO2008065681A2 (en) * | 2006-11-30 | 2008-06-05 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
CN101671265A (zh) * | 2008-09-12 | 2010-03-17 | 中国科学院上海药物研究所 | 新的苯并环丁烷,其制备方法与用途 |
-
2011
- 2011-07-04 CN CN201110184904.0A patent/CN102372642B/zh active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0043194A2 (en) * | 1980-06-19 | 1982-01-06 | FISONS plc | Bicyclo-octatriene derivatives, pharmaceutical compositions containing them and processes and intermediates for their production |
CN1659142A (zh) * | 2002-04-26 | 2005-08-24 | 石原产业株式会社 | 吡啶化合物或其盐和含有它们的除草剂 |
US20050261376A1 (en) * | 2004-05-19 | 2005-11-24 | Jean-Michel Lerestif | Process for the synthesis of (is)-4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane and addition salts thereof, and to the application thereof in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
WO2008065681A2 (en) * | 2006-11-30 | 2008-06-05 | Cadila Healthcare Limited | Process for preparation of ivabradine hydrochloride |
CN101671265A (zh) * | 2008-09-12 | 2010-03-17 | 中国科学院上海药物研究所 | 新的苯并环丁烷,其制备方法与用途 |
Non-Patent Citations (1)
Title |
---|
叶晓娟等: "伊伐布雷定的合成工艺改进", 《中国药物化学杂志》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10221141B2 (en) | 2015-06-03 | 2019-03-05 | Urquima, S.A. | Method for the preparation of highly pure ivabradine base and salts thereof |
CN107056706A (zh) * | 2015-12-21 | 2017-08-18 | 江苏恒瑞医药股份有限公司 | 一种用于制备盐酸伊伐布雷定α晶型的方法 |
CN107056706B (zh) * | 2015-12-21 | 2020-05-05 | 江苏恒瑞医药股份有限公司 | 一种用于制备盐酸伊伐布雷定α晶型的方法 |
Also Published As
Publication number | Publication date |
---|---|
CN102372642B (zh) | 2014-01-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2018309043B2 (en) | Processes for preparing pyrrolidine compounds | |
JP4148952B2 (ja) | (1s)−4,5−ジメトキシ−1−(メチルアミノメチル)ベンゾシクロブタン及びその付加塩合成の新規な方法、並びにイバブラジン、及び薬学的に許容され得る酸とのその付加塩の合成への適用 | |
EP3539965B1 (en) | An improved process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine | |
EP2129658A2 (en) | Process for the preparation of 6,6-dimethyl-3-azabicyclo- [3.1.0]- hexane compounds utilizing bisulfite intermediate | |
CN102229613B (zh) | 阿森纳平的合成工艺 | |
WO2016082583A1 (zh) | 消旋δ-羟基酯的不对称催化氢化动力学拆分及其应用 | |
CN103664677A (zh) | 一种(r,r)-福莫特罗酒石酸盐的不对称合成方法 | |
CN104130188B (zh) | 8-氯-1-甲基-2,3,4,5-四氢-1h-3-苯并氮杂卓的制备方法 | |
CN103540625B (zh) | 酶促合成伊伐布雷定的中间体的方法以及在合成伊伐布雷定和其盐中的应用 | |
CN102372642B (zh) | (1s)-4,5-二甲氧基-1-[(甲基氨基)甲基]苯并环丁烷的制备方法 | |
WO2008093142A1 (en) | Process for the preparation of o-desmethyl venlafaxine | |
CN102212015A (zh) | 制备手性β-氨基芳基丁酸衍生物的方法 | |
CN102250005B (zh) | 艾利西平的制备方法 | |
CN102321045B (zh) | 一种制备高吗啉盐酸盐的方法 | |
CN103787921B (zh) | 一种制备高光学纯度的反式1,2-环二胺的方法 | |
CN101481334B (zh) | 一种适于工业化生产的卡巴拉汀的制备方法 | |
CN101265201B (zh) | 一种盐酸曲马多的合成方法 | |
CN103922943B (zh) | 一种制备盐酸芬戈莫德的方法 | |
CN102070634B (zh) | 一种带保护基的1,7-二氮杂螺[4,5]葵烷的合成方法 | |
JP4508528B2 (ja) | α−アミノ置換カルボン酸アミドの製造方法 | |
CN102333775A (zh) | 制备二苯乙醇酸去甲托品酯和其盐的方法及其中所用的中间体 | |
KR101479986B1 (ko) | 이바브라딘 및 약제학적으로 허용되는 산과의 이의 부가염을 합성하는 새로운 방법 | |
CN110878042B (zh) | 一种n-取代基哌啶-3-酮的制备方法 | |
CN107879967A (zh) | 1‑氮杂螺[4.4]壬烷‑6‑酮的制备方法 | |
KR101072479B1 (ko) | 라세믹 또는 광학적으로 활성이 있는 3―하이드록시피롤리딘 및 그의 유도체의 제조방법 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
ASS | Succession or assignment of patent right |
Owner name: JIANGSU YUTIAN BIO-PHARMACEUTICAL TECHNOLOGY CO., Free format text: FORMER OWNER: LIANYUNGANG WANKE BIOLOGICAL TECHNOLOGY CO., LTD. Effective date: 20120419 |
|
C41 | Transfer of patent application or patent right or utility model | ||
COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 222100 LIANYUNGANG, JIANGSU PROVINCE TO: 222000 LIANYUNGANG, JIANGSU PROVINCE |
|
TA01 | Transfer of patent application right |
Effective date of registration: 20120419 Address after: 222000 Jiangsu Province Economic Development Zone Dapu Industrial Zone Lianyungang Linpu Road No. 22 Applicant after: JIANGSU YUTIAN PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Address before: 222100, No. 78, South Road, Qingkou Town, Ganyu County, Ganyu County, Lianyungang City, Jiangsu Province, Ganyu Applicant before: Lianyungang Wanke Biological Technology Co.,Ltd. |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee | ||
CP01 | Change in the name or title of a patent holder |
Address after: 222000 Jiangsu Province Economic Development Zone Dapu Industrial Zone Lianyungang Linpu Road No. 22 Patentee after: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Address before: 222000 Jiangsu Province Economic Development Zone Dapu Industrial Zone Lianyungang Linpu Road No. 22 Patentee before: JIANGSU YUTIAN PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |
|
PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of (1S) -4,5-dimethoxy-1-[(methylamino) methyl] benzocyclobutane Effective date of registration: 20190911 Granted publication date: 20140108 Pledgee: Bank of China Limited Lianyungang Economic and Technological Development Zone Branch Pledgor: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2019980000145 |
|
PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20201020 Granted publication date: 20140108 Pledgee: Bank of China Limited Lianyungang Economic and Technological Development Zone Branch Pledgor: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2019980000145 |
|
PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of (1s) - 4,5-dimethoxy-1 - [(methylamino) methyl] benzocyclobutane Effective date of registration: 20201021 Granted publication date: 20140108 Pledgee: Bank of China Limited Lianyungang Economic and Technological Development Zone Branch Pledgor: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020980007001 |
|
PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210907 Granted publication date: 20140108 Pledgee: Bank of China Limited Lianyungang Economic and Technological Development Zone Branch Pledgor: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2020980007001 |
|
PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation of (1s) - 4,5-dimethoxy-1 - [(methylamino) methyl] benzocyclobutane Effective date of registration: 20211013 Granted publication date: 20140108 Pledgee: Bank of China Limited Lianyungang Economic and Technological Development Zone Branch Pledgor: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980010606 |
|
PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20221130 Granted publication date: 20140108 Pledgee: Bank of China Limited Lianyungang Economic and Technological Development Zone Branch Pledgor: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980010606 |
|
PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of (1S) - 4,5-dimethoxy-1 - [(methylamino) methyl] benzocyclobutane Effective date of registration: 20221206 Granted publication date: 20140108 Pledgee: Bank of China Limited Lianyungang Economic and Technological Development Zone Branch Pledgor: JIANGSU YUTIAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2022980025301 |