CN103012268B - Novel preparation method for ivabradine - Google Patents
Novel preparation method for ivabradine Download PDFInfo
- Publication number
- CN103012268B CN103012268B CN201310001749.3A CN201310001749A CN103012268B CN 103012268 B CN103012268 B CN 103012268B CN 201310001749 A CN201310001749 A CN 201310001749A CN 103012268 B CN103012268 B CN 103012268B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- hydrogenation
- ivabradine
- per
- 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.)
- Active
Links
- 0 CNCNC(CC1B=C2)C1=*C=C2OC Chemical compound CNCNC(CC1B=C2)C1=*C=C2OC 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemical engineering, and relates to a novel synthesis method for ivabradine. The novel synthesis method for ivabradine comprises the following steps of: reacting a compound III with a compound IV in a reaction solvent under the catalysis of an alkali, performing post-treatment to obtain a compound II, and performing hydrogenation reaction under a system containing a catalyst and ammonium formate to obtain a compound I, namely, ivabradine. The method is short in synthesis route, simple to operate, greatly lowered in the difficulty of synthesis for ivabradine, low in cost and high in product yield; and most importantly, the method is good in safety, not involved with high-pressure hydrogenation, free from the use of an inflammable gas, namely, hydrogen, and great in industrialization base and application value.
Description
Technical field
The invention belongs to field of medicine and chemical technology, be specifically related to one group of preparation such as formula the benzocyclobutane compounds S 16257-2 shown in I.
Background technology
S 16257-2, such as formula compound shown in I, chemical name: 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3,4,5-tetrahydro--2 hydrogen-benzazepine-2-ketone, may be used for treating various myocardial ischemia clinically, such as stenocardia, myocardial infarction and relevant rhythm disturbance a kind ofly treat the boundless cardiovascular drugs of new generation of prospect.
I
At present, the synthesis of S 16257-2 mainly contains following several:
Method one:
R group represents halogen, dioxolane, dioxane etc.
Method two:
R group represents halogen, dioxolane, dioxane etc.
As can be seen from existing S 16257-2 synthetic method, no matter which kind of method, docking reaction yield is all lower, need to use autoclave in building-up process, need multistep recrystallization, solvent-oil ratio is large, cause the preparation manipulation of Compound I loaded down with trivial details, preparation cost is high.Directly results in that the preparation cost of hydrochloric acid Ivabradine is high and preparation difficulty is large, be not suitable for industry's enlarging production.
Summary of the invention
The larger difficulty of the pharmaceutical use huge in view of current S 16257-2 and its synthesis, the invention provides a kind of preparation method of new S 16257-2.The method synthetic route is short, simple to operate, and raw materials used existing detailed preparation method, preparation method is simple, with low cost, greatly reduces the synthesis difficulty of S 16257-2.
For achieving the above object, the technical scheme that the present invention takes is: a kind of preparation method of new S 16257-2, and synthetic route is as follows:
Concrete steps are: compound III is reacted in reaction solvent with compound IV under the catalysis of alkali, Compound II per is obtained through aftertreatment, Compound II per carries out hydrogenation under the system of catalyzer and ammonium formiate, reacts to obtain Compound I, i.e. S 16257-2.
Described alkali is the mixture of carbonate and iodized salt.
The mol ratio of described compound III and compound IV is: 1:(1-3).
Described aftertreatment is specially: cooling, adds the hydrochloric acid layering of 1mol/L, and collect water layer, water layer sodium hydroxide is adjusted to pH=9-11, extracts, anhydrous sodium sulfate drying, suction filtration by ethyl acetate, and concentrated filtrate is to dry.
Described reaction solvent is any one of acetone, butanone, hexone, ethyl acetate or dehydrated alcohol.
R in described compound III is fluorine, chlorine, bromine or iodine.
Described catalyzer is palladium charcoal, does not need any process and without moisture requirement.
The hydrogen source of described hydrogenation provides for ammonium formiate, and the mol ratio of reaction substrate and Compound II per is 1:(1-10), preferred 1:(3-7).
The pressure of described hydrogenation is 1-20atm, preferred normal pressure, i.e. 1atm.
The temperature of described hydrogenation is 20-80 DEG C, preferred 30-60 DEG C.
The solvent of described hydrogenation is alcohols, the alcohols that preferred boiling point is lower, more preferably methyl alcohol or ethanol.
The method of the invention synthetic route is short, simple to operate, greatly reduces the synthesis difficulty of S 16257-2, and with low cost, and product yield is high, and most importantly security is good, does not relate to high-pressure hydrogenation, has good conditions for sports industry and using value.
Embodiment
Below in conjunction with embodiment, the present invention is described in detail.
Embodiment 1:
Get 2.96g compound III, wherein R is Cl, 2.44g compound IV, 1.38g salt of wormwood and 1.50g sodium iodide back flow reaction 6h in 50mL hexone, cooling, add the hydrochloric acid of the 1N of 50mL, layering, collect water layer, water layer sodium hydroxide is adjusted to pH=10, extract by ethyl acetate, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing to obtain intermediate 4.5g, namely 7, 8-dimethoxy-3-(3-[[(1S) (4, 5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1, 3,-dihydro-2 hydrogen-benzazepine-2-ketone,
In 50 mL reaction flasks, add 2.0 g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 20 mL methyl alcohol, 0.3g ammonium formiate, 0.2g palladium charcoal, hydrogenation reaction pressure is 1atm, is warming up to 30 DEG C and stirs 4 hours, filter, filtrate is concentrated into dry 2.0g S 16257-2.Yield: 96.2%, HPLC:98.5%.
Embodiment 2:
Get 3.40g compound III, wherein R is Br, 2.44g compound IV, 0.69g salt of wormwood and 1.50g potassiumiodide back flow reaction 12h in 50mL acetone, filter, concentrated filtrate, residuum adds the hydrochloric acid of the 1N of 50mL, pH=9 is adjusted to sodium hydroxide, extract by ethyl acetate, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing to obtain intermediate 4.6g, i.e. 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone;
In 50 mL reaction flasks, add 2.0 g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 20 mL ethanol, 0.6g ammonium formiate, 0.5g palladium charcoal, hydrogenation reaction pressure is 3atm, is warming up to 60 DEG C and stirs 5 hours, filter, filtrate is concentrated into dry 1.9g S 16257-2.Yield: 93.7%, HPLC:98.8%.
Embodiment 3:
Get 3.86g compound III, wherein R is I, 2.44g compound IV, 0.69g salt of wormwood and 1.50g potassiumiodide back flow reaction 12h in 50mL butanone, filter, concentrated filtrate, residuum adds the hydrochloric acid of the 1N of 50mL, pH=11 is adjusted to sodium hydroxide, extract by ethyl acetate, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing to obtain intermediate 4.4g, i.e. 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone;
In 50 mL reaction flasks, add 2.3g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 23 mL ethanol, 3.1g ammonium formiate, 2.3g palladium charcoal, hydrogenation reaction pressure is 1atm, is warming up to 80 DEG C and stirs 1.5 hours, filter, filtrate is concentrated into dry 2.4g S 16257-2.Yield: 94.4%, HPLC:98.6%.
Embodiment 4:
Get 8.88g compound III, wherein R is Cl, 2.44g compound IV, 1.38g salt of wormwood and 1.50g potassiumiodide back flow reaction 12h in 50mL ethyl acetate, filter, concentrated filtrate, residuum adds the hydrochloric acid of the 1N of 50mL, pH=10 is adjusted to sodium hydroxide, extract by ethyl acetate, anhydrous sodium sulfate drying, suction filtration, concentrated filtrate is to doing to obtain intermediate 4.6g, namely 7, 8-dimethoxy-3-(3-[[(1S) (4, 5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1, 3,-dihydro-2 hydrogen-benzazepine-2-ketone,
In 50 mL reaction flasks, add 4.6 g 7,8-dimethoxy-3-(3-[[(1S) (4,5-dimethoxy benzo tetramethylene-1-base) methyl]-methylamino-] propyl group)-1,3 ,-dihydro-2 hydrogen-benzazepine-2-ketone, 20 mL methyl alcohol, 1.9g ammonium formiate, 4.6g palladium charcoal, hydrogenation reaction pressure is 5atm, is warming up to 50 DEG C and stirs 5 hours, filter, filtrate is concentrated into dry 4.5g S 16257-2.Yield: 95.6%, HPLC:98.1%.
Claims (6)
1. a preparation method for S 16257-2, synthetic route is as follows,
Step comprises: compound III is reacted in reaction solvent with compound IV under the catalysis of alkali, obtains Compound II per through aftertreatment, and Compound II per carries out hydrogenation under the system of catalyzer and ammonium formiate, reacts to obtain Compound I, i.e. S 16257-2;
Described alkali is the mixture of carbonate and iodized salt;
Described aftertreatment is specially: cooling, adds the hydrochloric acid layering of 1mol/L, and collect water layer, water layer sodium hydroxide is adjusted to pH=9-11, extracts, anhydrous sodium sulfate drying, suction filtration by ethyl acetate, and concentrated filtrate is to dry;
Described reaction solvent is any one of acetone, butanone, hexone, ethyl acetate or dehydrated alcohol;
Described catalyzer is palladium charcoal;
The pressure of described hydrogenation is normal pressure, i.e. 1atm;
The temperature of described hydrogenation is 20-80 DEG C;
The solvent of described hydrogenation is alcohols.
2. the preparation method of S 16257-2 according to claim 1, is characterized in that: the mol ratio of described compound III and compound IV is: 1:(1-3).
3. the preparation method of S 16257-2 according to claim 1, is characterized in that: the hydrogen source of described hydrogenation provides for ammonium formiate, and the mol ratio of reaction substrate and Compound II per is 1:(1-10).
4. the preparation method of S 16257-2 according to claim 3, is characterized in that: the hydrogen source of described hydrogenation provides for ammonium formiate, and the mol ratio of reaction substrate and Compound II per is 1:(3-7).
5. the preparation method of S 16257-2 according to claim 4, is characterized in that: the temperature of described hydrogenation is preferred 30-60 DEG C.
6. the preparation method of S 16257-2 according to claim 5, is characterized in that: the solvent of described hydrogenation is methyl alcohol or ethanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310001749.3A CN103012268B (en) | 2013-01-05 | 2013-01-05 | Novel preparation method for ivabradine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310001749.3A CN103012268B (en) | 2013-01-05 | 2013-01-05 | Novel preparation method for ivabradine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103012268A CN103012268A (en) | 2013-04-03 |
| CN103012268B true CN103012268B (en) | 2015-02-25 |
Family
ID=47961429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310001749.3A Active CN103012268B (en) | 2013-01-05 | 2013-01-05 | Novel preparation method for ivabradine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103012268B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447553B (en) * | 2013-09-22 | 2017-02-01 | 广东众生药业股份有限公司 | Preparation method for ivabradine and intermediate thereof |
| CN104788377B (en) * | 2015-03-06 | 2017-04-19 | 浙江美诺华药物化学有限公司 | Preparation method for ivabradine and pharmaceutical salt thereof |
| CN108424390A (en) * | 2018-01-25 | 2018-08-21 | 扬子江药业集团北京海燕药业有限公司 | A kind of preparation method of high-purity hydrochloric acid Ivabradine |
| CN109651234B (en) * | 2018-12-29 | 2021-01-01 | 山东罗欣药业集团股份有限公司 | Synthesis method of donepezil hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN1305856C (en) * | 2004-04-13 | 2007-03-21 | 瑟维尔实验室 | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| CN102464595A (en) * | 2010-11-17 | 2012-05-23 | 山东新时代药业有限公司 | Synthetic method of ivabradine midbody |
-
2013
- 2013-01-05 CN CN201310001749.3A patent/CN103012268B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
| CN1305856C (en) * | 2004-04-13 | 2007-03-21 | 瑟维尔实验室 | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| CN102464595A (en) * | 2010-11-17 | 2012-05-23 | 山东新时代药业有限公司 | Synthetic method of ivabradine midbody |
Non-Patent Citations (1)
| Title |
|---|
| "伊伐布雷定的合成工艺改进";叶晓娟 等;《中国药物化学杂志》;20100430;第20卷(第2期);第106-109页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103012268A (en) | 2013-04-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2910540B1 (en) | Novel ruthenium complex and method for preparing methanol and diol | |
| CN103012268B (en) | Novel preparation method for ivabradine | |
| CN102079737B (en) | Method for preparing apigenin | |
| CN105294534A (en) | Industrial method for preparing apremilast and intermediate thereof | |
| CN105330560A (en) | Enzalutamide intermediate preparation method | |
| CN104557845A (en) | Method for preparing lubiprostone compound | |
| CN104961787B (en) | Synthetic method of cordycepin | |
| CN103319356A (en) | One-step green synthesis process of antimalarial raw material benflumetol | |
| CN102718662A (en) | Method for preparing cinacalcet hydrochloride | |
| CN104326927B (en) | A kind of preparation method of 1-[2-amino-1-(4-methoxyphenyl) ethyl] Hexalin sulfate | |
| CN103755706B (en) | A kind of environment-friendly preparation method synthesizing folic acid | |
| CN103351291A (en) | Technology for semisynthesis of phloretin from natural phlorizin | |
| CN110330422B (en) | Preparation method of 2, 6-diethyl-4-methylphenylacetic acid | |
| CN104529726B (en) | A kind of preparation method of o-hydroxyacetophenone | |
| CN106674135A (en) | Uracil synthesizing method | |
| CN101906058A (en) | Method for preparing dithiocyano-methane | |
| CN106957235B (en) | A kind of preparation method of tamoxifen | |
| CN103408423A (en) | Nature active product L-cichoric acid synthesis process | |
| CN103242244B (en) | Canertinib preparation method | |
| CN104341359A (en) | Preparation method of tetramethyl-pyrazine | |
| CN105130808B (en) | Synthesis method of high-purity 2, 5-dimethyl-3, 4-dihydroxy methyl benzoate | |
| CN102702196A (en) | Method for synthesizing 3-methyl-7-diazaindene | |
| CN103554022A (en) | Synthetic method of higenamine hydrochloride | |
| CN106810467A (en) | Diamine compounds list Boc guard methods | |
| CN113801152B (en) | Synthesis method of 3-carboxyl-5-hydroxyphenylboric acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| 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: 222100 Jiangsu city of Lianyungang Province Economic and Technological Development Zone Industrial Zone Dapu Linpu Road No. 22 Patentee after: Jiangsu Yutian Pharmaceutical Co., Ltd. Address before: 222100 Jiangsu city of Lianyungang Province Economic and Technological Development Zone Industrial Zone Dapu Linpu Road No. 22 Patentee before: Jiangsu Yutian Biological Medical Technology Co., Ltd. |