CN103664829A - Ranolazine synthesis technology - Google Patents
Ranolazine synthesis technology Download PDFInfo
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- CN103664829A CN103664829A CN201410000722.7A CN201410000722A CN103664829A CN 103664829 A CN103664829 A CN 103664829A CN 201410000722 A CN201410000722 A CN 201410000722A CN 103664829 A CN103664829 A CN 103664829A
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- ranolazine
- production technique
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- xylyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a ranolazine production technology, which comprises the following steps of: (1) carrying out condensation on an intermediate Z1 and piperazine to obtain an intermediate Z2, i.e. [(2,6-xylyl) carbamoylmethyl] piperazine; (2) carrying out cycloaddition reaction on the intermediate Z2 and 1-(2-metoxybenzeneoxygroup)-2,3-epoxypropane, and carrying out salification so as to obtain ranolazine, wherein the intermediate Z1 is 2- chlorine-N-(2,6- xylyl) acetamide. The production technology has the advantages of simple reaction procedure and easiness in operation, and can be subjected to industrialized production.
Description
Technical field
The preparation method who the present invention relates to a kind of Fatty Acid Oxidation enzyme inhibitors class antianginal drug, belongs to medical technical field, particularly a kind of production technique of ranolazine.
Background technology
The Fatty Acid Oxidation enzyme inhibitors class antianginal drug of ranolazine (Ranolazine) Shi You U.S. Syntex development, the listing of the Xian Yi U.S..From traditional antianginal drug by reducing heart rate, reduce blood pressure or weaken cardiac pumping function and come the mechanism of action of allevating angina pectoris different; ranolazine pharmacological action is by suppressing the oxidation of lipid acid, to improve the oxidation ratio of glucose; thereby optimize energy metabolism of myocardial effect and reduce heart energy consumption, clinical application mainly contains antianginal, heart failure resistance, anti-arrhythmia and myocardial preservation.The synthetic ranolazine method of prior art is complicated, and product yield is not good, and side reaction is many, and impurity is many.
Summary of the invention
The shortcoming existing for existing technology of preparing, the invention provides a kind of reaction conditions gentle, economic environmental protection, and yield is high, is easy to the preparation method of industrial ranolazine.The present invention provides a kind of production technique of new ranolazine mainly for intermediate [(2,6-xylyl) carbamyl methyl] the piperazine yield problem more violent compared with low reaction condition.
A kind of production technique of ranolazine; step is as follows: (1) carries out condensation with intermediate Z1 and piperazine; condensation obtains intermediate Z2; [(2; 6-xylyl) carbamyl methyl] piperazine, (2) use intermediate Z2 and 1-(2-methoxyphenoxy)-2, and 3-propylene oxide carries out cycloaddition reaction; salify, obtains ranolazine.Described intermediate Z1 is the chloro-N-of 2-(2,6-xylyl) ethanamide.
Further, step (1) is prepared intermediate Z2, and Piperazine anhydrous, acetonitrile stir and be mixed, and drips Z1 reaction, adds after completion of the reaction inorganic weak bases reaction, and concentrating under reduced pressure obtains faint yellow oily matter, through washing and extraction, dry, recrystallization, obtains intermediate Z2.Preferred, described inorganic weak bases is the inorganic salt such as sodium carbonate, salt of wormwood.Preferably, with a kind of or mixture in the organic solvents such as methyl alcohol, ethanol, Virahol as solvent.
Further, step (2), by intermediate Z2 and Virahol stirring and dissolving, adds 1-(2-methoxyphenoxy)-2,3-propylene oxide, back flow reaction 2 ~ 5h after being mixed.Concentrating under reduced pressure, resistates adds acetone solution, with hydrochlorination, obtains white solid ranolazine hydrochloride.Preferably, use Virahol as solvent.
Further, intermediate Z1 preparation method is as follows: 2,6-xylidine and ethyl acetate are mixed, add weak base, drip 2-chloroacetyl chloride, product is separated out gradually from system, filters vacuum-drying, obtain intermediate Z1, the chloro-N-of 2-(2,6-xylyl) ethanamide.Preferably, described weak base is inorganic or organic bases such as sodium bicarbonate, pyridine, triethylamine.Further, in intermediate Z1 preparation process, use acetonitrile as solvent.
compared with prior art, the invention has the beneficial effects as follows: operational path is advanced, and processing condition are reasonable, has avoided using producing a large amount of toxic and harmfuls, easy to operate and safe, reaction yield height has improved 10% left and right, and reaction conditions is easy to control, and product purity is higher, and solvent is recyclable, environmental pollution is little, is applicable to industrial production.
Embodiment
Below in conjunction with embodiment, foregoing invention content of the present invention is described in further detail.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following embodiment.Without departing from the idea case in the present invention described above, according to ordinary skill knowledge and customary means, make various replacements and change, all should comprise within the scope of the invention.
Embodiment 1
What the present embodiment related to is the preparation of intermediate Z1, and concrete grammar is as follows:
In 100mL three-necked bottle, add 2,6-xylidine 6.1g (0.05mol), ethyl acetate 40mL, sodium bicarbonate 5.0g, stirring at room, drip 2-chloroacetyl chloride 7.3 g (0.065mol), finish stirring reaction 2 hours, adularescent solid is separated out, filter, vacuum-drying, obtains white solid N-(2,6-3,5-dimethylphenyl) chlor(o)acetamide (intermediate Z1) 9.2g, yield 93.2%.
Embodiment 2
What the present embodiment related to is the preparation of intermediate Z2, and concrete grammar is as follows:
In 100mL three-necked bottle, add Piperazine anhydrous 10.3g (0.06 mol) and ethanol 50mL, stir, be heated to 60 ℃, drip N-(2, 6-3,5-dimethylphenyl) solution that chlor(o)acetamide 7.90g (0.02mol) and 30mL ethanol are made into, finish, stirring reaction 3 ~ 5 hours, concentrating under reduced pressure, obtain faint yellow oily matter, add methylene dichloride and water, separatory, water layer dichloromethane extraction, merge organic layer, washing, anhydrous sodium sulfate drying, filter, concentrated, isopropyl ether recrystallization, obtain white crystal [(2, 6-xylyl) carbamyl methyl] piperazine (intermediate Z2) 7.40g, yield 74.8%.
Embodiment 3
What the present embodiment related to is the preparation of intermediate Z2, and concrete grammar is as follows:
In 150ml there-necked flask; add [(2; 6-xylyl) carbamyl methyl] piperazine (intermediate Z2) 2.47g (0.01mol); Virahol 20mL, toluene 40mL, stirring at room; after dissolution of solid, add 1-(2-methoxyphenoxy)-2; 3-propylene oxide 2.16g, (0.012mol), heating reflux reaction 2 hours.Concentrating under reduced pressure, resistates adds acetone solution, and ice bath is cooling, drips saturated ethanol solution of hydrogen chloride 2.5mL, separates out white solid, and suction filtration, dry, obtains white solid ranolazine hydrochloride 3.63g, yield 85.0%.
Claims (9)
1. a production technique for ranolazine, step is as follows:
(1) with intermediate Z1 and piperazine, carry out condensation, condensation obtains intermediate Z2, [(2,6-xylyl) carbamyl methyl] piperazine;
(2) with intermediate Z2 and 1-(2-methoxyphenoxy)-2,3-propylene oxide carries out cycloaddition reaction, and salify obtains ranolazine;
Described intermediate Z1 is the chloro-N-of 2-(2,6-xylyl) ethanamide.
2. the production technique of ranolazine as claimed in claim 1, it is characterized in that, step (1) is: Piperazine anhydrous, acetonitrile stir and be mixed, drip intermediate Z1 reaction, add after completion of the reaction inorganic weak bases reaction, concentrating under reduced pressure obtains faint yellow oily matter, through washing and extraction, dry, recrystallization, obtains intermediate Z2.
3. the production technique of ranolazine as claimed in claim 2, is characterized in that, described inorganic weak bases is sodium carbonate or salt of wormwood.
4. as described in as arbitrary in claim 1-3, the production technique of ranolazine, is characterized in that, step (1) by one or more in methyl alcohol, ethanol and Virahol as solvent.
5. the production technique of ranolazine as claimed in claim 2, is characterized in that, step (2) is as follows: by intermediate Z2 and organic solvent stirring and dissolving, add 1-(2-methoxyphenoxy)-2 after being mixed, 3-propylene oxide, back flow reaction 2 ~ 5 hours; Concentrating under reduced pressure, resistates adds acetone solution, with hydrochlorination, obtains white solid ranolazine hydrochloride.
6. the production technique of ranolazine as claimed in claim 5, is characterized in that, described organic solvent is Virahol.
7. the production technique of ranolazine as claimed in claim 1, it is characterized in that, intermediate Z1 preparation method is as follows: 2,6-xylidine and ethyl acetate are mixed, add weak base, drip 2-chloroacetyl chloride, product is separated out gradually from system, filters vacuum-drying, obtain the chloro-N-of 2-(2,6-xylyl) ethanamide.
8. the production technique of ranolazine as claimed in claim 7, is characterized in that, described weak base is sodium bicarbonate, pyridine or triethylamine.
9. the production technique of ranolazine as claimed in claim 1, is characterized in that, step (2) salify is and hydrochloric acid reaction salify, with methyl alcohol, ethanol, Virahol or acetone as solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410000722.7A CN103664829A (en) | 2014-01-02 | 2014-01-02 | Ranolazine synthesis technology |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410000722.7A CN103664829A (en) | 2014-01-02 | 2014-01-02 | Ranolazine synthesis technology |
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| CN103664829A true CN103664829A (en) | 2014-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410000722.7A Pending CN103664829A (en) | 2014-01-02 | 2014-01-02 | Ranolazine synthesis technology |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115745912A (en) * | 2022-10-31 | 2023-03-07 | 浙江海洲制药有限公司 | Method for preparing high-purity ranolazine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008047388A2 (en) * | 2006-10-20 | 2008-04-24 | Ind-Swift Laboratories Limited | Improved process for the preparation of ranolazine |
| CN101560196A (en) * | 2008-04-16 | 2009-10-21 | 北京万全阳光医学技术有限公司 | High-purity ranolazine and preparation method thereof |
-
2014
- 2014-01-02 CN CN201410000722.7A patent/CN103664829A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008047388A2 (en) * | 2006-10-20 | 2008-04-24 | Ind-Swift Laboratories Limited | Improved process for the preparation of ranolazine |
| CN101560196A (en) * | 2008-04-16 | 2009-10-21 | 北京万全阳光医学技术有限公司 | High-purity ranolazine and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| 李树春，等: "新型抗心绞痛药雷诺嗪的合成研究", 《中国药物化学杂志》 * |
| 秦明利，等: "雷诺嗪的合成工艺研究", 《信阳师范学院学报：自然科学版》 * |
| 陆文超，等: "雷诺嗓的合成", 《中国医药工业杂志》 * |
| 陈小林，等: "雷诺嗪的合成工艺研究", 《华西药学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115745912A (en) * | 2022-10-31 | 2023-03-07 | 浙江海洲制药有限公司 | Method for preparing high-purity ranolazine |
| CN115745912B (en) * | 2022-10-31 | 2024-04-26 | 浙江海洲制药股份有限公司 | Method for preparing high-purity ranolazine |
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Application publication date: 20140326 |