WO2016065576A1 - Procédé de préparation d'éther glycidique du gaïacol de haute pureté - Google Patents

Procédé de préparation d'éther glycidique du gaïacol de haute pureté Download PDF

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Publication number
WO2016065576A1
WO2016065576A1 PCT/CN2014/089914 CN2014089914W WO2016065576A1 WO 2016065576 A1 WO2016065576 A1 WO 2016065576A1 CN 2014089914 W CN2014089914 W CN 2014089914W WO 2016065576 A1 WO2016065576 A1 WO 2016065576A1
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WIPO (PCT)
Prior art keywords
guaiacol
glycidyl ether
mixture
stirred
process according
Prior art date
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PCT/CN2014/089914
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English (en)
Inventor
Honghai Song
Haiping Huang
Jiang Chen
Xiaodong Liu
Zhiyuan SUN
Song Lin
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Tianjin Weijie Pharmaceutical Co., Ltd.
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Publication date
Application filed by Tianjin Weijie Pharmaceutical Co., Ltd. filed Critical Tianjin Weijie Pharmaceutical Co., Ltd.
Priority to PCT/CN2014/089914 priority Critical patent/WO2016065576A1/fr
Publication of WO2016065576A1 publication Critical patent/WO2016065576A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/27—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms
    • C07D301/28—Condensation of epihalohydrins or halohydrins with compounds containing active hydrogen atoms by reaction with hydroxyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C07D303/23—Oxiranylmethyl ethers of compounds having one hydroxy group bound to a six-membered aromatic ring, the oxiranylmethyl radical not being further substituted, i.e.

Definitions

  • the present invention provides a process for the preparation of high-purity guaiacol glycidyl ether.
  • the present invention further relates to an improved process for the purification of guaiacol glycidyl ether of formula (I) .
  • the processes of the present invention are particularly useful for the preparation of ranolazine and pharmaceutically acceptable salts thereof.
  • Ranolazine chemically known as ( ⁇ )-N- (2, 6-dimethylplenyl) -4- [2-hydroxy-3- (2-methoxyphenoxy) propyl] -1-piperazineacetamide, is represented by the formula as given below.
  • Ranolazine could be used to treat myocardial infarction, congestive heart disease, angina and arhythmia etc.
  • the mechanism of action of ranolazine is to inhibit partial fatty acid oxidation, which changes fatty acid oxidation to glucose oxidation in heart, and thereby reduces the cardiac oxygen consumption.
  • Ranolazine is the only antianginal agent which does not alter heart rate or blood pressure.
  • Guaiacol glycidyl ether that is 2- ( (2-methoxyphenoxy) methyl) oxirane, is represented by the following formula (I)
  • Guaiacol glycidyl ether can be synthesized by the condensation of guaiacol (chemically known as 2-methoxyphenol) and epichlorohydrin (chemically known as 2- (chloromethyl) oxirane) , as below depicted:
  • GB2216520 discloses a process for the preparation of guaiacol glycidyl ether wherein guaiacol and epichlorohydrin are reacted in the presence of a phase transfer catalyst and of a base. After the reaction is completed, the reaction mixture is diluted with dichloromethane, extracted and distilled off to obtain crude guaiacol glycidyl ether. The final product is than afforded after fractional distillation under high vacuum. Said process requires the use of huge amounts of dichloromethane, being thus very expensive and having a strong impacting on the environment.
  • WO2008/047388 discloses a similar process, wherein the reaction of guaiacol and epichlorohydrin in carried out in the presence of a phase transfer catalyst, sodium hydroxide as base and toluene as the solvent. After extraction and washings with water, the reaction mixture is distilled under vacuum at 130-150 °C and 5 bar to achieve the product. Also in this case huge amounts of solvents are required, with the further drawback of creating emulsions during the extraction step. No reference to any purification can be found in WO2008047388, the final product having a purity of 96%.
  • WO2010/025370 discloses the reaction of guaiacol and epichlorohydrin in a 3%sodium hydroxide solution at 25-35 °C. Extracted after reaction, the organic layer is successively washed with 6%and 10%sodium hydroxide solutions and distilled under high vacuum, to collect the fraction at 85-89 °C, and obtaining the product with a 94%yield and a purity of 98.28%.
  • the process disclosed in WO2011/113228 comprises reacting guaiacol and epichlorohydrin in the presence of the phase transfer catalyst TBAB (tetrabutyl ammonium bromide) and a 25%sodium hydroxide solution at 55-60 °C.
  • the reaction mixture is washed with water, extracted, and the organic layer is distilled under vacuum to recycle epichlorohydrin.
  • the solution is heated and distilled off, collecting the fraction at 148-153 °C and 1.33 KPa to achieve the crude product which purity is 98%.
  • the crude product is than re-crystallized from a lower alcohol to obtain a high-purity product, which purity is more than 99.5%, with a total yield of about 60%.
  • guaiacol glycidyl ether can be obtained in good yield and high purity through an improved process which avoids the use of organic solvents and reduces the production of impurities rendering the process simple and cost-effective.
  • the present invention provides an industrially applicable and economically improved process for the preparation of high-purity guaiacol glycidyl ether, which is a useful material for the synthesis of ranolazine.
  • pharmaceutically acceptable salt refers to a non-toxic inorganic or organic salt.
  • examples of pharmaceutically acceptable salts include but are not limited to: carbonate, hydrochloride, hydrobromide, sulphate, hydrogen sulphate, citrate, maleate, fumarate, trifluoroacetate, 2-naphthalenesulphonate, and para-toluenesulphonate. Further information on pharmaceutically acceptable salts can be found in pharmaceutical chemistry manuals, for example: Handbook of pharmaceutical salts, P. Stahl, C. Wermuth, WILEY-VCH (Eds. , 2008, pp. 127-133) , herein incorporated by reference.
  • aqueous medium is intended to refer to aqueous solutions, emulsions or dispersions.
  • phase transfer catalyst is used herein to represent any catalyst which can effectively facilitate the transfer of ions or other reactive or functional chemical species or groups across the phase interface between one distinct liquid phase and a second distinct liquid phase, as in a heterogeneous system.
  • the present invention relates to a process for the preparation of guaiacol glycidyl ether which comprises reacting guaiacol with epichlorohydrin in the presence of water, of a base and of a phase transfer catalyst selected from a) PEG400, b) t-butanol or isopropanol or c) a mixture thereof.
  • the process involves adding the base to a mixture of guaiacol and the phase transfer catalyst in an aqueous medium, without any organic solvent.
  • Suitable bases are inorganic bases such as alkali metal hydroxides, carbonates and bicarbonates.
  • the alkali metal hydroxides, carbonates, and bicarbonates may be sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like.
  • the base used is sodium hydroxide.
  • the base may be used in its pure form or as a solution obtained by dissolving it in water.
  • the base is preferably added to the reaction mixture comprising guaiacol in aqueous medium in the form of aqueous solution.
  • the base may be added to the reaction mixture in single portion or in multiple portions, or it may be added slowly and continuously over a period of time.
  • the base is added to the reaction mixture slowly and continuously over a period of time of from 30 minutes to 2 hours.
  • the molar ratio of the base to guaiacol is preferably between 1 and 2, more preferably between 1.1 and 1.3.
  • the phase transfer catalyst may be present in an amount of about 0.5%w/w to about 5%w/w to guaiacol, preferably in an amount of about 1%w/w to about 4%w/w.
  • the phase transfer catalyst is PEG400 and it is present in an amount of 1%w/w to guaiacol.
  • the phase transfer catalyst is t-butanol or isopropanol and it is present in an amount of 3%w/w to guaiacol.
  • the phase transfer catalyst is a mixture of PEG400 and t-butanol or isopropanol, wherein PEG400 is present in an amount of 1%w/w to guaiacol and t-butanol or isopropanol is present in an amount of 3%w/w to guaiacol.
  • the reaction mixture comprising guaiacol and the base in aqueous medium is stirred for few minutes to few hours at a temperature in the range of 20 to 40 °C.
  • the reaction mixture is stirred for 1 hour at a temperature in the range of 33 to 37 °C.
  • reaction mixture is then added to epichlorohydrin and the reaction mass is further stirred for few hours.
  • the reaction mixture may be added to epichlorohydrin in a single portion or in multiple portions, or it may be added slowly and continuously over a period of time.
  • the reaction mixture is added to epichlorohydrin slowly and continuously over a period of few hours, preferably from 1 to 3 hours, more preferably over a period of 2 hours.
  • the reaction can be conducted until completion of the reaction.
  • the reaction time varies from about 1 hour to about 4 hours.
  • Suitable temperature for carrying out the reaction is comprised in the range from 30 to 45 °C, preferably from 33 to 37 °C.
  • reaction mixture is stirred for 3 hours at 33-37 °C.
  • the molar ratio of epichlorohydrin to guaiacol is preferably between 1.5 and 5, more preferably between 1.8 and 2.5, still more preferably is 2.
  • the organic layer containing the product may be washed with an aqueous solution of a base and/or with brine.
  • the combined organic layer is distilled to recover excess epichlorohydrin.
  • guaiacol glycidyl ether is distilled at 120-130 °C with reflux ratio 1: 6 under vacuum at 2 mmHg.
  • guaiacol glycidyl ether having purity of above 98%is achieved with a yield of above 70%.
  • phase transfer catalyst selected from PEG400, t-butanol or isopropanol or a mixture thereof resides in the improved purity and yield of the achieved guaiacol glycidyl ether.
  • the present invention avoids the use of organic solvent, making the process inexpensive and environmentally friendly for industrial scale production.
  • Another object of the present invention is a process for the purification of guaiacol glycidyl ether which comprises crystallizing guaiacol glycidyl ether from a solvent selected from n-hexane, cyclohexane or n-heptane.
  • the crystallization can be carried by suspending guaiacol glycidyl ether in n-hexane, cyclohexane or n-heptane, heating the mixture thus achieved until dissolution, stirring for few hours, cooling and recovering solid guaiacol glycidyl ether.
  • the ratio of the solvent to guaiacol glycidyl ether is preferably between 2 and 5 by weight, more preferably between 2.5 and 3.5 by weight.
  • the mixture may be heated at a temperature in the range of 40 to 70 °C, preferably from 50 to 60 °C, until dissolution.
  • the so formed solution is stirred for as period of time from 1 to 3 hours.
  • the solution is cooled to a temperature of 5 to 25 °C, preferably of 10 to 20 °C and stirred for few hours.
  • the mixture is stirred for a period of time of 1 to 4 hours, more preferably for 3 hours.
  • the solid mass so formed may be isolated by filtration or centrifugation, to yield highly pure guaiacol glycidyl ether.
  • the guaiacol glycidyl ether is obtained with a purity of at least 99.5%.
  • guaiacol glycidyl ether is dissolved in 3 w/w of n-hexane, cyclohexane or n-heptane and stirred for 1 hour; it is then slowly cooled to 10-20 °C and stirring is continued for 3 hours. Solid guaiacol glycidyl ether is recovered by centrifugation and dried.
  • Another object of the present invention is a process for the preparation of guaiacol glycidyl ether which comprises reacting guaiacol with epichlorohydrin in the presence of a base and of a phase transfer catalyst selected from a) PEG400, b) t-butanol or isopropanol or c) a mixture thereof, followed by the purification of the guaiacol glycidyl ether thus achieved by crystallization from a solvent selected from n-hexane, cyclohexane or n-heptane.
  • the process involves adding the base to a mixture of guaiacol and the phase transfer catalyst in an aqueous medium, without any organic solvent.
  • Suitable bases are inorganic bases such as alkali metal hydroxides, carbonates and bicarbonates.
  • the alkali metal hydroxides, carbonates, and bicarbonates may be sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like.
  • the base used is sodium hydroxide.
  • the base may be used in its pure form or as a solution obtained by dissolving it in water.
  • the base is preferably added to the reaction mixture comprising guaiacol in aqueous medium in the form of aqueous solution.
  • the base may be added to the reaction mixture in single portion or in multiple portions, or it may be added slowly and continuously over a period of time.
  • the base is added to the reaction mixture slowly and continuously over a period of time of from 30 minutes to 2 hours.
  • the molar ratio of the base to guaiacol is preferably between 1 and 2, more preferably between 1.1 and 1.3.
  • the phase transfer catalyst may be present in an amount of about 0.5%w/w to about 5%w/w to guaiacol, preferably in an amount of about 1%w/w to about 4%w/w.
  • the phase transfer catalyst is PEG400 and it is present in an amount of 1%w/w to guaiacol.
  • the phase transfer catalyst is t-butanol or isopropanol and it is present in an amount of 3%w/w to guaiacol.
  • the phase transfer catalyst is a mixture of PEG400 and t-butanol or isopropanol, wherein PEG400 is present in an amount of 1%w/w to guaiacol and t-butanol or isopropanol is present in an amount of 3%w/w to guaiacol.
  • the reaction mixture comprising guaiacol and the base in aqueous medium is stirred for few minutes to few hours at a temperature in the range of 20 to 40 °C.
  • the reaction mixture is stirred for 1 hour at a temperature in the range of 33 to 37 °C.
  • reaction mixture is then added to epichlorohydrin and the reaction mass is further stirred for few hours.
  • the reaction mixture may be added to epichlorohydrin in a single portion or in multiple portions, or it may be added slowly and continuously over a period of time.
  • the reaction mixture is added to epichlorohydrin slowly and continuously over a period of few hours, preferably from 1 to 3 hours, more preferably over a period of 2 hours.
  • the reaction can be conducted until completion of the reaction.
  • the reaction time varies from about 1 hour to about 4 hours.
  • Suitable temperature for carrying out the reaction is comprised in the range from 30 to 45 °C, preferably from 33 to 37 °C.
  • reaction mixture is stirred for 3 hours at 33-37 °C.
  • the molar ratio of epichlorohydrin to guaiacol is preferably between 1 and 3, more preferably between 1.5 and 2.5.
  • the organic layer containing the product may be washed with an aqueous solution of a base and/or with brine.
  • the combined organic layer is distilled to recover excess epichlorohydrin.
  • guaiacol glycidyl ether is distilled at 120-130 °C with reflux ratio 1: 6 under vacuum at 2 mmHg.
  • the crystallization can be carried by suspending guaiacol glycidyl ether in n-hexane, cyclohexane or n-heptane, heating the mixture thus achieved until dissolution, stirring for few hours, cooling and recovering solid guaiacol glycidyl ether.
  • the ratio of the solvent to guaiacol glycidyl ether is preferably between 2 and 5 by weight, more preferably between 2.5 and 3.5 by weight.
  • the mixture may be heated at a temperature in the range of 40 to 70 °C, preferably from 50 to 60 °C, until dissolution.
  • the so formed solution is stirred for as period of time from 1 to 3 hours.
  • the solution is cooled to a temperature of 5 to 25 °C, preferably of 10 to 20 °C and stirred for few hours.
  • the mixture is stirred for a period of time of 1 to 4 hours, more preferably for 3 hours.
  • the solid mass so formed may be isolated by filtration or centrifugation, to yield highly pure guaiacol glycidyl ether.
  • the guaiacol glycidyl ether is obtained with a purity of at least 99.5%.
  • guaiacol glycidyl ether is dissolved in 3 w/w of n-hexane, cyclohexane or n-heptane and stirred for 1 hour; it is then slowly cooled to 10-20 °C and stirring is continued for 3 hours. Solid guaiacol glycidyl ether is recovered by centrifugation and dried.
  • Guaiacol (7.0 kg) , PEG400 (70 g) , t-butanol (210 g) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is added into another 50 L reactor, and the temperature is kept at 33 °C. Then, the first solution is dropwise added into epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained under stirring for 3 hours.
  • Guaiacol (7.0 kg) , PEG400 (70 g) , t-butanol (210 g) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is added into a 50 L reactor, and the temperature is kept at 33 °C.
  • the resulting first solution is dropwise added to epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained under stirring for 3 hours.
  • Guaiacol (7.0 kg) , PEG400 (70 g) , isopropanol (210 g) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is charged into a 50 L reactor, and the temperature is kept at 33 °C. Then the resulting first solution is dropwise added to epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained for 3 hours.
  • Guaiacol (7.0 kg) , PEG400 (70 g) , isopropanol (210 g) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is charged into a 50 L reactor, and the temperature is kept at 33 °C. Then the resulting first solution is dropwise added to epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained for 3 hours.
  • Guaiacol (7.0 kg) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is charged into a 50 L reactor, and the temperature is kept at 33 °C.
  • the resulting first solution is dropwise added to epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained for 3 hours.
  • the stirring is stopped and the mixture is standing for 30 minutes.
  • the layers are separated.
  • Guaiacol (7.0 kg) , PEG400 (70 g) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is charged into a 50 L reactor, and the temperature is kept at 33 °C.
  • the resulting first solution is dropwise added to epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained for 3 hours.
  • the stirring is stopped and the mixture is kept standing for 30 minutes.
  • the layers are separated.
  • Guaiacol (7.0 kg) , t-butanol (210 g) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is charged into a 50 L reactor, and the temperature is kept at 33 °C.
  • the resulting first solution is dropwise added to epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained for 3 hours.
  • the stirring is stopped and the mixture is kept standing for 30 minutes.
  • the layers are separated.
  • Guaiacol (7.0 kg) , isopropanol (210 g) and water (14.5 kg) are charged into a 30 L reactor and stirred for 30 minutes at 28-30 °C.
  • a solution of sodium hydroxide (2.688 kg) in water (5 L) is added at 33-37 °C in 45 minutes.
  • the reaction mixture is maintained at 33-37 °C and stirred for 1 hour.
  • Epichlorohydrin (10.4 kg) is charged into a 50 L reactor, and the temperature is kept at 33 °C.
  • the resulting first solution is dropwise added to epichlorohydrin at 33-37 °C in 2 hours, and the mixture is maintained for 3 hours.
  • the stirring is stopped and the mixture is kept standing for 30 minutes.
  • the layers are separated.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epoxy Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation d'éther glycidique du gaïacol de haute pureté de formule (I). L'invention concerne également un procédé amélioré de purification de l'éther glycidique du gaïacol de formule (I). Les procédés de la présente invention servent notamment à la préparation de la ranolazine et de sels pharmaceutiquement acceptables de celle-ci.
PCT/CN2014/089914 2014-10-30 2014-10-30 Procédé de préparation d'éther glycidique du gaïacol de haute pureté WO2016065576A1 (fr)

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PCT/CN2014/089914 WO2016065576A1 (fr) 2014-10-30 2014-10-30 Procédé de préparation d'éther glycidique du gaïacol de haute pureté

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Application Number Priority Date Filing Date Title
PCT/CN2014/089914 WO2016065576A1 (fr) 2014-10-30 2014-10-30 Procédé de préparation d'éther glycidique du gaïacol de haute pureté

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440131A (zh) * 2020-04-27 2020-07-24 江苏惠利生物科技有限公司 一种易分解的愈创木酚缩水甘油醚的精制方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207662B1 (en) * 1996-08-23 2001-03-27 Neurosearch A/S Disubstituted morpholine, oxazepine or thiazepine derivatives, their preparation and their use as dopamine D4 receptor antagonists
CN101838249A (zh) * 2010-03-19 2010-09-22 浙江华海药业股份有限公司 一种制备高纯度愈创木酚缩水甘油醚的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207662B1 (en) * 1996-08-23 2001-03-27 Neurosearch A/S Disubstituted morpholine, oxazepine or thiazepine derivatives, their preparation and their use as dopamine D4 receptor antagonists
CN101838249A (zh) * 2010-03-19 2010-09-22 浙江华海药业股份有限公司 一种制备高纯度愈创木酚缩水甘油醚的方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
QIN, MINGLI ET AL.: "Study on Synthesis Process of Ranolazine.", JOURNAL OF XIUYNUG NORMAL UNIVERSITY, vol. 20, no. 2, 30 April 2007 (2007-04-30), pages 226 - 229 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440131A (zh) * 2020-04-27 2020-07-24 江苏惠利生物科技有限公司 一种易分解的愈创木酚缩水甘油醚的精制方法

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