CN104610051A - Method for preparing clinofibrate impurities - Google Patents

Method for preparing clinofibrate impurities Download PDF

Info

Publication number
CN104610051A
CN104610051A CN201510092263.4A CN201510092263A CN104610051A CN 104610051 A CN104610051 A CN 104610051A CN 201510092263 A CN201510092263 A CN 201510092263A CN 104610051 A CN104610051 A CN 104610051A
Authority
CN
China
Prior art keywords
compound
preparing
concentrated
hours
add
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.)
Pending
Application number
CN201510092263.4A
Other languages
Chinese (zh)
Inventor
李恩民
闫起强
马苏峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Original Assignee
Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Beijing Wanquan Dezhong Medical Biological Technology Co Ltd filed Critical Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
Priority to CN201510092263.4A priority Critical patent/CN104610051A/en
Publication of CN104610051A publication Critical patent/CN104610051A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/20—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms using aldehydes or ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a method for preparing clinofibrate impurities. The method comprises the following steps: synthesizing 2-(4-(1-(4-hydroxyphenyl)cyclohexyl)phenoxy)-2-methyl ethyl butyrate through bi-p-hydroxyphenyl cyclohexane prepared by reacting cyclohexanone and phenol and 2-bromo-2-methyl ethyl butyrate prepared from 2-methyl butyrate; and hydrolyzing, thereby obtaining 2-(4-(1-(4-hydroxyphenyl)cyclohexyl)phenoxy)-2-methylbutyric acid.

Description

A kind of method preparing S-8527 impurity
Technical field
The invention belongs to medicinal chemistry art, relate to S-8527 impurity 2-(4-(1-(4-hydroxy phenyl) cyclohexyl) phenoxy group) preparation of-2-methylbutyric.
Background technology
S-8527 is a kind of novel fibrates lipopenicillinase new drug of SUMITOMO CHEMICAL company research and development, within 1981, in Japan's listing, within 1985, in Korean market, records in Pharmacopeia of Japan 14 editions, clinically cures mainly various types of hyperlipidaemia.Its effect for reducing fat is more safe and effective, and has anti thrombotic action.2003-2004 Japan is these product of You Duo company list marketing again.The market requirement and the prediction S-8527 of this product are third generation benzene oxygen aromatic acid derivatives class lipid lowering agents, are also to use maximum medicines in the special class of current shellfish.
Relevant S-8527 impurity document is little at present, this brings very large difficulty to the quality approach of this medicine, we have found two process contaminants when studying the synthesis technique of S-8527, and by separation and concentration, we determine the structure (being respectively structure V and VI) of impurity.We illustrate the synthetic method of these two impurity in this patent.
Summary of the invention
The invention provides a kind of S-8527 impurity 2-(4-(1-(4-hydroxy phenyl) cyclohexyl) phenoxy group) preparation method of-2-Methyl Butyric Acid, comprise the following steps:
By structure icompound pimelinketone dissolve in concentrated hydrochloric acid after add phenol, temperature controls at 30-50 DEG C, reacts and adds sherwood oil return stirring after 7 hours, suction filtration while hot, obtains the compound of structure II after washing filter cake.
Dissolved in bromine by the compound 2-Methyl Butyric Acid of structure III, add phosphorus trichloride, control temperature, 70-90 DEG C of reaction one hour, is cooled to room temperature, slowly drips dehydrated alcohol, dropwise post-heating and reflux 2 hours.After petroleum ether extraction, the dry concentrated compound obtaining structure IV.
Compound heated and stirred in water of the compound of structure II and structure IV is dissolved, adds K 2cO 3,stirring and refluxing is suction filtration after 5 hours, sherwood oil filter wash cake, and filtrate adds petroleum ether separatory again, and concentrated underpressure distillation obtains the compound of structure V.
By the compound dissolve with methanol of structure V, add NaOH aqueous solution reflux 2 hours, concentrated removing methyl alcohol, add frozen water and methylene dichloride, regulate pH to be 3-4 with concentrated hydrochloric acid, separatory collects organic phase, within 30 minutes, obtains the compound of structure VI after concentrated by petroleum ether and stirring.
The advantage of the inventive method is: simple to operate, and reaction conditions is gentle, and product easily obtains.
Embodiment
Further illustrate the present invention by the following examples, but not as limitation of the present invention
embodiment 1:
23.6g pimelinketone and 45.4g phenol add in 45mL concentrated hydrochloric acid, and control temperature, at 40 DEG C, reacts 7 hours, adds 200mL sherwood oil return stirring, suction filtration while hot, and washing filter cake, to neutral, concentrates the two para hydroxybenzene butylcyclohexane 5.51g obtained, yield 85.1%.
By 14.7g 2-Methyl Butyric Acid and 19g phosphorus trichloride, stirring and dissolving, slowly drip 46g bromine, control temperature, at 80 DEG C, refluxes and is cooled to room temperature after 1 hour, slowly drips 34.7g ethanol, adds rear backflow 2 hours.Be cooled to room temperature.Add 200mL sherwood oil and 1%Na 2sO 3aqueous solution 200mL separatory, collect organic phase, underpressure distillation obtains the bromo-ethyl 2-methylbutyrate 25.9g of colourless transparent liquid 2-, yield 85.6%.
Two para hydroxybenzene butylcyclohexane 2.6g and the 2-bromo-ethyl 2-methylbutyrate 2.1g 50mL deionized water and stirring of reaction preparation is dissolved, adds 4.3g K 2cO 3,stirring and refluxing 5 hours, suction filtration after completion of the reaction, adds 100mL deionized water and 100mL sherwood oil in system, and separatory collects organic phase, obtains 2.2g2-(4-(1-(4-hydroxy phenyl) cyclohexyl) phenoxy group)-ethyl 2-methylbutyrate, yield 65.3%.
The 2-(4-(1-(4-hydroxy phenyl obtained by reaction) cyclohexyl) phenoxy group)-ethyl 2-methylbutyrate 2.2g 30mL methyl alcohol and 5mL deionized water dissolving, add 2.7g NaOH again, reflux 2 hours, concentrated removing methyl alcohol after completion of the reaction, use dichloromethane extraction again, add 8mL toluene and 10mL petroleum ether and stirring precipitation solid after organic phase drying, obtain 2-(4-(1-(4-hydroxy phenyl) cyclohexyl) phenoxy group)-2-methylbutyric 1.8g, yield 90.8%
embodiment 2:
23.6g pimelinketone and 45.4g phenol add in 22.5mL Glacial acetic acid, and control temperature, at 40 DEG C, reacts 7 hours, adds 200mL sherwood oil return stirring, suction filtration while hot, and washing filter cake, to neutral, concentrates the two para hydroxybenzene butylcyclohexane 5.39g obtained, yield 83.2%.
By 14.7g 2-Methyl Butyric Acid and 19g phosphorus trichloride, stirring and dissolving, slowly drip 46g bromine, control temperature, at 80 DEG C, refluxes and is cooled to room temperature after 1 hour, slowly drips 34.7g ethanol, adds rear backflow 2 hours.Be cooled to room temperature.Add 150mL normal hexane and 1%Na 2sO 3aqueous solution 200mL separatory, collect organic phase, underpressure distillation obtains the bromo-ethyl 2-methylbutyrate 24.3g of colourless transparent liquid 2-, yield 80.5%.
Two para hydroxybenzene butylcyclohexane 2.6g and the 2-bromo-ethyl 2-methylbutyrate 2.1g 50mL deionized water and stirring of reaction preparation is dissolved, adds 4.0g Na 2cO 3,stirring and refluxing 5 hours, suction filtration after completion of the reaction, adds 100mL deionized water and 100mL sherwood oil in system, and separatory collects organic phase, obtains 2.1g2-(4-(1-(4-hydroxy phenyl) cyclohexyl) phenoxy group)-ethyl 2-methylbutyrate, yield 64.8%.
The 2-(4-(1-(4-hydroxy phenyl obtained by reaction) cyclohexyl) phenoxy group)-ethyl 2-methylbutyrate 1.1g 30mL ethanol and 5mL deionized water dissolving, add 2.7g NaOH again, reflux 2 hours, concentrated removing methyl alcohol after completion of the reaction, use dichloromethane extraction again, add 8mL toluene and 10mL petroleum ether and stirring precipitation solid after organic phase drying, obtain 2-(4-(1-(4-hydroxy phenyl) cyclohexyl) phenoxy group)-2-methylbutyric 0.9g yield 88.6%.

Claims (4)

1. a preparation method for S-8527 impurity, is characterized in that, comprises the following steps:
(1) by structure icompound pimelinketone dissolve in concentrated hydrochloric acid after add phenol, temperature controls at 30-50 DEG C, reacts and adds sherwood oil return stirring after 7 hours, suction filtration while hot, obtains the compound of structure II after washing filter cake;
(2) the compound 2-Methyl Butyric Acid of structure III is dissolved in bromine, add phosphorus trichloride, control temperature was 70-90 DEG C of reaction one hour, be cooled to room temperature, slow dropping dehydrated alcohol, dropwise post-heating to reflux 2 hours, after petroleum ether extraction body, the dry concentrated compound obtaining structure IV;
(3) compound heated and stirred in water of the compound of structure II and structure IV is dissolved, add K 2cO 3,stirring and refluxing is suction filtration after 5 hours, sherwood oil filter wash cake, and filtrate adds petroleum ether separatory again, and concentrated underpressure distillation obtains the compound of structure V;
(4) by the compound dissolve with methanol of structure V, NaOH aqueous solution reflux is added 2 hours, concentrated removing methyl alcohol, add frozen water and methylene dichloride, regulate pH to be 3-4 with concentrated hydrochloric acid, separatory collects organic phase, within 30 minutes, obtains the compound of structure VI after concentrated by petroleum ether and stirring
。
2. method according to claim 1, is characterized in that:
(1) solvent preparing the compound of structure II used is concentrated hydrochloric acid and Glacial acetic acid;
(2) solvent preparing the compound of structure IV used is sherwood oil and normal hexane;
(3) reagent preparing the compound of structure V used is sodium carbonate and salt of wormwood;
(4) solvent preparing the compound of structure VI used is methyl alcohol and ethanol.
3. method according to claim 1, is characterized in that:
(1) temperature of reaction preparing the compound of structure II is 30-50 DEG C;
(2) temperature of reaction preparing the compound of structure III is 70-90 DEG C.
4. method according to claim 2, is characterized in that:
(1) solvent preparing the compound of structure II used is concentrated hydrochloric acid;
(2) solvent preparing the compound of structure IV used is sherwood oil;
(3) reagent preparing the compound of structure V used is salt of wormwood;
(4) solvent preparing the compound of structure VI used is methyl alcohol.
CN201510092263.4A 2015-03-02 2015-03-02 Method for preparing clinofibrate impurities Pending CN104610051A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510092263.4A CN104610051A (en) 2015-03-02 2015-03-02 Method for preparing clinofibrate impurities

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510092263.4A CN104610051A (en) 2015-03-02 2015-03-02 Method for preparing clinofibrate impurities

Publications (1)

Publication Number Publication Date
CN104610051A true CN104610051A (en) 2015-05-13

Family

ID=53144742

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510092263.4A Pending CN104610051A (en) 2015-03-02 2015-03-02 Method for preparing clinofibrate impurities

Country Status (1)

Country Link
CN (1) CN104610051A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105842361A (en) * 2016-03-29 2016-08-10 北京万全德众医药生物技术有限公司 Method for separating and determining clinofibrate-related substance through gas chromatographic method

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3716583A (en) * 1969-04-16 1973-02-13 Sumitomo Chemical Co Phenoxy carboxylic acid derivative
JPS5010308B1 (en) * 1969-10-03 1975-04-19
CN102816060A (en) * 2012-09-14 2012-12-12 瑞阳制药有限公司 Preparation method of high-purity clinofibrate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3716583A (en) * 1969-04-16 1973-02-13 Sumitomo Chemical Co Phenoxy carboxylic acid derivative
JPS5010308B1 (en) * 1969-10-03 1975-04-19
CN102816060A (en) * 2012-09-14 2012-12-12 瑞阳制药有限公司 Preparation method of high-purity clinofibrate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
陈年根 等: "克利贝特的合成", 《中国医药工业杂志》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105842361A (en) * 2016-03-29 2016-08-10 北京万全德众医药生物技术有限公司 Method for separating and determining clinofibrate-related substance through gas chromatographic method

Similar Documents

Publication Publication Date Title
CN102617450B (en) Polymer material stabilizer and preparation method thereof
WO2019214467A1 (en) Resolution method for axis chiral enantiomers of lesinurad
CN102146039B (en) Process for synthesizing gefarnate compound
CN104610051A (en) Method for preparing clinofibrate impurities
CN102181496A (en) Enzymatic synthesis method for fenpyroxim
CN101928214B (en) Method for synthesizing dexketoprofen trometamol
CN102010327B (en) Splitting method of (+/-)-2-(3-benzoyl)-phenylpropionic acid
CN103214421B (en) The industrialized preparing process of 2-sulfydryl-1-Methylimidazole
CN102796018B (en) Method for preparing D-valine by asymmetric transformation process
CN104829422A (en) Method for splitting D,L-menthol
CN100448866C (en) Compound 2-methylol-3-substituted phenyl propionic acid with optical activity and its resolving process
CN102070469B (en) Resolution method for preparing optically pure metoprolol
CN103772189B (en) Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A
CN101875603B (en) Preparation method for synthesizing intermediate mutilin from pleuromutilin antibiotics
CN104761599A (en) Preparation method of 5,4'-dihydroxy flavone-7-O-D-glucuronic acid
CN104803978A (en) Preparation method of esomeprazole magnesium
CN105198838A (en) Preparation method of repaglinide
CN114213260A (en) Preparation method of propranodiamide
CN102702138B (en) Repaglinide compound and novel production method thereof
CN101293841B (en) Process for synthesizing (1R,2R)-(-)-2-benzene methoxy cyclohexylamine
CN102898289B (en) Method for synthesizing 2-(4-benzylmethoxyphenyl)ethanol medical intermediate
CN103965038A (en) Refining method for high-purity clofibric acid blood-lipid regulating drug--fenofibric acid
CN103131747A (en) Method for synthesizing (S)-3-(4-hydroxyl phenyl)-3-methylamino propionic acid by using biological enzymes through chiral resolution
CN103833546B (en) The method of asymmetric synthesis of optical purity danshensu and its derivatives
CN103570618A (en) Preparation method of montelukast sodium

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20150513