CN105237492A - Synthetic method for ezetimibe intermediate - Google Patents

Synthetic method for ezetimibe intermediate Download PDF

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Publication number
CN105237492A
CN105237492A CN201510725473.2A CN201510725473A CN105237492A CN 105237492 A CN105237492 A CN 105237492A CN 201510725473 A CN201510725473 A CN 201510725473A CN 105237492 A CN105237492 A CN 105237492A
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CN
China
Prior art keywords
synthetic
phenyl
reaction
recrystallization
ezetimibe
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CN201510725473.2A
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Chinese (zh)
Inventor
王庆林
王涛
王彬彬
米靖宇
徐建国
张莹
虞佳媛
成梁
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无锡福祈制药有限公司
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Priority to CN201510725473.2A priority Critical patent/CN105237492A/en
Publication of CN105237492A publication Critical patent/CN105237492A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • C07D263/22Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms

Abstract

The invention discloses a synthetic method for an ezetimibe intermediate. The synthetic method comprises: by taking a compound I as a raw material, mixing the compound I with a reaction solution; under the action of an acid-binding agent, firstly activating the compound I by pivaloyl chloride; then coupling the compound with S-4-phenyl-2-oxazolidinone; then carrying out reduction reaction through (R)-2-mehtyl-CBS-oxazole borane; and then carrying out post-treatment to prepare (4S)-3-[(5S)-5-(4-fluorophenyl-5-hydroxyl valeryl)-4-phenyl-1,3- azacyclocyclopentane-2-(one) (II), wherein the formula is as shown in the description, and the reaction solution comprises tetrahydrofuran, chloroform, dioxane or dichloromethane. The synthetic method for the ezetimibe intermediate disclosed by the invention has the advantages of being simple to operate, short in synthetic line and relatively low in synthetic cost, and is suitable for large-scaled industrial production.

Description

A kind of synthetic method of Ezetimibe intermediate
Technical field
The present invention relates to field of pharmaceutical chemistry technology; be specifically related to the synthetic method of a kind of Ezetimibe intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1,3-oxazolidine-2-ketone (II).
Background technology
Ezetimibe is the first cholesterol absorption inhibitor being ratified listing by U.S. FDA, is jointly researched and developed by Schering Plough company and Merck & Co., Inc. to form, and takes the lead in ratifying listing in 2002 in the U.S..Medicament categories in the market for reducing blood-fat is various, Ezetimibe as the novel cholesterol absorption inhibitor of one, not only Be very effective, and side effect is less, also can with statins drug combination, respond well, market is huge.
(4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1; 3-oxazolidine-2-ketone (II) is the key intermediate in synthesis Ezetimibe route; existing synthetic route is two step synthesis, and reaction formula is as follows:
Visible; in prior art; key intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl the base]-4-phenyl-1 of synthesis Ezetimibe; 3-oxazolidine-2-ketone (II) needs two synthesis steps could prepare corresponding intermediate usually; there is synthetic route longer, the defect that synthesis cost is higher.
In view of this, be necessary to be improved the synthetic method of Ezetimibe intermediate of the prior art, to solve the problem.
Summary of the invention
The object of the invention is to open a kind of Ezetimibe intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1; the synthetic method of 3-oxazolidine-2-ketone (II); in order to shorten the synthetic route of the key intermediate of Ezetimibe; reduce synthesis cost, and be easy to suitability for industrialized production.
For achieving the above object, the invention provides a kind of Ezetimibe intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1, the synthetic method of 3-oxazolidine-2-ketone (II), this synthetic method take Compound I as raw material, Compound I is mixed with reaction soln, and under Fu's acid agent effect, first chemical compounds I is activated by pivaloyl chloride, then with the coupling of S-4-phenyl-2-oxazolidone, again through (R)-2-methyl-CBS-oxazaborolidine reduction reaction, obtained (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1 after aftertreatment again, 3-oxazolidine-2-ketone (II),
Wherein, reaction soln comprises tetrahydrofuran (THF), chloroform, dioxane or methylene dichloride.
In certain embodiments, Fu's acid agent comprises triethylamine, pyridine, sodium methylate or potassium hydroxide.
In certain embodiments, Fu's acid agent is triethylamine.
In certain embodiments, aftertreatment comprises cancellation reaction, acidification reaction, separatory process, concentration and recrystallization process.
In certain embodiments, the quenching medium in quench treatment is methyl alcohol.
In certain embodiments, the acidizing reagent in acidification reaction is sulfuric acid, hydrochloric acid or acetic acid.
In certain embodiments, the recrystallization solvent in recrystallization process is the mixture of organic solvent or organic solvent and deionized water.
In certain embodiments, the recrystallization solvent in recrystallization process is Virahol.
Compared with prior art, the invention has the beneficial effects as follows: the synthetic method of disclosed a kind of Ezetimibe intermediate has simple to operate, and synthetic route is short, synthesizes lower-cost advantage, be applicable to large-scale industrial production.
Embodiment
Below in conjunction with each embodiment, the present invention is described in detail; but should be noted that; these embodiments are not limitation of the present invention; those of ordinary skill in the art are according to these embodiment institute work energy, method or structural equivalent transformations or substitute, and all belong within protection scope of the present invention.
Unless had specified otherwise in specification sheets, the component in each embodiment in the present invention, raw material all adopt analytical pure rank.In addition, " g " in each embodiment is weight unit " gram "; " h " is time unit " hour "; " ml " is volume unit " milliliter "; " room temperature " is 23 DEG C; " HPLC " is " high performance liquid chromatography detection "." concentration " is mass percent.
The present invention adopts " one kettle way " to synthesize Ezetimibe intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1; 3-oxazolidine-2-ketone (II), has the advantage that synthetic route is short.One kettle way (one-potreaction) is a kind of methodology of organic synthesis efficiently.Polystep reaction in " one kettle way " reaction from raw material relatively simple and easy to get, without the separation of intermediate, directly can obtain baroque molecule, thus has the advantage of synthesis cost, and environmentally friendly.
First 42g compound (I) is dissolved in 420ml reaction soln.Reaction soln comprises: tetrahydrofuran (THF), chloroform, dioxane or methylene dichloride, and most preferably is methylene dichloride.In the present embodiment, this reaction soln is methylene dichloride, after join 1L three-necked bottle, three-necked bottle is placed in magnetic stirring apparatus and carries out mechanical stirring to mixing.The chemical structural formula of compound (I) is as follows:
Be positioned over by three-necked bottle in ice bath, ice bath temperature remains on 0 DEG C until the interior temperature in three-necked bottle is not higher than 10 DEG C.Successively drip Fu's acid agent 30ml and pivaloyl chloride 75ml.In the present embodiment, this Fu's acid agent is specially triethylamine.Keep the interior temperature of three-necked bottle not higher than 15 DEG C in dropping process.The acid that Fu's acid agent can produce in absorption reaction, weakly alkaline material and sour salify, avoid acid impact to react or molecular balance.Fu's acid agent comprises triethylamine, pyridine, sodium methylate or potassium hydroxide, and most preferably is triethylamine.Pivaloyl chloride is a kind of acylating reagent, and pivaloyl chloride the atom such as oxygen, nitrogen, carbon, sulphur in organic molecule can introduce acyl group in organic synthesis.
Room temperature reaction is risen to 4 hours after triethylamine and pivaloyl chloride dropwise.Add ice bath again to interior temperature not higher than 10 DEG C, drip the mixing solutions of S-4-phenyl-2-oxazolidone 20g and DMF 200ml, keep the interior temperature of three-necked bottle not higher than 20 DEG C, dropwise and be warming up to reflux temperature and react 2 hours.S-4-phenyl-2-oxazolidone is a kind of important medicine intermediate, is mainly used in asymmetric chirality organic synthesis.
Cryosel is bathed to interior temperature not higher than 0 DEG C, successively drip borane dimethylsulf iotade 15ml and (R)-2-methyl-CBS-oxazaborolidine 7.5ml, interior temperature in maintenance three-necked bottle is not higher than 5 DEG C, stirring at room temperature is warming up to 30 minutes after dropwising, add 150ml methylene dichloride, add rear continuation room temperature reaction 3 hours.Borane dimethylsulf iotade has the effect of synthesis of chiral location.
Drip the methyl alcohol cancellation reaction of 300ml, then in system, add 100ml5% hydrogen peroxide and 20ml2N sulfuric acid, stir 30 minutes, separate organic layer.Respectively wash once with 200ml2N sulfuric acid and 500ml5% sodium sulfite solution, organic layer is evaporated to dry.Wherein, F is fluorine, and Ph is phenyl.
Use 200ml Virahol dissolved residue again, drip 40ml deionized water.Separate out solid gradually in dropping process, dropwise stirring at room temperature 2-3h, suction filtration, filtration cakes torrefaction obtains 45g white solid.
Detection method: high performance liquid chromatography (Chinese Pharmacopoeia version in 2015 two annex V D).
Octadecylsilane key and silica gel are weighting agent, take acetonitrile as moving phase, and column temperature is 40 DEG C, and determined wavelength is 245nm, and flow velocity is 0.5ml/min.Take isomer and product respectively appropriate, dissolve by moving phase and be diluted to containing this product 0.01mg/ml, diastereomer 0.01mg/ml, the solution of isomer 0.01mg/ml, as system suitability solution.Precision measures system suitability solution 20ul, injection liquid chromatography, and record color atlas, diastereomer, this product, isomer go out peak successively, diastereomer appearance time is about 20min, main peak appearance time is about 15min, and isomer goes out peak and is about 25min, and the resolution of main peak and isomer should be greater than 2.0.
Take this product dissolve by moving phase in right amount and the solution be diluted to containing this product 1.0mg/ml as need testing solution.Precision measures need testing solution 20ul, injection liquid chromatography, by area normalization method calculate, as in the color atlas of trial-product if any corresponding isomer chromatographic peak, then its peak area should not be greater than 0.1% of main peak and isomer peak area summation.
Chromatographic condition and system suitability: be weighting agent with octadecylsilane key and silica gel, with methyl alcohol: water=45:55 is moving phase, column temperature is 30 DEG C, determined wavelength 245nm, flow velocity 1.0ml/min.Main peak theoretical plate number is not less than 2000.
In the present embodiment; this Ezetimibe intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1; the purity of 3-oxazolidine-2-ketone (II) is 98.5%; optical purity ee%=99.0% (CHCl3, C=0.5).
A series of detailed description listed is above only illustrating for feasibility embodiment of the present invention; they are also not used to limit the scope of the invention, all do not depart from the skill of the present invention equivalent implementations done of spirit or change all should be included within protection scope of the present invention.To those skilled in the art, obviously the invention is not restricted to the details of above-mentioned one exemplary embodiment, and when not deviating from spirit of the present invention or essential characteristic, the present invention can be realized in other specific forms.Therefore, no matter from which point, all should embodiment be regarded as exemplary, and be nonrestrictive, scope of the present invention is limited by claims instead of above-mentioned explanation, and all changes be therefore intended in the implication of the equivalency by dropping on claim and scope are included in the present invention.

Claims (8)

1. Ezetimibe intermediate (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1, the synthetic method of 3-oxazolidine-2-ketone (II), it is characterized in that, this synthetic method take Compound I as raw material, Compound I is mixed with reaction soln, and under Fu's acid agent effect, first chemical compounds I is activated by pivaloyl chloride, then with the coupling of S-4-phenyl-2-oxazolidone, again through (R)-2-methyl-CBS-oxazaborolidine reduction reaction, obtained (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl base]-4-phenyl-1 after aftertreatment again, 3-oxazolidine-2-ketone (II),
Wherein, reaction soln comprises tetrahydrofuran (THF), chloroform, dioxane or methylene dichloride.
2. synthetic method according to claim 1, is characterized in that, described Fu's acid agent comprises triethylamine, pyridine, sodium methylate or potassium hydroxide.
3. synthetic method according to claim 1, is characterized in that, described Fu's acid agent is triethylamine.
4. synthetic method according to claim 1, is characterized in that, described aftertreatment comprises cancellation reaction, acidification reaction, separatory process, concentration and recrystallization process.
5. synthetic method according to claim 4, is characterized in that, the quenching medium in described quench treatment is methyl alcohol.
6. synthetic method according to claim 4, is characterized in that, the acidizing reagent in described acidification reaction is sulfuric acid, hydrochloric acid or acetic acid.
7. synthetic method according to claim 4, is characterized in that, the recrystallization solvent in described recrystallization process is the mixture of organic solvent or organic solvent and deionized water.
8. synthetic method according to claim 7, is characterized in that, the recrystallization solvent in described recrystallization process is Virahol.
CN201510725473.2A 2015-10-29 2015-10-29 Synthetic method for ezetimibe intermediate CN105237492A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105754983A (en) * 2016-05-19 2016-07-13 河北周酶生物科技有限公司 Immobilized enzyme for preparing Ezetimibe midbody and preparation method of immobilized enzyme

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CN1329592A (en) * 1998-12-07 2002-01-02 先灵公司 Process for synthesis of beta-propanamide
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CN103965089A (en) * 2014-04-18 2014-08-06 上海方楠生物科技有限公司 Stereselective synthesis method for lipid-lowering drug ezetimibe
CN104513187A (en) * 2015-01-09 2015-04-15 安润医药科技(苏州)有限公司 Ezetimibe synthesis method and Ezetimibe intermediate synthesis method

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US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones
CN1329592A (en) * 1998-12-07 2002-01-02 先灵公司 Process for synthesis of beta-propanamide
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105754983A (en) * 2016-05-19 2016-07-13 河北周酶生物科技有限公司 Immobilized enzyme for preparing Ezetimibe midbody and preparation method of immobilized enzyme
CN105754983B (en) * 2016-05-19 2018-11-23 河北周酶生物科技有限公司 A kind of immobilised enzymes and preparation method thereof being used to prepare Ezetimibe intermediate

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