CN107474000A - The preparation method of Ezetimibe degradation impurity - Google Patents

The preparation method of Ezetimibe degradation impurity Download PDF

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Publication number
CN107474000A
CN107474000A CN201710635648.XA CN201710635648A CN107474000A CN 107474000 A CN107474000 A CN 107474000A CN 201710635648 A CN201710635648 A CN 201710635648A CN 107474000 A CN107474000 A CN 107474000A
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China
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preparation
ezetimibe
impurity
solvent
keto
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CN201710635648.XA
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张庆华
陈波
徐汨
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HUNAN FANGSHENG PHARMACEUTICAL CO Ltd
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HUNAN FANGSHENG PHARMACEUTICAL CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/22—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from lactams, cyclic ketones or cyclic oximes, e.g. by reactions involving Beckmann rearrangement
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses Ezetimibe degradation impurity --- the preparation method of open loop impurity and keto-acid impurity.This method reacts Ezetimibe through alkali or oxidation reaction respectively obtains open loop impurity and keto-acid impurity.This method is simple to operate, reaction is gentle, yield is higher, product purity is high, effective less environmental pollution, suitable for Ezetimibe bulk drug and its miscellaneous mass spectral analysis of preparation, guarantee can be provided for the further product quality of control Ezetimibe and its preparation as the content that catabolite in Ezetimibe and its preparation is detected about material reference substance.

Description

The preparation method of Ezetimibe degradation impurity
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to Ezetimibe degradation impurity --- open loop impurity and keto-acid The preparation method of impurity.
Background technology
Ezetimibe is a kind of selective intestines cholesterol absorption inhibitor, public by Schering Plough (Schering-Plough) Department's (being purchased in 2009 by Mo Shadong with 41,100,000,000 dollars of price) and MSD Corp. of the U.S. are (in America ＆ Canada quilt Referred to as Merck) develop jointly.The medicine in German Initial Public Offering, then lists in November, 2002 in the U.S., and first The individual cholesterol absorption selective depressant class medicine being approved listing by U.S. FDA, 2006 in China's approval listing, commodity Entitled benefit is suitable pure, at present in the world in more than 90 country's listings.
The principal degradation impurity of Ezetimibe is open loop impurity, oxinane impurity and keto-acid impurity.
(1) open loop impurity
The synthesis of oxinane impurity existing more document and patent report, and there is presently no text for the synthesis of open loop impurity Offer and patent report, in order to preferably carry out quality research to Ezetimibe bulk drug and its preparation, it is ensured that product quality, this hair The bright open loop impurity to Ezetimibe has carried out chemical synthesis research, obtains a kind of preparation method of high-purity open loop impurity, is The quality for improving Ezetimibe bulk drug and its preparation provides guarantee.
(2) keto-acid impurity
Cheng Jinbo etc. exists《Chinese new drug impurity》What the 14th phase of volume 22 in 2013 delivered《The conjunction of 3 kinds of impurity of Ezetimibe Into》In provide a kind of synthetic method of Ezetimibe keto-acid impurity, specific synthetic route is as follows：
This method is raw material with compound 2, and by cyclization, deprotection, hydrogenating reduction, totally 3 steps react to obtain keto-acid impurity, Reactions steps are longer, and the operation of each step reaction is more complicated, the total recovery about 44% of three-step reaction；And the source of compound 2 is not easy, In the market is more difficult to be bought, and need to customize synthesis, and the synthesis of the compound at least needs 4 steps to react, and manufacturing cycle is longer.In addition, should The hydrogenating reduction of route final step, larger potential safety hazard be present.
The synthetic method of Ezetimibe keto-acid impurity provided by the invention, compared with existing technical method, reactions steps Short, simple to operate, (yield is higher than 70% to high income, nearlyer 30%) than the yield raising of document multi-step, and the present invention uses Oxidant be easily handled, particularly manganese dioxide can activation cycle utilize, can be cost-effective and can effectively less environmental pollution.
The content of the invention
It is an object of the invention to provide it is a kind of in high yield, the Ezetimibe degradation impurity of high-purity --- open loop impurity and The preparation method of keto-acid impurity.
(1) synthesis of open loop impurity
The reaction equation of open loop impurity synthesis：
Ezetimibe is dissolved in solvent, the aqueous slkali prepared in advance is added, 0-30 DEG C of temperature control, reacts 2-10 hours, The post-treated open loop impurity for obtaining high-purity, i.e. (2S, 5S) -5- (4- fluorophenyls) -2- [(S)-(4- fluoroanilinos)-(4- hydroxyls Base phenyl)-methyl] -5- hydroxy-pentanoic acids.
The molar ratio of the Ezetimibe and alkali is 1:1.0~3.0.
The pH controls of the aqueous slkali are 7.5-9.
The solvent is the one or more in methanol, ethanol, tetrahydrofuran, N,N-dimethylformamide.
The alkali is the one or more in sodium acid carbonate, sodium carbonate, potassium carbonate, ammoniacal liquor, diisopropylethylamine.(2) ketone The synthesis of formula impurity
The reaction equation of keto-acid impurity synthesis：
Ezetimibe is dissolved in solvent, adds oxidant, back flow reaction 2-10 hours, the post-treated high-purity that obtains Keto-acid impurity, i.e. 1- (4- fluorophenyls) -3 (R)-[3- (4- fluorophenyls) -3- oxopropyls] -4 (S)-(4- hydroxyphenyls) -2- azepines Cyclobutanone.
The solvent be ethyl acetate, dichloromethane, methanol, tetrahydrofuran, one kind in N,N-dimethylformamide or It is several.
The oxidant is the one or more in manganese dioxide, potassium permanganate, hydrogen peroxide.
The molar ratio of the Ezetimibe and oxidant is 1:1.0~5.0.
The post processing mode is crystallization, and recrystallisation solvent is isopropanol and water.
The preparation method of the present invention, simple to operate, reaction is gentle, and yield is higher, and product purity is high, and effectively less environment is dirty Dye, suitable for Ezetimibe bulk drug and its miscellaneous mass spectral analysis of preparation, can be used as relevant material reference substance detection Ezetimibe and The content of catabolite in its preparation, guarantee is provided for the further product quality of control Ezetimibe and its preparation, is had Good commercial value.
Brief description of the drawings
Fig. 1：The hydrogen spectrum (HNMR) of open loop impurity prepared by the embodiment of the present invention 1；
Fig. 2：The infared spectrum of open loop impurity prepared by the embodiment of the present invention 1；
Fig. 3：The hydrogen spectrum (HNMR) of keto-acid impurity prepared by the embodiment of the present invention 4.
Embodiment
In conjunction with embodiments of the invention and correlation test, the invention will be further described：
Embodiment 1 (preparation of open loop impurity)：
Ezetimibe (1g, 2.44mmol) is added in 50ml reaction bulbs, is added 10ml methanol stirring and dissolvings, is cooled to 0 ℃.Then adding aqueous sodium carbonate, (0.26g sodium carbonate is dissolved in 10ml water, about 8.5) pH, finishes 0~5 DEG C of reaction 6 of temperature control Hour.TLC detection raw material reactions finish (dichloromethane：Methanol=20:1, V/V), add about 10% hydrochloric acid and adjust pH6~7.Temperature control 40~50 DEG C of concentrations remove methanol, then add 20ml dichloromethane and are extracted twice, merge organic phase.40~50 DEG C of concentrations of temperature control Organic phase is removed, obtains pale yellow oil.Through column chromatography for separation (dichloromethane：Methanol=20:1, V/V) high-purity is obtained Open loop impurity 0.74g, yield 70.9%.It is 96.7% through HPLC detection product purities.
Product infrared spectrum (cm-1)：
3396,2922,1726,1604,1566,1509,1442,1405,1302,1223,1175,1156,1104, 1046,1013,882,835,774,576,512,419。
Product nucleus magnetic hydrogen spectrum data：
1H NMR(DMSO-d6,400MHz)
δ9.22(1H,s,COOH),7.21-7.25(2H,m,Ph),7.03-7.09(4H,m,Ph),6.58-6.60(2H, m,Ph),6.30-6.32(2H,m,Ph),6.28-6.29(2H,m,Ph),4.38(1H,s,OH),3.99-4.05(2H,m,CH, OH),2.23(1H,s,CH),1.99(1H,s,NH),1.27-1.53(4H,m,CH2),1.16-1.19(1H,m,CH)。
Embodiment 2 (preparation of open loop impurity)：
Ezetimibe (1g, 2.44mmol) is added in 50ml reaction bulbs, adds 10ml tetrahydrofuran stirring and dissolvings, cooling To 0 DEG C.Then adding sodium bicarbonate aqueous solution, (0.31g sodium acid carbonates are dissolved in 10ml water, about 8.0) pH, finishes temperature control 5~10 DEG C reaction 4 hours.TLC detection raw material reactions finish (dichloromethane：Methanol=20:1, V/V), add about 10% hydrochloric acid and adjust pH6 ~7.40~50 DEG C of concentrations of temperature control remove tetrahydrofuran, then add 20ml dichloromethane and are extracted twice, merge organic phase.Temperature control 40~50 DEG C of concentrations remove organic phase, obtain pale yellow oil.Through column chromatography for separation (dichloromethane：Methanol=20:1, V/V) Obtain the open loop impurity 0.75g of high-purity, yield 71.8%.It is 96.1% through HPLC detection product purities.
Embodiment 3 (preparation of open loop impurity)：
Ezetimibe (1g, 2.44mmol) is added in 50ml reaction bulbs, adds 10mlN, dinethylformamide stirring Dissolving, is cooled to 0 DEG C.Then adding wet chemical, (0.40g potassium carbonate is dissolved in 10ml water, about 9.0) pH, finishes temperature control 20~30 DEG C are reacted 3 hours.TLC detection raw material reactions finish (dichloromethane：Methanol=20:1, V/V) about 10% hydrochloric acid, is added Adjust pH6~7.Add 20ml dichloromethane to be extracted twice, merge organic phase.40~50 DEG C of concentrations of temperature control remove organic phase, obtain Pale yellow oil.Through column chromatography for separation (dichloromethane：Methanol=20:1, V/V) the open loop impurity 0.65g of high-purity is obtained, Yield 62.3%.It is 95.5% through HPLC detection product purities.
Embodiment 4 (preparation of keto-acid impurity)
Ezetimibe (1g, 2.44mmol) is added in 50ml reaction bulbs, is added 10ml methanol stirring and dissolvings, is then added Manganese dioxide (0.42g, 4.88mmol), stirring temperature rising reflux react 5 hours.TLC detection raw material reactions finish (petroleum ether：Second Acetoacetic ester=3:1, V/V), filter off except solid, 40~50 DEG C of filtrate temperature control are concentrated to dryness, obtain red brown solid.To solid Middle addition 5ml isopropanols and 5ml water, rising temperature for dissolving is stirred, then stirring is cooled to 0-5 DEG C of crystallization 1 hour.Filtering, filter cake are used 2ml water wash, is drained.Filter cake is collected, 60 DEG C are dried to obtain keto-acid impurity 0.78g, yield 78.8%.It is pure through HPLC detection products Spend for 99.3%.
Product nucleus magnetic hydrogen spectrum data：
1H NMR(CDCl3,400MHz)
δ7.97-8.00(2H,m,Ph),7.19-7.26(4H,m,Ph),7.10-7.14(2H,m,Ph),6.91-6.95 (2H,m,Ph),6.81-6.83(2H,m,Ph),5.26(1H,s,OH),4.67(1H,m,CH),3.49-3.50(1H,m,C) 3.130-3.18(2H,m,CH2),2.25-2.41(2H,m,CH2)。
Embodiment 5 (preparation of keto-acid impurity)
Ezetimibe (1g, 2.44mmol) is added in 50ml reaction bulbs, adds 10ml tetrahydrofuran stirring and dissolvings, then Manganese dioxide (0.42g, 4.88mmol) is added, stirring temperature rising reflux reacts 5 hours.TLC detection raw material reactions finish (oil Ether：Ethyl acetate=3:1, V/V), filter off except solid, 40~50 DEG C of filtrate temperature control are concentrated to dryness, obtain red brown solid.To 5ml isopropanols and 5ml water are added in solid, stirs rising temperature for dissolving, then stirring is cooled to 0-5 DEG C of crystallization 1 hour.Filtering, filter Cake 2ml water wash, is drained.Filter cake is collected, 60 DEG C are dried to obtain keto-acid impurity 0.81g, yield 81.8%.Detect and produce through HPLC Product purity is 99.1%.
Embodiment 6 (preparation of keto-acid impurity)
Ezetimibe (1g, 2.44mmol) is added in 50ml reaction bulbs, adds 10ml tetrahydrofuran stirring and dissolvings, then Potassium permanganate (0.58g, 3.66mmol) is added, stirring temperature rising reflux reacts 5 hours.TLC detection raw material reactions finish (oil Ether：Ethyl acetate=3:1, V/V), filter off except solid, 40~50 DEG C of filtrate temperature control are concentrated to dryness, obtain red brown solid.To 5ml isopropanols and 5ml water are added in solid, stirs rising temperature for dissolving, then stirring is cooled to 0-5 DEG C of crystallization 1 hour.Filtering, filter Cake 2ml water wash, is drained.Filter cake is collected, 60 DEG C are dried to obtain keto-acid impurity 0.75g, yield 75.7%.Detect and produce through HPLC Product purity is 99.5%.
Embodiment 7 (preparation of keto-acid impurity)
Ezetimibe (1g, 2.44mmol) is added in 50ml reaction bulbs, adds 10mlN, dinethylformamide stirring Dissolving, then adds hydrogen peroxide (0.33g, 9.76mmol), and stirring temperature rising reflux reacts 5 hours.TLC detection raw material reactions finish (petroleum ether：Ethyl acetate=3:1, V/V), add 20 ethyl acetate mutually to extract with 20ml moisture, organic phase is eaten with 20ml saturations Salt solution be washed once, and then organic phase is concentrated to dryness by 40~50 DEG C of temperature control, obtains red brown solid.5ml is added into solid Isopropanol and 5ml water, rising temperature for dissolving is stirred, then stirring is cooled to 0-5 DEG C of crystallization 1 hour.Filtering, filter cake 2ml water wash, Drain.Filter cake is collected, 60 DEG C are dried to obtain keto-acid impurity 0.69g, yield 69.7%.It is through HPLC detections product purity 99.1%.

Claims (10)

1. a kind of preparation method of Ezetimibe degradation impurity, it is characterised in that Ezetimibe is dissolved in solvent, added advance The aqueous slkali prepared, 0-30 DEG C of temperature control, react 2-10 hours, the post-treated open loop impurity for obtaining high-purity, it synthesizes anti- Answer formula as follows：
2. preparation method according to claim 1, it is characterised in that the molar ratio of the Ezetimibe and alkali is 1: 1.0~3.0.
3. preparation method according to claim 1, it is characterised in that the pH controls of the aqueous slkali are 7.5-9.
4. preparation method according to claim 1, it is characterised in that the solvent is methanol, ethanol, tetrahydrofuran, N, One or more in dinethylformamide.
5. preparation method according to claim 1, it is characterised in that the alkali be sodium acid carbonate, sodium carbonate, potassium carbonate, One or more in ammoniacal liquor, diisopropylethylamine.
6. a kind of preparation method of Ezetimibe degradation impurity, it is characterised in that Ezetimibe is dissolved in solvent, adds oxidation Agent, back flow reaction 2-10 hours, the post-treated keto-acid impurity for obtaining high-purity, its synthetic reaction formula are as follows：
7. preparation method according to claim 6, it is characterised in that the solvent is ethyl acetate, dichloromethane, first One or more in alcohol, tetrahydrofuran, N,N-dimethylformamide.
8. preparation method according to claim 6, it is characterised in that the oxidant is manganese dioxide, potassium permanganate, double One or more in oxygen water.
9. preparation method according to claim 6, it is characterised in that the molar ratio of the Ezetimibe and oxidant is 1:1.0~5.0.
10. preparation method according to claim 6, it is characterised in that the post processing mode is crystallization, and recrystallisation solvent is Isopropanol and water.
CN201710635648.XA 2017-07-31 2017-07-31 The preparation method of Ezetimibe degradation impurity Pending CN107474000A (en)

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Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
AMIT BASAK，ET AL.: "L-Proline-Mediated One-Pot Synthesis of 3-Etxomethylene β-Lactams via Kinugasa Reaction", 《SYNLETT》 *
ANURADHA K. GAJJAR，ET AL.: "Isolation and structure elucidation of major alkaline degradant of Ezetimibe", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 *
JANA BAŤOVÁ;，ET AL.: "Kinetics and Mechanism of the Base-Catalyzed Rearrangement and Hydrolysis of Ezetimibe", 《JOURNAL OF PHARMACEUTICAL SCIENCES》 *
SEEMA KANWAR，ET AL.: "Use of 2,2’-Dibenzothiazolyl Disulfide-Triphenylphosphine and Lawesson’s Reagent in the Cyclization of β-Amino Acids", 《BULL. CHEM. SOC. JPN.》 *
STUART B. ROSENBLUM，ET AL.: "Discovery of 1-(4-Fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235):A Designed, Potent, Orally Active Inhibitor of Cholesterol Absorption", 《J. MED. CHEM.》 *
岳磊等: "胆固醇吸收抑制剂依折麦布中2 种杂质的合成", 《中国现代应用药学》 *
程进波等: "依折麦布3种杂质的合成", 《中国新药杂志》 *

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