CN107474000A - The preparation method of Ezetimibe degradation impurity - Google Patents
The preparation method of Ezetimibe degradation impurity Download PDFInfo
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- 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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- 239000012535 impurity Substances 0.000 title claims abstract description 55
- 229960000815 ezetimibe Drugs 0.000 title claims abstract description 37
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 230000015556 catabolic process Effects 0.000 title claims abstract description 8
- 238000006731 degradation reaction Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 150000004715 keto acids Chemical class 0.000 claims abstract description 19
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000007254 oxidation reaction Methods 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000007800 oxidant agent Substances 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000012286 potassium permanganate Substances 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 238000012805 post-processing Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 239000013558 reference substance Substances 0.000 abstract description 2
- 238000010183 spectrum analysis Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 17
- 238000001514 detection method Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 230000000630 rising effect Effects 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- -1 Ezetimibe keto-acid Chemical class 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- 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
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.
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2017
- 2017-07-31 CN CN201710635648.XA patent/CN107474000A/en active Pending
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