CN104513187A - Ezetimibe synthesis method and Ezetimibe intermediate synthesis method - Google Patents
Ezetimibe synthesis method and Ezetimibe intermediate synthesis method Download PDFInfo
- Publication number
- CN104513187A CN104513187A CN201510011797.XA CN201510011797A CN104513187A CN 104513187 A CN104513187 A CN 104513187A CN 201510011797 A CN201510011797 A CN 201510011797A CN 104513187 A CN104513187 A CN 104513187A
- Authority
- CN
- China
- Prior art keywords
- compound
- ezetimibe
- organic solvent
- reaction
- 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.)
- Granted
Links
- 0 *Oc1ccc(C=Nc(cc2)ccc2F)cc1 Chemical compound *Oc1ccc(C=Nc(cc2)ccc2F)cc1 0.000 description 1
- XHAXVDWUMCHTCY-UHFFFAOYSA-N CC(OCC(Cl)(Cl)Cl)=O Chemical compound CC(OCC(Cl)(Cl)Cl)=O XHAXVDWUMCHTCY-UHFFFAOYSA-N 0.000 description 1
- VNNJGDYPPLXJFF-OQLLNIDSSA-N Oc1ccc(/C=N/c(cc2)ccc2F)cc1 Chemical compound Oc1ccc(/C=N/c(cc2)ccc2F)cc1 VNNJGDYPPLXJFF-OQLLNIDSSA-N 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Abstract
The invention provides an Ezetimibe synthesis method comprising the following steps: (a) a compound (5) is subjected to asymmetric reduction reaction to obtain a compound (6), and the compound (6) and tert-butyldimethylsilyl chloride react in an organic solution under the action of alkali to obtain a compound (7); (b) the compound (7) and diisopropylethylamine are dissolved in the organic solution, titanium tetrachloride is added in the organic solution to react at 20-50 DEG C, and a compound (3) is added in the organic solution at minus 20 to minus 60 DEG C to react to obtain a compound (8); (c) the compound (8) and N,O-bis(trimethylsilyl) acetamide react in the organic solution at 20-80 DEG C, tetrabutylammonium fluoride trihydrate is added into the organic solution to react at 20-80 DEG C to obtain a compound (9); (d) the compound (9) is subjected to off-protection reaction to obtain Ezetimibe, wherein R is equal to TBS, Ac or COOCH2CCl3. The invention further provides an Ezetimibe intermediate and a preparation method thereof.
Description
Technical field
The present invention relates to small-molecule chemical pharmaceutical formulating art, relate more specifically to a kind of synthetic method of Ezetimibe.
Background technology
Ezetimibe (Ezetimibe) another name is according to ezetimibe, Zetia, the first selectivity cholesterol absorption inhibitor developed by Schering Plough (Schering-Plough) company and Merck (Merck) company joint research and development, this product is first cholesterol absorption selective depressant class medicine be approved listing by U.S. FDA.In November, 2002, the same period went on the market in the U.S. first in Germany's listing.
Ezetimibe is the selective depressant that first intestinal cholesterol absorbs, its mechanism of action is different from other fat-reducing medicament (as: Statins, cholic acid chelating agent, fibric acid spread out ox thing and vegetalitas sterol ester compound), separately or can be united and applied in HMG-CoA reductase inhibitor (Statins) and treat primary (heterozygote familial or non-familial) hypercholesterolemia, homozygote familial hypercholesterolemia (HoFH), homozygote Sitosterolemia (or plant sterol mass formed by blood stasis).Ezetimibe does not increase choleresis (as cholic acid chelating agent), and also do not suppress the synthesis of cholesterol in liver (as Statins), the time length is long.Since its listing, Ezetimibe has become the heavy bomb drugs on hypolipidemic market, wide market, so this medicine of Development and Production will have important social benefit and huge economic benefit.
There is the lactan of 3 chiral centres and 4 Yuans rings in the chemical structure of Ezetimibe, synthesis difficulty is comparatively large, and the synthetic route of existing bibliographical information has:
(1) people such as Vaccaro W.D.et al (Bioorg.Med.Chem.1998, p1429-1437) report, uses fluorobenzene to be raw material, at AlCl
3under catalysis, there is Friedel-Crafts reaction in Pyroglutaric acid and fluorobenzene, generates 5-(4-fluorophenyl)-5-oxopentanoic acid.Then 5-(4-fluorophenyl)-5-oxopentanoic acid and pivaloyl chloride reaction, generate mixed anhydride.Mixed anhydride and (S)-(+)-4-oxazolyl phenyl alkane reactive ketone, then use (R)-CBS/BH
3-Me
2s carries out asymmetric hydrogenation, obtains hand-type alcohol.Target product Ezetimibe is obtained through polystep reaction.
Article 1, synthetic route is longer, has 7 steps, and wherein the 5th step reaction needed uses TMSCl, and synthesis obtains the intermediate being with TMS protecting group.Due to the intermediate less stable that this TMS protects, at next step TiCl
4when carrying out linked reaction under/DIPEA condition, TMS protecting group easily comes off, and causes by product to generate, and affects next step cyclization reaction.
(2) patent US5767115 (Schering Plough company) discloses a kind of method of synthesizing Ezetimibe; by (4-benzyloxy-α-tolylene)-(4-fluorophenyl)-amine and the reaction of 4-chloroformyl methyl-butyrate; acyl chlorides is prepared into again after the product hydrolysis obtained; under three tetraphenyl phosphine palladiums do the condition of catalyzer and to the reaction of fluorophenyl zinc chloride, last chiral reduction, catalytic hydrogenation obtain Ezetimibe.This synthetic method step is grown and complex operation, especially preparing acyl chlorides, react the anhydrous requirement of step to system generating ketone again with zincon very high, and zincon is easy to continue to react with product generate more impurity under palladium catalyst exists, cause this step reaction yield very low, and product needs to carry out purifying by column chromatography, make this line cost very high, and be unwell to amplification production.
Article 2 synthetic route, use starting raw material 4-pentenoic acid price more expensive, the more difficult purchase in market, synthetic route is long, complex process, severe reaction conditions, is difficult to realize suitability for industrialized production.
(3) patent US5886171 discloses a kind of method of chiral synthesize Ezetimibe of improvement, with (4S)-hydroxyl tetrahydrofuran for raw material, through polystep reaction, obtains final product Ezetimibe.
Synthetic method 3, needs to use LDA, carries out low-temp reaction.Starting raw material (4S)-hydroxyl tetrahydrofuran is expensive in addition.
(4) patent US5856473 (Schering Plough company) discloses a kind of method of chiral synthesize Ezetimibe of improvement, with the 4-pentenoic acid replaced fluorophenyl for raw material is first prepared into Evans type agents, subsequently with imines generation asymmetric Mannich reaction.The intermediate formed generates trans azetidinone intermediate at acting in conjunction ShiShimonoseki ring of tetrabutyl fluoride amine and two (trimethylsilyl) ethanamide (BSA) of N, O-.Again at Pd (OAc)
2, HClO
4be oxidized double bond in the system of benzoquinones and become ketone, obtain target product Ezetimibe according to identical method subsequently.
Synthetic method 4, starting raw material and catalyst P d (OAc)
2price is more expensive, complex process, and severe reaction conditions not easily amplifies production.
In sum, long or the yield of synthetic route and all lower problem of purity is all there is in above-mentioned synthetic method, some synthetic route raw materials and precious metal palladium reagent expensive, need very low temperature to react in addition, the amount of CBS chiral reduction used agent is many, solvent toxicity is large.Therefore, in prior art, the cost compare of the synthetic method of Ezetimibe is high, is not suitable for suitability for industrialized production.
Summary of the invention
For overcoming the problems referred to above of the prior art, the invention provides a kind of Ezetimibe synthetic method, the method reaction conditions is gentle, productive rate and product purity high, be suitable for industrialized production.
The technical solution used in the present invention is:
On the one hand, the invention provides a kind of synthetic method of Ezetimibe, comprise the following steps:
Asymmetric reduction is there is in organic solvent and reacts to obtain compound (6) in (a) compound (5) at-15 ~ 0 DEG C, compound (6) and TERT-BUTYL DIMETHYL CHLORO SILANE are in organic solvent, react at 40 ~ 80 DEG C under the effect of alkali, obtain compound (7);
B the compound (7) obtained in () step (a) and diisopropylethylamine are dissolved in organic solvent, add titanium tetrachloride and react 5 ~ 60min at 20 ~ 50 DEG C, add compound (3) again and react 10 ~ 60min at-20 ~-60 DEG C, obtain compound (8), wherein, R=TBS, Ac or COOCH
2cCl
3;
The compound (8) obtained in (c) step (b) and N, two (trimethylsilyl) ethanamide of O-in organic solvent, at 20 ~ 80 DEG C of reaction 1-2 hour, add 4-butyl ammonium fluoride trihydrate again, 20 ~ 80 DEG C of reactions, obtain compound (9), wherein R implication as in step (b) define;
D there is deprotection reaction in the compound (9) obtained in () step (c), obtains compound (10) Ezetimibe in organic solvent;
Preferably, in step (a), use borane dimethylsulf iotade and (R)-2-methyl-CBS-oxazaborolidine to carry out asymmetric reduction reaction, or use DIPCl to carry out asymmetric reduction reaction.That is, CBS-DMS reduction method or DIPCl reduction method is utilized to carry out asymmetric reduction reaction.
More preferably, the concrete steps of CBS-DMS method are as follows: borane dimethylsulf iotade and (R)-2-methyl-CBS-oxazaborolidine are incubated 10 ~ 60min in organic solvent at-30 ~ 0 DEG C, then add compound (5) and obtain compound (6)-15 ~ 0 DEG C of generation reduction reaction.
More preferably, DIPCl reduction method concrete steps are as follows: compound (5) and DIPCl in organic solvent, at-20 ~ 50 DEG C, at preferred-20 ~ 20 DEG C, reduction reaction occur, obtains compound (6).
Further, in step (a), the reaction obtaining compound (6) and the organic solvent obtaining using in the reaction of compound (7) are separately selected from one or more in methylene dichloride, DMF, tetrahydrofuran (THF), methyltetrahydrofuran, ether and methyl tertiary butyl ether.
Further, the time of reduction reaction is 10 ~ 60 minutes, and the time obtaining the reaction of compound (7) is 1 ~ 3 hour.
Preferably, in step (a), alkali is selected from imidazoles, pyridine, piperidines or 1,8-diazabicylo 11 carbon-7-alkene.
Further, in step (b), organic solvent is selected from one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.
Further, in step (c), organic solvent is selected from one or more in toluene, ethylbenzene, dimethylbenzene, chlorobenzene and bromobenzene.
Preferably, in step (d), use tetrabutyl ammonium fluoride or HOAc-THF-H
2o carries out deprotection reaction.
More preferably, compound (9) in organic solvent with 4-butyl ammonium fluoride trihydrate, issue raw reduction reaction at 20 ~ 80 DEG C, obtain compound (10) Ezetimibe.
More preferably, compound (9) is dissolved in HOAc-THF-H
2in O, issue raw reduction reaction at 20 ~ 50 DEG C, obtain compound (10) Ezetimibe.
Further, in step (d), organic solvent is selected from one or more in tetrahydrofuran (THF), methyl tertiary butyl ether, methylene dichloride and chloroform.
On the other hand, present invention also offers a kind of compound (9) with following chemical formula:
On the other hand, present invention also offers the preparation method of a kind of above-claimed cpd (9), comprise the following steps:
Compound (8) and two (trimethylsilyl) ethanamide of N, O-in organic solvent, react 1-2 hour at 20 ~ 80 DEG C, add 4-butyl ammonium fluoride trihydrate again and 20 ~ 80 DEG C of reactions, obtain compound (9), wherein R=TBS, Ac or COOCH
2cCl
3, wherein organic solvent is selected from one or more in toluene, ethylbenzene, dimethylbenzene, chlorobenzene and bromobenzene.
The raw material used in synthetic method of the present invention directly can be bought by commercial sources, also can be obtained by conventional chemical process, such as, and compound (3) and (5).The preparation process of compound (3) and (5) will be provided further in the present invention.
Compared with prior art, the present invention has the following advantages: the synthetic method that the invention provides a kind of Ezetimibe, and in the method, starting raw material is cheaply easy to get, and processing condition are easy to control, and reaction conditions is gentle, and productive rate is high and product purity is high.The method is also avoided using expensive raw material and reagent, easy handling, is suitable for industrial amplification production.In addition; midbody compound (8) in the method for the present invention is when carrying out ring closure reaction and generating new compound (9); the protection group of Late Cambrian phenolic hydroxyl group can come off, and compound (9) is the key intermediate of synthesis Ezetimibe.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated.
Embodiment 1
Prepare compound (2)
Compound (1) (10g, 81.90mmol) with para-fluoroaniline (9g, 81.00mmol) be dissolved in Virahol (75ml), be heated to 50 DEG C, stir 1h, be down to room temperature, suction filtration, adds Virahol (10ml) drip washing, obtains light yellow solid, i.e. compound (2) (14.2g, 80% yield).
Embodiment 2
Prepare compound (3)
Example 2-1: prepare compound (3a) (that is, R=TBS in compound (3))
Compound (2) (6g, 27.88mmol), TBDMSCl (5.04g, 33.44mmol) and imidazoles (3.8g, 55.80mmol) are dissolved in DMF (12ml), be heated to 60 DEG C, stir 4h, be down to room temperature, add water (60ml), add ethyl acetate (20ml × 3) extraction, merge organic phase, organic phase adds water, and (20ml × 2) are washed, organic addition MgSO
4drying, concentrates and obtains light yellow solid, i.e. compound (3a) (9.0g, 97.5% yield).
1H-NMR(CDCl
3,400MHz,δppm):8.18(s,1H)，7.80(d,J＝8.8,2H,),7.19(m,2H),7.12(m,2H),6.95(d,J＝8.8,2H),1.05(s,9H),0.22(s,6H).
Example 2-2: prepare compound (3b) (that is, R=Ac in compound (3))
Compound (2) (6g, 27.88mmol), AcCl (2.62g, 33.44mmol) and Et
3n (5.6g, 55.80mmol) is dissolved in CH
2cl
2(15ml) in, stirred at ambient temperature 5h, adds water (60ml), and add ethyl acetate (20ml × 3) extraction, merge organic phase, organic phase adds water, and (20ml × 2) are washed, organic addition MgSO
4drying, concentrates and obtains light yellow solid, i.e. compound (3b) (7.03g, 98% yield).
1H-NMR(DMSO-d6,400MHz,δppm):8.60(s,1H),8.00(d,J＝8.6,2H),7.42(d,J＝8.6,2H),7.28-7.32(m,2H),7.20-7.24(m,2H),2.20(s,3H)。
Example 2-3: prepare compound (3c) (that is, in compound (3)
Compound (2) (6g, 27.88mmol), 2,2,2-Trichloro ethyl chloroformate 99 (7.08g, 33.44mmol) and Et
3n (5.6g, 55.80mmol) is dissolved in CH
2cl
2(25ml) in, stir 6h, then get back to room temperature at 0-5 DEG C, add water (60ml), add ethyl acetate (20ml × 3) extraction, merge organic phase, organic phase adds water, and (20ml × 2) are washed, organic addition MgSO
4drying, concentrates and obtains light yellow solid, i.e. compound (3c) (10.3g, 95% yield).
1H-NMR(DMSO-d6,400MHz,δppm):8.67(s,1H),8.02(d,J＝8.8,2H),7.46(d,J＝8.8,2H),7.30-7.35(m,2H),7.20-7.26(m,2H),5.09(s,2H)。
Embodiment 3
Prepare compound (5)
Compound (4) (30g, 142.72mmol), triethylamine (26g, 256.91mmol) be dissolved in methylene dichloride (150ml), be cooled to 5 to 10 DEG C, drip pivaloyl chloride (17.3g, 142.62mmol), system has heat release, 30min drips complete, 5 to 10 DEG C of insulation reaction 2h, (S)-4-phenyl-2-oxazolidone (23.3g is added in reaction system, 142.76mmol), DMAP (2.4g, 19.63mmol), DMF (15ml), heat release, temperature rises to 15 DEG C, be warming up to 45 DEG C of back flow reaction 3h, be down to room temperature, add methylene chloride (150ml), organic phase washed with water (60ml) is washed, 1N hydrochloric acid (120ml) is washed, water (60ml) is washed, 2.5% aqueous sodium hydroxide solution (180ml) is washed, add water (50ml) wash, organic phase is concentrated dry, add Virahol (60ml), stir 24h, suction filtration, add Virahol (10ml) drip washing, obtain white solid, i.e. compound (5) (34.4g, 68% yield).
1H-NMR(CDCl
3,400MHz,δppm):7.92(m,2H),7.29-7.40(m,5H),7.10(m,2H),5.42(m,1H),4.70(t,J＝8.8,1H),4.28(m,1H),3.05(m,2H),2.96(t,J＝7.22H),2.05(m,2H)。
Embodiment 4
Prepare compound (6)
Example 4-1: borane dimethylsulf iotade (34ml, 10M, 34mmol) be dissolved in methylene dichloride (40ml), be cooled to-10 to-5 DEG C, drip (R)-2-methyl-CBS-oxazaborolidine (14ml, 1M, 14mmol), drip and finish,-10 to-5 DEG C of insulation 15min, be cooled to-15 to-10 DEG C, drip compound (5) (10g, methylene dichloride (20ml) solution 28mmol), 20min drips complete,-10 to-5 DEG C of insulation reaction 20min, methyl alcohol (50ml) is dripped at-10 to 0 DEG C, heat release, hydrogen peroxide (30% is dripped at-10 to 0 DEG C, 40ml), heat release, dilute hydrochloric acid (1M is dripped at-10 to 10 DEG C, 50ml), heat release is violent, drip and finish, organic solvent in system is concentrated, add ethyl acetate (100ml) extraction, water (10ml) is used to wash successively, 5%NaHSO
3the aqueous solution (20ml) is washed, and concentrates and obtains light yellow oil, i.e. compound (6) (9.0g, 90% yield).
1H-NMR(CDCl
3,400MHz,δppm):7.13-7.29(m,7H),6.89(t,J＝8.4,2H),5.28(dd,J＝8.8,1H),4.49-4.57(m,2H),4.14(dd,J＝8.8,1H),2.85(m,2H),2.49(br,1H),1.48-1.65(m,4H)。
Example 4-2: borane dimethylsulf iotade (34ml, 10M, 34mmol) be dissolved in N, in dinethylformamide (DMF) (40ml), be cooled to-30 to-25 DEG C, drip (R)-2-methyl-CBS-oxazaborolidine (14ml, 1M, 14mmol), drip and finish,-30 to-25 DEG C of insulation 30min, be cooled to-15 to-10 DEG C, drip compound (5) (10g, DMF (20ml) solution 28mmol), 20min drips complete,-10 to-5 DEG C of insulation reaction 20min, methyl alcohol (50ml) is dripped at-10 to 0 DEG C, heat release, hydrogen peroxide (30% is dripped at-10 to 0 DEG C, 40ml), heat release, dilute hydrochloric acid (1M is dripped at-10 to 10 DEG C, 50ml), heat release is violent, drip and finish, organic solvent in system is concentrated, add ethyl acetate (100ml) extraction, water (10ml) is used to wash successively, 5%NaHSO
3the aqueous solution (20ml) is washed, and concentrated dryly obtains light yellow oil, i.e. compound (6) (8.7g, 87% yield).
Example 4-3: borane dimethylsulf iotade (34ml, 10M, 34mmol) be dissolved in tetrahydrofuran (THF) (40ml), be cooled to-10 to-5 DEG C, drip (R)-2-methyl-CBS-oxazaborolidine (14ml, 1M, 14mmol), drip and finish,-10 to-5 DEG C of insulation 60min, be cooled to-15 to-10 DEG C, drip compound (5) (10g, tetrahydrofuran (THF) (20ml) solution 28mmol), 20min drips complete,-10 to-5 DEG C of insulation reaction 60min, methyl alcohol (50ml) is dripped at-10 to 0 DEG C, heat release, hydrogen peroxide (30% is dripped at-10 to 0 DEG C, 40ml), heat release, dilute hydrochloric acid (1M is dripped at-10 to 10 DEG C, 50ml), heat release is violent, drip and finish, organic solvent in system is concentrated, add ethyl acetate (100ml) extraction, water (10ml) is used to wash successively, 5%NaHSO
3the aqueous solution (20ml) is washed, and concentrates and obtains light yellow oil, i.e. compound (6) (9.1g, 91% yield).
Example 4-4: compound (5) (10g, 28mmol) be dissolved in 1, in 4-dioxane (100ml),-20 DEG C of dropping (-) DIPCl (13.4g, 42mmol), keep-20 DEG C to react 2h, add water (50ml), use saturated NaHCO
3the aqueous solution regulates pH to equal 7, is extracted with ethyl acetate (30ml × 3), dry, obtains light yellow oil, i.e. compound (6) (8.2g, 82% yield) after concentrated.
Embodiment 5
Prepare compound (7)
Example 5-1: compound (6) (5.2g, 14.5mmol), TERT-BUTYL DIMETHYL CHLORO SILANE (2.6g, 17.5mmol) with imidazoles (1.9g, 29.0mmol) be dissolved in DMF (10.5ml), system be warming up to 60 DEG C of reaction 1 to 2h, be cooled to room temperature, add water (20ml), ethyl acetate (40ml) extracts, and ethyl acetate layer adds water, and (10ml × 2) are washed, organic addition MgSO
4drying, concentrates and obtains colourless transparent liquid 7 (4.2g, 61% yield).
1H-NMR(DMSO-d6,400MHz,δppm):7.43-7.54(m,7H),7.30(t,J＝8.8,2H),5.61(dd,J＝8.8,1H),4.89(m,2H),4.30(dd,J＝8.8,1H),3.10(m,1H),2.95(m,1H),1.62-1.77(m,4H),1.00(s,9H),0.18(s,3H),0.02(s,3H)。
Example 5-2: compound (6) (5.2g, 14.5mmol), TERT-BUTYL DIMETHYL CHLORO SILANE (2.6g, 17.5mmol) with pyridine (2.3g, 29.0mmol) be dissolved in DMF (10.5ml), system be warming up to 40 DEG C of reaction 2 to 3h, be cooled to room temperature, add water (20ml), ethyl acetate (40ml) extracts, and ethyl acetate layer adds water, and (10ml × 2) are washed, organic addition MgSO
4drying, concentrates and obtains colourless transparent liquid 7 (3.8g, 55% yield).
Example 5-3: compound (6) (5.2g, 14.5mmol), TERT-BUTYL DIMETHYL CHLORO SILANE (2.6g, 17.5mmol) He 1,8-diazabicylo 11 carbon-7-alkene (DBU, 4.4g, 29.0mmol) be dissolved in DMF (10.5ml), system is warming up to 80 DEG C of reaction 1 to 2h, be cooled to room temperature, add water (20ml), ethyl acetate (40ml) extracts, and ethyl acetate layer adds water, and (10ml × 2) are washed, organic addition MgSO
4drying, concentrates and obtains colourless transparent liquid 7 (4.3g, 62% yield).
Embodiment 6
Prepare compound (8)
Example 6-1:(R=TBS)
Compound (7) (800mg, 1.7mmol), diisopropylethylamine (1534mg, 11.8mmol) be dissolved in methylene dichloride (19ml), be cooled to-5 to 0 DEG C, drip titanium tetrachloride dichloromethane solution (6.1ml, 1M, 6.1mmol), drip and finish, be warming up to 20 to 25 DEG C of reaction 5 to 10min, be cooled to-40 to-30 DEG C, drip compound (3a) (1340mg, methylene dichloride (16ml) solution 4.1mmol), drip and finish,-40 to-30 DEG C of insulation reaction 20min, drip water (10ml) successively, methylene dichloride (10ml), separatory, organic phase adds water, and (10ml) washes, organic phase crosses silica gel suction filtration, concentrated, add ethanol (5ml), stir 1h, suction filtration obtains white solid, i.e. compound (8a) (694mg, 51% yield).
1H-NMR(DMSO-d6,400MHz,δppm):7.31(d,J＝7.6,2H),7.18-7.24(m,4H),7.00-7.11(m,5H),6.72-6.80(m,4H),6.51-6.55(m,2H),6.03(d,J＝9.2,1H),5.50-5.53(m,1H),4.70(t,J＝8.8,1H),4.46(m,1H),4.27(m,2H),4.02-4.05(m,1H),1.34-1.44(m,4H),0.94(s,9H),0.70(s,9H),0.17(d,J＝1.2,6H),-0.14(s,3H),-0.29(s,3H)。
Example 6-2:(R=TBS)
Compound (7) (800mg, 1.7mmol), diisopropylethylamine (1534mg, 11.8mmol) be dissolved in methylene dichloride (19ml), be cooled to-5 to 0 DEG C, drip titanium tetrachloride chloroformic solution (6.1ml, 1M, 6.1mmol), drip and finish, be warming up to 40 to 50 DEG C of reaction 5-10min, be cooled to-60 to-50 DEG C, drip compound (3a) (1340mg, chloroform (16ml) solution 4.1mmol), drip and finish,-30 to-40 DEG C of insulation reaction 20min, drip water (10ml) successively, methylene dichloride (10ml), separatory, organic phase adds water, and (10ml) washes, organic phase crosses silica gel suction filtration, concentrated, add ethanol (5ml), stir 1h, suction filtration obtains white solid, i.e. compound (8a) (500mg, 36% yield).Example 6-3:(R=Ac)
Example 6-3:(R=Ac)
Compound (7) (800mg, 1.7mmol), diisopropylethylamine (1534mg, 11.8mmol) be dissolved in methylene dichloride (20ml), be cooled to-5 to 0 DEG C, drip titanium tetrachloride dichloroethane solution (6.1ml, 1M, 6.1mmol), drip and finish, be warming up to 20 to 25 DEG C of reaction 5-10min, be cooled to-30 to-40 DEG C, drip compound (3b) (1053mg, ethylene dichloride (20ml) solution 4.1mmol), drip and finish,-30 to-40 DEG C of insulation reaction 20min, drip water (15ml) successively, methylene dichloride (20ml), separatory, organic phase adds water, and (20ml) washes, organic phase crosses silica gel suction filtration, concentrated, add ethanol (5ml), stir 1h, suction filtration obtains white solid, i.e. compound (8b) (681mg, 55% yield).
1H-NMR(DMSO-d6,400MHz,δppm):7.30(d,J＝7.6,2H),7.16-7.22(m,4H),7.02-7.13(m,5H),6.70-6.82(m,4H),6.50-6.56(m,2H),6.00(d,J＝9.2,1H),5.50-5.55(m,1H),4.68(t,J＝8.8,1H),4.48(m,1H),4.28(m,2H),4.00-4.02(m,1H),2.24(s,3H),1.32-1.42(m,4H),0.74(s,9H),0.15(d,J＝1.2,6H)。
Example 6-4:(R=Ac)
Compound (7) (800mg, 1.7mmol), diisopropylethylamine (1534mg, 11.8mmol) be dissolved in methylene dichloride (20ml), be cooled to-5 to 0 DEG C, drip titanium tetrachloride chloroformic solution (6.1ml, 1M, 6.1mmol), drip and finish, be warming up to 20 to 25 DEG C of reaction 15-20min, be cooled to-30 to-40 DEG C, drip compound (3b) (1053mg, chloroform (20ml) solution 4.1mmol), drip and finish,-40 to-50 DEG C of insulation reaction 40min, drip water (15ml) successively, methylene dichloride (20ml), separatory, organic phase adds water, and (20ml) washes, organic phase crosses silica gel suction filtration, concentrated, add ethanol (5ml), stir 1h, suction filtration obtains white solid, i.e. compound (8b) (581mg, 47% yield).
Example 6-5:(R=COCH
2cCl
3)
Compound (7) (800mg, 1.7mmol), diisopropylethylamine (1534mg, 11.8mmol) be dissolved in methylene dichloride (20ml), be cooled to-5 to 0 DEG C, drip titanium tetrachloride carbon tetrachloride solution (6.1ml, 1M, 6.1mmol), drip and finish, be warming up to 20 to 25 DEG C of reaction 60min, be cooled to-50 to-60 DEG C, drip compound (3c) (1594mg, tetracol phenixin (20ml) solution 4.1mmol), drip and finish,-50 to-60 DEG C of insulation reaction 35min, drip water (25ml) successively, methylene dichloride (25ml), separatory, organic phase adds water, and (20ml) washes, organic phase crosses silica gel suction filtration, concentrated, add ethanol (10ml), stir 1h, suction filtration obtains white solid, i.e. compound (8c) (880mg, 60% yield).
1H-NMR(DMSO-d6,400MHz,δppm):7.33(d,J＝7.6,2H),7.18-7.26(m,4H),7.03-7.13(m,5H),6.68-6.78(m,4H),6.52-6.52(m,2H),6.00(d,J＝9.2,1H),5.50-5.58(m,1H),5.00(s,2H),4.72(t,J＝8.8,1H),4.44(m,1H),4.24(m,2H),4.00-4.08(m,1H),2.20(s,3H),1.30-1.40(m,4H),0.68(s,9H),0.14(d,J＝1.2,6H)。
Example 6-6:(R=COCH
2cCl
3)
Compound (7) (800mg, 1.7mmol), diisopropylethylamine (1534mg, 11.8mmol) be dissolved in methylene dichloride (20ml), be cooled to-5 to 0 DEG C, drip titanium tetrachloride dichloromethane solution (6.1ml, 1M, 6.1mmol), drip and finish, be warming up to 40 to 50 DEG C of reaction 5-10min, be cooled to-50 to-40 DEG C, drip compound (3c) (1594mg, methylene dichloride (20ml) solution 4.1mmol), drip and finish,-50 to-40 DEG C of insulation reaction 20min, drip water (25ml) successively, methylene dichloride (25ml), separatory, organic phase adds water, and (20ml) washes, organic phase crosses silica gel suction filtration, concentrated, add ethanol (10ml), stir 1h, suction filtration obtains white solid, i.e. compound (8c) (680mg, 46% yield).
Embodiment 7
Prepare compound (9)
Example 7-1: compound 8a (R=TBS) (300mg, 0.37mmol) is dissolved in toluene (12ml), nitrogen replacement, add N, two (trimethylsilyl) ethanamide (556mg, 2.73mmol) of O-, 20 to 30 DEG C of reaction 1h.Add 4-butyl ammonium fluoride trihydrate (97mg, 0.31mmol), 20 to 30 DEG C of reaction 1h.Add 4-butyl ammonium fluoride trihydrate (209mg, 0.66mmol), 20 to 30 DEG C of reaction 1h, drip acetic acid (0.5ml), methyl alcohol (0.5ml), concentrated, add saturated aqueous sodium carbonate (10ml), ethyl acetate (10ml × 2) extracts, organic phase adds water, and (10ml) washes, concentrated, TLC is separated (PE:EA=5:1) and obtains white solid 9 (155mg, yield 79%).
1H-NMR(CDCl
3,400MHz,δppm):7.20-7.23(m,4H),7.15(d,J＝8.4,2H),6.89-6.99(m,4H),6.80(d,J＝8.8,2H),5.11(br,1H),4.64(t,J＝6,1H),4.49(d,J＝2,1H),2.96-3.02(m,1H),1.79-1.87(m,4H),0.86(s,9H),0.00(s,3H),-0.17(s,3H)。
Example 7-2: compound 8a (R=Ac) (270mg, 0.37mmol) is dissolved in toluene (15ml), nitrogen replacement, add N, two (trimethylsilyl) ethanamide (556mg, 2.73mmol) of O-, 20 to 30 DEG C of reaction 1h.Add 4-butyl ammonium fluoride trihydrate (97mg, 0.31mmol), 20 to 30 DEG C of reaction 1h.Add 4-butyl ammonium fluoride trihydrate (209mg, 0.66mmol), 20 to 30 DEG C of reaction 1h, drip acetic acid (0.5ml), methyl alcohol (0.5ml), concentrated, add saturated aqueous sodium carbonate (10ml), ethyl acetate (10ml × 2) extracts, organic phase adds water, and (10ml) washes, concentrated, TLC is separated (PE:EA=5:1) and obtains compound as white solid 9 (145mg, yield 74%).
Example 7-3: compound 8a (R=COCH
2cCl
3) (248mg, 0.37mmol) be dissolved in toluene (22ml), nitrogen replacement, adds N, two (trimethylsilyl) ethanamide (556mg, 2.73mmol) of O-, 20 to 30 DEG C of reaction 1h.Add 4-butyl ammonium fluoride trihydrate (97mg, 0.31mmol), 20 to 30 DEG C of reaction 1h.Add 4-butyl ammonium fluoride trihydrate (209mg, 0.66mmol), 20 to 30 DEG C of reaction 1h, drip acetic acid (0.5ml), methyl alcohol (0.5ml), concentrated, add saturated aqueous sodium carbonate (10ml), ethyl acetate (10ml × 2) extracts, organic phase adds water, and (10ml) washes, concentrated, TLC is separated (PE:EA=5:1) and obtains compound as white solid 9 (140mg, yield 71%).
Embodiment 8
Prepare compound (10) Ezetimibe
Example 8-1: compound 9 (100mg, 0.19mmol) is dissolved in tetrahydrofuran (THF) (10ml), nitrogen replacement, add 4-butyl ammonium fluoride trihydrate (173mg, 0.55mmol), 20 to 30 DEG C of reaction 4h, concentrated, add ethyl acetate (10ml), add water (5ml) wash, organic phase concentrate, TLC be separated (PE:EA=2:1) obtain compound as white solid 10 (40mg, yield 51%), i.e. Ezetimibe.
1H-NMR(DMSO-d6,400MHz,δppm):9.51(s,1H,7.27-7.31(m,2H),7.19-7.22(m,4H),7.08-7.14(m,4H),6.73(d,J＝8.4,2H),5.26(d,J＝4.4,1H),4.79(d,J＝2.4,1H),4.48(d,J＝4.4,1H),3.06-3.08(m,1H),1.70-1.83(m,4H)。
Example 8-2: compound 9 (100mg, 0.19mmol) is dissolved in methylene dichloride (10ml), nitrogen replacement, add 4-butyl ammonium fluoride trihydrate (173mg, 0.55mmol), 20 to 30 DEG C of reaction 4h, concentrated, add ethyl acetate (10ml), add water (5ml) wash, organic phase concentrate, TLC be separated (PE:EA=2:1) obtain compound as white solid 10 (38mg, yield 48%), i.e. Ezetimibe.
Example 8-3: compound 9 (100mg, 0.19mmol) is dissolved in chloroform (10ml), nitrogen replacement, add 4-butyl ammonium fluoride trihydrate (173mg, 0.55mmol), 40 to 45 DEG C of reaction 2h, concentrated, add ethyl acetate (10ml), add water (5ml) wash, organic phase concentrate, TLC be separated (PE:EA=2:1) obtain compound as white solid 10 (45mg, yield 57%), i.e. Ezetimibe.
Example 8-4: compound 9 (100mg, 0.19mmol) is dissolved in HOAc-THF-H
2o (V/V/V=1:1:1,15ml), room temperature reaction 16h, concentrated, add saturated sodium bicarbonate aqueous solution and adjust pH to 5-6, ethyl acetate (10ml) extracts, add water (5ml) wash, organic phase concentrate, TLC be separated (PE:EA=2:1) obtain compound as white solid 10 (54mg, yield 68%), i.e. Ezetimibe.
Above specific embodiment of the present invention is illustrated; but protection content of the present invention is not only limited to above embodiment; in art of the present invention, the usual knowledge of a GPRS, just can carry out diversified change within the scope of its technology main idea.
Claims (10)
1. a synthetic method for Ezetimibe, is characterized in that, comprises the following steps:
Asymmetric reduction is there is in organic solvent and reacts to obtain compound (6) in (a) compound (5) at-15 ~ 0 DEG C, compound (6) and TERT-BUTYL DIMETHYL CHLORO SILANE are in organic solvent, react at 40 ~ 80 DEG C under the effect of alkali, obtain compound (7);
B the compound (7) obtained in () step (a) and diisopropylethylamine are dissolved in organic solvent, add titanium tetrachloride and react 5 ~ 60min at 20 ~ 50 DEG C, add compound (3) again and react 10 ~ 60min at-60 ~-20 DEG C, obtain compound (8), wherein, R=TBS, Ac or COCH
2cH
3;
The compound (8) obtained in (c) step (b) and N, two (trimethylsilyl) ethanamide of O-in organic solvent, at 20 ~ 80 DEG C of reaction 1-2 hour, add 4-butyl ammonium fluoride trihydrate again, 20 ~ 80 DEG C of reactions, obtain compound (9), wherein R implication as in step (b) define;
In organic solvent, there is deprotection reaction, obtain compound (10) Ezetimibe in the compound (9) obtained in (d) step (c);
2. the synthetic method of Ezetimibe according to claim 1, it is characterized in that: in step (a), use borane dimethylsulf iotade and (R)-2-methyl-CBS-oxazaborolidine to carry out asymmetric reduction reaction, or use DIP-Cl to carry out asymmetric reduction reaction.
3. the synthetic method of Ezetimibe according to claim 1, it is characterized in that: in step (a), described organic solvent is separately selected from one or more in methylene dichloride, DMF, tetrahydrofuran (THF), methyltetrahydrofuran, ether and methyl tertiary butyl ether.
4. the synthetic method of Ezetimibe according to claim 1, is characterized in that: in step (a), and described alkali is selected from imidazoles, pyridine, piperidines or 1,8-diazabicylo 11 carbon-7-alkene.
5. the synthetic method of Ezetimibe according to claim 1, is characterized in that: in step (b), described organic solvent is selected from one or more in methylene dichloride, chloroform, tetracol phenixin and ethylene dichloride.
6. the synthetic method of Ezetimibe according to claim 1, is characterized in that: in step (c), described organic solvent is selected from one or more in toluene, ethylbenzene, dimethylbenzene, chlorobenzene and bromobenzene.
7. the synthetic method of Ezetimibe according to claim 1, is characterized in that: in step (d), uses tetrabutyl ammonium fluoride or HOAc-THF-H
2o carries out deprotection reaction.
8. the synthetic method of Ezetimibe according to claim 1, is characterized in that: in step (d), described organic solvent is selected from one or more in tetrahydrofuran (THF), methyl tertiary butyl ether, methylene dichloride and chloroform.
9. one kind has the compound (9) of following chemical formula:
10. prepare a method for compound as claimed in claim 9 (9), it is characterized in that, comprise the following steps:
Compound (8) and two (trimethylsilyl) ethanamide of N, O-in organic solvent, react 1-2 hour at 20 ~ 80 DEG C, add 4-butyl ammonium fluoride trihydrate again and 20 ~ 80 DEG C of reactions, obtain compound (9), wherein R=TBS, Ac or COOCH
2cCl
3;
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510011797.XA CN104513187B (en) | 2015-01-09 | 2015-01-09 | The synthetic method of Ezetimibe and its intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510011797.XA CN104513187B (en) | 2015-01-09 | 2015-01-09 | The synthetic method of Ezetimibe and its intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104513187A true CN104513187A (en) | 2015-04-15 |
| CN104513187B CN104513187B (en) | 2017-05-31 |
Family
ID=52789091
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510011797.XA Active CN104513187B (en) | 2015-01-09 | 2015-01-09 | The synthetic method of Ezetimibe and its intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104513187B (en) |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237492A (en) * | 2015-10-29 | 2016-01-13 | 无锡福祈制药有限公司 | Synthetic method for ezetimibe intermediate |
| CN105503937A (en) * | 2015-12-31 | 2016-04-20 | 山西普德药业股份有限公司 | Stationary bed continuous production method of ezetimibe intermediate |
| CN105566374A (en) * | 2015-12-31 | 2016-05-11 | 山西普德药业股份有限公司 | Slurry bed continuous production method of ezetimibe intermediate |
| CN105622661A (en) * | 2015-12-31 | 2016-06-01 | 山西普德药业股份有限公司 | Molecular sieve catalytic synthesis method of ezetimibe midbody |
| CN106699604A (en) * | 2017-01-09 | 2017-05-24 | 四川同晟生物医药有限公司 | Sacubitril and preparation method of midbody of sacubitril |
| CN107652214A (en) * | 2017-11-07 | 2018-02-02 | 河南师范大学 | A kind of preparation method of high fat of blood curative Ezetimibe |
| CN107793339A (en) * | 2017-11-07 | 2018-03-13 | 河南师范大学 | A kind of preparation method of high fat of blood curative Ezetimibe |
| CN107903200A (en) * | 2017-11-07 | 2018-04-13 | 河南师范大学 | A kind of preparation method of hyperlipidemia curative Ezetimibe |
| CN109293547A (en) * | 2018-12-10 | 2019-02-01 | 无锡福祈制药有限公司 | A new class of Ezetimibe derivative and preparation method thereof |
| CN109369491A (en) * | 2018-12-10 | 2019-02-22 | 无锡福祈制药有限公司 | A new class of ezetimibe derivative and preparation method thereof |
| CN109384700A (en) * | 2018-12-10 | 2019-02-26 | 无锡福祈制药有限公司 | A new class of Ezetimibe analog and preparation method thereof |
| CN111153844A (en) * | 2018-11-08 | 2020-05-15 | 罗欣药业(上海)有限公司 | Preparation method of ezetimibe optical isomer |
| CN112759528A (en) * | 2019-10-21 | 2021-05-07 | 中国石油化工股份有限公司 | Novel imidate compound and preparation method thereof |
| CN114621299A (en) * | 2020-12-14 | 2022-06-14 | 江苏阿尔法药业有限公司 | Preparation method of ezetimibe intermediate |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5767115A (en) * | 1993-09-21 | 1998-06-16 | Schering-Plough Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| US5856473A (en) * | 1995-11-02 | 1999-01-05 | Schering Corporation | Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-( phenyl or 4-fluorophenyl!)-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone |
| US5886177A (en) * | 1994-01-11 | 1999-03-23 | Isis Pharmaceuticals, Inc. | Phosphate linked oligomers |
| US6207822B1 (en) * | 1998-12-07 | 2001-03-27 | Schering Corporation | Process for the synthesis of azetidinones |
| CN1483021A (en) * | 2000-12-21 | 2004-03-17 | ���ĵ�˹ҩ��¹�����˾ | Novel 1, 2-diphenzylazetidinones, method for producing the same, medicaments containing said compounds, and the use thereof for treating disorders of the lipid metabolism |
| CN1878770A (en) * | 2003-10-07 | 2006-12-13 | 利皮德翁生物技术股份有限公司 | Novel hypocholesterolemic compounds |
| WO2008106900A1 (en) * | 2007-03-02 | 2008-09-12 | Zentiva, A.S. | Method of manufacturing (3r, 4s) -1- (4-fluorophenyl) -3- [ (3s) -3- (4 -fluorophenyl) -3-hydroxypropyl) ] -4- (4-hyd roxyphenyl) -2-azetidinone |
| CN101535249A (en) * | 2006-11-02 | 2009-09-16 | 塞诺菲-安万特德国有限公司 | Novel diphenylazetidinone substituted by piperazine-1-sulfonic acid having improved pharmacological properties |
| JP2010083880A (en) * | 2008-09-05 | 2010-04-15 | Teijin Pharma Ltd | 1-biaryl azetidinone derivative |
| CN103709086A (en) * | 2013-11-25 | 2014-04-09 | 四川大学 | Preparation method for ezetimibe optical isomers and intermediate applied in preparation method |
-
2015
- 2015-01-09 CN CN201510011797.XA patent/CN104513187B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5767115A (en) * | 1993-09-21 | 1998-06-16 | Schering-Plough Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
| US5886177A (en) * | 1994-01-11 | 1999-03-23 | Isis Pharmaceuticals, Inc. | Phosphate linked oligomers |
| US5856473A (en) * | 1995-11-02 | 1999-01-05 | Schering Corporation | Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-( phenyl or 4-fluorophenyl!)-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone |
| US6207822B1 (en) * | 1998-12-07 | 2001-03-27 | Schering Corporation | Process for the synthesis of azetidinones |
| CN1483021A (en) * | 2000-12-21 | 2004-03-17 | ���ĵ�˹ҩ��¹�����˾ | Novel 1, 2-diphenzylazetidinones, method for producing the same, medicaments containing said compounds, and the use thereof for treating disorders of the lipid metabolism |
| CN1878770A (en) * | 2003-10-07 | 2006-12-13 | 利皮德翁生物技术股份有限公司 | Novel hypocholesterolemic compounds |
| CN101535249A (en) * | 2006-11-02 | 2009-09-16 | 塞诺菲-安万特德国有限公司 | Novel diphenylazetidinone substituted by piperazine-1-sulfonic acid having improved pharmacological properties |
| WO2008106900A1 (en) * | 2007-03-02 | 2008-09-12 | Zentiva, A.S. | Method of manufacturing (3r, 4s) -1- (4-fluorophenyl) -3- [ (3s) -3- (4 -fluorophenyl) -3-hydroxypropyl) ] -4- (4-hyd roxyphenyl) -2-azetidinone |
| JP2010083880A (en) * | 2008-09-05 | 2010-04-15 | Teijin Pharma Ltd | 1-biaryl azetidinone derivative |
| CN103709086A (en) * | 2013-11-25 | 2014-04-09 | 四川大学 | Preparation method for ezetimibe optical isomers and intermediate applied in preparation method |
Non-Patent Citations (2)
| Title |
|---|
| KVRNO LISBET，等: "Synthesis and in Vitro Evaluation of Inhibitors of Intestinal Cholesterol Absorption", 《J. MED. CHEM.》 * |
| WAYNE D. VACCARO，等: "2-Azetidinone Cholesterol Absorption Inhibitors: Increased Potency by Substitution of the C-4 Phenyl Ring", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237492A (en) * | 2015-10-29 | 2016-01-13 | 无锡福祈制药有限公司 | Synthetic method for ezetimibe intermediate |
| CN105503937B (en) * | 2015-12-31 | 2018-05-25 | 山西普德药业有限公司 | A kind of fixed bed continuous producing method for producing Ezetimibe intermediate |
| CN105503937A (en) * | 2015-12-31 | 2016-04-20 | 山西普德药业股份有限公司 | Stationary bed continuous production method of ezetimibe intermediate |
| CN105566374A (en) * | 2015-12-31 | 2016-05-11 | 山西普德药业股份有限公司 | Slurry bed continuous production method of ezetimibe intermediate |
| CN105622661A (en) * | 2015-12-31 | 2016-06-01 | 山西普德药业股份有限公司 | Molecular sieve catalytic synthesis method of ezetimibe midbody |
| CN105622661B (en) * | 2015-12-31 | 2018-07-10 | 山西普德药业有限公司 | A kind of molecular sieve catalytic synthetic method of Ezetimibe intermediate |
| CN105566374B (en) * | 2015-12-31 | 2018-05-25 | 山西普德药业有限公司 | A kind of slurry bed system continuous producing method of Ezetimibe intermediate |
| CN106699604A (en) * | 2017-01-09 | 2017-05-24 | 四川同晟生物医药有限公司 | Sacubitril and preparation method of midbody of sacubitril |
| CN106699604B (en) * | 2017-01-09 | 2019-01-01 | 四川同晟生物医药有限公司 | One seed sand library is than bent and its intermediate preparation method |
| CN107652214A (en) * | 2017-11-07 | 2018-02-02 | 河南师范大学 | A kind of preparation method of high fat of blood curative Ezetimibe |
| CN107903200A (en) * | 2017-11-07 | 2018-04-13 | 河南师范大学 | A kind of preparation method of hyperlipidemia curative Ezetimibe |
| CN107793339A (en) * | 2017-11-07 | 2018-03-13 | 河南师范大学 | A kind of preparation method of high fat of blood curative Ezetimibe |
| CN111153844A (en) * | 2018-11-08 | 2020-05-15 | 罗欣药业(上海)有限公司 | Preparation method of ezetimibe optical isomer |
| CN109293547A (en) * | 2018-12-10 | 2019-02-01 | 无锡福祈制药有限公司 | A new class of Ezetimibe derivative and preparation method thereof |
| CN109369491A (en) * | 2018-12-10 | 2019-02-22 | 无锡福祈制药有限公司 | A new class of ezetimibe derivative and preparation method thereof |
| CN109384700A (en) * | 2018-12-10 | 2019-02-26 | 无锡福祈制药有限公司 | A new class of Ezetimibe analog and preparation method thereof |
| CN112759528A (en) * | 2019-10-21 | 2021-05-07 | 中国石油化工股份有限公司 | Novel imidate compound and preparation method thereof |
| CN112759528B (en) * | 2019-10-21 | 2023-10-13 | 中国石油化工股份有限公司 | Imine ester compound and preparation method thereof |
| CN114621299A (en) * | 2020-12-14 | 2022-06-14 | 江苏阿尔法药业有限公司 | Preparation method of ezetimibe intermediate |
| CN114621299B (en) * | 2020-12-14 | 2023-11-03 | 江苏阿尔法药业股份有限公司 | Preparation method of ezetimibe intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104513187B (en) | 2017-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104513187A (en) | Ezetimibe synthesis method and Ezetimibe intermediate synthesis method | |
| JP3328286B2 (en) | Furyl or thienylcarbonyl-substituted taxanes and pharmaceutical compositions containing the same | |
| RU2086538C1 (en) | Method of enantioselective synthesis of phenylisoserine derivatives | |
| SK43695A3 (en) | Method of preparing taxane derivatives | |
| CN102753537A (en) | Method for the preparation of rivaroxaban | |
| SK283932B6 (en) | Method for preparing derivatives of the taxoid class | |
| JP2007538041A (en) | Method for producing diphenylazetidinone derivative | |
| Zarei | A facile and effective synthesis of 2-azetidinones via phosphonitrilic chloride | |
| CN105254589B (en) | A method of preparing heart failure drugs intermediate | |
| CN103910671B (en) | Vismodegib and the preparation method of intermediate thereof | |
| CN108503549A (en) | Aromatic carboxylic acid trifluoroethyl ester type compound and preparation method thereof | |
| CN102924548B (en) | Synthesis method of capecitabine | |
| CN105315231A (en) | Preparation method of linezolid related substance | |
| Dai et al. | Asymmetric synthesis of β-trifluoromethyl-β-amino acids, including highly sterically constrained α, α-dialkyl derivatives | |
| CN105693555A (en) | Method for preparing arene beta-amino alcohol of optical voidness | |
| CN103113177B (en) | Preparation method of amide | |
| CN108530510A (en) | A kind of C19- is acylated the preparation method of triptolide | |
| CN105348212A (en) | Preparation method for Linezolid | |
| WO2008075834A1 (en) | Method of preparing taxane derivatives and intermediates used therein | |
| CN105461634A (en) | Preparation method of enzalutamide | |
| CN110551170B (en) | Synthesis method of C-19 single-acyl triptolide derivative | |
| WO2018108130A1 (en) | Process for preparation of novel androgen receptor antagonist | |
| CN107304194A (en) | The method for preparing Dapagliflozin | |
| SK280576B6 (en) | Method of stereoselective preparation of a derivative of b-phenylisoserine, n-carbonylamine as an intermediate for preparing, and the use of b-phenylisoserine in the preparation of taxane derivatives | |
| CN103906747A (en) | Process for cabazitaxel and intermediates thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |