CN105461649B - A kind of Ezetimible intermediate and preparation method thereof - Google Patents
A kind of Ezetimible intermediate and preparation method thereof Download PDFInfo
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- CN105461649B CN105461649B CN201410388343.XA CN201410388343A CN105461649B CN 105461649 B CN105461649 B CN 105461649B CN 201410388343 A CN201410388343 A CN 201410388343A CN 105461649 B CN105461649 B CN 105461649B
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Abstract
The present invention relates to medical synthesis technical fields, and in particular to a kind of Ezetimible intermediate compound and preparation method thereof, specially under the action of highly basic, and type I compoundWith P1III compound of-Cl and formulaII compound of preparation formula is reacted,, wherein P1For the alkoxy carbonyl group of C1-C8, the alkyl carbonyl or benzoyl of C1-C8；Preferably, P1For methoxycarbonyl group (), carbethoxyl group (), tertbutyloxycarbonyl () or pivaloyl group (
Description
Technical field
The invention belongs to medical synthesis technical fields, and in particular to a kind of preparation method of ezetimibe.
Background technique
Following structural formula of compound are as follows:
It is the intermediate for preparing ezetimibe, the route for preparing ezetimibe can refer to patent WO2010113175
(publication date 2010-10-7, applicant: Matrix laboratories Ltd), specific as follows:
。
Above-mentioned WO2010113175 provides the preparation route of the intermediate simultaneously, as follows:
,
6 compound of formula that R is phenyl is prepared in embodiment 9, specially with P1It is for 4 compound of formula of benzyl
Starting material, under the action of pivaloyl chloride, it is phenyl that preparation formula 6(R is reacted with compound 5) compound.
And WO2007017705(publication date 2013-3-21, applicant: Astellas Pharma Inc., Japan) mention
A kind of preparation route of 4 compound of starting materials of formulae of above-mentioned WO2010113175 Ezetimible intermediate compound 6 is supplied, such as
Under:
。
It, can be by from the aforegoing it can be seen that in Ezetimible intermediate 6 compound of formula for preparing above structure
III compound of WO2007017705 Chinese style first obtains IV compound of formula to protecting group on hydroxyl, is hydrolyzed as starting material
4 compound of formula is obtained, then under the action of pivaloyl chloride, is reacted with compound 5 and prepare above-mentioned 6 compound of formula.
In view of above-mentioned the step of preparing Ezetimible intermediate compound is a lot of, and the reason more than step is caused to be
The reaction of hydroxyl and carboxyl involved in reaction site, when to avoid participating in reaction, the two is interfered with each other, and above-mentioned patent forms
One complicated process route.Thus it is necessary to develop a simple process, it is suitble to the route of industrialized production.
Summary of the invention
The present invention provides a kind of midbody compounds of ezetimibe, and compared with disclosing route, simple process is fitted
Close industrialized production.
One aspect of the present invention provides a kind of II compound of intermediate formula of ezetimibe, and structural formula is as follows:
,
Wherein P1For the alkoxy carbonyl group of C1-C8, the alkyl carbonyl or benzoyl of C1-C8；Preferably, P1For methoxycarbonyl group (), carbethoxyl group (), tertbutyloxycarbonyl () or pivaloyl group ().
Another aspect of the present invention provides the preparation method of II compound of Ezetimible intermediate formula, and reaction equation is such as
Under:
,
Wherein P1For the alkoxy carbonyl group of C1-C8, the alkyl carbonyl or benzoyl of C1-C8；Preferably, P1For methoxycarbonyl group (), carbethoxyl group (), tertbutyloxycarbonyl () or pivaloyl group ().
I.e. under the action of highly basic, type I compound and P1- Cl and III compound of formula react II compound of preparation formula.
Specially under the action of highly basic, hydroxyl and carboxyl in type I compound with the alkoxy carbonyl group chlorine of C1-C8, C1-
The alkyl carbonyl chlorine or chlorobenzoyl chloride, that is, P of C81- Cl reaction is generated respectively containing after ester group and anhydride moiety, anhydride moiety further with
S-4- phenyl -2- oxazolidone, that is, III compound of formula
React II compound of preparation formula.
A kind of currently preferred embodiment be under the action of highly basic, hydroxyl and carboxyl in type I compound with
Pivaloyl chloride reaction is generated respectively containing after ester group and anhydride moiety, anhydride moiety further with III compound of formula
Reaction preparation protecting group is II compound of formula of pivaloyl group.
。
The above-mentioned reaction highly basic can be hydrogenated alkali metal, such as sodium hydrogen, lithium hydrogen, calcium hydrogen.
Above-mentioned reaction temperature can be -20 DEG C ~ 40 DEG C, be specifically form preferably -10 DEG C ~ 5 DEG C of temperature of acid anhydrides and ester, after
Acid anhydrides continues preferably 10 DEG C ~ 30 DEG C of temperature reacted with S-4- phenyl -2- oxazolidone.
II compound of formula of the invention can further prepare another IV compound of intermediate formula of ezetimibe, react road
Line is as follows:
,
Wherein P1For the alkoxy carbonyl group of C1-C8, the alkyl carbonyl or benzoyl of C1-C8；Preferably, P1For methoxycarbonyl group (), carbethoxyl group (), tertbutyloxycarbonyl () or pivaloyl group ()；It is highly preferred that P1For pivaloyl group (), reaction route is as follows:
。
The preparation method of II compound of Ezetimible intermediate formula provided by the invention, reaction process is simple, is prepared into
II compound yield of formula arrived is high, with high purity, which is suitble to industrialized production.
Specific embodiment
For a further understanding of the present invention, below with reference to embodiment to a kind of Ezetimible intermediate provided by the invention
And preparation method thereof be described in detail.It is to be appreciated that the description of these embodiments is only this hair of further description
Bright feature, rather than the limitation to the scope of the invention or scope of the invention as claimed.
Embodiment 1:
It takes the type I compound of the 21.2g DMF of 110ml to dissolve, and is replaced with nitrogen, be cooled to -10 ~ 0 under nitrogen protection
DEG C, temperature is controlled, puts into the sodium hydrogen of 16g in batches, keeps the temperature 0.5h, pivaloyl chloride 30.2g is slowly added dropwise, controls temperature -10 ~ 0 DEG C,
1h is kept the temperature after being added dropwise, is warming up to 20 ~ 25 DEG C, puts into S-4- phenyl -2- oxazolidone 15.5g, and feed intake end, heat preservation, instead
It should be extracted completely with water and methyl tertiary butyl ether(MTBE), stratification, organic layer saturated common salt water washing, vacuum distillation obtains oil
Shape object.With the mixture stirred crystallization of ethyl acetate and hexane, suction filtration is washed with hexane, and vacuum drying obtains white solid
38.9g, molar yield 93.1%, HPLC purity 95.8%.It need not refine, can be directly used for lower step.1H NMR(400 MHz,
CDCl3) δ 7.393-7.313 (m, 3H), 7.280-7.220 (m, 2H), 6.990 (t, J=8.6,2H), 5.632
(dd, J=6.0,7.6,1H), 5.394 (dd, J=3.6,8.4,1H), 4.679 (t, J=8.8,1H),
4.272 (dd, J=3.6,9.2,1H), 3.016-2.886 (m, 2H), 1.931-1.598 (m, 4H), 1.174
(s,9H)
[α] D 20=+18.703 ° (C=1mol/L, methanol).
Embodiment 2:
It takes the type I compound of the 21.2g DMF of 110ml to dissolve, and is replaced with nitrogen, be cooled to -10 ~ 0 under nitrogen protection
DEG C, temperature is controlled, puts into the lithium hydride of 16g in batches, 0.5h is kept the temperature, is slowly added dropwise methylchloroformate 30.2g, control temperature -10 ~
0 DEG C, 1h is kept the temperature after being added dropwise, is warming up to 20 ~ 25 DEG C, puts into S-4- phenyl -2- oxazolidone 15.5g, feed intake end, protects
Temperature, fully reacting are extracted, stratification, organic layer saturated common salt water washing with water and methyl tertiary butyl ether(MTBE), vacuum distillation,
Obtain grease.With the mixture stirred crystallization of ethyl acetate and hexane, suction filtration is washed with hexane, and it is solid that vacuum drying obtains white
Body 38.8g product, molar yield 92.9%, HPLC purity 95%.It need not refine, can be directly used for lower step.
Embodiment 3:
It takes the type I compound of the 21.2g DMF of 110ml to dissolve, and is replaced with nitrogen, be cooled to -10 ~ 0 under nitrogen protection
DEG C, temperature is controlled, puts into the lithium hydride of 16g in batches, 0.5h is kept the temperature, is slowly added dropwise phenyl chloroformate 30.2g, control temperature -10 ~
0 DEG C, 1h is kept the temperature after being added dropwise, is warming up to 20 ~ 25 DEG C, puts into S-4- phenyl -2- oxazolidone 15.5g, feed intake end, protects
Temperature, fully reacting are extracted, stratification, organic layer saturated common salt water washing with water and methyl tertiary butyl ether(MTBE), vacuum distillation,
Obtain grease.With the mixture stirred crystallization of ethyl acetate and hexane, suction filtration is washed with hexane, and it is solid that vacuum drying obtains white
Body 38.8g product, yield 92.9%, HPLC purity 94%.It need not refine, can be directly used for lower step.
Claims (6)
1. a kind of preparation method of II compound of formula, which is characterized in that under the action of highly basic, type I compound and P1- Cl and formula
II compound of formula is prepared in the reaction of III compound,
Wherein P1For the alkoxy carbonyl group of C1-C8, the alkyl carbonyl or benzoyl of C1-C8.
2. preparation method according to claim 1, which is characterized in that under the action of highly basic, type I compound and pivaloyl
Chlorine and III compound of formula reaction preparation protecting group are II compound of formula of pivaloyl group,
3. preparation method according to claim 1 or 2, which is characterized in that the highly basic is hydrogenated alkali metal.
4. preparation method according to claim 1 or 2, which is characterized in that the reaction temperature is -20 DEG C~40 DEG C.
5. preparation method according to claim 1 or 2, which is characterized in that further prepare ezetimibe it is another in
IV compound of mesosome formula,
Wherein P1Definition it is identical as in claim 1.
6. preparation method according to claim 5, which is characterized in that the P1For pivaloyl group.
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| CN201410388343.XA CN105461649B (en) | 2014-08-08 | 2014-08-08 | A kind of Ezetimible intermediate and preparation method thereof |
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| CN201410388343.XA CN105461649B (en) | 2014-08-08 | 2014-08-08 | A kind of Ezetimible intermediate and preparation method thereof |
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| CN105461649A CN105461649A (en) | 2016-04-06 |
| CN105461649B true CN105461649B (en) | 2019-10-22 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010113175A2 (en) * | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
| CN103102297A (en) * | 2012-09-28 | 2013-05-15 | 北京赛林泰医药技术有限公司 | Synthesis method of novel atorvastatin |
| CN103450065A (en) * | 2013-07-15 | 2013-12-18 | 和鼎（南京）医药技术有限公司 | Preparation method of ezetimibe |
| CN103739537A (en) * | 2013-12-24 | 2014-04-23 | 连云港恒运医药科技有限公司 | New synthesis method of ezetimibe |
-
2014
- 2014-08-08 CN CN201410388343.XA patent/CN105461649B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010113175A2 (en) * | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
| CN103102297A (en) * | 2012-09-28 | 2013-05-15 | 北京赛林泰医药技术有限公司 | Synthesis method of novel atorvastatin |
| CN103450065A (en) * | 2013-07-15 | 2013-12-18 | 和鼎（南京）医药技术有限公司 | Preparation method of ezetimibe |
| CN103739537A (en) * | 2013-12-24 | 2014-04-23 | 连云港恒运医药科技有限公司 | New synthesis method of ezetimibe |
Non-Patent Citations (3)
| Title |
|---|
| Synthesis of Fluorescent Biochemical Tools Related to the 2-Azetidinone Class of Cholesterol Absorption Inhibitors;Duane A. Burnett等;《Bioorganic & Medicinal Chemistry Letters》;20121231;第12卷;参见第316页图1 * |
| Synthesis of Iodinated Biochemical Tools Related to the 2-Azetidinone Class of Cholesterol Absorption Inhibitors;Duane A. Burnett等;《Bioorganic & Medicinal Chemistry Letters》;20021231;第12卷;参见第312页第2栏图2 * |
| 羟基的保护;李敬芬;《药物合成反应》;杭州：浙江大学出版社;20100831;第70页第4行—第71页第9行 * |
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