CN102952055A - Preparation method of ezetimibe and its intermediate - Google Patents
Preparation method of ezetimibe and its intermediate Download PDFInfo
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- CN102952055A CN102952055A CN2011102348824A CN201110234882A CN102952055A CN 102952055 A CN102952055 A CN 102952055A CN 2011102348824 A CN2011102348824 A CN 2011102348824A CN 201110234882 A CN201110234882 A CN 201110234882A CN 102952055 A CN102952055 A CN 102952055A
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- 0 Cc(cc1)ccc1C(CC[C@]([C@@](C1C=CC(O*)=CC1)N1c(cc2)ccc2F)C1=O)=O Chemical compound Cc(cc1)ccc1C(CC[C@]([C@@](C1C=CC(O*)=CC1)N1c(cc2)ccc2F)C1=O)=O 0.000 description 4
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a preparation method of an ezetimibe intermediate compound as shown in formula II. The method includes the step of: in an organic solvent, in the absence of water and oxygen, and under the effects of an asymmetric hydrogenation catalyst and an organic alkali, subjecting compound I and hydrogen to an asymmetric catalytic hydrogenation reaction as shown in the following. Specifically, R is a conventional protecting group in the field, can protect a phenolic hydroxyl group and is stable under alkaline conditions. The asymmetric hydrogenation catalyst is a ruthenium-diphosphine-diamine catalyst invented by Ryoji Noyori, a Japanese scientist and a Nobel Prize winner. The preparation method provided in the invention has mild reaction conditions, can prepare products with high optical purity, yield and purity, and has after-treatment that is convenient to operate, thus being easy to realize industrialized production.
Description
Technical field
The present invention is specifically related to the preparation method of a kind of ezetimibe and its intermediate.
Background technology
Ezetimibe (Ezetimibe, formula III), chemistry (3R by name, 4S)-1-4-(4-fluorophenyl)-3-(3S)-3-[3-(4-fluorophenyl)-3-hydroxyphenyl propyl group]-4-(4-hydroxyphenyl)-2-azetidinone, that Schering Plough company cooperates with the Merck ﹠ Co., Inc., the common a kind of novel hypolipidemic of developing will go on the market through drugs approved by FDA the end of the year 2002, and commodity are called Zetia.
Patent US5631365 and US6627757 report, ezetimibe can by compound I-a, in the presence of the Corey of catalytic amount reagent, behind borane reduction, take off benzyl through palladium carbon and obtain (route 1) again.In this method, contain the isomer of 8-10% in the product that obtains after the reduction suc as formula shown in the II-b.Wherein, II-a is the Ezetimible intermediate that needs, and II-b is unwanted intermediate configuration, and the intermediate of this configuration is difficult to remove.If obtain the very high ezetimibe bulk drug of purity, aftertreatment is just very difficult.
Route 1
Patent US6133001 has reported that the stereoselectivity of utilizing microorganism comes direct-reduction ezetimibe-ketone to be ezetimibe.The ezetimibe optical purity that this method obtains is very high, but yield is less than 70% (route 2).
Route 2
What patent WO200815132A1 adopted is enzymatic method, is obtained the intermediate II of ezetimibe through enzyme catalysis by formula I.Although the method can obtain the II of high-optical-purity, because this method yield is on the low side, and the restriction of enzyme production itself, be not suitable for industry's enlarging production (route 4).
Route 3
Summary of the invention
Technical problem to be solved by this invention is among the preparation method for the midbody compound II that overcomes existing ezetimibe, severe reaction conditions, optical purity is low, productive rate is low or be not suitable for the defectives such as suitability for industrialized production, and the preparation method of a kind of ezetimibe and midbody compound thereof is provided.Preparation method's reaction conditions of the present invention is gentle, and the optical purity of product, yield and purity are all very high, and post-processing operation is convenient, easily realizes suitability for industrialized production.
Therefore, the present invention relates to a kind of preparation method of the midbody compound suc as formula the ezetimibe shown in the II, it comprises the following step: in the organic solvent, under the anhydrous and oxygen-free condition, under the effect of asymmetric hydrogenation catalyzer and organic bases, compound I and hydrogen are carried out asymmetric catalytic hydrogenation reaction as follows, get final product;
Wherein, R be the phenolic hydroxyl group protected of this area routine and under alkaline condition stable protecting group, described asymmetric hydrogenation catalyzer is the class ruthenium-two phosphines-diamine catalyzer of Nobel Laureate Japan scientist Ryoji Noyori invention.
Wherein biphosphine ligand can be BINAP, TangPhos, SEHGPHOS, DuPhos or their derivative; Preferred BINAP or derivatives thereof wherein.Diamine compound is main with 1,2-diamine compounds, and it can be chirality, also can be achirality, such as (R, R)-1, and 2-diphenyl ethylene diamine, (S, S)-1,2-diphenyl ethylene diamine etc.
Among the present invention, described asymmetric hydrogenation catalyzer is RuCl particularly preferably
2[(R)-xylbinap] ((R)-daipen), its structure is as follows:
Wherein, Ar is 3,5-3,5-dimethylphenyl.
Among the present invention, the silica-based protecting group that can be used for protecting phenolic hydroxyl group, alkyl protecting group, aralkyl protecting group or acyl group protecting group etc. for routine that described R is better.What wherein, described silica-based protecting group was better is t-Butyldimethylsilyl or trimethyl silicon based.That described aralkyl protecting group is better is C
6～C
10The C that aryl replaces
1～C
3Alkyl (such as benzyl).That described alkyl protecting group is better is C
1～C
3Alkyl is such as methyl.That described acyl group protecting group is better is C
1～C
3Alkyl-acyl group is such as ethanoyl.
Among the present invention, described organic solvent can be the organic solvent that is used for asymmetric catalysis of this area routine, such as in methyl alcohol, ethanol, Virahol, the trimethyl carbinol and the tetrahydrofuran (THF) etc. one or more, one or more that better is in ethanol, methyl alcohol and the Virahol, better is ethanol.The consumption of organic solvent can be popular response institute expense, and is better, and what the volume mass of itself and compound I was better is 5 milliliters :～20 milliliters of 1 grams: 1 gram, better is 10 milliliters :～15 milliliters of 1 grams: 1 gram.
Among the present invention, described organic bases can be this area organic bases commonly used, and such as in sodium methylate, sodium ethylate and the potassium tert.-butoxide etc. one or more, better is potassium tert.-butoxide.The consumption of organic bases can be catalytic amount used in the conventional asymmetric catalysis, and what the mol ratio of organic bases (such as potassium tert.-butoxide) and compound I was better is 1: 5～1: 50, and better is 1: 10～1: 20.
Among the present invention, the consumption of described asymmetric hydrogenation catalyzer can be the conventional amount used in the asymmetric hydrogenation, and what the mol ratio of itself and compound I was better is 1: 100～1: 10000, and better is 1: 500～1: 3000.
Among the present invention, the pressure of the hydrogen during described asymmetric catalytic hydrogenation reaction can be the conventional pressure of this area catalytic hydrogenation, and that better is 10～40atm, and that better is 20～30atm.
Among the present invention, the temperature of described asymmetric catalytic hydrogenation reaction can be the conventional temperature of this area catalytic hydrogenation, and better is 20～50 ℃, and better is 30～40 ℃.
Among the present invention, the reaction times of described asymmetric catalytic hydrogenation reaction can determine by the monitoring of this area ordinary method, preferably complete with HPLC monitoring raw material reaction till, be generally 5～12 hours, be preferably 8～10 hours.
Among the present invention, after described asymmetric catalytic hydrogenation reaction finished, the hydrogenated products that obtains need not aftertreatment, can directly carry out subsequent reactions, as slough the R group among the compound I I, carry out conventional aftertreatment, get final product high yield, the highly purified ezetimibe that obtains.
Therefore, the invention still further relates to a kind of preparation method of the ezetimibe shown in formula III, it comprises the following step:
(1) preparation method according to above-mentioned preparation compound I I prepares compound I I:
(2) reaction that the compound I I that step (I) is obtained sloughs the protecting group R of phenolic hydroxyl group gets final product.
In the step (2), the method for the reaction of the described protecting group R that sloughs phenolic hydroxyl group and ordinary method and the condition that condition can be this type of reaction of this area are such as the method among the patent WO2009150038A1.The preferred following method of the present invention and condition: when R was benzyl, the material that step (1) is obtained was without aftertreatment, with compound I I under the effect of palladium carbon and hydrogen reaction take off benzyl and get final product.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination namely get the preferred embodiments of the invention.
The catalyzer that relates among the present invention can be bought from Aldrich or Strem company.Starting compound I can buy from Nanjing Ou Xin company.
Except specified otherwise, agents useful for same of the present invention and raw material be commercially available getting all.
Positive progressive effect of the present invention is: among the present invention, in the asymmetric catalytic hydrogenation reaction, reaction conditions is gentle, catalytic efficiency d.e. value and the yield high, hydrogenated products of catalyzer are all higher, and by product is few, is an environment amenable synthetic route.Therefore, preparation method of the present invention is suitable for industrial scale operation, has broad application prospects.
Embodiment
Mode below by embodiment further specifies the present invention, but does not therefore limit the present invention among the described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example according to ordinary method and condition, or is selected according to catalogue.
Because ezetimibe has three chiral centres, now diastereomeric excess (d.e.) is defined as follows:
S, R, S-diastereomer R, R, S-diastereomer
Synthetic (the R=CH wherein of embodiment 1 formula II compound
2Ph)
With 0.5g (1 * 10
-3Mol) formula I compound, 5mg (4.4 * 10
-5Mol) potassium tert.-butoxide, 13mg (1.1 * 10
-5Mol) RuCl
2[(R)-and xylbinap] ((R)-daipen) and the degassed Virahol of 10mL add in glove box in the hydrogenation reaction cauldron of 50mL.Then hydrogenation is heated to 30 ℃ to 30atm, reacts 10 hours.Concentration of reaction solution obtains product 0.47g, yield 94%.Use the liquid-phase chromatographic analysis reaction solution, the d.e. value is 99.3%.Purity is 99.1%.
Wherein, liquid-phase condition is as follows:
HPLC (ee and de test condition): AD-H, 65% normal hexane+35% Virahol; 210nm, 30 ℃, 0.7 ml/min, sample dissolve with ethanol.
HPLC (purity test condition): Max-Rp, acetonitrile/water (0.1%HClO
4): 0 minute (40%: 60%); 10 minutes (80%: 20%); 20 minutes (90%: 10%); 30 minutes (40%: 60%), 210nm, 25 ℃, 1.0 ml/min.
1H?NMR(400MHz，CDCl
3)：δ7.42-7.20(m，11H)，7.02-6.89(m，6H)，5.04(s，2H)，4.72-4.69(m，1H)，4.56(d，J＝4.0，1H)，3.08-3.04(m，1H)，2.0-1.85(m，4H)。
Synthesizing of embodiment 2～9 formula II compounds (R is benzyl)
Investigate S/C (mol ratio of substrate and the catalyzer) value, catalyzer, solvent of asymmetric catalytic hydrogenation reaction to the impact of the ee value of product formula II.
According to the operating process of embodiment 1, reaction conditions is except listed condition in the table 1, and remaining reaction condition and analysis condition are all with embodiment 1.Experimental result sees Table 1:
Table 1 solvent, S/C value, temperature and pressure are on the impact of product ee value
Wherein, transformation efficiency is the ratio that compound I is converted into compound I I.D.e. value and HPLC purity are the detected result of the reaction solution after detection reaction finishes.
The result of table 1 shows, considers from aspects such as S/C value, reaction times, pressure, and the reaction conditions of embodiment 6 is optimum, can obtain the product of higher d.e. value within the relatively short time, and product purity is very high.
Synthesizing of embodiment 9～16 formula II compounds (R is benzyl)
According to the operating process of embodiment 1, reaction conditions is except listed condition in the table 2, and remaining reaction condition and analysis condition are all with embodiment 1.Experimental result sees Table 2:
Table 2
Wherein, transformation efficiency is the ratio that compound I is converted into compound I I.D.e. value and HPLC purity are the detected result of the reaction solution after detection reaction finishes.
Synthesizing of embodiment 17 ezetimibes
The reaction solution that embodiment 8 is obtained adds palladium charcoal 3g (10%Pd/C), and hydrogenation 5psi under the room temperature stirred 5～8 hours, then filters, concentrated, obtain solid crude product, again with the trimethyl carbinol and water recrystallization, can obtain pure ezetimibe 3.8g, 99%, two step of purity yield 92%.
1H?NMR(400MHz，DMSO-d6)：δ9.82(s，1H)，9.16(s，1H)，7.57-7.55(m，2H)，7.31-7.29(m，2H)，7.14-7.10(m，4H)，7.0-6.95(m，2H)，6.66-6.63(m，2H)，5.22(d，J＝4.4，1H)，4.50-4.49(m，1H)，2.80-2.75(m，1H)，1.64-1.52(m，4H)。
Claims (23)
1. preparation method suc as formula the midbody compound of the ezetimibe shown in the II, it is characterized in that comprising the following step: in the organic solvent, under the anhydrous and oxygen-free condition, under the effect of asymmetric hydrogenation catalyzer and organic bases, compound I and hydrogen are carried out asymmetric catalytic hydrogenation reaction as follows, get final product;
Wherein, R be the phenolic hydroxyl group protected of this area routine and under alkaline condition stable protecting group, described asymmetric hydrogenation catalyzer is the class ruthenium-two phosphines-diamine catalyzer of Nobel Laureate Japan scientist Ryoji Noyori invention.
2. preparation method as claimed in claim 1, it is characterized in that: in described ruthenium-two phosphines-diamine catalyzer, described biphosphine ligand is BINAP, TangPhos, SEHGPHOS, DuPhos or their derivative; Described diamine compound is 1,2-diamine compounds, and it is chirality or achirality.
3. preparation method as claimed in claim 2 is characterized in that: described diamine compound is (R, R)-1, and 2-diphenyl ethylene diamine or (S, S)-1, the 2-diphenyl ethylene diamine.
4. such as each described preparation method of claim 1～3, it is characterized in that: described asymmetric hydrogenation catalyzer is RuCl
2[(R)-xylbinap] ((R)-daipen), its structure is as follows:
Wherein, Ar is 3,5-3,5-dimethylphenyl.
5. such as each described preparation method of claim 1～3, it is characterized in that: described R is silica-based protecting group, alkyl protecting group, aralkyl protecting group or the acyl group protecting group of protection phenolic hydroxyl group.
6. preparation method as claimed in claim 5, it is characterized in that: described silica-based protecting group is t-Butyldimethylsilyl or trimethyl silicon based.
7. preparation method as claimed in claim 5, it is characterized in that: described aralkyl protecting group is benzyl.
8. preparation method as claimed in claim 5, it is characterized in that: described alkyl protecting group is C
1～C
3Alkyl.
9. preparation method as claimed in claim 5, it is characterized in that: described acyl group protecting group is C
1～C
3Alkyl-acyl group.
10. such as each described preparation method of claim 1～3, it is characterized in that: described organic solvent is one or more in methyl alcohol, ethanol, Virahol, the trimethyl carbinol and the tetrahydrofuran (THF).
11. preparation method as claimed in claim 10 is characterized in that: described organic solvent is one or more in ethanol, methyl alcohol and the Virahol.
12. such as each described preparation method of claim 1～3, it is characterized in that: described organic solvent is 5 milliliters with the volume mass ratio of compound I :～20 milliliters of 1 grams: 1 gram.
13. preparation method as claimed in claim 12 is characterized in that: the mass ratio of described organic solvent and compound I is 10 milliliters :～15 milliliters of 1 grams: 1 gram.
14. such as each described preparation method of claim 1～3, it is characterized in that: described organic bases is one or more in sodium methylate, sodium ethylate and the potassium tert.-butoxide.
15. such as each described preparation method of claim 1～3, it is characterized in that: the mol ratio of described organic bases and compound I is 1: 5～1: 50.
16. preparation method as claimed in claim 15 is characterized in that: the mol ratio of described organic bases and compound I is 1: 10～1: 20.
17. such as each described preparation method of claim 1～3, it is characterized in that: the mol ratio of described asymmetric hydrogenation catalyzer and compound I is 1: 100～1: 10000.
18. preparation method as claimed in claim 17 is characterized in that: the mol ratio of described asymmetric hydrogenation catalyzer and compound I is 1: 500～1: 3000.
19. such as each described preparation method of claim 1～3, it is characterized in that: the pressure of the hydrogen during described asymmetric catalytic hydrogenation reaction is 10～40atm.
20. preparation method as claimed in claim 19 is characterized in that: the pressure of the hydrogen during described asymmetric catalytic hydrogenation reaction is 20～30atm.
21. such as each described preparation method of claim 1～3, it is characterized in that: the temperature of described asymmetric catalytic hydrogenation reaction is 20～50 ℃; Till the reaction times of described asymmetric catalytic hydrogenation reaction is complete with HPLC monitoring raw material reaction.
22. preparation method as claimed in claim 21 is characterized in that: the temperature of described asymmetric catalytic hydrogenation reaction is 30～40 ℃.
23. the preparation method of the ezetimibe shown in formula III is characterized in that comprising the following step:
(1) prepare compound I I according to each described preparation method of claim 1～22:
(2) reaction that the compound I I that step (I) is obtained sloughs the protecting group R of phenolic hydroxyl group gets final product;
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104059009A (en) * | 2013-03-21 | 2014-09-24 | 四川金辉药业有限公司 | Ezetimibe important intermediate synthetic method |
| CN104356041A (en) * | 2014-11-06 | 2015-02-18 | 成都森科制药有限公司 | Preparation method for Ezetimibe |
| CN104447473A (en) * | 2014-11-06 | 2015-03-25 | 成都森科制药有限公司 | Preparation method of Ezetimibe intermediate |
| CN104860862A (en) * | 2015-04-09 | 2015-08-26 | 浙江普洛得邦制药有限公司 | Synthesis method of ezetimibe and intermediate thereof |
| WO2015133405A1 (en) * | 2014-03-06 | 2015-09-11 | 日産化学工業株式会社 | Method for manufacturing optically active azetidinone compound |
| CN105272852A (en) * | 2014-07-16 | 2016-01-27 | 浙江九洲药物科技有限公司 | Ezetimibe intermediate and preparation method |
| CN107991410A (en) * | 2017-11-24 | 2018-05-04 | 中山奕安泰医药科技有限公司 | A kind of detection method of ezetimibe intermediate |
| CN109809967A (en) * | 2019-03-04 | 2019-05-28 | 陕西师范大学 | A kind of method of synthesis of chiral alcohol |
| CN111518046A (en) * | 2020-06-04 | 2020-08-11 | 中山奕安泰医药科技有限公司 | Ezetimibe intermediate and preparation method of ezetimibe |
| CN112390738A (en) * | 2019-08-16 | 2021-02-23 | 凯特立斯（深圳）科技有限公司 | Ezetimibe intermediate compound and synthetic method of ezetimibe |
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| WO2008089984A2 (en) * | 2007-01-24 | 2008-07-31 | Krka | Process for the preparation of ezetimibe and derivatives thereof |
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Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104059009A (en) * | 2013-03-21 | 2014-09-24 | 四川金辉药业有限公司 | Ezetimibe important intermediate synthetic method |
| WO2015133405A1 (en) * | 2014-03-06 | 2015-09-11 | 日産化学工業株式会社 | Method for manufacturing optically active azetidinone compound |
| JPWO2015133405A1 (en) * | 2014-03-06 | 2017-04-06 | 日産化学工業株式会社 | Method for producing optically active azetidinone compound |
| CN105272852B (en) * | 2014-07-16 | 2019-04-23 | 浙江九洲药物科技有限公司 | A kind of Ezetimible intermediate and preparation method thereof |
| CN105272852A (en) * | 2014-07-16 | 2016-01-27 | 浙江九洲药物科技有限公司 | Ezetimibe intermediate and preparation method |
| CN104356041A (en) * | 2014-11-06 | 2015-02-18 | 成都森科制药有限公司 | Preparation method for Ezetimibe |
| CN104447473A (en) * | 2014-11-06 | 2015-03-25 | 成都森科制药有限公司 | Preparation method of Ezetimibe intermediate |
| CN104860862A (en) * | 2015-04-09 | 2015-08-26 | 浙江普洛得邦制药有限公司 | Synthesis method of ezetimibe and intermediate thereof |
| CN107991410A (en) * | 2017-11-24 | 2018-05-04 | 中山奕安泰医药科技有限公司 | A kind of detection method of ezetimibe intermediate |
| CN109809967A (en) * | 2019-03-04 | 2019-05-28 | 陕西师范大学 | A kind of method of synthesis of chiral alcohol |
| CN109809967B (en) * | 2019-03-04 | 2022-03-18 | 陕西师范大学 | Method for synthesizing chiral alcohol |
| CN112390738A (en) * | 2019-08-16 | 2021-02-23 | 凯特立斯（深圳）科技有限公司 | Ezetimibe intermediate compound and synthetic method of ezetimibe |
| CN112390738B (en) * | 2019-08-16 | 2023-03-31 | 凯特立斯（深圳）科技有限公司 | Ezetimibe intermediate compound and synthetic method of ezetimibe |
| CN111518046A (en) * | 2020-06-04 | 2020-08-11 | 中山奕安泰医药科技有限公司 | Ezetimibe intermediate and preparation method of ezetimibe |
| CN111518046B (en) * | 2020-06-04 | 2022-04-15 | 中山奕安泰医药科技有限公司 | Ezetimibe intermediate and preparation method of ezetimibe |
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