CN104860862A - Synthesis method of ezetimibe and intermediate thereof - Google Patents
Synthesis method of ezetimibe and intermediate thereof Download PDFInfo
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- CN104860862A CN104860862A CN201510165655.9A CN201510165655A CN104860862A CN 104860862 A CN104860862 A CN 104860862A CN 201510165655 A CN201510165655 A CN 201510165655A CN 104860862 A CN104860862 A CN 104860862A
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- 0 *Oc1ccc([C@]([C@@](CCC(c(cc2)ccc2F)=O)C2=O)N2c(cc2)ccc2F)cc1 Chemical compound *Oc1ccc([C@]([C@@](CCC(c(cc2)ccc2F)=O)C2=O)N2c(cc2)ccc2F)cc1 0.000 description 3
- QCPXXURMJDPUPS-IQTBQJLQSA-N C/C=C\C(\F)=C/CC=C Chemical compound C/C=C\C(\F)=C/CC=C QCPXXURMJDPUPS-IQTBQJLQSA-N 0.000 description 1
- OAJDPLICMBYFCJ-XBXARRHUSA-N CC(C)CC/C(/F)=C\C Chemical compound CC(C)CC/C(/F)=C\C OAJDPLICMBYFCJ-XBXARRHUSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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Abstract
The invention discloses a synthesis method of ezetimibe and an intermediate thereof. According to the method, under the effect of a Ru catalyst, a ketone raw material and a hydrogen donor are subjected to an asymmetric transfer hydrogenation reaction, and post-treatment is carried out after the reaction is completed, such that ezetimibe and the intermediate thereof are obtained. The structure of the Ru catalyst is represented by the formula (III). According to the invention, a novel ruthenium (II)-pyridyl NNN complex is adopted as the catalyst, and the catalytic activity is excellent. The synthesis method is safe and environment-friendly, and has the advantages of mild conditions, less catalyst dose, high yield, and high product optical purity. The method is suitable for large-scale industrialized productions.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to the Chiral Synthesis of a kind of new Ezetimibe and intermediate thereof, more particularly, by a kind of Asymmetric hydrogen transfer reaction synthesis Ezetimibe and intermediate thereof of new chiral ruthenium complex catalysis.
Background technology
Ezetimibe is first the selectivity cholesterol absorption inhibitor class lipid lowerers developed jointly by Schering Plough and Merck & Co., Inc., in November, 2002 is in German Initial Public Offering, the same period goes on the market in the U.S., trade(brand)name benefit suitable pure (Ezetrol), preserves to can (Vytorin) also ratify to go on the market in July, 2004 through FDA with the compound preparation of Simvastatin.Ezetimibe related drugs wide market, exploitation Ezetimibe has significant society and economic benefit.
Up to now, report the synthetic route of many Ezetimibes in document, committed step common in these synthetic routes is the asymmetric reduction reaction to fluoro acetophenone intermediate of alpha-substitution.Wherein modal chiral reduction reaction is shown below:
Schering Plough company is at periodical literature (" A Novel One-step Diastereo-andEnantioselective Formation of trans-Azetidinones and Its Application to theTotal Synthesis of Cholesterol Absorption Inhibitors ", Guangzhong Wu etc., J.Org.Chem.1999, 64, 3714-3718) and describe formula II Ezetimibe intermediate in patent WO9745406 and prepare formula I target product by Corey-Bakshi-Shibata reduction reaction (be called for short CBS reduction), namely under the catalysis of chiral oxazaborolidine catalyzer, corresponding ketone is reduced with borane dimethylsulf iotade.CBS reduction method is widely used preparation method in Ezetimibe synthesis, but the maximum shortcoming of this operational path is safety and environmental protection problem.Borane dimethylsulf iotade is inflammable and explosive reagent, there is serious potential safety hazard, is unfavorable for suitability for industrialized production.Reaction produces stoichiometric borate abraum salt simultaneously, and environmental pollution is serious.
What Chinese patent application CN101423515 related to is reduces formula II Ezetimibe intermediate with (-)-diisopinocampheylchloroborane base chloroborane (abbreviation (-)-DIP-Cl).The shortcoming of this type of preparation method is that the borane dimethylsulf iotade that diisopinocampheylchloroborane base chloroborane and CBS reduction use exists identical safety and environmental protection problem, and cost is high.
International patent application WO2008151324 discloses formula II Ezetimibe intermediate under the catalysis of keto-aldehyde reductase enzyme Kred, reverts to formula I target product, and reductive agent is coenzyme NAD H or NADPH.The environmental protection of enzyme catalysis reduction method, but cost is higher.
International patent application WO2008089984 describes formula II Ezetimibe intermediate and revert to formula I target product by Asymmetric hydrogen transfer reaction under the catalysis of chiral ruthenium catalyst.The catalyzer adopted is ruthenium (II) title complex of chirality list sulfonic acid diamine part (abbreviation TsDPEN) coordination of Noroyi, and the hydrogen donor of use is carboxylic acid derivatives.In this technical scheme, the usage quantity of catalyzer is comparatively large, is generally 0.96 ~ 2.4mol% of substrate, due to catalyzer used and part price costly, be not suitable for large-scale application.
Summary of the invention
The object of this invention is to provide a kind of for the Ezetimibe of large-scale industrial production and the preparation method of intermediate thereof.
A synthetic method for Ezetimibe and intermediate thereof, comprising:
Under the effect of Ru catalyzer, ketone raw material and hydrogen donor carry out Asymmetric hydrogen transfer reaction, obtain described Ezetimibe and intermediate thereof after reacting completely through process later;
The structure of described Ru catalyzer is as shown in formula III:
The structure of described ketone raw material is as shown in formula II:
Described Ezetimibe and the structure of intermediate thereof are as shown in formula I:
Formula I is with in (II), and R is H, benzyl, replacement or unsubstituted C
1~ C
5alkyl;
Described C
1~ C
5substituting group on alkyl is halogen or phenyl.
The technique that the present invention adopts is the Asymmetric hydrogen transfer reaction of Noyori, is shown below:
The present invention, by adopting special catalyzer, greatly reduces the consumption of catalyzer, improves yield and the optical purity of product simultaneously, is applicable to large-scale industrial production.The preparation method of this catalyzer can with reference to (" the room temperature Asymmetric hydrogen transfer reaction of ruthenium-complex-catalyzed ketone of pyridyl NNN ", Yu Zhengkun etc., " catalysis journal " 2013,34,1373-1377)
The synthesis of catalyzer is shown below:
As preferably, the consumption of described Ru catalyzer is 0.2 ~ 0.5mol% of described ketone raw material.Through refining crystallization, product yield reaches as high as more than 90%, and optical purity is the highest more than 99%.So-called optical purity refers to, the percentage of formula I target product in formula I target product and its diastereomer.
As preferably, described R is H or Bn.As R=H in formula II, the target product of synthesis and Ezetimibe; As R=Bn in formula II, the target product of synthesis and the Ezetimibe of Ezetimibe intermediate-benzyl protection, can obtain Ezetimibe after catalytic hydrogenation debenzylation.
In the present invention, the selection of hydrogen donor can have a huge impact reaction effect, such as, when selecting Virahol-alkali (as potassium isopropoxide etc.) system, reaction effect is poor, easily produces multiple degradation impurity, and these impurity did not detect when adopting other hydrogen donor, the maximum contaminant relative retention time (RRT) that wherein ketone II a produces after reacting is 0.62, and structural formula is as shown in formula IV; As preferably, described hydrogen donor is formic acid-organic amine system or formate-aqueous systems; As further preferred, described hydrogen donor is formic acid-triethyl amine system or sodium formiate-aqueous systems.
Formic acid in described formic acid-triethyl amine system and the mol ratio of triethylamine are 5:1 ~ 5, most preferably are 5:2; Described sodium formiate-aqueous systems is environmentally friendly, and pollute few, the consumption of water is excessive, but reaction mostly is two phase reaction, sometimes needs to add phase-transfer catalyst, as cetyl trimethylammonium bromide (CTMAB).
Asymmetric hydrogen transfer reaction mild condition of the present invention, suitable range of reaction temperature, between 10 ~ 60 DEG C, is preferably 20 ~ 40 DEG C.
Described Asymmetric hydrogen transfer reaction carries out in a solvent, and described solvent is selected from least one in methylene dichloride, acetonitrile, DMF and methyl-sulphoxide.
When described hydrogen donor is formic acid-triethyl amine system, described solvent most preferably is methylene dichloride, and now, reaction yield is more than 90%, and the optical purity of reaction is more than 99%.
Described aftertreatment is included in alcohol-water system carries out recrystallization, and as preferably, described alcohol is methyl alcohol, ethanol or Virahol.
Compared with the existing technology, present invention employs a kind of new ruthenium (II)-pyridyl NNN title complex as catalyzer, being different from TsDPEN is a kind of bidentate nitrogen ligands, this raw catalyst coordination be a kind of three-tooth nitrogen ligand, catalytic activity is excellent, and synthesising method reacting condition is gentle, safety and environmental protection, catalyst levels is few, and the optical purity of yield and product is high, is applicable to the large-scale industrial production of Ezetimibe.
Embodiment
With reference to the following example, particular of the present invention is described.These embodiments illustrate the present invention, but not limit the present invention by any way.
Embodiment 1: ketone (II hydrogen transfer reactions a) taking formic acid-triethyl amine as hydrogen donor
Take 40.7g ketone II a (R=H, 0.1mol) in 1L reaction flask, vacuum nitrogen filling replaces three times.Add 250mL acetonitrile stirring and dissolving, temperature 10 DEG C in controlling.Again 0.17g ruthenium catalyst III (0.2mmol) and 52g formic acid-triethyl amine (mol ratio 5:2) are added reaction system, TLC follows the tracks of reaction to raw material point and disappears.Revolve and steam solvent to dry, residue volume ratio 1:2 Virahol: water recrystallization, suction filtration, washs three times, and wet product 40 DEG C of dried in vacuo overnight, obtain 37.6g Ezetimibe I a, yield 92%, and purity and optical purity detect through HPLC and be respectively 99.1%, 99.2%.Detection purity and optical purity (diastereomer) are same liquid phase process, lower same.
Embodiment 2: ketone (II hydrogen transfer reactions b) taking formic acid-triethyl amine as hydrogen donor
Take 49.8g ketone II b (R=Bn, 0.1mol) in 1L reaction flask, vacuum nitrogen filling replaces three times.Add 300mL methylene dichloride stirring and dissolving, temperature 30 DEG C in controlling.Again 0.17g ruthenium catalyst III (0.2mmol) and 52g formic acid-triethyl amine (mol ratio 5:2) are added reaction system, TLC follows the tracks of reaction to raw material point and disappears.Revolve and steam solvent to dry, residue volume ratio 1:2 ethanol: water recrystallization, suction filtration, wash three times, wet product 40 DEG C of dried in vacuo overnight, obtain 43.5g Ezetimibe intermediate I b, yield 87%, purity and optical purity detect through HPLC and are respectively 97.6%, 97.9%.
Embodiment 3: the ketone being hydrogen donor with sodium formiate-water (II hydrogen transfer reactions a)
Take 40.7g ketone II a (R=H, 0.1mol) and 3g cetyl trimethylammonium bromide (CTMAB), add in 1L reaction flask, vacuum nitrogen filling replaces three times.Add 200mL methylene dichloride and 200mL water stirring and dissolving, temperature 40 DEG C in controlling.Again 0.42g ruthenium catalyst III (0.5mmol) and 41g sodium formiate are added reaction system, TLC follows the tracks of reaction to raw material point and disappears.Reaction is cooled to room temperature, separate organic layer, wash three times again, organic phase is revolved and is steamed solvent to dry, residue volume ratio 1:3 methyl alcohol: water recrystallization, suction filtration, wash three times, wet product 40 DEG C of dried in vacuo overnight, obtain 33.6g Ezetimibe I a, yield 82%, purity and optical purity detect through HPLC and are respectively 92.3%, 92.4%.
Embodiment 4: the ketone being hydrogen donor with sodium formiate-water (II hydrogen transfer reactions b)
Take 49.8g ketone II b (R=Bn, 0.1mol) in 1L reaction flask, vacuum nitrogen filling replaces three times.Add 250mL methyl-sulphoxide and 150mL water stirring and dissolving, temperature 60 DEG C in controlling.Again 0.42g ruthenium catalyst III (0.5mmol), 41g sodium formiate are added reaction system, TLC follows the tracks of reaction to raw material point and disappears.Add 350mL water again, reaction is cooled to 0 DEG C, suction filtration, with volume ratio 1:2 Virahol: water washing three times, wet product 40 DEG C of dried in vacuo overnight, obtain 42.1g Ezetimibe intermediate I b, yield 84%, purity and optical purity detect through HPLC and are respectively 95.3%, 95.8%.
Embodiment 5: the ketone being hydrogen donor with potassium isopropoxide/Virahol (II hydrogen transfer reactions a)
Take 40.7g ketone II a (R=H, 0.1mol) in 1L reaction flask, vacuum nitrogen filling replaces three times.Add 250mL Virahol stirring and dissolving, temperature 20 DEG C in controlling.Again potassium isopropoxide/the aqueous isopropanol (20mL) of 0.17g ruthenium catalyst III (0.2mmol) and 0.1M is added reaction system, TLC follows the tracks of reaction to raw material point and disappears.Revolve and steam solvent to dry, residue volume ratio 1:2 Virahol: water recrystallization, suction filtration, washs three times, and wet product 40 DEG C of dried in vacuo overnight, obtain 31.1g Ezetimibe I a, yield 76%, and purity and optical purity detect through HPLC and be respectively 88.7%, 98.4%.Formula IV degradation impurity (RRT=0.62) is 4.6%, and unknown degradation impurity (RRT=0.26 and 1.92) is respectively 2.0%, 2.3%.
Claims (10)
1. a synthetic method for Ezetimibe and intermediate thereof, is characterized in that, comprising:
Under the effect of Ru catalyzer, ketone raw material and hydrogen donor carry out Asymmetric hydrogen transfer reaction, obtain described Ezetimibe and intermediate thereof after reacting completely through process later;
The structure of described Ru catalyzer is as shown in formula III:
The structure of described ketone raw material is as shown in formula II:
Described Ezetimibe and the structure of intermediate thereof are as shown in formula I:
Formula I is with in (II), and R is H, benzyl, replacement or unsubstituted C
1~ C
5alkyl;
Described C
1~ C
5substituting group on alkyl is halogen or phenyl.
2. the synthetic method of Ezetimibe according to claim 1 and intermediate thereof, is characterized in that, the consumption of described Ru catalyzer is 0.2 ~ 0.5mol% of described ketone raw material.
3. the synthetic method of Ezetimibe according to claim 1 and intermediate thereof, is characterized in that, described R is H or Bn.
4. the synthetic method of Ezetimibe according to claim 1 and intermediate thereof, is characterized in that, described hydrogen donor is formic acid-organic amine system or formate-aqueous systems.
5. the synthetic method of Ezetimibe according to claim 4 and intermediate thereof, is characterized in that, described hydrogen donor is formic acid-triethyl amine system or sodium formiate-aqueous systems.
6. the synthetic method of Ezetimibe according to claim 5 and intermediate thereof, is characterized in that, when described hydrogen donor is sodium formiate-aqueous systems, adds the phase-transfer catalyst of catalytic amount.
7. the synthetic method of Ezetimibe according to claim 1 and intermediate thereof, is characterized in that, the temperature of described Asymmetric hydrogen transfer reaction is 10 ~ 60 DEG C.
8. the synthetic method of Ezetimibe according to claim 1 and intermediate thereof, it is characterized in that, described Asymmetric hydrogen transfer reaction carries out in a solvent, and described solvent is selected from least one in methylene dichloride, acetonitrile, DMF and methyl-sulphoxide.
9. the synthetic method of Ezetimibe according to claim 1 and intermediate thereof, is characterized in that, described aftertreatment is included in alcohol-water system carries out recrystallization.
10. the synthetic method of Ezetimibe according to claim 9 and intermediate thereof, is characterized in that, described alcohol is methyl alcohol, ethanol or Virahol.
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| CN201510165655.9A CN104860862A (en) | 2015-04-09 | 2015-04-09 | Synthesis method of ezetimibe and intermediate thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285906A (en) * | 2007-01-24 | 2011-12-21 | 克尔克公司 | Preparation method of ezetimibe and derivatives thereof |
| CN102952055A (en) * | 2011-08-16 | 2013-03-06 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of ezetimibe and its intermediate |
| CN104059009A (en) * | 2013-03-21 | 2014-09-24 | 四川金辉药业有限公司 | Ezetimibe important intermediate synthetic method |
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2015
- 2015-04-09 CN CN201510165655.9A patent/CN104860862A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102285906A (en) * | 2007-01-24 | 2011-12-21 | 克尔克公司 | Preparation method of ezetimibe and derivatives thereof |
| CN102952055A (en) * | 2011-08-16 | 2013-03-06 | 凯瑞斯德生化(苏州)有限公司 | Preparation method of ezetimibe and its intermediate |
| CN104059009A (en) * | 2013-03-21 | 2014-09-24 | 四川金辉药业有限公司 | Ezetimibe important intermediate synthetic method |
Non-Patent Citations (1)
| Title |
|---|
| DU WANGMING，ET AL.: "Ru(II) pyridyl‐based NNN complex catalysts for (asymmetric) transfer hydrogenation of ketones at room temperature", 《CHINESE JOURNAL OF CATALYSIS》 * |
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