CN112390738A - Ezetimibe intermediate compound and synthetic method of ezetimibe - Google Patents
Ezetimibe intermediate compound and synthetic method of ezetimibe Download PDFInfo
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- 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 is applicable to the technical field of drug synthesis, and provides an ezetimibe intermediate compound and a synthetic method of ezetimibe, which comprise the following steps: adding an asymmetric hydrogenation reaction catalyst and alkali into a compound I in an organic solvent under anhydrous and oxygen-free conditions to carry out asymmetric catalytic hydrogenation reaction to obtain an ezetimibe intermediate compound, wherein the synthetic route is as follows:
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to an ezetimibe intermediate compound and a synthetic method of ezetimibe.
Background
Ezetimibe, chemically known as 1- (4-fluorophenyl) -3(R) - [3- (4-fluorophenyl) -3(S) -hydroxypropyl ] -4(S) - (4-hydroxyphenyl) -2-azetidine (azetidine) one, is a drug developed by the cooperation of pionba and merck for the regulation of blood lipids, is the first cholesterol-regulating inhibitor of monocyclic β -lactam functionality, and was approved by the FDA in the year 2002 for marketing in the united states under the trade name Zetia, otherwise known as yixichun.
There are many patents reporting methods for preparing key intermediates of ezetimibe, which are broadly classified into the following two categories: (1) obtained by reduction with borane in the presence of catalytic amounts of Corey reagent; about 8-10% of the isomers are produced in the process, are unwanted by-products, and are extremely difficult to remove; at the moment, if the ezetimibe bulk drug with high optical purity is to be obtained, recrystallization or resolution is needed, post-treatment is very difficult, and the reaction cost is correspondingly increased; (2) obtaining stereoselective products by microbial fermentation or enzyme catalysis; wherein, the microbial fermentation method is adopted to directly reduce ezetimibe ketone to obtain ezetimibe, and the obtained ezetimibe has high optical purity but low yield which is less than 70 percent; on the other hand, the enzyme catalysis method can obtain the ezetimibe intermediate with high optical purity, but the method is not suitable for industrial scale-up production due to low yield and production limit of the enzyme.
Therefore, the existing synthetic method of the ezetimibe intermediate generally has the problems of low yield, large impurities, high technical requirement, increased production cost and no contribution to industrial mass production.
Disclosure of Invention
The embodiment of the invention provides a synthetic method of an ezetimibe intermediate compound, and aims to solve the problems that the existing synthetic method of an ezetimibe intermediate is low in yield and large in impurity, or high in technical requirement, increases the production cost and is not beneficial to industrial mass production.
The embodiment of the invention is realized by a method for synthesizing an ezetimibe intermediate compound, which comprises the following steps:
adding an asymmetric hydrogenation reaction catalyst and alkali into a compound I in an organic solvent under anhydrous and oxygen-free conditions to carry out asymmetric catalytic hydrogenation reaction to obtain an ezetimibe intermediate compound, wherein the synthetic route is as follows:
the R group is one of a silicon-based protecting group for protecting a phenolic hydroxyl group, an alkyl protecting group, an aralkyl protecting group and an acyl protecting group.
The embodiment of the invention also provides a method for synthesizing ezetimibe, which comprises the following steps: the ezetimibe intermediate compound prepared by the synthesis method of the ezetimibe intermediate compound reacts with hydrogen under the action of palladium carbon to remove a protecting group R of a phenolic hydroxyl group, and the ezetimibe is obtained, wherein the synthesis equation is as follows:
compared with the existing similar intermediate, the synthetic method of the ezetimibe intermediate compound provided by the embodiment of the invention has the advantages that the stereoselectivity and the yield of the synthesized ezetimibe intermediate compound can be greatly improved, the stereoselectivity d.e. value is more than 99.9%, the catalytic efficiency of the catalyst is high, almost no by-product is generated, the whole process is rapid, simple and convenient, the cost is greatly reduced, the S/C reaches 100000, the post-treatment operation is convenient and simple, and the synthetic method is a green, efficient, environment-friendly route which can be applied to large-scale production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
According to the synthetic method of the ezetimibe intermediate compound provided by the embodiment of the invention, the compound I is added with an asymmetric hydrogenation reaction catalyst and alkali in an organic solvent under the anhydrous and oxygen-free conditions to carry out asymmetric catalytic hydrogenation reaction, so as to obtain the ezetimibe intermediate compound, and the synthetic route is as follows:
nomenclature for Compound I (3R,4S) -4- [4- (protecting group) phenyl ] -1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-oxopropyl ] azetidin-2-one.
Nomenclature for ezetimibe intermediate compounds (3R,4S) -1- (4-fluorophenyl) -3(R) - [3- (4-fluorophenyl) -3(S) -hydroxypropyl ] -4(S) - (4- (protecting group) phenyl) -2-azetidinone.
Wherein, the R group is a protecting group which is conventional in the field and can protect the phenolic hydroxyl group and is stable under alkaline conditions, and is one of a silicon-based protecting group, an alkyl protecting group, an aralkyl protecting group and an acyl protecting group for protecting the phenolic hydroxyl group; the silicon-based protecting group is tert-butyl dimethyl silicon-based or trimethyl silicon-based; the alkyl protecting group is C1-C3 alkyl; the aralkyl protecting group is benzyl; the acyl protecting group is C1-C3 alkyl-acyl.
In the present example, the asymmetric hydrogenation catalyst includes, but is not limited to, one of iridium complex catalysts of ferrocene type PNN type, PNO type tridentate ligands of commercially available dominant ligands; wherein, in the iridium PNN-based catalyst, the PNN ligand is f-amphox, f-amphetamine or derivatives thereof; in the iridium PNO catalyst, the PNO ligand is f-amphol, f-alpha or derivatives thereof.
Specifically, the asymmetric hydrogenation catalyst iridium PNN catalyst is prepared by in-situ complexing of f-amphox, f-amphamide and a metal precursor Ir complex in an organic solvent. The asymmetric hydrogenation catalyst iridium PNO catalyst is prepared by in-situ complexing of f-alpha, f-amphol and a metal precursor Ir complex in an organic solvent. The structure of the catalyst in the catalytic hydrogenation process is shown as follows:
among them, Ir- (R) -f-amphox mentioned above is a particularly preferred asymmetric hydrogenation catalyst in the examples of the present invention.
The transition metal Ir complex precursor includes: [ Ir (COD) Cl]2，Ir(COD)X，[Ir(COE)Cl]2，Ir(COD)X，[Ir(NBD)2Cl]2，[Ir(NBD)2]And (4) X. Wherein X is a counter anion such as BF4 -，ClO4 -，SbF6 -，PF6 -，CF3SO3 -And the like.
In the embodiment of the present invention, the organic solvent used is an organic solvent conventionally used in asymmetric hydrogenation catalytic reaction in the art, such as one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene, and 1, 2-dichloroethane, preferably one or more of dichloromethane, 1, 2-dichloroethane, and toluene. The amount of the organic solvent can be the amount required by the conventional reaction, and the volume ratio of the organic solvent to the compound I is preferably 1 ml: 1 g-20 ml: 1 g, more preferably 2 ml: 1 g-5 ml: 1 g, so that the S/C can be increased, the conversion rate can be increased, and the cost and the energy consumption can be reduced.
In the embodiment of the invention, the function of the alkali is to remove H on N on the catalyst, so as to facilitate subsequent synergistic hydrogenation on the substrate. The base used is conventional base in the art, such as one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium acetate, sodium carbonate, potassium carbonate, and cesium carbonate, preferably sodium hydroxide, potassium methoxide, and cesium carbonate. Most preferred is cesium carbonate. The amount of the base can be a catalytic amount used in a conventional reaction, and the preferable molar ratio of the base to the compound I is 1:100 to 1:1000, and more preferably 1:500 to 1: 1000.
In the embodiment of the present invention, the amount of the asymmetric hydrogenation catalyst is the conventional amount used in the asymmetric hydrogenation reaction, and the molar ratio of the asymmetric hydrogenation catalyst to the compound I is preferably 1:1000 to 200000, and more preferably 1:50000 to 100000.
In the embodiment of the present invention, the pressure of the asymmetric hydrogenation reaction is a conventional pressure of the asymmetric hydrogenation reaction. The pressure of hydrogen is preferably 20 to 80atm, more preferably 60 to 80 atm.
In the embodiment of the present invention, the temperature of the asymmetric hydrogenation is a common temperature for catalytic hydrogenation in the field, preferably 20 to 80 ℃, and more preferably 25 to 30 ℃.
The embodiment of the invention also provides a synthetic method of ezetimibe, which comprises the step of reacting an ezetimibe intermediate compound prepared by the synthetic method of the ezetimibe intermediate compound with hydrogen under the action of palladium carbon to remove a protective group R of a phenolic hydroxyl group, so that the ezetimibe is obtained, wherein the synthetic equation is as follows:
it is worth noting that the hydrogenation product can be directly subjected to subsequent protecting group removal reaction only by removing the solvent, and then the ezetimibe can be obtained with high yield and high optical purity by conventional post-treatment, and the method and conditions for removing the protecting group R of the phenolic hydroxyl group are conventional in the field of such reactions.
Compared with the existing similar intermediate, the ezetimibe intermediate compound synthesized by the embodiment of the invention has the advantages that the stereoselectivity and the yield can be greatly improved, the stereoselectivity d.e. value is more than 99.9%, the catalytic efficiency of the catalyst is high, almost no by-product is generated, the whole process is rapid, simple and convenient, the cost is greatly reduced, the S/C reaches 100000, the post-treatment operation is convenient and simple, and the ezetimibe intermediate compound is a green, efficient, environment-friendly route which can be applied to large-scale production.
The technical effects of the synthetic method of an ezetimibe intermediate compound of the present invention will be further described below by way of specific examples.
Example 1
Synthesis of catalyst metal complex:
in a glove box, (SC, SC, RFC) -f-amphox (6.1mg,0.011mmol,2.2equiv), [ Ir (COD) Cl]2(3.4mg,0.005mmol,1equiv), adding 1mL of ultra-dry isopropanol, stirring at room temperature for 1.0 h to prepare a catalyst metal complex with a concentration of 0.01mol/LAn agent;
taking the molar ratio S/C of the substrate to the catalyst as 50000 as an example:
in a glove box, the substrate ((3R,4S) -4- [ 4-benzylphenyl)]-1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-oxopropyl group]Azetidin-2-one, 4.97g,10mmol), adding Cs2CO3(32.5mg,0.10mmol), 10mL of toluene (concentration 1.0mol/L), and stirred at room temperature for 1 hour to dissolve the substrate and the base sufficiently. In a glove box, the above catalyst metal complex (20. mu.L, 0.2X 10) was added to the substrate solution with a micro-syringe-3mmol) and then the reaction flask was transferred to an autoclave, the reaction kettle was tightened and the kettle was removed from the glove box. Using 20atm H2After the autoclave body is replaced for three times, 60atm H is filled into the autoclave2The reaction was terminated immediately after closing the air inlet valve and stirring at room temperature for 60 hours. In a fume hood, the hydrogen in the kettle body is slowly exhausted by opening a deflation valve. The reaction solvent was spin-dried to obtain 4.74g of ezetimibe intermediate compound product with a yield of 95%, and the reaction solution was analyzed by liquid chromatography, d.e. value>99.9 percent and the purity is 99.6 percent.
Wherein, the liquid phase conditions are as follows:
d.e. value determination. Separation conditions are as follows: chiral OD-H column, Hex:iPrOH 85:15, flow rate 1.0mL/min, temperature 27 deg.C, time setting 30min, 210nm, tminor＝20.67min，Tmajor＝23.54min。
Purity determination conditions: poroshell 120 EC-C18(2.7 μm, 4.6 x 100mm), CH3CN:H2O70: 30, flow rate of 0.6mL/min, temperature of 27 °
1H NMR(400MHz，CDCl3):δ:7.42～7.25(m,11H)；7.05～6.93(m,6H)；5.08(s,2H)；4.75～4.72(m,1H)；4.60(d,J＝2.2Hz,1H)；3.11-3.08(m,1H)；2.03～1.90(m,4H)。
On the basis of example 1, the following example 2(200g scale up experiment) was carried out:
example 2
In a glove box, the substrate (198.8g,0.4mol) was added to the reaction kettle, and Cs was added2CO3(1.3g,4.0mmol), 400mL of toluene (concentration 1.0mol/L), stirring at room temperatureStirring for 1 hour to fully dissolve the substrate and the alkali. In a glove box, the catalyst metal complex (0.8mL, 0.2X 10) was added to the substrate solution with a syringe-3mmol), screwing down the reaction kettle, and moving the kettle out of the glove box. Using 20atm H2After the autoclave body is replaced for three times, 60atm H is filled into the autoclave2The reaction was terminated immediately after closing the air inlet valve and stirring at room temperature for 60 hours. In a fume hood, the hydrogen in the kettle body is slowly exhausted by opening a deflation valve. The reaction solvent was dried by spinning to obtain 193.3g of ezetimibe intermediate compound product with a yield of 96%, and the reaction solution was analyzed by liquid chromatography to obtain a d.e. value>99.9% and the purity is 99.4%.
In conclusion, compared with the existing similar intermediate, the ezetimibe intermediate compound synthesized by the embodiment of the invention has the advantages that the stereoselectivity and the yield can be greatly improved, the stereoselectivity d.e. value is more than 99.9%, the catalytic efficiency of the catalyst is high, almost no by-product is generated, the post-treatment operation is convenient and simple, and the ezetimibe intermediate compound is a green, efficient and environment-friendly route which can be applied to large-scale production.
Further, in order to examine the influence of the kind of the base used in the asymmetric catalytic hydrogenation reaction on the conversion rate and d.e. value of the ezetimibe intermediate compound, on the basis of the synthesis process of example 1, except the kind of the base, the following examples 3-14 were performed according to the same experimental conditions (0.5 g (1.0mmol) of the substrate, 1000S/C, 1mL (1.0 mol/L) of isopropanol as the organic solvent, 25-30 ℃ of temperature, 20atm of pressure, and 12 hours of time) except the change of the kind of the base, and the influence results of different bases on the conversion rate and d.e. value of the ezetimibe intermediate compound are shown in table 1.
TABLE 1
From Table 1, it is understood that when cesium carbonate is used as a base, the conversion rate is as high as 99% and the d.e. is as high as 96.8% under the conditions that the substrate is 0.5g (1.0mmol), the S/C is 1000, the solvent is 1mL of isopropyl alcohol, the temperature is room temperature, the pressure is 20atm, and the time is 12 hours, that is, the reaction effect is the best, and the base is cesium carbonate because the reaction effect is far superior to that when other bases are used.
Further, in order to examine the influence of the kind of the organic solvent used for the asymmetric catalytic hydrogenation reaction on the conversion rate of the ezetimibe intermediate compound and the d.e. value, in addition to the change of the kind of the organic solvent, conditions (0.5 g (1.0mmol) of the substrate, 1000S/C, Cs) were further changed in example 52CO33.25mg (0.01mg), concentration of organic solvent 1.0mol/L, temperature 25-30 ℃, pressure 20atm, time 12 hours) were kept constant, the following examples 15-21 were carried out, and the results of the effect of different organic solvents on the conversion rate and d.e. value of ezetimibe intermediate compound are shown in Table 2 below.
TABLE 2
| Examples | 15 | 16 | 17 | 18 | 19 | 20 | 21 |
| Solvent(s) | Methanol | Ethanol | Isopropanol (I-propanol) | DCM | DCE | THF | Toluene |
| Conversion (%) | 10 | 15 | 99 | 99 | 99 | 99 | 99 |
| d.e.(％) | -- | -- | 96.8 | 98.4 | 99.7 | 96.4 | 99.9 |
As can be seen from Table 2, the amount of Cs in the substrate was 0.5g (1.0mmol), S/C was 10002CO3Under the conditions of 3.25mg (0.01mg), 25-30 ℃ of temperature, 20atm of pressure and 12 hours of time, when the organic solvent adopts toluene, the conversion rate is up to 99 percent, and the d.e. is up to 99.9 percent, namely the reaction effect is best, and is far better than that of other organic solvents, so the organic solvent is preferably toluene.
Further, in the present invention, the alkali was determined as cesium carbonate and the organic solvent was determined as toluene based on the above examples, and the high S/C experiments and the scale-up experiments of examples 21 to 31 were carried out based on the synthetic process of example 1, and the experimental conditions and the results of the effects on the conversion rate and d.e. value of the ezetimibe intermediate compound are shown in table 3:
TABLE 3
In summary, as can be seen from table 3, in the synthetic method of an ezetimibe intermediate compound provided in the embodiment of the present invention, compared with the existing similar intermediate, the stereoselectivity and yield of the synthesized ezetimibe intermediate compound can be greatly improved, the stereoselectivity d.e. value is greater than 99.9%, the catalytic efficiency of the catalyst is high, almost no by-product is generated, the overall process is fast, simple and convenient, the cost is greatly reduced, the S/C is as high as 100000, and the post-treatment operation is convenient and simple, so that the synthetic method is a green, efficient, environment-friendly route applicable to large-scale production.
Further, in order to examine the influence of different R groups carried by the substrate on the conversion rate and d.e. value of the synthesized ezetimibe intermediate compound in the asymmetric hydrogenation reaction, on the basis of example 24, the substrate was 1.0mmol, S/C was 50000, and Cs was present2CO3The concentration of 3.25mg (0.01mmol) of the ezetimibe intermediate compound is controlled, the temperature is controlled to be 25-30 ℃, the substrate is changed, the R group of the substrate compound I is changed into Boc, TIPS, TBDPS, OAC, PMB and MOM groups in sequence, other components, contents and process conditions are not changed, the following examples 32-37 are carried out, and the influence results of different protection groups on the conversion rate and the d.e. value of the ezetimibe intermediate compound are shown in the following table 4.
TABLE 4
| Examples | 32 | 33 | 34 | 35 | 36 | 37 |
| Protecting group | Boc | TIPS | TBDPS | OAC | PMB | MOM |
| Conversion (%) | 90 | 70 | 65 | 75 | 95 | 40 |
| d.e.(％) | 99.9 | 99.6 | 99.5 | 99.0 | 99.9 | 98.0 |
From table 4, it is clear that the type of protecting group has little effect on the d.e. value of the ezetimibe intermediate compound, but has a significant effect on the conversion of the ezetimibe intermediate compound, and that the conversion of the synthesized ezetimibe intermediate compound is significantly higher than that of the other protecting groups selected in examples 32-37 when the protecting group is benzyl, as compared with example 24.
In addition, in order to examine the effect of the concentration of the organic solvent used in the asymmetric hydrogenation reaction on the conversion of the synthesized ezetimibe intermediate compound, 0.5g (1.0mmol) of the substrate, 50000 for S/C, and Cs for example 24 were used2CO33.25mg (0.01mmol), 25-30 ℃, the other components, the content and the process conditions are not changed, the concentration of the organic solvent is changed, and the examples 38-44 are carried out; the results of the effect of different organic solvent concentrations on the conversion of the ezetimibe intermediate compound are shown in table 5 below.
TABLE 5
From table 5, it is understood that the higher the concentration of the organic solvent is, the higher the conversion rate of the obtained ezetimibe intermediate compound is, but in example 44, it is shown that the conversion rate is lowered when the concentration of the organic solvent reaches 1.4mol/L, and therefore, the solubility of the organic solvent is preferably 0.8 to 1.0mol/L in view of cost.
Example 45
After the solvent was removed from the reaction solution obtained in example 24, 0.25g of ethanol and palladium on carbon (5% Pd/C) were added, and after evacuation, hydrogen gas 2atm was added, and the mixture was stirred at room temperature for 4 hours, followed by filtration, concentration, and recrystallization from acetonitrile and water to obtain 3.8g of pure ezetimibe product with a purity of 99% and a yield of 92% in two steps.
1H NMR(400MHz,CDCl3)δ:7.30～7.17(m,6H)；7.03～6.82(m,6H)；4.71(t,J＝5.6Hz 1H)；4.56(d,J＝1.8Hz,2H)；3.06～3.05(m,1H)；1.98～1.88(m,4H)。
According to the synthesis method of ezetimibe provided by the embodiment of the invention, the hydrogenation product can be directly subjected to subsequent protecting group removal reaction only by removing the solvent, and then the ezetimibe can be obtained with high yield and high optical purity by conventional post-treatment, so that the whole process is faster, simpler and more convenient and the cost is greatly reduced compared with the conventional synthesis method of ezetimibe.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. A method for synthesizing an ezetimibe intermediate compound, which is characterized by comprising the following steps:
adding an asymmetric hydrogenation reaction catalyst and alkali into a compound I in an organic solvent under anhydrous and oxygen-free conditions to carry out asymmetric catalytic hydrogenation reaction to obtain an ezetimibe intermediate compound, wherein the synthetic route is as follows:
the R group is one of a silicon-based protecting group for protecting a phenolic hydroxyl group, an alkyl protecting group, an aralkyl protecting group and an acyl protecting group.
2. The method for synthesizing an ezetimibe intermediate compound as claimed in claim 1, wherein the asymmetric hydrogenation catalyst is one of iridium complex catalysts of ferrocene type PNN tridentate ligands and PNO tridentate ligands.
3. The method for synthesizing an ezetimibe intermediate compound as claimed in claim 1, wherein the organic solvent is one or more of methanol, ethanol, isopropanol, dichloromethane, tetrahydrofuran, toluene, and 1, 2-dichloroethane.
4. The method for synthesizing an ezetimibe intermediate compound as claimed in claim 1, wherein the base is one or more of sodium hydroxide, potassium hydroxide, sodium methoxide, potassium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium acetate, sodium carbonate, potassium carbonate, and cesium carbonate.
5. The method for synthesizing an ezetimibe intermediate compound as claimed in claim 1, wherein the molar ratio of the base to the compound I is 1:10 to 1: 1000.
6. The method of synthesizing an ezetimibe intermediate compound of claim 1, wherein the molar ratio of the asymmetric hydrogenation catalyst to compound I is 1:1000 to 100000.
7. The method for synthesizing an ezetimibe intermediate compound as claimed in claim 1, wherein the volume-to-mass ratio of the organic solvent to the compound I is 1 ml: 1 g to 20 ml: 1 g.
8. The method for synthesizing an ezetimibe intermediate compound according to claim 1, wherein the pressure of hydrogen gas during the asymmetric hydrogenation catalytic reaction is 20 to 80 atm.
9. The method of synthesizing an ezetimibe intermediate compound as claimed in claim 1, wherein the temperature of the asymmetric hydrogenation catalytic reaction is 20-80 ℃.
10. A method for synthesizing ezetimibe, which is characterized by comprising the following steps: the ezetimibe intermediate compound prepared by the method for synthesizing the ezetimibe intermediate compound according to any one of claims 1 to 9, which is reacted with hydrogen under the action of palladium carbon to remove the protecting group R of phenolic hydroxyl, so that ezetimibe is obtained, wherein the synthesis equation is as follows:
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102126954A (en) * | 2009-12-15 | 2011-07-20 | 中国科学院成都有机化学有限公司 | New synthesis method of optically pure lactone |
| 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 |
| CN105153229A (en) * | 2015-06-18 | 2015-12-16 | 武汉凯特立斯科技有限公司 | Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation |
| CN105732725A (en) * | 2016-01-30 | 2016-07-06 | 武汉凯特立斯科技有限公司 | Chiral tridentate nitrogen-phosphine-oxygen ligands and application of related ligands in asymmetric catalytic reactions |
| CN106632511A (en) * | 2016-12-01 | 2017-05-10 | 武汉凯特立斯科技有限公司 | Chiral tridentate phosphonic amine ligand and application thereof in asymmetric catalytic reaction |
| CN107021884A (en) * | 2017-04-27 | 2017-08-08 | 武汉凯特立斯科技有限公司 | Method for efficiently synthesizing chiral 1, 2-amino alcohol by catalyzing alpha-aminoketone through Ir/f-amphox |
| CN107417562A (en) * | 2017-08-14 | 2017-12-01 | 凯特立斯（深圳）科技有限公司 | It is catalyzed the method for prochirality alpha ketoamide synthesis of chiral α hydroxy amides |
| CN107722068A (en) * | 2017-11-09 | 2018-02-23 | 凯特立斯（深圳）科技有限公司 | Three tooth aminophosphine ligands and its complex and its application in the asymmetric catalytic hydrogenation of ketone |
-
2019
- 2019-08-16 CN CN201910760279.6A patent/CN112390738B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102126954A (en) * | 2009-12-15 | 2011-07-20 | 中国科学院成都有机化学有限公司 | New synthesis method of optically pure lactone |
| 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 |
| CN105153229A (en) * | 2015-06-18 | 2015-12-16 | 武汉凯特立斯科技有限公司 | Chiral tridentate PNN ligand and application of same in asymmetric hydrogenation |
| CN105732725A (en) * | 2016-01-30 | 2016-07-06 | 武汉凯特立斯科技有限公司 | Chiral tridentate nitrogen-phosphine-oxygen ligands and application of related ligands in asymmetric catalytic reactions |
| CN106632511A (en) * | 2016-12-01 | 2017-05-10 | 武汉凯特立斯科技有限公司 | Chiral tridentate phosphonic amine ligand and application thereof in asymmetric catalytic reaction |
| CN107021884A (en) * | 2017-04-27 | 2017-08-08 | 武汉凯特立斯科技有限公司 | Method for efficiently synthesizing chiral 1, 2-amino alcohol by catalyzing alpha-aminoketone through Ir/f-amphox |
| CN107417562A (en) * | 2017-08-14 | 2017-12-01 | 凯特立斯（深圳）科技有限公司 | It is catalyzed the method for prochirality alpha ketoamide synthesis of chiral α hydroxy amides |
| CN107722068A (en) * | 2017-11-09 | 2018-02-23 | 凯特立斯（深圳）科技有限公司 | Three tooth aminophosphine ligands and its complex and its application in the asymmetric catalytic hydrogenation of ketone |
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