CN101974579A - Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid - Google Patents
Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid Download PDFInfo
- Publication number
- CN101974579A CN101974579A CN 201010540343 CN201010540343A CN101974579A CN 101974579 A CN101974579 A CN 101974579A CN 201010540343 CN201010540343 CN 201010540343 CN 201010540343 A CN201010540343 A CN 201010540343A CN 101974579 A CN101974579 A CN 101974579A
- Authority
- CN
- China
- Prior art keywords
- preparation
- ionic liquid
- lipase
- reaction
- fluorophenyl
- 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.)
- Pending
Links
- 0 CCOC(C(C(C(C(OCC)=O)C(N1*)=O)c(cc2)ccc2F)C1=O)=O Chemical compound CCOC(C(C(C(C(OCC)=O)C(N1*)=O)c(cc2)ccc2F)C1=O)=O 0.000 description 1
Landscapes
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention discloses a method for preparing a paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid, and relates to a method for preparing a chiral medicament intermediate based on bio-enzyme catalysis, in particular to a method for preparing (4R,5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxypiperidine-3-carboxylic acid (I) through biocatalysis. In the method, 4-(4-fluorophenyl)-1-R-2,6-dioxypiperidine-3,5-diethyl phthalate (II) is taken as a raw material, a bio-enzyme in a cosolvent-containing buffer solution system is taken as a catalyst, and the (4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxypiperidine-3-carboxylic acid (I) is prepared at the temperature of between 15 and 60 DEG C and the rotating speed of 100-250 revolutions per minute of a table concentrator. The provided preparation method has mild reaction condition, the maximum conversion rate of 98 percent, the highest purity of 96 percent and high atom utilization rate, meets the requirements of green chemistry and greatly reduces the production cost. The compound in the formula (I) can be prepare into an important paroxetine intermediate through decarboxylation, reduction and other steps, namely (3R,4S)-4-(4-fluorophenyl)-3-hydroxymethyl-1-R-piperidine (III).
Description
Technical field
The enzymatic selective hydrolysis prepares the novel method of paroxetine intermediate in a kind of ionic liquid, especially enzymatic selective hydrolysis preparation (4R in a kind of ionic liquid, 5S)-and 5-ethyl formate-4-(4-fluorophenyl)-1-R-2, the method for 6-dioxopiperidin-3-carboxylic acid belongs to the biocatalysis technology field.
Background technology
Along with the progress and the expanding economy of society, this novel illness of dysthymia disorders is just perplexing modern's life, has a strong impact on people's health level.The patients with depression whole world has reached more than 3.4 hundred million people at present, is the fourth-largest disease in the world, and it will rise to world's second largest disease (being only second to cardiovascular and cerebrovascular diseases) to predict the year two thousand twenty.A joint study of the World Health Organization, the World Bank and Harvard University shows, dysthymia disorders has become second serious disease of Chinese disease burden, but 10% the patient of only having an appointment has obtained effective treatment.Paroxetine is developed by U.S. Smith-Kline Beecham company the earliest, and released as thymoleptic in 1992, it is first serotonin reuptake inhibitor (SSRIs) medicine for the treatment of depressed and anxiety simultaneously, also is that one of the most general thymoleptic are used in the whole world at present.Paroxetine is as a kind of strong serotonin reuptake inhibitor, has curative effect aspect the depressant drug treatment certainly, side reaction has waited advantage less, and its domestic hospital administration amount of money increases year by year in recent years, therefore come first of all kinds of thymoleptic, develop paroxetine and intermediate will bring good economic and social benefit.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid (I) is synthetic (3S, 4R)-important intermediate of 4-(4-fluorophenyl)-3-methylol-1-R-piperidines (III), (3S, 4R)-4-(4-fluorophenyl)-3-methylol-1-R-piperidines (III) is called left-handed Paro alcohol again, is the important intermediate of synthetic thymoleptic paroxetine.Chinese patent CN200910101041.9 has reported that chirality 4-replaces-2,6-dioxopiperidin-3, and the preparation method of 5-diformate mono amides is shown below:
This method replaces-2 with 4-, 6-dioxopiperidin-3,5-dioctyl phthalate compounds is a raw material, under the effect of biological enzyme with organic amine or ammonia gas react, in organic solvent, replace-2,6-dioxopiperidin-3,5-diformate mono amides in 15-60 ℃ of preparation chirality 4-, yield＞85%, purity＞97%.
Core patent WO9322284A1, WO9403428A1, WO9802556A2 have reported and have utilized Carboxylesterase specificity hydrolyzing type (IV) compound paroxetine intermediate formula (IVA) compound, reduction can obtain the left-handed Paro alcohol of paroxetine important intermediate to this compound through a step, is shown below:
WO9322284A1 the mixed system of Tris damping fluid and DMSO (9: 1, adopt Pig Liver Esterase specificity hydrolyzing type (IV) compound paroxetine intermediate formula (IVA) compound in v/v), be 90: 10 (IVA) with (IVB) ratio of isomer.WO9403428A1 screens the bacterium producing multi enzyme preparation that obtains strain Achromobacter sp. by name at this route to surpassing 300 kinds of microorganisms, this reaction of enzyme catalysis of using separation and purification to obtain, and optimal pH is between 7-8, and final product ee value only is 30%.WO9802556A2 adopts molecular biology method to make up and produces the catalysis that the enzyme genetic engineering bacterium is used for this reaction, and yield is up to 90%-95%.The formula that this route uses (IV) compound is racemic modification, still has 50% isomer can not be used for the preparation of final paroxetine after the hydrolysis, so this route exists raw material availability low, the deficiency that production cost is high.
Core patent WO2009005647A2 has reported that biological enzyme selective hydrolysis formula V compound is through formula (VI) compound paroxetine intermediate formula (VII) compound, reduction can obtain the left-handed Paro alcohol of paroxetine important intermediate to this compound through a step, is shown below:
This method at first prepares the formula V compound, select then lytic enzymes such as esterase, lipase or proteolytic enzyme as catalyzer in buffer solution system behind the selectivity catalytic hydrolysis decarboxylation finally obtain formula (VII) compound, this route theoretical yield is 100%, with respect to the Split Method theoretical yield is for 50%, and this route raw material availability height, production cost be low, have more practical value.But for improving the mixed system that concentration of substrate has adopted damping fluid and organic solvent, the use of organic solvent is unfavorable for environment protection to this route in hydrolytic process.
Ionic liquid is as the existing more research report of the research of biocatalytic reaction medium and become the research focus gradually.Ionic liquid is called as " green liquid ", have a lot of organic solvents incomparable advantage: 1). a lot of organic compound are had good solvability; 2). there is not vapour pressure substantially, not flammable, excellent chemistry and thermostability are arranged, the easily separated compound that is dissolved in wherein can recycle; 3). designability is strong, can be by changing negatively charged ion or positively charged ion is regulated even thoroughly change ion liquid character, thus ionic liquid of " design " synthetic suitable certain special reaction; 4). can keep even improve catalytic activity, operational stability and the stereoselectivity of enzyme and microbe whole-cell.Therefore develop a kind of novel method that the enzymatic selective hydrolysis prepares the paroxetine intermediate of high-optical-purity in ionic liquid and will have good application prospects.
Summary of the invention
The purpose of this invention is to provide a kind of in ionic liquid the enzymatic selective hydrolysis prepare the novel method of the paroxetine intermediate of high-optical-purity, especially enzymatic selective hydrolysis preparation (4R in a kind of ionic liquid, 5S)-and 5-ethyl formate-4-(4-fluorophenyl)-1-R-2, the method for 6-dioxopiperidin-3-carboxylic acid.
The technical solution used in the present invention is:
With 4-(4-the fluorophenyl)-1-R-2 shown in the formula (II), 6-dioxopiperidin-3, the 5-dicarboxylate is a raw material, in the mixed system of ionic liquid and damping fluid, be catalyzer with the biological enzyme, 15-60 ℃, under the shaking speed 100-250rpm condition shown in the selective hydrolysis preparation formula (I) (4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, its reaction equation is:
Wherein, R is H, C
1-C
6Alkyl, C
2-C
6Alkylene, C
2-C
6Carbalkoxys such as alkynes base or tertbutyloxycarbonyl, carbobenzoxy-(Cbz), allyloxycarbonyl, fluorenylmethyloxycarbonyl, trimethylsilyl ethoxycarbonyl.
Described biological enzyme is selected from antarctic candidia lipase A (Lipase A from Candida antarctica), candida antarctica lipase B (Lipase B from Candida antarctica), porcine pancreatic lipase (Lipase from Porcine pancreatic), candida rugosa lipase (Lipase from Candida rugosa) onion burkholderia lipase (Lipase fromBurkholderia cepacia), aspergillus niger lipase (Lipase from Aspergillus niger), thermophilic fungus lipase (Lipasefrom Thermomyces lanuginosus), the rice mould lipase of black wool (Lipase from Mucor miehei), Pig Liver Esterase (Esterase from Porcine Liver), rabbit liver esterase (Esterase from Rabbit Liver), preferred antarctic candidia lipase A (Lipase A from Candida antarctica), candida antarctica lipase B (Lipase B from Candidaantarctica), Pig Liver Esterase (Esterase from Porcine Liver) or rabbit liver esterase (Esterase from Rabbit Liver).
Described formula (II) compound is 1 with the ratio of the quality of biological enzyme: 0.01-0.1, preferred 1: 0.02～0.03.
Described damping fluid is pH 6.0-8.0, the phosphate buffered saline buffer of 0.05-0.5M or pH 7.0-8.5, the Tris-HCl damping fluid of 0.05-0.5M.
Described ionic liquid is selected from [BMIm] [PF
6], [BMPy] [PF
6], [NMIm] [PF
6], [BMIm] [BF
4], [HMIm] [BF
4], [EMIm] [BF
4], [PMIm] [BF
4] or [BMIm] [NTf
2], preferred [BMIm] [PF
6], [BMPy] [PF
6] or [BMIm] [BF
4].
Described ionic liquid is 1 with the ratio of damping fluid: and 1-5 (W/V, g/ml).
Described reaction conditions is: temperature 15-60 ℃, and preferred 30 ℃; Rotating speed 100-250rpm; Reaction times 12-72h, preferred 18～30h.
This preparation method can pass through TLC monitoring reaction progress, and developping agent is that ethyl acetate and sherwood oil volume ratio are 1-2: 1 mixed solvent, developer are tetrabromo-mcresolsulfonphthalein solution.
This preparation method can pass through gas chromatographic detection reaction conversion ratio and product purity.
The method that the enzymatic selective hydrolysis prepares the paroxetine intermediate in the described ionic liquid is carried out according to following steps:
A. prepare the damping fluid of 0.05-0.5M, add ionic liquid, biological enzyme and formula (II) compound successively, described formula (II) compound concentration is 10mmol/L-150mmol/L, described formula (II) compound is 1 with the ratio of the quality of biological enzyme: 0.01-0.1, described ionic liquid is 1 with the ratio of damping fluid: and 1-5 (W/V, g/ml);
B. controlling reaction conditions is temperature 15-60 ℃, rotating speed 100-250rpm, and reaction times 12-48h, TLC tracking monitor reaction process is till reaction is no longer carried out;
C. centrifugal removal biological enzyme gets supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, adds ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
Reaction conversion ratio and product purity are passed through gas chromatography determination, Varian CP Wax 52CB polarity chromatographic column (30 * 0.25mm, 0.25 μ m), analytical conditions for gas chromatography is 250 ℃ of injection ports, 250 ℃ of detectors, column temperature keeps 2min for 140 ℃, is warming up to 240 ℃ with 10 ℃/min and keeps 10min, and carrier gas is H
2, flow velocity is 2.0mL/min, splitting ratio 1: 20, and tail blows N
2Flow velocity 25mL/min, burner H
2Flow velocity 30mL/min, air velocity 300mL/min.
Reaction conversion ratio c and product purity p are calculated as follows respectively:
A wherein, A
0---formula (II) compound concentrations before and after the reaction, g/L;
B---formula (I) compound concentrations that reaction generates, g/L;
B
0---the concentration of all products that reaction generates, g/L.
Beneficial effect of the present invention: the present invention has realized enzymatic selective hydrolysis preparation (4R in the ionic liquid, 5S)-and 5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, reaction conditions gentleness, simple to operate, the raw material availability height, the transformation efficiency theory can reach 100%, and actual conversion reaches 98%, purity reaches as high as 96%, and enzyme and ionic liquid can reuse, and environmental pollution is little, help reducing production costs.
The present invention uses the strong ionic liquid of the designability of the title with " green liquid " as reaction medium, ionic liquid has good solvability to a lot of organic compound, and it does not have vapour pressure substantially, have good chemistry and thermostability, help enzymatic activity, operational stability and stereoselective maintenance, it can recycle in addition, and product separates easily.The present invention has realized the preparation of paroxetine intermediate in ionic liquid, for the preparation of paroxetine provides a feasible approach.
Embodiment
Below in conjunction with specific embodiment the present invention is further described, but protection of the present invention is not limited in this:
Biological enzyme involved in the present invention and other reagent are market and buy gained, wherein antarctic candidia lipase A, porcine pancreatic lipase, candida rugosa lipase, onion burkholderia lipase, thermophilic fungus lipase, the mould lipase of rice black wool, pig liver esterase, rabbit liver esterase are available from sigma company, candida antarctica lipase B is available from novozymes (Novi's letter) company, and aspergillus niger lipase is available from Shenzhen green dimension health biotechnology company limited.
Adopt 4-(4-fluorophenyl)-1-methyl-2 among the embodiment, 6-dioxopiperidin-3,5-dicarboxylate are substrate, are called for short compound (IIA).
Embodiment 1.
Get 0.5g compound (IIA) in reactor, add 5.0ml, pH7.0, the phosphate buffered saline buffer of 0.2M, 1.5g ionic liquid [BMIm] [PF
6] and 10mg Lipase A from Candida antarctica, in water bath chader, react 24h under 30 ℃, 200rpm condition, during TLC follow the tracks of the detection reaction process.After reaction finished, centrifugal removal biological enzyme got supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, added ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds a small amount of anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, transformation efficiency 87%, purity 79%.
Embodiment 2.
Get 0.5g compound (IIA) in reactor, add 5.0ml, pH7.0, the phosphate buffered saline buffer of 0.2M, 1.5g ionic liquid [BMIm] [PF
6] and 10mg Lipase B from Candida antarctica, in water bath chader, react 18h under 30 ℃, 200rpm condition, during TLC follow the tracks of the detection reaction process.After reaction finished, centrifugal removal biological enzyme got supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, added ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds a small amount of anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, transformation efficiency 97%, purity 91%.
Embodiment 3.
Get 0.5g compound (IIA) in reactor, add 5.0ml, pH7.0, the phosphate buffered saline buffer of 0.2M, 1.5g ionic liquid [BMIm] [PF
6] and 15mg Esterase from Porcine Liver, in water bath chader, react 24h under 30 ℃, 200rpm condition, during TLC follow the tracks of the detection reaction process.After reaction finished, centrifugal removal biological enzyme got supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, added ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds a small amount of anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, transformation efficiency 98%, purity 88%.
Embodiment 4.
Get 0.5g compound (IIA) in reactor, add 5.0ml, pH7.0, the phosphate buffered saline buffer of 0.2M, 1.5g ionic liquid [BMIm] [PF
6] and 15mg Esterase from Rabbit Liver, in water bath chader, react 24h under 30 ℃, 200rpm condition, during TLC follow the tracks of the detection reaction process.After reaction finished, centrifugal removal biological enzyme got supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, added ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds a small amount of anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, transformation efficiency 94%, purity 96%.
Embodiment 5.
Get 0.5g compound (IIA) in reactor, add 5.0ml, pH7.5, the Tris-HCl damping fluid of 0.2M, 2.0g ionic liquid [BMPy] [PF
6] and 10mg Lipase B from Candida antarctica, in water bath chader, react 30h under 30 ℃, 200rpm condition, during TLC follow the tracks of the detection reaction process.After reaction finished, centrifugal removal biological enzyme got supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, added ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds a small amount of anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, transformation efficiency 79%, purity 93%.
Embodiment 6.
Get 0.5g compound (IIA) in reactor, add 5.0ml, pH7.5, the Tris-HCl damping fluid of 0.2M, 1.5g ionic liquid [BMIm] [BF
4] and 15mg Esterase from Rabbit Liver, in water bath chader, react 24h under 30 ℃, 200rpm condition, during TLC follow the tracks of the detection reaction process.After reaction finished, centrifugal removal biological enzyme got supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, added ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds a small amount of anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, transformation efficiency 85%, purity 89%.Embodiment 7.
Get 0.5g compound (IIA) in reactor, add 5.0ml, pH7.5, the Tris-HCl damping fluid of 0.2M, 1.5g ionic liquid [BMIm] [BF
4] and 15mg Esterase from Porcine Liver, in water bath chader, react 24h under 30 ℃, 200rpm condition, during TLC follow the tracks of the detection reaction process.After reaction finished, centrifugal removal biological enzyme got supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, added ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds a small amount of anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
(4R, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, transformation efficiency 75%, purity 86%.
Claims (10)
1. the enzymatic selective hydrolysis prepares the method for paroxetine intermediate in the ionic liquid, it is characterized in that described method is with 4-(4-the fluorophenyl)-1-R-2 shown in the formula (II), 6-dioxopiperidin-3, the 5-dicarboxylate is a raw material, in the mixed system of ionic liquid and damping fluid, be catalyzer with the biological enzyme, 15-60 ℃, (4R shown in the selective hydrolysis preparation formula (I) under the shaking speed 100-250rpm condition, 5S)-5-ethyl formate-4-(4-fluorophenyl)-1-R-2,6-dioxopiperidin-3-carboxylic acid, its reaction equation is:
Wherein, R is H, C
1-C
6Alkyl, C
2-C
6Alkylene, C
2-C
6Alkynes base or tertbutyloxycarbonyl, carbobenzoxy-(Cbz), allyloxycarbonyl, fluorenylmethyloxycarbonyl or trimethylsilyl ethoxycarbonyl.
2. preparation method as claimed in claim 1 is characterized in that described biological enzyme is selected from antarctic candidia lipase A, candida antarctica lipase B, porcine pancreatic lipase, candida rugosa lipase, onion burkholderia lipase, aspergillus niger lipase, thermophilic fungus lipase, the mould lipase of rice black wool, Pig Liver Esterase, the rabbit liver esterase, preferred antarctic candidia lipase A, candida antarctica lipase B, Pig Liver Esterase or rabbit liver esterase.
3. preparation method as claimed in claim 1 or 2 is characterized in that described formula (II) compound concentration is 10mmol/L-150mmol/L, and described formula (II) compound is 1 with the ratio of the quality of biological enzyme: 0.01-0.1, preferred 1: 0.02-0.03.
4. preparation method as claimed in claim 1 is characterized in that described damping fluid is pH 6.0-8.0, the phosphate buffered saline buffer of 0.05-0.5M or pH 7.0-8.5, the Tris-HCl damping fluid of 0.05-0.5M.
5. preparation method as claimed in claim 1 is characterized in that described ionic liquid is selected from [BMIm] [PF
6], [BMPy] [PF
6], [NMIm] [PF
6], [BMIm] [BF
4], [HMIm] [BF
4], [EMIm] [BF
4], [PMIm] [BF
4] or [BMIm] [NTf
2], preferred [BMIm] [PF
6], [BMPy] [PF
6] or [BMIm] [BF
4].
6. as claim 1,4 or 5 described preparation methods, it is characterized in that the described ionic liquid and the ratio of damping fluid are 1: 1-5 (W/V, g/ml).
7. preparation method as claimed in claim 1 is characterized in that described reaction conditions is: temperature 15-60 ℃, and preferred 30 ℃; Rotating speed 100-250rpm; Reaction times 12-72h, preferred 18～30h.
8. preparation method as claimed in claim 1 is characterized in that this preparation method can pass through TLC monitoring reaction progress, and developping agent is that ethyl acetate and sherwood oil volume ratio are 1-2: 1 mixed solvent, developer are tetrabromo-mcresolsulfonphthalein solution.
9. preparation method as claimed in claim 1 is characterized in that this preparation method can pass through gas chromatographic detection reaction conversion ratio and product purity.
10. preparation method as claimed in claim 1 is characterized in that reacting according to following steps and carries out:
A) damping fluid of preparation 0.05-0.5M, add ionic liquid, biological enzyme and formula (II) compound successively, described formula (II) compound concentration is 10mmol/L-150mmol/L, described formula (II) compound is 1 with the ratio of the quality of biological enzyme: 0.01-0.1, described ionic liquid is 1 with the ratio of damping fluid: and 1-5 (W/V, g/ml);
B) the control reaction conditions is temperature 15-60 ℃, rotating speed 100-250rpm, and reaction times 12-72h, TLC tracking monitor reaction process is till reaction is no longer carried out;
C) centrifugal removal biological enzyme gets supernatant liquor, and the supernatant liquor rotary evaporation is removed the ethanol of water and generation, adds ethyl acetate extraction, and raffinate reclaims ionic liquid, and extraction liquid adds anhydrous Na
2SO
4Drying, gas chromatographic analysis reaction conversion ratio and product purity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010540343 CN101974579A (en) | 2010-11-11 | 2010-11-11 | Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010540343 CN101974579A (en) | 2010-11-11 | 2010-11-11 | Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101974579A true CN101974579A (en) | 2011-02-16 |
Family
ID=43574487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010540343 Pending CN101974579A (en) | 2010-11-11 | 2010-11-11 | Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101974579A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103018350A (en) * | 2011-09-23 | 2013-04-03 | 石药集团中奇制药技术（石家庄）有限公司 | High performance liquid chromatography separation method of paroxol cis and trans isomers |
| CN103554010A (en) * | 2013-11-05 | 2014-02-05 | 衢州学院 | Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester |
| CN104892491A (en) * | 2015-05-06 | 2015-09-09 | 浙江海森药业有限公司 | Method for synthesizing paroxetine chiral intermediate |
-
2010
- 2010-11-11 CN CN 201010540343 patent/CN101974579A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103018350A (en) * | 2011-09-23 | 2013-04-03 | 石药集团中奇制药技术（石家庄）有限公司 | High performance liquid chromatography separation method of paroxol cis and trans isomers |
| CN103018350B (en) * | 2011-09-23 | 2014-06-25 | 石药集团中奇制药技术（石家庄）有限公司 | High performance liquid chromatography separation method of paroxol cis and trans isomers |
| CN103554010A (en) * | 2013-11-05 | 2014-02-05 | 衢州学院 | Synthetic process of 1-alkyl-4-p-fluorophenyl-2,6-piperadinedione-3-formic ester |
| CN103554010B (en) * | 2013-11-05 | 2015-11-04 | 衢州学院 | 1-alkyl-4-is to fluorophenyl-2,6-dioxopiperidine-3-manthanoate synthesis technique |
| CN104892491A (en) * | 2015-05-06 | 2015-09-09 | 浙江海森药业有限公司 | Method for synthesizing paroxetine chiral intermediate |
| CN104892491B (en) * | 2015-05-06 | 2017-05-17 | 浙江海森药业有限公司 | Method for synthesizing paroxetine chiral intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Kurbanoglu et al. | Asymmetric reduction of substituted acetophenones using once immobilized Rhodotorula glutinis cells | |
| CN100558905C (en) | A kind of enzyme splits the method for preparation (R)-6-hydroxyl-8-chloroctanoic acid ethyl ester | |
| Chen et al. | Efficient production of glycyrrhetic acid 3-O-mono-β-d-glucuronide by whole-cell biocatalysis in an ionic liquid/buffer biphasic system | |
| CN102321692A (en) | Preparation method for catalytic synthesis of caffeic acid phenethyl ester by using lipase in ionic liquid | |
| CN101974604B (en) | Method for preparing paroxetine intermediate through enzymatic resolution in ionic liquid | |
| Patti et al. | Breaking molecular symmetry through biocatalytic reactions to gain access to valuable chiral synthons | |
| Jin et al. | Enantioselective hydrolysis of epichlorohydrin using whole Aspergillus niger ZJB-09173 cells in organic solvents | |
| Liu et al. | Large‐scale synthesis of tert‐butyl (3R, 5S)‐6‐chloro‐3, 5‐dihydroxyhexanoate by a stereoselective carbonyl reductase with high substrate concentration and product yield | |
| CN102206686B (en) | Preparation method of methyl (R)-o-chloromandelate utilizing biocatalytic asymmetric reduction | |
| Singh et al. | Lipase catalyzed kinetic resolution for the production of (S)-3-[5-(4-fluoro-phenyl)-5-hydroxy-pentanoyl]-4-phenyl-oxazolidin-2-one: An intermediate for the synthesis of ezetimibe | |
| CN101974579A (en) | Method for preparing paroxetine intermediate by enzymatic selective hydrolysis in ionic liquid | |
| Koul et al. | Enzymatic resolution of naproxen | |
| CN102994429B (en) | Method for preparing (S)-alpha-ethyl-2-oxyen-1-pyrrolidine acetic acid ester through microorganism catalysis and bacterial strain | |
| Kurbanoglu et al. | Total production of (R)-3, 5-bistrifluoromethylphenyl ethanol by asymmetric reduction of 3, 5-bis (trifluoromethyl)-acetophenone in the submerged culture of Penicillium expansum isolate | |
| CN101319236A (en) | Method for biological catalysis of unsymmetrical reduction carbon based compound in water/ion liquid diphasic system | |
| Xie et al. | Stereoselective synthesis of a key chiral intermediate of (S)-Rivastigmine by AKR-GDH recombinant whole cells | |
| CN103966275A (en) | Method for preparing highly pure L-tertiary leucine through biological process | |
| CN103589665B (en) | Celebrating sheng, a reed pipe wind instrument rhodococcus and the application in preparation (S)-4-chloro-3-hydroxyl ethyl butyrate thereof | |
| de Aquino Bezerra et al. | Chemoenzymatic synthesis of both enantiomers of propafenone hydrochloride through lipase-catalyzed process | |
| CN102851238B (en) | Sphingobacterium and method for preparing levetiracetam acid by utilizing same | |
| CN101597626A (en) | Biocatalysis preparation (S)-(+)-2, the method for 2-dinethyl cyclopropane carboxylic acid | |
| CN104651425A (en) | Method for biological catalyzed synthesis of optically active alkyl lactone | |
| CN101709322A (en) | Method for synthesizing betulic acid by carrying out biocatalysis on betulin | |
| Yuan et al. | Kinetic model of resolution of 4-methoxymandelic acid enantiomers by lipase-catalyzed transesterification reaction | |
| CN1333068C (en) | Biological catalytic preparation of (S)-4-chlorine-3-hydroxy-butanoic acid ester and bacterium therewith |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20110216 |