CN111196781A - Improved method for preparing penfluridol - Google Patents
Improved method for preparing penfluridol Download PDFInfo
- Publication number
- CN111196781A CN111196781A CN201811365258.6A CN201811365258A CN111196781A CN 111196781 A CN111196781 A CN 111196781A CN 201811365258 A CN201811365258 A CN 201811365258A CN 111196781 A CN111196781 A CN 111196781A
- Authority
- CN
- China
- Prior art keywords
- fluorophenyl
- bis
- reaction
- penfluridol
- butyric acid
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses an improved method for preparing penfluridol, which comprises the following steps: 4, 4-bis (4-fluorophenyl) butyric acid is used as an initial raw material to synthesize an intermediate I [4, 4-bis (4-fluorophenyl) -1-butanol through reduction](ii) a Then the intermediate II [4, 4-bis (4-fluorophenyl) -1 (4-methyl-phenyl) -butyl sulfonate is synthesized by esterification with sulfonyl chloride compounds]Or [4, 4-bis (4-fluorophenyl) -1-methyl-sulfonic acid butyl ester](ii) a The method takes 4, 4-bis (4-fluorophenyl) butyric acid as a raw material, and obtains the penfluridol through reduction reaction, esterification reaction and condensation reaction, wherein the total yield is 81.3 percent, the whole process is convenient to operate, the reaction is mild, and the obtained product has high yield and good purity, so that the method is a more economic preparation method which is more suitable for industrial application. Solves the technical problems of lower yield and poor purity of the existing method. The reaction formula is as follows:
Description
Technical Field
The present invention relates to a process for the preparation of pentafluridol.
Background
The chemical name of the pentafluridol is [1- [4, 4-bis (4-fluorophenyl) butyl ] -4- [ 4-chloro-3- (trifluoromethyl) phenyl ] -4-piperidinol ], the English name is Penfluridol, and the chemical structural formula is as follows:
the penfluridol belongs to diphenylbutylpiperidine compounds, and is white or off-white crystalline powder; no odor and no taste; is soluble in methanol, ethanol, acetone or a trichloro-methyl; is practically insoluble in water; the melting point is 105-108 ℃. The penfluridol is a long-acting oral antipsychotic drug which is marketed in the 60 th of the 20 th century, is suitable for acute and chronic schizophrenia, is particularly convenient for long-term administration maintenance treatment, and prevents relapse.
Chinese patent document CN106187863A discloses a method for preparing penfluridol, which uses fluorobenzene as a starting material, and performs a side reaction, a reduction reaction, a Friedel-Crafts reaction, a condensation reaction, and a reduction reaction to finally obtain penfluridol, wherein the reaction formula is as follows:
however, the total yield of the three reactions from 4, 4-bis (4-fluorophenyl) butyric acid to pentafluridol is only 40-50%, and particularly, the final step of amide reduction reaction has more impurities and low product purity, and can meet the qualified requirement only by refining and purifying for many times.
Disclosure of Invention
It is an object of the present invention to provide an improved process for the preparation of penfluridol which overcomes the disadvantages of the prior art.
The method takes 4, 4-bis (4-fluorophenyl) butyric acid as an initial raw material, and synthesizes an intermediate I [4, 4-bis (4-fluorophenyl) -1-butanol ] through reduction;
then esterifying the intermediate II [4, 4-bis (4-fluorophenyl) -1 (4-methyl-phenyl) -butyl sulfonate ] or [4, 4-bis (4-fluorophenyl) -1-methyl-butyl sulfonate ];
then condensing with piperidinol to obtain the pentafluridol, wherein the reaction formula is as follows:
further, a method for synthesizing an intermediate I from 4, 4-bis (4-fluorophenyl) butyric acid, comprising the following steps:
mixing 4, 4-bis (4-fluorophenyl) butyric acid with an organic solvent at the temperature of 10-60 ℃, then adding a decolorizing agent, cooling to the temperature of-30-10 ℃, adding a reducing agent, reacting for 1-5h, then quenching with water, then sequentially adding an alkaline solution for water treatment, then stirring at the temperature of 0-45 ℃, then filtering, and finally collecting the intermediate I from the filtrate;
further, the alkali liquor is an aqueous solution of sodium hydroxide, wherein the concentration of the sodium hydroxide is 4.0-5.0 mol/L.
Further, the organic solvent is methyltetrahydrofuran, tetrahydrofuran, or the like;
the decolorant is potassium carbonate or neutral alumina and the like;
the reducing agent is lithium aluminum hydride or borane and the like.
Further, the volume ratio of the 4, 4-bis (4-fluorophenyl) butyric acid to the organic solvent is 0.1-1.0 g/mL;
the molar ratio of 4, 4-bis (4-fluorophenyl) butyric acid to reducing agent is: 1: 1-2;
the mol ratio of the 4, 4-bis (4-fluorophenyl) butyric acid to the decolorizing agent is as follows: 1.5-3.5: 1;
further, the method for synthesizing the intermediate II from the intermediate I comprises the following steps:
under the protection of inert gas, mixing the intermediate I with an organic solvent, dissolving, adding a sulfonyl chloride compound, cooling to-30-0 ℃ after dissolving, adding triethylamine, reacting for 3-9h at-15-30 ℃, and collecting an intermediate II from a reaction product;
the collection method comprises the following steps:
adding 10% hydrochloric acid to adjust the pH value to 7, standing and separating, washing the organic phase with water and saturated saline solution successively, and finally collecting the intermediate II from the organic phase;
further, the inert gas is nitrogen or argon;
the organic solvent is dichloromethane, trichloromethane or carbon tetrachloride and the like;
the sulfonyl chloride compound is p-toluenesulfonyl chloride, methanesulfonyl chloride or benzenesulfonyl chloride.
Further, the volume ratio of the intermediate I to the organic solvent is 0.1-1.0 g/mL;
the molar ratio of the intermediate I to sulfonyl chloride compounds is 1: 1.5-2.5;
the molar ratio of the intermediate I to triethylamine is as follows: 1:2.0-4.5.
The method for synthesizing the penfluridol from the intermediate II comprises the following steps:
under the protection of inert gas, mixing piperidinol and acetonitrile, then adding potassium carbonate at 30-70 ℃, uniformly stirring, then dropwise adding an acetonitrile solution of the intermediate II, reacting for 10-20 hours under heat preservation, and then collecting a target product of penfluridol from a reaction product.
Preferably, the collection method is as follows: cooling to-20-10 ℃, then filtering, adding active carbon into the filtrate, then heating and refluxing, filtering after refluxing is finished, concentrating and drying the filtrate to obtain yellow oily matter, mixing the yellow oily matter with chloroform for dissolving, then heating to 45-90 ℃, then dropwise adding petroleum ether, finally cooling to-20-30 ℃, preserving heat and crystallizing to obtain the penfluridol.
Further, the inert gas is nitrogen or argon.
Further, the temperature of the heat preservation reaction is 20-80 ℃, and the time is 1-24 h.
Further, the heating reflux time is 1-5h, and the heat preservation crystallization time is 1-5 h.
Further, the molar ratio of the intermediate II to the piperidinol is 1: 1.5-4.0; the molar ratio of the intermediate II to the potassium carbonate is 1: 2.0-5.0; the volume ratio of the intermediate II to the acetonitrile is 0.1-1.0 g/mL.
Compared with the prior art, the invention has the following advantages:
according to the invention, 4-bis (4-fluorophenyl) butyric acid is used as a raw material, penfluridol is obtained through reduction reaction, esterification reaction and condensation reaction, the total yield is 81.3% under an optimized condition, the whole process is convenient to operate, the reaction is mild, and the obtained product has high yield and good purity, so that the preparation method is more economic and is more suitable for industrial application. Solves the technical problems of lower yield and poor purity of the existing method.
The overall yield is defined as follows:
total yield is the product of molar yields per step.
Detailed Description
The invention provides an improved preparation method of penfluridol, which comprises the following steps of taking 4, 4-bis (4-fluorophenyl) butyric acid as an initial raw material, synthesizing an intermediate I through reduction, esterifying the intermediate I with sulfonyl chloride compounds to synthesize an intermediate II, and condensing the intermediate II with piperidinol to obtain the penfluridol, wherein the reaction general formula is as follows:
the synthesis of intermediate I from 4, 4-bis (4-fluorophenyl) butanoic acid comprises the steps of: mixing 4, 4-bis (4-fluorophenyl) butyric acid with an organic solvent such as methyltetrahydrofuran or tetrahydrofuran at 10-60 ℃, dissolving, adding a decolorizing agent such as potassium carbonate or neutral alumina into the system, cooling to-30-10 ℃, slowly adding a reducing agent such as lithium aluminum hydride or borane after cooling, stirring for reaction for 1-5h, quenching with water, sequentially adding alkali liquor, treating with water, stirring at 0-45 ℃, filtering, and finally collecting an intermediate I from the filtrate. Wherein the volume ratio of the 4, 4-bis (4-fluorophenyl) butyric acid to the organic solvent is 0.1-1.0 g/mL; the molar ratio of 4, 4-bis (4-fluorophenyl) butyric acid to reducing agent is: 1: 1.0-2.0; the mol ratio of the compound I to the decolorizing agent is as follows: 1.5-3.5: 1; an aqueous solution of sodium hydroxide having a sodium hydroxide concentration of 4.0 to 5.0 mol/L.
The step of synthesizing the intermediate II from the intermediate I comprises the following steps: under the protection of nitrogen or argon, mixing the intermediate I with organic solvents such as dichloromethane, trichloromethane, carbon tetrachloride and the like, dissolving, adding sulfonyl chloride compounds such as p-toluenesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride and the like, cooling to-30-0 ℃ after dissolving, then dropwise adding triethylamine, keeping the temperature at-15-30 ℃ after dropwise adding, reacting for 3-9 hours, adding dilute hydrochloric acid to adjust the pH to 7 after the reaction is finished, standing for liquid separation, washing the organic phase with water and saturated salt water in turn, and finally collecting the intermediate II from the organic phase. Wherein the volume ratio of the intermediate I to organic solvents such as dichloromethane, trichloromethane, carbon tetrachloride and the like is 0.1-1.0 g/mL; the molar ratio of the intermediate I to sulfonyl chloride compounds such as p-toluenesulfonyl chloride, methanesulfonyl chloride and benzenesulfonyl chloride is 1: 1.5-2.5; the molar ratio of the intermediate I to triethylamine is as follows: 1:2.0-4.5.
The step of synthesizing the penfluridol from the intermediate II comprises the following steps: under the protection of nitrogen or argon, mixing piperidinol and acetonitrile, adding potassium carbonate at 30-70 ℃, uniformly stirring, then dropwise adding an acetonitrile solution of an intermediate II, keeping the temperature at 20-80 ℃, reacting for 1-24h, after the reaction is finished, cooling to-20-10 ℃, filtering, adding activated carbon into filtrate, heating and refluxing for 1-5h, after the reflux is finished, filtering, concentrating and drying the filtrate to obtain yellow oily matter, mixing the yellow oily matter with chloroform, heating to 45-90 ℃, dissolving clearly, then dropwise adding petroleum ether, finally cooling to-20-30 ℃, keeping the temperature and crystallizing for 1-5h to obtain the penfluridol. Wherein the molar ratio of the intermediate II to the piperidinol is 1: 1.5-4.0; the molar ratio of the intermediate II to decolorants such as potassium carbonate or aluminum oxide is 1: 2.0-5.0; the volume ratio of the intermediate II to the dichloromethane is 0.1-1.0 g/mL.
Example 1
(1) Synthesis of intermediate I
20g (0.072 mol) of 4, 4-bis (4-fluorophenyl) butyric acid and 172g (2.00 mol) of methyltetrahydrofuran are put into a three-necked bottle and stirred to be dissolved, 5.4g (0.039 mol) of potassium carbonate is added, the temperature is controlled to be below 10 ℃, 2.89g (0.076 mol) of lithium aluminum hydride is slowly added, and the mixture is stirred for 1 to 2 hours at the temperature of between 0 and 10 ℃. After the reaction is finished, controlling the temperature below 10 ℃, dropwise adding water 2.9g (0.161 mol), 15% sodium hydroxide solution (mass fraction) 2.9g (0.011 mol) and water 8.7g (0.483 mol) in sequence, after quenching, naturally heating to 25-30 ℃ for filtering, washing a filter cake with methyltetrahydrofuran, merging filtrate, and concentrating to dryness to obtain a product, namely 17.5g of 4, 4-bis (4-fluorophenyl) -1-butanol (yield is 92.6%).
The reaction formula is as follows:
(2) synthesis of intermediate II
Under the protection of nitrogen, 9g (0.034 mol) of 4, 4-bis (4-fluorophenyl) -1-butanol obtained in step (1) and 96g (1.127 mol) of dichloromethane were put into a three-necked flask and dissolved by stirring. Then, 9.77g (0.051 mol) of p-toluenesulfonyl chloride was added to stir the solution. Cooling to below 0 ℃, dropwise adding 7.72g (0.077 mol) of triethylamine, and keeping the temperature at 0-5 ℃ for reaction for 5 hours after dropwise adding. After completion of the reaction, diluted hydrochloric acid was added to adjust pH to 7, and the mixture was allowed to stand, separated, the organic phase was washed with water and saturated brine in turn, and the organic phase was concentrated to dryness to obtain 13.2g of 4, 4-bis (4-fluorophenyl) -1 (4-methyl-phenyl) -sulfonic acid butyl ester (yield 93.3%).
The reaction formula is as follows:
(3) synthesis of penfluridol
Adding 3g (0.011 mol) of piperidinol and 30mL of acetonitrile into a three-necked bottle under the protection of nitrogen, heating to 50-60 ℃ for dissolving, adding 3g (0.022 mol) of potassium carbonate, stirring uniformly, dropwise adding a solution of 3g (0.007 mol) of the butyl 4, 4-bis (4-fluorophenyl) -1 (4-methyl-phenyl) -sulfonate obtained in the step (2) dissolved in 10mL of acetonitrile at 50-55 ℃, and preserving heat at 50-55 ℃ for reacting for 15 hours after dropwise adding. After the reaction is finished, the temperature is reduced to 20-25 ℃, the filtration is carried out, 0.3g of active carbon is added into the filtrate, the temperature is raised to 50-55 ℃, the stirring and the decoloration are carried out for 1 hour, the filtration is carried out, and the filtrate is concentrated to be dry to obtain 4.5g of yellow oily matter. Adding 4.5g of chloroform into the oily substance, dissolving to be clear, heating to 60-65 ℃, dropwise adding 9.9g of petroleum ether, stirring, cooling to 20-25 ℃, crystallizing for 1-2 hours, performing suction filtration, washing a filter cake by using the petroleum ether, and drying to obtain 3.6g of product penfluridol (the yield is 98.1%).
The reaction formula is as follows:
example 2
(1) Synthesis of intermediate I
20g (0.077 mol) of 4, 4-bis (4-fluorophenyl) butyric acid and 172g (2.38 mol) of tetrahydrofuran are put into a three-necked flask and stirred to be dissolved, 5.4g (0.052 mol) of neutral alumina is added, the temperature is controlled to be below 10 ℃, 2.00g (0.072 mol) of diborane is slowly added, and the mixture is stirred for 2 to 3 hours at the temperature of between 0 and 20 ℃. After the reaction is finished, controlling the temperature below 10 ℃, dropwise adding water 2.9g (0.016 mol), 15% sodium hydroxide solution 2.9g (0.011 mol) and water 8.7g (0.483 mol) in sequence, after quenching, stirring, naturally heating to 25-30 ℃, filtering, washing a filter cake with tetrahydrofuran, merging filtrate, and concentrating to dryness to obtain 17g (yield 84.1%) of the product 4, 4-bis (4-fluorophenyl) -1-butanol.
(2) Synthesis of intermediate II
Under the protection of nitrogen, 9g (0.034 mol) of 4, 4-bis (4-fluorophenyl) -1-butanol obtained in step (1) and 96g (1.127 mol) of dichloromethane were put into a three-necked flask and dissolved by stirring. Subsequently, 10.50g (0.091 mol) of methanesulfonyl chloride was added and the solution was stirred. Cooling to below 0 ℃, dropwise adding 7.79g (0.077 mol) of triethylamine, and after dropwise adding, keeping the temperature at 0-5 ℃ for reaction for 5 hours. After completion of the reaction, 10% diluted hydrochloric acid was added to adjust pH to 7, and the mixture was allowed to stand, separated, the organic phase was washed with water and saturated brine in turn, and the organic phase was concentrated to dryness to obtain 11.25g of 4, 4-bis (4-fluorophenyl) -1-methyl-sulfonic acid butyl ester (yield 97.8%).
(3) Synthesis of penfluridol
Adding 3g (0.011 mol) of piperidinol and 30mL of acetonitrile into a three-necked bottle under the protection of nitrogen, heating to 50-60 ℃ for dissolving, adding 3g (0.022 mol) of potassium carbonate, stirring uniformly, dropwise adding a solution of 3g (0.009 mol) of 4, 4-bis (4-fluorophenyl) -1-methyl-butyl sulfonate obtained in the step (2) dissolved in 10mL of acetonitrile at 50-55 ℃, and preserving the temperature at 50-55 ℃ for reacting for about 20 hours after dropwise adding. After the reaction is finished, the temperature is reduced to 20-25 ℃, the filtration is carried out, 0.3g of active carbon is added into the filtrate, the temperature is raised to 50-55 ℃, the stirring and the decoloration are carried out for 1 hour, the filtration is carried out, and the filtrate is concentrated to be dry to obtain 4.5g of yellow oily matter. Adding 4.5g of chloroform into the oily substance, dissolving to be clear, heating to 60-65 ℃, dropwise adding 9.9g of petroleum ether, stirring, cooling to separate out a solid, keeping the temperature at 20-25 ℃, crystallizing for 1-2 hours, performing suction filtration, washing a filter cake by using the petroleum ether, and drying to obtain 4.31g of the product of the penfluridol (the yield is 91.3%).
The above is a detailed embodiment and a specific operation process of the present invention, which are implemented on the premise of the technical solution of the present invention, but the protection scope of the present invention is not limited to the above-mentioned examples.
Claims (13)
1. An improved process for the preparation of penfluridol, comprising the steps of: 4, 4-bis (4-fluorophenyl) butyric acid is used as an initial raw material, and an intermediate I [4, 4-bis (4-fluorophenyl) -1-butanol ] is synthesized through reduction;
then esterifying the intermediate II [4, 4-bis (4-fluorophenyl) -1 (4-methyl-phenyl) -butyl sulfonate ] or [4, 4-bis (4-fluorophenyl) -1-methyl-butyl sulfonate ];
then condensing with piperidinol to obtain the pentafluridol, wherein the reaction formula is as follows:
2. the process of claim 1, wherein the synthesis of intermediate i from 4, 4-bis (4-fluorophenyl) butanoic acid comprises the steps of:
mixing 4, 4-bis (4-fluorophenyl) butyric acid with an organic solvent, adding a decolorizing agent, cooling, adding a reducing agent, reacting, quenching with water, filtering, and collecting the intermediate I from the filtrate.
3. The method of claim 2, wherein the alkali liquor is an aqueous solution of sodium hydroxide, the aqueous solution of sodium hydroxide with the sodium hydroxide concentration of 4.0-5.0mol/L, the decolorizing agent is potassium carbonate or neutral alumina, and the reducing agent is lithium aluminum hydride or borane.
4. The method according to claim 3, wherein the volume ratio of 4, 4-bis (4-fluorophenyl) butanoic acid to organic solvent is from 0.1 to 1.0 g/mL; the molar ratio of 4, 4-bis (4-fluorophenyl) butyric acid to reducing agent is: 1: 1-2; the mol ratio of the 4, 4-bis (4-fluorophenyl) butyric acid to the decolorizing agent is as follows: 1.5-3.5: 1.
5. the process of claim 2, wherein 4, 4-bis (4-fluorophenyl) butanoic acid is mixed with an organic solvent at 10 ℃ to 60 ℃, followed by addition of a decolorizing agent, cooling to-30 ℃ to 10 ℃, addition of a reducing agent, reaction for 1h to 5h, followed by quenching with water, followed by sequential addition of aqueous base solution for treatment, followed by stirring at 0 ℃ to 45 ℃, followed by filtration.
6. The process of claim 1, wherein the synthesis of intermediate ii from intermediate i comprises the steps of:
under the protection of inert gas, mixing the intermediate I with an organic solvent, dissolving, adding a sulfonyl chloride compound, cooling, adding triethylamine for reaction, and collecting an intermediate II from a reaction product.
7. The method according to claim 6, characterized in that the sulfonyl chloride compound is p-toluenesulfonyl chloride, methanesulfonyl chloride or benzenesulfonyl chloride.
8. The process of claim 7, wherein the molar ratio of intermediate I to sulfonyl chloride compound is 1: 1.5-2.5; the molar ratio of the intermediate I to triethylamine is as follows: 1:2.0-4.5.
9. The method as claimed in claim 6, wherein the intermediate I is mixed with an organic solvent under the protection of inert gas, then sulfonyl chloride compound is added, cooled to-30 ℃ to 0 ℃, and then triethylamine is added, and the mixture reacts for 3 to 9 hours at-15 ℃ to 30 ℃.
10. The process of claim 1, wherein the synthesis of penfluridol from intermediate ii comprises the steps of: and under the protection of inert gas, mixing piperidinol and acetonitrile, then adding potassium carbonate, uniformly stirring, then dropwise adding an acetonitrile solution of the intermediate II, carrying out heat preservation reaction, and then collecting a target product of penfluridol from a reaction product.
11. The method as claimed in claim 10, wherein potassium carbonate is added at 30-70 ℃ and stirred uniformly, and then the acetonitrile solution of the intermediate II is added dropwise and reacted for 10-20 hours under the condition of heat preservation.
12. The method as claimed in claim 11, wherein the molar ratio of the intermediate ii to the piperidinol is 1: 1.5-4.0; the molar ratio of the intermediate II to the potassium carbonate is 1: 2.0-5.0; the volume ratio of the intermediate II to the acetonitrile is 0.1-1.0 g/mL.
13. The method of claim 11, wherein the collecting is performed by: cooling to-20-10 ℃, then filtering, adding active carbon into the filtrate, then heating and refluxing, filtering after refluxing is finished, concentrating and drying the filtrate to obtain yellow oily matter, mixing the yellow oily matter with chloroform for dissolving, then heating to 45-90 ℃, then dropwise adding petroleum ether, finally cooling to-20-30 ℃, and carrying out heat preservation and crystallization for 1-5 hours to obtain the penfluridol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811365258.6A CN111196781B (en) | 2018-11-16 | 2018-11-16 | Improved method for preparing pentafluoride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811365258.6A CN111196781B (en) | 2018-11-16 | 2018-11-16 | Improved method for preparing pentafluoride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111196781A true CN111196781A (en) | 2020-05-26 |
| CN111196781B CN111196781B (en) | 2023-07-28 |
Family
ID=70743591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811365258.6A Active CN111196781B (en) | 2018-11-16 | 2018-11-16 | Improved method for preparing pentafluoride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111196781B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005111025A1 (en) * | 2004-04-29 | 2005-11-24 | Aventis Pharmaceuticals Inc. | 3-piperidinylisochroman-5-ols as dopamine agonists |
| CN106187863A (en) * | 2016-07-15 | 2016-12-07 | 湖南中南制药有限责任公司 | The preparation method of penfluridol |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08333340A (en) * | 1995-06-06 | 1996-12-17 | Fujirebio Inc | Production of aminoethylpiperidine derivative |
| CN103497146B (en) * | 2013-09-27 | 2016-04-13 | 山东大学 | 2-(N-arylmethyl piperidines-4-is amino)-4-(fortified phenol) phenyl ring derivative and preparation method thereof and application |
-
2018
- 2018-11-16 CN CN201811365258.6A patent/CN111196781B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005111025A1 (en) * | 2004-04-29 | 2005-11-24 | Aventis Pharmaceuticals Inc. | 3-piperidinylisochroman-5-ols as dopamine agonists |
| CN106187863A (en) * | 2016-07-15 | 2016-12-07 | 湖南中南制药有限责任公司 | The preparation method of penfluridol |
Non-Patent Citations (1)
| Title |
|---|
| MIROSLAV RAJSNER ET AL.: "4,4-bis(4-fluorophenyl)butylamines and their cyclic analogues;an efficient synthesis of the neuroleptic penfluridol" * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111196781B (en) | 2023-07-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110526859B (en) | Revinanexin intermediate, preparation method thereof and preparation method of Revinanexin | |
| CN109988132B (en) | Preparation method of amiodarone hydrochloride | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN106256824A (en) | A kind of preparation method of high-purity De Lasha star meglumine salt | |
| CN110790721B (en) | Synthetic method of ceftazidime side chain ethyl ester | |
| CN113651798A (en) | Preparation method of Voranolan fumarate | |
| EA006393B1 (en) | Technical synthesis method for producing tropenol | |
| CN113620868A (en) | Torasemide new impurity and preparation method thereof | |
| CN108864084B (en) | Apixaban related substances and preparation method thereof | |
| CN111196781B (en) | Improved method for preparing pentafluoride | |
| CN111116587A (en) | Preparation method of avibactam intermediate compound | |
| CN110511156A (en) | A kind of preparation method of di-lysine-aspirin | |
| CN106588888B (en) | Method for preparing high-purity L-sunitinib malate | |
| CN111072450B (en) | Synthesis method of allyl alcohol derivative | |
| KR20230026411A (en) | Method for producing aromatic ether compounds | |
| CN103664941B (en) | A kind of preparation method of vinpocetine analogue | |
| CN114507172A (en) | Synthesis method of (R) -2- (2, 5-difluorophenyl) pyrrolidine | |
| CN106748884B (en) | Preparation method of bicalutamide intermediate | |
| CN107629039B (en) | The preparation method and intermediate of deuterated acrylamide | |
| CN110655542A (en) | Crystal form of 2,3:4, 5-bis-O- (1-methylethylidene) -beta-D-fructopyranose chlorosulfonate | |
| CN114213343B (en) | Preparation and purification methods of celecoxib intermediate | |
| CN112225736B (en) | Preparation method of 6-bromoimidazo [1.2-a ] pyridine-3-formaldehyde | |
| CN115124506B (en) | Preparation method of digestive system medicine | |
| CN109535025B (en) | Preparation method of Evonib intermediate 3, 3-difluorocyclobutylamine hydrochloride | |
| CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |