CN115368327A - Escitalopram oxalate resolution process - Google Patents
Escitalopram oxalate resolution process Download PDFInfo
- Publication number
- CN115368327A CN115368327A CN202211089074.8A CN202211089074A CN115368327A CN 115368327 A CN115368327 A CN 115368327A CN 202211089074 A CN202211089074 A CN 202211089074A CN 115368327 A CN115368327 A CN 115368327A
- Authority
- CN
- China
- Prior art keywords
- isopropanol
- temperature
- dtta
- dichloromethane
- citalopram
- 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
- 238000000034 method Methods 0.000 title claims abstract description 19
- KTGRHKOEFSJQNS-BDQAORGHSA-N (1s)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3h-2-benzofuran-5-carbonitrile;oxalic acid Chemical compound OC(=O)C(O)=O.C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 KTGRHKOEFSJQNS-BDQAORGHSA-N 0.000 title claims abstract description 10
- 229960005086 escitalopram oxalate Drugs 0.000 title claims abstract description 10
- 239000013078 crystal Substances 0.000 claims abstract description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 claims description 15
- 229960001653 citalopram Drugs 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000004321 preservation Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 abstract description 5
- 230000035484 reaction time Effects 0.000 abstract description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses an escitalopram oxalate resolution process, which is characterized in that an escitalopram oxalate intermediate is dissolved in a solvent, and the resolution intermediate is obtained by accurately controlling the proportion of each component, the reaction time and the temperature in the solvent and the proportion of seed crystal addition.
Description
Technical Field
The invention relates to a resolution process of escitalopram oxalate.
Background
An intermediate obtained by splitting escitalopram oxalate is an important raw material of an antidepressant, the existing splitting process generally comprises the steps of dissolving a citalopram intermediate in a solvent, heating to 40 +/-3 ℃, dissolving, adding D-DTTA for reacting for 1 hour, cooling to 20-25 ℃, keeping the temperature for 13 hours for crystallization, centrifuging to obtain a wet product, continuously adding the solvent for dissolving, heating to 70-80 ℃ again, cooling to 20-25 ℃ after the solution is clarified, keeping the temperature for crystallization for 4 hours, centrifuging, drying to obtain a split intermediate, the process has very long operation time, the yield and the purity are low, and the drug property of the antidepressant prepared is difficult to guarantee.
Disclosure of Invention
The invention relates to a resolution process of escitalopram oxalate, which can shorten the process time and improve the yield on the premise of ensuring the purity.
In order to realize the purpose, the method adopted by the invention is as follows: a process for the resolution of escitalopram oxalate, said process comprising the steps of:
(1) Weighing a citalopram intermediate, isopropanol and dichloromethane, adding the citalopram intermediate, the isopropanol and the dichloromethane into a reaction bottle, heating to dissolve, wherein the citalopram intermediate: isopropyl alcohol: the mass ratio of the dichloromethane is 1:3:1.1, and the temperature is 40-45 ℃;
(2) After dissolution and clarification, D-DTTA, citalopram intermediate: the mass ratio of D-DTTA is 3;
(3) After the heat preservation is finished, reducing the temperature to 20-25 ℃, and continuing to preserve heat for 1h to separate out crystals;
(4) Carrying out suction filtration on the washed crystal, and washing a filter cake by using isopropanol;
(5) Adding the crystals obtained in the step (4) and isopropanol into a reaction bottle, and heating to reflux;
(6) After the solution is clear, immediately cooling to 20-25 ℃, and keeping the temperature for 3 hours for crystallization;
(7) Carrying out suction filtration on the washed crystal, and washing a filter cake by using isopropanol;
(8) Drying for 4h to obtain the target product.
The beneficial effects are as follows: the process has improved stability and yield while ensuring purity.
Detailed Description
All of the features disclosed in this specification, or all of the steps in any method or process so disclosed, may be combined in any combination, except combinations of features and/or steps that are mutually exclusive.
Any feature disclosed in this specification (including any accompanying claims, abstract) may be replaced by alternative features serving equivalent or similar purposes, unless expressly stated otherwise. That is, unless expressly stated otherwise, each feature is only an example of a generic series of equivalent or similar features.
The invention discloses a process for resolving escitalopram oxalate, which comprises the following steps:
(1) Weighing a citalopram intermediate, isopropanol and dichloromethane, adding the citalopram intermediate, the isopropanol and the dichloromethane into a reaction bottle, heating to dissolve, wherein the citalopram intermediate: isopropyl alcohol: the mass ratio of dichloromethane is 1;
(2) After dissolution and clarification, D-DTTA, citalopram intermediate: the mass ratio of D-DTTA is 3:0.54, seed crystals are added after the D-DTTA is dissolved and clear, the temperature is kept for reaction for 2 hours, and the mass ratio of the added citalopram intermediate to the seed crystals is 1;
(3) After the heat preservation is finished, reducing the temperature to 20-25 ℃, and continuing to preserve heat for 1h to separate out crystals;
(4) Carrying out suction filtration on the washed crystal, and washing a filter cake by using isopropanol;
(5) Adding the crystals obtained in the step (4) and isopropanol into a reaction bottle, and heating to reflux;
(6) After the solution is clear, immediately cooling to 20-25 ℃, and keeping the temperature for 3h for crystallization;
(7) Carrying out suction filtration on the washed crystal, and washing a filter cake by using isopropanol;
(8) Drying for 4h to obtain the target product.
The invention establishes a production process capable of producing qualified products by optimizing experimental conditions such as the resolution solvent and the proportion thereof, the reaction time and temperature, the heat preservation and crystallization time and temperature, the seed crystal adding proportion, the refining heat preservation and crystallization time and temperature and the like, enhances the stability of the process, improves the yield of the products, ensures that the molar yield of the obtained products can reach 33 percent, ensures that the enantiomeric purity reaches 99 percent,
the invention is not limited to the foregoing embodiments. The invention extends to any novel feature or any novel combination of features disclosed in this specification, and to any novel method or process steps or any novel combination of steps disclosed.
Claims (1)
1. The process for resolving escitalopram oxalate is characterized by comprising the following steps:
(1) Weighing a citalopram intermediate, isopropanol and dichloromethane, adding the citalopram intermediate, the isopropanol and the dichloromethane into a reaction bottle, heating to dissolve, wherein the citalopram intermediate: isopropyl alcohol: the mass ratio of the dichloromethane is 1:3:1.1, and the temperature is 40-45 ℃;
(2) After dissolution and clarification, D-DTTA, citalopram intermediate: the mass ratio of D-DTTA is 3:0.54, seed crystals are added after the D-DTTA is dissolved and clear, the temperature is kept for reaction for 2 hours, and the mass ratio of the added citalopram intermediate to the seed crystals is 1;
(3) After the heat preservation is finished, reducing the temperature to 20-25 ℃, and continuing to preserve heat for 1h to separate out crystals;
(4) Carrying out suction filtration on the washed crystal, and washing a filter cake by using isopropanol;
(5) Adding the crystals obtained in the step (4) and isopropanol into a reaction bottle, and heating to reflux;
(6) After the solution is clear, immediately cooling to 20-25 ℃, and keeping the temperature for 3h for crystallization;
(7) Carrying out suction filtration on the washed crystal, and washing a filter cake by using isopropanol;
(8) Drying for 4h to obtain the target product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211089074.8A CN115368327A (en) | 2022-09-07 | 2022-09-07 | Escitalopram oxalate resolution process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211089074.8A CN115368327A (en) | 2022-09-07 | 2022-09-07 | Escitalopram oxalate resolution process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115368327A true CN115368327A (en) | 2022-11-22 |
Family
ID=84072242
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211089074.8A Pending CN115368327A (en) | 2022-09-07 | 2022-09-07 | Escitalopram oxalate resolution process |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115368327A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008059514A2 (en) * | 2006-07-31 | 2008-05-22 | Cadila Healthcare Limited | Process for preparing escitalopram |
| US20090099375A1 (en) * | 2005-07-27 | 2009-04-16 | Vipin Kumar Kaushik | process for the preparation of escitalopram |
| US20100204493A1 (en) * | 2007-05-18 | 2010-08-12 | Cipla Limited | Process for the Preparation of Escitalopram |
| US20100249438A1 (en) * | 2009-03-30 | 2010-09-30 | Vijaya Bhaskar Bolugoddu | Preparation of escitalopram |
| JP2018012654A (en) * | 2016-07-20 | 2018-01-25 | 株式会社トクヤマ | PRODUCTION METHOD OF (1S)-4-[4-(DIMETHYLAMINO)-1-(4'-FLUOROPHENYL)-1-HYDROXYBUTYL]-3-(HYDROXYMETHYL)-BENZONITRILE HEMI(+)-DI-(p-TOLUOYL) TARTRATE, AND PRODUCTION METHOD OF (1S)-1-[3-(DIMETHYLAMINO)PROPYL]-1-(4-FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURAN-5-CARBONITRILE AND SALT THEREOF USING THE TARTRATE |
-
2022
- 2022-09-07 CN CN202211089074.8A patent/CN115368327A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090099375A1 (en) * | 2005-07-27 | 2009-04-16 | Vipin Kumar Kaushik | process for the preparation of escitalopram |
| WO2008059514A2 (en) * | 2006-07-31 | 2008-05-22 | Cadila Healthcare Limited | Process for preparing escitalopram |
| US20100204493A1 (en) * | 2007-05-18 | 2010-08-12 | Cipla Limited | Process for the Preparation of Escitalopram |
| US20100249438A1 (en) * | 2009-03-30 | 2010-09-30 | Vijaya Bhaskar Bolugoddu | Preparation of escitalopram |
| JP2018012654A (en) * | 2016-07-20 | 2018-01-25 | 株式会社トクヤマ | PRODUCTION METHOD OF (1S)-4-[4-(DIMETHYLAMINO)-1-(4'-FLUOROPHENYL)-1-HYDROXYBUTYL]-3-(HYDROXYMETHYL)-BENZONITRILE HEMI(+)-DI-(p-TOLUOYL) TARTRATE, AND PRODUCTION METHOD OF (1S)-1-[3-(DIMETHYLAMINO)PROPYL]-1-(4-FLUOROPHENYL)-1,3-DIHYDROISOBENZOFURAN-5-CARBONITRILE AND SALT THEREOF USING THE TARTRATE |
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| PB01 | Publication | ||
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20221122 |