OA11635A - Process for the preparation of paroxetine hydrochloride. - Google Patents
Process for the preparation of paroxetine hydrochloride. Download PDFInfo
- Publication number
- OA11635A OA11635A OA1200000182A OA1200000182A OA11635A OA 11635 A OA11635 A OA 11635A OA 1200000182 A OA1200000182 A OA 1200000182A OA 1200000182 A OA1200000182 A OA 1200000182A OA 11635 A OA11635 A OA 11635A
- Authority
- OA
- OAPI
- Prior art keywords
- paroxetine hydrochloride
- propan
- disorders
- paroxetine
- solvaté
- Prior art date
Links
- AHOUBRCZNHFOSL-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine Chemical compound C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 229960005183 paroxetine hydrochloride Drugs 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000006184 cosolvent Substances 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 9
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims description 6
- 229960002296 paroxetine Drugs 0.000 claims description 6
- 238000011282 treatment Methods 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000012453 solvate Substances 0.000 abstract 2
- 239000002904 solvent Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 2
- 206010036618 Premenstrual syndrome Diseases 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000002271 trichotillomania Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
A process for the preparation of paroxetine hydrochloride propan-2-ol solvate comprises forming a solution of paroxetine hydrochloride in a mixture of propan-2-ol and an effective co-solvent, and crystallising paroxetine hydrochloride propan-2-ol solvate from the solution.
Description
1 NOVELPROCESS w 1
The présent invention relates to a process for the préparation of a pharmaceuticallyactive compound, and to the use of the so-prepared compound in therapy. Inparticular this invention is concemed with a new process for the préparation of aparoxetine chloride propan-2-ol solvaté and its use to préparé a crystalline anhydrateform of paroxetine hydrochloride.
Pharmaceutical products with antidepressant and anti-Parkinson properties aredescribed in US-A-3912743 and US-A-4007196. An especially important compoundamong those disclosed is paroxetine, the (-)trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapyas the hydrochloride sait for the treatment and prophylaxis of inter alia dépréssion,obsessive compulsive disorder (OCD) and panic.
Paroxetine hydrochloride has been described in the literature as a crystallinehemihydrate (see EP-A-0223403 of Beecham Group) and as various crystallineanhydrate forms (see WO96/24595 of SmithKline Beecham). WO96/24595 describesthe préparation of the form A anhydrate via an intermediate solvaté with an organicsolvent such as propan-2-ol.
When prepared conventionally (crystallisation ffom anhydrous propan-2-ol),paroxetine hydrochloride propan-2-ol solvaté has very poor stirring properties, and isvery diffîcult to isolate, wash, and dry. It is also very difficult to desolvate by heattreatment under vacuum. In WO96/24595, the problem that conventional dryingtechniques were incapable of efficient removal of solvent was addressed by providingan additional displacement stage before the product was finally dried.
The présent invention is based on the fînding that crystallisation of paroxetinehydrochloride from a mixture of propan-2-ol and a co-solvent produces an improvedcrystalline form which is much easier to stir, filter, wash and dry. Surprisingly it hasalso been found that it is easier to remove solvent of crystallisation by heat treatment.
Accordingly the présent invention provides a process for the préparation of paroxetinehydrochloride propan-2-ol solvaté which comprises forming a solution of paroxetinehydrochloride in a mixture of propan-2-ol and an effective co-solvent, andcrystallising paroxetine hydrochloride propan-2-ol solvaté from the solution. 2 011635
Typically an effective cosolvent is one which will form a clear solution when added toa solution of paroxetine hydrochloride in propan-2-ol and which does not form acompeting solvaté during crystallisation. Suitable cosolvents include toluene, heptaneand hexane. Surprisingly toluene has been found to be particularly useful despite thefact that a toluene solvaté of paroxetine hydrochloride can exist.
The cosolvent mixture may formed before addition of paroxetine hydrochloride, or byaddition of a cosolvent to a solution of paroxetine hydrochloride in propan-2-ol, or byaddition of propan-2-ol to a solution of paroxetine hydrochloride in an effectivecosolvent. In a preferred procedure, the final stage of the préparation of paroxetinehydrochloride is carried out in an effective cosolvent, to which propan-2-ol may beadded for crystallisation in accordance with the invention. For example when tolueneis used as the cosolvent it can be used conveniently in the preceding manufacturingstep. After washing and acidification, only partial évaporation is necessary, foliowedby addition of propan-2-ol and crystallisation.
Crystallisation may be initiated by conventional procedures such as cooling a heatedsolution, or removing solvent by évaporation or heating. It may be advantageous toadd seeds of crystalline paroxetine hydrochloride propan-2-ol solvaté prepared by theprocedure of this invention or by the procedure of WO96/24595. A crystalline anhydrate of paroxetine hydrochloride may be formed by heating thepropan-2-ol solvaté to remove bound propan-2-ol. The résultant product desirablycontains less than 2% of the solvated solvent, preferably less than 1%, morepreferably less than 0.5%, and most preferably less than 0.1%. Advantageously thecrystalline product is the Form A anhydrate of paroxetine hydrochloride.
The crystalline paroxetine hydrochloride product of this invention may be formulatedfor therapy as described in EP-A-0223403 or W096/00477.
Therapeutic uses of the paroxetine product of this invention include treatment of:alcoholism, anxiety, dépréssion, obsessive compulsive disorder, panic disorder,chronic pain, obésitÿ, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent dépréssion, trichotillomania, dysthymia, andsubstance abuse, referred to below as "the disorders".
Accordingly, the présent invention also provides: 3 011635 a pharmaceutical composition for treatment or prophylaxis of the disorderscomprising paroxetine hydrochloride anhydrate prepared by this invention and apharmaceutically acceptable carrier; 5 the use of paroxetine hydrochloride anhydrate prepared by the process of thisinvention to manufacture a médicament for the treatment or prophylaxis of thedisorders; and a method of treating the disorders which comprises administering an effective or 10 prophylactic amount of paroxetine hydrochloride anhydrate prepared by this inventionto a person suffering from one or more of the disorders.
The invention is illustrated by the following Examples: 15 Example 1
Paroxetine hydrochloride hemihydrate (160 g) was suspended in a mixture of toluene : (250 mil) and isopropanol (1000 ml) and heated to boiling. Solvent was removed by distillation and replaced by fresh isopropanol (3 x 500 ml). The boiling point was 20 then 81.2°C. Further solvent was removed by distillation until the volume was about1000 ml. The well stirred mixture was allowed to cool to about 70°C, then hexane(500 ml) was added slowly to give a clear solution at 57°C. Seeds of paroxetinehydrochloride isopropanol solvaté were added, and as the crystallisation proceeded thetempérature increased to 60°C. Stirring was continued until the température had 25 fallen to about 30°C, then the product was collected, washed on the filter with hexane(2 x 500 ml) and dried in vacuo at ambient température.
Yield 171g isopropanol content by NMR: 10.5% wt/wt 30 Example 2 (-)-Trans-4-(4-fluorophenyl)-3 -(3 ',4'-methylenedioxyphenoxymethyl)-1 -phenoxycarbonylpiperidine (90 g) is heated with potassium hydroxide (8.5 g) intoluene (1500 ml) at reflux for 3 hours, cooled, washed with hot water, acidified with 35 hydrochloric acid, and distilled to approximately one quarter volume under vacuum.
Hot propan-2-ol (2000 ml) is added and the mixture cooled slowly with vigorousstirring until the température reaches 20°C. After stirring for a further 2 hours, the 4 011635 product is filtered, washed with propan-2-ol, and dried under vacuum, to give paroxetine hydrochloride propan-2-ol solvaté.
Example 3 5
Paroxetine hydrochloride hemihydrate (122 g) was suspended in toluene (1000 ml)and heated to reflux for 2 hours under Dean & Stark apparatus to remove water. Thetoluene solution was concentrated to approximately 250 ml volume at which point itwas still mobile and easy to stir. Warm propan-2-ol was added (1300 ml at about 10 50°C) and the reaction mixture stirred vigorously; the mixture crystallised slowly but did not become unstirrable. After about 30 minutes a further quantity of propan-2-ol(300 ml) and n-heptane (300 ml) was added, and the mixture was cooled to ambienttempérature (approximately 20°C), stirred for a further 30 minutes, filtered and dried. 15 One part of the product was dried under vacuum at approximately 20°C to give paroxetine hydrochloride propan-2-ol solvaté with a composition ratio ofapproximately 1:1.
Another part was dried under vacuum at a final température of 65°C to give 20 paroxetine hydrochloride containing approximately 1.6% propan-2-ol. By comparison, a conventionally prepared sample of solvaté heated ovemight in avacuum oven at 70°C for 24 hours contained 4.1% propan-2-ol.
Example 4 25
Paroxetine hydrochloride hemihydrate (50 g) was heated to reflux with stirring intoluene (500 ml) and the water removed using a Dean and Stark apparatus. Thesolution was allowed to cool to about 40°C, diluted with isopropanol (200 ml), andallowed to crystallize at ambient température. The product was collected, washed 30 with toluene and dried at 40°C to give paroxetine hydrochloride isopropanol solvaté.
Yield 23 g
Claims (6)
- 4. 011635 Claims F,· •1. A process for the préparation of paroxetine hydrochloride propan-2-ol solvatéwhich comprises forming a solution of paroxetine hydrochloride in a mixture of 5 propan-2-ol and an effective co-solvent, and crystallising paroxetine hydrochloridepropan-2-ol solvaté from the solution.
- 2. A process according to claim 1 wherein the cosolvent comprises toluene,heptane or hexane. 10
- 3. A process according to claim 1 or 2 wherein the final stage of the préparationof paroxetine hydrochloride is carried out in the cosolvent, to which propan-2-ol issubsequently added for crystallisation. 15 4. A process for the préparation of a crystalline anhydrate of paroxetine hydrochloride which comprises heating a propan-2-ol solvaté , obtained using theprocess of any one of the preceding claims, to remove bound propan-2-ol.
- 5. A pharmaceutical composition for treatment or prophyIaxis of the disorders 20 comprising paroxetine hydrochloride anhydrate prepared by the process of claim 4 and a pharmaceutically acceptable carrier.
- 6. The use of paroxetine hydrochloride anhydrate prepared by the process of claim 4to manufacture a médicament for the treatment or prophy Iaxis of the disorders. 25
- 7. A method of treating the disorders which comprises administering an effective orprophylactic amount of paroxetine hydrochloride anhydrate prepared by the process ofclaim 4 to a person suffering from one or more of the disorders.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9726907.0A GB9726907D0 (en) | 1997-12-19 | 1997-12-19 | Novel compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA11635A true OA11635A (en) | 2004-11-22 |
Family
ID=10823933
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| OA1200000182A OA11635A (en) | 1997-12-19 | 1998-12-18 | Process for the preparation of paroxetine hydrochloride. |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1042318A1 (en) |
| JP (1) | JP2001526288A (en) |
| KR (1) | KR20010033317A (en) |
| CN (1) | CN1281448A (en) |
| AP (1) | AP2000001836A0 (en) |
| AU (1) | AU1769899A (en) |
| BG (1) | BG104604A (en) |
| BR (1) | BR9813638A (en) |
| CA (1) | CA2315066A1 (en) |
| EA (1) | EA200000689A1 (en) |
| GB (1) | GB9726907D0 (en) |
| HU (1) | HUP0004503A3 (en) |
| ID (1) | ID24733A (en) |
| IL (1) | IL136590A0 (en) |
| NO (1) | NO20003145D0 (en) |
| OA (1) | OA11635A (en) |
| PL (1) | PL341358A1 (en) |
| SK (1) | SK9242000A3 (en) |
| TR (1) | TR200001933T2 (en) |
| WO (1) | WO1999032484A1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9919001D0 (en) * | 1999-08-12 | 1999-10-13 | Smithkline Beecham Plc | Novel process |
| GB9923439D0 (en) * | 1999-10-04 | 1999-12-08 | Smithkline Beecham Plc | Novel process |
| NL1017421C2 (en) | 2001-02-21 | 2002-01-15 | Synthon Bv | Process for the production of paroxetine. |
| AU2002259114A1 (en) * | 2002-02-22 | 2003-09-09 | Teva Pharmaceutical Industries Ltd. | Preparation of paroxetine involving novel intermediates |
| KR100672184B1 (en) | 2004-09-21 | 2007-01-19 | 주식회사종근당 | Choline or Choline Derivative Salts of Paroxetine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2058061T3 (en) * | 1985-10-25 | 1994-11-01 | Beecham Group Plc | DERIVED FROM PIPERIDINE, ITS PREPARATION AND ITS USE AS A MEDICINAL PRODUCT. |
| SK283608B6 (en) * | 1995-02-06 | 2003-10-07 | Smithkline Beecham Plc | Anhydrous paroxetine hydrochloride, process for its preparation and use |
| CA2187128A1 (en) * | 1996-10-04 | 1997-06-26 | K. S. Keshava Murthy | New and useful polymorph of anhydrous paroxetine hydrochloride |
-
1997
- 1997-12-19 GB GBGB9726907.0A patent/GB9726907D0/en not_active Ceased
-
1998
- 1998-12-18 CN CN98811920A patent/CN1281448A/en active Pending
- 1998-12-18 ID IDW20001158A patent/ID24733A/en unknown
- 1998-12-18 CA CA002315066A patent/CA2315066A1/en not_active Abandoned
- 1998-12-18 AU AU17698/99A patent/AU1769899A/en not_active Abandoned
- 1998-12-18 BR BR9813638-0A patent/BR9813638A/en not_active Application Discontinuation
- 1998-12-18 KR KR1020007006764A patent/KR20010033317A/en not_active Withdrawn
- 1998-12-18 HU HU0004503A patent/HUP0004503A3/en unknown
- 1998-12-18 SK SK924-2000A patent/SK9242000A3/en unknown
- 1998-12-18 WO PCT/GB1998/003836 patent/WO1999032484A1/en not_active Ceased
- 1998-12-18 JP JP2000525421A patent/JP2001526288A/en active Pending
- 1998-12-18 EP EP98962563A patent/EP1042318A1/en not_active Withdrawn
- 1998-12-18 EA EA200000689A patent/EA200000689A1/en unknown
- 1998-12-18 PL PL98341358A patent/PL341358A1/en unknown
- 1998-12-18 OA OA1200000182A patent/OA11635A/en unknown
- 1998-12-18 IL IL13659098A patent/IL136590A0/en unknown
- 1998-12-18 AP APAP/P/2000/001836A patent/AP2000001836A0/en unknown
- 1998-12-18 TR TR2000/01933T patent/TR200001933T2/en unknown
-
2000
- 2000-06-16 NO NO20003145A patent/NO20003145D0/en not_active Application Discontinuation
- 2000-07-13 BG BG104604A patent/BG104604A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ID24733A (en) | 2000-08-03 |
| PL341358A1 (en) | 2001-04-09 |
| IL136590A0 (en) | 2001-06-14 |
| KR20010033317A (en) | 2001-04-25 |
| HUP0004503A2 (en) | 2002-03-28 |
| EP1042318A1 (en) | 2000-10-11 |
| CA2315066A1 (en) | 1999-07-01 |
| WO1999032484A1 (en) | 1999-07-01 |
| NO20003145L (en) | 2000-06-16 |
| NO20003145D0 (en) | 2000-06-16 |
| AU1769899A (en) | 1999-07-12 |
| AP2000001836A0 (en) | 2000-06-30 |
| BG104604A (en) | 2001-03-30 |
| GB9726907D0 (en) | 1998-02-18 |
| JP2001526288A (en) | 2001-12-18 |
| HUP0004503A3 (en) | 2002-04-29 |
| SK9242000A3 (en) | 2001-01-18 |
| BR9813638A (en) | 2000-10-17 |
| CN1281448A (en) | 2001-01-24 |
| TR200001933T2 (en) | 2000-12-21 |
| EA200000689A1 (en) | 2000-12-25 |
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