AP404A - Process for stereospecific hydrolysis oof piperidinedione. derivatives. - Google Patents
Process for stereospecific hydrolysis oof piperidinedione. derivatives. Download PDFInfo
- Publication number
- AP404A AP404A APAP/P/1993/000501A AP9300501A AP404A AP 404 A AP404 A AP 404A AP 9300501 A AP9300501 A AP 9300501A AP 404 A AP404 A AP 404A
- Authority
- AP
- ARIPO
- Prior art keywords
- formula
- compound
- process according
- paroxetine
- isomer
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 36
- 230000007062 hydrolysis Effects 0.000 title 1
- 238000006460 hydrolysis reaction Methods 0.000 title 1
- CNMOHEDUVVUVPP-UHFFFAOYSA-N piperidine-2,3-dione Chemical compound O=C1CCCNC1=O CNMOHEDUVVUVPP-UHFFFAOYSA-N 0.000 title 1
- 230000000707 stereoselective effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 108010051152 Carboxylesterase Proteins 0.000 claims abstract description 14
- 102000013392 Carboxylesterase Human genes 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 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 15
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 claims description 15
- 229960002296 paroxetine Drugs 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 210000004185 liver Anatomy 0.000 claims description 7
- 239000012453 solvate Substances 0.000 claims description 6
- 108090000371 Esterases Proteins 0.000 claims description 5
- 239000003125 aqueous solvent Substances 0.000 claims description 4
- 241000283690 Bos taurus Species 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000003791 organic solvent mixture Substances 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- CEXCHYIGFUAPKW-UHFFFAOYSA-N methanol;piperidine Chemical compound OC.C1CCNCC1 CEXCHYIGFUAPKW-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000007983 Tris buffer Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- -1 carboxy esterone Chemical compound 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000002253 acid Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- VLLPYAIUEKEIRQ-AAEUAGOBSA-N ethyl (3s,4r)-4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate Chemical compound C1C(=O)N(C)C(=O)[C@@H](C(=O)OCC)[C@@H]1C1=CC=C(F)C=C1 VLLPYAIUEKEIRQ-AAEUAGOBSA-N 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/84—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 two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
A process for stereospecifically hydrolysing a mixture of the (+)and (-)isomers of a compound of formula (ii)in which r is c1-6 alkyl using a carboxyl esterase enzyme (i)ro form a compound of formula (iiia), ane thereafter separating the resulting compound of formula (iiia)from the remaining (-)isomer of formula (ii); or (ii)to form a compound of formula (iiib): and thereafter separating the resulting compound of formula (iiib)from the remaining (=)isomer of formula (ii).
Description
Novel Process
The present invention is concerned with a new process and certain novel intermediates.
US Patent No. 4,007,196 describes a class of compounds which possess antidepressant activity. One specific compound mentioned in the patent is paroxetine which is described as possessing anti-depressant activity.
N
H paroxetine
This compound has now been approved for human use in some countries and is being sold as an anti-depressant agent
All described processes for preparing paroxetine involve chemical reactions such as those described in US Patent 4902801. It will be appreciated that paroxetine is actually the (-) isomer (as shown above) and that all chemical methods of preparing paroxetine involve a chemical resolution step which wastes substrate and reactants and necessitates the use of expensive resolving agents and is a fairly expensive reaction to perform.
The present invention involves the use of an enzymatic resolution step which allieviates or overcomes a number of problems associated with a purely chemical resolution step.
Accordingly, the present invention provides a process for stereospecifically hydrolysing a mixture of the (+) and (-) isomers of a compound of formula (II):
F
O IM U
Me in which R is Cj.g alkyl; using a carboxyl esterase enzyme,
BAD ORIGINAL
P30386
AP 0 0 0 4 0 4
-2(i) to form a compound of formula (ΠΙΑ),
and thereafter separating the resulting compound of formula (ΠΙΑ) from the remaining (-) isomer of formula (II); or ii) to form a compound of formula (IIIB):
and thereafter separating the resulting compound of formula (ΠΕΒ) from the remaining (+) isomer of formula (Π).
It should be appreciated that the choice of carboxy esterase enzyme will determine which isomer of formula (II) is hydrolysed to the corresponding acid, which may be determined by routine experimentation.
Process variant i) is preferred.
When using process variant (i) the stereoselectivity of the process is such that from a racemic mixture of a compound of formula (II), after the action of the carboxyl esterase enzyme the ratio of (-) to (+) isomer of formula (Π), is greater than 60%, preferably greater than 70%, more preferably greater than 80% and most preferably greater than 85%.
When using process variant (ii) the stereoselectivity of the process is such that from a racemic mixture of a compound of formula (II), after the action of the carboxy esterone enzyme, the ratio of (+) to (-) isomer of a compound of formula (Π), is greater than 60%, preferably greater than 70%, more preferably greater than 80% and
BAD ORIGINAL ft
P3O386
AP 0 0 0 4 0 4
-3most preferably greater than 85%.
The process is suitably carried out by dissolving the (±) unresolved compound of formula (II) into a suitable solvent such as an aqueous/organic solvent mixture and adding the carboxyl esterase enzyme and stirring the resulting mixture until the reaction is completed.
Suitable temperatures for performing the reaction include 0-50°C more suitably 10-40°C and yet more suitably 25 to 35°C and most suitably at 30°C.
Suitably aqueous/organic solvent mixtures include buffered aqueous solvents such as tris buffer which is mixed with DMSO.
Suitable pH's for the reaction to be carried out and include pH 4 to 8, more suitably pH 5 to 7 and preferably at pH 5.5.
Suitable values for the variable R include methyl and ethyl. Preferably R is ethyl.
The term carboxyl esterase enzyme is internationally recognised as being those enzymes which fall within the class EC 3.1.1.
Suitable carboxyl esterase enzymes include Porcine liver esterase and Bovine liver esterase both of which are commercially available or may be extracted from Porcine liver or Bovine liver respectively by using procedures available in the literature.
It should also be appreciated that carboxyl esterase enzymes produced by microbes are also suitable for use in the present invention.
In process variant i) where the carboxyl esterase enzyme stereospecifically hydrolyses the (+) form of a compound of formula (Π), the remaining (-) form of a compound of formula (II) is separated by conventional techniques such as solvent extraction of the compound of formula (Π) using a non-aqueous miscible solvent such as ethyl acetate and the resulting (-) compound of formula (Π) may then be isolated using conventional techniques such as precipitation.
The present invention also extends to a process for subsequently converting the (-) compound of formula (II) prepared as described above to paroxetine or a pharmaceutically acceptable salt and/or solvate thereof such as the hydrochloride hemi-hydrate, for example, using the procedures outlined in US Patent No. 4,902,801 and US Patent 4,721,723.
In process variant ii) where the carboxyl esterase enzyme stereospecifically hydrolyses the (-) form of a compound of formula (Π) to yield the (-) form of a compound of formula (ΙΠ), the remaining (+) form of a compound of formula (Π) may be separated from the (-) form of a compound of formula (III) as mentioned above.
The (-) compound of formula (III) may be converted to paroxetine by first
QAD ORIGINAL
P30386
AP Ο Ο Ο 4 Ο 4
-4converting it to a (-) compound of formula (II) using conventional esterification techniques. The ester may then be converted to paroxetine or a pharmaceutically acceptable salt and/or solvate thereof such as the hydrochloride hemi-hydrate, for example, using the procedures outlined in US Patent No. 4,902,801 and US Patent
4,721,723.
Alternatively, the (-) compound of formula (III) may be directly converted to paroxetine by reducing the carboxylic acid group to a hydroxymethyl group and reducing the two keto groups in the piperidine ring using conventional reducing agents such as lithium aluminium hydride. Subsequently, the resulting piperidine carbinol compound may be converted to paroxetine or a pharmaceutically acceptable salt and/or solvate thereof such as the hydrochloride hemi-hydrate, for example, using the procedures outlined in US Patent No. 4,902,801 and US Patent 4,721,723.
It is believed that both the (-) and (+) forms of a compound of formula (ΠΙ) are novel as are any mixtures thereof including the racemate. The present invention also extends to a compound of formula (III) or a salt or hydrate thereof, the (-) and (+) forms and any mixtures thereof including the racemate.
Compounds of formula (Π) may be prepared according to the procedures outlined in US Patent 4,902,801.
The present invention is illustrated by the following example.
BAD ORIGINAL &
P30386
AP 0 0 0 4 0 4
-5Example 1 (-) trans-3-Ethoxycarbonyl-4-(4'fluorophenyl)-N-methyI piperidine-2,6-dione
A solution of (±) trans-3-Ethoxycarbonyl-4-(4'-fluorophenyl)-N-methyl piperidine-2,6-dione (1.51 g 5.15mmol) in DMSO (100ml) was added to Tris buffer (900ml, 0.2m, pH 5.5). The pH was readjusted to 5.5, pig liver esterase (Sigma Chemical Co, 19ml, 5340 units) added and the reaction stirred for twenty hours. The pH was maintained by addition of aqueous sodium hydroxide (0.105m, 25ml, 2.63mmol).
The reaction mixture was extracted with ether (3 x 300ml), the combined organic extracts washed with Tris buffer (0.1M, pH 8.5, 2 x 250ml), the Tris buffer extracts washed with ether (lx 200ml) and the combined organic extracts dried over anhydrous magnesium sulphate.
The reaction mixture was assayed at 16,18 and 20 hours. On each occasion the enantiomeric ratio was 90:10 (-):(+).
The solution evaporated to an oil and replaced with toluene/THF. This solution was then reduced with lithium aluminium hydride. The final solution containing a 0.15g of reduced material in 30ml THF/toluene had a rotation of -16.5°. Chiral HPLC indicated an isomer ratio of 86:14 (-):(+).
Claims (12)
- Claims1. A process for stereospecifically hydrolysing a mixture of the (+) and (-) isomers of a compound of formula (Π):FΟ NOR (II)Me in which R is C jalkyl; using a carboxyl esterase enzyme, (i) to form a compound of formula (ΙΠΑ),BAD ORIGINALP30386AP Ο 0 0 4 0 4 (ΙΙΙΑ) and thereafter separating the resulting compound of formula (IIIA) from the remaining (-) isomer of formula (ID; or ii) to form a compound of formula (IIIB):(MB) ( 10 and thereafter separating the resulting compound of formula (IIIB) from the remaining (+) isomer of formula (Π).
- 2. A process according to variant (i) in claim 1 in which the stereoselectivity of the process is such that from a racemic mixture of a compound of formula (ID, after the action of the carboxyl esterase enzyme, the ratio of (-) to (+) isomer of formula (U), is greater than 60%.
- 3. A process according to variant (ii) in claim 1 in which the stereoselectivity of the process is such that from a racemic mixture of a compound of formula (II), after the action of the carboxy ootewncenzyme, the ratio of (+) to (-) isomer of a compound of formula (Π), is greater than 60%.
- 4. A process according to any one of claims 1 to 3 which is carried out by dissolving (±) unresolved compound of formula (Π) into an aqueous/organic solvent mixture and adding the carboxyl esterase enzyme and stirring the resulting mixture until the reaction is completed.
- 5. A process according to any one of claims 1 to 4 in which the temperature for performing the reaction is 0-50°C.
- 6. A process according to any one of claim 1 to 5 in which the pH of the reaction is pH 4 to 8.
- 7. A process according to any one of claims 1 to 6 in which the variableBAD ORIGINALP30386AP Ο Ο Ο 4 Ο 4-7R in formula (II) is methyl or ethyl.
- 8. A process according to claim 1 in which the carboxyl esterase enzyme is Porcine liver esterase or Bovine liver esterase.
- 9. A process for subsequently converting a (-) compound of formula (Π), 5 prepared as described in claim 1, to paroxetine or a pharmaceutically acceptable salt and/or solvate thereof.
- 10. A process for subsequently converting a (-) compound of formula (ΠΙ), prepared as described in claim 1, to paroxetine by first converting it to a (-) compound of formula (II), as defined in claim 1, using conventional esterification10 techniques followed by subsequent convertion to paroxetine or a pharmaceutically acceptable salt and/or solvate thereof.
- 11. A process for subsequently converting a (-) compound of formula (III) directly to paroxetine by reducing the carboxylic acid group to a hydroxymethyl group and reducing the two keto groups in the piperidine ring and subsequently,15 converting the resulting piperidine carbinol to paroxetine or a pharmaceutically acceptable salt and/or solvate thereof.
- 12. A compound of formula (III) or a salt or hydrate thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929209687A GB9209687D0 (en) | 1992-05-06 | 1992-05-06 | Novel process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9300501A0 AP9300501A0 (en) | 1993-04-30 |
| AP404A true AP404A (en) | 1995-09-02 |
Family
ID=10715029
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1993/000501A AP404A (en) | 1992-05-06 | 1993-03-25 | Process for stereospecific hydrolysis oof piperidinedione. derivatives. |
Country Status (32)
| Country | Link |
|---|---|
| US (1) | US20010018205A1 (en) |
| EP (1) | EP0639180B1 (en) |
| JP (1) | JPH07507277A (en) |
| KR (1) | KR100287082B1 (en) |
| CN (2) | CN1059898C (en) |
| AP (1) | AP404A (en) |
| AT (1) | ATE194329T1 (en) |
| AU (1) | AU673166B2 (en) |
| BR (1) | BR9306326A (en) |
| CA (1) | CA2135169A1 (en) |
| CZ (1) | CZ283702B6 (en) |
| DE (1) | DE69328969T2 (en) |
| DK (1) | DK0639180T3 (en) |
| ES (1) | ES2147196T3 (en) |
| FI (1) | FI106855B (en) |
| GB (1) | GB9209687D0 (en) |
| GR (1) | GR3034034T3 (en) |
| HU (1) | HU215411B (en) |
| IL (1) | IL105162A (en) |
| MA (1) | MA22848A1 (en) |
| MX (1) | MX9301754A (en) |
| MY (1) | MY110188A (en) |
| NO (1) | NO944215L (en) |
| NZ (1) | NZ251404A (en) |
| PL (1) | PL172067B1 (en) |
| PT (1) | PT639180E (en) |
| RU (1) | RU2108393C1 (en) |
| SI (1) | SI9300158A (en) |
| SK (1) | SK281767B6 (en) |
| TW (1) | TW258732B (en) |
| WO (1) | WO1993022284A1 (en) |
| ZA (1) | ZA932212B (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9325644D0 (en) * | 1993-12-15 | 1994-02-16 | Smithkline Beecham Plc | Novel formulation |
| JP2000514653A (en) * | 1996-07-15 | 2000-11-07 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | Screening of esterases for stereospecific resolution and its use |
| GB9618967D0 (en) * | 1996-09-11 | 1996-10-23 | Smithkline Beecham Plc | Pharmaceuticals |
| EE200200633A (en) | 1997-06-10 | 2003-02-17 | Synthon B.V. | Method for the preparation of the salt and base forms of the trisubstituted 4-phenylpiperidine compound, the resulting salt and base forms |
| CH689805A8 (en) * | 1998-07-02 | 2000-02-29 | Smithkline Beecham Plc | Paroxetine methanesulfonate, process for its preparation and pharmaceutical compositions containing it. |
| IT1308629B1 (en) | 1999-02-23 | 2002-01-09 | Recordati Chem Pharm | PROCESS FOR THE PRODUCTION OF PAROXETIN. |
| ES2161167B1 (en) * | 1999-09-24 | 2002-07-01 | Vita Invest Sa | Enzymatic hydrolysis for paroxetine synthesis intermediates production consists of enantio selective hydrolysis of a racemic ester based mixture |
| AU2000246280A1 (en) | 2000-05-12 | 2001-11-20 | Synthon B.V. | Tosylate salts of 4-(p-fluorophenyl)-piperidine-3-carbinols |
| WO2009005647A2 (en) * | 2007-06-27 | 2009-01-08 | Bioverdant, Inc. | Compounds and process to prepare chiral intermediates for synthesis of paroxetine |
| CN104892491B (en) * | 2015-05-06 | 2017-05-17 | 浙江海森药业有限公司 | Method for synthesizing paroxetine chiral intermediate |
| KR102168129B1 (en) | 2018-11-28 | 2020-10-20 | 장영선 | Vine stalks a hand-held claw |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223334A1 (en) * | 1985-08-10 | 1987-05-27 | Beecham Group Plc | Process for the preparation of aryl-piperidine carbinols |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
| DE3010104A1 (en) * | 1980-03-15 | 1981-10-01 | Basf Ag, 6700 Ludwigshafen | AMINOAZO CONNECTIONS |
| EP0223403B1 (en) * | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
| DK716088D0 (en) * | 1988-12-22 | 1988-12-22 | Ferrosan As | REDUCTION OF PIPERIDIN-DION DERIVATIVES AND INTERMEDIATE |
| US5258517A (en) * | 1992-08-06 | 1993-11-02 | Sepracor, Inc. | Method of preparing optically pure precursors of paroxetine |
-
1992
- 1992-05-06 GB GB929209687A patent/GB9209687D0/en active Pending
-
1993
- 1993-03-25 AP APAP/P/1993/000501A patent/AP404A/en active
- 1993-03-25 IL IL10516293A patent/IL105162A/en not_active IP Right Cessation
- 1993-03-29 ZA ZA932212A patent/ZA932212B/en unknown
- 1993-03-29 MX MX9301754A patent/MX9301754A/en not_active IP Right Cessation
- 1993-03-31 MY MYPI93000567A patent/MY110188A/en unknown
- 1993-03-31 MA MA23143A patent/MA22848A1/en unknown
- 1993-03-31 SI SI9300158A patent/SI9300158A/en unknown
- 1993-04-01 CN CN93104523A patent/CN1059898C/en not_active Expired - Fee Related
- 1993-04-06 AT AT93908004T patent/ATE194329T1/en not_active IP Right Cessation
- 1993-04-06 ES ES93908004T patent/ES2147196T3/en not_active Expired - Lifetime
- 1993-04-06 NZ NZ251404A patent/NZ251404A/en unknown
- 1993-04-06 RU RU94046012A patent/RU2108393C1/en active
- 1993-04-06 AU AU38999/93A patent/AU673166B2/en not_active Ceased
- 1993-04-06 CZ CZ942712A patent/CZ283702B6/en not_active IP Right Cessation
- 1993-04-06 WO PCT/GB1993/000721 patent/WO1993022284A1/en active IP Right Grant
- 1993-04-06 PL PL93305801A patent/PL172067B1/en unknown
- 1993-04-06 SK SK1315-94A patent/SK281767B6/en unknown
- 1993-04-06 EP EP93908004A patent/EP0639180B1/en not_active Expired - Lifetime
- 1993-04-06 PT PT93908004T patent/PT639180E/en unknown
- 1993-04-06 DK DK93908004T patent/DK0639180T3/en active
- 1993-04-06 CA CA002135169A patent/CA2135169A1/en not_active Abandoned
- 1993-04-06 BR BR9306326A patent/BR9306326A/en not_active Application Discontinuation
- 1993-04-06 HU HU9403189A patent/HU215411B/en not_active IP Right Cessation
- 1993-04-06 JP JP5519022A patent/JPH07507277A/en active Pending
- 1993-04-06 DE DE69328969T patent/DE69328969T2/en not_active Expired - Fee Related
- 1993-04-14 TW TW082102827A patent/TW258732B/zh active
-
1994
- 1994-11-04 FI FI945209A patent/FI106855B/en active
- 1994-11-04 NO NO944215A patent/NO944215L/en not_active Application Discontinuation
- 1994-11-05 KR KR1019940703956A patent/KR100287082B1/en not_active Expired - Fee Related
-
2000
- 2000-04-03 CN CN00104973A patent/CN1291653A/en active Pending
- 2000-07-27 GR GR20000401724T patent/GR3034034T3/en not_active IP Right Cessation
-
2001
- 2001-03-21 US US09/813,755 patent/US20010018205A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0223334A1 (en) * | 1985-08-10 | 1987-05-27 | Beecham Group Plc | Process for the preparation of aryl-piperidine carbinols |
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