WO2001025236A2 - A stereoselective process for the preparation of endo-3-aminoazabicycloalkanes - Google Patents
A stereoselective process for the preparation of endo-3-aminoazabicycloalkanes Download PDFInfo
- Publication number
- WO2001025236A2 WO2001025236A2 PCT/IB2000/001360 IB0001360W WO0125236A2 WO 2001025236 A2 WO2001025236 A2 WO 2001025236A2 IB 0001360 W IB0001360 W IB 0001360W WO 0125236 A2 WO0125236 A2 WO 0125236A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amount
- carbon atoms
- palladium
- solvent
- respect
- 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.)
- Ceased
Links
- 0 *C(C(CC1)C2)C1CC2(C=C)N Chemical compound *C(C(CC1)C2)C1CC2(C=C)N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
Definitions
- the object of the present invention relates to a stereoselective process for the preparation of endo-3- aminoazabicycloalkanes from azabicycloalkanones, which are intermediates used in the preparation of pharmaceutical compounds .
- R represents hydrogen, a linear or branched alkyl having 1-6 carbon atoms, an alkyl having 1-3 carbon atoms substituted with a phenyl group, the latter optionally substituted with one or more alkyl radicals having 1-6 carbon atoms and/or with one or more alkoxy radicals having 1-6 carbon atoms and n represents 0 or an integer selected between 1 or 2, by means of reductive amination of azabicycloalkanones
- R and n have the above-mentioned meanings, said amination being performed in a single step by adding to a hydroalcoholic solution of azabicycloalkanone (II) ammonium formate, at ambient temperature and pressure, in the presence of a suitable catalyst.
- a suitable catalyst may be represented by a metal in an appropriate form.
- the alkyl radicals having 1-6 carbon atoms the preferred one is the methyl radical; among the alkoxy radicals having 1-6 carbon atoms the preferred one is the methoxy radical; among the alkyl radicals having 1-3 carbon atoms which are substituted with a phenyl group the preferred one is the benzyl radical and between the integers represented by n, the integer 1 is the preferred one.
- the endo-3-aminoazabicycloalkanes (I) represent an important element of the structure of widely used pharmaceuticals.
- their corresponding amides are particularly interesting as receptor antagonists of 5-hydroxytryptamine (5-HT 3 ) : encompassed among them are zatosetron maleate, granisetron and BRL 46470A the syntheses of which are described in United States patents n°4,921,982 and n°4,886,808 and in European patent application n°247266.
- An endotropylamide namely 7- azaindolylcarboxytropylamide, is an effective antitussive drug described and claimed in the United States patent n°5,750,536 in the name of the Applicant.
- the process of the present invention for the preparation of endo- 3-aminoazabicycloalkanes (I), as well as providing high total yields and a high stereoselectivity degree has the advantage of being extremely simple and economical.
- high temperatures or pressures are not used, and neither are reagents requiring particular operations: the desired endo-3- aminoazabicycloalkanes (I) are obtained in single reaction step by adding ammonium formate to a solution, in a hydroalcoholic solvent, of azabicycloalkanones (II), at ambient temperature and pressure and in the presence of a suitable metal acting as a catalyst for the hydrogen transfer.
- ammonium formate employed in a molar quantity in excess in respect to the substrate to be aminated, surprisingly acts simultaneously as hydrogen transfer and also as nitrogen donor without giving rise to any formation of N-formylamine intermediate, as one would expect in reductive amination according to Leuckart.
- Suitable catalysts for the process of the invention are those commonly used in the amination processes such as nickel, rhodium, ruthenium, palladium and platinum: platinum in the form of platinum dioxide and the palladium on charcoal are the preferred ones, also because they can easily be recycled.
- the catalyst after separation of the catalyst by filtration from the reaction medium, it can be reactivate, without appreciable lost of activity and yield, by simply washing it with diluted mineral acids, for example with IN chloridric acid.
- the so reactivated catalyst may be used, at least, in five consecutive productive cycles.
- catalyst palladium on charcoal is particularly preferred.
- Suitable alcohols to be employed in the hydroalcoholic solvent are those which are mixable with water and which contain 1-4 carbon atoms, such as, for example, methanol, ethanol and isopropanol, methanol being particularly preferred.
- ammonium formate in a weight ratio comprised between 3:1 and 8:1, preferably in a 5:1 weight ratio, in respect to the substrate to be aminated, is added under stirring to an alcoholic solution of azabicycloalkanone (II), prepared using a solvent : solute ratio of 5-20ml:lg, preferably a ratio of 10-12ml:lg.
- the suspension is gradually diluted with a total amount of demineralized water to represent 5-15% with respect to the amount of alcohol used as solvent (v/v) .
- the amount of water corresponds to 10% of the total amount of alcoholic solvent.
- the catalyst consisting of Pd/C
- a weight ratio between palladium and substrate to be aminated of 5-15:100, preferably 8-12:100, and more preferably of about 10:100.
- the reaction mixture is maintained under stirring at temperature and pressure ambient for a period of time varying from 8-10 hours up to 24-30 hours.
- the catalyst is separated, the solvent is removed and from the residue, taken up with alcohol, separate the crystals of endo-3-aminoazabicycloalkane (I) by adding an excess of an aqueous solution of a mineral or organic acid.
- Aqueous solutions of mineral acids are those of pharmaceutically acceptable mineral acids such as, sulphuric, chloridric, phosphoric and nitric acid.
- Aqueous solutions of organic acids are those of pharmaceutically acceptable carboxylic acids which are characterized by a high solubility in alcohol such, for example, benzoic acid.
- Rrt l
- Rrt 1.03
- Rrt 1.15 ⁇ -tropylamine* or endo-3-amino-8-methyl-8-azabicyclo [3.2.1] octane; ⁇ -tropylamine** or eso-3-amino-8- methyl-8-azabicyclo [3.2.1] octane; tropinone*** or 8- methyl-8-azabicyclo [3.2.1] octan-3-one.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Cosmetics (AREA)
Abstract
A one-step stereoselective process for the preparation of endo-3-aminoazabicycloalkanes from azabicycloalkanones by means of reductive amination is described.
Description
Description A stereoselective process for the preparation of endo- 3-aminoazabicycloalkanes
The object of the present invention relates to a stereoselective process for the preparation of endo-3- aminoazabicycloalkanes from azabicycloalkanones, which are intermediates used in the preparation of pharmaceutical compounds .
More particularly the said process relates to the preparation of endo-3-aminoazabicycloalkanes having structure formula:
The endo-3-aminoazabicycloalkanes (I) represent an important element of the structure of widely used pharmaceuticals. In particular their corresponding amides are particularly interesting as receptor antagonists of 5-hydroxytryptamine (5-HT3) : encompassed among them are zatosetron maleate, granisetron and BRL 46470A the syntheses of which are described in United States patents n°4,921,982 and n°4,886,808 and in European patent application n°247266. An endotropylamide, namely 7- azaindolylcarboxytropylamide, is an effective antitussive drug described and claimed in the United States patent n°5,750,536 in the name of the Applicant.
The corresponding amides which originate from 3-exo- aminoazabicycloalkanes (III) :
wherein R and n have the above-mentioned meanings, are practically inactive substances. As a consequent result, in processes for the preparation of 3- aminoazabicycloalkanes it is deemed necessary to remove as much as possible of the exo-isomer (III), which is formed together with the desired endo-isomer (I), before to proceeding further with obtaining the above pharmaceutically used amides.
Procedures of synthesis for the preparation of 3- aminoazabicycloalkanes, in which the problem consisting of the presence of the exo-isomer has tried to be solved, are well known in the art. With regard to the synthesis of tropylamine (I,R=CH3, n=l) a stereoselective amination process has recently been described in the United States patent n°5,625,065 according to which a reductive amination is carried out on azabicycloalkanones by amines in the presence of sterically hindered acyloxyborohydrides followed by removal of the radical originally bound to the amine. It is evident that such a process does not allow the direct formation of primary endo-amines (I) since, in order to obtain these amines, it is necessary to carry out a further step on the intermediates consisting of the secondary amines. More recently the United States patent n°5,856,489 describes a process for the preparation of endo-3-aminoazabicycloalkanes, among which granatylamine is included (I, R=CH3, n=2), by catalytic hydrogenation of oximes and/or O-
methyloximes of azabicycloalkanones, in the presence of rhodium, as catalyst, in alcoholic ambience at a temperature from 25 to 70°C, preferably 50CC, and under high pressure.
In respect to the above-mentioned methods, the process of the present invention for the preparation of endo- 3-aminoazabicycloalkanes (I), as well as providing high total yields and a high stereoselectivity degree, has the advantage of being extremely simple and economical. In the said process high temperatures or pressures are not used, and neither are reagents requiring particular operations: the desired endo-3- aminoazabicycloalkanes (I) are obtained in single reaction step by adding ammonium formate to a solution, in a hydroalcoholic solvent, of azabicycloalkanones (II), at ambient temperature and pressure and in the presence of a suitable metal acting as a catalyst for the hydrogen transfer. In the process of the invention, ammonium formate, employed in a molar quantity in excess in respect to the substrate to be aminated, surprisingly acts simultaneously as hydrogen transfer and also as nitrogen donor without giving rise to any formation of N-formylamine intermediate, as one would expect in reductive amination according to Leuckart. Suitable catalysts for the process of the invention are those commonly used in the amination processes such as nickel, rhodium, ruthenium, palladium and platinum: platinum in the form of platinum dioxide and the palladium on charcoal are the preferred ones, also because they can easily be recycled. In fact, after
separation of the catalyst by filtration from the reaction medium, it can be reactivate, without appreciable lost of activity and yield, by simply washing it with diluted mineral acids, for example with IN chloridric acid. The so reactivated catalyst may be used, at least, in five consecutive productive cycles.
Particularly preferred is the catalyst palladium on charcoal.
Suitable alcohols to be employed in the hydroalcoholic solvent are those which are mixable with water and which contain 1-4 carbon atoms, such as, for example, methanol, ethanol and isopropanol, methanol being particularly preferred.
According to the process of the invention, ammonium formate, in a weight ratio comprised between 3:1 and 8:1, preferably in a 5:1 weight ratio, in respect to the substrate to be aminated, is added under stirring to an alcoholic solution of azabicycloalkanone (II), prepared using a solvent : solute ratio of 5-20ml:lg, preferably a ratio of 10-12ml:lg. The suspension is gradually diluted with a total amount of demineralized water to represent 5-15% with respect to the amount of alcohol used as solvent (v/v) . Preferably the amount of water corresponds to 10% of the total amount of alcoholic solvent. To the obtained solution the catalyst, consisting of Pd/C, is added in such a quantity as to give a weight ratio between palladium and substrate to be aminated of 5-15:100, preferably 8-12:100, and more preferably of about 10:100. The reaction mixture is maintained under stirring at
temperature and pressure ambient for a period of time varying from 8-10 hours up to 24-30 hours. Thereafter the catalyst is separated, the solvent is removed and from the residue, taken up with alcohol, separate the crystals of endo-3-aminoazabicycloalkane (I) by adding an excess of an aqueous solution of a mineral or organic acid.
Aqueous solutions of mineral acids are those of pharmaceutically acceptable mineral acids such as, sulphuric, chloridric, phosphoric and nitric acid. Aqueous solutions of organic acids are those of pharmaceutically acceptable carboxylic acids which are characterized by a high solubility in alcohol such, for example, benzoic acid.
The following Examples serve to illustrate the invention without, however, limiting it. Example 1 endo-3-Amino-8-methyl-8-azabicyclo [3.2.1] octane dihydrochloride
To a solution consisting of 6g 8-methyl-8- azabicyclo [3.2.1] octan-3-one (tropinone) in 112.5ml methanol, 25g finely subdivided ammonium formate and 12.5ml demineralized water are added under stirring. After total dissolution of the salt 5.1g 10% Pd/C are added thereto and the reaction mixture is kept under stirring at ambient temperature. The solution obtained is filtered over a celite panel on Buckner, the filter washed with methanol, the eluates collected together, the solvent distilled off under reduced pressure in vacuo and the oily residue so obtained dissolved in 100ml ethanol. To the solution, 7.5ml of a 37.5%
chloridric acid aqueous solution are added, and crystallization is trigged by adding a few crystals of endo-3-amino-8-methyl-8-azabicyclo [3.2.1] octane dihydrochloride. The reaction mixture is maintained under stirring, first at ambient temperature for one hour, then at 4°C for five hours. The crystalline precipitate is filtered, washed with assolute ethanol and dried in vacuo at 40 °C to give a first crop of 4.7g endo-3-amino-8-methyl-8-azabicyclo [3.2.1] octane dihydrochloride. From the mother waters, by concentrating them to half of their volume, after filtration and drying, are obtained a further 2.9g of the desired product. Melting point >360°C.
Humidity (Karl-Fisher) 1.03%; potentiometric title (HC104) 97.3%
1H-NMR (DMSO) δ (ppm) 11.2-11.0 (bs, 1H,NHCH3 +) 8.7-8.2 (bs,3H, NH3 +) 4.0-3.8 (bs,2H), 3,7-3.5 (m,lH), 2.8-2.55 (m, 5H), 2.4-2.05 (m, 6H) .
A sample of the salt is dissolved in an excess of a 5% sodium carbonate aqueous solution until it is clearly alkalized and it gives an oily mass which is extracted with diethyl ether and evaporated to dryness to provide the free base consisting of endo-3-amino-8- methyl-8-azabicyclo [3.2.1] octane as an oil having the following data:
^-NMR (CDCI3) δ (ppm) 9.0-7.0 (bs,2H) 3.7-3.6 (bs,2H) 4.0-3.8 (bs,2H), 3.5-3.4 (m,lH), 2.7-2.5 (m,5H), 2.3- 2.1 (m,4H), 2.9-1.9 (d,2H) . Example 2 The purity of endo-3-amino-8-methyl-8-
azabicyclo [3.2.1] octane dihydrochloride, obtained according to the previous Example, was measured equal to 98.98% as endo-tropylamine (or α-tropylamine) using gas-chromatography at the experimental conditions as follows :
Sulpeco column SPBt -35 30mx0, 53mmx0, 5μm column temperature 60 o cl°c/min 98°C(xlmin)10°c/min
250°C (x 20 min) type and temp, of injector ON-COLUMN, 220 °C type and temperature detector FID, 250°C FID attenuation 4 x 11 carrier helium, 3ml/min volume injected lμl run time 60min
Rt (α-tropylamine*) 24.34min Rrt=l Rt (β-tropylamine**) 25.07min Rrt=1.03 Rt (tropinone***) 28.03min Rrt=1.15 α-tropylamine* or endo-3-amino-8-methyl-8-azabicyclo [3.2.1] octane; β-tropylamine** or eso-3-amino-8- methyl-8-azabicyclo [3.2.1] octane; tropinone*** or 8- methyl-8-azabicyclo [3.2.1] octan-3-one.
Claims
1. A stereoselective process for the preparation of endo-3-aminoazabicycloalkanes having structure formula:
2. A process according to claim 1, characterized by the fact that the catalyst used is selected between platinum dioxide and palladium on charcoal.
3. A process according to claim 2, characterized by the fact that the alcohol is an alcohol mixable with water containing from 1 to 4 carbon atoms and that ammonium formate, in respect to the substrate azabicycloalkanone (II), is a weight ratio comprised between 3:1 and 8:1, and that the catalyst is palladium on charcoal and that the ratio between the weight amount of palladium and the weight amount of azabicycloalkanone (II) is comprised in the range 5- 15:100 and that the ratio between the volume of alcoholic solvent: amount of azabicycloalkanone (II) is comprised in the range 5-20ml/g and that the amount of water in the hydroalcoholic solvent represents 5- 15% with respect to the amount of alcohol used as solvent.
4. A process according to claim 3, characterized by the fact that palladium on charcoal is in a weight ratio in respect to the azacycloalkanone substrate (II) of about 10:100 and that ammonium formate is in a weight ratio in respect to the quantity of azacycloalkanone (II) of 5:1 and that the ratio between the volume of the alcoholic solvent and the amount of azabicycloalkanone (II) is comprised in the range 10-12ml/g and that the amount of water in the hydroalcoholic solvent represents 10% in respect to alcohol used as solvent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU73061/00A AU7306100A (en) | 1999-10-01 | 2000-09-26 | A stereoselective process for the preparation of endo-3-aminoazabicycloalkanes |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT1999MI002048A IT1313660B1 (en) | 1999-10-01 | 1999-10-01 | STEREOSELECTIVE PROCEDURE FOR THE PREPARATION OF ENDO-3-AMINOAZABICICLOALCANI. |
| ITMI99A002048 | 1999-10-01 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2001025236A2 true WO2001025236A2 (en) | 2001-04-12 |
| WO2001025236A3 WO2001025236A3 (en) | 2002-01-17 |
Family
ID=11383702
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2000/001360 Ceased WO2001025236A2 (en) | 1999-10-01 | 2000-09-26 | A stereoselective process for the preparation of endo-3-aminoazabicycloalkanes |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU7306100A (en) |
| IT (1) | IT1313660B1 (en) |
| WO (1) | WO2001025236A2 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7351704B2 (en) | 2004-02-18 | 2008-04-01 | Theravance, Inc. | Indazole-carboxamide compounds as 5-HT4 receptor agonists |
| US7396933B2 (en) | 2004-11-05 | 2008-07-08 | Theravance, Inc. | Quinolinone-carboxamide compounds |
| US7399862B2 (en) | 2004-11-05 | 2008-07-15 | Theravance, Inc. | 5-HT4 receptor agonist compounds |
| US7419989B2 (en) | 2004-12-22 | 2008-09-02 | Theravance, Inc. | Indazole-carboxamide compounds |
| US7446114B2 (en) | 2005-03-02 | 2008-11-04 | Theravance, Inc. | Quinolinone compounds as 5-HT4 receptor agonists |
| US7671198B2 (en) | 2006-02-16 | 2010-03-02 | Theravance, Inc. | Process for preparing intermediates to 5-HT4 receptor agonist compounds |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL59004A0 (en) * | 1978-12-30 | 1980-03-31 | Beecham Group Ltd | Substituted benzamides their preparation and pharmaceutical compositions containing them |
| US5625065A (en) * | 1994-06-27 | 1997-04-29 | Eli Lilly And Company | Stereoselective process for making endo-tropanamine and like compounds |
| GB9414900D0 (en) * | 1994-07-23 | 1994-09-14 | Smithkline Beecham Plc | Novel process |
-
1999
- 1999-10-01 IT IT1999MI002048A patent/IT1313660B1/en active
-
2000
- 2000-09-26 AU AU73061/00A patent/AU7306100A/en not_active Abandoned
- 2000-09-26 WO PCT/IB2000/001360 patent/WO2001025236A2/en not_active Ceased
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7674908B2 (en) | 2004-02-18 | 2010-03-09 | Theravance, Inc. | Indazole-carboxamide compounds as 5-HT4 receptor agonists |
| US7351704B2 (en) | 2004-02-18 | 2008-04-01 | Theravance, Inc. | Indazole-carboxamide compounds as 5-HT4 receptor agonists |
| US8044045B2 (en) | 2004-02-18 | 2011-10-25 | Theravance, Inc. | Indazole-carboxamide compounds as 5-HT4 receptor agonists |
| US7396933B2 (en) | 2004-11-05 | 2008-07-08 | Theravance, Inc. | Quinolinone-carboxamide compounds |
| US7399862B2 (en) | 2004-11-05 | 2008-07-15 | Theravance, Inc. | 5-HT4 receptor agonist compounds |
| US7498442B2 (en) | 2004-11-05 | 2009-03-03 | Theravance, Inc. | Quinolinone-carboxamide compounds |
| US7534889B2 (en) | 2004-11-05 | 2009-05-19 | Theravance, Inc. | 5-HT4 receptor agonist compounds |
| US7419989B2 (en) | 2004-12-22 | 2008-09-02 | Theravance, Inc. | Indazole-carboxamide compounds |
| US7786136B2 (en) | 2004-12-22 | 2010-08-31 | Theravance, Inc. | Indazole-carboxamide compounds |
| US8003664B2 (en) | 2004-12-22 | 2011-08-23 | Theravance, Inc. | Indazole-carboxamide compounds |
| US7875629B2 (en) | 2005-03-02 | 2011-01-25 | Theravance, Inc. | Quinolinone compounds as 5-HT4 receptor agonists |
| US7446114B2 (en) | 2005-03-02 | 2008-11-04 | Theravance, Inc. | Quinolinone compounds as 5-HT4 receptor agonists |
| US7671198B2 (en) | 2006-02-16 | 2010-03-02 | Theravance, Inc. | Process for preparing intermediates to 5-HT4 receptor agonist compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| ITMI992048A0 (en) | 1999-10-01 |
| IT1313660B1 (en) | 2002-09-09 |
| WO2001025236A3 (en) | 2002-01-17 |
| AU7306100A (en) | 2001-05-10 |
| ITMI992048A1 (en) | 2001-04-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2734507B1 (en) | Process for the synthesis of n-substituted cyclic alkylene ureas | |
| KR19990013522A (en) | Process for preparing substituted perhydroisoindole | |
| WO2001025236A2 (en) | A stereoselective process for the preparation of endo-3-aminoazabicycloalkanes | |
| EP2236510B1 (en) | Process for isolation of a mixture of rrrs and sssr configurations of nebivolol intermediates | |
| EP1636199A2 (en) | Method for the production of phenylacetic acid derivatives | |
| CN101410374A (en) | Improved synthesis and preparation of intermediates and novel polymorphs thereof for the preparation of donepezil hydrochloride | |
| CN116496214B (en) | Preparation method of chiral 3- (N-methyl-1, 2,3, 4-tetrahydroisoquinoline) propionate benzenesulfonate | |
| US4751298A (en) | Production of 1-(3-hydroxy-propyl)-1,4-diazepane and 1,4-bis(3,4,5-trimethoxy-benzoyloxy)-propyl-diazepane derivatives thereof | |
| US5723667A (en) | Method of producing optically active tert-leucinol and its use | |
| CN120271495B (en) | A method for synthesizing (3R, 4R)-N-PG-4-amino-3-methylpiperidine | |
| CA1329212C (en) | Process for the preparation of n-(2-chlorobenzyl)-2- (2-thienyl) ethylamine | |
| US6743944B1 (en) | Process for producing optically active aminoalcohol | |
| KR101365849B1 (en) | Process for the preparation of solifenacin or salt thereof and novel intermediates used in the process | |
| US4290971A (en) | Method of preparing 2-(phenylamino)-imidazolines-(2) | |
| US4150229A (en) | 2,5-Di-(ω-aminoalkyl-1')-pyrazines | |
| JP2682713B2 (en) | Production of optically active tetrahydrofuran | |
| EP0781270B1 (en) | Ring-opening amidation process | |
| US4376860A (en) | Pyridyl ketone | |
| JP5247699B2 (en) | Resolution process of chiral piperidine alcohol and synthesis process of pyrazolo- [1,5] -pyrimidine derivatives using piperidine alcohol | |
| JP3594201B2 (en) | Method for producing optically active 2-lower alkylpiperazine | |
| CN112300151A (en) | Preparation method of maririptan intermediate | |
| CN118479984A (en) | Tartaric acid derivative resolving agent, preparation method thereof and non-neridrone resolving method using tartaric acid derivative resolving agent | |
| CN117088829A (en) | Synthesis method of 1-isopropyl-4-(p-methoxyphenyl)piperazine or its hydrohalide | |
| KR20220011669A (en) | Methods and intermediates for the preparation of BTK inhibitors | |
| MXPA98000764A (en) | Continuous procedure for the elaboration of 4-aminopiperidine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: JP |
|
| DPE2 | Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101) |