IE59990B1 - New process for the enantiospecific preparation of (s)-2-ethylamino-1-[3-(trifluoromethyl)phenyl]propane - Google Patents
New process for the enantiospecific preparation of (s)-2-ethylamino-1-[3-(trifluoromethyl)phenyl]propaneInfo
- Publication number
- IE59990B1 IE59990B1 IE133588A IE133588A IE59990B1 IE 59990 B1 IE59990 B1 IE 59990B1 IE 133588 A IE133588 A IE 133588A IE 133588 A IE133588 A IE 133588A IE 59990 B1 IE59990 B1 IE 59990B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- compound
- propane
- ethylamino
- benzyl
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/08—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with only one hydroxy group and one amino group bound to the carbon skeleton
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
New process for the enantiospecific preparation of (S)-2-ethylamino-1-(3-trifluoromethylphenyl)propane, characterised in that benzaldehyde is condensed with (S)-alaninol and that, after reduction, the product originating from the reaction is condensed with acetaldehyde to obtain (S)-N-benzyl-N-ethyl alaninol, which is subjected to the action of thionyl chloride to give, after neutralisation, (S)-2-(N-benzyl-N-ethylamino)-1-chloropropane, which is in its turn condensed with 3-trifluoromethylphenylmagnesium bromide to give (S)-2-(N-benzyl-N-ethylamino)-1-(3-trifluoromethylphenyl)- propane which, after debenzylation by hydrogenolysis, produces (S)-2-ethylamino-1-(3-trifluoromethylphenyl)propane.
Description
The present invention concerns a new process for the enantiospecific preparation of (S)-2-ethylamino-l-(3trifluoromethyIphenyl) propane.
This compound has very interesting pharmacological properties, and especially very powerful anorexigenic properties without, however, exhibiting the undesirable effects of the known amphetamine derivatives (Goodman and Gilman, The Pharmacological Basis of Therapeutics, 7th Ed, MacMillan Ed.
N.Y., 1985 p.178)« According to the earlier patent (FR 1 324 220), the compound of the formula I is obtained in its racemic form from racemic 2-amino~l"(3-trifluoromethyIphenyl)propane, for which several methods of synthesis are proposed. More recently, Patent DD 108 971 described a new method of synthesising the compound of the formula I in racemic form.
It is known, however, that racemic 2-ethylamino-l-(3trifluoromethyIphenyl)propane is very resistant to the customary resolution processes (GB Patent 814 339) . French Patent 1 468 724 describes an effective process for separating the racemate by the action of d-camphoric acid in order to obtain dextrorotatory (S)- 2-ethy1amino-1-(3~ trifluoromethyIphenyl)propane. But however effective the separation process may be, there is always a double problem.
On the one hand, the large number of operations necessitated * by the separation complicates industrial preparation, and on the other hand the cost of preparation of this compound is too high in view of the fact that its laevorotatory isomer is not of the same pharmacological interest.
The Applicant has now discovered a new process for the enantiospecific preparation of (S)-2ethylamino"l"(3trifluoromethylphenyl)propane which is very advantageous compared with the known processes which require resolution of the racemate.
More precisely, the object of the invention is a process for the enantiospecific preparation of (S)~2-ethylamino-l"(3trifluoromethylphenyl)propane of the formula I, CFg □32 - CH - CH3 .» fil H Cfi2 - CB3 (SJ (S)-2-aminopropan-l-ol, compound of CB$S CS) (II) characterised in that: - (S)-alaninol or the formula II C83 - CH is condensed with benzaldehyde, at ambient temperature, and in an anhydrous alcoholic solvent, and then reduced by means of an alkali metal borohydride to obtain (S)-N-bensylalaninol or (S)~2-benzylaminopropan-l-ol, compound of the formula III: (III) which is reacted with acetaldehyde in the same reaction medium, to obtain, after reduction by means of an alkali metal borohydride, (S)-N-benzyl-N-ethylalaninol, or (S)-2-(N-foensyl5 N-efchylamino)propan-l-ol, compound of the formula IV: (S) (IV) which is subjected to the action of thionyl chloride in solution in ether and in the presence of an aprotic solvent, to form (S)-2"(N-benzyl-N-ethylamino)-l-chloro-propane hydrochloride, compound of the formula V: » CB% - ca - CrSg - Cl s . sci / \ 0¾ - e-3 (33 (V) the base of which is liberated by the action of an alkaline inorganic salt such as sodium carbonate, and which is condensed in tha presence of a copper halide, in 5 an inert organic solvent, with an organometallic compound of tha formula VI:, C?3 to form, after basic hydrolysis, (S)-2-(N-bensvl-Nethylamino)-1-(3-trifluoromethylphenyl)propane, compound of the formula VII: Ο —i 1-\ o CSg- CS » 083 I S’ / x £35g CEa " C&3 (VII) which is subjected to catalytic hydrogenation under pressure, in the presence of a transition metal and at a temperature ranging between 20°C and 60°C to obtain (S) -2-ethylamino-l-(3 trifluoromethylphenyl)propane of the formula I.
According to the process of the invention, the condensation of (S)-alaninol, compound of the formula II, with benzaldehyde and of (S)-N-benzylalaninol, compound of the formula III, with acetaldehyde is carried out in an anhydrous alcoholic solvent, preferably methanol, at a temperature ranging between 0"C and + 10°C.
For the reduction of the condensation products of benzaldehyde with (S)-alaninol and of acetaldehyde with (S)~Nbenzvlalaninol, it is preferred to use sodium borohydride.
The reaction of (S)-N-benzyl-N-ethvlalaninol, compound of the formula IV, with thionyl chloride is carried out in an inert organic solvent, preferably an ether, in the presence of an aprotic solvent such as hexamethyl phosphoric triamide (HMPT), at a temperature ranging between -lO’C and 20"G„ The condensation of the organometallic compound of the formula VI with (S)-2-(N-bensyl-N-ethylamino)-1-chloropropane is carried out in the presence of a catalyst selected from the copper(I) halides, in an inert organic solvent such as an ether or preferably tetrahydrofuran, at a temperature ranging between ~20°C and 10°C. The product of the reaction is first hydrolysed with a saturated solution of ammonium chloride, then with concentrated ammonium hydroxide solution.
The hydrogenolysis of the compound VII is carried out with hydrogen under a pressure ranging between 5 and 15 bars, at a temperature ranging between 2 0°C and 60°C in the presence of a catalyst selected from the transition metals, for example 5% palladium on charcoal.
The compound of the formula III is described in the literature in its racexaic form (J.Med. Chem., 1971, 14,, No. 7, p.104) but the (S) enantiomer has never been described. The compounds IV, V and VII are new and as such also form part of the invention.
The (S)-alaninol used as starting material, as well as the benzaldehyde and acetaldehyde used as reagents, are commercially available products. The preparation of the compound VI is known (Marvel C.S., Overberger C.G., Alley R.E., Saunders J.H., J.Am.Chem., (1946), 68, p. 736-738).
The process described above, which is the subject of the present invention, makes it possible to obtain, with good yields, (S) -2--ethylamino~l- (3-tr.if luoromethy lphenyl) -propane identical to the (S) enantiomer obtained by resolution of tha racemate of (R,S)~2"ethylamino-l"(3~trifluoromethylphenyl) propane.
The novelty of the invention lies in the particular choice of the simple starting materials which allow a particularly advantageous process and which, above all, make it possible to obtain the (S) enantiomer selectively, thus avoiding the delicate operation of resolution of the racemate, which inevitably involves a significant loss of product.
The present invention is illustrated in more detail by means of tha Examples which follow: Tha carbon (13C) nuclear magnetic resonance spectra ware recorded at 50 MHz in solution in deuterochloroform.
EXAMPLE 1 : (S) -Mrbe_nzyl-M-ethvlalaninol Place in a beaker, equipped with magnetic stirrer, 30 g of (S)-alaninol and 400 ml of pure anhydrous methanol. Rapidly pour in 42.4 g of benzaldehyde in solution in 200 ml of anhydrous methanol. Continue stirring for 1 hour at ambient temperature. Cool the reaction medium with an iced water bath and add over 20 minutes, without exceeding 2 O’C, 7.6 g of sodium borohydride. stir for 30 minutes at ambient temperature. After cooling with an iced vater bath, add, without exceeding 17°C, 35.2 g of acetaldehyde. Continue stirring for 30 minutes at 17°C, then cool again with iced water and add 11.4 g of sodium borohydride over 30 minutes without exceeding + 17’C. Stir for 15 hours at ambient temperature, then add 25 ml of a saturated sodium chloride solution and 325 ml of diehloromethane. Stir, and a white precipitate forms which is filtered after stirring for 15 minutes. The filtrate is evaporated at 5O’C under a pressure of 13 mmHg. Take up the evaporation residue with a mixture containing 500 ml of diehloromethane, 50 ml of a saturated sodium chloride solution and 50 ml of water. Stir for 30 minutes, then decant. Extract the aqueous phase with 50 ml of diehloromethane. Wash the organic phase with 25 ml of water and dry over anhydrous sodium carbonate. Evaporate the solvent at 50°C under a pressure of 13 mmHg. 73.7 g of crude product are obtained. After distillation at 120°C under 0.2 mmHg, 64.5 g of (S)-N-benzyl-N-ethylalaninol are obtained.
The purity of the product is above 95%. It was determined by gas chromatography, on a SE-52 capillary column, 25 m long, in temperature isotherm at 220°C.
Yield : 83.5 % csD ; +84.06°.
EXAMPLE 2 : f S)-2-(N-benzvl-N-ethylamino)-1-chloropropane Place in a three-necked flask equipped with stirrer and placed under a nitrogen atmosphere 19.3 g of (S)-N-benzyl-Nethylalaninol, 350 ml of anhydrous ethyl ether, then 60 ml of hexamethyl phosphoric triamide (HMPT).
By means of a salt/ice mixture, cool the reaction medium to 5 °C and pour in 13g of thionyl chloride diluted in 100 ml of ether, while keeping at the same temperature. A beige precipitate forms. Remove the cooling bath and continue stirring for 15 hours with a gradual rise to ambient temperature. Under vacuum and while stirring, remove the sulphur dioxide formed.
The (S)-2-(N-benzyl-N-efchylamino)-1-chloropropane hydrochloride formed is in suspension in the ether. Pour in 157 ml of a saturated sodium carbonate solution in order to liberate the base. The pH of the reaction medium is then 6.5.
Decant, then wash the organic layer with 2 x 25 ml of water to eliminate the traces of HMPT. After drying over magnesium sulphate, evaporate the solvent. 21.4 g of crude product are obtained which are distilled under vacuum (b.p. 94-96°C/0.5 mmHg)» 18»16 g of 2-(N-benzyl-N-ethylamino)-1-chloropropane are obtained.
The purity of the product is above 96%. It was determined by gas chromatography on a SE-52 capillary column, 25 m long, in temperature isotherm at 180°C.
Yield : 85.9% aD = +32.39° EXAMPLE 3 : (S)-2-(N-benzyl-N-ethvlamino)-1-(3°triflupromethylphenyl) propane Place in a three-necked 500 ml flask equipped with stirrer 15.86 g of (S)-2-(N-benzyl-N-ethylamino)-1-chloropropane, 200 ml of anhydrous tetrahydrofuran and 1.6 g of cuprous iodide. After cooling the reaction medium to -15°C, pour in 100 ml of a molar solution of 3-trifluoromethyIphenyl magnesium bromide. Bring to reflux for approximately 3 hours. Cool the reaction medium in tetrahydrofuran to -10°C, then hydrolyse with 100 ml of a saturated ammonium chloride solution then with 100 ml of concentrated ammonium hydroxide. Continue stirring for 15 minutes. Decant, then extract the aqueous phase with 2 x 100 ml of diethyl ether. Wash the combined organic phases with 2 x 50 ml of a saturated ammonium chloride solution, then dry over anhydrous sodium carbonate. Evaporate under vacuum to obtain 27.8 g of crude product. After distillation at 138°C under 0.3 mmHg, (S)"2-(N-ben2yl-N-ethylamino)-l-(3trifluoromethyIphenyl)propane is obtained.
The purity of the product is above 86%. It was determined by gas chromatography under the conditions described in Example 1. aD = + 44.51 Yield : 67.5% based on the (S) -2-ethylbensylamino) -1chloropropane. (13C) nuclear magnetic resonance spectrum (T.M.S.) : 15.5 ppm? 40 ppm; 43 ppm; 54 ppm; 56 ppm; 126-128-141-142 ppm.
EXAMPLE 4 : f S)-2-ethvlamino-l-f3-trifluoromethylohenvl)propane Introduce into a hydrogenation bomb 5 g of (S)-2-(N-bensvl-Nethylamino)-1-(3-trifluoromethylphenyl)propane with 250 ml of anhydrous ethanol and 5 g of 5% palladium on charcoal. After flushing the bomb with nitrogen, stir for 4 hours under 10 bars of hydrogen at +5 O’C. Then remove the catalyst by filtration and the ethanol by evaporation, and distil the crude product under vacuum. 2.29 g of (S)~2-ethylamino-l-(3~ trifluoromethylphenyl)propane are obtained.
Purity 87.5%.
Yield : 56% by titre.
(I3C) nuclear magnetic resonance spectrum (T.M.S.) : 15.5 ppm; .3 ppm; 41.7 ppm; 43.7 ppm; 54.7 ppm; 126-128-141 ppm.
Claims (13)
1.,, Process for the enantiospecif ic preparation of (3)-2ethylamino-1-(3-trifluoromethylphenyl)propane of the formula (I): S CSg - 03 (S> characterised in that: (S)-alaninol, or (S)-2-aminopropan-l-ol, compound of the formula II: CB3 - CS - CHgQH (Π) I «fc (SS 10 is condensed with benzaldehyde, at ambient temperature, and in an anhydrous alcoholic solvent, and then reduced by means of an alkali metal borohydride to obtain (S)-Nbenzylalaninol or (S)-2-bensylaminopropan-l-ol of the formula III: φ •GS - eagCH {ΣΠ3 which is reacted with acetaldehyde in the same reaction medium, to obtain, after reduction by means of an alkali metal borohydride, (S)-N-benzyl-N-ethylalaninol, or (S)5 2~(N-benzyl-N~ethylamino)propan-l-ol, compound of the formula IV: CH 3 - CS - CH2 M which is subjected to the action of thionyl chloride in solution in ether and in the presence of an aprotic solvent, to form (S)-2-(N-benzyl-N-ethylamino)-1chloropropane hydrochloride, compound of the formula V: - 14 CH3 - CS - - Cl I s / \ ΟΪ2 0¾ EC1 (s> tha base of which is liberated by the action of an alkaline salt such as sodium carbonate, and which is condensed in the presence of a copper 5 halide, in an inert organic solvent, with an organometallic compound of the formula VI; cm to form, after basic hydrolysis, (S)~2=(N-benzyl-Nethylamino)-1~(3-trifluoromethylphenyl)propane, compound of the formula VII: I cf 3 , ο *-/ )- - ο * CH2- CH - Οϊ 3 082 CH2 - CH3 evil) which is subjected to catalytic hydrogenation under pressure, in the presence of a transition metal and at a temperature ranging between 20° and 60°C to obtain (5)-25 ethylamino-1”(3-trifluoromethvlphenyl)propane of the formula X.
2. ,. Process according to Claim 1, characterised in that the condensation of (S)-alaninol with benzaldehyde and of N~ bensylalaninol with acetaldehyde is carried out in an 10 alcoholic solvent, such as methanol, and at a temperature ranging between 0° and 20°C.
3. Process according to Claim 1, characterised in that the reducing agent used to reduce the condensation product of (S)-alaninol with benzaldehyde and of N-benzvlalaninol 15 with acetaldehyde is sodium borohydride.
4. Process according to Claim l, characterised in that the reaction of thionyl chloride with N-benzyl-Nethylalaninol is carried out in diethyl ether, in the presence of hexamethyl phosphoric triamide.
5. Process according to claim 1, wherein the catalyst used to condense the compound VI with the compound of formula V is cuprous chloride, bromide or iodide.
6. Process according to Claim 1, characterised in that the catalyst used for the hydrogenolysis of the compound of formula VII is 5% palladium supported on charcoal.
7. Process according to Claim 1, characterised in that tha hydrogenolysis of the compound of formula VII is carried out under a hydrogen pressure ranging between 5 and 15 bars, at a temperature ranging between 20“ and 6O’C and in an alcoholic solvent.
8. (S)-2~(N-benzyl-M-ethylamino)propan-l-ol whan used, as an intermediate product for the preparation of (8)-2ethylamino-1-(3-trifluoromethyIpheny1) propane according to the process of Claim l.
9. (8) -2-(bi-benzyl“N-ethylamino) -1-chloropropane, when used as an intermediate product for the preparation of (S)-2ethylamino-1-(3-trifluoromethylphenyl)propane according to the process of Claim 1.
10. (S) -2- (N-bensyl-N-ethy lamino) -1- (3-trif luoromethy lphenyl) propane, when used as an intermediate product for the preparation of (8)-2-ethylamino-l-(3-trifluoromethylphenyl)propane according to the process of Claim 1.
11. A process substantially as hereinbefore described with reference to the Examples.
12. An intermediate substantially as hereinbefore described with reference to the Examples. - 17
13. A compound of formula I as defined in Claim 1 whenever prepared by a process as claimed in any of Claims 1 to 7 oft , or 11.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8710020A FR2618148B1 (en) | 1987-07-16 | 1987-07-16 | NEW PROCESS FOR THE ENANTIOSPECIFIC PREPARATION OF ETHYLAMINO-2 (TRIFLUOROMETHYL-3 PHENYL) -1 PROPANE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE881335L IE881335L (en) | 1989-01-16 |
| IE59990B1 true IE59990B1 (en) | 1994-05-18 |
Family
ID=9353184
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE133588A IE59990B1 (en) | 1987-07-16 | 1988-05-04 | New process for the enantiospecific preparation of (s)-2-ethylamino-1-[3-(trifluoromethyl)phenyl]propane |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0301925B1 (en) |
| AT (1) | ATE68783T1 (en) |
| AU (1) | AU602101B2 (en) |
| DE (1) | DE3865765D1 (en) |
| DK (1) | DK172313B1 (en) |
| ES (1) | ES2009944A6 (en) |
| FR (1) | FR2618148B1 (en) |
| GR (1) | GR1002241B (en) |
| IE (1) | IE59990B1 (en) |
| NZ (1) | NZ224499A (en) |
| OA (1) | OA08845A (en) |
| PT (1) | PT88011B (en) |
| ZA (1) | ZA883484B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1292595B1 (en) * | 1997-06-03 | 1999-02-08 | Alfa Chem Ital | PROCESS FOR THE PRODUCTION OF DEXFENFLURAMINE HYDROCHLORIDE. |
| EP3170807B1 (en) | 2015-11-23 | 2019-12-11 | Frau Pharma S.r.l. | New method for synthesis of fenfluramine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH204708A (en) * | 1937-07-21 | 1939-05-15 | Chem Fab Vormals Sandoz | Process for the preparation of an amino alcohol. |
| US3198834A (en) * | 1964-07-27 | 1965-08-03 | Snc Science Union Et Compagnie | Optical isomers of trifluoromethylated phenethylamines |
| US3792048A (en) * | 1970-10-29 | 1974-02-12 | Pacific Res Labor | Process for hydrolyzing 3-trifluoromethyl phenethylamines |
-
1987
- 1987-07-16 FR FR8710020A patent/FR2618148B1/en not_active Expired
-
1988
- 1988-05-03 DE DE8888401067T patent/DE3865765D1/en not_active Expired - Lifetime
- 1988-05-03 EP EP88401067A patent/EP0301925B1/en not_active Expired - Lifetime
- 1988-05-03 AT AT88401067T patent/ATE68783T1/en not_active IP Right Cessation
- 1988-05-04 IE IE133588A patent/IE59990B1/en not_active IP Right Cessation
- 1988-05-05 NZ NZ224499A patent/NZ224499A/en unknown
- 1988-05-05 GR GR880100293A patent/GR1002241B/en not_active IP Right Cessation
- 1988-05-11 OA OA59350A patent/OA08845A/en unknown
- 1988-05-17 ZA ZA883484A patent/ZA883484B/en unknown
- 1988-06-22 ES ES8801937A patent/ES2009944A6/en not_active Expired
- 1988-07-05 DK DK373888A patent/DK172313B1/en not_active IP Right Cessation
- 1988-07-15 PT PT88011A patent/PT88011B/en active IP Right Grant
- 1988-07-15 AU AU19083/88A patent/AU602101B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| DK172313B1 (en) | 1998-03-16 |
| AU602101B2 (en) | 1990-09-27 |
| ES2009944A6 (en) | 1989-10-16 |
| DK373888D0 (en) | 1988-07-05 |
| GR880100293A (en) | 1989-04-12 |
| DK373888A (en) | 1989-01-17 |
| GR1002241B (en) | 1996-04-22 |
| PT88011B (en) | 1995-03-01 |
| EP0301925B1 (en) | 1991-10-23 |
| NZ224499A (en) | 1990-07-26 |
| FR2618148B1 (en) | 1989-10-27 |
| PT88011A (en) | 1989-06-30 |
| EP0301925A1 (en) | 1989-02-01 |
| FR2618148A1 (en) | 1989-01-20 |
| AU1908388A (en) | 1989-01-19 |
| DE3865765D1 (en) | 1991-11-28 |
| ATE68783T1 (en) | 1991-11-15 |
| IE881335L (en) | 1989-01-16 |
| ZA883484B (en) | 1988-11-21 |
| OA08845A (en) | 1989-03-31 |
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| Date | Code | Title | Description |
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| MM4A | Patent lapsed |