IE59015B1 - Process for preparing (z)-1-phenyl-1-diethyl amino carbonyl-2-aminomethylcyclopropanehydrochloride - Google Patents
Process for preparing (z)-1-phenyl-1-diethyl amino carbonyl-2-aminomethylcyclopropanehydrochlorideInfo
- Publication number
- IE59015B1 IE59015B1 IE105786A IE105786A IE59015B1 IE 59015 B1 IE59015 B1 IE 59015B1 IE 105786 A IE105786 A IE 105786A IE 105786 A IE105786 A IE 105786A IE 59015 B1 IE59015 B1 IE 59015B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- phenyl
- process according
- reaction
- organic solvent
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
1. Process for the industrial preparation of (Z)-1-phenyl-1-diethylaminocarbonyl-2- aminomethylcyclopropane of formula I : see diagramm : EP0200638,P7,F2 characterized by the use of the following successive reaction steps : i) 1-phenyl-2-oxo-3-oxa(3: 1: 0) bicyclohexane of formula II : see diagramm : EP0200638,P8,F1 is opened by treatment with a phthalimide salt in an organic solvent ; ii) (Z)-1-phenyl-2-phthalimidomethylcyclopropane-carboxylic acid of formula III thus obtained see diagramm : EP0200638,P8,F2 is treated with an acid chloride, and then the acid chloride thus formed is amidified by condensation with diethylamine in an organic solvent ; and iii) (Z)-1-phenyl-1-diethylaminocarbonyl-2- phthalimidomethylcyclopropane of formula IV thus obtained : see diagramm : EP0200638,P8,F3 is then treated with an alkylamine or a primary hydroxyalkylamine by itself or in the presence of a solvent to obtain, after hydrochlorination, the compound of abovementioned formula I.
Description
The present invention, carried out at P. F.
MEBICAHEMT Research Centre, relates to a new industrial process for preparing H£DALC£PSAH (international nonpropr ietory name for (2)~1~phenyl-1-diethyla«inocar~ $ T bonyl-2-aminomethylcyclopropane hydrochloride) which corresponds to the formula I: HXDALCXPRAN is currently finding increasing clinical use as ara antidepressant.
In the prior art, illustrated by French Patent A-2,508,035, this compound was prepared according to a S-stage process from 1-phenyl-2"Oxo-3-oxabicycloC3.1.03 hexane, this latter derivative being described in French Patent A=2 ,302,994.
According t© this prior art, the limiting stage of the preparation process occurs at the stage of the reaction of chloride of the l-phenyl-2-aeinoBethylcyclopropane hydrochloride with diethylamine. During this reaction, in effect, a sice reaction takes place, namely an intramolecular cyclization which leads to the formation of a lactam: 1-phenyl"2"Oxo-3-azabicyclo(3.1.Q)" 5901 5 - 2 SCHEME FOR THE EXTRANEOUS SIDE REACTION io Removal s# the lactam requires aft «additional purification, which lowers the yield of M10ALCIPRAH.
The subject of the present invention relates to a new industrial process for preparing HIDALCIPRAN in 3 synthetic stages. It is a feature of this process that, already at the first stage, the amine group is created in a protective form, this thereby enabling the carboxyl group to be activated for the purpose of condensation with diethylamine without a by-product being formed.
The process of the invention can be shown schematically as follows: REACTION SCHEME Ph chai irnids salt ’ GA t (III) (in ISO " 200*C - 3 2nd stage kA ϊ o=c OE (Ill) 3rd stage The first stage of the process consists in condensation of the lactone of formula ΙΪ with a phthalimide salt, in particular potassium phthalimide, in an organic solvent preferably chosen from dimethyIformamide, dimethyI acetaraide and methyIpyrrο Iidone . Th e reaction temperature is preferably between 150 and 200°C, and the reaction time varies from 5 to 15 hours.
During the second stage of the reaction, the IS acid of formula 111 is treated with an acid chloride, in particular thionyl chloride, preferably used in stoichiometric excess. The reaction is advantageously performed by beating under reflux, for a period of between 0.5 and 2 hours. After removal of the thionyl chloride, the acid chloride formed is condensed with - 4 diethyl sm-i π e in an organic solvent, preferably chosen from methylene chloride, chloroform, tetrahydrofuran and dioxane. The temperature of this amidation is advantageously between 5 and 30°C.
During the third stag® of the reaction, the primary amine group is liberated by treating the amide of formula IV with a low molecular weight alkylamine or hydroxy a IkyIaaine, in particular ethanolamine, used alone or in the presence of a solvent such as water or a low molecular weight alcohol (methanol, ethanol, propanol or isopropanol). This reaction is performed at a teassarature between rccm tasperatuxe «aid ths boiling point of ths reaction medium namely, between 60°C and 100°C in the case of hydroxyalky lamine.
After extraction of the reaction medium with a solvent such as methylene chloride, chloroform or ethyl acetate, the residual oil obtained after removal of the solvent is hydrochIorinated, for example using sn ethanolic solution of hydrochloric acid, and the compound of formula I is crystallized by adding ether, isopropyl ether or methylal.
PROCEDURE s t s t a g e (Z)-1Phenyl-2-pht hal im i dome thy I -cyclopropane-1-carjboxylic acid (compound III) A suspension of 52.56 g (0.3 mole) of 1-phenyl2-oxo-3-oxabicycloC3»1-Q)hexane (compound II) and 61 g (0.33 mole) of potassium phthal imide in 270 cm1 of dimethylformamide is maintained with stirring at 1500C for 12 hours.
The solution obtained after the mixture has «L returned to room temperature is poured into 1000 cm of water, iter extraction with ethyl acetate, the aqueous phase is acidified with an excess of acetic acid and then cooled in ice. The acid which crystallizes is drained, washed with water and recrystallized in ethanol to give 62.6 g of compound III (yields 65X).
Melting point: 186° Formula: C-joH -)5^04: 321.22 TLC (Merck silica GF 254) Rf: 0-6 (chloroform/methanol 85:15) IR: (KBr) 0 c=0: 1775, 1710 and 1650 cm11H NMR (CDCI3) δ ppm (TMS): 1.1 to 2 (m, 3H, cyclopropane); 3-9 (0, 2H, CHjjN); 7. 1S (s, 5H, aromatic); 7.75 (s, 4H, aromatic). 2nd stage (Z) " 1 - P h eny I -1 -d i et h y I am i noc a rbony l-2-phthal imidomathyleyclopropgne (compound IV) 16.2 g (0.05 mole) of 1 -phenyL-2-phtha Iiraidome thyIcyc I opropane- 1 -carboxyIic acid (compound III) are 3 added to 30 cm of thionyl chloride at room temperature with stirring. Dissolution is complete after 2 hours at room temperature.
The solution is then maintained under reflux for hours- After removal of the excess thionyl chloride, the crude acid chloride, dissolved in 50 cm of methylene chloride, is introduced dropwise into a solution of 10.3 ca° (0.1 mole) of diethylamine and 150 caJ of methylene chloride with stirring in an ieebath. After the mixture has been left overnight with stirring at room temperature, the solution obtained is washed with water, dried over filtered and concentrated under reduced pressure. On addition of isopropyl ether, 15„4 g of compound IV are obtained (yield: 82*)» Melting point: 13 Ί0 Formula: ^23^24^2θ3 376.46 TLC (Merck silica GF 254); Rf = 0.66 (chloroform/methanol 95:5) IR (KBr) ti C = 0 1630, 1705 and 1770 cm NMR (CDCI3) δ PPia (TMS): 0.65 (t, 5H, CH3); 1.15 (t, 3H , C H3 ) ; 1.25 ( m, IH, cyclopropane); 1.5-2.3 (m, 2H, cyclopropane); 3-3.7 (m, 5H, CHjN, cyclo-CH-N); 4.15 (dd, IH, cycIo-CH-N); 7.1 (s, 5H, aromatic); 7.6 (m, 4Η, aromatic). 3rd stage (Z)-1-Phenyl-l-diethylaminocarbonyl-2-am i nome thy I eye 10 propane hydrochloride (compound I), MIDALCIPRAH a) The suspension of 18.82 g (0.05 mole) of 1-phenyl-1-diethylaminocarbonyl-2-phthaliraidoraethylcyclopropane (compound IV) in 95 cm of a 40* strength aqueous solution of me thy I amine is maintained with stirring at rooc temperature for 5 hours.
Dissolution takes place, followed by crystallization of N,N-d 1 methyI phtha I amide. The suspension is extracted 3 times with ethyl acetate. The organic phase is washed with water, dried over Nap SO/, and filtered, and the solvent is resovec under the addition of an ethanolic acid followed by ether, 10 g I are obtained (yield: 7IX) reduced pressure. After solution of hydrochloric of crystals of the comoound - Ί - Melting points 18 0 0 Formula: C15H23CIN2G: 282.82 TLC (Merck silica GF 245) S Rf: 0.43 (chloroform /methanol/NH4OH 84:14:2) IR (KBr ) ΐ 4 C-.Q 1010 ca11H NMR (D2Q) δ ppm (TSP) 0.8 (t, 3H„ CH3); 1.15 (t 3H, CH3); 1.5-2.1 (m, 3H, cyclopropane); 3-3.7 (ra, CHjN); 7.3 (s, aromatic). b) The suspension of 60 g (0.159 mole) of 1-phenyl· 1~diethyla»inocarbonyl-2-phthalimidomethylcyclopropane in 60 cra^ of ethanolaraine is maintained for 1 hour at 90°C with stirring.
After addition of 300 ral of ice-cold water, the mixture is extracted 3 times with ethyl acetate.
The organic phase is washed with water, dried over Na^SOt and filtered, and the solvent is removed under reduced pressure.
After addition of a 5N ethanolic solution of hydrochloric acid followed by ether, 39.7 g of crystals of the compound I are obtained (yield; 88%) Melting point: 178 -
Claims (11)
1. Process for the industrial preparation of (
2. )-1phenyl-1-diethyl9rainocarbonyl -2 -asainoisethylcy clo propane hydrochloride of formula I: characterised by the use of the following successive reac tion steps: i) 1-phenyl-2-oxo-3-oxaC3;1:0)bicyclohexane of is opened by treatment with a phthalinide salt in an organic solvent; i i5 (I)-1-pheny l-2-pfotfoalinidosethyI eyelopropanecarboxylic acid of foreula Eli thus obtained chloride thus formed is amidified by condensation with diethylamine in an organic solvent; and iii) (Z3“1-phenyl“1“diethylatftinocarbonyl“2“phthaI iaidoaethyI cyclopropane of formula IV thus obtained: IV is then treated with an elkylaaine or a primary hydroxyalkylamine by itself or in the presence of a solvent to obtain, after hydrochlorination, the compound of abovementioned forsula ΧΙΟ 2.. Process according to Claim 1, characterized in that the phthalimide salt employed is potassium phthal imide»
3., Process according to (either of Cla ias 1 arid 2, characterized in that the treatment of the lactone of 15 formula II with the phthalimide salt is performed in an organic solvent chosen from dimethyI formamide, dimethylacetamide and methylpyrrolidone.
4. „ Process according to one of Claims 1 to 3, characterized in that the first step of condensation of 20 the phthal imide salt with the lactone of formula 2Z is performed at a reaction temperature situated in the range of the boiling points ©f the solvent employed during this step, preferably between 1SO ! °C and 200°'c„ »
5. Process according to one of Claims 1 to 4, charac· in that the acid chloride «splayed during the step is thionyl chloride. according to one of Claims 1 to 5, characthe treatment of the compound of formula XXI with the acid chloride is performed by heating under 30 reflux,, 7. Process according to one of Claims 1 to 6, characterised in that the acidification of the second reaction t e r ι x« second reaction
6. „ Process terized in that step is performed in an organic solvent chosen from aethylen© chloride, chloroform, tetrahydrofuran and dioxane.
7. 8. Process according to one of Cl a ias 1 to 7, characterised in that the reaction teaperature of the an id if i5 cation in the second step is between 5°C and 30°C.
8. 9. Process-according to one of Claims 1 to 8, characterised in that the primary aa ine eaployed during the third reaction step is ethanolaaine.
9. 10- Process according to one of Claims 1 to 9, charac10 terised in that the final hydrochlorination is effected with the aid of an ethanolic solution of hydrochloric acid.
10. 11. A process according to dais 1 for the industrial preparation of (Z)-l-phenyl-l-diethylaninocarbonyl~2~aaino15 methylcyclopropane hydrochloride of the formula I given in Claim 1,. substantially as hereinbefore described and exemplified.
11. 12 e (z) -l-Phenyl-i-diethylaminocarbonyl'-2->aainomethyl“ 20 cyclopropane hydrochloride of the formula I given in Claim 1 whenever prepared by a process claimed in a preceding claim.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8506335A FR2581059B1 (en) | 1985-04-25 | 1985-04-25 | PROCESS FOR THE PREPARATION OF PHENYL-1 HYDROCHLORIDE DIETHYL AMINO CARBONYL-1 AMINOMETHYL-2 CYCLOPROPANE (Z) |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE861057L IE861057L (en) | 1986-10-25 |
| IE59015B1 true IE59015B1 (en) | 1993-12-15 |
Family
ID=9318686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE105786A IE59015B1 (en) | 1985-04-25 | 1986-04-21 | Process for preparing (z)-1-phenyl-1-diethyl amino carbonyl-2-aminomethylcyclopropanehydrochloride |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP0200638B1 (en) |
| JP (1) | JPS61251650A (en) |
| KR (1) | KR940006764B1 (en) |
| AR (1) | AR240695A1 (en) |
| AT (1) | ATE42273T1 (en) |
| AU (1) | AU587613B2 (en) |
| CA (1) | CA1266486A (en) |
| DE (1) | DE3662877D1 (en) |
| DK (1) | DK170888B1 (en) |
| ES (1) | ES8704449A1 (en) |
| FI (1) | FI87196C (en) |
| FR (1) | FR2581059B1 (en) |
| GE (1) | GEP19970789B (en) |
| GR (1) | GR860980B (en) |
| HU (1) | HU195182B (en) |
| IE (1) | IE59015B1 (en) |
| MX (1) | MX162896B (en) |
| NO (1) | NO165143C (en) |
| OA (1) | OA08241A (en) |
| PT (1) | PT82461B (en) |
| SU (1) | SU1443797A3 (en) |
| YU (1) | YU44915B (en) |
| ZA (1) | ZA862929B (en) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2640972B1 (en) * | 1988-12-28 | 1991-04-19 | Pf Medicament | |
| US5621142A (en) * | 1994-02-22 | 1997-04-15 | Asahi Kasei Kogyo Kabushiki Kaisha | Aminoalkylcyclopropane derivatives |
| FR2752732B1 (en) * | 1996-08-28 | 1998-11-20 | Pf Medicament | EXTENDED RELEASE GALENIC FORM OF MILNACIPRAN |
| JP4418717B2 (en) * | 2004-06-24 | 2010-02-24 | 住友化学株式会社 | Process for producing (Z) -1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane hydrochloride |
| JP4828863B2 (en) | 2005-01-28 | 2011-11-30 | 住友化学株式会社 | Process for producing (Z) -1-phenyl-1- (N, N-diethylaminocarbonyl) -2-phthalimidomethylcyclopropane |
| EP1894565B1 (en) | 2005-06-10 | 2013-10-30 | Pierre Fabre Médicament S.A. | Stabilized milnacipran formulation |
| KR100772244B1 (en) * | 2005-07-20 | 2007-11-01 | 안국약품 주식회사 | Method for the preparation of milnacipran hydrogen chloride salt |
| CN101415677B (en) * | 2006-04-17 | 2012-05-23 | 住友化学株式会社 | Method for producing polycyclic lactam compounds |
| JP5338035B2 (en) * | 2006-04-17 | 2013-11-13 | 住友化学株式会社 | Process for producing polycyclic lactams |
| WO2008104957A2 (en) * | 2007-02-28 | 2008-09-04 | Ranbaxy Laboratories Limited | Novel polymorphic forms of milnacipran hydrochloride |
| FR2941454B1 (en) | 2009-01-29 | 2011-04-01 | Pf Medicament | PROCESS FOR THE SYNTHESIS OF (1S, 2R) -MILNACIPRAN |
| US20100274050A1 (en) * | 2009-04-23 | 2010-10-28 | Glenmark Generics Limited | Solid milnacipran and process for the preparation of the same |
| EP2699539B1 (en) | 2011-04-21 | 2019-03-06 | Emory University | Cyclopropyl derivatives and methods of use |
| CN103242289B (en) * | 2012-02-03 | 2015-01-07 | 暨明医药科技（苏州）有限公司 | Preparation method of N,N-diallyl-(1R,2R)-2-aminomethyl-1-(2-thienyl)cyclopropanecarboxamide hydrochloride |
| WO2014009767A1 (en) | 2012-07-07 | 2014-01-16 | Micro Labs Limited | An improved process for the preparation of 1-aryl 2-aminomethyl cyclopropane carboxyamide (z) derivatives, their isomers and salts |
| WO2014058744A2 (en) | 2012-10-09 | 2014-04-17 | California Institute Of Technology | In vivo and in vitro olefin cyclopropanation catalyzed by heme enzymes |
| FR2998892B1 (en) * | 2012-12-04 | 2015-01-02 | Pf Medicament | AMINOCYCLOBUTANE DERIVATIVES, PROCESS FOR PREPARING THEM AND THEIR USE AS MEDICAMENTS |
| CN103613513B (en) * | 2013-12-09 | 2016-01-20 | 上海现代制药股份有限公司 | Milnacipran hydrochloride intermediate and its preparation method and application |
| US9399762B2 (en) | 2014-02-18 | 2016-07-26 | California Institute Of Technology | Methods and systems for sulfimidation or sulfoximidation of organic molecules |
| CN104058992A (en) * | 2014-06-13 | 2014-09-24 | 上海现代制药股份有限公司 | Crystal form of levomilnacipran hydrochloride |
| EP3230258B1 (en) | 2014-11-04 | 2019-06-26 | Química Sintética, S.A. | Process for the preparation of (1s,2r)-milnacipran |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2508035A1 (en) * | 1981-06-23 | 1982-12-24 | Fabre Sa Pierre | ARYL-1-AMINOMETHYL-2 CYCLOPROPANES CARBOXAMIDE (Z) DERIVATIVES, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS USEFUL IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM DISORDERS |
-
1985
- 1985-04-25 FR FR8506335A patent/FR2581059B1/en not_active Expired
-
1986
- 1986-04-14 GR GR860980A patent/GR860980B/en unknown
- 1986-04-17 AU AU56343/86A patent/AU587613B2/en not_active Expired
- 1986-04-18 ZA ZA862929A patent/ZA862929B/en unknown
- 1986-04-21 IE IE105786A patent/IE59015B1/en not_active IP Right Cessation
- 1986-04-22 DE DE8686400873T patent/DE3662877D1/en not_active Expired
- 1986-04-22 YU YU655/86A patent/YU44915B/en unknown
- 1986-04-22 AT AT86400873T patent/ATE42273T1/en not_active IP Right Cessation
- 1986-04-22 EP EP86400873A patent/EP0200638B1/en not_active Expired
- 1986-04-22 NO NO861573A patent/NO165143C/en unknown
- 1986-04-23 CA CA000507320A patent/CA1266486A/en not_active Expired - Lifetime
- 1986-04-23 KR KR1019860003133A patent/KR940006764B1/en not_active IP Right Cessation
- 1986-04-24 ES ES554321A patent/ES8704449A1/en not_active Expired
- 1986-04-24 SU SU864027356A patent/SU1443797A3/en active
- 1986-04-24 DK DK191286A patent/DK170888B1/en not_active IP Right Cessation
- 1986-04-24 HU HU861711A patent/HU195182B/en unknown
- 1986-04-24 PT PT82461A patent/PT82461B/en unknown
- 1986-04-24 MX MX2307A patent/MX162896B/en unknown
- 1986-04-24 JP JP61095850A patent/JPS61251650A/en active Granted
- 1986-04-25 FI FI861755A patent/FI87196C/en not_active IP Right Cessation
- 1986-04-25 OA OA58846A patent/OA08241A/en unknown
- 1986-04-25 AR AR30375986A patent/AR240695A1/en active
-
1993
- 1993-03-04 GE GEAP1993566A patent/GEP19970789B/en unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| IE59015B1 (en) | Process for preparing (z)-1-phenyl-1-diethyl amino carbonyl-2-aminomethylcyclopropanehydrochloride | |
| SU628812A3 (en) | Organic compound producing method | |
| FI81338B (en) | 4- / 4- (DIMETHYLAMINO) -1- (4'-FLUORPHENYL) -1-HYDROXIBUTYL / -3- (HYDROXIMETHYL) BENZONITRILE FORM FARING FRAMSTATING WITH DENNA OCH DESS ANVAENDNING VID FRAMSTAELLING AV 1- (3-DIMING) (4'-FLUORPHENYL) -1,3-DIHYDROISOBENSOFURAN-5-CARBONITRIL. | |
| PL203275B1 (en) | Method for the preparation of 5-cyanophthalide | |
| US20090012313A1 (en) | 3-Carboxy-2-Oxo-1-Pyrrolidine Derivatives and Their Uses | |
| US3153092A (en) | 1-methyl-2-phenylcyclopropylamine derivatives | |
| SE449358B (en) | PROCEDURE FOR THE PREPARATION OF 4-AMINOHEX-5-ACID ACID OR SALTS THEREOF | |
| EP0179254A1 (en) | 4,5-Dihydro-4-oxo-2- [(2-trans-phenylcyclopropyl)amino]-3-furancarboxylic acids and derivatives thereof | |
| KR20030014619A (en) | A process for the preparation of high purity Pemirolast | |
| KR20010076278A (en) | 3-(1-Hydroxy-Pentylidene)-5-Nitro-3H-Benzofuran-2-One, a Process for the Preparation thereof and the Use thereof | |
| AU744272B2 (en) | Method for preparing alkyloxy furanone derivatives, compounds obtained by said method and use of said compounds | |
| JPH0524158B2 (en) | ||
| NO771771L (en) | PROCEDURES FOR THE PREPARATION OF NEW DERIVATIVES OF DIBENZO (DE, H) QUINOLINE | |
| US4029647A (en) | Synthesis of biotin | |
| IE41999B1 (en) | Preparation of 6,11-dihydro-11-oxodiben(b,e)-oxepin-alkanoic acids | |
| US4559178A (en) | Resolution of 3-benzoylthio-2-methyl-propanoic acid with (+)-dehydroabietylamine | |
| US4595755A (en) | 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolones | |
| NO162019B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE PYRIMIDOISKINOLIN DERIVATIVES. | |
| PL172906B1 (en) | Method of obtaining indobufene in pharmaceutically advantageous crystalline form | |
| FI76782B (en) | AMID INNEHAOLLANDE D-2- (6-METOXY-2-NAFTYL) -PROPIONSYRANS KINCONIDINSALT OCH FOERFARANDE FOER DESS FRAMSTAELLNING. | |
| EP0437567B1 (en) | Phenyl-glycine derivatives | |
| SI8610655A8 (en) | Process for preparation of 1-phenyl-1-diethylaminocarbonyl-2- aminomethyl-cyclopropanhydrochloride | |
| FI64348C (en) | FOERFARANDE FOER UPPDELNING AV EN BLANDNING AV D- OCH 1-2- (6-METOXY-2-NAPHTHYL) -PROPIONSYROR I OPTICAL ACTIVE ISOMER | |
| GB2376945A (en) | Citalopram preparation | |
| JPH0383969A (en) | Production of indole-3-carbonitrile compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |