DK170888B1 - Process for the preparation of hydrochloride of 1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane (Z) - Google Patents
Process for the preparation of hydrochloride of 1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane (Z) Download PDFInfo
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- DK170888B1 DK170888B1 DK191286A DK191286A DK170888B1 DK 170888 B1 DK170888 B1 DK 170888B1 DK 191286 A DK191286 A DK 191286A DK 191286 A DK191286 A DK 191286A DK 170888 B1 DK170888 B1 DK 170888B1
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- 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
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- 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
Description
DK 170888 B1DK 170888 B1
Den foreliggende opfindelse udført på Centre de RecherchesThe present invention performed at the Center de Recherches
P.F. MEDICAMENT angår en særlig industriel fremgangsmåde til fremstilling af MIDALCIPRAN (international betegnelse for hydrochloridet af l-phenyl-l-diethylaminocarbonyl-2-5 aminomethyl-cyclopropan(Z) med formlen IP.F. MEDICAMENT relates to a particular industrial process for the preparation of MIDALCIPRAN (international term for the hydrochloride of 1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane (Z) of formula I
Q-xx © © ci 0-C _ pu >u \ / CHjCHj \ CH,CHj MIDALCIPRAN er på nuværende tidspunkt udviklet til klinisk brug som antidepressivum.Q-xx © © ci 0-C _ pu> u \ / CHjCHj \ CH, CHj MIDALCIPRAN is currently developed for clinical use as an antidepressant.
I den kendte teknik, jfr. FR-A 2.508.035, blev denne for-10 bindelse fremstillet ifølge en fremgangsmåde med fem trin, med udgangspunkt i l-phenyl-2-oxo-3-oxa-bicyclo(3:l:0)-hexan; dette sidstnævnte derivat er beskrevet i FR-A 2.302.994.In the prior art, cf. FR-A 2,508,035, this compound was prepared according to a five step process, starting from 1-phenyl-2-oxo-3-oxa-bicyclo (3: 1: 0) -hexane; this latter derivative is disclosed in FR-A 2,302,994.
Ifølge denne kendte teknik er det begrænsende trin i fremstillingen reaktionen mellem chloret i hydrochloridet af l-15 phenyl-2-aminomethyl-cyclopropan og diethylamin. I løbet af denne reaktion sker der reelt en sekundær reaktion, nemlig den intramolekylære cyclisering, som fører til dannelsen af en lactam, nemlig: 1-phenyl-2-oxo-3-aza-bicyclo(3:1:0)-hexan.According to this prior art, the limiting step in the preparation is the reaction between the chlorine in the hydrochloride of 1-phenyl-2-aminomethyl-cyclopropane and diethylamine. In the course of this reaction, a secondary reaction, namely, the intramolecular cyclization, which leads to the formation of a lactam, namely: 1-phenyl-2-oxo-3-aza-bicyclo (3: 1: 0) -hexane, is actually done.
DK 170888 B1 2DK 170888 B1 2
Reaktionsskema for den sekundære bireaktion , HXEt, 0=C cl® \rlScheme for the secondary side reaction, HXEt, 0 = C cl® \ rl
Cl o ,Cl o,
HH
Fjernelsen af lactamen kræver en yderligere oprensning, som nedsætter udbyttet af MIDALCIPRAN.The removal of the lactam requires further purification, which reduces the yield of MIDALCIPRAN.
Den foreliggende opfindelse angår en hidtil ukendt industriel 5 fremgangsmåde til fremstilling af MIDALCIPRAN ved hjælp af tre syntesetrin. Denne fremgangsmåde er ejendommelig ved, at der allerede fra første trin skabes en aminfunktionen under en beskyttet form, som således tillader aktivering af carboxyl funktionen med henblik på kondensering med diethylamin 10 uden dannelse af biprodukt.The present invention relates to a novel industrial process for the preparation of MIDALCIPRAN by three synthetic steps. This process is characterized in that, from the first step, an amine function is created under a protected form, thus allowing activation of the carboxyl function for condensation with diethylamine 10 without formation of by-product.
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af MIDALCIPRAN med formlen I, som er ejendommelig ved det i den kendetegnende del af krav l angivne.The present invention relates to a particular process for the preparation of MIDALCIPRAN of formula I, which is characterized by the characterizing part of claim 1.
Fremgangsmåden ifølge den foreliggende opfindelse kan skema-15 tiseres på følgende måde: DK 170888 B1 3The process of the present invention can be schematized as follows: DK 170888 B1 3
Reakt i ons skema 1. trin ilh; t^Vv6oReact in our schedule 1st step ilh; t ^ Vv6o
0 150 - 200eC 0=c Y0 150 - 200eC 0 = c Y
Vh 0Vh 0
IIII
IIIIII
2. trin 0.Step 2.
q Vq V
Q-./\ /Vi ^Ά/νΟ jrv*>- ο^τν x°h \tQ -. / \ / Vi ^ Ά / νΟ jrv *> - ο ^ τν x ° h \ t
IVIV
IIIIII
3. trin t"Vv£0 £V\a?i °-C\ /Et 0^ °< /* N« x \cStage t "Vv £ 0 £ V \ a? I ° -C \ / Et 0 ^ ° </ * N« x \ c
IVIV
DK 170888 B1 4DK 170888 B1 4
Det første trin i fremgangsmåden består af kondensering af lactonen med formlen II med et phthalimidsalt, især kalium-phthalimid, opløst i et organisk opløsningsmiddel, som med fordel er valgt blandt dimethylformamid, dimethylacetamid og 5 methylpyrrolidon. Reaktionstemperaturen ligger fortrinsvis mellem 150°C og 200°C, og reaktionstiden varierer mellem 5 og 15 timer.The first step of the process consists of condensing the lactone of formula II with a phthalimide salt, especially potassium phthalimide, dissolved in an organic solvent which is advantageously selected from dimethylformamide, dimethylacetamide and methylpyrrolidone. The reaction temperature is preferably between 150 ° C and 200 ° C, and the reaction time varies between 5 and 15 hours.
Under det andet reaktionstrin behandles syren med formlen III med et syrechlorid, især thionylchlorid, som fortrinsvis 10 anvendes i støkiometrisk overskud. Reaktionen kan med fordel udføres ved opvarmning under tilbagesvaling i et tidsrum på mellem 1/2 og 2 timer. Efter fjernelse af thionylchloridet kondenseres det dannede syrechlorid med diethylamin i et organisk opløsningsmiddel, fortrinsvis valgt blandt methylen-15 chlorid, chloroform, tetrahydrofuran og dioxan. Temperaturen ved denne amidering er fortrinsvis mellem 5 og 30°C.During the second reaction step, the acid of formula III is treated with an acid chloride, especially thionyl chloride, which is preferably used in stoichiometric excess. The reaction can advantageously be carried out by reflux heating for a period of between 1/2 and 2 hours. After removal of the thionyl chloride, the acid chloride formed is condensed with diethylamine in an organic solvent, preferably selected from methylene chloride, chloroform, tetrahydrofuran and dioxane. The temperature of this amidation is preferably between 5 and 30 ° C.
Under det tredje reaktionstrin frigøres den primære amin-funktion ved behandling af amidet med formlen IV med en alkylamin eller en hydroxyalkylamin med lav molekylvægt, især 20 ethanolamin, anvendt alene eller i nærværelse af et opløsningsmiddel såsom vand eller en alkohol med lav molekylvægt (methanol, ethanol, propanol, isopropanol). Denne reaktion udføres ved en temperatur mellem omgivelsestemperatur og reaktionsmediets kogepunkt.During the third reaction step, the primary amine function is released by treating the amide of formula IV with an alkylamine or a low molecular weight hydroxyalkylamine, especially 20 ethanolamine, used alone or in the presence of a solvent such as water or a low molecular weight alcohol (methanol, ethanol, propanol, isopropanol). This reaction is carried out at a temperature between ambient temperature and the boiling point of the reaction medium.
25 Efter ekstraktion fra reaktionsmediet med et opløsningsmiddel såsom methylenchlorid, chloroform eller ethylacetat bliver den resterende olie, der fås efter fjernelse af opløsningsmidlet, chlorhydreret fx ved hjælp af en ethanolisk opløsning af chlorbrinte, og forbindelsen med formlen I krystalliseres 30 ved tilsætning af ether, isopropylether eller methylal.After extraction from the reaction medium with a solvent such as methylene chloride, chloroform or ethyl acetate, the residual oil obtained after removal of the solvent is chlorinated, for example, by an ethanolic solution of hydrochloric acid, and the compound of formula I is crystallized by the addition of ether, isopropyl ether. or methylal.
DK 170888 B1 5DK 170888 B1 5
Metode 1. trin 1- Phenyl-2-phthalimidomethyl-cyclopropan-1-carboxylsyre(Z) (forbindelse III) 5 En opløsning af 52,56 g (0,3 mol) l-phenyl-2-oxo-3-oxa-bicyclo(3:1:0)-hexan (forbindelse II) og 61 g (0,33 mol) kaliumphthalimid i 270 ml dimethylformamid holdes under omrøring ved 150°C i 12 timer.Method 1 Step 1- Phenyl-2-phthalimidomethyl-cyclopropane-1-carboxylic acid (Z) (Compound III) A solution of 52.56 g (0.3 mole) of 1-phenyl-2-oxo-3-oxa bicyclo (3: 1: 0) -hexane (Compound II) and 61 g (0.33 mol) of potassium phthalimide in 270 ml of dimethylformamide are kept under stirring at 150 ° C for 12 hours.
Den opløsning, der opnås efter afkøling til omgivelses-10 temperatur, hældes ud i 1000 ml vand. Efter ekstraktion med ethylacetat gøres den vandige fase sur med et overskud af eddikesyre og afkøles derefter. Syren, som krystalliserer, tørres, vaskes med vand og omkrystalliseres i ethanol, hvilket giver 62,6 g af forbindelse III (udbytte: 65%).The solution obtained after cooling to ambient temperature is poured into 1000 ml of water. After extraction with ethyl acetate, the aqueous phase is acidified with an excess of acetic acid and then cooled. The acid which crystallizes is dried, washed with water and recrystallized in ethanol to give 62.6 g of Compound III (yield: 65%).
COOHCOOH
00
15 Smeltepunkt: 186°CMelting point: 186 ° C
Formel: CigH15N04: 321,22 TLC (silicagel - GF 254 Merck)Formula: CigH15NO4: 321.22 TLC (silica gel - GF 254 Merck)
Rf: 0,6 (chloroform/methanol 85:15) IR: (KBr) V C=0: 1775, 1710 og 1650 cm'1 20 1H-NMR (CDC13) δ ppm (TMS) = 1,1-2 (m, 3H, cyclopropan); 3,9 (d, 2H, CH2N); 7,15 (s, 5H, aromatiske); 7,75 (s, 4H, aromatiske) .Rf: 0.6 (chloroform / methanol 85:15) IR: (KBr) V C = 0: 1775, 1710 and 1650 cm cm'H-NMR (CDCl)) δ ppm (TMS) = 1.1-2 (m , 3H, cyclopropane); 3.9 (d, 2H, CH 2 N); 7.15 (s, 5H, aromatic); 7.75 (s, 4H, aromatic).
DK 170888 B1 6 2. trin 1- Phenyl-1-diethylaminocarbonyl-2 -phthalimidomethyl-cyclopropan(Z) (forbindelse IV)DK 170888 B1 6 2nd stage 1- Phenyl-1-diethylaminocarbonyl-2-phthalimidomethyl cyclopropane (Z) (compound IV)
Til 30 ml thionylchlorid sættes der under omrøring ved 5 omgivelsestemperatur portionsvis 16,2 g (0,05 mol) 1-phenyl- 2- phthalimidomethyl-cyclopropancarboxylsyre (forbindelse III). Der fås en opløsning efter 2 timer ved omgivelses-temperatur.To 30 ml of thionyl chloride, 16.2 g (0.05 mole) of 1-phenyl-2-phthalimidomethyl-cyclopropane carboxylic acid (Compound III) are added portionwise with stirring at 5 ambient temperature. A solution is obtained after 2 hours at ambient temperature.
Opløsningen holdes derefter ved tilbagesvaling i 2 timer.The solution is then held at reflux for 2 hours.
10 Efter fjernelse af overskud af thionylchlorid sættes det rå syrechlorid opløst i 50 ml methylenchlorid dråbevis til en opløsning af 10,3 ml (0,1 mol) diethylamin og 150 ml methylenchlorid under omrøring på isbad. Efter omrøring natten over ved omgivelsestemperatur vaskes den vundne op-15 løsning med vand, tørres over Na2S04, filtreres og koncentreres under reduceret tryk. Efter tilsætning af isopropyl-ether fås 15,4 g af forbindelse IV (udbytte: 82%).After removing excess thionyl chloride, the crude acid chloride dissolved in 50 ml of methylene chloride is added dropwise to a solution of 10.3 ml (0.1 mole) of diethylamine and 150 ml of methylene chloride while stirring in an ice bath. After stirring overnight at ambient temperature, the solution obtained is washed with water, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. After the addition of isopropyl ether, 15.4 g of compound IV are obtained (yield: 82%).
oisland
Smeltepunkt: 131°C Formel: C23H24N203: 376,46 20 TLC (silicagel - GF 254 Merck)Melting point: 131 ° C Formula: C23H24N2O3: 376.46 TLC (silica gel - GF 254 Merck)
Rf: 0,66 (chloroform/methanol 95:5) IR: (KBr) v C=0: 1630, 1705 og 1770 cm'1 DK 170888 B1 7 iH-NMR (CDCI3) 6 ppm (TMS): 0,65 (t, 3H, CH3); 1,15 (t, 3H, CH3); 1,25 (m, IH, eye1opropan); 1,5-2,3 (m, 2H eye1opropan); 3-3,7 (m, 5H, CH2N, cyclo-CH-N); 4,15 (dd, IH, cyclo-CH-N); 7,1 (s, 5H, aromatiske); 7,6 (m, 4H, aromatiske).Rf: 0.66 (chloroform / methanol 95: 5) IR: (KBr) ν C = 0: 1630, 1705 and 1770 cm -1 DK 170888 B1 7 H-NMR (CDCl (t, 3H, CH 3); 1.15 (t, 3H, CH 3); 1.25 (m, 1H, eye lopropane); 1.5-2.3 (m, 2H eyeopropane); 3-3.7 (m, 5H, CH 2 N, cyclo-CH-N); 4.15 (dd, 1H, cyclo-CH-N); 7.1 (s, 5H, aromatic); 7.6 (m, 4H, aromatic).
5 3. trin 1- Phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropan(Z)-hydrochlorid (forbindelse I) (MIDALCIPRAN) a) En suspension af 18,82 g (0,05 mol) 1-phenyl-1-diethylaminocarbonyl -2-phthalimidomethyl-cyclopropan (forbindelse 10 IV) i 95 ml af en vandig opløsning af 40% methylamin omrøres ved omgivelsestemperatur i 5 timer.Step 3 Phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane (Z) hydrochloride (Compound I) (MIDALCIPRAN) a) A suspension of 18.82 g (0.05 mole) of 1-phenyl-1 diethylaminocarbonyl -2-phthalimidomethyl-cyclopropane (Compound 10 IV) in 95 ml of an aqueous solution of 40% methylamine is stirred at ambient temperature for 5 hours.
Opløsning efterfulgt af krystallisation af N,N-dimethyl-phthalamid. Suspensionen ekstraheres tre gange med ethyl-acetat. Den organiske fase vaskes med vand, tørres over 15 Na2S04 og filtreres, og opløsningsmidlet fjernes under reduceret tryk. Efter tilsætning af en ethanolisk opløsning af chlorbrinte og derefter ether fås 10 g krystaller af forbindelse I (udbytte 71%).Solution followed by crystallization of N, N-dimethyl-phthalamide. The suspension is extracted three times with ethyl acetate. The organic phase is washed with water, dried over Na 2 SO 4 and filtered and the solvent removed under reduced pressure. After adding an ethanolic solution of hydrochloric acid and then ether, 10 g of Compound I crystals are obtained (yield 71%).
@./\ .@. / \.
J c,® C0NEt2J c, ® C0NEt2
Smeltepunkt: 180°C 20 Formel: C15h23C1N20: 282,82 TLC (silicagel GF 254 Merck)Melting point: 180 ° C Formula: C 15 H 23 ClN 2 O: 282.82 TLC (silica gel GF 254 Merck)
Rf: 0,43 (chloroform/methanol 84:14 - NH4OH) IR: (KBr) υ C=0: 1610 cm'1 DK 170888 B1 8 1H-NMR (D20) δ ppm (T.S.P.): 0,8 (t, 3H, CH3); 1,15 (t, 3H, CH3); 1,5-2,1 (m, 3H, cyclopropan); 3-3,7 (m, CH2N) ; 7,3 (s, aromatiske).Rf: 0.43 (chloroform / methanol 84:14 - NH 4 OH) IR: (KBr) υ C = 0: 1610 cm -1 DK 170888 B1 1 H NMR (D 2 O) δ ppm (TSP): 0.8 (t 3H, CH3); 1.15 (t, 3H, CH 3); 1.5-2.1 (m, 3H, cyclopropane); 3-3.7 (m, CH 2 N); 7.3 (s, aromatic).
b) En suspension af 60 g (0,159 mol) 1-phenyl-l-5 diethylaminocarbonyl-2-phthalimidomethyl-cyclopropan i 60 ml ethanolamin holdes under omrøring i 1 time ved 90°C.b) A suspension of 60 g (0.159 mol) of 1-phenyl-1-5 diethylaminocarbonyl-2-phthalimidomethyl cyclopropane in 60 ml of ethanolamine is kept stirring for 1 hour at 90 ° C.
Efter tilsætning af 300 ml isvand ekstraheres tre gange med ethylacetat.After adding 300 ml of ice water, extract three times with ethyl acetate.
Den organiske fase vaskes med vand, tørres over Na2S04 og 10 filtreres, og opløsningsmidlet fjernes under reduceret tryk.The organic phase is washed with water, dried over Na 2 SO 4 and filtered and the solvent removed under reduced pressure.
Efter tilsætning af en 3N ethanolisk opløsning af chlorbrinte og derefter ether fås 39,7 g krystaller af forbindelse I (udbytte 88%).After addition of a 3N ethanolic solution of hydrogen chloride and then ether, 39.7 g of crystals of compound I are obtained (yield 88%).
Smeltepunkt: 178-180°C.Melting point: 178-180 ° C.
Claims (11)
Applications Claiming Priority (2)
| 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) |
| FR8506335 | 1985-04-25 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK191286D0 DK191286D0 (en) | 1986-04-24 |
| DK191286A DK191286A (en) | 1986-10-26 |
| DK170888B1 true DK170888B1 (en) | 1996-03-04 |
Family
ID=9318686
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK191286A DK170888B1 (en) | 1985-04-25 | 1986-04-24 | Process for the preparation of hydrochloride of 1-phenyl-1-diethylaminocarbonyl-2-aminomethyl-cyclopropane (Z) |
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 |
| US8309128B2 (en) | 2005-06-10 | 2012-11-13 | Pierre Fabre Medicament | Stabilized milnacipran formulation |
| KR100772244B1 (en) * | 2005-07-20 | 2007-11-01 | 안국약품 주식회사 | Method for the preparation of milnacipran hydrogen chloride salt |
| SG160362A1 (en) * | 2006-04-17 | 2010-04-29 | Sumitomo Chemical Co | Cyclic carboxylic acid |
| JP5338035B2 (en) * | 2006-04-17 | 2013-11-13 | 住友化学株式会社 | Process for producing polycyclic lactams |
| EP2114868A2 (en) * | 2007-02-28 | 2009-11-11 | 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 |
| US20140045936A1 (en) | 2011-04-21 | 2014-02-13 | Wake Forest University Health Sciences | 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 |
| EP2906518A4 (en) | 2012-10-09 | 2016-07-27 | California Inst Of Techn | 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 |
| WO2016071303A1 (en) | 2014-11-04 | 2016-05-12 | Quimica Sintetica, 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 AT AT86400873T patent/ATE42273T1/en not_active IP Right Cessation
- 1986-04-22 NO NO861573A patent/NO165143C/en unknown
- 1986-04-22 EP EP86400873A patent/EP0200638B1/en not_active Expired
- 1986-04-22 DE DE8686400873T patent/DE3662877D1/en not_active Expired
- 1986-04-22 YU YU655/86A patent/YU44915B/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 DK DK191286A patent/DK170888B1/en not_active IP Right Cessation
- 1986-04-24 MX MX2307A patent/MX162896B/en unknown
- 1986-04-24 PT PT82461A patent/PT82461B/en unknown
- 1986-04-24 HU HU861711A patent/HU195182B/en unknown
- 1986-04-24 JP JP61095850A patent/JPS61251650A/en active Granted
- 1986-04-24 SU SU864027356A patent/SU1443797A3/en active
- 1986-04-24 ES ES554321A patent/ES8704449A1/en not_active Expired
- 1986-04-25 OA OA58846A patent/OA08241A/en unknown
- 1986-04-25 AR AR30375986A patent/AR240695A1/en active
- 1986-04-25 FI FI861755A patent/FI87196C/en not_active IP Right Cessation
-
1993
- 1993-03-04 GE GEAP1993566A patent/GEP19970789B/en unknown
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| PUP | Patent expired |