FI87196B - FOR EXAMINATION OF FRAMSTAELLNING AV (Z) -1-PHENYL-1-DIETHYLAMINOCARBONYL-2-AMINOMETHYLCYCLOPROPHANE HYDROCHLORIDE - Google Patents
FOR EXAMINATION OF FRAMSTAELLNING AV (Z) -1-PHENYL-1-DIETHYLAMINOCARBONYL-2-AMINOMETHYLCYCLOPROPHANE HYDROCHLORIDE Download PDFInfo
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- 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
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Description
8719687196
Menetelmä (Z)-l-fenyyli-l-dietyyliaminokarbonyyli-2-ami-nometyylisyklopropaani hydrokloridin valmistamiseksiProcess for the preparation of (Z) -1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane hydrochloride
Esillä oleva keksintö on toteutettu P.F. Medica-5 ment-tutkimuskeskuksessa ja koskee "Midalcipran"in ((Z)-l-fenyyli-l-dietyyliaminokarbonyyli-2-aminometyylisyklo-propaanin hydrokloridin yhtenäinen kansainvälinen nimitys) uutta teollista valmistusmenetelmää, jolla yhdisteellä on rakennekaava (I) 10 n ^ 0=C , ΓΗ ΓΗ 15 \ / 2 3 \ CH2CH3The present invention is embodied in P.F. Medica-5 ment and relates to a new industrial process for the preparation of "Midalcipran" in ((Z) -1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane hydrochloride) with a compound of structural formula (I) 10 n ^ 0 = C, ΓΗ ΓΗ 15 \ / 2 3 \ CH2CH3
Midalcipran on tällä hetkellä kehitetty kliinisesti anti-20 depressiivisenä aineena käytettäväksi.Midalcipran is currently being developed clinically for use as an anti-20 depressant.
Aikaisemmin käytetyssä menetelmässä, joka on kuvattu patentissa FR-A-2 508 035, yhdiste on valmistettu vii-sivaiheisella menetelmällä käyttäen lähtöaineena 1-fenyy-li-2-okso-3-oksabisyklo(3:1:0)heksaania, jolloin tämä vii-. 25 meinen johdannainen on kuvattu patentissa FR-A-2 302 994.In the previously used process described in FR-A-2,508,035, the compound was prepared by a five-step process starting from 1-phenyl-2-oxo-3-oxabicyclo (3: 1: 0) hexane, whereby this -. The 25-derivative is described in patent FR-A-2 302 994.
Tunnetun tekniikan mukaisesti menetelmän rajoittava vaihe on l-fenyyli-2-aminometyylisyklopropaanihappoklori-din hydrokloridin reaktio dietyyliamiinin kanssa. Tämän reaktion aikana tapahtuu sivureaktio, nimittäin molekyy-30 linsisäinen syklisaatio, josta on seurauksena laktaamin, so. l-fenyyli-2-okso-3-atsa-bisyklo(3:1:0)heksaanin muodostuminen .According to the prior art, the limiting step of the process is the reaction of 1-phenyl-2-aminomethylcyclopropanoic acid chloride hydrochloride with diethylamine. During this reaction, a side reaction takes place, namely intramolecular cyclization, resulting in lactam, i. Formation of 1-phenyl-2-oxo-3-aza-bicyclo (3: 1: 0) hexane.
2 871962 87196
Rinnakkaisen sekundaarisen reaktion reaktioyhtälö 5 ^ H"Ee‘ o=c C1 A. J" \ /\N/Reaction equation for the parallel secondary reaction 5 ^ H "Ee 'o = c C1 A. J" \ / \ N /
Cl o ,Cl o,
HB
1010
Laktaamin eliminoinnin vuoksi on tehtävä ylimääräinen puhdistus, joka pienentää Midalcipranin saantoa.Due to lactam elimination, additional purification is required to reduce the yield of Midalcipran.
Esillä oleva keksintö koskee Midalcipranin uutta teollista valmistusmenetelmää, joka käsittää kolme syn-15 teesivaihetta. Menetelmälle on tunnusomaista, että ensim mäisestä vaiheesta lähtien muodostuu suojatussa muodossa oleva funktionaalinen amiini, joka täten sallii funktionaalisen karboksyylin aktivoinnin dietyyliamiinin konden-saatiota ajatellen ilman sekundaarisen tuotteen muodostu-20 mistä.The present invention relates to a new industrial process for the manufacture of Midalcipran comprising three synthetic steps. The process is characterized in that, from the first step, a functional amine in protected form is formed, thus allowing the activation of the functional carboxyl for the condensation of diethylamine without the formation of a secondary product.
Keksinnön mukainen menetelmä voidaan esittää seu-raavilla reaktioyhtälöillä: J 87196The process according to the invention can be represented by the following reaction equations: J 87196
Reaktiokaavio 1. vaihe /\ o / \ ftaali-imidin f 11 JV suola; liuo-Reaction Scheme Step 1 / p / imide of phthalimide f 11 JV; solvent
^ τΓ- 200-c ’ o=/v^yXJ^ τΓ- 200-c 'o = / v ^ yXJ
^OH 0 (II) (I IL) (1. vaihe tunnettu julkaisustaOH 0 (II) (IL) (1st step known from
Boll. Chim. Farm. 117 (1978), s. 331-342) 2. vaiheBoll. Chim. Farm. 117 (1978), pp. 331-342) Step 2
°/νίθ ίΗΞτ ^'Λ/yQ° / νίθ ίΗΞτ ^ 'Λ / yQ
°=\ // /'Λ OH ( f) (III) (IV) 3. vaihe o.y\.· \/ 0 0=CN Et \t \ (IV) (I) Et 4 87196° = \ // / 'Λ OH (f) (III) (IV) Step 3 o.y \. · \ / 0 0 = CN Et \ t \ (IV) (I) Et 4 87196
Menetelmän ensimmäinen vaihe käsittää kaavan II mukaisen laktonin kondensaation ftaali-imidin suolan, erikoisesti kaliumftaali-imidin kanssa, orgaanisessa liuotti-messa, joka on edullisesti valittu seuraavista: dimetyyli-5 formamidi, dimetyyliasetamidi ja metyylipyrrolidoni. Reak-tiolämpötila pidetään edullisesti 150°C:n ja 200°C:n välillä ja reaktioaika vaihtelee ollen 5-15 tuntia.The first step of the process comprises the condensation of a lactone of formula II with a phthalimide salt, especially potassium phthalimide, in an organic solvent, preferably selected from dimethyl-formamide, dimethylacetamide and methylpyrrolidone. The reaction temperature is preferably maintained between 150 ° C and 200 ° C, and the reaction time varies from 5 to 15 hours.
Toisessa reaktiovaiheessa kaava III mukainen happo käsitellään happokloridillä, erikoisesti tionyylikloridil-10 la, edullisesti käyttäen stökiömetristä ylimäärää. Reaktio toteutetaan edullisesti palautusjäähdytyksellä lämmittäen 0,5 - 2 tunnin ajan. Tionyylikloridin poistamisen jälkeen muodostunut happokloridi kondensoidaan dietyyli-amiinilla orgaanisessa liuottimessa, joka valitaan edulli-15 sesti seuraavista: metyleenikloridi, kloroformi, tetrahyd-rofuraani ja dioksaani. Tämän amidoinnin lämpötila on edullisesti alueella 5 - 30°C.In the second reaction step, the acid of formula III is treated with an acid chloride, especially thionyl chloride-10a, preferably using a stoichiometric excess. The reaction is preferably carried out under reflux with heating for 0.5 to 2 hours. The acid chloride formed after removal of the thionyl chloride is condensed with diethylamine in an organic solvent, preferably selected from methylene chloride, chloroform, tetrahydrofuran and dioxane. The temperature of this amidation is preferably in the range of 5 to 30 ° C.
Kolmannessa reaktiovaiheessa primaarinen funktionaalinen amiiniryhmä vapautetaan käsittelemällä kaavan IV 20 mukaista amidia alkyyliamiinilla tai pienen moolimassan omaavalla hydroksialkyyliamiinilla (erikoisesti etanoli-amiinilla), sellaisenaan tai liuottimen, kuten veden tai pienen molekyylipainon omaavan alkoholin (metanolin, etanolin, propanolin, isopropanolin) läsnäollessa. Tämä reak-25 tio suoritetaan ympäristön lämpötilan ja reaktioväliaineen kiehumispisteen välillä.In the third reaction step, the primary amine functional group is liberated by treating the amide of formula IV with an alkylamine or low molecular weight hydroxyalkylamine (especially ethanolamine), as such or in the presence of a solvent such as water or isol, propanol), ethanol, ethanol. This reaction is carried out between ambient temperature and the boiling point of the reaction medium.
Reaktioliuos ekstrahoidaan metyleenikloridilla, kloroformilla tai etyyliasetaatilla, ja liuottimen poistamisen jälkeen saatu jäännösöljy hydrokloorataan esim.The reaction solution is extracted with methylene chloride, chloroform or ethyl acetate, and the residual oil obtained after removal of the solvent is hydrochlorinated, e.g.
30 kloorivetyhapon etanoliliuoksen avulla, ja kaavan I mukainen yhdiste kiteytetään lisäämällä eetteriä (isopropyyli-eetteri tai formaldehydimetyylietyyliasetaali).30 with ethanolic hydrochloric acid, and the compound of formula I is crystallized by adding ether (isopropyl ether or formaldehyde methylethyl acetal).
5 871965 87196
Valmi stusohj e 1. vaihe (Z)-l-fenyyli-2-ftaali-imidimetyylisyklopropaani- 1- karboksyylihappo (yhdiste III) 5 Suspensiota, jossa on 52,56 g (0,3 mol) 1-fenyyli- 2- okso-3-oksabisyklo(3:1:0)heksaania (yhdiste II) ja 61 g (0,33 mol) kaliumftaali-imidiä 270 cm3:ssa dimetyyliform-amidia, lämmitetään 150°C:ssa samalla sekoittaen 12 tunnin ajan.Preparation Step 1 (Z) -1-Phenyl-2-phthalimidimethylcyclopropane-1-carboxylic acid (Compound III) A suspension of 52.56 g (0.3 mol) of 1-phenyl-2-oxo- 3-Oxabicyclo (3: 1: 0) hexane (compound II) and 61 g (0.33 mol) of potassium phthalimide in 270 cm 3 of dimethylformamide are heated at 150 ° C with stirring for 12 hours.
10 Liuos jäähdytetään ympäristön lämpötilaan ja lisä tään 1 000 cm3:iin vettä. Ekstrahoidaan etyyliasetaatilla, minkä jälkeen vesifaasi tehdään happameksi ylimäärällä etikkahappoa ja jäähdytetään jäissä. Kiteytynyt happo suodatetaan, pestään vedellä ja uudelleenkiteytetään etano-15 lista, jolloin saadaan 62,6 g yhdistettä III (saanto 65 %).10 Cool the solution to ambient temperature and add 1 000 cm3 of water. Extract with ethyl acetate, then acidify the aqueous phase with excess acetic acid and cool on ice. The crystallized acid is filtered, washed with water and recrystallized from ethanol-15 to give 62.6 g of compound III (yield 65%).
' ®7^<S§) C00H j 0 25'®7 ^ <S§) C00H j 0 25
Sulamispiste: 186°CMelting point: 186 ° C
Kaava: C19H15N04 : 321,22 CCM (piidioksidi - GF 254 Merck)Formula: C19H15NO4: 321.22 CCM (silica - GF 254 Merck)
Rf: 0,6 (kloroformi 85 - metanoli 15) 30 IR : (KBr) υ C=0 : 1775, 1710 ja 1650 cm'1 *H NMR (CDC13) 6 ppm (TMS) : 1,1 - 2 (m, 3H, syklopropaa-nit); 3,9 (d, 2H, CH2N); 7,15 (s, 5H, aromaattiset); 7,75 (s, 4H, aromaattiset) 35 6 87196 2. vaihe (Z )-l-fenyyli-l-dietyyliaminokarbonyyli-2-ftaali-imidometyylisyklopropaani (yhdiste IV) 30 cm3:iin tionyylikloridia lisätään vähitellen 5 sekoittaen ympäristön lämpötilassa 16,2 g (0,05 mol) 1-fenyyli-2-ftaali-imidometyylisyklopropaanikarboksyylihap-poa (yhdiste III). Ympäristön lämpötilassa saadaan 2 tunnin kuluttua homogeeninen liuos.Rf: 0.6 (chloroform 85 - methanol 15) δ IR: (KBr) υ C = 0: 1775, 1710 and 1650 cm -1 1 H NMR (CDCl 3) δ ppm (TMS): 1.1 - 2 (m , 3H, cyclopropanes); 3.9 (d, 2H, CH 2 N); 7.15 (s, 5H, aromatic); 7.75 (s, 4H, aromatic) 35 6 87196 Step 2 (Z) -1-Phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclopropane (Compound IV) To 30 cm 3 of thionyl chloride are gradually added with stirring at ambient temperature 16, 2 g (0.05 mol) of 1-phenyl-2-phthalimidomethylcyclopropanecarboxylic acid (compound III). After 2 hours at ambient temperature a homogeneous solution is obtained.
Liuosta pidetään sitten palautusjäähdyttimessä 2 10 tuntia. Ylimääräisen tionyylikloridin poistamisen jälkeen liuos, jossa on raaka happokloridi 50 cm3:ssa metyleeni-kloridia, lisätään vähitellen liuokseen, jossa on 10,3 cm3 (0,1 mol) dietyyliamiinia ja 150 cm3 metyleenikloridia, jäähauteessa samalla sekoittaen. Yhden yön ympäristön läm-15 pötilassa tapahtuvan sekoituksen jälkeen saatu liuos pestään vedellä, kuivataan Na2S04:llä, suodatetaan ja konsentroidaan alipaineessa. Lisäämällä isopropyylieetteriä saadaan 15,4 g yhdistetä IV (saanto 82 %).The solution is then kept at reflux for 2 to 10 hours. After removal of the excess thionyl chloride, a solution of the crude acid chloride in 50 cm3 of methylene chloride is gradually added to a solution of 10.3 cm3 (0.1 mol) of diethylamine and 150 cm3 of methylene chloride in an ice bath with stirring. After stirring overnight at ambient temperature, the resulting solution is washed with water, dried over Na 2 SO 4, filtered and concentrated in vacuo. Addition of isopropyl ether gives 15.4 g of compound IV (yield 82%).
20 p. /\20 pp. / \
25 J25 J
00
Sulamispiste 131°C Kaava : C23H24N203 : 376,46 30 CCM (piidioksidi GF 254 Merck); RF : 0,66 (kloroformi 95 - metanoli 5) IR (KBr) υ C=0 1630, 1705 ja 1770 cm"1 XH NMR (CDC13) δ ppm (TMS) : 0,65 (t, 3H, CH3); 1,15 (t, 3H, CH3); 1,25 (m, 1H, syklopropaanit); 1,5 - 2,3 (m, 35 2H, syklopropaanit); 3 - 3,7 (m, 5H, CH2N, syklo-CH-N); 7 87196 4,15 (dd, 1H, syklo-CH-N); 7,1 (s, 5H, aromaattiset); 7,6 (m, 4H, aromaattiset).Melting point 131 ° C Formula: C23H24N2O3: 376.46 CCM (silica GF 254 Merck); RF: 0.66 (chloroform 95 - methanol δ) IR (KBr) δ C = 0 1630, 1705 and 1770 cm -1 1 H NMR (CDCl 3) δ ppm (TMS): 0.65 (t, 3H, CH 3); 1.15 (t, 3H, CH 3), 1.25 (m, 1H, cyclopropanes), 1.5-2.3 (m, 35 2H, cyclopropanes), 3-3.7 (m, 5H, CH 2 N, cyclo-CH-N); δ 87196 4.15 (dd, 1H, cyclo-CH-N); 7.1 (s, 5H, aromatic); 7.6 (m, 4H, aromatic).
3. vaihe (Z )-l-fenyyli-l-etyyliaminokarbonyyli-2-aminometyy-5 lisyklopropaanlhydrokloridi (yhdiste I). Midalclpran a) Suspensiota, jossa 18,82 g (0,05 mol) 1-fenyyli-l-dietyyliaminokarbonyyli-2-ftaali-imidometyylisyklopro-paania (yhdiste IV) 95 cm3:ssä metyyliamiinin 40 %:ista vesiliuosta, sekoitetaan ympäristön lämpötilassa 5 tunnin 10 ajan.Step 3 (Z) -1-Phenyl-1-ethylaminocarbonyl-2-aminomethyl-5-cyclopropane hydrochloride (Compound I). Midalclpran a) A suspension of 18.82 g (0.05 mol) of 1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclopropane (Compound IV) in 95 cm 3 of a 40% aqueous solution of methylamine is stirred at ambient temperature. for 10 hours.
Tuote liuotetaan ja sitten kiteytetään Ν,Ν-dimetyy-liftaaliamidista. Suspensio ekstrahoidaan 3 kertaa etyyliasetaatilla. Orgaaninen faasi pestään vedellä, kuivataan Na2S04:llä, suodatetaan ja liuotin poistetaan alipaineessa. 15 Kloorivetyhapon etanoliliuoksen ja sitten eetterin lisäyksen jälkeen saadaan 10 g kiteistä yhdistettä I (saanto 71 %).The product is dissolved and then crystallized from Ν, Ν-dimethylphthalamide. The suspension is extracted 3 times with ethyl acetate. The organic phase is washed with water, dried over Na2SO4, filtered and the solvent is removed under reduced pressure. After addition of ethanolic hydrochloric acid solution and then ether, 10 g of crystalline compound I are obtained (yield 71%).
0../X.0 X ../.
j e,® CONEtj 25j e, ® CONEtj 25
Sulamispiste: 180°C Kaava: C15H23C1NH40H: 282,82 CCM (piidioksidi GF 245 Merck)Melting point: 180 ° C Formula: C15H23ClNH4OH: 282.82 CCM (silica GF 245 Merck)
Rf: 0,43 (kloroformi 84 - metanoli 14 - NH OH) 30 IR (KBr): υ C=0 1610 cm'1 3H NMR (D20) 6 ppm (T.S.P.) 0,8 (t, 3H, CH3); 1,15 (t, 3H, CH3); 1,5 - 2,1 (m, 3H, syklopropaanit); 3 - 3,7 (m, CH2N); 7,3 (s, aromaattiset).Rf: 0.43 (chloroform 84 - methanol 14 - NH OH) δ IR (KBr): υ C = 0 1610 cm -1 13 H NMR (D 2 O) δ ppm (T.S.P.) 0.8 (t, 3H, CH 3); 1.15 (t, 3H, CH 3); 1.5-2.1 (m, 3H, cyclopropanes); 3 - 3.7 (m, CH 2 N); 7.3 (s, aromatic).
b) Suspensiota, jossa on 60 g (0,159 mol) 1-fenyy- 35 li-l-dietyyliaminokarbonyyli-2-f taali-imidometyy li syklo- 8 87196 propaania 60 cm3:ssa etanoliamiinia, sekoitetaan 1 tunnin ajan 90°C:ssa.b) A suspension of 60 g (0.159 mol) of 1-phenyl-1-diethylaminocarbonyl-2-phthalimidomethylcyclo-8 87196 propane in 60 cm 3 of ethanolamine is stirred for 1 hour at 90 ° C. .
Lisätään 300 ml jäävettä, minkä jälkeen ekstrahoi-daan 3 kertaa etyyliasetaatilla.300 ml of ice water are added, followed by extraction 3 times with ethyl acetate.
5 Orgaaninen faasi pestään vedellä, kuivataan5 The organic phase is washed with water and dried
Na2S04:llä, suodatetaan ja liuotin poistetaan alipaineessa.Na 2 SO 4, filtered and the solvent removed under reduced pressure.
3N kloorivetyhapon etanoliliuoksen ja sitten eetterin lisäyksen jälkeen saadaan 39,7 g kiteistä yhdistettä I (saanto 88 %).After addition of 3N hydrochloric acid in ethanol and then ether, 39.7 g of crystalline compound I are obtained (yield 88%).
10 Sulamispiste: 178 - 180°C.Melting point: 178-180 ° C.
Claims (11)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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FR8506335 | 1985-04-25 | ||
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) |
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FI861755A0 FI861755A0 (en) | 1986-04-25 |
FI861755A FI861755A (en) | 1986-10-26 |
FI87196B true FI87196B (en) | 1992-08-31 |
FI87196C FI87196C (en) | 1992-12-10 |
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ES (1) | ES8704449A1 (en) |
FI (1) | FI87196C (en) |
FR (1) | FR2581059B1 (en) |
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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 |
WO2006132307A1 (en) | 2005-06-10 | 2006-12-14 | Pierre Fabre Medicament S.A. | Stabilized milnacipran formulation |
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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 |
WO2012145234A2 (en) * | 2011-04-21 | 2012-10-26 | 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 |
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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 |
ES2746081T3 (en) | 2014-11-04 | 2020-03-04 | Quim Sintetica S A | Procedure for the preparation of (1S, 2R) -milnacipran |
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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 |
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1985
- 1985-04-25 FR FR8506335A patent/FR2581059B1/en not_active Expired
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1986
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1993
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Owner name: P. F. MEDICAMENT |
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