NO165143B - PROCEDURE FOR THE PREPARATION OF THE HYDROCHLORIDE OF PHENYL-1-DIETHYLAMINOCARBONYL-1-AMINOMETHYL-2-CYCLOPROPANE (Z). - Google Patents
PROCEDURE FOR THE PREPARATION OF THE HYDROCHLORIDE OF PHENYL-1-DIETHYLAMINOCARBONYL-1-AMINOMETHYL-2-CYCLOPROPANE (Z). Download PDFInfo
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- NO165143B NO165143B NO861573A NO861573A NO165143B NO 165143 B NO165143 B NO 165143B NO 861573 A NO861573 A NO 861573A NO 861573 A NO861573 A NO 861573A NO 165143 B NO165143 B NO 165143B
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- phenyl
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- 238000000034 method Methods 0.000 title claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 6
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical class C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000009833 condensation Methods 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 230000009435 amidation Effects 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 150000002596 lactones Chemical class 0.000 claims description 3
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000007038 hydrochlorination reaction Methods 0.000 claims 2
- 238000009776 industrial production Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- GJJFMKBJSRMPLA-HIFRSBDPSA-N (1R,2S)-2-(aminomethyl)-N,N-diethyl-1-phenyl-1-cyclopropanecarboxamide Chemical compound C=1C=CC=CC=1[C@@]1(C(=O)N(CC)CC)C[C@@H]1CN GJJFMKBJSRMPLA-HIFRSBDPSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 229960000600 milnacipran Drugs 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 3
- 125000004005 formimidoyl group Chemical group [H]\N=C(/[H])* 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- FCVIWMMSEWILOP-UHFFFAOYSA-N 2-n,2-n-dimethylbenzene-1,2-dicarboxamide Chemical compound CN(C)C(=O)C1=CC=CC=C1C(N)=O FCVIWMMSEWILOP-UHFFFAOYSA-N 0.000 description 1
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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)
Description
Den foreliggende oppfinnelse angår en ny industriell fremgangsmåte til fremstilling av Midalcipran (felles inter-nasjonal betegnelse for hydrokloridet av fenyl-l-diétylamino-karbonyl-l-aminometyl-2-cyklopropan "Z") med formelen: The present invention relates to a new industrial process for the production of Midalcipran (common international designation for the hydrochloride of phenyl-1-diethylamino-carbonyl-1-aminomethyl-2-cyclopropane "Z") with the formula:
Midalcipran har i realiteten vært utviklet på klinikk som antidepressivt middel. Midalcipran has in reality been developed in the clinic as an antidepressant.
I tidligere teknikk som representert ved FR-A-2 508 035, ble denne forbindelse fremstilt ved en fremgangsmåte i 5 trinn ut fra fenyl-1-okso-2-oksa-3-bicyklo-(3:1:0)-heksan, som har vært beskrevet i FR-A-2 302 994. In the prior art as represented by FR-A-2 508 035, this compound was prepared by a 5 step process starting from phenyl-1-oxo-2-oxa-3-bicyclo-(3:1:0)-hexane, which has been described in FR-A-2 302 994.
Ifølge denne tidligere teknikk ligger det begrensende trinn ved fremstillingsmåten på stadiet for reaksjonen av kloridet hos fenyl-1-aminometyl-2-cyklopropanhydrokloridet med dietylamin. Således inntrer der i løpet av denne reaksjon en sekundær reaksjonseffekt, nemlig intramolekylær .cyklisering. som fører til dannelsen av et laktam: fenyl-1-okso-2-aza-3-bicyklo-(3:1:0)-heksan. According to this prior art, the limiting step in the method of preparation is the stage of reaction of the chloride of the phenyl-1-aminomethyl-2-cyclopropane hydrochloride with diethylamine. Thus, a secondary reaction effect occurs during this reaction, namely intramolecular cyclization. leading to the formation of a lactam: phenyl-1-oxo-2-aza-3-bicyclo-(3:1:0)-hexane.
Fjernelsen av laktamet krever en ekstra rensning som minsker utbyttet av Midalcipran. The removal of the lactam requires an additional purification which reduces the yield of Midalcipran.
Den foreliggende oppfinnelse går ut på en ny industriell fremgangsmåte til fremstilling av Midalcipran i 3 syntesetrinn. Denne fremgangsmåte er karakterisert ved at der etter første trinn gjennomføres en frembringelse av aminfunksjonen i en beskyttet form som dermed tillater aktivering av karboksyl-funksjonen med henblikk på kondensasjonen av dietylaminet uten dannelse av sekundært produkt. The present invention concerns a new industrial method for the production of Midalcipran in 3 synthesis steps. This method is characterized by the fact that, after the first step, the amine function is produced in a protected form which thus allows activation of the carboxyl function with a view to the condensation of the diethylamine without the formation of a secondary product.
Fremgangsmåten ifølge oppfinnelsen kan anskueliggjøres skjematisk som følger: The method according to the invention can be visualized schematically as follows:
Fremgangsmåtens første trinn består i kondensasjon av laktonet med formel II med et ftalimidsalt, særlig kaliumftalimid, i et organisk oppløsningsmiddel som fortrinnsvis er valgt blant dimetylformamid, dimetylacetamid og metylpyrro-lidon. Reaksjonstemperaturen ligger fortrinnsvis mellom 150 The first step of the process consists in condensation of the lactone of formula II with a phthalimide salt, especially potassium phthalimide, in an organic solvent which is preferably selected from dimethylformamide, dimethylacetamide and methylpyrrolidone. The reaction temperature is preferably between 150
og 200°C og reaksjonstiden kan variere mellom 5 og 15 timer. and 200°C and the reaction time can vary between 5 and 15 hours.
I løpet av annet reaksjonstrinn blir syren med formel During the second reaction step, the acid becomes the formula
III behandlet med et syreklorid, særlig tionylklorid, som fortrinnsvis benyttes i støkiometrisk overskudd. Reaksjonen blir fortrinnsvis realisert ved oppvarmning under tilbakestrøm-ning og i et tidsrom mellom 0,5 og 2 timer. Etter at tionyl-kloridet er fjernet, blir det dannede syreklorid kondensert på dietylaminet i et organisk oppløsningsmiddel, fortrinnsvis valgt blant metylenklbrid, kloroform, tetrahydrofuran og dioksan. Temperaturen ved denne amidering ligger fortrinnsvis mellom 5 og 30°C. III treated with an acid chloride, especially thionyl chloride, which is preferably used in stoichiometric excess. The reaction is preferably realized by heating under reflux and for a period of between 0.5 and 2 hours. After the thionyl chloride has been removed, the acid chloride formed is condensed onto the diethylamine in an organic solvent, preferably selected from methylene chloride, chloroform, tetrahydrofuran and dioxane. The temperature during this amidation is preferably between 5 and 30°C.
I løpet av tredje reaksjonstrinn blir den primære amin-funksjon frigjort ved at amidet med formel IV behandles med et alkylamin eller et hydroksyalkylamin med liten molekylvekt, særlig' etanolamin, som benyttes alene eller i nærvær av et oppløsningsmiddel som f.eks. vann eller en alkohol med lav molekylvekt (metanol, etanol, propanol, isopronalol). During the third reaction step, the primary amine function is released by treating the amide of formula IV with an alkylamine or a hydroxyalkylamine of low molecular weight, especially ethanolamine, which is used alone or in the presence of a solvent such as e.g. water or a low molecular weight alcohol (methanol, ethanol, propanol, isopronalol).
Denne reaksjon gjennomføres ved en temperatur mellom omgivelsestemperatur og reaksjonsmiljøets kokepunkt. This reaction is carried out at a temperature between ambient temperature and the boiling point of the reaction medium.
Etter ekstraksjon av reaksjonsmiljøet med et oppløsnings-middel som f.eks. metylenklorid, kloroform eller etylacetat blir den restolje som fås etter fjernelse av oppløsnings-middelet, hydroklorert, f.eks. ved hjelp av en etanolopp-løsning av saltsyre, og forbindelsen med formel I krystallisert ved tilsetning av eter, isopropyleter eller metylal. After extraction of the reaction medium with a solvent such as e.g. methylene chloride, chloroform or ethyl acetate, the residual oil obtained after removal of the solvent is hydrochlorinated, e.g. by means of an ethanol solution of hydrochloric acid, and the compound of formula I crystallized by the addition of ether, isopropyl ether or methyl alcohol.
UTFØRELSESFORM EXECUTION FORM
Første trinn First step
Fenyl-1-ftalimidometyl-2-cyklopropan-1 Phenyl-1-phthalimidomethyl-2-cyclopropane-1
karboksyl- Z- syre ( forbindelse III) carboxylic Z-acid (compound III)
Suspensjon av 52,56 g (0,3 mol) fenyl-1-okso-2-oksa-3-bicyklo-(3:1:0)-heksan (forbindelse II) og 61 g (0,33 mol) kaliumftalimid i 270 cm 3 dimetylformamid vedlikeholdes under omrøring ved 150°C i 12 timer. Suspension of 52.56 g (0.3 mol) of phenyl-1-oxo-2-oxa-3-bicyclo-(3:1:0)-hexane (compound II) and 61 g (0.33 mol) of potassium phthalimide in 270 cm 3 of dimethylformamide is maintained under stirring at 150°C for 12 hours.
Den oppnådde oppløsning etter tilbakegang til omgivelsestemperatur helles i 1000 cm"^ vann. Etter ekstraksjon med etylacetat blir den vandige fase syrnet med et overskudd av eddik-syre og derpå frosset. Den syre som krystalliserer blir tørket, vasket med vann og rekrystallisert i etanol for å gi 62,6 g av forbindelse III (utbytte 65%). The solution obtained after returning to ambient temperature is poured into 1000 cm"^ of water. After extraction with ethyl acetate, the aqueous phase is acidified with an excess of acetic acid and then frozen. The acid that crystallizes is dried, washed with water and recrystallized in ethanol for to give 62.6 g of compound III (yield 65%).
Smeltepunkt: 186 C Melting point: 186 C
Formel: C^H^NC^: 321,22 Formula: C^H^NC^: 321.22
CCM (Si02 - GF 254 Merck) CCM (SiO2 - GF 254 Merck)
Rf: 0,6 (kloroform 85 - metanol 15) Rf: 0.6 (chloroform 85 - methanol 15)
IR: (KBr) v C=0 : 1775, 1710 og 1650 cm"<1>IR: (KBr) v C=0 : 1775, 1710 and 1650 cm"<1>
<1>H RMN (CDC13) 6 ppm (TMS) : 1,1-2 (m, 3H, cyklopropaniske); 3,9 (d, 2H, CH2N); 7,15 (s, 5H, aromatiske); <1>H NMR (CDCl 3 ) 6 ppm (TMS) : 1,1-2 (m, 3H, cyclopropaneic); 3.9 (d, 2H, CH2N); 7.15 (s, 5H, aromatic);
7,75 (s, 4H, aromatiske). 7.75 (s, 4H, aromatic).
A nnet trinn Another step
Fenyl-1-dietylaminokarbonyl-1-ftalimidometyl-2- Phenyl-1-diethylaminocarbonyl-1-phthalimidomethyl-2-
cyklopropan ( Z) (' forbindelse IV) cyclopropane (Z) (' compound IV)
I 30 cm^ tionylklorid blir der under omrøring ved omgivelsestemperatur porsjonsvis tilsatt 16,2 g (0,05 mol) fenyl-1 -f talimidomety.l-2-cyklopropankarboksylsyre ( forbindelse III) . Man får en oppløsning etter 2 timer ved omgivelsestemperatur. 16.2 g (0.05 mol) of phenyl-1-phthalimidomethyl-1-2-cyclopropanecarboxylic acid (compound III) are added in portions to 30 cm3 of thionyl chloride while stirring at ambient temperature. A solution is obtained after 2 hours at ambient temperature.
Oppløsningen blir så holdt på tilbakeløp i 2 timer. Etter fjernelse av overskytende tionylklorid blir det rå syreklorid i oppløsning i 50 cm^ metylenklorid innført dråpevis The solution is then kept at reflux for 2 hours. After removal of excess thionyl chloride, the crude acid chloride in solution in 50 cm^ of methylene chloride is introduced dropwise
3 3 3 3
i oppløsningen av 10,3 cm (0,1 mol) dietylamin og 150 cm metylenklorid under omrøring på isbad. Etter en natt under omrøring ved værelsetemperatur blir den oppnådde oppløsning in the solution of 10.3 cm (0.1 mol) diethylamine and 150 cm methylene chloride while stirring in an ice bath. After one night under stirring at room temperature, the obtained solution becomes
vasket med vann, tørket på Na2S04, filtrert og konsentrert under redusert trykk. Ved tilsetning av isopropyleter får man 15,4 g av forbindelse IV (utbytte: 82%). washed with water, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. By adding isopropyl ether, 15.4 g of compound IV are obtained (yield: 82%).
Smeltepunkt 131° Melting point 131°
Formel: C^H-.N 0 • <3>76,46Formula: C^H-.N 0 • <3>76.46
23 24 2 3 23 24 2 3
CCM (Si02 GF 254 Merck); CCM (SiO 2 GF 254 Merck);
Rf: 0,66 (kloroform 95 - metanol 5) Rf: 0.66 (chloroform 95 - methanol 5)
IR (KBr) v C=0 1630, 1705'og 1770 cm<-1>IR (KBr) v C=0 1630, 1705'and 1770 cm<-1>
<1>H RMN (CDC13) <5 ppm (TMS): 0,65 (t, 3H, CH3); 1,15 <1>H NMR (CDCl 3 ) <5 ppm (TMS): 0.65 (t, 3H, CH 3 ); 1.15
(t, 3H, CH3); 1,25 (m, 1H, cyklopropanisk); (t, 3H, CH3); 1.25 (m, 1H, cyclopropanic);
1,5-2,3 (m, 2H, cyklopropaniske); 3-3,7 (m, 5H, CH2N, cyklo-CH-N); 4,15 (dd, 1H, cyklo-CH-N); 7,1 (s, 5H, aromatiske); 7,6 (m, 4H, aromatiske). 1.5-2.3 (m, 2H, cyclopropanic); 3-3.7 (m, 5H, CH2N, cyclo-CH-N); 4.15 (dd, 1H, cyclo-CH-N); 7.1 (s, 5H, aromatic); 7.6 (m, 4H, aromatic).
Tredje trinn Third step
Fenyl-1-dietylaminokarbonyl-1-aminometyl-2-cyklopropan-( 2)- hydroklorid ( forbindelse I). Midalcipran Phenyl-1-diethylaminocarbonyl-1-aminomethyl-2-cyclopropane-(2)-hydrochloride (compound I). Middle Cyprus
a) Suspensjon av 18,82 g (0,05 mol) fenyl-1-dietyl-aminokarbonyl-1-ftalimidometyl-2-cyklopropan (forbindelse a) Suspension of 18.82 g (0.05 mol) phenyl-1-diethyl-aminocarbonyl-1-phthalimidomethyl-2-cyclopropane (compound
IV) i 95 cm? vandig 40%'s oppløsning av metylamin blir vedlike-holdt under omrøring ved omgivelsestemperatur i 5 timer. IV) in 95 cm? aqueous 40% solution of methylamine is maintained under stirring at ambient temperature for 5 hours.
Oppløsning og deretter krystallisasjon av N,N-dimetyl-ftalamid. Suspensjonen ekstraheres 3 ganger med etylacetat. Den organiske fase vaskes med vann, tørkes på Na2S04 og filtreres, og oppløsningsmiddelet fjernes under redusert trykk. Etter tilsetning av en etanoloppløsning av saltsyre og deretter eter får man 10 g krystaller av forbindelse I (utbytte : 71%). Dissolution and then crystallization of N,N-dimethyl-phthalamide. The suspension is extracted 3 times with ethyl acetate. The organic phase is washed with water, dried over Na 2 SO 4 and filtered, and the solvent is removed under reduced pressure. After adding an ethanolic solution of hydrochloric acid and then ether, 10 g of crystals of compound I are obtained (yield: 71%).
Smeltepunkt: 180°C v Melting point: 180°C v
Formel: C15H23C1N20: 282,82 Formula: C15H23C1N20: 282.82
CCM (Si02 GF 245 Merck) CCM (Si02 GF 245 Merck)
Rf: 0,43 (kloroform 84 - metanol 14 - NH4OH) Rf: 0.43 (chloroform 84 - methanol 14 - NH4OH)
IR (KBr): v C=0 1610 cmA IR (KBr): v C=0 1610 cmA
<1>H RMN (D20) 6 ppm (T.S.P.) 0,8 (t, 3H, CH3); 1,15 (t, <1>H NMR (D 2 O) 6 ppm (T.S.P.) 0.8 (t, 3H, CH 3 ); 1.15 (h,
3H, CH3); 1,5-2,1 (m, 3H, cyklopropanisk); 3-3,7 (m, CH2N); 3H, CH3); 1.5-2.1 (m, 3H, cyclopropanic); 3-3.7 (m, CH2N);
7,3 (s, aromatiske). 7.3 (s, aromatic).
b) Suspensjon av 60 g (0,159 mol) fenyl-1-dietyl-aminokarbonyl-1 -ftalimidometyl-2-cyklopropan i 60 cm"* etanolamin b) Suspension of 60 g (0.159 mol) phenyl-1-diethyl-aminocarbonyl-1-phthalimidomethyl-2-cyclopropane in 60 cm"* ethanolamine
vedlikeholdes i 1 time ved 90°C under omrøring. maintained for 1 hour at 90°C with stirring.
Etter tilsetning av 300 ml isvann ekstraherer man 3 ganger med etylacetat. After adding 300 ml of ice water, extract 3 times with ethyl acetate.
Den organiske fase vaskes med vann, tørkes på Na2S04The organic phase is washed with water, dried over Na 2 SO 4
og filtreres, og oppløsningsmiddelet fjernes under redusert trykk. and filtered, and the solvent removed under reduced pressure.
Etter tilsetning av en etanoloppløsning av saltsyre 3N After adding an ethanol solution of hydrochloric acid 3N
og deretter eter får man 39,7 g krystaller av forbindelse I (utbytte: 88%). 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 (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 (3)
| Publication Number | Publication Date |
|---|---|
| NO861573L NO861573L (en) | 1986-10-27 |
| NO165143B true NO165143B (en) | 1990-09-24 |
| NO165143C NO165143C (en) | 1991-01-09 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO861573A NO165143C (en) | 1985-04-25 | 1986-04-22 | PROCEDURE FOR THE PREPARATION OF THE HYDROCHLORIDE OF PHENYL-1-DIETHYLAMINOCARBONYL-1-AMINOMETHYL-2-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 | |
| WO1995022521A1 (en) * | 1994-02-22 | 1995-08-24 | Asahi Kasei Kogyo Kabushiki Kaisha | Aminoalkylcyclopropane derivative |
| 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 |
| CA2611724C (en) | 2005-06-10 | 2014-07-29 | Pierre Fabre Medicament S.A. | Stabilized milnacipran formulation |
| KR100772244B1 (en) * | 2005-07-20 | 2007-11-01 | 안국약품 주식회사 | Method for the preparation of milnacipran hydrogen chloride salt |
| JP5338035B2 (en) * | 2006-04-17 | 2013-11-13 | 住友化学株式会社 | Process for producing polycyclic lactams |
| US20090118519A1 (en) * | 2006-04-17 | 2009-05-07 | Sumitomo Chemical Company, Limited | Production Method of Polycyclic Lactams |
| US20100145099A1 (en) * | 2007-02-28 | 2010-06-10 | 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 |
| 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 |
| 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 |
| JP2015534464A (en) | 2012-10-09 | 2015-12-03 | カリフォルニア インスティチュート オブ テクノロジー | 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 YU YU655/86A patent/YU44915B/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 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 SU SU864027356A patent/SU1443797A3/en active
- 1986-04-24 ES ES554321A patent/ES8704449A1/en not_active Expired
- 1986-04-24 JP JP61095850A patent/JPS61251650A/en active Granted
- 1986-04-24 MX MX2307A patent/MX162896B/en unknown
- 1986-04-24 DK DK191286A patent/DK170888B1/en not_active IP Right Cessation
- 1986-04-24 PT PT82461A patent/PT82461B/en unknown
- 1986-04-24 HU HU861711A patent/HU195182B/en unknown
- 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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