ITMI970058A1 - PROCEDURE FOR THE PREPARATION OF N-METHYL-3 (4- TRIFLUOROMETYLPHENOXY) -3-FENYL PROPILAMINE AND ITS SALTS - Google Patents
PROCEDURE FOR THE PREPARATION OF N-METHYL-3 (4- TRIFLUOROMETYLPHENOXY) -3-FENYL PROPILAMINE AND ITS SALTS Download PDFInfo
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- ITMI970058A1 ITMI970058A1 IT97MI000058A ITMI970058A ITMI970058A1 IT MI970058 A1 ITMI970058 A1 IT MI970058A1 IT 97MI000058 A IT97MI000058 A IT 97MI000058A IT MI970058 A ITMI970058 A IT MI970058A IT MI970058 A1 ITMI970058 A1 IT MI970058A1
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- 238000000034 method Methods 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title claims description 8
- 150000003839 salts Chemical class 0.000 claims description 23
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- -1 N-benzhydryl-N-methyl-3-phenyl-3-oxopropylamine Chemical compound 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 10
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 9
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 229960002464 fluoxetine Drugs 0.000 claims description 9
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- RXMTUVIKZRXSSM-UHFFFAOYSA-N 2,2-diphenylethanamine Chemical compound C=1C=CC=CC=1C(CN)C1=CC=CC=C1 RXMTUVIKZRXSSM-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 239000003880 polar aprotic solvent Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910052987 metal hydride Inorganic materials 0.000 claims description 3
- 150000004681 metal hydrides Chemical class 0.000 claims description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 3
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims 2
- 239000000852 hydrogen donor Substances 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims 1
- 150000004678 hydrides Chemical class 0.000 claims 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims 1
- 235000015497 potassium bicarbonate Nutrition 0.000 claims 1
- 239000011736 potassium bicarbonate Substances 0.000 claims 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 13
- 239000008367 deionised water Substances 0.000 description 12
- 229910021641 deionized water Inorganic materials 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- GIYXAJPCNFJEHY-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine hydrochloride (1:1) Chemical compound Cl.C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 GIYXAJPCNFJEHY-UHFFFAOYSA-N 0.000 description 4
- 229960000389 fluoxetine hydrochloride Drugs 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- QULYNCCPRWKEMF-UHFFFAOYSA-N parachlorobenzotrifluoride Chemical compound FC(F)(F)C1=CC=C(Cl)C=C1 QULYNCCPRWKEMF-UHFFFAOYSA-N 0.000 description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- MYEPNXQROVPAFL-UHFFFAOYSA-N n-methyl-1,1-diphenylmethanamine;hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(NC)C1=CC=CC=C1 MYEPNXQROVPAFL-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- HPZCAKYHISJOIK-UHFFFAOYSA-N 2-amino-1-phenylpropan-1-one;hydron;chloride Chemical compound Cl.CC(N)C(=O)C1=CC=CC=C1 HPZCAKYHISJOIK-UHFFFAOYSA-N 0.000 description 1
- XXSDCGNHLFVSET-UHFFFAOYSA-N 3-(methylamino)-1-phenylpropan-1-ol Chemical compound CNCCC(O)C1=CC=CC=C1 XXSDCGNHLFVSET-UHFFFAOYSA-N 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- MLHBZVFOTDJTPK-UHFFFAOYSA-N n-methyl-3-phenylpropan-1-amine Chemical compound CNCCCC1=CC=CC=C1 MLHBZVFOTDJTPK-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
Description
Descrizione dell'invenzione industriale Description of the industrial invention
La presente invenzione concerne un procedimento per la preparazione della N-metil-3-(4-trifluorometilfenossi)-3-fenilpropilamina e dei suoi sali farmaceuticamente accettabili. The present invention relates to a process for the preparation of N-methyl-3- (4-trifluoromethylphenoxy) -3-phenylpropylamine and its pharmaceutically acceptable salts.
La N-metil-3-(4-trifIuorometilfenossi)-3-fenilpropilamina, caratterizzata dalla formula I N-methyl-3- (4-trifiuoromethylphenoxy) -3-phenylpropylamine, characterized by the formula I
è un composto ad attività antidepressiva noto con la sua Denominazione Comune Internazionale "fluoxetina", utilizzato in terapia sotto forma di cloridrato contro la depressione. is a compound with antidepressant activity known by its International Common Name "fluoxetine", used in therapy in the form of hydrochloride against depression.
La fluoxetina ed i suoi sali sono descritti in US 4,314,081 ed i metodi più recenti e validi per la sua fabbricazione, come ad esempio quelli descritti in GB 2,050,618, WO 94/00416 ed in EP 391.070, prevedono la preparazione della N-metil-3-idrossi-3-fenilpropilamina e l'introduzione del gruppo 4-trifluorometilfenile al termine della sequenza di reazioni. Fluoxetine and its salts are described in US 4,314,081 and the most recent and valid methods for its manufacture, such as for example those described in GB 2,050,618, WO 94/00416 and EP 391.070, provide for the preparation of N-methyl-3 -hydroxy-3-phenylpropylamine and the introduction of the 4-trifluoromethylphenyl group at the end of the reaction sequence.
E' stato ora trovato che, operando su N-metil-3-fenilpropilamina N-protetta con un gruppo benzidrilico, la fluoxetina pura viene preparata con ottime rese attraverso nuovi intermedi che hanno la proprietà di cristallizzare nel mezzo di reazione e che possono quindi essere facilmente isolati ad uno stato di purezza elevato, superiore al 90%. It has now been found that, by operating on N-methyl-3-phenylpropylamine N-protected with a benzhydryl group, pure fluoxetine is prepared with excellent yields through new intermediates which have the property of crystallizing in the reaction medium and which can therefore be easily isolated to a state of high purity, greater than 90%.
Cosi, la presente invenzione concerne, secondo uno dei suoi aspetti, un procedimento per la preparazione della fluoxetina e dei suoi sali farmaceuticamente accettabili, caratterizzato dal fatto che: Thus, the present invention relates, according to one of its aspects, to a process for the preparation of fluoxetine and its pharmaceutically acceptable salts, characterized in that:
(a) si tratta la benzidrilmetilamina di formula II (a) it is benzhydrylmethylamine of formula II
od un suo sale, con acetofenone in presenza di formaldeide; or a salt thereof, with acetophenone in the presence of formaldehyde;
(b) si sottopone a riduzione la N-bcnzidril-N-mctil-3-fcnil-3-oxopropilamina cosi ottenuta di formula III (b) the thus obtained N-bcnzidril-N-methyl-3-phenyl-3-oxopropylamine of formula III is subjected to reduction
oppure un suo sale; or one of its salt;
(c) si tratta la N-benzidril-N-metil-3-fenil-3-idrossipropilamina così ottenuta di formula IV (c) it is the N-benzhydryl-N-methyl-3-phenyl-3-hydroxypropylamine thus obtained of formula IV
con un 4-trifluorometil-alogenobenzene di formula V with a 4-trifluoromethyl-halogenobenzene of formula V
in cui 2 rappresenta un atomo di alogeno; wherein 2 represents a halogen atom;
(d) si rimuove il gruppo benzidrilico del composto cosi ottenuto di formula VI (d) the benzhydryl group of the thus obtained compound of formula VI is removed
e si isola la fluoxetina come base libera o sotto forma di uno dei suoi sali, ed eventualmente si trasforma la base libera, ottenuta direttamente o per neutralizzazione di detto sale, in un altro sale farmaceuticamente accettabile. and fluoxetine is isolated as a free base or in the form of one of its salts, and optionally the free base, obtained directly or by neutralization of said salt, is transformed into another pharmaceutically acceptable salt.
Nel passaggio (a) la reazione tra la benzidrilmetilamina, l’acetofenone e la formaldeide viene effettuata ad una temperatura di 70÷120°C, preferibilmente tra 110°C e 120°C, in un solvente organico miscibile con acqua ed in ambiente acido. Come solvente organico si usa preferibilmente un alcool, come metanolo, etanolo, isopropanolo o n-butanolo e l'ambiente acido è preferibilmente fornito da acido cloridrico acquoso. L'intervallo di temperatura sopra indicato si riferisce alle condizioni ottimali di reazione, benché questa avvenga anche a temperature inferiori a 70°C, anche se in tempi più lunghi. In generale, ad una temperatura di circa 115°C, la reazione è completa dopo circa 30 minuti ed il composto di formula II cristallizza dalla miscela di reazione, per semplice raffreddamento, sotto forma di sale di addizione con l'acido utilizzato, da cui la base libera può essere isolata per neutralizzazione. Le rese di questo passaggio sono elevate, normalmente di almeno il 90% del teorico. In step (a) the reaction between benzhydrylmethylamine, acetophenone and formaldehyde is carried out at a temperature of 70 ÷ 120 ° C, preferably between 110 ° C and 120 ° C, in an organic solvent miscible with water and in an acid environment . An alcohol, such as methanol, ethanol, isopropanol or n-butanol, is preferably used as the organic solvent and the acid medium is preferably provided by aqueous hydrochloric acid. The temperature range indicated above refers to the optimal reaction conditions, although this also occurs at temperatures below 70 ° C, even if in longer times. In general, at a temperature of about 115 ° C, the reaction is complete after about 30 minutes and the compound of formula II crystallizes from the reaction mixture, by simple cooling, in the form of an addition salt with the acid used, from which the free base can be isolated by neutralization. The yields of this step are high, normally at least 90% of the theoretical.
La benzidrilmetilamina di partenza può essere utilizzata come base libera o sotto forma di un suo sale. Nel primo caso la reazione è condotta con un eccesso del 20÷50% dell'acido prescelto, rispetto alla quantità molare. Nel secondo caso è bene utilizzare 0,15÷0,40 moli di acido corrispondente al sale di addizione impiegato. The starting benzhydrylmethylamine can be used as a free base or in the form of a salt thereof. In the first case the reaction is carried out with an excess of 20 ÷ 50% of the selected acid, with respect to the molar quantity. In the second case it is advisable to use 0.15 ÷ 0.40 moles of acid corresponding to the addition salt used.
Nel passaggio (b) la riduzione del composto di formula III viene condotta con un idruro metallico, preferibilmente con boroidruro di sodio, ad una temperatura di 30÷35°C, avendo cura di effettuare l'addizione del reattivo a bassa temperatura (0÷5°C) e controllando poi l'esotermicità della reazione. La riduzione avviene in ambiente basico, preferìbilmente in presenza di un bicarbonato alcalino, per esempio bicarbonato di sodio, in un solvente alcoolico, preferibilmente metanolo, ed il composto di formula IV è isolato mediante precipitazione da un solvente organico, di preferenza idrocarburico, dopo essere stato estratto dalla miscela di reazione con toluene. In questa operazione è preferibile concentrare preventivamente la miscela di reazione eliminando così parte del solvente. In step (b) the reduction of the compound of formula III is carried out with a metal hydride, preferably with sodium borohydride, at a temperature of 30 ÷ 35 ° C, taking care to add the reagent at low temperature (0 ÷ 5 ° C) and then checking the exothermicity of the reaction. The reduction takes place in a basic environment, preferably in the presence of an alkaline bicarbonate, for example sodium bicarbonate, in an alcoholic solvent, preferably methanol, and the compound of formula IV is isolated by precipitation from an organic solvent, preferably hydrocarbon, after being was extracted from the reaction mixture with toluene. In this operation it is preferable to previously concentrate the reaction mixture thus eliminating part of the solvent.
Alternativamente, il passaggio (b) può essere condotto estraendo il composto di formula IV direttamente dalla miscela di reazione con un solvente alogenato, per esempio diclorometano o 1,1,1-tricloroetano, evaporando il solvente e lasciando poi cristallizzare il prodotto così ottenuto. Alternatively, step (b) can be carried out by extracting the compound of formula IV directly from the reaction mixture with a halogenated solvent, for example dichloromethane or 1,1,1-trichloroethane, evaporating the solvent and then allowing the product thus obtained to crystallize.
Nel passaggio (c), la reazione tra il composto di formula IV, od un suo sale, con il 4-trifluoro metilalogenobenzene viene effettuata in ambiente fortemente alcalino a pH > 10, in particolare in presenza di un idrossido alcalino, come idrossico sodico o potassico oppure un alcoolato alcalino come metilato sodico o potassico o t-butilato sodico o potassico, e di uno ioduro dello stesso metallo alcalino, in un solvente aprotico polare come dimetilformamide, dimetilsolfossido o N-metilpirrolidone, ad una temperatura di 80÷150°C, preferibilmente a 100÷140°C. In step (c), the reaction between the compound of formula IV, or a salt thereof, with 4-trifluoro methylhalogenobenzene is carried out in a strongly alkaline environment at pH> 10, in particular in the presence of an alkaline hydroxide, such as sodium hydroxide or potassium or an alkaline alcoholate such as sodium or potassium methylate or sodium or potassium t-butylate, and an iodide of the same alkali metal, in a polar aprotic solvent such as dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone, at a temperature of 80 ÷ 150 ° C , preferably at 100 ÷ 140 ° C.
Come 4-trifluorometilalogenobenzene sì impiega preferibilmente il 4-trifluorometilclorobenzene. Le condizioni di O-alchilazione della presente invenzione sfavoriscono notevolmente la formazione di sottoprodotti. As 4-trifluoromethylhalogenobenzene, 4-trifluoromethylchlorobenzene is preferably used. The O-alkylation conditions of the present invention considerably disadvantage the formation of by-products.
I prodotto di formula V così ottenuto viene isolato secondo metodi convenzionali, mediante dissoluzione in acqua ed estrazione successiva con un solvente idrocarburico, dalla cui soluzione esso precipita per aggiunta di un alcool. The product of formula V thus obtained is isolated according to conventional methods, by dissolution in water and subsequent extraction with a hydrocarbon solvent, from whose solution it precipitates by adding an alcohol.
Nel passaggio (d) il gruppo benzidrilico viene rimosso secondo i metodi convenzionali adatti alla deprotezione dei gruppi aminici cosi protetti. Vantaggiosamente, il composto di formula V viene sottoposto a riduzione catalitica, per esempio ad idrogenazione o riduzione con cicloesene, in presenza di palladio su carbone. Preferibilmente si opera con cicloesene in presenza di palladio su carbone con acido acetico glaciale, ad una temperatura di 70÷110°C, preferibilmente a 85÷100°C. La tecnica di rimozione del gruppo benzidrilico della presente invenzione ha un'elevata selettività, con conseguente ottenimento di prodotto ad elevato grado di purezza. In step (d) the benzhydryl group is removed according to conventional methods suitable for deprotection of the amine groups thus protected. Advantageously, the compound of formula V is subjected to catalytic reduction, for example to hydrogenation or reduction with cyclohexene, in the presence of palladium on carbon. Preferably one operates with cyclohexene in the presence of palladium on carbon with glacial acetic acid, at a temperature of 70 ÷ 110 ° C, preferably at 85 ÷ 100 ° C. The removal technique of the benzhydryl group of the present invention has a high selectivity, with consequent obtaining of a product with a high degree of purity.
La fluoxetina così ottenuta viene isolata secondo le tecniche note, eliminando il catalizzatore per filtrazione ed i sottoprodotti mediante lavaggio con acqua o con sue miscele con alcooli ed evaporando il solvente. The fluoxetine thus obtained is isolated according to known techniques, eliminating the catalyst by filtration and the by-products by washing with water or its mixtures with alcohols and evaporating the solvent.
La fluoxetina può essere isolata direttamente sotto forma di cloridrato, che rappresenta il sale utilizzato in terapia, oppure come base o sotto forma di un altro sale da cui la base può essere liberata per neutralizzazione ed eventualmente trasformata in cloridrato. Fluoxetine can be isolated directly in the form of hydrochloride, which represents the salt used in therapy, or as a base or in the form of another salt from which the base can be freed by neutralization and possibly transformed into hydrochloride.
Il procedimento della presente invenzione permette così la preparazione della fluoxetina e dei suoi sali, in particolare del suo cloridrato, con rese elevatissime ed elevato grado di purezza, facilitato dal fatto che gli intermedi rispondenti alle formule III, IV e VI cristallizzano facilmente e possono essere cosi isolati dalle miscela di reazione con gradi di purezza di almeno il 90%. The process of the present invention thus allows the preparation of fluoxetine and its salts, in particular its hydrochloride, with very high yields and a high degree of purity, facilitated by the fact that the intermediates corresponding to formulas III, IV and VI crystallize easily and can be thus isolated from the reaction mixture with degrees of purity of at least 90%.
I prodotti di formula IV e VI, riuniti nella formula generale A The products of formula IV and VI, gathered in the general formula A
in cui X rappresenta idrogeno, Y rappresenta un gruppo idrossi o 4-trifluorometilfenossi, sono nuovi e costituiscono un altro aspetto dell'invenzione. where X represents hydrogen, Y represents a hydroxy or 4-trifluoromethylphenoxy group, are new and constitute another aspect of the invention.
Cosi, secondo questo suo aspetto, la presente invenzione ha per oggetto i composti di formula A ed i loro sali di addizione con acidi. Thus, according to this aspect, the present invention relates to the compounds of formula A and their addition salts with acids.
I seguenti esempi illustrano l'invenzione senza, tuttavia, limitarla. The following examples illustrate the invention without, however, limiting it.
ESEMPIO 1 EXAMPLE 1
fa) 3-fN-benzidril-N-metil)aminopropiofenone cloridrato fa) 3-fN-benzhydryl-N-methyl) aminopropiophenone hydrochloride
Si riscalda sotto agitazione a riflusso (t = 115÷118°C) una miscela di 200 g (0,85 m) di N-benzidril-N-metilamina cloridrato, 700 mi di alcool n-butilico, 266 g (8,86 m) di paraformaldeide, 190 g (1,58 m) di acetofenone e 4 mi (0,046 m) di acido cloridrico acquoso 30%, ottenendo una soluzione limpida. Si mantiene a riflusso per 15÷30 minuti a 115÷116°C, quindi si raffredda fino a 0°C circa e si mantiene sotto agitazione a questa temperatura per almeno 2 ore. Si isola quindi il prodotto di reazione mediante filtrazione, lavando con 500 mi di acetone, e si essicca sotto vuoto a 55°C. Si ottengono 281,7 g (0,770 m) di 3-(N-benzidril-N-metil)aminopropiofenone cloridrato con purezza HPLC > 92% e p.f. = = 175÷178°C. A mixture of 200 g (0.85 m) of N-benzhydryl-N-methylamine hydrochloride, 700 ml of n-butyl alcohol, 266 g (8.86 m) of paraformaldehyde, 190 g (1.58 m) of acetophenone and 4 ml (0.046 m) of 30% aqueous hydrochloric acid, obtaining a clear solution. It is kept under reflux for 15 ÷ 30 minutes at 115 ÷ 116 ° C, then it is cooled down to about 0 ° C and kept under stirring at this temperature for at least 2 hours. The reaction product is then isolated by filtration, washing with 500 ml of acetone, and dried under vacuum at 55 ° C. 281.7 g (0.770 m) of 3- (N-benzhydryl-N-methyl) aminopropiophenone hydrochloride are obtained with HPLC purity> 92% and m.p. = = 175 ÷ 178 ° C.
(b) 3 -(N-benzidril-N-metil)amino- 1 -fenilpropan- 1 -olo (b) 3 - (N-benzhydryl-N-methyl) amino- 1 -phenylpropan- 1 -ol
Si caricano 200 g (0,55 m) di 3-(N-benzidril-N-metil)aminopropiofenone cloridrato, 3000 ml di Ν,Ν-dimetilformamide 1000 mi di isopropanolo e, sotto agitazione, si raffredda la miscela a 0÷+5°C. Si addizionano lentamente 1000 ml (0,95 m) di sodio bicarbonato acquoso 8%, regolando l'aggiunta in modo tale da non superare la temperatura di 20°C. Si raffredda quindi la miscela a 5÷+10°C e si aggiunge lentamente una soluzione costituita da 50 ml di acqua deionizzata, 2,5 mi di sodio idrossido acquoso al 30% e 25 g (0,66 m) di boroidruro di sodio, regolando l'aggiunta in modo da non superare la temperatura di 30°C. Si tiene la miscela sotto agitazione in queste condizioni per 2÷4 ore, si raffredda a 0÷+5°C e si aggiungono quindi 2000 ml di acqua deionizzata e 2000 ml di toluene. Si separano le fasi e si estrae quella acquosa con (1000 500) ml di toluene. Si riuniscono le fasi organiche, si lavano con 500 ml di acqua deionizzata e si concentrano sotto vuoto. Alla soluzione concentrata si addizionano 500 mi di n-eptano e si lascia raffreddare lentamente fino a 0°C. Si filtra, si lava con n-eptano e si essicca sotto vuoto a 40°C. Si ottengono 164,8 g (0,497 m) di 3 -(N-benzidril-N-metil)amino-1 -fenilpropan- 1 -olo con purezza HPLC > 92% e p.f. = 96÷98°C. 200 g (0.55 m) of 3- (N-benzhydryl-N-methyl) aminopropiophenone hydrochloride, 3000 ml of Ν, Ν-dimethylformamide 1000 ml of isopropanol are added and, under stirring, the mixture is cooled to 0 ÷ + 5 ° C. 1000 ml (0.95 m) of 8% aqueous sodium bicarbonate are slowly added, adjusting the addition so as not to exceed a temperature of 20 ° C. The mixture is then cooled to 5 ÷ + 10 ° C and a solution consisting of 50 ml of deionized water, 2.5 ml of aqueous sodium hydroxide at 30% and 25 g (0.66 m) of sodium borohydride is slowly added. , adjusting the addition so as not to exceed the temperature of 30 ° C. The mixture is kept under stirring under these conditions for 2 ÷ 4 hours, it is cooled to 0 ÷ + 5 ° C and then 2000 ml of deionized water and 2000 ml of toluene are added. The phases are separated and the aqueous one is extracted with (1000 500) ml of toluene. The organic phases are combined, washed with 500 ml of deionized water and concentrated under vacuum. 500 ml of n-heptane are added to the concentrated solution and it is allowed to cool slowly to 0 ° C. It is filtered, washed with n-heptane and dried under vacuum at 40 ° C. 164.8 g (0.497 m) of 3 - (N-benzhydryl-N-methyl) amino-1 -phenylpropan- 1 -ol are obtained with HPLC purity> 92% and m.p. = 96 ÷ 98 ° C.
(c) N-benzidril-N-metil-3-[(4-trifluorometil)fenossil-3-fenilDropilamina (c) N-benzhydryl-N-methyl-3 - [(4-trifluoromethyl) phenoxyl-3-phenylDropylamine
Si caricano 180 g (0,54 m) di 3 -(N-benzidril-N-metil)amino- 1 -fenilpropan- 1 -olo, 500 ml di N-metilpirrolidone, 99,6 g (0,814 m) di potassio ter-butilato, 5 g (0,03 m) di potassio ioduro, 144 g (0,8 m) di 4-trifluorometilclorobenzene. Sotto agitazione si riscalda la miscela ad una temperatura di 100÷140°C, pervenendo a soluzione di colore viola. Si tiene in queste condizioni per 1÷2 ore, quindi si raffredda a 0°C. Si addizionano, sotto agitazione, 800 ml di toluene e 1000 ml di acqua deionizzata. Si separano le fasi e si estrae quella acquosa con (300 200) ml di toluene, quindi si lavano le fasi organiche riunite con 300 mi di acqua deionizzata. Si concentra la fase organica e si addizionano al residuo 800 ml di alcool isopropilico pervenendo a soluzione che si raffredda a 0°C. Si tiene sotto agitazione a 0°C per almeno 3 ore, si filtra il precipitato e si essicca sotto vuoto a 40°C. Si ottengono 206,6 g (0,434 m) di N-benzidril-N-metil-3-[(4-trifluorometil)fenossi)-3-fenilpropilamina con purezza 180 g (0.54 m) of 3 - (N-benzhydryl-N-methyl) amino- 1 -phenylpropan- 1 -ol, 500 ml of N-methylpyrrolidone, 99.6 g (0.814 m) of potassium ter -butylate, 5 g (0.03 m) of potassium iodide, 144 g (0.8 m) of 4-trifluoromethylchlorobenzene. Under stirring, the mixture is heated to a temperature of 100 ÷ 140 ° C, reaching a purple solution. It is kept under these conditions for 1 ÷ 2 hours, then it is cooled to 0 ° C. 800 ml of toluene and 1000 ml of deionized water are added under stirring. The phases are separated and the aqueous one is extracted with (300-200) ml of toluene, then the combined organic phases are washed with 300 ml of deionized water. The organic phase is concentrated and 800 ml of isopropyl alcohol are added to the residue, reaching a solution which is cooled to 0 ° C. It is kept under stirring at 0 ° C for at least 3 hours, the precipitate is filtered and dried under vacuum at 40 ° C. 206.6 g (0.434 m) of N-benzhydryl-N-methyl-3 - [(4-trifluoromethyl) phenoxy) -3-phenylpropylamine with purity
(d) N-metil-3-[(4-trifluorometillfenossil-3-fenilpropilamina cloridrato (fluoxetina cloridrato) Si caricano 100 g (0,201 m) di N-benzidril-N-metil-3-[(4-trifluorometil)fenossi]-3-fenilpropil amina, 200 ml di acido acetico glaciale e 10 g di Pd/C 10%. Si riscalda la miscela a 85÷100°C e si aggiunge, in 3 ore, una soluzione di 26 ml (0,26 m) di cicloesene in 194 ml di acido acetico glaciale. A fine aggiunta si tiene la miscela per un'ora a 85÷100°C. Si raffredda a circa 20°C, si filtra e si evapora il filtrato sotto vuoto a 40°C fino a residuo oleoso incolore. Si raffredda il residuo a 0÷+5°C e si addiziona, sotto agitazione, una soluzione di 500 mi di acqua deionizzata ed 80 mi di NaOH 30%. Si estrae la miscela con 500 mi di acetato di isobutile, si separano le fasi e si riestrae quella acquosa con 200 mi di acetato di isobutile. Si riuniscono le fasi organiche, si lavano con 200 mi di acqua deionizzata e si con centrano sotto vuoto a 45+50°C. Si raffredda il residuo a 0°C e si aggiunge, sotto agitazione, una soluzione di acido clorìdrico in isopropanolo. Si tiene sotto agitazione fino a completa cristallizzazione, si filtra lavando con etere metil-ter.butilico e si essicca sotto vuoto a 40°C. Si ottengono 50 g (0,14 m) di fluoxetina cloridrato con titolo HPLC = 98,5%, purezza HPLC = 98,8% e p.f. = 158÷160°C. (d) N-methyl-3 - [(4-trifluoromethylphenoxyl-3-phenylpropylamine hydrochloride (fluoxetine hydrochloride) 100 g (0,201 m) of N-benzhydryl-N-methyl-3 - [(4-trifluoromethyl) phenoxy] are loaded -3-phenylpropyl amine, 200 ml of glacial acetic acid and 10 g of Pd / C 10%. The mixture is heated to 85 ÷ 100 ° C and a solution of 26 ml (0.26 m ) of cyclohexene in 194 ml of glacial acetic acid. At the end of the addition, the mixture is kept for one hour at 85 ÷ 100 ° C. It is cooled to about 20 ° C, filtered and the filtrate evaporated under vacuum at 40 ° C until a colorless oily residue. The residue is cooled to 0 ÷ + 5 ° C and a solution of 500 ml of deionized water and 80 ml of 30% NaOH is added under stirring. The mixture is extracted with 500 ml of acetate isobutyl, the phases are separated and the aqueous one is re-extracted with 200 ml of isobutyl acetate. The organic phases are combined, washed with 200 ml of deionized water and concentrated under vacuum at 45 + 50 ° C. The residue is cooled. at 0 ° C and add , under stirring, a solution of hydrochloric acid in isopropanol. It is kept under stirring until complete crystallization, filtered by washing with methyl-tert-butyl ether and dried under vacuum at 40 ° C. 50 g (0.14 m) of fluoxetine hydrochloride are obtained with HPLC titer = 98.5%, HPLC purity = 98.8% and m.p. = 158 ÷ 160 ° C.
ESEMPIO 2 EXAMPLE 2
Si opera come descrìtto nell’Esempio 1, conducendo il passaggio (b) nel modo seguente: We operate as described in Example 1, carrying out step (b) as follows:
(b) si caricano 200 g (0,55 m) di 3-(N-benzidril-N-metil)aminopropiofenone cloridrato, 1000 ml di alcool metilico e 300 mi di acqua deionizzata. Sotto agitazione si raffredda la miscela a -5°C e si aggiungono, a porzioni, 50 g (1,32 m) di boroidruro di sodio, regolando l'aggiunta in modo da non superare la temperatura di 10°C. Ad aggiunta ultimata si lascia salire cautamente la temperatura in modo da non superare i 30°C. Si tiene sotto agitazione la miscela in queste condizioni per 3÷4 ore, quindi si versa in 1500 ml di acqua deionizzata e 1000 mi di metilene cloruro, ad una temperatura non superiore a 5°C. Si separano le fasi e si estrae quella acquosa con (300 200)ml di metilene cloruro. Si lavano le fasi organiche riunite con 600 ml di acqua deionizzata e si concentrano sotto vuoto fino a residuo oleoso incolore che cristallizza spontaneamente. Si ottengono 180 g (0,54 m) di 3>(N-benzidril-N-metil)amino-1-fenilpropan-1-olo con purezza HPLC > 90% e p.f. = 96÷98°C. (b) 200 g (0.55 m) of 3- (N-benzhydryl-N-methyl) aminopropiophenone hydrochloride, 1000 ml of methyl alcohol and 300 ml of deionized water are added. Under stirring, the mixture is cooled to -5 ° C and 50 g (1.32 m) of sodium borohydride are added in portions, adjusting the addition so as not to exceed the temperature of 10 ° C. When the addition is complete, the temperature is left to rise carefully so as not to exceed 30 ° C. The mixture is kept under stirring under these conditions for 3 ÷ 4 hours, then poured into 1500 ml of deionized water and 1000 ml of methylene chloride, at a temperature not exceeding 5 ° C. The phases are separated and the aqueous one is extracted with (300 200) ml of methylene chloride. The combined organic phases are washed with 600 ml of deionized water and concentrated under vacuum to a colorless oily residue which crystallizes spontaneously. 180 g (0.54 m) of 3> (N-benzhydryl-N-methyl) amino-1-phenylpropan-1-ol are obtained with HPLC purity> 90% and m.p. = 96 ÷ 98 ° C.
In questa seconda preparazione è stato ottenuto il clorìdrato di fluoxetina con purezza HPLC > 98%, con una resa globale, rispetto alla N-benzidril-N-metilamina clorìdrato di partenza, del 40% rispetto al teorico. In this second preparation fluoxetine hydrochloride was obtained with HPLC purity> 98%, with an overall yield, with respect to the starting N-benzhydryl-N-methylamine hydrochloride, of 40% with respect to the theoretical one.
ESEMPIO 3 EXAMPLE 3
Si opera come descritto nell'sempio 1, conducendo il passaggio (c) nel modo seguente: We operate as described in example 1, carrying out step (c) as follows:
(c) si caricano 180 g (0,54 m) di 3-(N-benzidril-N-metil)amino-1-fenilpropan-1-olo, 500 ml di dimetilsolfossido e 91 g (1,62 m) di potassio idrossido scaglie. Sotto agitazione si riscalda la miscela ad una temperatura di 120÷140°C e si tiene per 30 minuti, quindi si addizionano 144 g (0,8 m) di 4-trifluorometilclorobenzene. Si tiene a 120÷140°C per 1÷2 ore, quindi si raffredda a 10°C e si aggiungono, sotto agitazione, 800 ml di toluene e 1000 ml di acqua deionizzata. Si separano le fasi e si estrae quella acquosa con (300 200) ml di toluene, quindi si lavano le fasi organiche riunite con 300 ml di acqua deionizzata. Si concentra la fase organica sotto vuoto ed al residuo oleoso si addizionano 800 mi di alcool isopropilico, ottenendosi soluzione limpida. Si raffredda la soluzione a 0°C e si lascia cristallizzare a questa temperatura per circa 2 ore. Si filtra il prodotto, si lava con alcool isopropilico freddo e si essicca sotto vuoto a 40°C. Si ottengono 214,2 (0,45 m) di N-benzidril-N-metil-3-[(4-trifluorometil)fenossi]-3-fenilpropilamina con purezza HPLC > 95% e p.f. = 91÷95°C. (c) add 180 g (0.54 m) of 3- (N-benzhydryl-N-methyl) amino-1-phenylpropan-1-ol, 500 ml of dimethyl sulfoxide and 91 g (1.62 m) of potassium hydroxide flakes. Under stirring, the mixture is heated to a temperature of 120 ÷ 140 ° C and kept for 30 minutes, then 144 g (0.8 m) of 4-trifluoromethylchlorobenzene are added. It is kept at 120 ÷ 140 ° C for 1 ÷ 2 hours, then it is cooled to 10 ° C and 800 ml of toluene and 1000 ml of deionized water are added under stirring. The phases are separated and the aqueous one is extracted with (300-200) ml of toluene, then the combined organic phases are washed with 300 ml of deionized water. The organic phase is concentrated under vacuum and 800 ml of isopropyl alcohol are added to the oily residue, obtaining a clear solution. The solution is cooled to 0 ° C and left to crystallize at this temperature for about 2 hours. The product is filtered, washed with cold isopropyl alcohol and dried under vacuum at 40 ° C. 214.2 (0.45 m) of N-benzhydryl-N-methyl-3 - [(4-trifluoromethyl) phenoxy] -3-phenylpropylamine are obtained with HPLC purity> 95% and m.p. = 91 ÷ 95 ° C.
In questa preparazione è stato ottenuto il clorìdrato di fluoxetina con purezza > 98,5%. In this preparation, fluoxetine hydrochloride with purity> 98.5% was obtained.
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