MXPA97009314A - Process for the production of dexfenfluram chlorhydrate - Google Patents
Process for the production of dexfenfluram chlorhydrateInfo
- Publication number
- MXPA97009314A MXPA97009314A MXPA/A/1997/009314A MX9709314A MXPA97009314A MX PA97009314 A MXPA97009314 A MX PA97009314A MX 9709314 A MX9709314 A MX 9709314A MX PA97009314 A MXPA97009314 A MX PA97009314A
- Authority
- MX
- Mexico
- Prior art keywords
- ethyl
- methyl
- trifluoromethyl
- phenylethyl
- organic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000011780 sodium chloride Substances 0.000 claims abstract description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 24
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 14
- ZXKXJHAOUFHNAS-FVGYRXGTSA-N (S)-fenfluramine hydrochloride Chemical compound [Cl-].CC[NH2+][C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 ZXKXJHAOUFHNAS-FVGYRXGTSA-N 0.000 claims abstract description 11
- 229960001096 Dexfenfluramine Hydrochloride Drugs 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000006264 debenzylation reaction Methods 0.000 claims abstract description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
- 238000005755 formation reaction Methods 0.000 claims abstract description 8
- 238000006200 ethylation reaction Methods 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 10
- 239000002798 polar solvent Substances 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 229960004597 Dexfenfluramine Drugs 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 7
- DBGIVFWFUFKIQN-VIFPVBQESA-N ethyl[(2S)-1-[3-(trifluoromethyl)phenyl]propan-2-yl]amine Chemical compound CCN[C@@H](C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-VIFPVBQESA-N 0.000 claims description 7
- 150000001298 alcohols Chemical class 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000003512 tertiary amines Chemical class 0.000 claims description 4
- RDHPKYGYEGBMSE-UHFFFAOYSA-N Bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N Ethyl iodide Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- DENRZWYUOJLTMF-UHFFFAOYSA-N Diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 claims description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 2
- DLMICMXXVVMDNV-UHFFFAOYSA-N N,N-di(propan-2-yl)propan-1-amine Chemical compound CCCN(C(C)C)C(C)C DLMICMXXVVMDNV-UHFFFAOYSA-N 0.000 claims description 2
- XRKQMIFKHDXFNQ-UHFFFAOYSA-N N-cyclohexyl-N-ethylcyclohexanamine Chemical compound C1CCCCC1N(CC)C1CCCCC1 XRKQMIFKHDXFNQ-UHFFFAOYSA-N 0.000 claims description 2
- XQQLJWFNDMEBHP-UHFFFAOYSA-N N-ethyl-2-methyl-N-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CN(CC)CC(C)C XQQLJWFNDMEBHP-UHFFFAOYSA-N 0.000 claims description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N Triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 229940008406 diethyl sulfate Drugs 0.000 claims description 2
- VRZVPALEJCLXPR-UHFFFAOYSA-N ethyl 4-methylbenzenesulfonate Chemical compound CCOS(=O)(=O)C1=CC=C(C)C=C1 VRZVPALEJCLXPR-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000012021 ethylating agents Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 2
- 239000001184 potassium carbonate Substances 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 239000001187 sodium carbonate Substances 0.000 claims description 2
- 235000011182 sodium carbonates Nutrition 0.000 claims description 2
- 239000002830 appetite depressant Substances 0.000 abstract description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 abstract description 2
- 229950008597 drug INN Drugs 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000005712 crystallization Effects 0.000 description 3
- 230000003287 optical Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- IQFVPQOLBLOTPF-HKXUKFGYSA-L Congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- -1 aliphatic ketones Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 230000001603 reducing Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 230000000707 stereoselective Effects 0.000 description 2
- YONLFQNRGZXBBF-KBPBESRZSA-N (2S,3S)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- BKMMTJMQCTUHRP-VKHMYHEASA-N (S)-2-aminopropan-1-ol Chemical compound C[C@H](N)CO BKMMTJMQCTUHRP-VKHMYHEASA-N 0.000 description 1
- LSPHULWDVZXLIL-UHFFFAOYSA-N (±)-Camphoric acid Chemical compound CC1(C)C(C(O)=O)CCC1(C)C(O)=O LSPHULWDVZXLIL-UHFFFAOYSA-N 0.000 description 1
- 229960001582 Fenfluramine Drugs 0.000 description 1
- 229960001877 Fenfluramine Hydrochloride Drugs 0.000 description 1
- DBGIVFWFUFKIQN-UHFFFAOYSA-N Obedrex Chemical class CCNC(C)CC1=CC=CC(C(F)(F)F)=C1 DBGIVFWFUFKIQN-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000003466 anti-cipated Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- ZXKXJHAOUFHNAS-UHFFFAOYSA-N fenfluramine hydrochloride Chemical compound [Cl-].CC[NH2+]C(C)CC1=CC=CC(C(F)(F)F)=C1 ZXKXJHAOUFHNAS-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
Abstract
Process for the production of an anorectic drug dexfenfluramine hydrochloride (INN) which comprises the ethylation of (S), (S) -N- (1-phenylethyl) -alpha-methyl-3- (trifluoromethyl) benzeneethamine or a salt of it with an organic or inorganic acid, the debenzylation of the resulting intermediate (S), (S) -N-ethyl-N- (1-phenylethyl) -alpha-methyl-3- (trifluoromethyl) benzeneethamine or of a salt of it with an organic or inorganic acid by catalytic hydrogenation and, optionally, the formation of salts with hydrochloric acid
Description
"PROCESS FOR THE PRODUCTION OF DEXPHENFLURAMINE CHLORHYDRATE", FIELD AND BACKGROUND OF THE INVENTION
Dexfenflurane hydrochloride (INN), the dextrorotatory isomer 10 of fenfluramine hydrochloride (INN), is well known as an anorexic drug described in US Pat. No. 3,198,833 wherein the separation of the two optical isomers of fenfluramine is reported to obtain Is the dextrorotatory isomer much more active? f- that the levorotatory isomer.
This separation is itself based on a classical method or optical resolution through the formation of salts of diastereoisomers first with (+) - dibenzoyltartaric acid and then with (+) - camphoric acid.
REF: 26312 The performance of dexfenfluramine is very low, about 11% calculated on the racemate, and the process is very problematic since it requires crystallization of two different salts of diastereoisomers.
The stereospecific synthesis has been treated to obtain only dexfenfluramine to avoid the low yields and high own costs for the separation of the optical isomers through the crystallization of the salts of diastereoisomers with optically active acids.
European Patent 0,301,925 describes the enantiospecific production of dexfenfluramine starting from (S) -2-amino-1-propanol through a series of stereospecific condensations and reductions.
The European Patent 0,441,160 in turn describes the enantiospecific production of dexfenfluramine starting from (S) -1- (3-trifluoromethyl) phenyl-2-propanol obtained in turn by enantioselective enzymatic reduction of the corresponding ketone.
The present invention relates to a new process for the production of dexfenfluramine hydrochloride starting from new preferred intermediates described in the application of Italian Patent BO97A000252, that is (S), (S) -N- (1-phenylethyl) ) -cc-methyl-3- (trifluoromethyl) benzene-ethanamine and salts thereof with organic and inorganic acids.
The process focuses on a first stage which is made by the ethylation of (S), (S) -N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethenamine or a salt thereof with an acid organic or inorganic followed by a reductive debenzylation of the resulting new intermediate (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine or a salt thereof with a organic or inorganic acid and, optionally, the formation of salts with hydrochloric acid.
DESCRIPTION OF THE INVENTION
The process for the production of dexfenfluramine hydrochloride of the formula
which comprises:
a) reacting the (S), (S) -N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine of the formula
or a salt thereof with an organic or inorganic acid with an ethylating agent to obtain (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethenamine of the formula
b) the compound of the formula III or a salt thereof with an organic or inorganic acid must be zylated by hydrogenation in the presence of a catalyst;
c) carry out, optionally, the formation of salts with hydrochloric acid.
The intermediate of formula III and salts thereof with organic and inorganic acids are new products and are claimed as such.
The preferred salt in carrying out the invention is the hydrochloride.
The ethylation reaction is carried out by reacting a molar equivalent (S), S) -N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethenamine or a salt thereof with an organic or inorganic acid with 1 to 3 molar equivalents of an alkylating agent in the presence of 1 to 3 molar equivalents of a non-quaternizable tertiary amine or of an alkaline carbonate for a period of time between 4 and 80 hours at a temperature between 20 ° C and 150 C. In a preferred aspect of the invention the alkylating agent is selected from ethyl bromide, ethyl iodide, diethyl sulfate, ethyl metasulfonate and ethyl p-toluenesulfonate, the polar solvent is selected from N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide and triethylphosphate, the tertiary amine is selected from N, N-diisopropylethylamine, N, N-diisopropylpropylamine, N, N-diisobutylethylamine, N, N-diisopropylamine and N, N-dicyclohexylethylamine and the alkali carbonate is selected from sodium and potassium carbonates.
The intermediate (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine can be used as such for the subsequent dezfenfluramine debenzylation reaction or can be transformed into a crystalline salt with an organic or inorganic acid.
In a preferred aspect of the invention it is dissolved in a water-immiscible organic solvent, preferably an aromatic hydrocarbon such as toluene, and the hydrochloride in the form of a crystalline precipitate is obtained by adding a concentrated aqueous solution of hydrochloric acid.
The debenzylation reaction is carried out by subjecting the intermediate (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethenamine or a salt thereof with an organic acid or inorganic, preferably hydrochloric, by catalytic hydrogenation in a polar solvent or polar and non-polar solvent mixture under 1 to 20 atmospheres of hydrogen, at a temperature between 20 ° C and 100 ° C for a period of time from 1 to 8 hours. The preferred polar solvent for carrying out the invention is selected from alcohols containing 1 to 6 carbon atoms while 5% palladium on carbon is the preferred catalyst. At the end of the debenzylation reaction, the raw product of the reaction can be transformed into the pure dexfenfluramine hydrochloride, directly obtained in the debenzylation of the intermediate of the formula III or by treatment with an aqueous solution of an alkali hydroxide when the debenzilation is carried out with an organic or inorganic salt or an intermediate of the formula III, with gaseous hydrochloric acid in a solvent or a mixture of solvents.
The dexfenfluramine base is dissolved in a solvent or a mixture of solvents selected from aliphatic ketones containing from 3 to 8 carbon atoms, the alcohols containing from 1 to 6 carbon atoms, the acetates of alcohols containing from 1 to 6 carbon atoms. , and the alkyl ethers contained 4 to 8 carbon atoms and the anhydrous hydrochloric acid qaseous by bubbling into the solution until the color of the Congo red indicator changes.
When crude dexfenfluramine hydrochloride is obtained directly from the debenzylation reaction, it can also be directly purified without an anticipated transformation within the dexfenfluramine base.
In this case, the crude dexfenfluramine hydrochloride, obtained by evaporation of the solvent used in the debenzylation reaction, is crystallized by hot solubilization in a solvent or mixture of solvents previously described by the formation of salts with hydrochloric acid gas. Aliphatic ketones containing from 3 to 8 carbon atoms are preferred.
The examples reported below are additional illustrations of the invention and should not be taken as a limitation.
EXAMPLE 1
Hydrochloride dm (S), (3) -N-phenyl-N- (1-phenylethyl) -a-pfethyl-3- (trifluoromethyl) benzene »tanamine
A mixture made of 100 g (0.326 mol) of (S), (S) -N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine, 71 g (0.456 mol) of ethyl iodide and 58.9 g (0.456 moles) of N, N-diisopropylethylamine in 200 ml of N, N-dimethylformamide is heated at 60 ° C under stirring for 60 hours. Thus the reaction mixture is concentrated at 90 ° C under vacuum, at a pressure of 10 mm Hg, and the crude product thus obtained is added with 200 ml of water and 200 ml of toluene and the mixture alkalized to a pH of 12 by means of an aqueous solution of sodium hydroxide 30% (w / w). The two layers are then separated, the aqueous layer is discharged while the organic layer is added with 200 ml of water acidified with 37% (w / w) hydrochloric acid aqueous solution. The mixture is cooled for 30 minutes at 5 ° C under stirring and the precipitated solid is filtered, washed first with water and then with toluene and dried under vacuum at 65 ° C for 12 hours.
116 g of product with m.p. = 196 ° - 198 ° C and [a] 25 = + 49.6 ° (c = 2% in absolute ethanol) are obtained with a yield equal to 95.5%.
EXAMPLE 2
(S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine hydrochloride
A mixture made of 461 g (1.505 moles) of (S), (S) -N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine, 254 g (2,331 moles) of ethyl bromide, 290 g (2.235 moles) of N, -diisopropylethylamine and 600 ml of N, N-dimethylformamide is placed in an autoclave. The autoclave was closed and the reaction mixture was maintained at 100 ° C for 40 hours under agitation. The reaction mixture was then cooled to 50 ° C and added with 500 ml of water and 225 ml of 30% aqueous sodium hydroxide solution (w / w). The mixture was added with 500 ml of toluene after 30 minutes under stirring and kept under stirring for another 30 minutes. The phases were then separated, the aqueous layer is removed while the organic layer is filtered through a bed of decolorizing earth, added with 200 ml of water and then, for 30 minutes, 230 ml of aqueous solution of hydrochloric acid 37% ( p / p). The crystallization of the product is initiated with 2 grams of crystals of the pure product and another aqueous solution of hydrochloric acid 37% (w / w) is added until the pH of the mixture is brought to a constant value of 1.5.
The suspension is then cooled to 5 ° C and filtered and the crystalline solid is washed with water and dried under vacuum at 70 ° C for 12 hours.
502 g of pure product were obtained with a yield equal to 90%.
EXAMPLE 3
(S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine hydrochloride
50 g of (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine hydrochloride and 17 ml of 30% aqueous sodium hydroxide solution (p / p) are added, with stirring, to a mixture made of 200 ml of water and 200 ml of methylene chloride.
The phases are separated, the aqueous layer is discharged while the organic layer is washed twice with 100 ml of water and then evaporated under vacuum to completely remove the solvent.
42. 7 g of (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine were obtained in the form of a colorless oil having [a] 25 = + 54.1 ° (c = 2% in absolute ethanol) are obtained with a yield equal to 95%.
EXAMPLE 4
(S) -N-Ethyl-a-methyl-3- (trifluoromethyl) benzeneethanamine hydrochloride (dexfenfluramine hydrochloride)
49. 5 g (0.133 mol) of (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine hydrochloride, 250 ml of methanol and 1.0 g of palladium on 50% wet carbon are put in a hydrogenator.
An atmosphere of hydrogen at a constant pressure of 5 atmospheres at a temperature of 75 ° C for a period of 2 hours is maintained within the hydrogenator. The reaction mixture is then filtered and the solvent is evaporated under vacuum obtaining a solid which is treated with a mixture made by 100 ml of water and 60 ml of toluene. The organic layer is discharged while the aqueous layer is alkalized to a pH of 11.4 with an alkaline aqueous solution of sodium hydroxide 30% (w / w). The oily suspension thus obtained is extracted once with 100 ml of methylene chloride and twice with 30 ml of methylene chloride and the organic extracts are collected, washed twice with 20 ml of water and evaporated in vacuo. The clear colorless oil thus obtained is dissolved at room temperature in 330 ml of methyl ethyl ketone and gaseous anhydrous hydrochloric acid is bubbled into the solution until the red congo red color changes. The suspension thus obtained is cooled under stirring at 5 ° C and filtered.
The solid obtained is washed with 30 ml of methyl ethyl ketone and dried under vacuum for 12 hours at 60 ° C to give 30 g of pure dexfenfluramine hydrochloride having a p. of f. = 160.2 ° C with a yield equal to 84.4%.
The corresponding free base has [a] 25 = + 9.25 ° (c = 8% in absolute ethanol).
EXAMPLE 5
(S) -N-Ethyl-a-methyl-3- (trifluoromethyl) benzeneethanamine hydrochloride (dexfenfluramine hydrochloride)
400 g (1075 mole) of (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine hydrochloride, 400 ml of methanol and 2.0 g of 5% of palladium on 50% wet carbon are placed in a hydrogenator. A hydrogen atmosphere at a constant pressure of 5 atmospheres at a temperature of 50 ° C for a period of 4 hours within the hydrogenator. The reaction mixture is then cooled to 20 ° C and filtered to remove the catalyst and the obtained solution is concentrated by drying to obtain a crystalline solid. The solid is dissolved with 500 ml of boiling methyl isobutyl ketone, then 300 ml of the solvent are distilled and 300 ml of methyl isobutyl ketone are added.
The pure product is crystallized by cooling to 0 ° C for two hours, then filtered, washed on the filter with 200 ml of methyl isobutyl ketone and dried under vacuum at 60 ° C for 12 hours.
260 grams of dexfenfluramine hydrochloride are obtained with a yield equal to 90%.
The corresponding free base has [a] 25 = + 9.4 ° (c = 8% in absolute ethanol).
Having described the invention as above, the content of the following is claimed as property
Claims (2)
1. A process for the production of dexfenfluramine hydrochloride of formula characterized because it comprises: A) reacting the (S), (S) -N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine of the formula or a salt thereof with an organic or inorganic acid with an ethylating agent to obtain (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethenamine of the formula or a salt of it with an organic or inorganic acid; B) the compound of the formula III or a salt thereof with an organic or inorganic acid must be zylated by hydrogenation in the presence of a catalyst; C) carry out, optionally, the formation of salts with hydrochloric acid.
2. The process according to claim 1 characterized in that the ethylation reaction is carried out in a polar solvent in the presence of 1 to 3 molar equivalents of a non-quaternizable tertiary amine or of an alkaline carbonate with respect to (S), (S) -N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethenamine or a salt thereof with an organic or inorganic acid at a temperature between 20 ° C and 150 ° C, for a period of time between 4 and 80 hours using 1 to 3 molar equivalents of an alkylating agent selected from ethyl bromide, ethyl iodide, diethyl sulfate, ethyl metasulfonate and ethyl p-toluenesulfonate, which must be carried out in a hydrogenator in a solvent made by a polar solvent or a mixture of polar and non-polar solvents under 1 to 20 atmospheres of hydrogen at a temperature between 20 ° C and 100 ° C for a period of time between 1 and 8 hours using a 5% palladium catalyst on ca The formation of salts occurs by treatment of the dexenfluramine dissolved in a solvent or a mixture of solvents with gaseous hydrochloric acid. The process according to claim 2, characterized in that the non-quaternizable tertiary amine is selected from N, N-diisopropylethylamine, N, N-diisobutylethylamine, N, N-diisopropylpropylamine, N, N-diisopropylamine and N, N-dicyclohexylethylamine and the carbonate. Alkaline is selected from the sodium and potassium carbonates, that the polar solvent in which the ethylation is carried out is selected from N, N-dimethylformamide, N, -methylpyrrolidone, N, N-dimethylacetamide and triethylphosphate, which the The polar solvent in which the debenzylation is carried out is selected from the alcohols containing from 1 to 6 carbon atoms and the solvent used for the formation of salts of the dexfenfluramine is selected from the alcohols containing from 3 to 8 carbon atoms , the acetates of alcohols containing from 1 to 6 carbon atoms, the alkyl ethers containing from 4 to 8 carbon atoms or mixtures thereof. ) A compound characterized in that it is (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethanamine. A compound characterized in that they are the salts of (S), (S) -N-ethyl-N- (1-phenylethyl) -a-methyl-3- (trifluoromethyl) benzeneethenamine with organic and inorganic acids. A salt according to claim 5 characterized in that it is a hydrochloride.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT97BO000331A IT1292595B1 (en) | 1997-06-03 | 1997-06-03 | PROCESS FOR THE PRODUCTION OF DEXFENFLURAMINE HYDROCHLORIDE. |
BOBO97A000331 | 1997-06-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
MX9709314A MX9709314A (en) | 1998-12-31 |
MXPA97009314A true MXPA97009314A (en) | 1999-02-01 |
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