JPWO2019154770A5 - - Google Patents

Claims (20)

Starting from N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine (II) and s-triazodone- [4,3-a] -pyridin-3-one (III) according to reaction scheme 2. Is a continuous method for preparing trazodone base (IV):

In a flow reaction vessel, an alkaline aqueous solution of s-triazodone [4,3-a] -pyridine-3-one (III) and N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine ( A method comprising continuously mixing an organic solution of II) and continuously recovering the trazodone base (IV). The continuous method of claim 1, comprising the following steps:
(I) Continuously supplying an aqueous solution of s-triazolo- [4,3-a] -pyridine-3-one (III) and at least one basic compound to the first channel of the flow reaction vessel;
(Ii) An organic solution of N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine (II) in at least one organic solvent is continuously supplied to the second channel of the flow reaction vessel. To do;
(Iii) The s-triazolo- [4,3-a] -pyridine-3-one is obtained by continuously mixing the alkaline aqueous solution and the organic solution at a temperature of at least 90 ° C. in the flow reaction vessel. (III) is continuously reacted with the N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine (II); and (iv) the reaction mixture is continuously fed from the flow reaction vessel. Collect and isolate the resulting product trazodone base (IV). The method according to any one of claims 1 to 2, wherein the trazodone base (IV) is obtained in a conversion yield of at least 70% by HPLC. The method according to any one of claims 1 to 3, wherein the trazodone base (IV) has a purity of at least 90% by HPLC. The method according to any one of claims 2 to 4 , wherein the temperature of the continuous reaction in the step (iii) is 130 ° C to 160 ° C. The basic compound in step (i) is sodium hydroxide, potassium hydroxide, sodium hydride, sodium amide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, hydroxylation. The method according to any one of claims 2 to 5 , which is an inorganic base selected from the group containing ammonium, magnesium oxide, and a mixture thereof. The method of claim 6 , wherein the inorganic base is selected from the group comprising sodium hydroxide, potassium hydroxide, sodium carbonate, and mixtures thereof. The method according to any one of claims 2 to 7 , wherein the basic compound in step (i) is an organic base selected from the group containing an aliphatic amine and an aromatic amine, and a mixture thereof. 8. Claim 8 , wherein the amine is selected from the group comprising trimethylamine, triethylamine, N, N-diisopropylethylamine, triethanolamine, N, N-dimethylethanolamine, N-methylethanolamine, and mixtures thereof. the method of. The organic solvent in step (ii) is a polar aprotic solvent selected from the group containing dimethylformamide, dimethylsulfoxide, acetone, tetrahydrofuran, acetonitrile, dioxane, or selected from the group containing toluene, diethyl ether. The protictic solvent according to any one of claims 2 to 9 , which is a non-polar solvent or a polar protic solvent selected from the group containing methanol, ethanol, propanol, isopropanol, butyl alcohol, isobutyl alcohol and benzyl alcohol. the method of. The method of any one of claims 1-10 , further comprising the step (v) of converting the trazodone base (IV) to trazodone hydrochloride (V) and isolating it according to reaction scheme 3.

Further prior reaction of m-chlorophenyl-piperazine (I) and 1-bromo-3-chloropropane to N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine (II) by reaction scheme 4. The continuous method according to any one of claims 1 to 11 , which comprises.

12. The method of claim 12 , wherein m-chlorophenyl-piperazine (I) and 1-bromo-3-chloropropane are reacted in continuous mode. 12. The method of claim 12 , wherein m-chlorophenyl-piperazine (I) and 1-bromo-3-chloropropane are reacted in batch mode. 13. The method of claim 13 , comprising the following steps:
(A) An aqueous solution of m-chlorophenyl-piperazine (I) and at least one basic compound is continuously fed to the first channel of the flow reaction vessel to provide an alkaline aqueous phase;
(B) The organic phase of 1-bromo-3-chloropropane is optionally combined with at least one organic solvent and continuously fed to the second channel of the flow reaction vessel;
(C) The alkaline aqueous phase and the organic phase are continuously mixed at a temperature of at least 70 ° C. in the flow reaction vessel, and the m-chlorophenyl-piperazine (I) is mixed with the 1-bromo-3-chloropropane. The reaction is continuous; and (d) the reaction mixture is continuously removed from the flow reaction vessel and the resulting product N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine ( II) is isolated, which is further mixed with at least one organic solvent;
(I) Continuously supplying an aqueous solution of s-triazolo- [4,3-a] -pyridine-3-one (III) and at least one basic compound to the first channel of the flow reaction vessel;
(Ii) An organic solution of N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine (II) and at least one organic solvent is continuously supplied to the second channel of the flow reaction vessel. To do;
(Iii) In the flow reaction vessel, the alkaline aqueous solution and the organic solution are continuously mixed at a temperature of at least 90 ° C. to continuously mix the s-triazolo- [4,3-a] -pyridine-3-one (III). ) Is continuously reacted with the N- (3-chlorophenyl) -N'-(3-chloropropyl) -piperazine (II); and (iv) the reaction mixture is continuously removed from the flow reaction vessel. , The resulting product trazodone base (IV) is isolated according to reaction scheme 5.

The method of any one of claims 12-15 , further comprising the step (v) of converting the trazodone base (IV) to trazodone hydrochloride (V) and isolating it according to reaction scheme 3.

The method according to any one of claims 15 to 16 , wherein the temperature of the continuous reaction in step (c) is 80 ° C to 100 ° C. The basic compounds in step (a) are sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, ammonium hydroxide, magnesium oxide, hydrazine, hydroxyl. The method according to any one of claims 15 to 17 , which is an inorganic base selected from the group containing amines and mixtures thereof. The basic compound in step (a) comprises trimethylamine, triethylamine, N, N-diisopropylethylamine, triethanolamine, N, N-dimethylethanolamine, quinoline, pyridine, morpholine, N-methylmorpholine, and mixtures thereof. The method according to any one of claims 15 to 18 , which is an organic base selected from the group. The organic solvent in step (b) is a polar aprotic solvent selected from the group comprising N-methylpyrrolidone, dimethylformamide, dimethyl sulfoxide, acetone, ethyl acetate, tetrahydrofuran and acetonitrile, or toluene, benzene and diethyl. The method according to any one of claims 15 to 19 , which is a non-polar solvent selected from the group containing ether.