Process for preparing 4-amino-pyridazines

Abstract

Provided herein is a process for preparing a pyridazine amine compound of formula V, and a process for preparing dichloropyridazine amine compounds of formula IVa, IVb, and mixtures thereof. Further, provided herein are novel dichloropyridazine amine compounds of formula IVa, IVb, and mixtures thereof, wherein the amino group is an ethylamino group.

Claims

1. A process for preparing at least one of (a) at least one of a dichloropyridazine amine compound of formula IVa, a salt thereof, a tautomer thereof, and an N- oxide thereof, (b) at least one of a dichloropyridazine amine compound of formula IVb, a salt thereof, a tautomer thereof, and an N-oxide thereof, and (c) a mixture of (a) and (b) ##STR00054## comprising a step of reacting a trichloropyridazine compound of formula III ##STR00055## with at least one of an amine compound R.sup.1—NH.sub.2 and a salt thereof, wherein R.sup.1 is CH.sub.2CH.sub.3.

2. The process according to claim 1, wherein the process further comprises a step of preparing the trichloropyridazine compound of formula III ##STR00056## by reacting a compound of formula II ##STR00057## with POCI.sub.3.

3. The process according to claim 1, wherein the step of reacting a trichloropyridazine compound of formula III with at least one of an amine compound R.sup.1-N H.sub.2 and a salt thereof, wherein R.sup.1 is CH.sub.2CH.sub.3, is performed at a temperature of from 25° C. to 60° C.

4. At least one of a dichloropyridazine amine compound of formula IVa, a salt thereof, a tautomer thereof, and an N-oxide thereof; ##STR00058## wherein R.sup.1 is CH.sub.2CH.sub.3; or at least one of a dichloropyridazine amine compound of formula IVb, salt thereof, a tautomer thereof, and an N-oxide thereof, ##STR00059## wherein R.sup.1 is CH.sub.2CH.sub.3 or a mixture.

5. A mixture of the at least one of the dichloropyridazine amine compound of formula IVa, the salt thereof, the tautomer thereof, and the N-oxide thereof, and the at least one of the dichloropyridazine amine compound of formula IVb, the salt thereof, the tautomer thereof, and the N-oxide thereof as defined in claim 4.

Description

EXAMPLES

I. Characterization

(1) The characterization can be done by coupled High Performance Liquid Chromatography/mass spectrometry (HPLC/MS), by NMR or by their melting points.

(2) HPLC: Agilent Extend 1.8 μm C18 4.6×100 mm; mobile phase: A: water+0.1% H.sub.3PO.sub.4; B: acetonitrile (MeCN)+0.1% H.sub.3PO.sub.4; gradient: 5-95% A in 10 minutes; 0-10 minutes is 5:95 A:B then gradient from 10-10.1 minutes to 95:5 A:B flow: 1.2 ml/min in 10 minutes at 60° C.

(3) TABLE-US-00001 min A B Flow Pressure (bar) 8 5 95 1.2 400 10 5 95 1.2 400 10.1 95 5 1.2 400 .sup.1H-NMR: The signals are characterized by chemical shift (ppm) vs. tetramethylsilane, by their multiplicity and by their integral (relative number of hydrogen atoms given). The following abbreviations are used to characterize the multiplicity of the signals: m = multiplett, q = quartett, t = triplett, d = doublet and s = singulett.

(4) Abbreviations used are: h for hour(s), min for minute(s) and room temperature for 20-25° C.

II. Preparation Examples

1. Preparation of a Mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine in a One-Pot Procedure Starting from 4,5-dichloro-3-hydroxypyridazine

(5) 200 g of 4,5-dichloro-3-hydroxypyridazine was placed in a reactor at 20° C. under N.sub.2, and POCl.sub.3 (930 g, 5 equiv) was added and the reaction mixture was heated to 100° C. The reaction mixture was further stirred for ˜1 hour until full conversion was achieved. The excess POCl.sub.3 was removed via distillation. The reaction mixture was dosed into 1200 g H.sub.2O controlling the temperature at 30° C. Butyl acetate (1200 g) was added and the biphasic mixture was stirred for 30 minutes at 30° C. and then the phases were separated. Another portion of butyl acetate (400 g) was used to wash the aqueous phase. The combined organic phases were washed with 10% HCl and then H.sub.2O.

(6) To the mixture of trichloropyridazine in butyl acetate was added a solution of ethylamine in water with a concentration of 70 wt.-% of ethylamine based on the total weight of the solution (234 g, 3 equiv) at 35° C. The reaction was held at 45° C. for 3 hours (or until full conversion is observed). The phases were separated at 40° C. and the organic phase was washed once with H.sub.2O. The combined aqueous phases were once extracted with butyl acetate. Butyl acetate from the combined organic phases was distilled (15 mbar, 35° C.) to concentrate the reaction mixture. During this process, the product precipitated from solution. The reaction mixture was cooled to 10° C. and the product was filtered off. The mother liquor was next concentrated and the crude material was recrystallized from MTBE to isolate the remainder of the product.

2. Preparation of 4-Ethylaminopyridazine

(7) 600 g (3.09 mol) of a mixture of 3,4-dichloro-5-ethylaminopyridazine and 3,5-dichloro-4-ethylaminopyridazine was dissolved in EtOH (3.5 liters). 15 g (0.01 mol) of 10% Pd/C was added and the pressure reactor was purged with nitrogen. The pressure reactor was pressurized to 0.2 bar with H.sub.2 and heated to 35° C. As the reaction is exothermic, the temperature was controlled at 55° C. for 4 hours. Afterwards, the pressure was released and the reactor was purged with N.sub.2. The reaction mixture was filtered at room temperature to remove the catalyst. The catalyst can be reused in the next batch without purification.

(8) In a second reactor, a mixture of K.sub.2CO.sub.3 (1 kg) and 1 liter of EtOH was prepared. The reaction mixture was dosed into the potassium carbonate solution over 60 minutes and the temperature was controlled at 20-25° C. The reaction mixture was further stirred for 3 hours. The salts produced in the process were filtered off. A portion of solvent from the reaction mixture was distilled off and MTBE was added to precipitate out the pure ethylaminopyridazine (354 g, 91% purity, 85% yield).