Process for the preparation of 3-(3-chloro-1h-pyrazol-1-yl)pyridine
A pyridine and pyrazole technology, which is applied in the directions of botanical equipment and methods, pharmaceutical formulations, and medical preparations containing active ingredients, etc., can solve the problems of difficult preparation, difficult separation of pure substances in products, and low yields.
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[0020] The present invention provides an improved process for the preparation of 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) by cyclizing 3-hydrazinopyridine dihydrochloride with acrylonitrile to give 1- (Pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a), 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a) by oxidation , and the amino group is converted to a chloro group by the Sandmeyer reaction.
[0021] In the first step, the alkali metal (C 1 -C 4 ) In the presence of alkoxide, 3-hydrazinopyridine·dihydrochloride was treated with acrylonitrile in (C 1 -C 4 ) fatty alcohol to give 1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine. Although stoichiometric amounts of 3-hydrazinopyridine·dihydrochloride and acrylonitrile are required, about 1.5-fold to about 2-fold excess of acrylonitrile is often routinely used. In alkali metal (C 1 -C 4 ) in the presence of an alkoxide base. From about 2-fold to about 5-fold excess of base is often routinely used. at (C 1 -C 4 ) in fatty alcohol...
Embodiment
[0029] 1. Preparation of 1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a)
[0030]
[0031] A four-neck round bottom flask (250 mL) was charged with sodium ethoxide (21 wt% in ethanol, 32 mL). Addition of 3-hydrazinopyridine·dihydrochloride (5.00 g, 27.5 mmol) resulted in an exotherm from 20°C to 58°C. The mixture was allowed to cool to 20°C and acrylonitrile (2.91 g, 54.9 mmol) was added. The reaction was heated at 60°C for 5 hours and cooled to 20°C. Excess sodium ethoxide was quenched with hydrochloric acid (4M in 1,4-dioxane, 6.88 mL, 27.5 mmol) at 1 H NMR (400MHz, CDCl 3 )δ8.24(dd, J=2.8,0.8Hz,1H), 8.01(dd,J=4.6,1.4Hz,1H), 7.22(ddd,J=8.4,2.8,1.5Hz,1H), 7.12(ddd ,J=8.4,4.6,0.8Hz,1H), 4.20(s,2H), 3.70(t,J=9.3Hz,2H), 2.92(t,J=9.3Hz,2H); 13 C NMR (101MHz, CDCl 3 )δ154.23, 144.78, 139.22, 135.08, 123.44, 119.44, 49.23, 32.74; ESIMS m / z 163 ([M+H] + ).
[0032] 2. Preparation of 3-(3-amino-1H-pyrazol-1-yl)pyridine (8a)
[0033]
[0034] A three-neck round ...
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