RU2537848C1 - Method of obtaining 2-chloro-5-hydroxymethylpyridine - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of obtaining 2-chloro-5-hydroxymethylpyridine, which includes activation of carboxyl group of 6-chloronicotinic acid and reduction of 6-chloronicotinoylchloride. Method is characterised by the fact that reaction of carboxyl group activation is carried out with cyanuric chloride at temperature of reaction mixture 20°C in presence of N-methylmorpholine, with application of dimethoxyethane as solvent, and reduction of activated ester is realised with sodium borohydride solution in water for 10 minutes. Obtained compound is applied in organic synthesis of biologically active substances, modelling activity of proteinkinases and yohimbine alkaloids.

EFFECT: obtaining 2-chloro-5-hydroxymethylpyridine with high output, increased safety of process, activation of carboxyl group is realised at low temperature of reaction mixture, with reducing time for activated ester reduction to 10 minutes.

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Description

The invention relates to the field of organic chemistry, in particular to a method for producing 2-chloro-5-hydroxymethylpyridine.

2-Chloro-5-hydroxymethylpyridine is used in the organic synthesis of biologically active substances. In particular, for the synthesis of drugs modulating the activity of protein kinases [1], and iohimban alkaloids [2].

Several methods are known for preparing 2-chloro-5-hydroxymethylpyridine from commercially available 6-chloronicotinic acid.

A known method of producing 2-chloro-5-hydroxymethylpyridine by reducing 6-chloronicotinic acid in a solution of dioxane with a 1M solution of boron hydride in tetrahydrofuran at a reaction temperature of 75 ° C for 2.5 hours. The reaction is carried out according to scheme 1. The yield of the target compound is 54% of theoretical [1].

The disadvantages of this method are the use of a fire-hazardous solution of boron hydride in tetrahydrofuran, the elevated temperature of the reaction mixture, and the low yield of the target 2-chloro-5-hydroxymethylpyridine.

Closest to the proposed method for producing 2-chloro-5-hydroxymethylpyridine is the method presented in scheme 2 [2, 3].

In this method, the target substance is obtained by sequentially carrying out two reactions, including activation of the carboxyl group of 6-chloronicotinic acid with phosphorus pentachloride and phosphorus oxychloride at a temperature of the reaction mixture of 100 ° C for 1 hour and the reduction of 6-chloronicotinoyl chloride with a solution of sodium borohydride in water at a temperature of the reaction mixture 20 ° C for 1 hour [2]. The total yield of the target compound is 88% of theoretical.

The disadvantage of this method is the increased temperature of the activation reaction, the long recovery time of 6-chloronicotinoyl chloride, as well as the use of phosphorus oxychloride during the activation of the carboxyl group, which is an extremely hazardous substance (MPC 0.05 mg / m ³ , hazard class 1) [4] .

The objective of the invention is to increase the safety of the process and optimize the conditions for obtaining the target substance: lowering the temperature of the reaction medium upon activation of the carboxyl group and reducing the recovery time of the activated ester.

The problem is solved due to the fact that the activation reaction of the carboxyl group is carried out by cyanuric chloride at a temperature of the reaction mixture of 20 ° C in the presence of N-methylmorpholine, dimethoxyethane is used as a solvent, and the recovery of the activated ester is carried out within 10 minutes.

The technical result achieved in the claimed invention is expressed in the use of less hazardous for human health cyanuric chloride (MPC 0.1 mg / m, hazard class 2), lowering the temperature of the reaction medium to 20 ° C upon activation of the carboxyl group and reducing the recovery time of the activated ester up to 10 minutes. The yield of the target compound according to the claimed method is at least 87% of theoretical.

The difference of the proposed method, shown in Scheme 3, is that the activation of the carboxyl group is carried out by cyanuric chloride in the presence of N-methylmorpholine at a temperature of the reaction mixture of 20 ° C, dimethoxyethane is used as a solvent, and the activation of the activated ester is carried out within 10 minutes.

The purity and structure of the obtained compound was confirmed by proton magnetic resonance methods using a Varian model FT-80A NMR spectrometer, chromatography-mass spectrometry using an Agilent 6890N / 5973N HMS.

For a better understanding of the essence of the present invention, the following example.

Example

In a flask equipped with a stirrer, place a solution containing 0.92 g (5 mmol) of cyanuric chloride in 30 ml of dimethoxyethane. With stirring, 0.55 ml (0.55 mol) of N-methylmorpholine is added. To the resulting suspension was added a solution containing 0.78 g (5 mmol) of 6-chloronicotinic acid in 20 ml of dimethoxyethane. The reaction mixture was stirred at 20 ° C for 2 hours. The reaction mixture is filtered and added with stirring to a solution cooled in an ice bath containing 0.28 g (7.5 mmol) of sodium borohydride and 15 ml of water. It is kept for 10 minutes, 20 ml of diethyl ether are added and acidified with 10% potassium hydrogen sulfate solution. The organic layer was separated, the aqueous was extracted 5 times with 15 ml of diethyl ether. The organic layer was combined with ether extracts, washed with 10% sodium carbonate in water, saturated sodium chloride in water, dried over sodium sulfate, filtered, the solvent was evaporated, the residue was distilled, and the boiling fraction was collected at a temperature of 120 ° C and a pressure of 0.4 mm Hg Obtain 0.62 g of 2-chloro-5-hydroxymethylpyridine with a yield of 87% of theoretical and T _pl = 39-40 ° C.

¹ H NMR Spectrum ((CD ₃ ) ₂ SO, δ, ppm): 8.33 (1H, d, J 1.9 Hz), 7.77 (1H, dd, J ₁ 8.2, J ₂ 2.7 Hz), 5.35 (1H, t, J 5.0 Hz), 4.52 (2H, d, J 5.0 Hz).

Mass spectrum, m / z (I _Rel ,%): 143 (70.7) [M ⁺ ], 78 (100), 114 (79.4), 142 (61.1), 51 (59.2) 50 (36.2), 53 (32.8), 52 (29.6), 108 (25.5), 116 (23.5).

Thus, the proposed method for producing 2-chloro-5-hydroxymethylpyridine can increase the safety of the process, reduce the activation temperature of the carboxyl group to 20 ° C and reduce the recovery time of complex activated ether to 10 minutes.

Literature

1. Pat. US 2002103203 (A1), IPC 7 A61K 31/519. Amide compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use [Text] // S.L. Bender, D. Bhumralkar, M.R. Collins et al .; Applicant and patent holder Shanks & Herbert TransPotomac Plaza, US-No. 09/76306 01/19/2001. - 203 p.

2. Ziegler F.E., Sweeny J.G. Synthetic studies related to the yohimbine alkaloids // Journal of Organic Chemistry - 1969. - V.34. - No. 11. P.3545-3548.

3. Ziegler F.E., Sweeny J.G. A Synthesis of dihydrocoryantheol and 3-epi-dihydrocoryantheol // Tetrahedron Lett. - 1969. - No. 14. - P.1097-1100.

4. Harmful substances in industry. T.III. - L .: Chemistry, 1977. - S.134-135.

Claims (1)

A method of producing 2-chloro-5-hydroxymethylpyridine by reacting 6-chloronicotinic acid with an activator of a carboxyl group and then reducing the resulting compound with a solution of sodium borohydride in water, characterized in that the activation reaction of the carboxyl group is carried out with cyanuric chloride at a reaction temperature of 20 ° C in the presence of N- methylmorpholine, dimethoxyethane is used as the solvent, and the recovery of the activated activated ester is carried out within 10 minutes.