SU1325045A1 - Method of producing 3,5-dichloropyridine derivatives - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular to the preparation of 3,5-dichloro-2-hydroxy-6-methylpyridine (1a) or 2,3,5-trichloro-6-methyl (16), or 2,3, 5-trichloro-6-ethylpyridine (IB) used in the synthesis of biologically active substances. Increasing the yield and expanding the range of target substances is achieved by using other source reagents, processed and certain conditions. Synthesis of lead is carried out from trichloroacetonitrile (AH) and vinylalkyl ketone (molar ratio 1-1.5: 1) in the presence of CuCl, mainly in the medium of benzene, hexane or an excess of AH, at 80-90 ° C (6-7 h The solvent is then distilled off, and a stream of HC1 is passed into the dimethylformamide medium (preferably in the presence of P205 or POCl3, taken in an amount of 1-1.2 mol per 1 mol of oxoalkoic acid nitrile). To obtain compound 1a, chlorination is carried out for 45–60 min, and dp (1b) or (1c) is 10–15 min. Exit, so pl. : (Ta) 93%, 218 ° C;

Description

The invention relates to a process for the preparation of 3,5-dichloropyridine derivatives of the general formula

C1 R

C1

P,

N

Where

X R

C1 or OH;

low alkyl, which can be used in the synthesis of biologically active substances.

The aim of the invention is to noBbmie the yield of 3,5-dichloropyridine derivatives and expand their range by reacting trichloroacetonitrile with vinylalkyl ketone in the presence of copper monochloride followed by cyclization of the resulting oxoalkanoic acid nitrile in dimethylformamide in current hydrogen chloride.

Example 1. Synthesis of nitrile 2,2, 4-trichloro-5-oxohexanoic acid (Na).

A mixture of 14.4 g (0.1 M) trichloroacetonitrile, 7.0 g (0.1 M) methyl vinyl ketone (1: 1 molar ratio), 1 g (0.01 M) CuCl in 100 ml abs. . The benzene is heated in a stainless steel autoclave at 90 ° C for 7 hours. At the end of the reaction, the solvent is distilled off in vacuo, and the residue is distilled. 16.7 g (78%) of compound (Ha) are obtained.

PR and M e p 2. Synthesis of nitrile 2,2, 4-trichloro-5-oxoheptanoic acid (116).

A mixture of 18.7 g (0.13 M) of trichloroacetonitrile, 8.4 g (0.1 M) of ethyl vinyl keto (molar ratio 1.3: 1) and 1 g (0.01 M) of CuCl per 100 ml of n-hexane are placed in a glass, which is cooled, sealed and then heated at 85 ° C for 6 hours. Upon completion of the reaction, excess trichloroacetonitrile is distilled off, the residue is rectified and 19.0 g (83%) of the compound (116 ).

PRI and MER 3. Synthesis of nitrile 2,2, 4 trichloro-5-oxooctanoic acid (Iv).

A mixture of 21.6 g (0.15 M) of trichloroacetonitrile, 9.8 g (0.1 M) of propyl vinyl ketone (molar ratio 1.5: 1) and 0.8 g (0.008 M) of CuCl are placed in the glass vial, which is cooled, is sealed and heated at 80 ° C for 6.5 hours. After the completion of the reaction, the excess trichloroacetonyl alcohol is distilled off and the residue is distilled. 19.4 g (80%) of the compound (Iv) are obtained.

Physico-chemical constants and data analysis of compounds (Ea-in) are given in table.1.

PR and ME 4. Synthesis of 3,5-dichloro-2-hydroxy-6-methylpyridine (Ta).

A (Pa) 3.1 g (0.0145 M) in 30 ml of dimethylformamide (DMF) is placed in a flask equipped with an air cooler with a calcium chloride tube, a capillary for introducing gas and a thermometer and slowly passing a HC1 current through the solution for 45 min. . The temperature spontaneously rises to 105 ° C. After cooling, the reaction mixture is poured into ice water,

The precipitated Belgian precipitate is removed, washed, and dried to obtain (1a) 2.4 g (93%), m.p. 218 C.

PRI and MER 5. Synthesis of 2,3,5-trn-chloro-6-methylpyridine (16).

Into the device described in Example 4, (Na) 1.4 g (0.0065 M) in 10 ml of DMF are placed and HC1 is passed for 15 minutes. The temperature at the same time reaches 107 ° C. After cooling, the reaction mass is poured into ice water, the precipitate is filtered off and dried, and (16) 1.1 g (86%) are obtained, m.p.

71 ° C.

PRI and MER 6. 5 POClj

0

five

0

five

Synthesis (16) at priV the device described in example 4 is placed (On) 1.0 g (0.0047 M), 0.72 g (0.0047 M) POClj (ratio of Na: POC1 1: 1) in 15 ml of DMF and let the flow of dry HC1 for 10 minutes The temperature reaches 118 ° C. Upon completion of the reaction, the reaction mass is poured into ice water. The residue is filtered, dried, and receive (16) 0.85 g (92%), so pl. 71 ° C.

PRI and MER 7. Synthesis of 2,3,5-trichloro-6-ethylpyridine (1 g).

In the device described in example 4, placed (Nb) 2 g (0,0088 M) 1.49 g

(0.01 M)

(Ilf: P ratio, 0

1: 1.2) in 20 ml of DMF and a current of dry HC1 is passed through the solution for 12 minutes. The temperature at the same time reaches 121 ° C. At the end of the reaction, the reaction mixture is poured into water, extracted with 2x50 ml of ether, an ethereal solution of CaCl suptane, the ether is evaporated and the residue is rectified. Get

(Ir) 1.63 g (88%), bp 58-59 c /. 1.5 mmHg

Example 8: Synthesis (16) without prior isolation of oxonitrile (Na).

Preparation of oxonitrile (Na) is carried out analogously to example 1. After distilling off the solvent, 50 ml of diethyl ether are added to the residue, the precipitated precipitate is filtered off, the ether is evaporated, 20 g of yellow oil are obtained. The resulting oil is dissolved in 200 ml of DMF and HCl current is passed for 15 minutes. After cooling, the reaction mixture is poured into ice-water, the precipitate is filtered off, (16) 14.8 g (75%) are obtained, m.p. 69-70 ° C.

Compounds (1c, d, e) are prepared analogously.

Data on the yields and melting or boiling points of the compounds (I a-e), as well as their PMR spectra and elemental analysis data are given in Table 2.

Claims (5)

Thus, the proposed method allows increasing the yield of 3,5-dichloropyridine derivatives by 35-40% and expanding their range. Invention Formula t. The method of producing 3,5-dichlopyridine derivatives of the general formula gh p-x and 1 l where X is C1 or OH; R is lower alkyl, characterized in that, in order to increase the yield and expand the range of target products, trichloroacetonitrile is reacted with vinyl allyl ketone in a molar ratio of 1-1.5: 1 in the presence of copper monochloride in an organic solvent at 80-90 ° for 6-7 h, the solvent is distilled off, a stream of hydrogen chloride in a mixture of dimethylformamide is passed into the resulting oxoalkanoic acid nitrile. 2. Method pop. 1, characterized by the fact that benzene, hexane or an excess of trichloroacetonitrile are used as an organic solvent. 3. Method POP.1, differing from the fact that at X - C1 time is 10-15 minutes. 4. Method pop. 1, which differs from the fact that at X-OH the passing time of hydrogen chloride is 45-60 minutes. 5. The method according to Clause 3, Lt. H and W - W and also so that the transmission of hydrogen chloride is carried out in the presence of phosphoric anhydride or phosphorus oxychloride, taken in an amount of 1-1.2 mol per 1 mol of oxoalkanoic acid nitrile. R I at g S g yy chg sh about m g " J.H and | H  ner u u GSO 8;: st b 5 s oh " " : jf g " ate g S "G " m " TO J ABOUT and Jg j about at J S four p l five - 3 9 about  t Jl "" five Js CISS C o g; S .% $ ° §