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DESCRIPTION CN109761888A
10 A kind of synthetic method of 4-chloromethylpyridine hydrochloride

[0001]
14 technical field

[0002]
18 The invention belongs to the field of organic synthesis, and in particular relates to a synthesis method of 4-
chloromethylpyridine hydrochloride.

[0003]
23 Background technique

[0004]
27 Chloromethylpyridine hydrochloride is an important chemical raw material for various pesticides,
pharmaceutical intermediates, insecticides, herbicides, and fungicides.
29 The current production method adopts pyridine to directly add methyl groups, uses precious metal chemical

raw materials such as methyl lithium, and then passes chlorine gas to carry out chlorination reaction.
31 After pyridine chloromethylation, it is easier to connect other groups to synthesize chemical raw material

intermediates and raw materials with high added value.

33 However, the use of methyllithium as a raw material has high cost and price pressures, and it is troublesome to

recover precious metals. Dimethyl sulfate is highly toxic and dangerous to operators.

[0005]
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38 Contents of the invention

[0006]
42 The purpose of the present invention is to overcome the shortcomings of high cost and high toxicity of
reagents in the prior art, and provide a synthetic method of 4-chloromethylpyridine hydrochloride with low
cost, high yield and mild reaction conditions.

[0007]
48 A kind of synthetic method of 4-chloromethylpyridine hydrochloride provided by the invention, preparation
method comprises the following steps:

[0008]
53 (1) Use 4-picoline as raw material, use water as solvent, and oxidize it to 4-pyridinecarboxylic acid with
potassium permanganate, wherein the molar ratio of 4-picoline to potassium permanganate is 1:2.1 -2.3, the
oxidation temperature is 75-80°C, heat for 35 minutes, adjust the reaction solution to acidity after the
reaction is complete, then cool and filter to obtain 4-pyridinecarboxylic acid;

[0009]
60 (2) 4-picolinic acid and methanol generate 4-picolinic acid methyl ester under acidic conditions, wherein the
mol ratio of 4-picolinic acid and methanol is 1:1.3;

[0010]
65 (3) reduction of 4-pyridinecarboxylic acid methyl ester is 4-pyridinemethanol;

[0011]
69 (4) 4-pyridinemethanol is reacted with thionyl chloride to obtain the target product 4-chloromethylpyridine
hydrochloride, and the molar ratio of 4-pyridinemethanol to thionyl chloride is 1:1.1-1.3.

[0012]
74 Further, in the step (1), potassium permanganate is added in batches under the condition of 80°C.

[0013]
78 Further, the pH adjustment in the step (1) is to adjust the pH value of the reaction solution to 3-4 with 2 mol/l
hydrochloric acid.

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[0014]
83 Further, the cooling and filtering temperature in the step (1) is 25°C.

[0015]
87 Further, the reducing agent adopted in the step (3) is sodium borohydride, the molar ratio of methyl 4-
pyridinecarboxylate to sodium borohydride is 1:4-5, and the reduction reaction uses Lewis acid as a catalyst .

[0016]
92 Further, the Lewis acid is aluminum trichloride.

[0017]
96 Further, the solvent used in the reduction reaction is a mixed solvent formed by mixing THF and toluene at a
volume ratio of 1:1.

[0018]
101 The reaction equation of the inventive method is:

[0020]
105 The beneficial effects of adopting the technical scheme of the invention are: few reaction steps, low cost, high
purity, high yield and safe operation, and the method of the invention is suitable for large-scale industrial
production.

[0021]
111 Detailed ways

[0022]
115 In order to further illustrate the present invention, some examples are given below.
116 These examples are entirely illustrative, and they are only used to specifically describe the present invention,

and should not be construed as limiting the present invention.

[0023]
121 Example 1

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[0024]
125 (1) Add 4-picoline (18.6g, 0.2mol) and 150ml of water into a 250ml flask, heat to 80°C, add potassium
permanganate (66.36g, 0.42mol) in batches, and maintain the temperature at 75- Heating and stirring at
80°C for 35 minutes, followed by thin-layer chromatography analysis, after the reaction is complete, adjust
the pH value of the reaction solution to 3 with 2mol/l hydrochloric acid, cool the temperature of the reaction
solution to 25°C and suction filter to obtain 4-pyridinecarboxylic acid.

[0025]
133 (2) 4-pyridinecarboxylic acid and methanol (12g, 0.26mol) were reacted with concentrated sulfuric acid to
generate 4-picolinic acid methyl ester.

[0026]
138 (3) Methyl 4-pyridinecarboxylate was dissolved in a solvent mixed with 75ml THF and 75ml toluene, and
sodium borohydride (30.24g, 0.8mol) and aluminum trichloride were added in batches at 0-5°C, and the
reaction continued for 3 -4h, TLC follow-up analysis until the reaction is complete to obtain 4-
pyridinemethanol.

[0027]
145 (4) 4-pyridinemethanol is reacted with thionyl chloride (26.18g, 0.22mol) in methanol solution, followed by
thin-layer chromatography analysis, and the reaction is stopped after all the reactions are converted into 4-
chloromethylpyridine hydrochloride, After suction filtration, 26.2 g of the product was obtained with a yield
of 80% (molar yield).

[0028]
152 Example 2

[0029]
156 (1) Add 4-picoline (18.6g, 0.2mol) and 150ml of water into a 250ml flask, heat to 80°C, add potassium
permanganate (69.5g, 0.44mol) in batches, and maintain the temperature at 75- Heat and stir at 80°C for
35min, track and analyze by thin layer chromatography, adjust the pH value of the reaction solution to 4 with
2mol/l hydrochloric acid after the reaction is complete, cool the temperature of the reaction solution to
25°C and suction filter to obtain 4-pyridinecarboxylic acid.

[0030]
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164 (2) 4-pyridinecarboxylic acid and methanol (12g, 0.26mol) were reacted with concentrated sulfuric acid to
generate 4-picolinic acid methyl ester.

[0031]
169 (3) Methyl 4-pyridinecarboxylate was dissolved in a solvent mixed with 75ml THF and 75ml toluene, and
sodium borohydride (34g, 0.9mol) and aluminum trichloride were added in batches at 0-5°C, and the
reaction was continued 3- 4h, TLC follow-up analysis until the reaction is complete to get 4-
pyridinemethanol.

[0032]
176 (4) 4-pyridinemethanol is reacted with thionyl chloride (26.18g, 0.22mol) in methanol solution, followed by
thin-layer chromatography analysis, and the reaction is stopped after all the reactions are converted into 4-
chloromethylpyridine hydrochloride, After suction filtration, 26.9 g of the product was obtained with a yield
of 82% (molar yield).

[0033]
183 Example 3

[0034]
187 (1) Add 4-picoline (18.6g, 0.2mol) and 150ml of water into a 250ml flask, heat to 80°C, add potassium
permanganate (72.7g, 0.46mol) in batches, and maintain the temperature at 75- Heat and stir at 80°C for
35min, track and analyze by thin layer chromatography, adjust the pH value of the reaction solution to 4 with
2mol/l hydrochloric acid after the reaction is complete, cool the temperature of the reaction solution to
25°C and suction filter to obtain 4-pyridinecarboxylic acid.

[0035]
195 (2) 4-pyridinecarboxylic acid and methanol (12g, 0.26mol) were reacted with concentrated sulfuric acid to
generate 4-picolinic acid methyl ester.

[0036]
200 (3) Methyl 4-pyridinecarboxylate was dissolved in a solvent mixed with 75ml THF and 75ml toluene, and
sodium borohydride (37.8g, 1.0mol) and aluminum trichloride were added in batches at 0-5°C, and the
reaction was continued for 3 -4h, TLC follow-up analysis until the reaction is complete to obtain 4-
pyridinemethanol.

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[0037]
207 (4) 4-pyridinemethanol is reacted with thionyl chloride (26.18g, 0.22mol) in methanol solution, followed by
thin-layer chromatography analysis, and the reaction is stopped after all the reactions are converted into 4-
chloromethylpyridine hydrochloride, After suction filtration, 25.6 g of the product was obtained with a yield
of 78% (molar yield).

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