CN104387301B - The synthetic method of the fluoro-4-Methyl benzenesulfonyl of a kind of 2-methyl isonitrile - Google Patents

Abstract

The invention discloses the synthetic method of the fluoro-4-Methyl benzenesulfonyl of a kind of 2-methyl isonitrile: it is raw material that the present invention adopts SPTS, make tosyl methyl isonitrile through similar Mannich condensation and dehydration of amide reaction, and add wherein hydrofluoric acid aqueous solution and Ni-CO catalyst, under nitrogen protection, it is fully reacted, through suction filtration, washing, dry to obtain the fluoro-4-Methyl benzenesulfonyl of light yellow crystal 2-methyl isonitrile, productive rate reaches more than 92%, purity is 99.8%, this technique has reaction raw materials and is easy to get, mild condition, product yield is high, be applicable to the advantages such as suitability for industrialized production.

Description

A kind of synthetic method of 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile

technical field

The invention is a compound synthesis method, a synthesis method of 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile.

Background technique

Methylbenzenesulfonylmethyl isonitrile is widely used in organic synthesis, and it is an important intermediate in the synthesis of five-membered nitrogen-containing heterocyclic compounds such as imidazole, thiazole, oxazole, triazole, etc., because methyl In addition to the electrophilic center and nucleophilic center of the isonitrile group, benzenesulfonylmethyl isonitrile also has a good nucleophobic leaving group—Tos, which can be used to synthesize a variety of products. For example, it has a wide range of applications in pharmaceuticals, pesticides and other fine organic synthesis.

Synthesize 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile with Leusen’s method. Traditionally, ethers, mainly 1,2-dimethoxyethane, are used as solvents, but the price of this solvent in the market is relatively high Expensive, and not recycled after reaction. When using THF or dioxane, the yields are not reduced, but they have the same problem, that is, because they are mixed with water, generally do not recycle, increase the cost and pollute the environment when preparing in large quantities, according to the characteristics of the reaction, consider It is replaced by cheap or easy-to-recover solvents. Therefore, the present invention uses chlorinated alkanes as solvents, and under an optimized environment, better yields are obtained.

Contents of the invention

The invention provides a method for synthesizing 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile with simple reaction conditions, high yield, low cost and less environmental pollution.

In order to achieve the above object, the synthetic route of 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile of the present invention is:

The synthetic process of 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile involved in the present invention comprises the following steps:

1. Synthesis of p-toluenesulfonylmethylformamide

(1) Put 92.1g of sodium p-toluenesulfinate, 75.2g of paraformaldehyde, and 113.1g of formamide with a mass fraction of 97% in a 500mL four-neck flask with mechanical stirring, reflux condenser and thermometer, and stir Dropping 157.2g mass fraction is 88% formic acid;

(2) After the dropwise addition, raise the temperature to 90°C, keep it warm for 2 hours, then cool the reaction solution to below 50°C, add 100mL of cold water, stir, and cool in an ice-salt bath to below 0°C;

(3) Filtrate, rinse the filter cake with 20 mL of cold water, and vacuum-dry to obtain white crystals.

2. Synthesis of p-methylsulfonylmethylisonitrile

(1) Put 42.8g of p-toluenesulfonylmethylformamide, 300mL of dichloromethane, and 71.2g of triethylamine into a 1000mL three-neck flask in sequence, stir to dissolve, and cool to -4—-2°C with an ice-salt bath;

(2) Add dropwise a mixed solution of 21mL phosphorus oxychloride and 21mL dichloromethane into the dropping funnel, keep the temperature between -4-0°C during the dropping process, and drop it in about 2-3 hours;

(3) Reaction for 1 hour after dripping, slowly add 50mL of water, continue to stir for 30min, stand for stratification, add 300mL of 7% sodium hydroxide solution and stir to adjust to pH=14, stand to separate the triethylamine layer, and After drying, reclaiming triethylamine can be directly used for reaction;

(4) Separation, the organic layer was washed once with 60 mL of 10% sodium carbonate, the organic layer was separated and dried with anhydrous sodium sulfate, first normal pressure on a water bath, and then vacuum distillation to recover dichloromethane until crystallization appeared on the edge , and then slowly add petroleum ether 2.5 times the volume of the content, let stand for more than 30min, filter with suction, dry, and weigh 40.6g of light yellow-brown crystals.

3, the synthetic method of 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile

(1) Under the protection of nitrogen, put 35.2g of p-methylsulfonylmethyl isonitrile, 30mL of hydrofluoric acid aqueous solution and 0.23g of Ni-Co into the reaction kettle, stir and dissolve for 2-3h, then use Cool in an ice-salt bath to below 5°C; (2) Separation, wash the organic layer once with 100 mL of water, dry with anhydrous sodium sulfate, filter with suction, weigh, and calculate the yield and detect its purity.

specific implementation plan

The synthetic process of a kind of 2-fluoro-4-methylbenzenesulfonylmethyl isonitrile that the present invention relates to comprises the following steps:

Put 92.1g of sodium p-toluenesulfinate, 75.2g of paraformaldehyde, and 113.1g of formamide with a mass fraction of 97% in a 500mL four-neck flask with mechanical stirring, reflux condenser, and thermometer, and add 157.2 g of formamide dropwise under stirring. g of formic acid with a mass fraction of 88%; after the dropwise addition, raise the temperature to 90°C, keep it warm for 2 hours, then cool the reaction solution to below 50°C, add 100mL of cold water, stir, and cool in an ice-salt bath to below 0°C; filter, filter The cake was rinsed with 20 mL of cold water and dried in vacuum to obtain white crystals. Put 42.8g of p-toluenesulfonylmethylformamide, 300mL of dichloromethane, and 71.2g of triethylamine into a 1000mL three-necked bottle in turn, and stir to dissolve , cooled to -4—-2°C with an ice-salt bath; add dropwise a mixed solution of 21mL phosphorus oxychloride and 21mL dichloromethane into the dropping funnel, and keep the temperature between -4—0°C during the dropping process After dripping, react for 1 hour, slowly add 50mL of water, continue to stir for 30min, let stand for stratification, add 300mL of 7% sodium hydroxide solution, stir to adjust to pH = 14, stand to separate triethyl After drying the amine layer, the recovered triethylamine can be directly used in the reaction; liquid separation, the organic layer was washed once with 60mL of 10% sodium carbonate water, and the organic layer was separated and dried with anhydrous sodium sulfate, and firstly placed in a water bath under normal pressure , and then dichloromethane was recovered by distillation under reduced pressure until crystallization appeared on the edge, then slowly add petroleum ether 2.5 times the volume of the content, let it stand for more than 30min, filter with suction, dry, and weigh 40.6g of light yellow-brown crystals. Under the protection of nitrogen, put 35.2g of p-methylsulfonylmethyl isonitrile, 30mL of hydrofluoric acid aqueous solution and 0.23g of Ni-Co into the reaction kettle, stir and dissolve for 2-3h, then use ice salt bath Cool to below 5°C; separate the liquids, wash the organic layer once with 100 mL of water, dry over anhydrous sodium sulfate, filter with suction, weigh, and calculate its yield and purity.

Example 1

Put 92.1g of sodium p-toluenesulfinate, 75.2g of paraformaldehyde, and 113.1g of formamide with a mass fraction of 97% in a 500mL four-neck flask with mechanical stirring, reflux condenser, and thermometer, and add 157.2 g of formamide dropwise under stirring. g of formic acid with a mass fraction of 88%; after the dropwise addition, raise the temperature to 90°C, keep it warm for 2 hours, then cool the reaction solution to below 50°C, add 100mL of cold water, stir, and cool in an ice-salt bath to below 0°C; filter, filter The cake was rinsed with 20 mL of cold water and dried in vacuum to obtain white crystals. Put 42.8g of p-toluenesulfonylmethylformamide, 300mL of dichloromethane, and 71.2g of triethylamine into a 1000mL three-necked bottle in turn, and stir to dissolve , cooled to -4°C with an ice-salt bath; add dropwise a mixed solution of 21mL phosphorus oxychloride and 21mL dichloromethane into the dropping funnel, keep the temperature between -4°C during the dropping process, and drop it in about 2 hours ;React for 1 hour after dripping, slowly add 50mL of water, continue to stir for 30min, let it stand for stratification, add 300mL of 7% sodium hydroxide solution and stir to adjust to pH=14, let it stand to separate the triethylamine layer, and dry it , the recovery of triethylamine can be directly used in the reaction; liquid separation, the organic layer was washed once with 60mL of 10% sodium carbonate, and the organic layer was separated and dried with anhydrous sodium sulfate. Chloromethane until crystals appear on the edge, then slowly add petroleum ether 2.5 times the volume of the content, let stand for more than 30min, filter with suction, dry, and weigh 40.6g of light yellow-brown crystals. Under the protection of nitrogen, put 35.2g of p-methylsulfonylmethyl isonitrile, 30mL of hydrofluoric acid aqueous solution and 0.23g of Ni-Co into the reaction kettle, stir and dissolve for 2-3h, then use ice salt bath Cool to below 5°C; separate liquid, wash the organic layer once with 100mL water, dry with anhydrous sodium sulfate, suction filter, weigh, the yield is more than 92%, and the purity is 99.8%.

Example 2

Put 92.1g of sodium p-toluenesulfinate, 75.2g of paraformaldehyde, and 113.1g of formamide with a mass fraction of 97% in a 500mL four-neck flask with mechanical stirring, reflux condenser, and thermometer, and add 157.2 g of formamide dropwise under stirring. g of formic acid with a mass fraction of 88%; after the dropwise addition, raise the temperature to 90°C, keep it warm for 2 hours, then cool the reaction solution to below 50°C, add 100mL of cold water, stir, and cool in an ice-salt bath to below 0°C; filter, filter The cake was rinsed with 20 mL of cold water and dried in vacuum to obtain white crystals. Put 42.8g of p-toluenesulfonylmethylformamide, 300mL of dichloromethane, and 71.2g of triethylamine into a 1000mL three-necked bottle in turn, and stir to dissolve , cooled to -3°C with an ice-salt bath; add dropwise a mixed solution of 21mL phosphorus oxychloride and 21mL dichloromethane into the dropping funnel, and keep the temperature between -2°C during the dropping process, about 2.5h Finish; react for 1 hour after dripping, slowly add 50mL of water, continue to stir for 30min, stand for stratification, add 300mL of 7% sodium hydroxide solution, stir to adjust to pH = 14, stand to separate the triethylamine layer, and dry it Finally, the recovered triethylamine can be directly used in the reaction; liquid separation, the organic layer was washed once with 60mL of 10% sodium carbonate, and the organic layer was separated and dried with anhydrous sodium sulfate. Dichloromethane, until crystals appear on the edge, then slowly add petroleum ether 2.5 times the volume of the content, let stand for more than 30min, filter with suction, dry, and weigh to obtain 40.6g of light yellow-brown crystals. Under the protection of nitrogen, put 35.2g of p-methylsulfonylmethyl isonitrile, 30mL of hydrofluoric acid aqueous solution and 0.23g of Ni-Co into the reaction kettle, stir and dissolve for 2.5h, then cool with ice-salt bath to below 5°C; liquid separation, the organic layer was washed once with 100 mL of water, dried with anhydrous sodium sulfate, suction filtered, and weighed. The yield was over 92%, and the purity was 99.8%.

Example 3

Put 92.1g of sodium p-toluenesulfinate, 75.2g of paraformaldehyde, and 113.1g of formamide with a mass fraction of 97% in a 500mL four-neck flask with mechanical stirring, reflux condenser, and thermometer, and add 157.2 g of formamide dropwise under stirring. g of formic acid with a mass fraction of 88%; after the dropwise addition, raise the temperature to 90°C, keep it warm for 2 hours, then cool the reaction solution to below 50°C, add 100mL of cold water, stir, and cool in an ice-salt bath to below 0°C; filter, filter The cake was rinsed with 20 mL of cold water and dried in vacuum to obtain white crystals. Put 42.8g of p-toluenesulfonylmethylformamide, 300mL of dichloromethane, and 71.2g of triethylamine into a 1000mL three-necked bottle in turn, and stir to dissolve , cooled to -2°C with an ice-salt bath; add dropwise a mixed solution of 21mL of phosphorus oxychloride and 21mL of dichloromethane into the dropping funnel, and keep the temperature between 0°C during the dropping process, and drop it within 3 hours; After dripping, react for 1 hour, slowly add 50 mL of water, continue to stir for 30 minutes, let stand for stratification, add 300 mL of 7% sodium hydroxide solution and stir to adjust to pH = 14, let stand to separate the triethylamine layer, after drying, The recovered triethylamine can be directly used in the reaction; the liquid is separated, the organic layer is washed once with 60mL of 10% sodium carbonate water, the organic layer is separated and dried with anhydrous sodium sulfate, and the dichloromethane is recovered in a water bath under normal pressure, and then distilled under reduced pressure. Methane until crystals appear on the edge, then slowly add petroleum ether 2.5 times the volume of the content, let it stand for more than 30 minutes, filter it with suction, dry it, and weigh 40.6g of light yellow-brown crystals. Under the protection of nitrogen, 35.2g of p-methylsulfonylmethyl isonitrile, 30mL of hydrofluoric acid aqueous solution and 0.23g of Ni-Co were put into the reaction kettle, stirred and dissolved for 3h, then cooled to Below 5°C; liquid separation, the organic layer was washed once with 100mL water, dried with anhydrous sodium sulfate, suction filtered, weighed, the yield was over 92%, and the purity was 99.8%.

Claims (1)

1. a synthetic method of 2-fluoro-4-methylbenzenesulfonylmethyl isocyanide, is characterized in that concrete synthetic steps are: (1) Put 92.1g of sodium p-toluenesulfinate, 75.2g of paraformaldehyde, and 113.1g of formamide with a mass fraction of 97% in a 500mL four-neck flask with mechanical stirring, reflux condenser and thermometer, and stir Dropping 157.2g mass fraction is 88% formic acid; (2) After the dropwise addition, raise the temperature to 90°C, keep it warm for 2 hours, then cool the reaction solution to below 50°C, add 100mL of cold water, stir, and cool in an ice-salt bath to below 0°C; (3) filter, the filter cake is rinsed with 20mL of cold water, and vacuum-dried to obtain white crystals; (4) Weigh 42.8g of the white crystals obtained by vacuum drying above, 300mL of dichloromethane, and 71.2g of triethylamine into a 1000mL three-neck flask in sequence, stir and dissolve, and cool to -4--2°C with an ice-salt bath; (5) Add dropwise a mixed solution of 21mL phosphorus oxychloride and 21mL dichloromethane into the dropping funnel, and keep the temperature between -4-0°C throughout the dropping process, and drop it in about 2-3 hours; (6) React for 1 hour after dripping, slowly add 50mL of water, continue to stir for 30min, let stand for stratification, add 300mL of 7% sodium hydroxide solution and stir to adjust to pH=14, let stand to separate the triethylamine layer, and After drying, reclaiming triethylamine can be directly used for reaction; (7) Liquid separation, the organic layer was washed once with 60 mL of 10% sodium carbonate water, the organic layer was separated and dried with anhydrous sodium sulfate, first normal pressure on a water bath, and then vacuum distillation to recover dichloromethane until crystallization appeared on the edge , then slowly add petroleum ether 2.5 times the volume of the content, let stand for more than 30min, filter with suction, dry, and weigh 40.6g of light yellow-brown crystals; (8) Under the protection of nitrogen, put 35.2g of the light yellow-brown crystal obtained above, 30mL of hydrofluoric acid aqueous solution and 0.23g of Ni-Co into the reaction kettle, stir and dissolve for 2-3h, and then use an ice-salt bath to Cool to below 5°C; (9) Liquid separation, the organic layer was washed once with 100 mL of water, dried with anhydrous sodium sulfate, suction filtered, weighed, and the yield was calculated and its purity was detected.