CN114751856A - A kind of synthetic method of 5-iodo-6-methylnicotinonitrile - Google Patents

Abstract

The invention belongs to the technical field of compound synthesis, and in particular relates to a method for synthesizing 5-iodine-6-methylnicotinonitrile. In the present invention, compound A is used as a basic raw material, and the three-step reaction of nucleophilic substitution, electrophilic substitution and Sandmeyer reaction is carried out successively, and then 5-iodine-6-methylnicotinonitrile is prepared. Methylnicotinonitrile has high yield, good purity, and is simple and easy to operate.

Description

A kind of synthetic method of 5-iodo-6-methylnicotinonitrile

technical field

The invention belongs to the technical field of compound synthesis, and in particular relates to a method for synthesizing 5-iodo-6-methylnicotinonitrile.

Background technique

Niacin is a white crystal. Sublimation, soluble in alcohol, ether, chloroform, benzene and petroleum ether, slightly soluble in water. The main use is as an intermediate for medicine, food additives, feed additives, pesticides, etc. 5-Iodo-6-methylnicotinonitrile is an important derivative of nicotinonitrile.

5-iodo-6-methylnicotinonitrile is an important chemical intermediate, but no synthetic method has been reported so far.

SUMMARY OF THE INVENTION

In view of the above-mentioned problems, the present invention provides a method for synthesizing 5-iodo-6-methylnicotinonitrile with simple operation and high yield.

In order to solve the above-mentioned problems, the technical scheme provided by the present invention is:

A synthetic method of 5-iodo-6-methylnicotinonitrile, the synthetic method comprises the steps:

(1) Put compound A, ammonia water and ethanol into the reactor, heat to 120～125℃, set the pressure to 1MPa, and react to obtain compound B

；

;

(2) Add compound B, N,N-dimethylformamide and N-iodosuccinimide to the reactor, and react to obtain compound C

；

;

(3) Add compound C, DMF, and isoamyl nitrite to the reactor, under nitrogen protection, heat to 90°C, react, and then add copper powder to react to obtain 5-iodo-6-methyl-nicotinonitrile

。

.

Preferably, in the step (1), the ammonia water is ammonia water with a mass fraction of 25%, the solid-liquid g/mL ratio of compound A and the ammonia water is 1:13, and the volume ratio of ammonia water to ethanol is 2:1.

Preferably, in the step (2), the mass ratio of compound B and N-iodosuccinimide is 7:13, and the solid-liquid g/mL ratio of compound B and N,N-dimethylformamide is 7:110.

Preferably, in the step (3), the mass ratio of compound C, isoamyl nitrite, and copper powder is 6:3 to 5:2, and the solid-liquid g/mL ratio of compound C and DMF is 3:50.

Beneficial effects:

In the present invention, compound A is used as the basic raw material, and the three-step reaction of nucleophilic substitution, electrophilic substitution and Sandmeyer reaction is carried out in turn, and then 5-iodo-6-methylnicotinonitrile is prepared. The 5-iodo-6-methylnicotinonitrile prepared by the present invention Methylnicotinonitrile has high yield, good purity, and is simple and easy to operate.

Detailed ways

A synthetic method of 5-iodo-6-methylnicotinonitrile, the synthetic method comprises the steps:

(1) According to compound A, the solid-liquid g/mL ratio of 25% ammonia water is 1:13, and the volume ratio of ammonia water and ethanol is 2:1, take the material, put compound A, ammonia water and ethanol into the reaction In the device, heat to 120～125℃, set the pressure to 1MPa, and react to obtain compound B;

(2) According to the mass ratio of compound B and N-iodosuccinimide as 7:13, and the solid-liquid g/mL ratio of compound B and N,N-dimethylformamide as 7:110 , add compound B, N,N-dimethylformamide and N-iodosuccinimide to the reactor, and react to obtain compound C;

(3) According to the mass ratio of compound C, isoamyl nitrite and copper powder of 6:3 to 5:2, and the solid-to-liquid g/mL ratio of compound C and DMF to 3:50, take the material and put it into the reactor. Add compound C, DMF, isoamyl nitrite, nitrogen protection, heat to 90 ℃, react, then add copper powder, react to obtain 5-iodo-6-methyl-nicotinonitrile.

Example 1

A synthetic method of 5-iodo-6-methylnicotinonitrile, the synthetic method comprises the steps:

(1) Put 15g of compound A, 195mL of ammonia water with a mass fraction of 25%, and 97.5mL of ethanol into the reactor, heat it to 120°C, set the pressure to 1MPa, react for 3h, check by TLC, the raw materials have basically reacted, take out the kettle The reaction solution was concentrated in ethanol, filtered and washed with water to obtain 11.9 g of a yellow solid, that is, compound B was obtained with a yield of 90.9% and a purity of 96.8%;

(2) Add 7g of compound B, 110mL of N,N-dimethylformamide and 13g of N-iodosuccinimide to the reactor, react for 15h, check by TLC, the reaction of the raw materials is completed, add 300mL of water to the reaction solution , 200 mL of ethyl acetate was stirred for 10 min, celite was added for filtration, the liquid was separated, the aqueous phase was continuously extracted once with 200 mL of ethyl acetate, the organic phases were combined, concentrated, MTBE (20 mL) was added to make a slurry, and filtered to obtain 11.2 g of a brown solid, namely Compound C was obtained with a yield of 82.2% and a purity of 95.2%;

(3) Add 3g compound C, 50mL DMF, 1.5g isoamyl nitrite to the reactor, nitrogen protection, heat to 90 ° C, react for 2 hours, then add 1 copper powder, react for 4 hours, TLC detection, the reaction of the raw materials is completed, add water 100 mL, extracted with ethyl acetate (100 mL*2), combined the organic phases, concentrated, mixed samples, passed through column, n-hexane/ethyl acetate=3% ethyl acetate. Concentrated to obtain 2.2 g of white solid, namely 5-iodo-6-methyl-nicotinonitrile, with a yield of 77.8% and a purity of 99.1%.

NMR data of the product: 1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 2.72 (s, 3H).

Example 2

A synthetic method of 5-iodo-6-methylnicotinonitrile, the synthetic method comprises the steps:

(1) Put 15g of compound A, 195mL of ammonia water with a mass fraction of 25%, and 97.5mL of ethanol into the reactor, heat it to 123°C, set the pressure to 1MPa, react for 3h, check by TLC, the raw materials have basically reacted, take out the kettle The reaction solution was concentrated in ethanol, filtered and washed with water to obtain 12.4 g of a yellow solid, that is, compound B was obtained with a yield of 94.7% and a purity of 97.3%;

(2) Add 7g of compound B, 110mL of N,N-dimethylformamide and 13g of N-iodosuccinimide to the reactor, react for 15h, check by TLC, the reaction of the raw materials is completed, add 300mL of water to the reaction solution , 200 mL of ethyl acetate was stirred for 10 min, celite was added for filtration, the liquid was separated, the aqueous phase was continuously extracted once with 200 mL of ethyl acetate, the organic phases were combined, concentrated, added MTBE (20 mL) to make a slurry, and filtered to obtain 12.6 g of brown solids, namely Compound C was obtained with a yield of 92.5% and a purity of 97.8%;

(3) Add 3g compound C, 50mL DMF, 2g isoamyl nitrite to the reactor, under nitrogen protection, heat to 90℃, react for 2h, then add 1g copper powder, react for 4h, TLC detection, the reaction of the raw materials is completed, add water 100 mL, extracted with ethyl acetate (100 mL*2), combined the organic phases, concentrated, mixed samples, passed through column, n-hexane/ethyl acetate=3% ethyl acetate. Concentrated to obtain 2.8 g of white solid, namely 5-iodo-6-methyl-nicotinonitrile, with a yield of 99.1% and a purity of 98.6%.

NMR data of the product: 1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 2.72 (s, 3H).

Example 3

A synthetic method of 5-iodo-6-methylnicotinonitrile, the synthetic method comprises the steps:

(1) Put 15g of compound A, 195mL of ammonia water with a mass fraction of 25%, and 97.5mL of ethanol into the reactor, heat it to 125°C, set the pressure to 1MPa, react for 3h, check by TLC, the raw materials have basically reacted, and take out the kettle The reaction solution was concentrated in ethanol, filtered and washed with water to obtain 12 g of a yellow solid, that is, compound B was obtained with a yield of 91.7% and a purity of 95.2%;

(2) Add 7g of compound B, 110mL of N,N-dimethylformamide and 13g of N-iodosuccinimide to the reactor, react for 15h, check by TLC, the reaction of the raw materials is completed, add 300mL of water to the reaction solution , 200 mL of ethyl acetate was stirred for 10 min, celite was added for filtration, the liquid was separated, the aqueous phase was continuously extracted once with 200 mL of ethyl acetate, the organic phases were combined, concentrated, added MTBE (20 mL) to make a slurry, and filtered to obtain 12.3 g of a brown solid, namely Compound C was obtained with a yield of 90.3% and a purity of 96.8%;

(3) Add 3g compound C, 50mL DMF, 2.5g isoamyl nitrite into the reactor, nitrogen protection, heat to 90 ° C, react for 2h, then add 1g copper powder, react for 4h, TLC detection, the reaction of the raw materials is completed, add water 100 mL, extracted with ethyl acetate (100 mL*2), combined the organic phases, concentrated, mixed samples, passed through column, n-hexane/ethyl acetate=3% ethyl acetate. Concentrated to obtain 2.5 g of white solid, namely 5-iodo-6-methyl-nicotinonitrile, with a yield of 88.5% and a purity of 98.2%.

NMR data of the product: 1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 2.0 Hz, 1H), 8.75 (d, J = 2.0 Hz, 1H), 2.72 (s, 3H).

Claims (4)

1. a synthetic method of 5-iodo-6-methylnicotinonitrile, is characterized in that, this synthetic method comprises the steps: (1) Put compound A, ammonia water and ethanol into the reactor, heat to 120～125℃, set the pressure to 1MPa, and react to obtain compound B

; (2) Add compound B, N,N-dimethylformamide and N-iodosuccinimide to the reactor, and react to obtain compound C

; (3) Add compound C, DMF, and isoamyl nitrite to the reactor, under nitrogen protection, heat to 90°C, react, and then add copper powder to react to obtain 5-iodo-6-methyl-nicotinonitrile

. 2. The synthetic method of 5-iodo-6-methylnicotinonitrile according to claim 1, characterized in that, in the step (1), the ammoniacal liquor is the ammoniacal liquor whose mass fraction is 25%, and the solid of compound A and the ammoniacal liquor is 25%. The liquid g/mL ratio is 1:13, and the volume ratio of ammonia water to ethanol is 2:1. 3. The synthetic method of 5-iodo-6-methylnicotinonitrile according to claim 1, wherein the mass ratio of compound B and N-iodosuccinimide in the step (2) is 7:13, the solid-liquid g/mL ratio of compound B and N,N-dimethylformamide is 7:110. 4. the synthetic method of 5-iodo-6-methylnicotinonitrile according to claim 1, is characterized in that, in described step (3), the mass ratio of compound C, isoamyl nitrite, copper powder is 6 : 3～5:2, the solid-liquid g/mL ratio of compound C and DMF is 3:50.