CN114751842A - Preparation method of bromoacetonitrile - Google Patents
Preparation method of bromoacetonitrile Download PDFInfo
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- CN114751842A CN114751842A CN202210437370.6A CN202210437370A CN114751842A CN 114751842 A CN114751842 A CN 114751842A CN 202210437370 A CN202210437370 A CN 202210437370A CN 114751842 A CN114751842 A CN 114751842A
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Abstract
The invention relates to a preparation method of bromoacetonitrile in the technical field of medicine production, which comprises the steps of reacting cyanomethyl sulfonate with bromide salt, and obtaining a crude product through reactive distillation; and then rectifying to obtain bromoacetonitrile. Aiming at the current situation of poor product quality of the prior art, the crude product contains about 5 percent of hydroxyl acetonitrile, and the process of removing water by a reaction system is adopted, so that the generation of the hydroxyl acetonitrile is avoided, and the rectification efficiency is improved. The new preparation method provided by the invention overcomes the defects of the prior art, has the advantages of short reaction time, high product purity and yield and the like, and is suitable for industrial amplification.
Description
Technical Field
The invention relates to a preparation method of bromoacetonitrile, belonging to the technical field of medicine production.
Background
The english name of bromoacetonitrile is: cyanomethyl bromide, bromoacetonitrile; CAS # (590-17-0); boiling points of 60-62 ℃ per 24 mmHg (lit.), 150-151 ℃ per 752 mmHg; density 1.722 g/mL at 25 ℃ (lit.)
The structural formula is as follows:
bromoacetonitrile is a very useful synthetic intermediate, especially in the production of new drugs. For example, 1: synthetic fragments of neoguano drugs:
the intermediate is as follows:
a process for the preparation of (S) -methyl 2- (BOC-amino) -3- [ (S) -2-oxo-3-pyrrolidinyl ] propanoate (CAS Registry Number (S): 328086-60-8).
For example, 2: synthetic fragment of novel anticancer drug:
the following intermediates were synthesized using bromoacetonitrile:
6-chloro-imidazo[1,2-b]pyridazine-3-carbonitrile
CAS Registry Number(s): 123531-54-4
6-chloroimidazo [1,2-b ] pyridazine-3-carbonitrile is a key intermediate of a novel TGF-beta R1 inhibitor BMS-986260 as a novel anti-cancer drug.
At present, the synthesis routes of bromoacetonitrile mainly include the following:
1. the bromoacetonitrile is obtained by bromination of chloroacetonitrile serving as a raw material.
In chinese patent CN113582874 (a), ningxia sheng medicine limited company discloses a method for producing bromoacetonitrile, wherein tetramethyl ammonium bromide and chloroacetonitrile are used as raw materials to react in acetone, the formed by-product tetramethylammonium chloride is removed by filtration, and the filtrate is rectified to obtain bromoacetonitrile.
The reaction equation is as follows:
the method is a process route commonly adopted in China at present, but the reaction time of the raw material chloroacetonitrile is long, and the water in the reaction system causes the bromoacetonitrile to be hydrolyzed into the hydroxyacetonitrile and the like, so that the content of the obtained product is low; additional measures are required to obtain a satisfactory product. In the post-treatment of Chinese patent CN113582874, solid in a reaction system is removed by filtration, and chloroacetonitrile and bromoacetonitrile are known to have strong irritation and poor working environment; the solid contains a large amount of products and needs to be washed by a solvent for many times, so that the production operation is relatively complicated, and meanwhile, the solvents acetone and methanol are flammable and explosive solvents and have great potential safety hazards; in addition, a large amount of waste residues generated in the production contain a small amount of chloroacetonitrile, bromoacetonitrile, hydroxyacetonitrile and the like, which are difficult to treat, and the environmental pollution is very serious.
2. Japanese patent: JP2000247941 (a) discloses that acetonitrile is used as a raw material, hydrogen chloride gas is blown into an acetonitrile reaction system, and bromine is dropped into the system under light irradiation, and for example, a 100w high-pressure mercury lamp emits ultraviolet rays having a wavelength of 3650 to 3690A. The reaction conditions of the reaction are rigorously controlled, and the photochemical reaction glass container and equipment are relatively complex.
Japanese patent: JPS6447751 (a) avoids the use of photoreactor by brominating acetonitrile with bromine in the presence of phosphorus tribromide.
The reaction equation is as follows:
the processes of the Japanese patent documents all use bromine as a raw material, have high risk in the processes of operation, transportation and storage, are not easy to use and produce in a large scale, and have poor safety.
3. A process for preparing bromoacetonitrile by dehydrating 2-bromoacetamide in the presence of phosphorus pentoxide.
The reaction equation is as follows:
adding solid phosphorus pentoxide into 2-bromoacetamide, heating for dehydration, and evaporating bromoacetonitrile while heating, wherein hydrolysis impurities are easily generated due to the fact that a part of water is removed in the reaction; from the viewpoint of environmental protection, phosphorus pentoxide has large three wastes and is not suitable for mass production.
In conclusion, a process route of bromoacetonitrile with the advantages of low raw material cost, high product purity and yield and less three wastes is sought, and a technical problem to be solved is urgently needed.
Disclosure of Invention
The invention aims to improve the defects of the existing synthesis technology, provides a preparation method of bromoacetonitrile, has the advantages of low raw material cost, short reaction time, high product purity and yield and the like, is very environment-friendly, and meets the requirements of green chemical processes.
Therefore, the preparation method of bromoacetonitrile provided by the invention comprises the following steps:
s1, preparation of compound 1:
reacting cyanomethyl sulfonate 2 with bromide 3, and obtaining a crude product through reactive distillation; then rectifying to obtain a compound 1;
the reaction formula is as follows:
in compound 2, R is a linear or branched alkyl group representing up to 4 carbon atoms, a linear or branched haloalkyl group representing up to 10 carbon atoms and up to 21 halogen atoms, or is optionally mono-, di-or trisubstituted by identical or different substituents including halogen, nitro, cyano or alkyl.
In formula 3, M is hydrogen, lithium, sodium, potassium. Potassium is preferred.
In a further improvement, in compound 2R is phenyl, p-tolyl, methyl or trifluoromethyl. Preferably p-tolyl
More specifically, in step S1, bromide salt 3 and a solvent are put into a reaction bottle, the temperature is raised to 50-90 ℃, and partial solvent is removed under reduced pressure to remove water in the system; removing vacuum with nitrogen, cooling to 30 +/-2 ℃, and adding cyanomethyl sulfonate 2; after the addition is finished, slowly heating to 100-120 ℃, and performing reduced pressure distillation to separate out a crude product of bromoacetonitrile while performing chemical reaction by a reactive distillation method; rectifying the crude product under reduced pressure to obtain a high-purity compound bromoacetonitrile 1;
the solvent is sulfolane, diethylene glycol, ethylene glycol phenyl ether or N-methyl pyrrolidone. Preferably sulfolane.
The source and theoretical basis of the innovative technical method of the invention are as follows:
the bromine displacement reaction of sulfonate esters is one of the classical methods of organic synthesis, converting an alcohol with sulfuryl chloride to the corresponding sulfonate ester, which is then reacted with a nucleophilic brominating reagent to produce the desired bromide. Because of the higher sulfonate activity, both sulfonate and bromine metathesis reactions are carried out under milder conditions and are often more efficient than halogen exchange reactions. Common brominating agents include sodium bromide, lithium bromide, potassium bromide, magnesium bromide, etc.; the reaction solvent is polar solvent such as acetone, alcohol, DMF, etc.
The preparation method of the cyanomethyl sulfonate is mature, and the corresponding cyanomethyl sulfonate can be efficiently synthesized from sodium cyanide, formaldehyde and corresponding sulfonyl chloride.
According to the above-mentioned prior organic synthesis methods and techniques, the inventors have surprisingly found that the crude bromoacetonitrile can be separated out in time by carrying out chemical reaction and distillation in a solvent by using corresponding cyanomethyl sulfonate and bromide salt through a reactive distillation method; finally, the high-quality bromoacetonitrile product is obtained by rectification, and an unexpected effect is achieved. Compared with the prior art, the invention has the beneficial effects that: the invention provides a new process route for preparing bromoacetonitrile, wherein a stronger sulfonate leaving group is selected, so that the condition that sulfonate is replaced by bromine is mild; meanwhile, a polar solvent with high boiling point is used, and a method for collecting products by reactive distillation is adopted, so that the original operation of filtering and desalting is eliminated, and the production efficiency is greatly improved. Aiming at the current situation that the product quality of the original process is poor, the crude product contains about 5 percent of hydroxyl acetonitrile, and the process of removing water by a reaction system is adopted, so that the generation of the hydroxyl acetonitrile is avoided, and the rectification efficiency is improved. The new preparation method provided by the invention overcomes the defects of the prior art, has the advantages of short reaction time, high product purity and yield and the like, and is suitable for industrial amplification.
Drawings
FIG. 1 is a GC spectrum of the bromoacetonitrile purity test of example 1.
Detailed Description
The preparation method of bromoacetonitrile comprises the following steps:
adding bromide salt 3 and solvent into a reaction bottle, heating to 50-90 ℃, and removing part of solvent under reduced pressure to remove water in the system; removing vacuum with nitrogen, cooling to 30 +/-2 ℃, and adding cyanomethyl sulfonate 2; after the addition, slowly heating to 100-120 ℃, and performing reduced pressure distillation to separate a crude product of bromoacetonitrile by a reactive distillation method while performing a chemical reaction; rectifying the crude product under reduced pressure to obtain a high-purity compound bromoacetonitrile 1;
the reaction formula is as follows:
in compound 2, R is a linear or branched alkyl group representing up to 4 carbon atoms, a linear or branched haloalkyl group representing up to 10 carbon atoms and up to 21 halogen atoms, or is optionally mono-, di-or trisubstituted by identical or different substituents including halogen, nitro, cyano or alkyl. Preferably p-tolyl.
In formula 3, M is hydrogen, lithium, sodium, potassium. Potassium is preferred.
The solvent may be sulfolane, diethylene glycol, ethylene glycol phenyl ether or N-methylpyrrolidone. Preferably sulfolane.
The invention is further illustrated by the following examples:
example 1
Preparation method of bromoacetonitrile
Putting 120g of anhydrous sodium bromide and 300g of sulfolane into a 1000mL reaction bottle, heating to 90 ℃, and removing about 10g of solvent under reduced pressure; removing vacuum with nitrogen, cooling to 30 +/-2 ℃, and adding 135g of cyanomethyl methanesulfonate; after the addition is finished, slowly heating to 100-120 ℃, and performing reduced pressure distillation to separate out a crude product of bromoacetonitrile while performing chemical reaction by a reactive distillation method; the crude product is rectified by a water pump under reduced pressure, and 80-85 ℃/40-50mmHg fractions are collected to obtain 102.0g of product 1, the GC purity is 99.52%, and the yield is 85.15%.
Example 2
Preparation method of bromoacetonitrile
Putting 135g of anhydrous sodium bromide and 300g N-methylpyrrolidone into a 1000mL reaction bottle, heating to 90 ℃, and removing water in the system under reduced pressure; vacuumizing with nitrogen, cooling to 30 +/-2 ℃, and adding 210g of cyanomethyl p-toluenesulfonate; after the addition, slowly heating to 100-120 ℃, and performing reduced pressure distillation to separate a crude product of bromoacetonitrile by a reactive distillation method while performing a chemical reaction; the crude product was vacuum distilled through a water pump and 80-85 deg.C/40-50 mmHg fractions were collected to yield 97.9g of product 1, GC purity 99.58%, yield 81.6%.
Example 3
Preparation method of bromoacetonitrile
Putting 132g of anhydrous potassium bromide and 400g of diethylene glycol into a 1000mL reaction bottle, heating to 90 ℃, and removing water in the system under reduced pressure; vacuumizing with nitrogen, cooling to 30 +/-2 ℃, and adding 200g of cyanomethyl benzene sulfonate; after the addition, slowly heating to 100-120 ℃, and performing reduced pressure distillation to separate a crude product of bromoacetonitrile by a reactive distillation method while performing a chemical reaction; and carrying out reduced pressure rectification on the crude product by a water pump, and collecting fractions at 80-85 ℃/40-50mmHg to obtain 99.2g of a product 1, wherein the GC purity is 99.61 percent, and the yield is 82.7 percent.
Example 4
Preparation method of bromoacetonitrile
Putting 95.0g of lithium bromide and 100g of sulfolane into a 1000mL reaction bottle, heating to 90 ℃, and removing water in the system under reduced pressure; vacuumizing with nitrogen, cooling to 30 +/-2 ℃, and adding 210g of cyanomethyl p-methylbenzenesulfonate; after the addition is finished, slowly heating to 100-120 ℃, and performing reduced pressure distillation to separate out a crude product of bromoacetonitrile while performing chemical reaction by a reactive distillation method; the crude product is rectified by a water pump under reduced pressure, and 80-85 ℃/40-50mmHg fractions are collected to obtain 94.3g of product 1, the GC purity is 99.4%, and the yield is 78.6%.
The method selects a stronger sulfonate leaving group, so that the replacement condition of the sulfonate by bromine is mild; meanwhile, a polar solvent with high boiling point is used, and a method for collecting products by reactive distillation is adopted, so that the original operation of filtering and desalting is eliminated, and the production efficiency is greatly improved.
The present invention is not limited to the above-mentioned embodiments, and based on the technical solutions disclosed in the present invention, those skilled in the art can make some substitutions and modifications to some technical features without creative efforts according to the disclosed technical contents, and these substitutions and modifications are all within the protection scope of the present invention.
Claims (6)
1. A preparation method of bromoacetonitrile is characterized by comprising the following steps:
s1, preparation of compound bromoacetonitrile (1):
reacting cyanomethyl sulfonate (2) with bromide (3), and obtaining a crude product through reactive distillation; then rectifying to obtain a compound bromoacetonitrile (1);
the reaction formula is as follows:
in compound (2), R represents a linear or branched alkyl group having up to 4 carbon atoms, a linear or branched haloalkyl group having up to 10 carbon atoms and up to 21 halogen atoms, or is optionally mono-, di-or trisubstituted by identical or different substituents, including halogen, nitro, cyano or alkyl;
in formula (3), M is hydrogen, lithium, sodium, potassium.
2. The method for preparing bromoacetonitrile according to claim 1, wherein the method comprises the following steps: in the compound (2), R is phenyl, p-tolyl, methyl or trifluoromethyl.
3. The method for preparing bromoacetonitrile according to claim 1, wherein the method comprises the following steps: m is potassium.
4. A process for the preparation of bromoacetonitrile according to any one of claims 1 to 3, wherein:
adding bromide salt (3) and a solvent into a reaction bottle, heating to 50-90 ℃, and removing part of the solvent under reduced pressure to remove water in the system; removing vacuum with nitrogen, cooling to 30 +/-2 ℃, and adding cyanomethyl sulfonate (2); after the addition is finished, slowly heating to 100-120 ℃, and performing reduced pressure distillation to separate out a crude product of bromoacetonitrile while performing chemical reaction by a reactive distillation method; rectifying the crude product under reduced pressure to obtain a high-purity compound bromoacetonitrile (1);
the solvent is sulfolane, diethylene glycol, ethylene glycol phenyl ether or N-methylpyrrolidone.
5. The method for preparing bromoacetonitrile according to claim 4, wherein the method comprises the following steps: in the compound (2), R is p-tolyl.
6. The method for preparing bromoacetonitrile according to claim 4, wherein the method comprises the following steps: the solvent used in step S1 is sulfolane.
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| CN202210437370.6A CN114751842A (en) | 2022-04-25 | 2022-04-25 | Preparation method of bromoacetonitrile |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230753A (en) * | 2014-08-27 | 2014-12-24 | 杭州拜善晟生物科技有限公司 | Method for synthesizing fluoroacetonitrile |
| CN113582874A (en) * | 2021-09-10 | 2021-11-02 | 宁夏常晟药业有限公司 | Synthesis method of bromoacetonitrile |
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- 2022-04-25 CN CN202210437370.6A patent/CN114751842A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104230753A (en) * | 2014-08-27 | 2014-12-24 | 杭州拜善晟生物科技有限公司 | Method for synthesizing fluoroacetonitrile |
| CN113582874A (en) * | 2021-09-10 | 2021-11-02 | 宁夏常晟药业有限公司 | Synthesis method of bromoacetonitrile |
Non-Patent Citations (1)
| Title |
|---|
| 张顺泽，等: "《分离工程》", vol. 1, 中国矿业大学出版社, pages: 91 - 92 * |
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