NL2031389B1

NL2031389B1 - METHOD FOR PREPARING a-CARBONYL BUTYRAMIDE THROUGH REACTION IN WATER PHASE

Info

Publication number: NL2031389B1
Application number: NL2031389A
Authority: NL
Inventors: Wang Bo
Original assignee: Univ Shandong Science & Tech
Priority date: 2022-03-23
Filing date: 2022-03-23
Publication date: 2023-10-06

Abstract

The present disclosure discloses a method for preparing d—carbonyl butyramide through reaction in a water phase, wherein water serves as a solvent, dimethyl sulfoxide serves as a cosolvent, iodine or iodized salt serves as a catalyst, and d—carbonyl butyramide is directly generated through reaction of butanone, ammonium chloride and an oxidizing agent in the presence of alkali. In the present disclosure, butanone and ammonium chloride are taken as the raw materials to directly synthesize the compound d—carbonyl butyramide. The method, can be carried, out at a relatively low temperature, is mild, in reaction condition, simple to operate, pollution—free, environment—friendly and simple in post—treatment, and can be used for remarkably lowering the production cost. The method can be used for overcoming the defects of high—toxicity, pollution—free and relatively high—cost chemical raw materials used, in the prior art, and, has good, technical application. and industrialization prospects.

Description

P1229/NLpd

METHOD FOR PREPARING a-CARBONYL BUTYRAMIDE THROUGH REACTION IN

WATER PHASE

TECHNICAL FIELD

The present disclosure relates to a method for directly syn- thesizing a-carbonyl butyramide, particularly relates to a method for directly synthesizing a-carbonyl butyramide through reaction in a water phase system, and belongs to the technical field of chemical synthesis.

BACKGROUND ART

The compound a-carbonyl butyramide is an amide compound with double carbonyl groups. Because of its special double carbonyl structure in its molecular structure, it has very important bio- logical activities in vivo and is widely used to synthesize inhib- itors of various biological enzymes and biological tissue pro- teins. In addition, most importantly, a-carbonyl butyramide is a precursor compound for the synthesis of a series of structurally complex drugs. The main function of a-carbonyl butyramide (the structural formula shown in formula I) is mainly used as an inhib- itor for synthetic drugs and synthetic biological enzymes. As a synthetic drug intermediate, it is mainly used as a biological in- hibitor and biologically active peptide in the synthesis of anti- hyperlipidemia drugs-statins (bestatin analoges), some anti-cancer drugs and anti-AIDS (HIV) drugs.

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Statins are hydroxymethylglutaryl coenzyme A (HMG-CoA) reduc- tase inhibitors and are one of the most commonly used antihyper- lipidemic drugs in the world. Many people are suffering from chronic diseases, and more and more people have high blood lipids around the world. According to statistics, with the change of lifestyle and the acceleration of the aging process in China, the incidence rate has further increased and the rate of patient vis- its has increased. The market size of blood lipid-lowering drugs has grown from 9.228 billion yuan in 2009 to 20.181 billion yuan in 2014 in China, with a compound annual growth rate of about 16.94%. Because statins have the characteristics of strong lipid- lowering effect, exact curative effect, diverse functions and few- er side effects, they currently occupy an absolute dominant share in the blood lipid-lowering drug market. From 2010 to 2014, stating accounted for 81.07%, 83.34%, 87.02%, 88.43% and 89.73% of the total blood lipid-lowering drug market, showing an upward trend year by year. We expect that blood lipid-lowering drugs will maintain a rapid growth trend in the future, and statins will maintain a sustained high growth. a-carbonyl amide is an important intermediate in the synthesis of potent hydroxymethylglutaryl co- enzyme A (HMG-CoA) reductase inhibitors, so the demand for a- carbonyl amide will also increase.

At present, the main method of producing a-carbonyl butyra- mide at home and abroad is as follows: ethyl alkylene cyanoacetate is hydrolyzed to generate corresponding acid after generating epoxy amide under the action of alkali and oxidant, and then in the presence of a small amount of water, heated to decompose and generate the corresponding product. This method has many disad- vantages such as many production steps, low production efficiency and high environmental pollution, etc.

SUMMARY

The invention aims at providing a method for preparing a- carbonyl butyramide through reaction in a water phase. According to the method, butanone and ammonium chloride serve as raw materi- als, a-carbonyl butyramide is synthesized through reaction in the water phase at low temperature, the reaction conditions are mild, environmental friendliness is achieved, cost is low, and good in- dustrial application prospects are achieved.

In the present disclosure, butanone and ammonium chloride are used as the raw materials, and a-carbonyl butyramide can be di- rectly synthesized through oxidative amination coupling reaction.

The method has the advantages of being easy to operate, mild, en-

vironmentally friendly, low in cost, etc., and has large industri- al prospects and social and economic benefits.

The specific technical solutions of the present disclosure are as follows:

A method for preparing a-carbonyl butyramide through reaction in a water phase is characterized in that water serves as a sol- vent, dimethyl sulfoxide serves as a cosolvent, iodine or iodized salt serves as a catalyst, and a-carbonyl butyramide is directly generated through reaction of butancne, ammonium chloride and an oxidizing agent in the presence of alkali.

The reaction formula of the method can be shown as follows: u . Catalyst Alkali & & © H20O(small amount of dmso) Oxidant Ea DA

U

Butanone Ammonium a-carbonyl butyramide

In the method, the molar ratio of butanone to ammonium chlo- ride is (1: 1.2) - (1: 4.0), wherein ammonium chloride is prefera- bly added excessively to increase the yield.

In the method, the catalyst is one or more of I2, Cul, tet- rabutylammonium iodide and potassium iodide, preferably tetrabu- tylammonium iodide. The dosage of the catalyst is generally 2-4% of the molar number of butanone.

In the method, the alkali is Na:CO:, K:CO:, NaHCO:, CaCo,

Sec0:, NaOH, triethylamine or DBU. The alkali is used for providing an alkaline environment for reaction, various alkaline properties are similar, and Na,C0; and NaHCO; with lower cost are preferably adopted. The dosage of the alkali is generally 1.0-1.5 times of the molar number of ammonium chloride.

In the method, the oxidant is one or more of air, 0., H:0: and

TBHP (tert-butyl hydroperoxide}, preferably H:0,.

In the method, water is used as a main solvent, dimethyl sul- foxide is used as the cosolvent, and a small amount of cosolvent is added to promote the dissolution of butanone, so that the reac- tion is carried out in a homogeneous system. The volume ratio of water to dimethyl sulfoxide is (7-10): 1, the dosage of water meets the requirement that all materials can fully react, the dos- age of cosolvent meets the requirement that butanone can be fully dissolved, and the dosages of water and butanone can be selected according to actual needs.

According to the present disclosure, through selecting the raw materials, the catalyst, alkali and the solvent, the reaction can be carried out at a relatively low temperature, and the reac- tion temperature is 25-70°C, for example, the reaction can be car- ried out at 25°C, 30°C, 40°C, 50°C, 60°C and 70°C. The fluctuation range of the reaction temperature is controlled to be 15°C in the reaction process. The product yield can be affected by too high or too low temperature.

The method specifically comprises the following steps: (1) adding butanone into a mixed solution of water and dime- thyl sulfoxide, and uniformly stirring; and (2) adding ammonium chloride, alkali and the catalyst into the mixture in the step (1), reacting for 30-40 min, adding the oxidant, continucusly reacting until the butanone disappears, and extracting the reaction liquid after the reaction, thereby obtain- ing the a-carbonyl butyramide.

In the step (2), after the ammonium chloride, alkali and cat- alyst are added, the temperature is controlled to be 25-70°C, the reaction is performed, and the fluctuation range of the reaction temperature is controlled to be +5°C.

In the step (2), when the oxidant is air or oxygen, air or oxygen is continuously introduced into the system in the reaction process until the reaction is complete; when the oxidant is H:C:, the oxidant is added dropwise into the system in the form of an aqueous hydrogen peroxide solution, the dropwise adding time is 30-120 min, and the mass ratio of the H,0; to the butanone is (1.25-5): 1; and when the oxidant is TBHP, the oxidant is directly added into the system at a time, and the molar ratio of the TBHP to the butanone is (1.25-5): 1.

In the step (2), after reaction, reaction liquid is extracted by an extracting agent, and the extracting agent is recovered un- der reduced pressure after extraction to obtain a-carbonyl butyra- mide, wherein the extracting agent is diethyl ether, methylben- zene, chlorobenzene, ethyl acetate, isopropyl ether, n-hexane,

ethyl formate or cyclohexane. The recovered extracting agent can be repeatedly used after simple treatment.

In the step (2), a TLC (thin-layer chromatography) silica gel plate is adopted to track and monitor the reaction progress or 5 high performance liquid chromatography is adopted to monitor the reaction progress, and the reaction reaches the end point after butanone disappears. Generally, the reaction can reach the end point after an oxidizing agent is added and the reaction is car- ried out for 8-24 h. When the TLC silica gel plate (TLC) is used for tracking and monitoring the reaction progress, a developing solvent is a mixed reagent of ethyl acetate and n-hexane in a vol- ume ratio of (1-2): 5, and the reaction end point is judged by monitoring the concentration of newly generated points and the concentration of the rest points in the reaction. When the high performance liquid chromatography is used for monitoring the reac- tion progress, the reaction end point is judged by monitoring the formation of a-carbonyl butyramide and the disappearance of buta- none in the liquid chromatography.

According to the present disclosure, butanone and ammonium chloride are taken as the raw materials to directly synthesize the compound a-carbonyl butyramide. The method can be carried out at a relatively low temperature, is mild in reaction condition, simple to operate, pollution-free, environment-friendly and simple in post-treatment, and can be used for remarkably lowering the pro- duction cost. The method can be used for overcoming the defects of high-toxicity, pollution-free and relatively high-cost chemical raw materials used in the prior art, and has good technical appli- cation and industrialization prospects.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The technical solutions of the present disclosure are de- scribed in detail below with reference to specific embodiments.

The following description is only exemplary and does not consti- tute limitation to the protection scope of the present disclosure.

Example 1

To a 25 mL three-mouth round-bottom flask, 1.5 mL of water was added, then 0.2 mL of DMSO was added, and then 0.5 mmol of bu-

tanone was measured and added into the round-bottom flask and uni- formly stirred, then 2 mmol of ammonium chloride and 2 mmol of Na-

HCO; were added, then 0.01 mmol of tetrabutylammonium iodide was added, and condensation reflux reaction was carried out at 50°C for half an hour. Then a hydrogen peroxide solution {containing 2.5 mmol of H:0, and 1 mL of water) was added dropwise into the three- mouth round-bottom flask, and dropwise adding was completed within 2 h. After completing dropwise adding, condensation reflux reac- tion was carried out at 50°C for 16 h, and the reaction progress was monitored by using a TLC (thin layer chromatography) silica gel plate or high performance liquid chromatography during the re- action. After completing reaction, 20 mL of ethyl acetate was add- ed for extraction, and then the ethyl acetate was removed under reduced pressure to obtain a yellow solid. The obtained yellow solid was purified, and then structure identification was carried out, wherein nuclear magnetic data of the yellow solid is as fol- lows: 1H NMR (400 MHz, CDC13): 3 0.64 (t, J = 7.2 Hz, 3H) , 2.44 (d, J = 4.0Hz, 2H), 16.17 (s, 2H), 13C NMR (100 MHz, CDC13): ò 7.9, 24.9, 165.5, 199.2.

It could be determined from the nuclear magnetic data that the obtained product was a-carbonyl butyramide. Based on butanone, the yield of a-carbonyl butyramide was 82%, and the purity of the product was 99% through HPLC test.

Example 2

To a 25 mL three-mouth round-bottom flask, 1.5 mL of water was added, then 0.2 mL of DMSO was added, and then 0.5 mmol of bu- tanone was measured and added into the round-bottom flask and uni- formly stirred, then 2 mmol of ammonium chloride and 2 mmol of Na-

HCO; were added, then 0.01 mmol of tetrabutylammonium iodide was added, and condensation reflux reaction was carried out at 70°C for half an hour. Then a hydrogen peroxide solution (containing 2.5 mmol of H,0, and 1 mL of water) was added dropwise into the three- mouth round-bottom flask, and dropwise adding was completed within 2 h. After completing dropwise adding, condensation reflux reac- tion was carried out at 70°C for 16 h, and the reaction progress was monitored by using a TLC (thin layer chromatography) silica gel plate or high performance liquid chromatography during the re- action. After completing reaction, 20 mL of ethyl acetate was add- ed for extraction, and then the ethyl acetate was removed under reduced pressure to obtain a yellow solid, namely, a-carbonyl bu- tyramide. Based on butanone, the yield of a-carbonyl butyramide was 80%, and the purity of the product was 99% through HPLC test.

Example 3

To a 25 mL three-mouth round-bottom flask, 1.5 mL of water was added, then 0.2 mL of DMSO was added, and then 0.5 mmol of bu- tancne was measured and added into the round-bottom flask and uni- formly stirred, then 2 mmol of ammonium chloride and 2 mmol of

KCO: were added, then 0.01 mmol of Cul was added, and condensation reflux reaction was carried out at 70°C for half an hour. Then a hydrogen peroxide solution (containing 2.5 mmol of H:0; and 1 mL of water) was added dropwise into the three-mouth round-bottom flask, and dropwise adding was completed within 2 h. After completing dropwise adding, condensation reflux reaction was carried out at 70°C for 14 h, and the reaction progress was monitored by using a

TLC (thin layer chromatography) silica gel plate or high perfor- mance liquid chromatography during the reaction. After completing reaction, 20 mL of ethyl acetate was added for extraction, and then the ethyl acetate was removed under reduced pressure to ob- tain a yellow solid, namely, a-carbonyl butyramide. Based on buta- none, the yield of a-carbonyl butyramide was 73%, and the purity of the product was 97% through HPLC test.

Example 4

To a 25 mL three-mouth round-bottom flask, 1.5 mL of water was added, then 0.15 mL of DMSO was added, and then 0.5 mmol of butanone was measured and added into the round-bottom flask and uniformly stirred, then 2 mmol of ammonium chloride and 2 mmol of

NaHCO; were added, then 0.01 mmol of tetrabutylammonium iodide was added, and condensation reflux reaction was carried out at 50°C for half an hour. Then a hydrogen peroxide solution (containing 2.5 mmol of H,0, and 1 mL of water) was added dropwise into the three- mouth round-bottom flask, and dropwise adding was completed within 2 h. After completing dropwise adding, condensation reflux reac-

tion was carried out at 50°C for 16 h, and the reaction progress was monitored by using a TLC (thin layer chromatography) silica gel plate or high performance liquid chromatography during the re- action. After completing reaction, 20 mL of ethyl acetate was add- ed for extraction, and then the ethyl acetate was removed under reduced pressure to obtain a yellow solid, namely, a-carbonyl bu- tyramide. Based on butanone, the yield of a-carbonyl butyramide was 82%, and the purity of the product was 99% through HPLC test.

Example 5

To a 25 mL three-mouth round-bottom flask, 1.5 mL of water was added, then 0.2 mL of DMSO was added, and then 0.5 mmol of bu- tanone was measured and added into the round-bottom flask and uni- formly stirred, then 1.5 mmol of ammonium chloride and 2 mmol of triethylamine were added, then 0.01 mmol of potassium iodide was added, and condensation reflux reaction was carried out at 60°C for half an hour. Then a hydrogen peroxide solution (containing 2.5 mmol of H:0, and 1 mL of water) was added dropwise into the three- mouth round-bottom flask, and dropwise adding was completed within 2 h. After completing dropwise adding, condensation reflux reac- tion was carried out at 60°C for 16 h, and the reaction progress was monitored by using a TLC (thin layer chromatography) silica gel plate or high performance liquid chromatography during the re- action. After completing reaction, 20 mL of ethyl acetate was add- ed for extraction, and then the ethyl acetate was removed under reduced pressure to obtain a yellow solid, namely, a-carbonyl bu- tyramide. Based on butanone, the yield of a-carbonyl butyramide was 70%, and the purity of the product was 97% through HPLC test.

Example 6

HCO; were added, then 0.01 mmol of I2 was added, and condensation reflux reaction was carried out at 70°C for half an hour. Then a hydrogen peroxide solution (containing 2.5 mmol of H;0, and 1 mL of water) was added dropwise into the three-mouth round-bottom flask,

and dropwise adding was completed within 2 h. After completing dropwise adding, condensation reflux reaction was carried out at 70°C for 16 h, and the reaction progress was monitored by using a

TLC (thin layer chromatography) silica gel plate or high perfor- mance liquid chromatography during the reaction. After completing reaction, 20 mL of ethyl acetate was added for extraction, and then the ethyl acetate was removed under reduced pressure to ob- tain a yellow solid, namely, a-carbonyl butyramide. Based on buta- none, the yield of a-carbonyl butyramide was 76%, and the purity of the product was 98% through HPLC test.

Comparative Example 1

The operation procedures were the same as those in Example 1, to prepare a-carbonyl butyramide. The differences from Example 1 were as follows: the condensation reflux reaction was maintained at 95-105°C. Based on butanone, the yield of a-carbonyl butyramide was 53%, and the purity of the product was 97% through HPLC test.

Comparative Example 2

The operation procedures were the same as those in Example 1, to prepare a-carbonyl butyramide. The differences from Example 1 were as follows: the catalyst used was 0.01 mmol of tetrabu- tylammonium bromide. Based on butanone, the yield of a-carbonyl butyramide was 43%, and the purity of the product was 95% through

HPLC test.

Comparative Example 3

The operation procedures were the same as those in Example 1, to prepare a-carbonyl butyramide. The differences from Example 1 were as follows: the catalyst used was 0.01 mmol of copper chlo- ride. Based on butanone, the yield of a-carbonyl butyramide was 40%, and the purity of the product was 93% through HPLC test.

Comparative Example 4

The operation procedures were the same as those in Example 1, to prepare a-carbonyl butyramide. The differences from Example 1 were as follows: the amount of butanone was 3 mmol. Based on ammo- nium chloride, the yield of a-carbonyl butyramide was 65%, and the purity of the product was 97% through HPLC test.

Comparative Example 5

The operation procedures were the same as those in Example 1,

to prepare a-carbonyl butyramide. The differences from Example 1 were as follows: ammonium chloride was changed to formamide. Based on butanone, the yield of a-carbonyl butyramide was 15%, and the purity of the product was 90% through HPLC test.

Comparative Example 6

The operation procedures were the same as those in Example 1, to prepare a-carbonyl butyramide. The differences from Example 1 were as follows: butanone was changed to butyne. Based on buta- none, the yield of a-carbonyl butyramide was 0%.

Claims

CONCLUSIONS

1. Process for the preparation of α-carbonylbutyramide by reaction in an aqueous phase, in which water serves as solvent, dimethyl sulfoxide as cosolvent, iodine or iodised salt serves as catalyst and α-carbonylbutyramide is generated directly by reaction of butanone, ammonium chloride and an oxidizing agent in the presence of alkali.

Process according to claim 1, characterized in that the catalyst is one or more of 1:C1, tetrabutylammonium iodide and potassium iodide, preferably tetrabutylammonium iodide.

A method according to claim 1 or 2, wherein the molar ratio of butanone to ammonium chloride is (1:1.2) to (1:4.0); the dosage of the catalyst is 2 to 4% of the molar number of butanone.

A method according to claim 1 or 2, wherein the alkali is Na;CO:,

K.CO;, NaHCO;, CaCO;, SeCO;, NaOH, triethylamine or DBU; the oxidizing agent is one or more of air, 0,, HO; and TBHP, preferably Hs0:.

A method according to claim 1 or 4, wherein the dosage of the alkali is 1.0 to 1.5 times the molar amount of ammonium chloride; the volume ratio of water to dimethyl sulfoxide is (7 to 10):

1.

A method according to any one of claims 1 to 5, comprising the following steps: (1) adding butanone to a mixed solution of water and dimethyl sulfoxide, and stirring uniformly; and (2) adding ammonium chloride, alkali and the catalyst to the mixture in step (1), reacting for 30 to 40 minutes, adding the oxidizing agent, reacting continuously until the butanone disappears, and extracting the reaction liquid after the reaction, thereby the a-

carbonylbutyramide is obtained.

A method according to claim 6, wherein when the oxidizing agent is air or oxygen, continuously feeding air or oxygen into the system during the reaction process until the reaction is completed; when the oxidant is H:0:2, adding the oxidant dropwise to the system in the form of an aqueous hydrogen peroxide solution, the dropwise addition time being 30 to 120 min, and the mass ratio of the H .0, until the butanone is (1.25 to 5): 1; and when the oxidant is TBHP, the oxidant is added directly to the system at a time and the molar ratio of the TBHP to the butanone is (1.25 to 5): 1.