CN101544580B - The synthetic method of R-alpha- amino-4-methoxyl phenyl acetamide - Google Patents

Abstract

The present invention relates to the preparation methods of compound.The synthetic method of R-alpha- amino-4-methoxyl phenyl acetamide, the first step are acylated: raw material homoanisic acid, organic solvent, thionyl chloride, reflux condensation mode obtain acetanisole chlorine；It separately takes reaction kettle that D-pHPG and water is added, raw material sodium hydrate aqueous solution and acetanisole chlorine obtained above is added, reaction obtains a step product；Second step methylation: being added a step product in the reactor, organic solvent, Anhydrous potassium carbonate, iodomethane, and reaction obtains white solid secondary product；Third step ammonolysis: being added secondary product and ammonium hydroxide, fully reacting in a high pressure reaction kettle, and filtering obtains solid crude product.Present invention process route is reasonable, and process is simple, strong operability；Process conditions are mild, safety and stability, high income；Final products purity is high, it is high-quality.

Description

The synthetic method of R-alpha- amino-4-methoxyl phenyl acetamide

One, technical field:

The present invention relates to the synthetic methods of compound, especially the synthetic method for the compound of medicine intermediate.

Two, background technique:

R-alpha- amino-4-methoxyl phenyl acetamide is the intermediate of medicine synthesis, and dosage is huge, but the product at present By literature search, it has no document report, is noval chemical compound, document does not provide the specific synthesis technology of the compound yet.

Three, summary of the invention:

The object of the present invention is to provide a kind of synthetic method of R-alpha- amino-4-methoxyl phenyl acetamide, technique is closed Reason, raw material are easy to get, and product quality is good.

Present invention technical solution used for the above purpose is: R-alpha- amino-4-methoxyl phenyl acetamide Synthetic method, specific reaction step point three steps:

The first step is acylated: reaction equation are as follows:

In a kettle, raw material homoanisic acid is added, organic solvent is heated to flowing back, protochloride is then added Sulfone, reflux condensing tube exit connect bubbler, and bubbler 0.5h bubble-free stops reaction after occurring, organic solvent is evaporated off, kettle is residual It is liquid after cooling, vacuum distillation obtains sterling acetanisole chlorine；

It separately takes reaction kettle that D-pHPG and water is added, is cooled to 0 DEG C under agitation, while feed hydrogen is added Aqueous solution of sodium oxide and acetanisole chlorine obtained above control 0~5 DEG C of temperature when addition, control pH value 9~11, Keeping 5 DEG C of insulation reaction 2h end of reaction of temperature after addition, filtering, in obtained solid plus excess base is to Quan Rong, merging filtrate, to Hydrochloric acid is added dropwise in filtrate, controlled at 0~5 DEG C during dropwise addition, when system pH value 3~4, stops that hydrochloric acid, heat preservation is added dropwise It is filtered after stirring 0.5h, obtains a step product；

Second step methylation: reaction equation are as follows:

It is firstly added a step product in the reactor, organic solvent, Anhydrous potassium carbonate, after 35 DEG C of reaction 1h of temperature, room temperature Lower addition iodomethane, sampling analysis after 35 DEG C of reaction 23h of temperature, reaction terminate, and filter, organic solvent is evaporated off, and it is solid to obtain yellow Body (contains a large amount of salts substances), is dissolved, is washed respectively with 1~3% sodium hydrate aqueous solution of concentration, water washing with solvent liquid, Organic layer is separated, solvent is evaporated off, obtains yellow solid crude product, crude product ethyl acetate and n-hexane recrystallize, and are slowly dropped to room Temperature, room temperature filtering, filter cake are washed with ethyl acetate and n-hexane mixing, washing liquid, obtain white solid secondary product；

Third step ammonolysis: reaction equation are as follows:

Secondary product is added in a high pressure reaction kettle and ammonium hydroxide, the two mass ratio are about 1: 10, closing is heated to bath temperature 130 DEG C, it controls pressure in kettle and is up to 0.8MPa, react sampling analysis after 4~6h, fully reacting, filtering obtains solid crude product, crude product White needle-like crystals are obtained with ethyl alcohol recrystallization, product fusing point is 197~199 DEG C.

The first step is acylated: raw material homoanisic acid: the molar ratio of thionyl chloride is 1: 1.1~4, preferably mole Than 1: 1.2；Raw material sodium hydrate aqueous solution and acetanisole cl molar ratio are 1.5~3.5: 1, preferred molar ratio 1.9: 1。

The first step is acylated: organic solvent used is acetonitrile, thionyl chloride, toluene.

The second step methylation: one step product of raw material: iodomethane: the molar ratio of potassium carbonate is 1: 3~5: 3~6, preferably Molar ratio 1: 4: 4.

The second step methylation: organic solvent used is acetone, acetonitrile or n,N-Dimethylformamide.It is described molten Agent liquid is methylene chloride, with chloroform, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), ethyl acetate or isopropyl acetate etc..

The second step methylation: recrystallization solvent is that ethyl acetate and n-hexane 1: 3~6 are prepared by volume, reflux When it is just complete molten.

The second step methylation: ethyl acetate is 1: 4~10 with n-hexane mixing, washing liquid volume ratio.

The third step ammonolysis: the mass concentration of ammonium hydroxide used is 25~28%.

The present invention has outstanding feature compared with similar product synthesis technology:

1, Process Route Planning is reasonable, and process flow is simple, strong operability；

2, process conditions are mild, safety and stability, high income；

3, final products purity is high, it is high-quality, it is suitable for industrialized production.

Specific embodiment:

Invention is further described in detail combined with specific embodiments below, but the invention is not limited to specific implementations Example.

Embodiment 1

Synthesize R-alpha- amino-4-methoxyl phenyl acetamide by following raw materials and processing step: the first step is acylated:

Ingredient proportion:

Name of material	Feed intake quality/g	Molar ratio	Remarks
				Homoanisic acid	32	1.28	AR
Thionyl chloride	27.5	1.54	AR
				Acetonitrile	54		Solvent
D-pHPG	25.1	1
				Sodium hydroxide	14.6	2.4
Water	155		Solvent

Processing step:

Mechanical stirring, reflux condensing tube are being housed, tail gas reception device in the 250ml reaction kettle of thermometer, is added to first Oxygroup phenylacetic acid 32g, acetonitrile 54g are heated to flowing back, and thionyl chloride 27.5g is added dropwise.Reflux condensing tube exit connects bubbler, Bubbler 0.5h bubble-free stops reaction after occurring.Solvent is evaporated off, is liquid after the residual cooling of kettle, vacuum distillation obtains sterling 29.3g, gas phase purity are 93.8%, yield 77.4%；

It separately takes 500ml reaction kettle that D-pHPG 25.1g is added, 135g water is added, is cooled to 0 under agitation DEG C, while sodium hydroxide (14.6g is dissolved in 20ml water) solution is added dropwise and acetanisole chlorine 29.3g obtained above is (pure 93.8%) degree, controls 0~5 DEG C of temperature, pH value is controlled when dropwise addition 9~11, after dripping, 5 DEG C of insulation reaction 2h, and filtering, Gu Body adds excess base to Quan Rong, and merging filtrate, reducing filtrate temperature is 0~5 DEG C, and hydrochloric acid is added dropwise into filtrate under stiring, is added dropwise In the process controlled at 0~5 DEG C, when system pH value 3~4, stops that hydrochloric acid is added dropwise, filter, filter after insulated and stirred 0.5h Obtain a step product 36.6g, liquid phase purity 93.0%, yield 72.0%.Two step total recoverys are as follows: 55.7%, a step product is molten Point is 192~196 DEG C；

Second step methylation:

Ingredient proportion:

Name of material	Feed intake quality/g	Molar ratio	Remarks
				One step product	19.3	1	AR
Iodomethane	34.8	4	AR
				Acetone	200		AR
Potassium carbonate	33.8	4	AR

Processing step:

Mechanical stirring is being housed, thermometer is firstly added a step product in the 500ml four-hole boiling flask of reflux condensing tube (purity: 93.0%), after Anhydrous potassium carbonate 33.8g, 35 DEG C of reaction 1h, iodomethane is added in acetone 200g to 20.75g at room temperature Sampling analysis after 29.8g, 35 DEG C of reaction 23h.Reaction terminates, and filtering is evaporated off acetone, obtains yellow solid crude product dry weight 44.5g (containing a large amount of salts substances) is dissolved with 200ml methylene chloride, is washed respectively with 200g1% sodium hydrate aqueous solution, 200g water Washing, separates organic layer, solvent is evaporated off, obtain yellow solid crude product dry weight 24.7g, crude product is tied with ethyl acetate with n-hexane again Brilliant when reflux (ethyl acetate 89ml, n-hexane 56ml, just complete molten), is slowly dropped to room temperature, room temperature filtering, filter cake acetic acid second (ethyl acetate: n-hexane volume ratio=1: 4) washing, obtain white solid secondary product, does by ester and n-hexane mixed liquor 50ml It is 19.7g after dry, liquid phase purity is 99.0%, and yield 93.7%, secondary product fusing point is 107~109 DEG C；

Third step ammonolysis:

Ingredient proportion:

Name of material	Inventory	Molar ratio	Remarks
				Secondary product	17.2g	1	AR
Ammonium hydroxide	210ml		AR (25%~28%)

Processing step:

Equipped with secondary product 17.2g, ammonium hydroxide 210ml are added in churned mechanically 500ml autoclave, closing is heated To 130 DEG C of bath temperature (pressure reaches as high as 0.8MPa in kettle), sampling analysis after clock reaction 4h, fully reacting, filtering obtains solid Product dry weight be 9.4g, purity 97.5%, crude yield 57.1%, with 525ml ethyl alcohol recrystallization obtain white needles crystalline substance Soma weight 8.9g, purity 98.7%, total recovery 53.9%, target product fusing point are 197~199 DEG C.

Embodiment 2

R-alpha- amino-4-methoxyl phenyl acetamide is synthesized according to method described in embodiment 1, each step reaction is used former Expect specific as follows:

The first step is acylated:

Ingredient proportion:

Name of material	Feed intake quality/g	Molar ratio	Remarks
				Homoanisic acid	32	1.28	AR
Thionyl chloride	90	5.04	As solvent
				N,N-Dimethylformamide	1		Catalyst
D-pHPG	25.1	1
				Sodium hydroxide	14.6	2.4
Water	155		Solvent

Processing step:

Mechanical stirring, reflux condensing tube are being housed, tail gas reception device in the 250ml reaction kettle of thermometer, is added to first Oxygroup phenylacetic acid 32g, thionyl chloride 90g, n,N-Dimethylformamide 1g are heated to flowing back.Reflux condensing tube exit connects drum Bubbler, bubbler 0.5h bubble-free stop reaction after occurring.Reaction time is 8~10h.It is recovered under reduced pressure after having reacted with water pump more Remaining thionyl chloride is liquid after the residual cooling of kettle, and vacuum distillation obtains sterling 31.2g, and gas phase purity is 96%, and yield is 84.3%；

It separately takes 500ml reaction kettle that D-pHPG 25.1g is added, 135g water is added, is cooled to 0 under agitation DEG C, while sodium hydroxide (14.6g is dissolved in 20ml water) solution is added dropwise and acetanisole chlorine 31.2g obtained above is (pure 96%) degree, controls 0~5 DEG C of temperature, pH value is controlled when dropwise addition 9~11, after dripping, 5 DEG C of insulation reaction 2h, and filtering, solid Add excess base to Quan Rong, merging filtrate, reducing filtrate temperature is 0~5 DEG C, and hydrochloric acid is added dropwise into filtrate under stiring, was added dropwise Controlled at 0~5 DEG C in journey, when system pH value 3~4, stops that hydrochloric acid is added dropwise, a step is obtained by filtration after insulated and stirred 0.5h Product 37.1g, liquid phase purity 94.9%, yield 74.2%.Two step total recoverys are as follows: 62.6%.

Second step methylation:

Ingredient proportion:

Name of material	Feed intake quality/g	Molar ratio	Remarks
				One step product	19.3	1	AR
Iodomethane	34.8	4	AR
				Acetonitrile	200		AR
Potassium carbonate	33.8	4	AR

Processing step:

Mechanical stirring is being housed, thermometer is firstly added a step product in the 500ml four-hole boiling flask of reflux condensing tube (purity: 93.0%), after Anhydrous potassium carbonate 33.8g, 35 DEG C of reaction 1h, iodomethane is added in acetonitrile 200g to 20.75g at room temperature Sampling analysis after 29.8g, 35 DEG C of reaction 23h.Reaction terminates, and filtering is evaporated off acetonitrile, obtains yellow solid crude product dry weight 47.2g, It is dissolved with 200ml dichloroethanes, is washed respectively with 200g2% sodium hydrate aqueous solution, 200g water washing separates organic layer, steams Except solvent, yellow solid crude product dry weight 26.3g is obtained, and crude product ethyl acetate and n-hexane recrystallization (ethyl acetate 90ml, just Hexane 60ml), it is slowly dropped to room temperature, room temperature filtering, filter cake ethyl acetate and n-hexane mixed liquor 50ml (ethyl acetate: just Hexane volume ratio=1: 6) washing, and obtains white solid secondary product, is 20.0g after dry, and liquid phase purity is 99.0%, yield It is 95.2%.

Third step ammonolysis:

Ingredient proportion:

Name of material	Inventory	Molar ratio	Remarks
				Secondary product	17.2g	1	AR
Ammonium hydroxide	191g		AR (25%~28%)

Processing step:

Equipped with secondary product 17.2g, ammonium hydroxide 191g are added in churned mechanically 500ml autoclave, closing is heated To 130 DEG C of bath temperature (pressure reaches as high as 0.8MPa in kettle), sampling analysis after clock reaction 4h, reaction raw materials surplus < 1%, Reaction solution filters after being cooled to room temperature, and obtaining solid product dry weight is 9.4g, and purity 97.5% is obtained with 525ml ethyl alcohol recrystallization To white needle-like crystals dry weight 8.9g, purity 98.7%, yield 53.9%.

Embodiment 3

R-alpha- amino-4-methoxyl phenyl acetamide is synthesized according to method as described in example 2, each step reaction is used former Expect specific as follows:

The first step is acylated:

Ingredient proportion:

Name of material	Feed intake quality/g	Molar ratio	Remarks
				Homoanisic acid	32	1.28	AR
Thionyl chloride	27.5	1.54	AR

Toluene	54		Solvent
				D-pHPG	25.1	1
Sodium hydroxide	14.6	2.4
				Water	155		Solvent

Processing step:

Mechanical stirring, reflux condensing tube are being housed, tail gas reception device in the 250ml reaction kettle of thermometer, is added to first Oxygroup phenylacetic acid 32g, thionyl chloride 27.5g, toluene 54g are heated to flowing back.Reflux condensing tube exit connects bubbler, is bubbled Device 0.5h bubble-free stops reaction after occurring.Reaction time is 5~7h.After having reacted, solvent toluene, the residual cooling of kettle is recovered under reduced pressure It is afterwards liquid, vacuum distillation obtains sterling 28.5g, and gas phase purity is 95.6%, yield 75.6%；

It separately takes 500ml reaction kettle that D-pHPG 25.1g is added, 135g water is added, is cooled to 0 under agitation DEG C, while sodium hydroxide (14.6g is dissolved in 20ml water) solution is added dropwise and acetanisole chlorine 28.5g obtained above is (pure 95.6%) degree, controls 0~5 DEG C of temperature, pH value is controlled when dropwise addition 9~11, after dripping, 5 DEG C of insulation reaction 2h, and filtering, Gu Body adds excess base to Quan Rong, and merging filtrate, reducing filtrate temperature is 0~5 DEG C, and hydrochloric acid is added dropwise into filtrate under stiring, is added dropwise In the process controlled at 0~5 DEG C, when system pH value 3~4, stops that hydrochloric acid is added dropwise, be obtained by filtration one after insulated and stirred 0.5h Walk product 34.9g, liquid phase purity 95.7%, yield 70.0%.Two step total recoverys are as follows: 52.9%.

Second step methylation:

Ingredient proportion:

Name of material

Feed intake quality/g

Molar ratio

Remarks

One step product	19.3	1	AR
				Iodomethane	34.8	4	AR
N, N- dimethyl methyl Amide	200		AR
				Potassium carbonate	33.8	4	AR

Processing step:

Mechanical stirring is being housed, thermometer is firstly added a step product in the 500ml four-hole boiling flask of reflux condensing tube (purity: 95.7%), after Anhydrous potassium carbonate 33.8g, 35 DEG C of reaction 1h, iodomethane is added in DMF 200g to 20.17g at room temperature Sampling analysis after 29.8g, 35 DEG C of reaction 23h.Reaction terminates, and 1000g water is added into filtrate for filtering, filters after stirring 0.5h, Yellow solid crude product dry weight 45.4g is obtained, is dissolved with 200ml dichloroethanes, is washed respectively with 200g5% sodium hydrate aqueous solution Wash, 200g water washing separates organic layer, solvent is evaporated off, obtain yellow solid crude product dry weight 27.7g, crude product ethyl acetate with N-hexane recrystallization when reflux (ethyl acetate 90ml, n-hexane 60ml, entirely molten), is slowly dropped to room temperature, room temperature filtering, and filter cake is used Ethyl acetate and n-hexane mixed liquor 50ml (ethyl acetate: n-hexane volume ratio=1: 10) wash, obtain two step of white solid Product is 20.6g after dry, and liquid phase purity is 99.0%, yield 98%.

Third step ammonolysis:

Ingredient proportion:

Name of material	Inventory	Molar ratio	Remarks
				Secondary product	17.2g	1	AR
Ammonium hydroxide	191g		AR (25%-28%)

Processing step:

Equipped with secondary product 17.2g, ammonium hydroxide 172g are added in churned mechanically 500ml autoclave, closing is heated To 130 DEG C of bath temperature (pressure reaches as high as 0.8MPa in kettle), sampling analysis after clock reaction 4h, reaction raw materials surplus < 1%, Reaction solution filters after being cooled to room temperature, and obtaining solid product dry weight is 10.8g, and purity 98.2% is obtained with 525ml ethyl alcohol recrystallization To white needle-like crystals dry weight 9.3g, purity 98.8%, yield 56.4%.

Claims (10)

1. The synthesis of (1. R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxyphenyl) acetamide Method, it is characterized in that: three steps of specific reaction step point:

   The first step is acylated: in a kettle, raw material homoanisic acid is added, organic solvent is heated to flowing back, then be added Thionyl chloride, reflux condensing tube exit connect bubbler, and bubbler 0.5h bubble-free stops reaction after occurring, is evaporated off organic molten Agent, is liquid after the residual cooling of kettle, and vacuum distillation obtains sterling acetanisole chlorine；

   It separately takes reaction kettle that D-pHPG and water is added, is cooled to 0 DEG C under agitation, while raw material hydroxide is added Sodium water solution and acetanisole chlorine obtained above control 0~5 DEG C of temperature when addition, control pH value 9~11, are added 5 DEG C of insulation reaction 2h end of reaction of temperature are kept afterwards, are filtered, and add excess base to Quan Rong, merging filtrate, to filtrate in obtained solid Middle dropwise addition hydrochloric acid, when system pH value 3~4, stops that hydrochloric acid, insulated and stirred is added dropwise controlled at 0~5 DEG C during dropwise addition It is filtered after 0.5h, obtains a step product；

   Second step methylation: it is firstly added a step product in the reactor, organic solvent, Anhydrous potassium carbonate, 35 DEG C of temperature anti- After answering 1h, iodomethane, sampling analysis after 35 DEG C of reaction 23h of temperature are added at room temperature, reaction terminates, and organic solvent is evaporated off in filtering, Yellow solid (containing a large amount of salts substances) are obtained, is dissolved with solvent liquid, is washed respectively with 1~3% sodium hydrate aqueous solution of concentration It washs, water washing separates organic layer, and solvent is evaporated off, and obtains yellow solid crude product, and crude product ethyl acetate and n-hexane recrystallize, It is slowly dropped to room temperature, room temperature filtering, filter cake is washed with ethyl acetate and n-hexane mixing, washing liquid, obtains two step of white solid Product；

   Third step ammonolysis: secondary product is added in a high pressure reaction kettle and ammonium hydroxide, the two mass ratio are about 1:10, closing is heated to It 130 DEG C of bath temperature, controls pressure in kettle and is up to 0.8MPa, react sampling analysis after 4~6h, fully reacting, filtering obtains solids crude Product, crude product obtain white needle-like crystals with ethyl alcohol recrystallization, and product fusing point is 197~199 DEG C.
2. 2. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: the first step is acylated: raw material homoanisic acid: mole of thionyl chloride Than for 1:1.1~4；Raw material sodium hydrate aqueous solution and acetanisole cl molar ratio are 1.5~3.5:1.
3. 3. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: the first step is acylated: raw material homoanisic acid: mole of thionyl chloride Compare 1:1.2；Raw material sodium hydrate aqueous solution and acetanisole cl molar ratio are 1.9:1.
4. 4. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: the first step is acylated: organic solvent used is acetonitrile, thionyl chloride or first Benzene.
5. 5. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: second step methylate: one step product of raw material: iodomethane: potassium carbonate rubs You are than being 1:3~5:3~6
6. 6. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: second step methylate: one step product of raw material: iodomethane: potassium carbonate rubs You are than being 1:4:4.
7. 7. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: second step methylate: organic solvent used be acetone, acetonitrile or N, Dinethylformamide；The solvent liquid is methylene chloride, chloroform, 1,2- dichloroethanes, methyl tertiary butyl ether(MTBE), ethyl acetate Or isopropyl acetate.
8. 8. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: second step methylates: recrystallization solvent is that ethyl acetate and n-hexane are pressed Volume ratio 1:3~6 is prepared, just complete molten when reflux.
9. 9. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- methoxy according to claim 1 Base phenyl) acetamide synthetic method, it is characterized in that: second step methylate: ethyl acetate and n-hexane mixing, washing liquid product Than for 1:4~10.
10. 10. (R)-N- [2- amino -1- (4- methoxyphenyl) -2- oxoethyl] -2- (4- first according to claim 1 Phenyl) acetamide synthetic method, it is characterized in that: third step ammonolysis: the mass concentration of ammonium hydroxide used be 25~28%.