CN104402757A - Preparation method of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxyphenyl) methyl acetate - Google Patents
Preparation method of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxyphenyl) methyl acetate Download PDFInfo
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- CN104402757A CN104402757A CN201410713644.5A CN201410713644A CN104402757A CN 104402757 A CN104402757 A CN 104402757A CN 201410713644 A CN201410713644 A CN 201410713644A CN 104402757 A CN104402757 A CN 104402757A
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- oxoethyl
- dimethylamino
- methyl acetate
- hydroxy phenyl
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Abstract
The invention discloses a preparation method of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxyphenyl) methyl acetate, which comprises the steps of allowing dimethylamine to react with chloroacetyl chloride to generate N,N-dimethyl-2-chloroacetamide, allowing N,N-dimethyl-2-chloroacetamide to react with p-hydoxyphenylactic acid to generate a crude product of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxyphenyl) methyl acetate, and refining the crude product to form a fine product of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxyphenyl) methyl acetate. 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxyphenyl) methyl acetate prepared by the method is high in quality and purity, and the preparation method is simple, low in energy consumption and low in cost.
Description
Technical field
The present invention relates to medicine and manufacture field, specifically a kind of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate.
Background technology
2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate is the key intermediate of synthesis non-peptide proteinoid enzyme inhibitors camostat mesilate (Camostat mesilate).Camostat mesilate, chemical name is 4-(4-guanidine radicals benzoyloxy group) toluylic acid-N, N-dimethyl carbamoyl methyl esters mesylate, be the non-peptide proteinoid enzyme inhibitors of Japanese little Ye medicine Co., Ltd. exploitation, first in January, 1985 go on the market with trade(brand)name Foipan in Japan.Pharmacological evaluation shows: camostat mesilate has very strong restraining effect to trypsinase, kallikrein, Tryptase, zymoplasm, C1 esterase, oral rear kassinin kinin generation system, fibrinolytic system, blood coagulation system and the complement system acting on rapidly body, suppress the exception of the enzymic activity of these systems hyperfunction, thus control the symptom of chronic pancreatitis, alleviating pain, reduce amylase value, the clinical alleviation for chronic pancreatitis acute symptom.In addition, this product is also used for the treatment of diffusivity blood vessel blood coagulation disease.Pharmacological evaluation also finds, camostat mesilate also has the effects such as anticancer, antiviral, and effectively can reduce proteinuria, and play the effect of preliminary conditioning, further research is still underway.Current this product not yet in Discussion on Chinese Listed, also without the report succeeded in developing.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, its preparation method is simple, and yield is high.
Technical scheme of the present invention is:
A kind of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, comprise the steps:
(1), first by methylene dichloride join in reaction vessel and stir, be cooled to-10-0 DEG C to start to drip dimethylamine, drip chloroacetyl chloride simultaneously; Drip process control temp-10-5 DEG C, system pH controls 4-7, react 1 hour at-10-5 DEG C DEG C after dripping off, reaction process control pH 5-7, reaction terminates rear standing, separatory, and water layer extracts, organic layer concentrating under reduced pressure, underpressure distillation, obtain N, N-dimethyl-2-chlor(o)acetamide distillation product;
(2), by N obtained for step (1), N-dimethyl-2-chlor(o)acetamide joins stirring at low speed in reaction vessel together with triethylamine, then sodium bisulfite and p-hydroxyphenylaceticacid is continued to add wherein, continue stirring at low speed, the last triethylamine that drips again stirs, dropping temperature 40-95 DEG C, drip off rear maintenance 80-95 DEG C reaction 3 hours, add sodium sulfite solution again, cooling crystallization, filtration, filter cake washing, drain after obtain thick 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate wet product;
(3), sodium sulfite solution is joined in reaction vessel, then the thick 2-(dimethylamino that step (2) is obtained is added)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate wet product and ethyl acetate, heating for dissolving, after having dissolved, cooling crystallization, suction filtration, filter cake washing, drain, drying under reduced pressure, finally dried filter cake is joined in acetonitrile and stir, heating for dissolving, after dissolving terminates, cooling crystallization, suction filtration, filter cake washing, drain, drying under reduced pressure obtains 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate fine work.
Dimethylamine in described step (1) select mass percent be 50% dimethylamine solution, the mass ratio of methylene dichloride, 50% dimethylamine solution and chloroacetyl chloride is 5.3-5.4:1.6-1.8 in step (1): 1.
In described step (2), the mass ratio of N, N-dimethyl-2-chlor(o)acetamide and p-hydroxyphenylaceticacid is 1: 1.2-1.4.
In described step (2), the temperature of cooling crystallization is 0-5 DEG C, crystallization time 2 h.
In described step (3), the temperature of cooling crystallization is 0-5 DEG C, 1 hour crystallization time.
Advantage of the present invention:
The 2-(dimethylamino of the present invention's synthesis)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate quality is good, and purity is high, and preparation method is simple, and less energy consumption, cost is low.
Embodiment
A kind of 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, comprise the steps:
(1), first by 160g methylene dichloride join in reaction vessel and stir, be cooled to-10-0 DEG C to start to drip the dimethylamine solution that 51g mass percent is 50%, drip 30g chloroacetyl chloride simultaneously; Drip process control temp-10-5 DEG C, system pH controls 4-7, reacts 1 hour after dripping off at-10-5 DEG C DEG C, reaction process control pH 5-7, reaction terminates rear standing 20min, separatory, organic layer, in lower floor, is released stand-by, and water layer is with 54g dichloromethane extraction, merge organic layer, concentrating under reduced pressure, thickening temperature less than 80 DEG C, after concentrated end, underpressure distillation within 130 DEG C, obtains N, N-dimethyl-2-chlor(o)acetamide distillation product;
(2), the N obtained by step (1), N-dimethyl-2-chlor(o)acetamide joins stirring at low speed in reaction vessel together with 9g triethylamine, then 0.4g sodium bisulfite and 40g p-hydroxyphenylaceticacid is continued to add wherein, continue stirring at low speed, the last 17.6g triethylamine that drips again stirs, dropping temperature 40-95 DEG C, drip off rear maintenance 80-95 DEG C reaction 3 hours, add 90g sodium sulfite solution (0.05gNaHSO3+90gH2O) again, add and start more than temperature 70 C, add finishing temperature more than 48 DEG C, add rear cooling crystallization (cooling temperature 0-5 DEG C, crystallization time 2 h), filter, filter cake washing, thick 2-(dimethylamino is obtained after draining)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate wet product,
(3), 20.2g sodium sulfite solution (0.2g NaHSO3+20g H2O) is joined in reaction vessel, then the thick 2-(dimethylamino that step (2) is obtained is added)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate wet product and 50mL ethyl acetate, heating for dissolving, after having dissolved, cooling crystallization (recrystallization temperature 0-5 DEG C, the 1 hour crystallization time), suction filtration, filter cake is with 10mL water washing, wash with 20mL ethyl acetate again after draining, drain, drying under reduced pressure (60 ± 3 DEG C, 2 hours), finally dried filter cake is joined in 30mL acetonitrile and stir, heating for dissolving, after dissolving terminates, cooling crystallization (recrystallization temperature 0-5 DEG C, the 1 hour crystallization time), suction filtration, filter cake is with 17mL acetonitrile wash, drain, drying under reduced pressure (60 ± 3 DEG C, 2 hours) obtain 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate fine work, output is about 45g.
Claims (5)
1. 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, it is characterized in that: comprise the steps:
(1), first by methylene dichloride join in reaction vessel and stir, be cooled to-10-0 DEG C to start to drip dimethylamine, drip chloroacetyl chloride simultaneously; Drip process control temp-10-5 DEG C, system pH controls 4-7, react 1 hour at-10-5 DEG C DEG C after dripping off, reaction process control pH 5-7, reaction terminates rear standing, separatory, and water layer extracts, organic layer concentrating under reduced pressure, underpressure distillation, obtain N, N-dimethyl-2-chlor(o)acetamide distillation product;
(2), by N obtained for step (1), N-dimethyl-2-chlor(o)acetamide joins stirring at low speed in reaction vessel together with triethylamine, then sodium bisulfite and p-hydroxyphenylaceticacid is continued to add wherein, continue stirring at low speed, the last triethylamine that drips again stirs, dropping temperature 40-95 DEG C, drip off rear maintenance 80-95 DEG C reaction 3 hours, add sodium sulfite solution again, cooling crystallization, filtration, filter cake washing, drain after obtain thick 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate wet product;
(3), sodium sulfite solution is joined in reaction vessel, then the thick 2-(dimethylamino that step (2) is obtained is added)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate wet product and ethyl acetate, heating for dissolving, after having dissolved, cooling crystallization, suction filtration, filter cake washing, drain, drying under reduced pressure, finally dried filter cake is joined in acetonitrile and stir, heating for dissolving, after dissolving terminates, cooling crystallization, suction filtration, filter cake washing, drain, drying under reduced pressure obtains 2-(dimethylamino)-2-oxoethyl-2-(4-hydroxy phenyl) methyl acetate fine work.
2. a kind of 2-(dimethylamino according to claim 1)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, it is characterized in that: the dimethylamine in described step (1) select mass percent be 50% dimethylamine solution, the mass ratio of methylene dichloride, 50% dimethylamine solution and chloroacetyl chloride is 5.3-5.4:1.6-1.8 in step (1): 1.
3. a kind of 2-(dimethylamino according to claim 1)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, it is characterized in that: in described step (2), the mass ratio of N, N-dimethyl-2-chlor(o)acetamide and p-hydroxyphenylaceticacid is 1: 1.2-1.4.
4. a kind of 2-(dimethylamino according to claim 1)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, it is characterized in that: in described step (2), the temperature of cooling crystallization is 0-5 DEG C, crystallization time 2 h.
5. a kind of 2-(dimethylamino according to claim 1)-2-oxoethyl-2-(4-hydroxy phenyl) preparation method of methyl acetate, it is characterized in that: in described step (3), the temperature of cooling crystallization is 0-5 DEG C, 1 hour crystallization time.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4021472A (en) * | 1974-11-01 | 1977-05-03 | Ono Pharmaceutical Co., Ltd. | Guanidinobenzoic acid derivatives |
| JPH03223241A (en) * | 1990-01-29 | 1991-10-02 | Daicel Chem Ind Ltd | Production of n,n-dimethylchloroacetamide |
| CN1721392A (en) * | 2004-07-15 | 2006-01-18 | 上海化学试剂研究所 | Process for preparing N,N-dimethyl chloroacetamide |
-
2014
- 2014-12-02 CN CN201410713644.5A patent/CN104402757B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4021472A (en) * | 1974-11-01 | 1977-05-03 | Ono Pharmaceutical Co., Ltd. | Guanidinobenzoic acid derivatives |
| JPH03223241A (en) * | 1990-01-29 | 1991-10-02 | Daicel Chem Ind Ltd | Production of n,n-dimethylchloroacetamide |
| CN1721392A (en) * | 2004-07-15 | 2006-01-18 | 上海化学试剂研究所 | Process for preparing N,N-dimethyl chloroacetamide |
Non-Patent Citations (1)
| Title |
|---|
| 刘宝玉等: "合成对(对氨基苯甲酰氧基)苯乙酸-N,N-二甲氨基甲酰甲酯方法的改进", 《化学试剂》 * |
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Denomination of invention: Method for preparing 2- (two methyl amino) -2- oxo ethyl -2- (4- hydroxy phenyl) methyl acetate Effective date of registration: 20170103 Granted publication date: 20160608 Pledgee: Bank of Communications Ltd Anhui branch Pledgor: Wan Hui Pharmaceutical (Anhui) Co., Ltd. Registration number: 2016340000154 |
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Denomination of invention: Method for preparing 2- (two methyl amino) -2- oxo ethyl -2- (4- hydroxy phenyl) methyl acetate Effective date of registration: 20170724 Granted publication date: 20160608 Pledgee: Bank of Communications Ltd Anhui branch Pledgor: Wan Hui Pharmaceutical (Anhui) Co., Ltd. Registration number: 2017340000125 |