CN102321043A - Preparation method for 4-methyl-5-ethyoxyl-oxazole - Google Patents
Preparation method for 4-methyl-5-ethyoxyl-oxazole Download PDFInfo
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- CN102321043A CN102321043A CN201110193140A CN201110193140A CN102321043A CN 102321043 A CN102321043 A CN 102321043A CN 201110193140 A CN201110193140 A CN 201110193140A CN 201110193140 A CN201110193140 A CN 201110193140A CN 102321043 A CN102321043 A CN 102321043A
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Abstract
The invention relates to a preparation method for 4-methyl-5-ethyoxyl-oxazole. The preparation method for the 4-methyl-5-ethyoxyl-oxazole comprises the following steps of: performing cyclization reaction on N-ethoxyl oxalyl alanine ethyl ester under the action of phosphorus oxychloride/triethylamine/dimethylformamide used as a cyclization dehydrating agent at the temperature of between 40 and 60 DEG C for 0.5 to 1 hour; heating to 75 to 100 DEG C and reacting for 5 to 10 hours; hydrolyzing the reaction materials and separating out a water layer; adding an aqueous solution of sodium hydroxide into an organic layer to hydrolyze, adjusting the pH value to be 12 to 14, distilling to obtain ethanol and adjusting the pH value to be 2.0 to 3.0 by adding sulfuric acid; heating to 65 DEG C to perform decarboxylation; adjusting the pH value to 8.0 to 10.0 by using alkali; after chloroform extraction, drying the organic layer by using anhydrous sodium sulfate; and distilling the chloroform under normal pressure to obtain the target product 4-methyl-5-ethyoxyl-oxazole. The process is easy to operate and by the preparation method, industrialized production is easy to realize; the reaction condition is mild, side reaction is few, reaction yield is high and the product content is high; and toxic methylbenzene is not used, so physical health of staff and environmental protection are facilitated.
Description
Technical field
The present invention relates to a kind of vitamins B
6The preparation method of key intermediate 4-methyl-5-oxyethyl group-oxazoles.
Background technology
The working method of often doing at present is that N-ethoxalyl alanine ethyl ester is synthesized 4-methyl-5-oxyethyl group-2-oxazole ethyl ester in POCl3/triethylamine/toluene cyclization system dehydration, and the latter has synthesized title product through hydrolysis, acid out and decarboxylation three-step reaction.
Above-mentioned used cyclization dewatering agent has phosgene/fat tertiary amine/chloroform, Vanadium Pentoxide in FLAKES/chloroform, POCl3/triethylamine/toluene etc., adopts above-mentioned cyclization dewatering agent reaction more or less to exist: shortcomings such as ring-closure reaction is incomplete, and impurity is many, and yield is low; Adopt Vanadium Pentoxide in FLAKES/chloroform cyclization dewatering agent, material is formed lump easily in the reaction process, and operation is difficulty very; Use Vanadium Pentoxide in FLAKES/chloroform give cyclization dewatering agent, not only ring-closure reaction is incomplete, and phosgene be severe toxicity, and transportation is unusual inconvenience also; Adopt that POCl3/triethylamine/toluene cyclization dewatering agent is at 80 ℃ of ring-closure reactions, the ring-closure reaction side reaction is many, and product impurity is many, and the used toluene of reaction process is poisonous, has not only influenced HUMAN HEALTH, and has caused environmental pollution.
Summary of the invention
The present invention provides a kind of preparation method who does not use virose toluene, reaction yield height, good product quality, is easy to 4-methyl-5-oxyethyl group-oxazoles of suitability for industrialized production.
For realizing the object of the invention, the present invention adopts following technical scheme:
A kind of vitamins B
6The preparation method of 4-methyl-5-oxyethyl group-oxazoles, comprising:
Make the cyclization dewatering agent with POCl3/triethylamine/N, the ring-closure reaction of N-ethoxalyl alanine ethyl ester in above-mentioned cyclization dewatering agent is 40～60 ℃ of reactions 0.5～1 hour, is warming up to 75～100 ℃ of reactions 5～10 hours again; After reaction was accomplished, cooling with the reaction mass hydrolysis, divided water-yielding stratum, and water layer reclaims triethylamine after adding alkaline purification; In organic layer, add the aqueous sodium hydroxide solution hydrolysis, adjust pH 12～14, underpressure distillation goes out the second alcohol and water, adds sulfuric acid adjust pH 2.0～3.0; Be warming up to 65 ℃ of decarboxylations, with alkali pH value 8.0～10.0, behind chloroform extraction, organic layer is used anhydrous sodium sulfate drying again, and the air distillation chloroform gets purpose product 4-methyl-5-oxyethyl group-oxazoles.
N-ethoxalyl alanine ethyl ester in the cyclization dewatering agent: triethylamine: N: the material mol ratio of POCl3 is 1:3～6:0.05～0.3:1～2.
Ring-closure reaction is 40～60 ℃ of reactions 0.5～1 hour, is warming up to 75～85 ℃ of reactions 5～8 hours again.
The preferred pH value of described basic hydrolysis is 12～13, and said sulfuric acid adjust pH is 2.0～2.5, and the said adjusting PH with base value of using again is 8.0～9.0.
The present invention elder generation in ring-closure reaction reacted 0.5～1 hour for 40～60 ℃, can avoid the generation of the high side reaction of temperature like this, had increased reaction yield, had improved product purity.
The present invention and original compared with techniques, advantage is embodied in:
Technological operation is simple, is easy to suitability for industrialized production;
Reaction conditions is gentle, and side reaction is few, and reaction yield is high, product content is high;
Do not use virose toluene, help employee's healthy and environment protection.
Embodiment
In order further to understand the present invention, the present invention is elaborated below in conjunction with specific examples.
Embodiment 1
In the four-hole boiling flask that has prolong, mechanical stirring, TM; Add triethylamine 264g (2.6mol), N-ethoxalyl alanine ethyl ester 200g (content 96% successively; 0.88mol), N 3.2g (0.0438 mol); Slowly add POCl3 133g (0.87mol) then, 60 ℃ were reacted 1 hour, were warming up to 80～85 ℃ of reactions 7 hours again.Be cooled to 50 ℃ and add water 350g hydrolysis, divide water-yielding stratum, water layer reclaims triethylamine after adding alkaline purification; In organic layer, add 20% aqueous sodium hydroxide solution (about 250ml) hydrolysis, adjust pH 12, underpressure distillation goes out the second alcohol and water, is cooled to below 30 ℃, adds sulfuric acid adjust pH 2.0.Be warming up to 65 ℃～70 ℃ decarboxylations, until no CO
2Gas produces, and again with adjusting PH with base value 8.0, through chloroform extraction, organic layer use anhydrous sodium sulfate drying, the air distillation chloroform, to 100 ℃ only, must purpose product 4-methyl-5-oxyethyl group-oxazole 92.2g, content 97.3%, yield 80.2%.
Embodiment 2
In the four-hole boiling flask that has prolong, mechanical stirring, TM; Add triethylamine 352g (3.48mol), N-ethoxalyl alanine ethyl ester 200g (content 96% successively; 0.88mol), N 13g (0.18 mol); Slowly add POCl3 143g (0.93mol) then, 60 ℃ were reacted 1 hour, were warming up to 80～85 ℃ of reactions 7 hours again.Be cooled to 50 ℃ and add water 380g hydrolysis, divide water-yielding stratum, water layer reclaims triethylamine after adding alkaline purification; In organic layer, add 20% aqueous sodium hydroxide solution (about 260ml) hydrolysis, adjust pH 13, underpressure distillation goes out the second alcohol and water, is cooled to below 30 ℃, adds sulfuric acid adjust pH 2.5.Be warming up to 65 ℃～70 ℃ decarboxylations, until no CO
2Gas produces, and again with adjusting PH with base value 8.5, through chloroform extraction, organic layer use anhydrous sodium sulfate drying, the air distillation chloroform, to 100 ℃ only, must purpose product 4-methyl-5-oxyethyl group-oxazole 94.1g, content 97.5%, yield 82.0%.
Embodiment 3
In the four-hole boiling flask that has prolong, mechanical stirring, TM; Add triethylamine 264g (2.6mol), N-ethoxalyl alanine ethyl ester 200g (content 96% successively; 0.88mol), N 13g (0.18 mol); Slowly add POCl3 133g (0.87mol) then, 60 ℃ were reacted 1 hour, were warming up to 80～85 ℃ of reactions 7 hours again.Be cooled to 50 ℃ and add water 350g hydrolysis, divide water-yielding stratum, water layer reclaims triethylamine after adding alkaline purification; In organic layer, add 20% aqueous sodium hydroxide solution (about 250ml) hydrolysis, adjust pH 14, underpressure distillation goes out the second alcohol and water, is cooled to below 30 ℃, adds sulfuric acid adjust pH 3.0; Be warming up to 65 ℃～70 ℃ decarboxylations, until no CO
2Gas produces, and again with adjusting PH with base value 9.0, through chloroform extraction, organic layer use anhydrous sodium sulfate drying, the air distillation chloroform, to 100 ℃ only, must purpose product 4-methyl-5-oxyethyl group-oxazole 93.4g, content 97.3%, yield 81.2%.
Claims (4)
1. vitamins B
6The preparation method of 4-methyl-5-oxyethyl group-oxazoles; Comprise: make the cyclization dewatering agent with POCl3/triethylamine/N; The ring-closure reaction of N-ethoxalyl alanine ethyl ester in above-mentioned cyclization dewatering agent is 40～60 ℃ of reactions 0.5～1 hour, is warming up to 75～100 ℃ of reactions 5～10 hours again; After reaction was accomplished, cooling with the reaction mass hydrolysis, divided water-yielding stratum, and water layer reclaims triethylamine after adding alkaline purification; In organic layer, add the aqueous sodium hydroxide solution hydrolysis, adjust pH 12～14, underpressure distillation goes out the second alcohol and water, adds sulfuric acid adjust pH 2.0～3.0; Be warming up to 65 ℃ of decarboxylations, with alkali pH value 8.0～10.0, behind chloroform extraction, organic layer is used anhydrous sodium sulfate drying again, and the air distillation chloroform gets purpose product 4-methyl-5-oxyethyl group-oxazoles.
2. like the described method of claim 1, it is characterized in that: N-ethoxalyl alanine ethyl ester in the described cyclization dewatering agent: triethylamine: N: the material mol ratio of POCl3 is 1:3～6:0.05～0.3:1～2.
3. like claim 1 or 2 described methods, it is characterized in that: described be warming up to again 75～85 ℃ the reaction 5～8 hours.
4. like claim 1 or 2 described methods, it is characterized in that: described basic hydrolysis pH value is 12～13, and said sulfuric acid adjust pH is 2.0～2.5, and the said alkali pH value of using again is 8.0～9.0.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110193140A CN102321043A (en) | 2011-07-12 | 2011-07-12 | Preparation method for 4-methyl-5-ethyoxyl-oxazole |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447605A (en) * | 2014-12-09 | 2015-03-25 | 湖北惠生药业有限公司 | Industrial preparation method of 4-methyl-5-ethyoxyl oxazole |
| CN109305946A (en) * | 2018-11-29 | 2019-02-05 | 湖北惠生药业有限公司 | A kind of synthetic method of 4- methyl -5- ethyoxyl oxazole |
| CN109627226A (en) * | 2019-01-15 | 2019-04-16 | 威海迪素制药有限公司 | A kind of preparation method of 4- methyl -5- ethyoxyl oxazole |
| CN110423226A (en) * | 2019-08-30 | 2019-11-08 | 山东新和成精化科技有限公司 | The preparation method of 4- methyl -5- alkoxy oxazole |
| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN111793038A (en) * | 2019-04-08 | 2020-10-20 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| CN113336717A (en) * | 2021-06-01 | 2021-09-03 | 江西天新药业股份有限公司 | Process for preparing oxazole carboxylic acid esters |
| WO2022077196A1 (en) | 2020-10-12 | 2022-04-21 | 新发药业有限公司 | Environmentally friendly preparation method for substituted oxazole compound |
-
2011
- 2011-07-12 CN CN201110193140A patent/CN102321043A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 杭德余等: "4-甲基-5-乙氧基噁唑合成工艺研究", 《精细化工》 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447605A (en) * | 2014-12-09 | 2015-03-25 | 湖北惠生药业有限公司 | Industrial preparation method of 4-methyl-5-ethyoxyl oxazole |
| CN109305946A (en) * | 2018-11-29 | 2019-02-05 | 湖北惠生药业有限公司 | A kind of synthetic method of 4- methyl -5- ethyoxyl oxazole |
| CN109627226A (en) * | 2019-01-15 | 2019-04-16 | 威海迪素制药有限公司 | A kind of preparation method of 4- methyl -5- ethyoxyl oxazole |
| CN109627226B (en) * | 2019-01-15 | 2022-05-31 | 迪嘉药业集团有限公司 | Preparation method of 4-methyl-5-ethoxy oxazole |
| CN111793038B (en) * | 2019-04-08 | 2022-08-12 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| CN111793038A (en) * | 2019-04-08 | 2020-10-20 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| CN110423226B (en) * | 2019-08-30 | 2021-01-05 | 山东新和成精化科技有限公司 | Preparation method of 4-methyl-5-alkoxy oxazole |
| CN110423226A (en) * | 2019-08-30 | 2019-11-08 | 山东新和成精化科技有限公司 | The preparation method of 4- methyl -5- alkoxy oxazole |
| CN111153869B (en) * | 2020-01-19 | 2021-06-01 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| CN111153869A (en) * | 2020-01-19 | 2020-05-15 | 浙江新和成股份有限公司 | Method for preparing oxazole compound |
| WO2022077196A1 (en) | 2020-10-12 | 2022-04-21 | 新发药业有限公司 | Environmentally friendly preparation method for substituted oxazole compound |
| CN113336717A (en) * | 2021-06-01 | 2021-09-03 | 江西天新药业股份有限公司 | Process for preparing oxazole carboxylic acid esters |
| CN113336717B (en) * | 2021-06-01 | 2024-04-05 | 江西天新药业股份有限公司 | Process for preparing oxazolecarboxylic acid esters |
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Application publication date: 20120118 |