CN105985297A - Synthesis technology of vitamin B6 intermediate 4-methyl-5-ethyoxyl-2-oxazole acid ethyl - Google Patents
Synthesis technology of vitamin B6 intermediate 4-methyl-5-ethyoxyl-2-oxazole acid ethyl Download PDFInfo
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Abstract
The invention belongs to the technical field of production of vitamin, and provides a key intermediate 4-methyl-5-ethyoxyl-2-oxazole acid ethyl for producing vitamin B6. The technology is characterized in that N-ethoxalyl alanine ethyl ester is taken as a raw material, and 4-methyl-5-ethyoxyl-2-oxazole acid ethyl is synthesized under a solid phosgene-aliphatic amine-catalyst system. According to the invention, phosphorous oxychloride, phosphoric pentoxide and phosgene are not used, operation is simple, phosphorus exhaust gas is not generated, and the technology is suitable for large-tonnage grade industrial production.
Description
Technical field
The present invention relates to the preparation method of the key intermediate 4-methyl-5-ethyoxyl-azoles of a kind of vitamin B6.
Background technology:
Prepared by the most common azoles (4-methyl-5 ethyoxyl azoles) the method technique using advanced person, technical process is broadly divided into three operations: esterification prepares N-ethoxy oxalyl alanine ethyl ester, ring-closure reaction prepares 4-methyl-5-ethyoxyl azoles, vitamin B6 crude product is prepared (Disls-Alder reacts, aromatisation and hydrolysis) and refines
And 4-methyl-5 ethyoxyl azoles by intermediate 4-methyl-5-ethyoxyl 2-azoles acetoacetic ester through saponification, decarboxylation and obtain, vitamin B6 azoles synthetic method beginning of the sixties is with ALANINE as raw material.
First synthesis N-alcoxyl oxalyl group-ALANINE ester; then under phosphorus pentoxide-oxygen replication, synthesize key intermediate 4-methyl-5-alkoxy-oxazole; aginomoto company of Japan (British patent GB1195854) then selects phosgene trialkylamine chloroform as cyclizing agent system; N-alcoxyl oxalyl group-ALANINE ester cyclization is become 2-alcoxyl oxalyl group-4-methyl-5-alkoxy-oxazole, prepares above-mentioned key intermediate 4-methyl-5-alkoxy-oxazole through basic hydrolysis, acidifying, decarboxylation.N-alkyloxy oxalyl-ALANINE ester dehydration cyclization in phosphorus oxychloride-fat tertiary amine-aromatic hydrocarbon ring binder system prepared by Shanghai Institute of Pharmaceutical Industry (Chinese patent CN1003515) ALANINE, oxalic acid synchronization esterification oxalyl becomes 4-base-5-alkoxyl-2-azoles acid esters, and the latter generates 4-methyl-5-alkoxy-oxazole through hydrolysis, acidifying, decarboxylation.
China application publication number CN 102321043A, the preparation method of the 4-methyl-5-ethyoxyl-azoles of invention entitled a kind of vitamin B6, is also to use N-ethoxy oxalyl alanine ethyl ester/phosphorus oxychloride/triethylamine/dimethylformamide to make cyclization dehydrant.
China application publication number CN 103435568 A, is also with N-ethoxalyl-α-aminopropionic acid ethyl ester as raw material, phosphorus oxychloride, triethylamine cyclization system in carry out ring-closure reaction, and adding catalyst is DMAP.
The problem that above-mentioned technique and patent are primarily present has:
Above method or use phosphorus pentoxide, or use phosgene, or use phosphorus oxychloride can produce a large amount of phosphorus waste water, and transport brings a series of safety in production needing and solving with technological operation aspect to producer, safety operation, the problems such as environmental pollution treatment is difficult, ultimately cause the rising of production cost.
Summary of the invention
The offer one of the present invention has that yield is high, discharging of waste liquid amount is few, and pollutant are easily administered, the industrial production process of the 4-methyl-5-ethyoxyl azoles that production cost is low.
Present invention provide the technical scheme that the synthesis technique of vitamin B6 intermediate 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester, it is characterised in that comprise the steps:
Step 1: put into N-ethoxy oxalyl alanine ethyl ester, triethylamine, solvent, catalyst in ring-closure reaction still successively；0～4 DEG C it is cooled under said mixture ice bath, solid phosgene being dissolved in solvent the most again and is cooled to 0～8 DEG C simultaneously, after dissolving, cool down, solid phosgene loads in addition funnel, limit regulation temperature, limit stirring instills in reactor and carries out ring-closure reaction, insulation reaction after dropping；
Wherein said catalyst is Cu-lyt.；
The primary raw material mol ratio of described ring-closure reaction is: N acetyl oxalyl group-alanine ethyl ester: solid phosgene: fatty amine: catalyst=1 (0.3～0.5) (3～5) (0.01～0.2)；
Step 2: be cooled to 25-30 DEG C, adds 50ml water and is layered, water layer solvent extraction 2 again～3 times, merges organic layer, and decompression boils off solvent concentration and obtains 4-methyl-5-ethyoxyl-2-isoxazole carboxylate.
Further, above-mentioned primary raw material mol ratio ratio is: N acetyl oxalyl group-alanine ethyl ester: solid phosgene: fatty amine: catalyst=1 (0.4～0.45) (3.5～3.8) (0.06～0.09).
Further, above-mentioned primary raw material mol ratio ratio is: N acetyl oxalyl group-alanine ethyl ester: solid phosgene: fatty amine: catalyst=1 0.42 3.72 0.08.
Further, above-mentioned fatty amine is triethylamine or diisopropyl ethyl amine or diethylamine or tripropyl amine (TPA) class.
Further, the dropping temperature of above-mentioned ring-closure reaction is 0 ~ 4 DEG C, and the time is 1～2 hour, the insulation 2～3h at 20～40 DEG C of described ring-closure reaction, then at 50-80 DEG C, is incubated 4～6h.
Further, needed for above-mentioned reaction, solvent is dichloromethane or chloroform or benzene or toluene or trimethylbenzene.
Further, above-mentioned N acetyl oxalyl group-alanine ethyl ester and solvent molar ratio ratio are: N acetyl oxalyl group-alanine ethyl ester solvent=1 (8～10).
Present invention have the advantage that
1. the dropping temperature of ring-closure reaction is 0 ~ 4 DEG C, and reaction condition is gentle, to equipment without particular/special requirement；
2. the present invention does not use phosphorus pentoxide, phosgene or phosphorus oxychloride are as a part for cyclization system, but use solid phosgene, easily operated, post processing is simple, yield is high and safety does not produce substantial amounts of phosphorus-containing wastewater, significantly reduces cost of sewage disposal, the vitamin B6 product of more applicable safety in production tonne.
Accompanying drawing explanation
Fig. 1 is the reaction process flow chart of the present invention.
Detailed description of the invention
For being further appreciated by the present invention, below result instantiation the present invention is elaborated.
The reaction principle of the present invention is as follows:
The reaction process flow chart of the present invention is as shown in Figure 1.
(amount of the material that feeds intake is than for N-oxalyl thing: triethylamine: Cu-lyt.: BTC=1:2.81:0.1:0.436), with chloroform give solvent for the preparation of example one: 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester.
N-ethoxalyl alanine ethyl ester 4.2kg is added in the reactor of 50L, chloroform 13kg, triethylamine 5.5kg, Cu-lyt. 200g, it is cooler than 0 DEG C, solid phosgene 2.5kg is dissolved in 12kg chloroform, then dissolve in reactor, temperature is controlled below 6 DEG C during dropping, after completion of dropwise addition, question response temperature in the kettle is cooled to room temperature, insulation 2h, then heat to 50-60 DEG C, react 4 hours, GC monitoring reaction is to terminating, react complete, add water 6L, layering, aqueous phase 6L chloroform back extraction 2 times, combined chloroform layer, three times are washed with water (6L), finally wash once with saturated aqueous common salt (3L), recovered under reduced pressure chloroform, obtain concentrate, GC quantitative yield 78.9%(GC analyzes 87% purity).
Example 2:
(amount of the material that feeds intake is than for N-oxalyl thing: triethylamine: Cu-lyt.: BTC=1:3.72:0.08:0.42), make solvent with toluene for the preparation of 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester.
nullN-ethoxy oxalyl alanine ethyl ester 2.88kg(13.26mol it is sequentially added into) in three mouthfuls of reaction bulbs，5000ml toluene，5kg(49.41mol) triethylamine and catalyst Cu-lyt. 0.105kg (1.06mol)，0～4 DEG C it is cooled under ice bath，Then the temperature controlling reaction bulb drips two (trichloromethyl) carbonate solution (1.650kg under the conditions of 0～4 DEG C，5.56molBTC is dissolved in 6000～6500ml toluene，Stirring and dissolving is uniform，Dropping is started) after being cooled to 0～8 DEG C，Control about 1.5h and drip complete，2h-3h it is incubated under the conditions of 23～28 DEG C，It is then heated to 50-60 DEG C of reaction 4～5h，Reaction terminates，It is cooled to 25～30 DEG C，Add 5000ml water to be layered，Water layer extracts 2～3 times with 5000ml toluene again，Merge organic layer，Decompression boils off solvent concentration and obtains 4-methyl-5-ethyoxyl-2-isoxazole carboxylate，Yield 87.5%(GC content: 83%).
Example 3:
The preparation of 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester, feeds intake as 0.131kg by Cu-lyt., and other conditions are identical with example two, obtain 4-methyl-5-ethyoxyl-2-isoxazole carboxylate, yield 88%(GC content: 82.7%).
Example 4:
The preparation of 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester, feeds intake as 1.53kg by BTC, and other conditions are identical with example two, obtain 4-methyl-5-ethyoxyl-2-isoxazole carboxylate, yield 85.4%(GC content: 84.7%).
Example 5:
The preparation of 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester, feeds intake as 1.77kg by BTC, and other conditions are identical with example two, obtain 4-methyl-5-ethyoxyl-2-isoxazole carboxylate, yield 81.1%(GC content: 84%).
Example 6: the preparation of 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester, the inventory of triethylamine is 6.72kg, Cu-lyt. is fed intake into 0.26251kg, BTC is fed intake into 1.1786kg, his condition is identical with example two, obtain 4-methyl-5-ethyoxyl-2-isoxazole carboxylate, yield 80.2%(GC content: 83.6%).
Example 7: the preparation of 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester, the inventory of triethylamine is 4.03kg, is fed intake by Cu-lyt. as 0.0131kg, BTC is fed intake into 1.964kg, his condition is identical with example two, obtains 4-methyl-5-ethyoxyl-2-isoxazole carboxylate, yield 80 %(GC content: 83.8%).
Above-mentioned dehydration condensation agent is solid phosgene, has another name called triphosgene, and chemical name is two (trichloromethyl) carbonic ester.
Above-mentioned fatty amine is triethylamine, diisopropyl ethyl amine, diethylamine, the alkyl amine of tripropyl amine (TPA) class, preferably triethylamine.
On have application for a patent for invention another change, above-mentioned catalyst can be sodium chloride, Cu-lyt., copper chloride, calcium chloride, preferably Cu-lyt..
Needed for above-mentioned reaction, solvent is dichloromethane, chloroform, benzene, toluene, trimethylbenzene, preferably toluene.
The present invention compares with comparative example, it is provided that a kind of reaction yield height, good product quality, the method for 4-methyl-5-ethyoxyl azoles of industrialized production that discharging of waste liquid amount is few, has bigger development prospect.
Claims (7)
1. the synthesis technique of vitamin B6 intermediate 4-methyl-5-ethyoxyl-2-azoles acetoacetic ester, it is characterised in that comprise the steps:
Step 1: put into N-ethoxy oxalyl alanine ethyl ester, triethylamine, solvent, catalyst in ring-closure reaction still successively；0～4 DEG C it is cooled under said mixture ice bath, solid phosgene being dissolved in solvent the most again and is cooled to 0～8 DEG C simultaneously, after dissolving, cool down, solid phosgene loads in addition funnel, limit regulation temperature, limit stirring instills in reactor and carries out ring-closure reaction, insulation reaction after dropping；
Wherein said catalyst is Cu-lyt.；
The primary raw material mol ratio of described ring-closure reaction is: N acetyl oxalyl group-alanine ethyl ester: solid phosgene: fatty amine: catalyst=1 (0.3～0.5) (3～5) (0.01～0.2)；
Step 2: be cooled to 25-30 DEG C, adds 50ml water and is layered, water layer solvent extraction 2 again～3 times, merges organic layer, and decompression boils off solvent concentration and obtains 4-methyl-5-ethyoxyl-2-isoxazole carboxylate.
2. synthesis technique as claimed in claim 1, it is characterised in that described primary raw material mol ratio ratio is: N acetyl oxalyl group-alanine ethyl ester: solid phosgene: fatty amine: catalyst=1 (0.4～0.45) (3.5～3.8) (0.06～0.09).
3. synthesis technique as claimed in claim 1 or 2, it is characterised in that described primary raw material mol ratio ratio is: N acetyl oxalyl group-alanine ethyl ester: solid phosgene: fatty amine: catalyst=1 0.42 3.72 0.08.
4. synthesis technique as claimed in claim 1 or 2, it is characterised in that described fatty amine is triethylamine or diisopropyl ethyl amine or diethylamine or tripropyl amine (TPA) class.
5. synthesis technique as claimed in claim 1 or 2, it is characterised in that the dropping temperature of described ring-closure reaction is 0 ~ 4 DEG C, and the time is 1～2 hour, the insulation 2～3h at 20～40 DEG C of described ring-closure reaction, then at 50-80 DEG C, it is incubated 4～6h.
6. synthesis technique as claimed in claim 1 or 2, it is characterised in that: needed for described reaction, solvent is dichloromethane or chloroform or benzene or toluene or trimethylbenzene.
7. synthesis technique as claimed in claim 1 or 2, it is characterised in that: described N acetyl oxalyl group-alanine ethyl ester and solvent molar ratio ratio be: N acetyl oxalyl group-alanine ethyl ester solvent=1 (8～10).
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110240573A (en) * | 2019-07-04 | 2019-09-17 | 山东新和成精化科技有限公司 | A method of preparing polysubstituted evil azole compounds |
| CN110483433A (en) * | 2019-08-30 | 2019-11-22 | 厦门金达威维生素有限公司 | The synthetic method of 4- methyl -5- ethyoxyl oxazole acetoacetic ester |
| CN111793038A (en) * | 2019-04-08 | 2020-10-20 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| WO2021143181A1 (en) * | 2020-01-19 | 2021-07-22 | 上虞新和成生物化工有限公司 | Method for preparing oxazole compound |
| WO2021209269A1 (en) | 2020-04-17 | 2021-10-21 | Dsm Ip Assets B.V. | A process for preparation of substituted enamine compounds |
| WO2022218734A1 (en) | 2021-04-15 | 2022-10-20 | Dsm Ip Assets B.V. | A process for preparation of substituted enamine compounds |
| WO2022218733A1 (en) | 2021-04-15 | 2022-10-20 | Dsm Ip Assets B.V. | A process for preparation of substituted enamine compounds |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111793038A (en) * | 2019-04-08 | 2020-10-20 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| CN111793038B (en) * | 2019-04-08 | 2022-08-12 | 新发药业有限公司 | Environment-friendly preparation method of substituted oxazole compound |
| CN110240573A (en) * | 2019-07-04 | 2019-09-17 | 山东新和成精化科技有限公司 | A method of preparing polysubstituted evil azole compounds |
| CN110483433A (en) * | 2019-08-30 | 2019-11-22 | 厦门金达威维生素有限公司 | The synthetic method of 4- methyl -5- ethyoxyl oxazole acetoacetic ester |
| WO2021143181A1 (en) * | 2020-01-19 | 2021-07-22 | 上虞新和成生物化工有限公司 | Method for preparing oxazole compound |
| WO2021209269A1 (en) | 2020-04-17 | 2021-10-21 | Dsm Ip Assets B.V. | A process for preparation of substituted enamine compounds |
| WO2022218734A1 (en) | 2021-04-15 | 2022-10-20 | Dsm Ip Assets B.V. | A process for preparation of substituted enamine compounds |
| WO2022218733A1 (en) | 2021-04-15 | 2022-10-20 | Dsm Ip Assets B.V. | A process for preparation of substituted enamine compounds |
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