CN104557581A - Preparation method for homoserine - Google Patents
Preparation method for homoserine Download PDFInfo
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- CN104557581A CN104557581A CN201410818638.6A CN201410818638A CN104557581A CN 104557581 A CN104557581 A CN 104557581A CN 201410818638 A CN201410818638 A CN 201410818638A CN 104557581 A CN104557581 A CN 104557581A
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Abstract
The invention relates to a preparation method for homoserine and mainly solves the technical problems that an existing preparation method cannot purify the midbody, is poor in safety and not favorable to industrial production. According to the technical scheme, the preparation method for homoserine is characterized by comprising the following steps: reacting L-methionine with methyl iodide, dissolving the L-methionine in water during reaction, adding methane as a reaction solvent, distilling a reaction product under reduced pressure, leaching and crystallizing the reaction product to obtain the midbody, and hydrolyzing the midbody under the action of potassium bicarbonate to obtain the L-homoserine. High-purity L-homoserine can be obtained through the method.
Description
Technical field
The present invention relates to a kind of preparation method of homoserine.
Background technology
Traditional method preparing homoserine (HomoSer-OH), be dissolved in water by L-Methionine (L-MET-OH), add methyl alcohol (MeOH), add monobromethane (MeBr) after cooling, sealed reaction a couple of days obtains intermediate.Then intermediate is dissolved in water, adds saleratus (KHCO
3) be hydrolyzed, obtain homoserine after process.But there is following problem in traditional preparation method:
1. need use monobromethane when synthesizing homoserine, be gas under normal temperature, and it can be caused after also absorbing to play blister for contact human skin and suppuration is rotted, and very greatly, it is careful to need during operation, is unfavorable for industrialized production very much for nocuity;
2. monobromethane boiling point is very low, is-4 DEG C, and temperature of reaction is 20 DEG C, and the temperature difference is comparatively large, is difficult to control, unfavorable to production;
3. intermediate is when the effect of saleratus issues unboiled water solution, can generate Potassium Bromide (KBr), and it is water-soluble very little, lumps together not easily remove with product, causes purity not high.
Summary of the invention
The object of this invention is to provide a kind of preparation method of homoserine, mainly solving existing preparation method cannot to purification of intermediate and the lower technical problem being unfavorable for suitability for industrialized production of security.
Technical scheme of the present invention is: a kind of preparation method of homoserine, comprise the following steps: L-Methionine and iodomethane reaction, reaction product is through underpressure distillation, suction filtration crystallization obtains intermediate, and intermediate is hydrolyzed and obtains homoserine under the effect of saleratus.Concrete reactions steps is as follows:
A, be dissolved in water by L-Methionine, add methyl alcohol, be cooled to 0-5 DEG C, L-Methionine and methyl iodide press the ratio 1:(3-6 of amount of substance) add, reaction unit seals, pressure 20-40N/cm
2, be slowly warming up to 30 DEG C, react 48 hours in this case;
B, be warming up to 60 DEG C of decompression distilleds and separate out to a large amount of solids, add raw spirit, treat that intermediate is fully separated out, be cooled to 0 DEG C to-5 DEG C (12-16 hour that spend the night, same afterwards), next day suction filtration, rinsing solid obtains white powdery solids, then heats water to dissolution of solid, suction filtration while hot, anti-dandruff, add raw spirit crystallization, suction filtration, oven dry obtain solid intermediate;
C, solid intermediate add water in the ratio of 1g:4-6mL makes it dissolve, then saleratus hydrolysis is added, intermediate and saleratus mass ratio are 1: (0.3-0.4), then temperature rising reflux 6 hours gradually, in reflux course and the time-division remove by product dimethyl sulphide, decompression distilled is separated out to portion of product, adds raw spirit and acetone and stirs, be cooled to 0 to-5 DEG C of crystallised overnight, next day, suction filtration must glue shape solid;
D, glue shape solid by water heating for dissolving, add raw spirit and acetone stirred crystallization, obtain solid, need recrystallize once to obtain the higher solid of purity.
The invention has the beneficial effects as follows: when tradition adopts monobromethane pressure synthesis, the time cycle is shorter, but can not take out intermediate and directly synthesize next step form, and yield is higher, but purity compares and is difficult to improve.The present invention surprisingly finds under study for action, changes monobromethane into methyl iodide, and the cycle in reaction times lengthens, first can carry out purifying to intermediate, the purity being beneficial to the finished product improves, and improves the security of operation, overall yield of reaction decreases, but content >99%.
Embodiment
embodiment 1:
The first step: by 300g(2.01mol) L-Methionine is dissolved in 6.5L water, adds 1.5L methyl alcohol, be cooled to 5 DEG C, adds 1200g (8.46mol) methyl iodide, sealed reaction equipment, container pressure 20 N/cm
2, reaction solution volume, about 2/3rds, naturally heats up half a day about about 10 DEG C, is slowly warming up to 30 DEG C, maintains this state response two days.Temperature is 60 DEG C time, and underpressure distillation is to volume at about 80ml, and a large amount of solid is separated out, and spends the night when being cooled to 0 DEG C ~-5 DEG C, next day suction filtration, 150mL dehydrated alcohol rinsing solid obtains white powder and is about about 600g.200mL water is heated to 80 DEG C, and add above-mentioned dissolution of solid, suction filtration is anti-dandruff, adds the crystallization of 1L ~ 800mL raw spirit, suction filtration, dries to obtain intermediate 510g.
Second step: be dissolved in 1.8L water by 380g intermediate, adds 140g (1.4mol) saleratus (KHCO
3) hydrolysis, then temperature rising reflux 6 hours gradually, in reflux course and the time-division remove by product dimethyl sulphide.Underpressure distillation is separated out to portion of product, adds 200mL ethanol, and 800mL acetone stirs, and is cooled to-5 DEG C of crystallised overnight, suction filtration, and solid has a little sticky shape.150mL water heating for dissolving glues shape solid, adds 200mL ethanol, 450mL acetone, and stirred crystallization, obtains solid.Recrystallize once, obtains product 75g.Thin plate chromatography, shows a principal point.Yield 36%, specific rotatory power+8.0.
embodiment 2,
The first step: by 300g(2.01mol) L-Methionine is dissolved in 6.5L water, adds 1.5L methyl alcohol, be cooled to 0 DEG C, adds 900g (6.35mol) methyl iodide, sealed reaction equipment, container pressure 30 N/cm
2, reaction solution volume, about 2/3rds, naturally heats up half a day about about 10 DEG C, is slowly warming up to 30 DEG C, maintains this state 24 hours.Temperature 60 DEG C time, underpressure distillation to volume at about 80ml, solid separate out, spend the night when being cooled to 0 DEG C ~-5 DEG C, next day suction filtration, 150mL dehydrated alcohol rinsing solid obtains white powder and is about about 400g.165mL water is heated to 80 DEG C, and add above-mentioned dissolution of solid, suction filtration is anti-dandruff, adds the crystallization of 600mL raw spirit, suction filtration, dries to obtain intermediate 315g.
Second step: be dissolved in 1.44L water by 304g intermediate, adds 93g (0.93mol) saleratus (KHCO
3) hydrolysis, then temperature rising reflux 6 hours gradually, in reflux course and the time-division remove by product dimethyl sulphide.Underpressure distillation is separated out to portion of product, adds 160mL ethanol, and 650mL acetone stirs, and is cooled to-5 DEG C of crystallised overnight, suction filtration, and solid has a little sticky shape.150mL water heating for dissolving glues shape solid, adds 160mL ethanol, 360mL acetone, and stirred crystallization, obtains solid.Recrystallize once, obtains product 50g.Thin plate chromatography, shows a principal point.Yield 30%, specific rotatory power+7.9.
embodiment 3,
The first step: by 300g(2.01mol) L-Methionine is dissolved in 6.5L water, adds 1.5L methyl alcohol, be cooled to 2 DEG C, adds 1420g (10mol) methyl iodide, sealed reaction equipment, container pressure 40 N/cm
2, reaction solution volume, about 2/3rds, naturally heats up half a day about about 10 DEG C, is slowly warming up to 30 DEG C, maintains this state response two days.Temperature is 60 DEG C time, and underpressure distillation is to volume at about 80ml, and a large amount of solid is separated out, and spends the night when being cooled to 0 DEG C ~-5 DEG C, next day suction filtration, 150mL dehydrated alcohol rinsing solid obtains white powder and is about about 600g.200mL water is heated to 80 DEG C, and add above-mentioned dissolution of solid, suction filtration is anti-dandruff, adds the crystallization of 1L ~ 800mL raw spirit, suction filtration, dries to obtain intermediate 518g.
Second step: be dissolved in 1.8L water by 380g intermediate, adds 140g (1.4mol) saleratus (KHCO
3) hydrolysis, then temperature rising reflux 6 hours gradually, in reflux course and the time-division remove by product dimethyl sulphide.Underpressure distillation is separated out to portion of product, adds 200mL ethanol, and 800mL acetone stirs, and is cooled to-5 DEG C of crystallised overnight, suction filtration, and solid has a little sticky shape.150mL water heating for dissolving glues shape solid, adds 200mL ethanol, 450mL acetone, and stirred crystallization, obtains solid.Recrystallize once, obtains product 76g.Thin plate chromatography, shows a principal point.Yield 36.5%, specific rotatory power+8.0.
Claims (4)
1. the preparation method of a homoserine, it is characterized in that comprising the following steps: L-Methionine and iodomethane reaction, during reaction, L-Methionine is dissolved in water, add methyl alcohol as reaction solvent, reaction product is through underpressure distillation, suction filtration crystallization obtains intermediate, and intermediate is hydrolyzed and obtains homoserine under the effect of saleratus.
2. the preparation method of a kind of Kosé acid according to right 1, is characterized in that: concrete reactions steps is as follows:
A, be dissolved in water by L-Methionine, add methyl alcohol, be cooled to 0-5 DEG C, L-Methionine and methyl iodide press the ratio 1:(3-6 of amount of substance) add, reaction unit seals, and is slowly warming up to 30 DEG C, reacts 48 hours in this case;
Be warming up to 60 DEG C of decompression distilleds to separate out to a large amount of solid, add raw spirit, treat that intermediate is fully separated out, be cooled to 0 DEG C and spend the night to-5 DEG C, next day suction filtration, rinsing solid obtains white powdery solids, heat water to dissolution of solid again, while hot suction filtration, anti-dandruff, add raw spirit crystallization, suction filtration, oven dry obtain solid intermediate;
Solid intermediate adds water in the ratio of 1g:4-6mL makes it dissolve, then saleratus hydrolysis is added, intermediate and saleratus mass ratio are 1: (0.3-0.4), then temperature rising reflux 6 hours gradually, in reflux course and the time-division remove by product dimethyl sulphide, decompression distilled is separated out to portion of product, adds raw spirit and acetone and stirs, be cooled to 0 to-5 DEG C of crystallised overnight, next day, suction filtration must glue shape solid;
D, glue shape solid by water heating for dissolving, add raw spirit and acetone stirred crystallization, obtain solid, need recrystallize once to obtain the higher solid of purity.
3. the preparation method of a kind of Kosé acid according to right 1 or 2, is characterized in that: L-Methionine and iodomethane reaction need at pressure 20-40N/cm
2encloses container in carry out.
4. the preparation method of a kind of Kosé acid according to right 2, is characterized in that: in step c reflux course, and need and time-division remove by product dimethyl sulphide.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410818638.6A CN104557581A (en) | 2014-12-25 | 2014-12-25 | Preparation method for homoserine |
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| CN201410818638.6A CN104557581A (en) | 2014-12-25 | 2014-12-25 | Preparation method for homoserine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989026A (en) * | 2022-06-23 | 2022-09-02 | 苏州润亚旭日生物科技有限公司 | Refining and purifying method of L-homoserine fermentation broth |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110224458A1 (en) * | 2010-03-09 | 2011-09-15 | Novus International Inc. | Preparation of methionine or selenomethionine from homoserine via a 4-substituted 2-aminobutanoic acid intermediate |
| CN102485718A (en) * | 2010-12-03 | 2012-06-06 | 浙江海翔药业股份有限公司 | Sitagliptin intermediate and its preparation method |
-
2014
- 2014-12-25 CN CN201410818638.6A patent/CN104557581A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110224458A1 (en) * | 2010-03-09 | 2011-09-15 | Novus International Inc. | Preparation of methionine or selenomethionine from homoserine via a 4-substituted 2-aminobutanoic acid intermediate |
| CN102485718A (en) * | 2010-12-03 | 2012-06-06 | 浙江海翔药业股份有限公司 | Sitagliptin intermediate and its preparation method |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114989026A (en) * | 2022-06-23 | 2022-09-02 | 苏州润亚旭日生物科技有限公司 | Refining and purifying method of L-homoserine fermentation broth |
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