CN101033208A - Method of preparing methylselenocysteine from alpha-amino acrylic acid derivative - Google Patents
Method of preparing methylselenocysteine from alpha-amino acrylic acid derivative Download PDFInfo
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- CN101033208A CN101033208A CN 200710051362 CN200710051362A CN101033208A CN 101033208 A CN101033208 A CN 101033208A CN 200710051362 CN200710051362 CN 200710051362 CN 200710051362 A CN200710051362 A CN 200710051362A CN 101033208 A CN101033208 A CN 101033208A
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- jibingxisuan
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Abstract
This invention discloses a method for synthesizing seleno-methyl selenocysteine with alpha amido crylic acid derivant, in which, methyl-hydroselenide or its salt solution generates addition reaction with alpha-amido acrylic acid derivant to generate beta-methyl-alpha-amido methyl acetic acid derivant, then the ester compound in it is hydrolyzed and saponified by NaHCO3, NaOH or KOH and acidified by HCl or H2SO4 to get its carboxy compound, then the N-acyl in it is hydrolyzed and taken off by HCl or H2SO4 plus hot water to get beta-methyl-alpha-amido propionate or sulfate and finally neutralized with ammonia or TEA to get seleno-methyl selenocysteine.
Description
Technical field
The present invention relates to amino acid medicine preparation method, it relates to a kind of method of utilizing alpha-amino acrylic acid derivative to prepare methylselenocysteinefrom In-particular.
Background technology
Selenium is the necessary trace element of human body.Selenium deficiency can cause diseases such as Keshan disease, Kaschin-Beck disease, heart disease, thyroprivia and immunologic hypofunction.Methylselenocysteinefrom is one of existence form of organoselenium in the rich selenium whole food, have supplement selenium element, anti-curing cancers, anti-oxidant, anti-ageing, treat cardiovascular and cerebrovascular diseases, separate effect such as heavy metal poison, be a kind of stable, efficient, safe benefit selenium composition, be widely used in aspects such as medicine, nutritive health-care and agricultural.The research and development methylselenocysteinefrom is the preparation method have important practical significance.
The preparation of methylselenocysteinefrom at present mainly contains following several method:
(1) chlorine L-Ala two sodium selenide methods: at first the reaction of chlorine L-Ala and two sodium selenides is generated selenocystine, uses sodium Metal 99.5/liquefied ammonia (70 ℃) reductive cleavage then, methylate again methylselenocysteinefrom.This method relates to very low temperature and active hazardous metals sodium, severe reaction conditions, and processing unit requires high, is unfavorable for scale operation (Tanaka, H; Soda, K; Selenocysteine.Methods Enzymol., 1987,143,240-243; Andreadou, I; Menge, W.M.P.B.; Commandeur, J.N.M.; Worthington, E.A.; Vermeulen, N.P.E.; J.Med.Chem., 1996,39,2040-2046);
(2) uncle's fourth oxygen acyl group protection Serine method: in the presence of basic phosphorus of three alkane (virtue) or phosphite; uncle's fourth oxygen acyl group Serine and the reaction of azoformic acid diester generate the β lactone; generate the methylselenocysteinefrom of uncle's fourth oxygen acyl group protection then with methyl-hydroselenide or its reactant salt, last deprotection gets methylselenocysteinefrom.This method technology is tediously long, and product yield is low, raw material thread propylhomoserin and protection reagent costliness, so production cost is very high, is unfavorable for scale operation (Spallholz, J.E.; Reid, T.W.; Walkup, R.D.; A methodof using synthetic L-Se-methylselenocysteine as a nutraceutical and a method of itssynthesis, EP 1 205 471, and 2001);
(3) sodium methyl-hydroselenide replaces chlorine L-Ala method: the chlorine with in sodium methyl-hydroselenide replacement chlorine L-Ala or the chlorine alanine methyl ester gets methylselenocysteinefrom.This method is because of chlorine L-Ala raw material sources difficulty, and the production cost height is unfavorable for scale operation (Majeed; Muhammed (Piscataway, NJ); Nagabhushanam; Kalyanam (North Brunswick, NJ); Manufacturing processes forSe-methyl-L-selenocysteine, US 6794537 B1,2004).
Above preparation method has exists the raw material sources difficulty, costing an arm and a leg causes production cost too high, have have operational path complexity, contaminate environment, productive rate is low, product purity is low, what have exists defectives such as severe reaction conditions, equipment requirements height and difficult management, be unfavorable for scale operation, be difficult to satisfy the growing market requirement.
Summary of the invention
The method that the object of the present invention is to provide that a kind of technology is simple, productive rate is high, environmental protection, economical utilization alpha-amino acrylic acid derivative prepares methylselenocysteinefrom.
The present invention realizes by following synthetic method and concrete implementation step.
(1) addition:
The α-An Jibingxisuan derivative (is specially α-An Jibingxisuan, the α-An Jibingxisuan methyl esters, the α-An Jibingxisuan ethyl ester, N-acetyl-α-An Jibingxisuan, a kind of in N-acetyl-α-An Jibingxisuan methyl esters or the N-acetyl-α-An Jibingxisuan ethyl ester) be dissolved in tetrahydrofuran (THF), add suitable quantity of water, add sodium bicarbonate solid to saturated, feed methyl-hydroselenide then or add methyl-hydroselenide salt and (be specially sodium methyl-hydroselenide, a kind of in methyl-hydroselenide potassium or the methyl-hydroselenide lithium) aqueous solution, generate β-first seleno-α-An Jibingsuan derivative, according to the difference of α-An Jibingxisuan derivative raw material, product is followed successively by: β-first seleno-α-An Jibingsuan salt, β-first seleno-α-An Jibingsuan methyl esters, β-first seleno-α-An Jibingsuan ethyl ester, N-acetyl-β-first seleno-α-An Jibingsuan salt, N-acetyl-β-first seleno-α-An Jibingsuan methyl esters, N-acetyl-β-first seleno-α-An Jibingsuan ethyl ester;
Reaction equation is:
①CH
2C(NHR
1)COOR
2+CH
3SeH→CH
3SeCH
2CH(NHR
1)COOR
2
②2CH
2C(NHR
1)COOR
2+2CH
3SeM+
2NaHCO
3→2CH
3SeCH
2CH(NHR
1)COOR
2+Na
2CO
3+M
2CO
3
R
1＝H、CH
3CO；R
2＝H、Me、Et；M＝Na、K、Li；
(2) hydrolysis of ester:
The hydrolysis of methyl esters:
β-first seleno-α-An Jibingsuan methyl esters and N-acetyl-β-first seleno-α-An Jibingsuan methyl esters gets its carboxylate salt through sodium bicarbonate or sodium hydroxide or potassium hydroxide hydrolysis saponification, gets β-first seleno-α-An Jibingsuan and N-acetyl-β-first seleno-α-An Jibingsuan with hydrochloric acid or sulfuric acid acidation then;
Reaction equation is:
①CH
3SeCH
2CH(NHR
1)COOMe+NaHCO
3→CH
3SeCH
2CH(NHR
1)COONa+MeOH+CO
2
②CH
3SeCH
2CH(NHR
1)COOMe+MOH→CH
3SeCH
2CH(NHR
1)COOM+MeOH
③CH
3SeCH
2CH(NHR
1)COOM+HCl→CH
3SeCH
2CH(NHR
1)COOH+MClR
1＝H、CH
3CO；M＝Na、K；
The hydrolysis of ethyl ester:
β-first seleno-α-An Jibingsuan ethyl ester and N-acetyl-β-first seleno-α-An Jibingsuan ethyl ester gets its carboxylate salt through sodium hydroxide or potassium hydroxide hydrolysis saponification, gets β-first seleno-α-An Jibingsuan and N-acetyl-β-first seleno-α-An Jibingsuan with hydrochloric acid or sulfuric acid acidation then;
Reaction equation is:
①CH
3SeCH
2CH(NHR
1)COOEt+MOH→CH
3SeCH
2CH(NHR
1)COOM+EtOH
②CH
3SeCH
2CH(NHR
1)COOM+HCl→CH
3SeCH
2CH(NHR
1)COOH+MCl
R
1＝H、CH
3CO；M＝Na、K；
(3) acyl group is sloughed in hydrolysis:
N-acetyl-β-first seleno-α-An Jibingsuan or its salt get β-first seleno-α-An Jibingsuan hydrochloride or vitriol through hydrochloric acid or sulfuric acid heating hydrolysis deacetylate, then with ammonia or triethylamine neutralize methylselenocysteinefrom.
Reaction equation is:
①CH
3SeCH
2CH(NHOCCH
3)COOH+HCl+H
2O→CH
3SeCH
2CH(NH
3Cl)COOH+CH
3COOH
②CH
3SeCH
2CH(NH
3Cl)COOH+NH
3→CH
3SeCH
2CH(NH
2)COOH+NH
4Cl。
This method has that technology is simple, productive rate is high, environmental protection, low cost and other advantages, is fit to large-scale industrial production.
Description of drawings
Fig. 1 is a synthetic route synoptic diagram of the present invention.
Embodiment
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1:
Utilize N-acetyl-α-An Jibingxisuan to prepare methylselenocysteinefrom:
39 gram N-acetyl-α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate to saturated, add solid sodium bicarbonate 40 grams again, then in 25 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 48 hours to N-acetyl-α-An Jibingxisuan react completely (thin-layer chromatography detection); After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 58 grams, productive rate 86%.
34 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 90 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 22 grams, productive rate 80%.
Embodiment 2:
Utilize N-acetyl-α-An Jibingxisuan to prepare methylselenocysteinefrom:
39 gram N-acetyl-α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 40 hours to N-acetyl-α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 57 grams, productive rate 84%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 29 grams, productive rate 79%.
Embodiment 3:
Utilize N-acetyl-α-An Jibingxisuan to prepare methylselenocysteinefrom:
39 gram N-acetyl-α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of feeding methyl-hydroselenides, and sealing keeps 10kg/cm
2Pressure, stirring reaction 30 hours to N-acetyl-α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 56 grams, productive rate 83%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 300ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 95 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 30 grams, productive rate 82%.
Embodiment:
Utilize N-acetyl-α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
43 gram N-acetyl-α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 25 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 48 hours to N-acetyl-α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 51 grams, productive rate 76%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 5:
Utilize N-acetyl-α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
43 gram N-acetyl-α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of feeding methyl-hydroselenides, and sealing keeps 6kg/cm
2Pressure, stirring reaction 40 hours to N-acetyl-α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 52 grams, productive rate 77%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) sulfuric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 90 ℃.Be neutralized to pH with ammoniacal liquor and be about 10, the evaporated under reduced pressure solvent is removed residue ammonia, gets solid, uses dissolve with methanol, and insolubles is filtered, and filtrate is placed, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 29 grams, productive rate 79%.
Embodiment 6:
Utilize N-acetyl-α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
43 gram N-acetyl-α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of feeding methyl-hydroselenides, and sealing keeps 10kg/cm
2Pressure, stirring reaction 24 hours to N-acetyl-α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 55 grams, productive rate 82%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 7:
Utilize N-acetyl-α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
47 gram N-acetyl-α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 25 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 50 hours to N-acetyl-α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 100 gram sodium hydroxide, make dissolving, refluxed 5 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back use anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent gets solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 48 grams, productive rate 72%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, separate out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 8:
Utilize N-acetyl-α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
47 gram N-acetyl-α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of feeding methyl-hydroselenides, and sealing keeps 6kg/cm
2Pressure, stirring reaction 40 hours to N-acetyl-α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 90 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back use anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent gets solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 51 grams, productive rate 76%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 90 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 29 grams, productive rate 79%.
Embodiment 9:
Utilize N-acetyl-α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
47 gram N-acetyl-α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of feeding methyl-hydroselenides, and sealing keeps 10kg/cm
2Pressure, stirring reaction 30 hours to N-acetyl-α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back use anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent gets solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 54 grams, productive rate 80%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) sulfuric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 90 ℃.The pressure reducing and steaming solvent gets solid, uses dissolve with methanol.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 29 grams, productive rate 79%.
Embodiment 10:
Utilize the α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
30 gram α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 25 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 40 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 41 grams, productive rate 76%.
Embodiment 11:
Utilize the α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
30 gram α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 40 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 40 grams, productive rate 74%.
Embodiment 12:
Utilize the α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
30 gram α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of feeding methyl-hydroselenides, and sealing keeps 10kg/cm
2Pressure, stirring reaction 30 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 36 grams, productive rate 66%.
Embodiment 13:
Utilize the α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
35 gram α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 25 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 40 hours to α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 30 grams, productive rate 54%.
Embodiment 14:
Utilize the α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
35 gram α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of feeding methyl-hydroselenides, and sealing keeps 6kg/cm
2Pressure, stirring reaction 40 hours to α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, separate out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 32 grams, productive rate 58%.
Embodiment 15:
Utilize the α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
35 gram α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of feeding methyl-hydroselenides, and sealing keeps 10kg/cm
2Pressure, stirring reaction 30 hours to α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 50%.
Embodiment 16:
Utilize α-An Jibingxisuan to prepare methylselenocysteinefrom:
26 gram α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 25 ℃ of feeding methyl-hydroselenides, and sealing keeps 2kg/cm
2Pressure, stirring reaction 40 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).Solid filtering is removed, and solution is neutralized to pH with (1+1) hydrochloric acid and is about 1 in ice-water bath.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 35 grams, productive rate 64%.
Embodiment 17:
Utilize α-An Jibingxisuan to prepare methylselenocysteinefrom:
26 gram α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of feeding methyl-hydroselenides, and sealing keeps 6kg/cm
2Pressure, stirring reaction 40 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The pressure reducing and steaming solvent gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 33 grams, productive rate 61%.
Embodiment 18:
Utilize α-An Jibingxisuan to prepare methylselenocysteinefrom:
17 gram α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), add 400ml water, add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of feeding methyl-hydroselenides, and sealing keeps 10kg/cm
2Pressure, stirring reaction 30 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 21 grams, productive rate 59%.
Embodiment 19:
Utilize N-acetyl-α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
43 gram N-acetyl-α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 25 ℃ of stirring reactions 48 hours to N-acetyl-α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 57 grams, productive rate 85%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 20:
Utilize N-acetyl-α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
43 gram N-acetyl-α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 65 ℃ of stirring reactions 6 hours to N-acetyl-α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 56 grams, productive rate 83%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) sulfuric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 90 ℃.Be neutralized to pH with ammoniacal liquor and be about 10, the evaporated under reduced pressure solvent is removed residue ammonia, gets solid, uses dissolve with methanol, and insolubles is filtered, and filtrate is placed, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 27 grams, productive rate 74%.
Embodiment 21:
Utilize N-acetyl-α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
43 gram N-acetyl-α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 42 gram methyl-hydroselenide potassium (methyl-hydroselenide potassium 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 100 ℃ of stirring reactions 6 hours to N-acetyl-α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 50 grams, productive rate 74%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 27 grams, productive rate 74%.
Embodiment 22:
Utilize N-acetyl-α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
47 gram N-acetyl-α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 25 ℃ of stirring reactions 40 hours to N-acetyl-α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, slowly adding 100 gram sodium hydroxide in solution, refluxed 5 hours in 100 ℃ in the dissolving back.Be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back use anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent gets solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 52 grams, productive rate 78%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 23:
Utilize N-acetyl-α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
47 gram N-acetyl-α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 65 ℃ of stirring reactions 8 hours to N-acetyl-α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back use anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent gets solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 54 grams, productive rate 80%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) sulfuric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 90 ℃.Be neutralized to about pH 2 with sodium hydroxide, the pressure reducing and steaming solvent gets solid, uses dissolve with methanol, the elimination insolubles.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 29 grams, productive rate 79%.
Embodiment 24:
Utilize N-acetyl-α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
47 gram N-acetyl-α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 32 gram methyl-hydroselenide lithiums (methyl-hydroselenide lithium 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 100 ℃ of stirring reactions 7 hours to N-acetyl-α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 95 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back use anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent gets solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 51 grams, productive rate 76%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 90 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 25:
Utilize N-acetyl-α-An Jibingxisuan to prepare methylselenocysteinefrom:
39 gram N-acetyl-α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 39 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 25 ℃ of stirring reactions 40 hours to N-acetyl-α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 58 grams, productive rate 86%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 95 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 30 grams, productive rate 82%.
Embodiment 26:
Utilize N-acetyl-α-An Jibingxisuan to prepare methylselenocysteinefrom:
39 gram N-acetyl-α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 32 gram methyl-hydroselenide lithiums (methyl-hydroselenide lithium 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 65 ℃ of stirring reactions 5 hours to N-acetyl-α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 59 grams, productive rate 87%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 400ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 100 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 27:
Utilize N-acetyl-α-An Jibingxisuan to prepare methylselenocysteinefrom:
39 gram N-acetyl-α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 42 gram methyl-hydroselenide potassium (methyl-hydroselenide potassium 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 100 ℃ of stirring reactions 5 hours to N-acetyl-α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1, use the equal-volume ethyl acetate extraction then, organic phase is merged the back anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent, get solid, use dissolve with methanol, remove by filter insolubles, methanol solution is placed, separate out white solid, recrystallizing methanol gets N-acetyl-β-first seleno-α-An Jibingsuan 57 grams, productive rate 84%.
45 gram N-acetyl-β-first seleno-α-An Jibingsuans are dissolved in 300ml (1+1) hydrochloric acid, reflux 3 hours to N-acetyl-β-first seleno-α-An Jibingsuan hydrolysis complete (thin-layer chromatography detection) in 95 ℃.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 28 grams, productive rate 77%.
Embodiment 28:
Utilize the α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
30 gram α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 25 ℃ of stirring reactions 50 hours to α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 40 grams, productive rate 74%.
Embodiment 29:
Utilize the α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
30 gram α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 65 ℃ of stirring reactions 10 hours to α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 39 grams, productive rate 72%.
Embodiment 30:
Utilize the α-An Jibingxisuan methyl esters to prepare methylselenocysteinefrom:
30 gram α-An Jibingxisuan methyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 42 gram methyl-hydroselenide potassium (methyl-hydroselenide potassium 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 100 ℃ of stirring reactions 8 hours to α-An Jibingxisuan methyl esters react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 38 grams, productive rate 70%.
Embodiment 31:
Utilize the α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
35 gram α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 25 ℃ of stirring reactions 56 hours to α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 33 grams, productive rate 60%.
Embodiment 32:
Utilize the α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
35 gram α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of sealing backflow stirring reactions 12 hours to α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, separate out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 32 grams, productive rate 58%.
Embodiment 33:
Utilize the α-An Jibingxisuan ethyl ester to prepare methylselenocysteinefrom:
35 gram α-An Jibingxisuan ethyl esters are dissolved in the 300ml tetrahydrofuran (THF), are added drop-wise to then in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of sealing backflow stirring reactions 10 hours to α-An Jibingxisuan ethyl ester react completely (thin-layer chromatography detection).After solid filtering removed, in solution, slowly add 140 gram potassium hydroxide, make dissolving, refluxed 2 hours in 100 ℃.Be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 30 grams, productive rate 54%.
Embodiment 34:
Utilize α-An Jibingxisuan to prepare methylselenocysteinefrom:
26 gram α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), this drips of solution is added in the aqueous solution that contains 37 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.Be sealed in 25 ℃ of stirring reactions 40 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).Solid filtering is removed, and solution is neutralized to pH with (1+1) hydrochloric acid and is about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 39 grams, productive rate 72%.
Embodiment 35:
Utilize α-An Jibingxisuan to prepare methylselenocysteinefrom:
26 gram α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), this drips of solution is added in the aqueous solution that contains 42 gram methyl-hydroselenide potassium (methyl-hydroselenide potassium 400ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 65 ℃ of sealing backflow stirring reactions 6 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) sulfuric acid and be about 1.The pressure reducing and steaming solvent gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Logical ammonia is about 10 to pH in methanol solution, and the evaporated under reduced pressure solvent is removed the residue ammonia again, gets solid, use dissolve with methanol, insolubles is filtered, filtrate is placed, and separates out white solid, water-recrystallizing methanol gets methylselenocysteinefrom 35 grams, productive rate 64%.
Embodiment 36:
Utilize α-An Jibingxisuan to prepare methylselenocysteinefrom:
17 gram α-An Jibingxisuans are dissolved in the 300ml tetrahydrofuran (THF), this drips of solution is added in the aqueous solution that contains 26 gram sodium methyl-hydroselenides (sodium methyl-hydroselenide 300ml water dissolution), add solid sodium bicarbonate, add solid sodium bicarbonate 40 grams again to saturated.In 100 ℃ of sealing backflow stirring reactions 6 hours to α-An Jibingxisuan react completely (thin-layer chromatography detection).After solid filtering removed, be neutralized to pH with (1+1) hydrochloric acid and be about 1.The evaporated under reduced pressure solvent is removed unreacted hydrochloric acid, gets solid, uses dissolve with methanol, and insolubles is filtered, and uses dissolve with methanol behind the filtrate decompression evaporate to dryness again.Methanol solution is adjusted to pH 6-7 with triethylamine, places, and separates out white solid, and water-recrystallizing methanol gets methylselenocysteinefrom 21 grams, productive rate 59%.
Claims (6)
1, a kind of method of utilizing alpha-amino acrylic acid derivative to prepare methylselenocysteinefrom is characterized in that may further comprise the steps:
(1) addition: with methyl-hydroselenide or methyl-hydroselenide salt and α-An Jibingxisuan derivative generation addition reaction generation β-first seleno-α-An Jibingsuan derivative;
(2) hydrolysis of ester: the methyl compound in the β that step (1) obtains-first seleno-α-An Jibingsuan derivative is through sodium bicarbonate or sodium hydroxide or potassium hydroxide hydrolysis saponification, ethyl ester compound gets its carboxylate salt through sodium hydroxide or potassium hydroxide hydrolysis saponification, further gets its carboxylic acid cpd with hydrochloric acid or sulfuric acid acidation;
(3) acyl group is sloughed in hydrolysis: N-acetyl-β-first seleno-α-An Jibingsuan that step (1) and step (2) obtain or its salt are sloughed acyl group through hydrochloric acid or sulfuric acid heating hydrolysis and are got β-first seleno-α-An Jibingsuan hydrochloride or vitriol, at last with ammonia or triethylamine neutralize methylselenocysteinefrom.
2, the method for utilizing alpha-amino acrylic acid derivative to prepare methylselenocysteinefrom as claimed in claim 1, it is characterized in that: described methyl-hydroselenide salt is a kind of in sodium methyl-hydroselenide, methyl-hydroselenide potassium, the methyl-hydroselenide lithium, and described α-An Jibingxisuan derivative is a kind of in α-An Jibingxisuan, α-An Jibingxisuan methyl esters, α-An Jibingxisuan ethyl ester, N-acetyl-α-An Jibingxisuan, N-acetyl-α-An Jibingxisuan methyl esters, the N-acetyl-α-An Jibingxisuan ethyl ester.
3, the method for utilizing alpha-amino acrylic acid derivative to prepare methylselenocysteinefrom as claimed in claim 1 is characterized in that: step (1) generates β-first seleno-α-An Jibingsuan derivative with methyl-hydroselenide or methyl-hydroselenide salt and alpha-amino acrylic acid derivative generation addition reaction and carries out in saturated solution of sodium bicarbonate.
4, the method for utilizing alpha-amino acrylic acid derivative to prepare methylselenocysteinefrom as claimed in claim 1, it is characterized in that: step (1) generates β-first seleno-α-An Jibingsuan derivative with methyl-hydroselenide salt and alpha-amino acrylic acid derivative generation addition reaction and carries out under 25-100 ℃, it is at 25-100 ℃ that methyl-hydroselenide and alpha-amino acrylic acid derivative generation addition reaction generate β-first seleno-α-An Jibingsuan derivative, 2-10kg/cm
2Carry out under the pressure.
5, the method for utilizing alpha-amino acrylic acid derivative to prepare methylselenocysteinefrom as claimed in claim 1, it is characterized in that: the ester cpds hydrolysis saponification in step (2) β-first seleno-α-An Jibingsuan derivative gets its carboxylate salt to be carried out under 25-100 ℃, further gets its carboxylic acid cpd to pH＜2 with hydrochloric acid or sulfuric acid acidation.
6, the method for utilizing alpha-amino acrylic acid derivative to prepare methylselenocysteinefrom as claimed in claim 1; it is characterized in that: step (3) N-acetyl-β-first seleno-α-An Jibingsuan or its salt through (1+1) hydrochloric acid or (1+1) sulfuric acid slough acyl group in 90-100 ℃ of heating hydrolysis and get β-first seleno-α-An Jibingsuan hydrochloride or vitriol, at last with ammonia or triethylamine be neutralized to pH＞10 methylselenocysteinefrom.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108947881A (en) * | 2018-08-08 | 2018-12-07 | 济源希健生物医药科技发展有限公司 | A method of preparing optical voidness L-type selenium-methyl selenium substituted aminothiopropionic |
| CN109369482A (en) * | 2018-12-07 | 2019-02-22 | 济源市万洋华康生物科技有限公司 | A kind of preparation method of L- selenocystine |
| CN109535052A (en) * | 2018-12-07 | 2019-03-29 | 济源市万洋华康生物科技有限公司 | A kind of preparation method of L- methylselenocysteinefrom |
| CN113773229A (en) * | 2021-09-03 | 2021-12-10 | 西安交通大学 | Alpha, beta-unsaturated amino acid derivative and DL-selenium-methyl seleno amino acid derivative thereof, synthetic method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102146050A (en) * | 2010-02-10 | 2011-08-10 | 王玲 | Synthesis method, racemization method and separation method of Se-methylselenocysteine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108947881A (en) * | 2018-08-08 | 2018-12-07 | 济源希健生物医药科技发展有限公司 | A method of preparing optical voidness L-type selenium-methyl selenium substituted aminothiopropionic |
| CN108947881B (en) * | 2018-08-08 | 2020-10-27 | 济源希健生物医药科技发展有限公司 | Method for preparing optically pure L-type selenium-methyl selenocysteine |
| CN109369482A (en) * | 2018-12-07 | 2019-02-22 | 济源市万洋华康生物科技有限公司 | A kind of preparation method of L- selenocystine |
| CN109535052A (en) * | 2018-12-07 | 2019-03-29 | 济源市万洋华康生物科技有限公司 | A kind of preparation method of L- methylselenocysteinefrom |
| CN109369482B (en) * | 2018-12-07 | 2020-08-28 | 济源市万洋华康生物科技有限公司 | Preparation method of L-selenocysteine |
| CN113773229A (en) * | 2021-09-03 | 2021-12-10 | 西安交通大学 | Alpha, beta-unsaturated amino acid derivative and DL-selenium-methyl seleno amino acid derivative thereof, synthetic method and application |
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