CN1566080A - Resolution of DL-phenylalanine - Google Patents
Resolution of DL-phenylalanine Download PDFInfo
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- CN1566080A CN1566080A CN 03141446 CN03141446A CN1566080A CN 1566080 A CN1566080 A CN 1566080A CN 03141446 CN03141446 CN 03141446 CN 03141446 A CN03141446 A CN 03141446A CN 1566080 A CN1566080 A CN 1566080A
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Abstract
The invention relates to a resolution method of DL-phenylalanine disintegrating DL-phenylalanine with L(-)dibenzoyl tartaric acid, the reaction temperature is 80-95 deg. C, the reaction media is hydrochloric acid, methanol and water mixed solvent, the reacting time is 2-4 hours, lowering the temperature to 40-60 deg. C, recrystallizing, filtering, scouring to obtain filtration liquid and double salt, and processing the filtration liquid and double salt again.
Description
Technical field
The present invention relates to the method for splitting of DL-phenylalanine.
Background technology
As everyone knows, phenylalanine has two enantiomers, D-phenylalanine and L-phenylalanine, and wherein, the L-phenylalanine is the raw material of high intensity sweetner aspartame, is again important medical material and medicine intermediate; The D-phenylalanine is the basic material of the glad and Remedies for diabetes Na Geliena of antitumor drug hundred scholars, is important medicine intermediate.
Asymmetric synthesis is a kind of important method of preparation L-phenylalanine, but the stereoselectivity for asymmetric reaction in most of the cases is difficult to have uniqueness, so the product of gained is the mixture of inequality DL-phenylalanine enantiomorph often, need to separate just can obtain the L-phenylalanine.
In the aspartame preparation, nearly 50% L-phenylalanine needs to recycle, always being attended by racemization reaction in removal process takes place, generating portion D-phenylalanine, regenerant becomes and contains the excessive mixture of enantiomers of L-phenylalanine, so regenerant need could be reused after removing the D-phenylalanine through refining.
Split from inequality DL-phenylalanine enantiomorph and prepare the D-phenylalanine and the L-phenylalanine can carry out with the method that racemic modification splits, the fractionation of racemic modification needs the existence of the optical induction factor, as chiral reagent, enzyme etc.; DL-phenylalanine Separation of Enantiomers mainly adopts the power method for splitting (Mirviss, Ind.Eng.Chem.Res.1990,29,511.) under the enzyme catalysis.Though these class methods split the efficient height, the product optical purity is good, resolution reagent cost of manufacture costliness is so only be applicable to the phenylalanine separation of racemates usually.When adopting these class methods that the inequality mixture of enantiomers of phenylalanine is separated, the enantiomeric excess part also can participate in relevant chemical reaction, and the reaction of enantiomeric excess subparticipation is an abortive response, cause optical induction factor wastes in the use such as chiral reagent or enzyme, reduced separation efficiency, production cost increases.
Summary of the invention
The objective of the invention is the above-mentioned deficiency at prior art, propose a kind of method for splitting of new DL-phenylalanine, this method is applicable to the fractionation of DL-phenylalanine enantiomorph.
Above-mentioned purpose of the present invention is achieved by following technical proposals: a kind of method for splitting of DL-phenylalanine comprises the steps:
(1) with L (-) dibenzoyl tartaric acid the DL-phenylalanine is split under the condition of continuously stirring; The mol ratio of L (-) dibenzoyl tartaric acid and the reaction of DL-phenylalanine is (1-2): 1, temperature of reaction is 80-95 ℃, reaction medium is hydrochloric acid, methyl alcohol and water mixed solvent, reaction times is 2-4 hour, is cooled to 40-60 ℃, reduces to room temperature again, crystallization, filter, washing gets filtrate I and double salt;
(2) double salt is dropped in 12% hydrochloric acid, stirring reaction 0.5-1.5 hour, to filter, water washing gets filtrate II and throw out, throw out vacuum-drying is reclaimed make L (-) dibenzoyl tartaric acid;
(3) with the filtrate II concentrating under reduced pressure, and cool to-5-0 ℃, filter, D-phenylalanine hydrochloride wet salt I and filtrate II I, with filtrate II I concentrating under reduced pressure, and in the cryosel water-bath, cool off, filter, D-phenylalanine hydrochloride wet salt II and filtrate IV;
(4) filtrate IV and filtrate I are merged, concentrating under reduced pressure is cooled to-5-0 ℃, filter, L-phenylalanine hydrochloride wet salt I and filtrate V, with filtrate V evaporated under reduced pressure, the ethylene dichloride washing is filtered, L-phenylalanine hydrochloride wet salt II and filtrate VI;
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, be dissolved in methyl alcohol and water mixed solvent, methanol=10/1-5/1 (volume ratio), mixed solvent/wet salt=5-10 milliliter/1 gram wet salt, heated and stirred is with the pH value 4-7 of ammoniacal liquor adjusting mixing solutions, generate white precipitate, filter, washing, vacuum-drying gets the D-phenylalanine;
(6) L-phenylalanine hydrochloride wet salt I and L-phenylalanine hydrochloride wet salt II are merged, be dissolved in methyl alcohol and water mixed solvent, methanol=10/1-5/1 (volume ratio), mixed solvent/wet salt=5-10 milliliter/1 gram, heated and stirred is with the pH value 4-7 of ammoniacal liquor or sodium hydroxide solution adjusting mixing solutions, generate white precipitate, filter, washing, vacuum-drying gets the L-phenylalanine.
In the above-mentioned method for splitting, preferably the double salt that step () is obtained is dissolved in methyl alcohol and water mixed solvent, methanol=1: 1, and mixed solvent/double salt=5-10 milliliter/1 gram is cooled to 40-60 ℃, and recrystallization is used further to subsequent step after filtering and washing.
The another kind of method for splitting of the present invention comprises the steps:
(1) with L (-) dibenzoyl tartaric acid the DL-phenylalanine is split under the condition of continuously stirring; The mol ratio of L (-) dibenzoyl tartaric acid and the reaction of DL-phenylalanine is (1-2): 1, and temperature of reaction is 80-95 ℃, reaction medium is hydrochloric acid, methyl alcohol and water mixed solvent, reaction times is 2-4 hour, is cooled to 40-60 ℃, crystallization, filter, washing gets filtrate I and double salt;
(2) double salt is dropped in 12% hydrochloric acid, stirring reaction 0.5-1.5 hour, to filter, water washing gets filtrate II and throw out, throw out vacuum-drying is reclaimed make L (-) dibenzoyl tartaric acid;
(3) with the filtrate II concentrating under reduced pressure, and cool to-5-0 ℃, filter, D-phenylalanine hydrochloride wet salt I and filtrate II I, with filtrate II I concentrating under reduced pressure, and in the cryosel water-bath, cool off, filter, D-phenylalanine hydrochloride wet salt II and filtrate IV;
(4) filtrate IV and filtrate I are merged, concentrating under reduced pressure, temperature 55-60 ℃, filter, get filtrate V, 0.3/10～1/10 gac that adds L-phenylalanine theoretical yield makes filtrate V clarification, add methyl alcohol again, regulate pH value 4-7 with ammoniacal liquor or sodium hydroxide solution at last, filter, drying promptly gets the L-phenylalanine;
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, be dissolved in methyl alcohol and water mixed solvent, methanol=10/1-5/1 (volume ratio), mixed solvent/wet salt=5-10 milliliter/1 gram, heated and stirred is with the pH value 4-6 of ammoniacal liquor adjusting mixing solutions, generate white precipitate, filter, washing, vacuum-drying gets the D-phenylalanine.
In the above-mentioned method for splitting, preferably the double salt that step (1) is obtained is dissolved in methyl alcohol and water mixed solvent, methanol=1: 1, and mixed solvent/double salt=5-10 milliliter/1 gram is cooled to 40-60 ℃, and recrystallization is used further to subsequent step after filtering and washing.
In terms of existing technologies, method for splitting of the present invention have split route weak point, process stabilizing, simple to operate, resolution reagent L (-) dibenzoyl tartaric acid is with low cost, and good separating effect, advantage that product purity is high.
Embodiment
DL-phenylalanine (content is 99%), L (-) dibenzoyl tartaric acid (self-control, content 〉=98%)
Embodiment 1.1
(1) take by weighing DL-phenylalanine-3,4-quinone 5 gram, add 245 ml waters and 21 milliliters of 5M hydrochloric acid are formed in the mixed solution, stirring heating is warming up to 90 ℃ dissolves the DL-phenylalanine fully.Then, add the solution that 40 gram L (-) dibenzoyl tartaric acids and 105 ml methanol are formed.Slowly be cooled to 53 ℃ and become turbid, insulated and stirred 3 hours is cooled to room temperature, filter, washing, must leach thing is double salt 53.5 grams, simultaneously mother liquor and washing lotion are merged filtrate I;
(2) 53.5 gram double salt are added in 175 milliliter of 12% hydrochloric acid, stirring reaction 1 hour filters, water washing, and filtrate and washing lotion merge filtrate II; To leach thing vacuum-drying simultaneously, and reclaim L (-) dibenzoyl tartaric acid 37.0 grams, the rate of recovery of resolving agent is 92.5%;
(3) filtrate II is evaporated to 70 milliliters, and is cooled to 0 ℃, filter, get D-phenylalanine hydrochloride wet salt I, obtain filtrate II I simultaneously; Filtrate II I is evaporated to 1/2 of original volume, puts into ice-water bath and cool off, part D-phenylalanine hydrochloride wet salt II gets filtrate IV simultaneously again;
(4) filtrate IV and filtrate I are merged, be evaporated to 70 milliliters, and be cooled to 0 ℃, make crystallization complete, filter, get L-phenylalanine hydrochloride wet salt I, get filtrate V simultaneously; With filtrate V evaporated under reduced pressure, wash out with ethylene dichloride, filter, get L-phenylalanine hydrochloride wet salt II;
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, 162 milliliters of (methyl alcohol: water=10: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, PH=6.5 with ammoniacal liquor accent mixing solutions separates out white precipitate, filters, washing, vacuum-drying gets D-phenylalanine 14.0 grams, fractionation rate 80%.Record the specific rotation light value and be+35.0 ° (c=1, water).
(6) L-phenylalanine hydrochloride wet salt I and L-phenylalanine hydrochloride wet salt II are merged, 182 milliliters of (methyl alcohol: water=10: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, transfer the PH=6.5 of mixing solutions with ammoniacal liquor, separate out white precipitate, filter, washing, vacuum-drying gets L-phenylalanine 15.5 grams, and the fractionation rate is 88.5%.Record the specific rotation light value and be-34.0 ° (c=1, water).
Embodiment 1.2
The double salt that step () among the embodiment 1 is obtained is dissolved in 321 milliliters of methyl alcohol and water mixed solvents, methanol=1: 1, mixed solvent/double salt=6 milliliter/1 gram, be cooled to 40 ℃, recrystallization is after filtering and washing, must leach thing 52.8 grams, will leach thing 52.8 grams and be used for subsequent step.All the other are with embodiment 1.Get D-phenylalanine 13.9 grams at last, record specific rotation light value+35.0 ° (c=1, water).
Embodiment 1.3
(1) take by weighing DL-phenylalanine 50 gram, add 290 ml waters and 30 milliliters of 5M hydrochloric acid are formed in the mixed solution, stirring heating is warming up to 95 ℃ dissolves the DL-phenylalanine fully.Then, add the solution that 120.0 gram L (-) dibenzoyl tartaric acids and 210 ml methanol are formed.Slowly be cooled to 40 ℃ and become turbid, insulated and stirred 2 hours is cooled to room temperature, filter, washing, must leach thing is double salt 53.5 grams, simultaneously mother liquor and washing lotion are merged filtrate I;
(2) 121.3 gram double salt are added in 400 milliliter of 12% hydrochloric acid, stirring reaction 1.5 hours filters, water washing, and filtrate and washing lotion merge filtrate II; To leach thing vacuum-drying simultaneously, and reclaim L (-) dibenzoyl tartaric acid 111.6 grams, the rate of recovery of resolving agent is 93.0%;
(3) filtrate II is evaporated to 150 milliliters, and is cooled to-5 ℃, filter, get D-phenylalanine hydrochloride wet salt I, obtain filtrate II I simultaneously; Filtrate II I is evaporated to 1/2 of original volume, puts into ice-water bath and cool off, part D-phenylalanine hydrochloride wet salt II gets filtrate IV simultaneously again;
(4) filtrate IV and filtrate I are merged, be evaporated to 150 milliliters, and be cooled to-5 ℃, make crystallization complete, filter, get L-phenylalanine hydrochloride wet salt I, get filtrate V simultaneously; With filtrate V evaporated under reduced pressure, wash out with ethylene dichloride, filter, get L-phenylalanine hydrochloride wet salt II;
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, 370 milliliters of (methyl alcohol: water=5: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, with concentration is the PH=5 that 17% sodium hydroxide solution is transferred mixing solutions, separates out white precipitate, filters, washing, drying gets D-phenylalanine 19.6 grams, fractionation rate 78.5%.Record the specific rotation light value and be+34.9 ° (c=1, water).
(6) L-phenylalanine hydrochloride wet salt I and L-phenylalanine hydrochloride wet salt II are merged, 182 milliliters of (methyl alcohol: water=5: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, transfer the PH=5 of mixing solutions with ammoniacal liquor, separate out white precipitate, filter, washing, vacuum-drying gets L-phenylalanine 22.3 grams, and the fractionation rate is 89.0%.Record the specific rotation light value and be-34.6 ° (c=1, water).
Embodiment 1.4
The double salt that step () among the embodiment 3 is obtained is dissolved in 1213.0 milliliters of methyl alcohol and water mixed solvents, methanol=1: 1, mixed solvent/double salt=10 milliliter/1 gram, be cooled to 60 ℃, recrystallization is after filtering and washing, must leach thing 119.5 grams, will leach thing 119.5 grams and be used for subsequent step.All the other are with embodiment 3.Get D-phenylalanine 19.5 grams at last, record specific rotation light value+35.0 ° (c=1, water).
Embodiment 1.5
(1) take by weighing DL-phenylalanine 40 gram, add 275 ml waters and 31 milliliters of 5M hydrochloric acid are formed in the mixed solution, stirring heating is warming up to 80 ℃ dissolves the DL-phenylalanine fully.Then, add the solution that 65.0 gram L-(-)-benzene toluene L-Ala and 170.0 ml methanol are formed.Slowly be cooled to 60 ℃ and become turbid, insulated and stirred 4 hours is cooled to room temperature, filter, washing, must leach thing is double salt 61.2 grams, simultaneously mother liquor and washing lotion are merged filtrate I;
(2) 61.2 gram double salt are added in 200.0 milliliter of 12% hydrochloric acid, stirring reaction 0.5 hour filters, water washing, and filtrate and washing lotion merge filtrate II; To leach thing vacuum-drying simultaneously, and reclaim L (-) dibenzoyl tartaric acid 58.5 grams, the rate of recovery of resolving agent is 90.0%;
(3) filtrate II is evaporated to 85 milliliters, and is cooled to-3 ℃, filter, get D-phenylalanine hydrochloride wet salt I, obtain filtrate II I simultaneously; Filtrate II I is evaporated to 1/2 of original volume, puts into ice-water bath and cool off, part D-phenylalanine hydrochloride wet salt II gets filtrate IV simultaneously again;
(4) filtrate IV and filtrate I are merged, be evaporated to 85 milliliters, and be cooled to-3 ℃, make crystallization complete, filter, get L-phenylalanine hydrochloride wet salt I, get filtrate V simultaneously; With filtrate V evaporated under reduced pressure, wash out with ethylene dichloride, filter, get L-phenylalanine hydrochloride wet salt II;
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, 185 milliliters of (methyl alcohol: water=7.5: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, PH=4.5 with ammoniacal liquor accent mixing solutions separates out white precipitate, filters, washing, vacuum-drying gets D-phenylalanine 16.2 grams, fractionation rate 81.0%.Record the specific rotation light value and be+34.8 ° (c=1, water).
(6) L-phenylalanine hydrochloride wet salt I and L-phenylalanine hydrochloride wet salt II are merged, 208 milliliters of (methyl alcohol: water=7.5: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, transfer the PH=4 of mixing solutions with ammoniacal liquor, separate out white precipitate, filter, washing, vacuum-drying gets L-phenylalanine 17.8 grams, and the fractionation rate is 89.0%.Record the specific rotation light value and be-34.2 ° (c=1, water).
Embodiment 2.1
(1) take by weighing DL-phenylalanine-3,4-quinone 5 gram, add 245 ml waters and 21 milliliters of 5M hydrochloric acid are formed in the mixed solution, stirring heating is warming up to 90 ℃ dissolves the DL-phenylalanine fully.Then, add the solution that 40 gram L (-) dibenzoyl tartaric acids and 105 ml methanol are formed.Slowly be cooled to 53 ℃ and become turbid, insulated and stirred 3 hours is cooled to room temperature, filter, washing, must leach thing is double salt 53.5 grams, simultaneously mother liquor and washing lotion are merged filtrate I;
(2) 53.5 gram double salt are added in 175 milliliter of 12% hydrochloric acid, stirring reaction 1 hour filters, water washing, and filtrate and washing lotion merge filtrate II; To leach thing vacuum-drying simultaneously, and reclaim L (-) dibenzoyl tartaric acid 37.0 grams, the rate of recovery of resolving agent is 92.5%;
(3) filtrate II is evaporated to 70 milliliters, and is cooled to 0 ℃, filter, get D-phenylalanine hydrochloride wet salt I, obtain filtrate II I simultaneously; Filtrate II I is evaporated to 1/2 of original volume, puts into ice-water bath and cool off, part D-phenylalanine hydrochloride wet salt II gets filtrate IV simultaneously again;
(4) filtrate IV and filtrate I are merged, be evaporated to 70 milliliters, 55 ℃ of following elimination throw outs get filtrate V, add 0.45 gram gac and make filtrate V clarification, add methyl alcohol again, regulate PH=4 with ammoniacal liquor at last, filter, drying promptly gets L-phenylalanine 15.3 grams, and the fractionation rate is 87.4%.Record the specific rotation light value and be-33.9 ° (c=1, water).
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, 162 milliliters of (methyl alcohol: water=10: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, PH=6 with ammoniacal liquor accent mixing solutions separates out white precipitate, filters, washing, vacuum-drying gets D-phenylalanine 14.0 grams, fractionation rate 80%.Record the specific rotation light value and be+35.0 ° (c=1, water).
Embodiment 2.2
The double salt that step (1) among the embodiment 2.1 is obtained is dissolved in 321 milliliters of methyl alcohol and water mixed solvents, methanol=1: 1, mixed solvent/double salt=6 milliliter/1 gram, be cooled to 40 ℃, recrystallization is after filtering and washing, must leach thing 52.8 grams, will leach thing 52.8 grams and be used for subsequent step.All the other are with embodiment 2.1.Get D-phenylalanine 13.9 grams at last, record specific rotation light value+35.0 ° (c=1, water).
Embodiment 2.3
(1) take by weighing DL-phenylalanine 50 gram, add 290 ml waters and 30 milliliters of 5M hydrochloric acid are formed in the mixed solution, stirring heating is warming up to 95 ℃ dissolves the DL-phenylalanine fully.Then, add the solution that 120.0 gram L (-) dibenzoyl tartaric acids and 210 ml methanol are formed.Slowly be cooled to 40 ℃ and become turbid, insulated and stirred 2 hours is cooled to room temperature, filter, washing, must leach thing is double salt 53.5 grams, simultaneously mother liquor and washing lotion are merged filtrate I;
(2) 121.3 gram double salt are added in 400 milliliter of 12% hydrochloric acid, stirring reaction 1.5 hours filters, water washing, and filtrate and washing lotion merge filtrate II; To leach thing vacuum-drying simultaneously, and reclaim L (-) dibenzoyl tartaric acid 111.6 grams, the rate of recovery of resolving agent is 93.0%;
(3) filtrate II is evaporated to 150 milliliters, and is cooled to-5 ℃, filter, get D-phenylalanine hydrochloride wet salt I, obtain filtrate II I simultaneously; Filtrate II I is evaporated to 1/2 of original volume, puts into ice-water bath and cool off, part D-phenylalanine hydrochloride wet salt II gets filtrate IV simultaneously again;
(4) filtrate IV and filtrate I are merged, be evaporated to 150 milliliters, 60 ℃ of following elimination throw outs get filtrate V, add 2.2 gram gacs and make filtrate V clarification, add methyl alcohol again, regulate PH=6 with 17% sodium hydroxide solution at last, filter drying, promptly get L-phenylalanine 21.9 grams, the fractionation rate is 87.6%.Record the specific rotation light value and be-34.4 ° (c=1, water).
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, 370 milliliters of (methyl alcohol: water=5: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, with concentration is the PH=5 that 17% sodium hydroxide solution is transferred mixing solutions, separates out white precipitate, filters, washing, drying gets D-phenylalanine 19.6 grams, fractionation rate 78.5%.Record the specific rotation light value and be+34.9 ° (c=1, water).
Embodiment 2.4
The double salt that step (1) among the embodiment 2.3 is obtained is dissolved in 1213.0 milliliters of methyl alcohol and water mixed solvents, methanol=1: 1, mixed solvent/double salt=10 milliliter/1 gram, be cooled to 60 ℃, recrystallization, after filtering and washing, must leach thing 119.5 grams, will leach thing 119.5 grams and be used for subsequent step.All the other are with embodiment 2.3.Get D-phenylalanine 19.5 grams at last, record specific rotation light value+35.0 ° (c=1, water).
Embodiment 2.5
(1) take by weighing DL-phenylalanine 40 gram, add 275 ml waters and 31 milliliters of 5M hydrochloric acid are formed in the mixed solution, stirring heating is warming up to 80 ℃ dissolves the DL-phenylalanine fully.Then, add the solution that 65.0 gram L (-) dibenzoyl tartaric acids and 170.0 ml methanol are formed.Slowly be cooled to 60 ℃ and become turbid, insulated and stirred 4 hours stops to stir at last, is cooled to room temperature, filter, washing, must leach thing is double salt 61.2 grams, simultaneously mother liquor and washing lotion are merged filtrate I;
(2) 61.2 gram double salt are added in 200.0 milliliter of 12% hydrochloric acid, stirring reaction 0.5 hour filters, water washing, and filtrate and washing lotion merge filtrate II; To leach thing vacuum-drying simultaneously, and reclaim L (-) dibenzoyl tartaric acid 58.5 grams, the rate of recovery of resolving agent is 90.0%;
(3) filtrate II is evaporated to 85 milliliters, and is cooled to-3 ℃, filter, get D-phenylalanine hydrochloride wet salt I, obtain filtrate II I simultaneously; Filtrate II I is evaporated to 1/2 of original volume, puts into ice-water bath and cool off, part D-phenylalanine hydrochloride wet salt II gets filtrate IV simultaneously again;
(4) filtrate IV and filtrate I are merged, be evaporated to 85 milliliters, 58 ℃ of following elimination throw outs get filtrate V, add 1.22 gram gacs and make filtrate V clarification, add methyl alcohol again, regulate PH=5.5 with ammoniacal liquor at last, filter, dry that L-phenylalanine 17.4 restrains, the fractionation rate is 87.0%.Record the specific rotation light value and be-34.3 ° (c=1, water).
(5) D-phenylalanine hydrochloride wet salt I and D-phenylalanine hydrochloride wet salt II are merged, 185 milliliters of (methyl alcohol: water=7.5: 1 of mixed solvent with methyl alcohol and water, volume ratio) heated and stirred dissolving, PH=5 with ammoniacal liquor accent mixing solutions separates out white precipitate, filters, washing, vacuum-drying gets D-phenylalanine 16.2 grams, fractionation rate 81.0%.Record the specific rotation light value and be+34.9 ° (c=1, water).
Claims (4)
1, a kind of method for splitting of DL-phenylalanine comprises the steps:
(1) with L (-) dibenzoyl tartaric acid the DL-phenylalanine is split under the condition of continuously stirring; The mol ratio of L (-) dibenzoyl tartaric acid and the reaction of DL-phenylalanine is (1-2): 1, and temperature of reaction is 80-95 ℃, reaction medium is hydrochloric acid, methyl alcohol and water mixed solvent, reaction times is 2-4 hour, is cooled to 40-60 ℃, crystallization, filter, washing gets filtrate I and double salt;
(2) double salt is dropped in 12% hydrochloric acid, stirring reaction 0.5-1.5 hour, to filter, water washing gets filtrate II and throw out, with throw out vacuum-drying, reclaims and makes L (-) dibenzoyl tartaric acid;
(3) with the filtrate II concentrating under reduced pressure, and cool to-5-0 ℃, filter, D-phenylalanine hydrochloride I wet salt and filtrate II I, with filtrate II I concentrating under reduced pressure, and in the cryosel water-bath, cool off, filter, D-phenylalanine hydrochloride II and filtrate IV;
(4) filtrate IV and filtrate I are merged, concentrating under reduced pressure is cooled to-5-0 ℃, filter, L-phenylalanine hydrochloride I wet salt and filtrate V, with filtrate V evaporated under reduced pressure, the ethylene dichloride washing is filtered, L-phenylalanine hydrochloride II wet salt and filtrate VI;
(5) D-phenylalanine hydrochloride I wet salt and D-phenylalanine hydrochloride II wet salt are merged, be dissolved in methyl alcohol and water mixed solvent, methanol=10/1-5/1 (volume ratio), mixed solvent/wet salt=5-10 milliliter/1 gram wet salt, heated and stirred is with the pH value 4-7 of ammoniacal liquor adjusting mixing solutions, generate white precipitate, filter, washing, vacuum-drying gets the D-phenylalanine;
(6) L-phenylalanine hydrochloride I wet salt and L-phenylalanine hydrochloride II wet salt are merged, be dissolved in methyl alcohol and water mixed solvent, methanol=10/1-5/1 (volume ratio), mixed solvent/wet salt=5-10 milliliter/1 gram, heated and stirred is with the pH value 4-7 of ammoniacal liquor or sodium hydroxide solution adjusting mixing solutions, generate white precipitate, filter, washing, vacuum-drying gets the L-phenylalanine.
2, according to the method for splitting of the described DL-phenylalanine of claim 1, it is characterized in that the double salt that step () obtains is dissolved in methyl alcohol and water mixed solvent, methanol=1: 1, mixed solvent/double salt=5-10 milliliter/1 gram, be cooled to 40-60 ℃, recrystallization is used further to subsequent step after filtering and washing.
3, a kind of method for splitting of DL-phenylalanine comprises the steps:
(1) with L (-) dibenzoyl tartaric acid the DL-phenylalanine is split under the condition of continuously stirring; The mol ratio of L (-) dibenzoyl tartaric acid and the reaction of DL-phenylalanine is (1-2): 1, temperature of reaction is 80-95 ℃, reaction medium is hydrochloric acid, methyl alcohol and water mixed solvent, reaction times is 2-4 hour, be cooled to 40-60 ℃, be cooled to crystallizing at room temperature again, filter, washing gets filtrate I and double salt;
(2) double salt is dropped in 12% hydrochloric acid, stirring reaction 0.5-1.5 hour, to filter, water washing gets filtrate II and throw out, throw out vacuum-drying is reclaimed make L (-) dibenzoyl tartaric acid;
(3) with the filtrate II concentrating under reduced pressure, and cool to-5-0 ℃, filter, D-phenylalanine hydrochloride I wet salt and filtrate II I, with filtrate II I concentrating under reduced pressure, and in the cryosel water-bath, cool off, filter, D-phenylalanine hydrochloride II and filtrate IV;
(4) filtrate IV and filtrate I are merged, concentrating under reduced pressure, filters by temperature 55-60 ℃, get filtrate V, add 0.3/10～1/10 gac of L-phenylalanine theoretical yield, make filtrate V clarification, add methyl alcohol again, use ammoniacal liquor (or sodium hydroxide) solution to regulate pH value 4-7 at last, filter, drying promptly gets the L-phenylalanine;
(5) D-phenylalanine hydrochloride I wet salt and D-phenylalanine hydrochloride II wet salt are merged, be dissolved in methyl alcohol and water mixed solvent, methanol=10/1-5/1 (volume ratio), mixed solvent/wet salt=5-10 milliliter/1 gram, heated and stirred is with the pH value 4-6 of ammoniacal liquor adjusting mixing solutions, generate white precipitate, filter, washing, vacuum-drying gets the D-phenylalanine.
4, according to the method for splitting of the described DL-phenylalanine of claim 3, it is characterized in that the double salt that step (1) obtains is dissolved in methyl alcohol and water mixed solvent, methanol=1: 1, mixed solvent/double salt=5-10 milliliter/1 gram, be cooled to 40-60 ℃, recrystallization is used further to subsequent step after filtering and washing.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101289410B (en) * | 2008-06-06 | 2011-03-16 | 山东奥克特化工有限公司 | Method for preparing D-phenylalanine |
| CN101012181B (en) * | 2007-01-31 | 2012-08-08 | 上海化学试剂研究所 | Resolution method of DL-p-chlorophenylalanine |
| CN103664670A (en) * | 2012-09-06 | 2014-03-26 | 济南大学 | Method for extracting and separating phenylalanine by using N-alkyl-L-phenylalanine methyl ester |
| WO2017183835A1 (en) * | 2016-04-19 | 2017-10-26 | 주식회사 아미노로직스 | Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester |
| CN110467539A (en) * | 2019-08-30 | 2019-11-19 | 浙江普洛家园药业有限公司 | The method for splitting of one kind 2,6- dimethyltyrosine ester and its application |
-
2003
- 2003-07-08 CN CN 03141446 patent/CN1566080A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012181B (en) * | 2007-01-31 | 2012-08-08 | 上海化学试剂研究所 | Resolution method of DL-p-chlorophenylalanine |
| CN101289410B (en) * | 2008-06-06 | 2011-03-16 | 山东奥克特化工有限公司 | Method for preparing D-phenylalanine |
| CN103664670A (en) * | 2012-09-06 | 2014-03-26 | 济南大学 | Method for extracting and separating phenylalanine by using N-alkyl-L-phenylalanine methyl ester |
| WO2017183835A1 (en) * | 2016-04-19 | 2017-10-26 | 주식회사 아미노로직스 | Method for preparing d-4,4'-biphenylalanine alkyl ester or l-4,4'-biphenylalanine alkyl ester from dl-4,4'-biphenylalanine alkyl ester |
| CN109071415A (en) * | 2016-04-19 | 2018-12-21 | 阿米洛吉斯有限公司 | The method that D-4,4 '-biphenyl alanine Arrcostab or L-4,4 '-biphenyl alanine Arrcostab are prepared by DL-4,4 '-biphenyl alanine Arrcostab |
| CN110467539A (en) * | 2019-08-30 | 2019-11-19 | 浙江普洛家园药业有限公司 | The method for splitting of one kind 2,6- dimethyltyrosine ester and its application |
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