CN1939906A - Synthesis of DL-tryptophane-alpha-N - Google Patents

Synthesis of DL-tryptophane-alpha-N Download PDF

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CN1939906A
CN1939906A CN 200510030037 CN200510030037A CN1939906A CN 1939906 A CN1939906 A CN 1939906A CN 200510030037 CN200510030037 CN 200510030037 CN 200510030037 A CN200510030037 A CN 200510030037A CN 1939906 A CN1939906 A CN 1939906A
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tryptophane
synthetic method
ammonium
indole
hydroxide
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CN100424073C (en
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卢伟京
张亮
徐建飞
宋明鸣
张静梅
李良君
杜晓宁
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Shanghai Research Institute of Chemical Industry SRICI
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Abstract

Synthesis of DL-tryptophan-alpha-15N is carried out by taking ammonium salt-15N or NH3-15N and indole-3-pyruvic acid as raw materials, catalytic ammonifying and reducing to obtain the final product. Its recovery rate reaches to 92%, 15N abundance is >99% atom and its purity is >99%. DL-tryptophan-alpha-15N is an important amino-acid mark, and can be used as label or intermediate to synthesize other marks.

Description

A kind of DL-tryptophane-α- 15The synthetic method of N
Technical field
The present invention relates to amino acid whose synthetic method, relate in particular to a kind of DL-tryptophane-α- 15The synthetic method of N.
Background technology
DL-tryptophane-α- 15N (DL-Tryptophan-α- 15N), promptly 15N amino labeled racemize tryptophane, have another name called DL-Tryptophan-α- 15N (DL-α-amino-3-Indolepropioni acid-α- 15N), its structure is:
Figure A20051003003700031
Purified racemize DL-tryptophane-α- 15N is white or the faint yellow crystallization or the crystalline powder of slightly sweet taste, is dissolved in diluted acid or diluted alkaline, and solubleness is little in the water, is slightly soluble in ethanol, 289 ℃ of fusing points (decomposition).
Aspect medical science, in vivo, tryptophane participates in multiple pathways metabolism, uses 15N mark tryptophane can more convenient ground researching human body physiological metabolism process, research various diseases pathogenesis, especially hepatopathy pathogenesis.Aspect life science, 15N mark tryptophane can be used for synthesizing 15N mark peptide, albumen are used for proteic structural analysis etc.
At present synthetic DL-tryptophane-α- 15N has following method:
(1) glycine- 15N-indole-3-formaldehyde method.This method with glycine- 15N be the synthetic urobenzoic acid of raw material- 15N, urobenzoic acid- 15N and indole-3-formaldehyde are synthetic through 5 step reaction such as condensation, hydrolysis and reduction, obtain DL-tryptophane-α- 15N.Wherein, amino- 15N by glycine- 15The N introducing (Tang G H, Wang S C, Wu S Q, Jiang G H, Synthesis of DL-α- 15N-tryptophan and 2- 15N-perlolyrine.J.Labelled Compd.Radiopharm., 1998XLI (2): 139-142).
(2) indoles-glycolylurea- 15The N method.This method with indoles and glycolylurea- 15N etc. are raw material, through 4 step reaction such as condensation and reduction, obtain DL-tryptophane-α- 15N, wherein glycolylurea- 15N by glycine ethyl ester- 15N and Zassol are synthetic, have characteristics simple to operate (Kotlyarevskaya, B.M.; Gubenko, I.I .D, L-Tryptophan, MetodyPoluch.Khim.Reakt.Prep., 26,273-6; Moriya, et al, Chem.Pharm.Buil, 1980,28:1931).
(3) donaxine-acetamino diethyl malonate- 15N method, this method be traditional synthesis of natural abundance tryptophane method (Hollmann, H, H, Phsiol.Chem.1949 284:163), also can synthesize 15N mark tryptophane.This method is a raw material with indoles etc., through 6 step reaction such as addition, condensation and hydrolysis, obtain DL-tryptophane-α- 15N.Wherein, amino- 15N by diethyl malonate through (Sodium Nitrite- 15N) nitrated, reduction is introduced.
(4) reductive amination method, this method with indole-3-pyruvic acid (IPyA) and ammonium nitrate- 15N is a raw material, is that reductive agent prepares tryptophane with the sodium cyanoborohydride, amino- 15N by ammonium nitrate- 15The N introducing (Borch R F, Bernstein MD, Durst H D, The cyanohydridoborate anion as a selective reducing agent[J] .J.Amer.Chem.Soc.1971,93:2897-2904).This method is " treating different things alike " mode, has short, the simple to operate characteristics of route.
In the method (1), reactions steps is more, amino- 15N introduces when the first step, therefore total yield be not very high (with glycine- 15N counts 46.9%).As again by ammonium salt- 15N synthesize glycine- 15N, DL-tryptophane-α- 15The N yield reduce (with ammonium salt- 15N counts about 32%), reactions steps also increases.In method (2) and (3), introducing amino- 15The raw material of N, with 15N calculates, the amidomalonic acid diethyl ester- 15N, glycolylurea- 15The yield of N is all lower, and reactions steps is more, makes that the yield of tryptophane is not high.In method (4), amino directly by ammonium nitrate- 15N introduces, and reaction is the consecutive reaction of a multistep, but its yield has only 23%.
In above method, the amino of method (4) is introduced the simplest, this patent uses catalyzer to promote this reaction, promptly adopt catalytic ammoniation reductive mode (Duan Hangxin (editor: Pei Guifang, Wang Suping), practical Minute Organic Synthesis handbook [M]. Beijing: Chemical Industry Press, 2000, p318-321) to improve the yield of tryptophane.Catalytic ammoniation reductive method can be used for amino acid synthetic (Schoenheimer R.and Ratner S, Studies in proteinmetabolism, Synthesis of amino acids containing isotopic nitrogen, J.Biol.Chem., 1939,127,301; Hirai, Kenji; Fujita, Makoto; Fuchigami, Takamasa, Phenylalanine, JP61091159,1986 Wu Guang-wen, Li Guang-xing), but do not see be used for DL-tryptophane-α- 15N's is synthetic.
Summary of the invention
The purpose of this invention is to provide a kind of mode that adopts catalytic reduction, with ammonium salt- 15N or ammonia- 15N and indole-3-pyruvic acid be the synthetic DL-tryptophane-α of raw material- 15The method of N.
Purpose of the present invention can be achieved through the following technical solutions:
A kind of DL-tryptophane-α- 15The synthetic method of N is characterized in that, this method comprises: ammonium salt- 15N and alkali, or 15N-NH 3With indole-3-pyruvic acid under catalyst action, in used solvent alcohol, react, with crystallization separate out obtain DL-tryptophane-α- 15N.
Described ammonium salt- 15N ammonium sulfate- 15N, ammonium chloride- 15N, volatile salt- 15N, bicarbonate of ammonia- 15N, ammonium nitrate- 15N, ammonium phosphate- 15N, ammonium formiate- 15N, ammonium acetate- 15N, propionic acid ammonium- 15N or butyric acid ammonium- 15Select for use among the N.
Described alkali is selected for use in sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, hydrated barta, yellow soda ash, sodium bicarbonate, sodium formiate, sodium acetate, Sodium Propionate, Sodium propanecarboxylate, natrium valericum, salt of wormwood, saleratus, potassium formiate, potassium acetate, potassium propionate, potassium butyrate or valeric acid potassium.
Described catalyzer is selected for use in palladium, rhodium, ruthenium, platinum or nickel; Wherein the form of palladium, rhodium, ruthenium, platinum or nickel is metal, salt, oxide compound, loading type or matrix type.
Described ammonium salt- 15N or 15N-NH 3With the mol ratio of indole-3-pyruvic acid be 15N: indole-3-pyruvic acid=0.5～20: 1, this mol ratio is especially in 1～10mol scope.
The weight ratio of described catalyzer and indole-3-pyruvic acid is 0.005～100: 1, and this weight ratio is especially 0.01～50: in 1 scope.
Described reaction system pH is 3～11, especially in 5～9 scopes.
Described reaction pressure is normal pressure～10MPa, especially in normal pressure～5MPa scope.
Described temperature of reaction is-20～80 ℃, especially in 0～60 ℃ of scope.
Described solvent is at C 1～C 4Select for use in alkyl alcohol, the tetrahydrofuran (THF) Huo diox.
Described C 1～C 4Alkyl alcohol is to select for use in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol or the trimethyl carbinol.
Described solvent load is 1～400ml solvent/1 gram indole-3-pyruvic acid, especially in 2～200ml solvent/1 gram indole-3-pyruvic acid scope.
A kind of new DL-tryptophane-α of the present invention- 15The N synthetic method, promptly with ammonium salt- 15N or 15N-NH 3With indole-3-pyruvic acid be raw material, adopt catalytic ammoniation reductive mode prepare DL-tryptophane-α- 15N, reaction formula is:
Figure A20051003003700051
DL-tryptophane-α of the present invention- 15The analysis of N
Product 15The N abundance detects and adopts Delta S gas isotope mass spectrograph (Finnigan company) to analyze.
Product purity is measured and is used the conductometric titration analysis.Instrument is DDB-303A type electric conductivity instrument and DJS-1C type conductance electrode (Shanghai Precision ﹠ Scientific Instrument Co., Ltd. Leici Instrument Factory).
The analysis of raw material and product, the monitoring of reaction process adopts Waters Breeze type high performance liquid chromatograph (Waters company) to carry out, and analysis condition is: C-18 reversed-phase column, moving phase are sodium-acetate/methyl alcohol (volume ratio 65: 35), Waters 2487 UV-detector, the detection wavelength is 280nm.
The fusing point of product adopts measures WRS-1B numeral fusing point instrument (Shanghai precision instrument company limited) measurement (proofreading and correct).
Embodiment
Further narrate the present invention below in conjunction with specific embodiment, embodiment just represents a kind of typical example, and claim is not limited by the represented scope of embodiment.
Embodiment 1
The 1000mL reactor adds 4 gram 5%Pd/C, 20 gram indole-3-pyruvic acids (self-control, purity 〉=99%), contains 4.5 gram NH3- 15N ( 15The N abundance is 99.3%atom) the 500mL ethanolic soln.Sealed reactor is used nitrogen, hydrogen exchange respectively, hydrogen pressure 1MPa, and at 30 ℃ of magnetic agitation reaction 10h, the DL-tryptophane-α of generation- 15N separates out with white crystal, release, the logical unreacted NH of nitrogen recycling 32.8 gram.Filter, washing, concentrate, crystallization, recrystallization, white DL-tryptophane-α- 15N 16.2 grams, yield ( 15The N utilization ratio) is 87.0% (with the NH3-that consumes 15N calculates), 15The N abundance is 99.3%atom, purity 99.6%, 288 ℃ of fusing points.
Embodiment 2
In embodiment 1, restrain NH with 10 4NO 3- 15N ( 15The N abundance is 99.3%atom) and 20 gram sodium-acetates (AR) replacement NH3- 15N, white DL-tryptophane-α- 15N 16.8 grams, 15The N abundance is 99.3%atom, purity 99.5%, and DL-tryptophane-α- 15The N yield is 88.2%, 288 ℃ of fusing points.
Embodiment 3
In embodiment 1, replace Pd/C with skeleton nickel (10 gram), 40 ℃ of temperature of reaction, hydrogen pressure 5MPa, white DL-tryptophane-α- 15N 15.0 grams, 15The N abundance is 99.3% atom, purity 99.0%, and DL-tryptophane-α- 15The N yield is 78.8%, 287 ℃ of fusing points.
Embodiment 4
In embodiment 1, replace Pd/C with Pt/C, white DL-tryptophane-α- 15N 15.8 grams, 15The N abundance is 99.3%atom, purity 99.5%, and DL-tryptophane-α- 15The N yield is 84.8%, 289 ℃ of fusing points.
Embodiment 5
In embodiment 1, replace Pd/C with palladium black, 10 ℃ of temperature of reaction, hydrogen pressure 3Mpa, 40 hours reaction times, white DL-tryptophane-α- 15N 16.4 grams, 15The N abundance is 99.3%atom, purity 99.7%, and DL-tryptophane-α- 15The N yield is 88.0%, 289 ℃ of fusing points.
Embodiment 6
In embodiment 1, replace ethanol with Virahol, white DL-tryptophane-α- 15N 16.0 grams, 15The N abundance is 99.3%atom, purity 99.6%, and DL-tryptophane-α- 15The N yield is 85.9%, 288 ℃ of fusing points.
Embodiment 7
Usefulness ammonium acetate in embodiment 2- 15N replaces NH 4NO 3- 15N ( 15The N abundance is 99.3%atom) and yellow soda ash replace sodium-acetate, white DL-tryptophane-α- 15N 15.6 grams, 15The N abundance is 99.3%atom, purity 99.6%, and DL-tryptophane-α- 15The N yield is 83.7%, 288 ℃ of fusing points.
Embodiment 8
In embodiment 7 with sodium hydroxide replace yellow soda ash to pH be 9, white DL-tryptophane-α- 15N 15.2 grams, 15The N abundance is 99.3%atom, purity 99.6%, and DL-tryptophane-α- 15The N yield is 81.6%, 288 ℃ of fusing points.
Embodiment 9
In embodiment 1, increase 15N-NH 3Extremely 15N-NH 3With the ratio of indole-3-pyruvic acid be 10: 1 (mol), white DL-tryptophane-α- 15N 17.6 grams, 15The N abundance is 99.3%atom, purity 99.6%, and DL-tryptophane-α- 15The N yield is 89.5%, 288 ℃ of fusing points.
Embodiment 10
The ratio that increases Pd/C to Pd/C and indole-3-pyruvic acid in embodiment 1 is 2: 1 (weight), white DL-tryptophane-α- 15N 17.3 grams, 15The N abundance is 99.3%atom, purity 99.6%, and DL-tryptophane-α- 15The N yield is 87.1%, 289 ℃ of fusing points.

Claims (12)

  1. A DL-tryptophane-α- 15The synthetic method of N is characterized in that, this method comprises: ammonium salt- 15N and alkali, or 15N-NH 3With indole-3-pyruvic acid under catalyst action, in used solvent alcohol, react, with crystallization separate out obtain DL-tryptophane-α- 15N.
  2. 2. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described ammonium salt- 15N ammonium sulfate- 15N, ammonium chloride- 15N, volatile salt- 15N, bicarbonate of ammonia- 15N, ammonium nitrate- 15N, ammonium phosphate- 15N, ammonium formiate- 15N, ammonium acetate- 15N, propionic acid ammonium- 15N or butyric acid ammonium- 15Select for use among the N.
  3. 3. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N, it is characterized in that described alkali is selected for use in sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, hydrated barta, yellow soda ash, sodium bicarbonate, sodium formiate, sodium acetate, Sodium Propionate, Sodium propanecarboxylate, natrium valericum, salt of wormwood, saleratus, potassium formiate, potassium acetate, potassium propionate, potassium butyrate or valeric acid potassium.
  4. 4. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described catalyzer is selected for use in palladium, rhodium, ruthenium, platinum or nickel; Wherein the form of palladium, rhodium, ruthenium, platinum or nickel is metal, salt, oxide compound, loading type or matrix type.
  5. 5. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described ammonium salt- 15N or 15N-NH 3With the mol ratio of indole-3-pyruvic acid be 15N: indole-3-pyruvic acid=0.5～20: 1, this mol ratio is especially in 1～10mol scope.
  6. 6. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, the weight ratio of described catalyzer and indole-3-pyruvic acid is 0.005～100: 1, and this weight ratio is especially 0.01～50: in 1 scope.
  7. 7. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described reaction system pH is 3～11, especially in 5～9 scopes.
  8. 8. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described reaction pressure is normal pressure～10MPa, especially in normal pressure～5MPa scope.
  9. 9. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described temperature of reaction is-20～80 ℃, especially in 0～60 ℃ of scope.
  10. 10. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described solvent is at C 1～C 4Select for use in alkyl alcohol, the tetrahydrofuran (THF) Huo diox.
  11. 11. DL-tryptophane-α as claimed in claim 10- 15The synthetic method of N is characterized in that, described C 1～C 4Alkyl alcohol is to select for use in methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol or the trimethyl carbinol.
  12. 12. DL-tryptophane-α as claimed in claim 1- 15The synthetic method of N is characterized in that, described solvent load is 1～400ml solvent/1 gram indole-3-pyruvic acid, especially in 2～200ml solvent/1 gram indole-3-pyruvic acid scope.
CNB200510030037XA 2005-09-27 2005-09-27 Synthesis of DL-tryptophane-alpha-N Expired - Fee Related CN100424073C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435531A (en) * 2013-09-05 2013-12-11 长沙道勤生物科技有限公司 Method for preparing feed additive DL-tryptophan

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* Cited by examiner, † Cited by third party
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JPS578792A (en) * 1980-06-17 1982-01-18 Asahi Chem Ind Co Ltd Preparation of l-amino acid by microorganism
JP2000342294A (en) * 1999-06-03 2000-12-12 Mitsui Chemicals Inc Production of l-tryptophan
CN1256325C (en) * 2004-08-04 2006-05-17 南京工业大学 Process for cascade reaction preparation of N-acetyl-DL-tryptophan

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103435531A (en) * 2013-09-05 2013-12-11 长沙道勤生物科技有限公司 Method for preparing feed additive DL-tryptophan
CN103435531B (en) * 2013-09-05 2016-02-03 长沙道勤生物科技有限公司 The preparation method of fodder additives DL-Trp

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