CN101153013B - Method of producing DL-tyrosine -15N - Google Patents

Method of producing DL-tyrosine -15N Download PDF

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CN101153013B
CN101153013B CN2006101164678A CN200610116467A CN101153013B CN 101153013 B CN101153013 B CN 101153013B CN 2006101164678 A CN2006101164678 A CN 2006101164678A CN 200610116467 A CN200610116467 A CN 200610116467A CN 101153013 B CN101153013 B CN 101153013B
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tyrosine
diethyl malonate
diethyl
synthetic
methoxybenzyl
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CN101153013A (en
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徐建飞
卢伟京
杜晓宁
李良君
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Shanghai Research Institute of Chemical Industry SRICI
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Shanghai Research Institute of Chemical Industry SRICI
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Abstract

The present invention relates to a preparation method of DL-tyrosine-<15>N using the Na<15>NO2 as isotope nitrogen source to synthesize the DL-tyrosine-<15>N. The method comprises: (1) the synthesis of oximide diethyl malonate-<15>N; (2) the synthesis of acetylamino diethyl malonate-<15>N; (3) the synthesis of 2-acetylamino-2-(p-methoxybenzyl) diethyl malonate-<15>N; (4) the synthesis of DL-tyrosine-<15>N; and (5) the purification of DL-tyrosine-<15>N. Compared with the prior art, the present invention is simple in method and device, high in utilization rate of raw materials and yield of product D-tyrosine-<15>N, and high in chemical purity with no decrease in abundance.

Description

A kind of DL-tyrosine- 15The preparation method of N
Technical field
The present invention relates to cold labeling the preparation method of organic compound, relate in particular to 15The synthetic method of N mark DL-tyrosine.
Background technology
15N is the stable isotope of nitrogen element, 15The N marker can be used as tracer agent, is widely used in fields such as biological chemistry, medical science, pharmacology, agricultural sciences, especially life science is had very important meaning.DL-tyrosine- 15N can come postgraduate's object intracellular metabolic as tracer agent, in the metabolism in vivo of research medicine irreplaceable effect is arranged.Employing organic synthesis DL-tyrosine- 15N, at present domestic not report.Knoop, F and Oesterlin, H (Z.Physiol.Chem., 1927,170:186) reported that ethyl-para-hydroxyphenyl ketone acid is catalyzer at Pd/C, 15Prepared in reaction DL-tyrosine under the effect of N-ammonia and hydrogen- 15N.The raw material ethyl-para-hydroxyphenyl ketone acid of this method is not suitable for being used for producing because unstable being difficult to synthesized, and purchase price is too high again, is not suitable method.Boyd, W.J.and Robson, W. (Biochem.J., 1935,29 (54): 459) adopt the product that obtains after the reaction of p-Hydroxybenzaldehyde and glycolylurea to obtain DL-tyrosine through after the hydrolysis.This method need synthesize glycolylurea- 15N, the synthetic yield is very low, is not suitable for producing.
Above synthetic method, do not have comparatively suitable preparation DL-tyrosine- 15The N method, need to explore new DL-tyrosine- 15The synthetic route of N, and synthesis technique improved.
Summary of the invention
Purpose of the present invention be exactly provide in order to overcome the weak point that above-mentioned prior art exists a kind of product yield height, DL-tyrosine that raw material availability is high- 15The preparation method of N.
Purpose of the present invention can be achieved through the following technical solutions:
A kind of DL-tyrosine- 15The N preparation method is characterized in that, with Na 15NO 2Z for the synthetic DL-tyrosine of isotropic substance nitrogenous source- 15N, this method may further comprise the steps:
A. with Na 15NO 2With diethyl malonate be raw material, under condition for validity, synthetic Diethyl Oximinomalonate- 15N;
B. by the Diethyl Oximinomalonate of above-mentioned a gained- 15N synthesis of acetyl amidomalonic acid diethyl ester- 15N;
C. by the acetamino diethyl malonate of above-mentioned b gained- 15N Synthetic 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N;
D. by 2-acetylaminohydroxyphenylarsonic acid 2-(to the methoxybenzyl) diethyl malonate of above-mentioned c gained- 15N, hydrolysis under condition for validity, synthetic DL-tyrosine- 15N;
E. by the DL-tyrosine of above-mentioned d gained- 15N, through the decolouring and isoelectric point crystallizing after obtain pure product DL-tyrosine- 15N.
Aforesaid method specifically may further comprise the steps:
A. Diethyl Oximinomalonate- 15N's is synthetic: take by weighing a certain amount of Na 15NO 2, diethyl malonate, toluene and water, make Na 15NO 2: the diethyl malonate mol ratio is 0.1～20: 1, toluene: diethyl malonate is a volume ratio 0.2～10: 1, and water: Na 15NO 2Mass ratio is 0.01～2: 1, adds in the reactor and stirs, and the temperature of reaction system is reduced to 0～10 ℃, is added dropwise to acetate, acetate in about 1～4 hour: Na 15NO 2Mol ratio is 0.1～15: 1; Again temperature is raise 10～80 ℃, continue to stir 3～15 hours, reaction finishes the back and adds toluene and water, by extracting and separating obtain containing Diethyl Oximinomalonate- 15The toluene phase of N, through washing dry and underpressure distillation remove toluene obtain Diethyl Oximinomalonate- 15N;
B. acetamino diethyl malonate- 15N's is synthetic: will (1) middle gained Diethyl Oximinomalonate- 15N and acetate, diacetyl oxide and reductive agent are according to acetate: Diethyl Oximinomalonate- 15N: diacetyl oxide: the reductive agent mol ratio is 1～10: 1: 1～10: 1～5, join in the reactor and stir, under 0～120 ℃, continue reaction 1～20 hour, solids removed by filtration, and,, add dichloromethane solution with the dissolution of crystals of separating out with the acetate pressure reducing and steaming with the acetate washing leaching cake 3～4 times of heat, with saturated common salt water washing 3～4 times, spend the night with anhydrous sodium sulfate drying, methylene dichloride is steamed remove again, obtain the crystal of white, use acetic acid ethyl dissolution, add sherwood oil, placement is spent the night, and the crystal of separating out is filtered, drying obtain acetamino diethyl malonate- 15N, with the mother liquor secondary crystal can also the recovery part acetamino diethyl malonate- 15N;
C.2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N's is synthetic: will (2) middle gained acetamino diethyl malonate- 15N with to methoxybenzyl bromine, toluene, according to the methoxybenzyl bromine: acetamino diethyl malonate- 15N is a mol ratio 1～15: 1, add in the reactor, and in base catalysis ,-10～50 ℃ were reacted 1～4 hour down, obtain muddy solution; Add 100～150ml water crystallization, be placed in the refrigerator 24～72 hours, obtain 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15The N crystal;
D.DL-tyrosine- 15N's is synthetic: 2-acetylaminohydroxyphenylarsonic acid 2-(to the methoxybenzyl) diethyl malonate that obtains by (3)- 15N add be equivalent to 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 151～30: 1 times acid of N molar weight under 10～150 ℃, was reacted 1～10 hour, and the products therefrom vacuum is steamed deacidification liquid, and solid dissolves with small amount of acid, uses activated carbon decolorizing, regulates pH=3～6, and the solid of separating out is 15N-DL-tyrosine crystal;
E.DL-tyrosine- 15The purifying of N: the thick DL-tyrosine that obtains by (4)- 15N is made into 0.01～1mol/L solution, is to use activated carbon decolorizing at 3～8 o'clock in the pH value, regulates pH=4～6, obtain behind the isoelectric point crystallizing DL-tyrosine- 15The N crystal.
Described acetamino diethyl malonate- 15Go back original reagent in N synthetic and be selected from one or more of zinc, iron, magnesium, nickel, alumel, form of metal is selected from particle, powder or its mixture.
Described DL-tyrosine- 15The synthetic middle acid of N is selected from one or more of hydrofluoric acid, hydrochloric acid, Hydrogen bromide, acetate, phosphoric acid or its mixture.
Described Diethyl Oximinomalonate- 15The synthetic middle Na of N 15NO 2: the diethyl malonate mol ratio is 0.5～10: 1, acetate: Na 15NO 2Mol ratio is 1～10: 1, toluene: diethyl malonate is a volume ratio 0.5～5: 1, and water: Na 15NO 2Mass ratio is 0.01～1: 1.
Described 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15In N synthetic to the methoxybenzyl bromine: acetamino diethyl malonate- 15The mol ratio of N is 1～8: 1, and temperature of reaction is-10～30 ℃.
Described DL-tyrosine- 15The synthetic middle acid of N: 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15The mol ratio of N is 2～20: 1, and temperature of reaction is 30～100 ℃, and the reaction times is 2～6 hours.
Described DL-tyrosine- 15The pH value in when decolouring is 3～8 in the purifying of N, and the pH value of isoelectric point crystallizing is 5～6, after obtain DL-tyrosine- 15The N crystal.
Compared with prior art, the present invention is with Na 15NO 2With diethyl malonate be raw material, synthesis of acetyl amidomalonic acid diethyl ester- 15N, by the acetamino diethyl malonate that obtains- 15N Synthetic 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N, then hydrolysis just can obtain DL-tyrosine- 15N, the inventive method is terse, device is simple, raw material availability is higher, use the D-tyrosine that this method obtains- 15N product yield height, chemical purity height, abundance do not descend.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
DL-tyrosine of the present invention- 15The analytical procedure that is adopted among the preparation technology of N:
Product 15The N abundance detects and adopts Delta S gas isotope mass spectrograph (Finnigan company) to analyze.Adopt Waters 2487 high performance liquid chromatography (HPLC) that raw material, product are carried out qualitative and semi-quantitative analysis, when sample be DL-tyrosine- 15During N, testing conditions is: C-18 reversed-phase column, moving phase are KH 2PO 4(0.02mol/L, H 2O): acetonitrile=95: 5, flow velocity are 0.5ml/min, Waters 2487 UV-detector, and the detection wavelength is 210nm, column temperature is 30 ℃; When sample be Diethyl Oximinomalonate- 15N and amido diethyl malonate- 15N, moving phase is CH 3OH: H 2O=1: 1, flow velocity is 1ml/min, and the detection wavelength is 230nm, and other conditions are the same.Adopt the purity of nitriding specimen.Use the infrared instrument of Magna-IR-550 type (Nicolet company) to carry out FT-IR analysis; Use AVANCE500 type nuclear magnetic resonance analyser (BRUKER company) to carry out the nuclear magnetic resonance spectroscopy of sample, solvent is a heavy water; Adopt the fusing point (thermometer is calibration not) of WRS-1B numeral fusing point instrument (Shanghai precision instrument company limited) measure sample.
Embodiment 1
(1) Diethyl Oximinomalonate- 15N's is synthetic:
With 0.15mol Na 15NO 2(abundance is 99.3%), 0.3mo1 diethyl malonate, 80ml toluene and 10g water join in the there-necked flask of 500ml and stir, and the temperature of reaction system is reduced to 0 ℃, are added dropwise to 1mol acetate in about 1 hour; Temperature is increased to 30 ℃, continues to stir 10 hours.Reaction finishes the back and adds toluene and water, by extracting and separating obtain containing Diethyl Oximinomalonate- 15The toluene phase of N, through washing dry and underpressure distillation remove toluene obtain Diethyl Oximinomalonate- 15N, productive rate 89.8% (press Na 15NO 2Meter), the HPLC collection of illustrative plates is unimodal, and fusing point is 85.6～87.8 ℃, and is close with 87～88 ℃ of literature values.
(2) acetamino diethyl malonate- 15N's is synthetic:
With 0.2mol synthetic Diethyl Oximinomalonate- 15N, 0.4mol acetate, 0.8mol diacetyl oxide and magnesium powder join in the 500ml reactor and stir, and temperature of reaction is 100 ℃, continue reaction 10 hours.Solids removed by filtration, and with the acetate washing leaching cake 3 times of heat, with the acetate pressure reducing and steaming.Add dichloromethane solution with the dissolution of crystals of separating out,, spend the night with anhydrous sodium sulfate drying with saturated common salt water washing 3 times.The methylene dichloride steaming is removed, obtain the crystal of white, with the acetic acid ethyl dissolution of 60ml, add sherwood oil 300ml, placement is spent the night.With the crystal of separating out filter, drying obtains acetamino diethyl malonate- 15N, with the mother liquor secondary crystal can also the recovery part acetamino diethyl malonate- 15N, productive rate be 87.5% (with Diethyl Oximinomalonate- 15N 2Meter), the HPLC collection of illustrative plates is unimodal, and fusing point is 95.6～96.8 ℃, and is close with 96～97 ℃ of literature values.
(3) 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N's is synthetic:
0.1mol acetamino diethyl malonate- 15N, 0.1mol join in the there-necked flask of 250ml methoxybenzyl bromine and 70ml toluene, add 1 gram sodium Metal 99.5, react 1 hour down at-10 ℃, obtain muddy solution; Add the 120ml water crystallization, be placed in the refrigerator 48 hours, obtain 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N crystal, productive rate be 75.5% (with acetamino diethyl malonate- 15The N meter), purity is 99.3%, and fusing point is 95.5～96.3 ℃, and is more consistent with 96～97 ℃ of literature values.
(4) DL-tyrosine- 15Synthetic and the purifying of N:
With 0.1mol 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N and 0.5mol 48% Hydrogen bromide, reflux 2 hours.Reaction finishes final vacuum and steams except that Hydrogen bromide liquid.Solid dissolves with small amount of acid, uses activated carbon decolorizing, regulates pH=5.6, and the solid of separating out is 15N-DL-tyrosine crystal. 15The N abundance is 98.4%, and chemical purity is 98.8%, productive rate be 92% (with 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15The N meter), the HPLC collection of illustrative plates is unimodal.
Embodiment 2
In embodiment 1 step (1), Na 15NO 2, toluene, water and acetate amount change 1.5mol, 40ml, 4g and 0.5mol respectively into, the temperature of rising changes 60 ℃ into, the reaction times is 3 hours, all the other are identical with embodiment 1, obtain Diethyl Oximinomalonate- 15N, productive rate 88.5% (press Na 15NO 2Meter), the HPLC collection of illustrative plates is unimodal.
In embodiment 1 step (2), the amount of acetate and diacetyl oxide changes 2mol and 2mol respectively into, goes back original reagent and adopts iron powder, and temperature of reaction and reaction times change 60 ℃ and 8 hours respectively into, and all the other are identical with embodiment 1, obtain acetamino diethyl malonate- 15N, productive rate are 87.8%, and the HPLC collection of illustrative plates is unimodal.
In embodiment 1 step (3), to methoxybenzyl bromine 0.8mol; Temperature and time changes 20 ℃ and 8 hours into; All the other are identical with embodiment 1, obtain 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N crystal, productive rate are 73.5%, and purity is 99.2%.
In embodiment 1 step (4), the amount of concentrated hydrochloric acid, temperature and time changes 2mol, 80 ℃, 6 hours respectively into, all the other are identical with embodiment 1, obtain DL-tyrosine- 15The N crystal, 15The N abundance is 98.4%, and chemical purity is 98.8%, productive rate be 89.5% (with 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15The N meter), the HPLC collection of illustrative plates is unimodal.
Embodiment 3
(1) Diethyl Oximinomalonate- 15N's is synthetic: take by weighing a certain amount of Na 15NO 2, diethyl malonate, toluene and water, make Na 15NO 2: the diethyl malonate mol ratio is 20: 1, toluene: diethyl malonate is volume ratio 10: 1, water: Na 15NO 2Mass ratio is 2: 1, adds in the reactor and stirs, and the temperature of reaction system is reduced to 10 ℃, is added dropwise to acetate, acetate in about 4 hours: Na 15NO 2Mol ratio is 15: 1; Again temperature is raise 80 ℃, continue to stir 15 hours, reaction finishes the back and adds toluene and water, by extracting and separating obtain containing Diethyl Oximinomalonate- 15The toluene phase of N, through washing dry and underpressure distillation remove toluene obtain Diethyl Oximinomalonate- 15N, productive rate 88.8% (press Na 15NO 2Meter), the HPLC collection of illustrative plates is unimodal, and fusing point is 85.8～87.8 ℃, and is close with 87～88 ℃ of literature values;
(2) acetamino diethyl malonate- 15N's is synthetic: will (1) middle gained Diethyl Oximinomalonate- 15N and acetate, diacetyl oxide and iron powder are according to acetate: Diethyl Oximinomalonate- 15N: diacetyl oxide: the iron powder mol ratio is 10: 1: 10: 5, join in the reactor and stir, under 120 ℃, continue reaction 20 hours, solids removed by filtration, and,, add dichloromethane solution with the dissolution of crystals of separating out with the acetate pressure reducing and steaming with the acetate washing leaching cake 3～4 times of heat, with saturated common salt water washing 3～4 times, spend the night with anhydrous sodium sulfate drying, methylene dichloride is steamed remove again, obtain the crystal of white, use acetic acid ethyl dissolution, add sherwood oil, placement is spent the night, with the crystal of separating out filter, drying obtains acetamino diethyl malonate- 15N, with the mother liquor secondary crystal can also the recovery part acetamino diethyl malonate- 15N, productive rate be 86.5% (with Diethyl Oximinomalonate- 15N 2Meter), the HPLC collection of illustrative plates is unimodal, and fusing point is 95.8～96.8 ℃, and is close with 96～97 ℃ of literature values;
(3) 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N's is synthetic: will (2) middle gained acetamino diethyl malonate- 15N with to methoxybenzyl bromine, toluene, according to the methoxybenzyl bromine: acetamino diethyl malonate- 15N is mol ratio 15: 1, adds in the reactor, and in base catalysis, 50 ℃ were reacted 1～4 hour down, obtain muddy solution; Add the 150ml water crystallization, be placed in the refrigerator 72 hours, obtain 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N crystal, productive rate be 75.5% (with acetamino diethyl malonate- 15The N meter), purity is 99.3%, and fusing point is 95.5～96.3 ℃, and is more consistent with 96～97 ℃ of literature values;
(4) DL-tyrosine- 15N's is synthetic: 2-acetylaminohydroxyphenylarsonic acid 2-(to the methoxybenzyl) diethyl malonate that obtains by (3)- 15N add be equivalent to 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 1530: 1 times hydrofluoric acid of N molar weight under 150 ℃, reacted 10 hours, and the products therefrom vacuum is steamed and removed hydrofluoric acid liquid, and solid dissolves with small amount of hydrochloric acid, uses activated carbon decolorizing, regulates pH=6, and the solid of separating out is 15N-DL-tyrosine crystal;
(5) DL-tyrosine- 15The purifying of N
The thick DL-tyrosine that obtains by (4)- 15N is made into 1mol/L solution, is to use activated carbon decolorizing at 8 o'clock in the pH value, regulates pH=6, obtain behind the isoelectric point crystallizing DL-tyrosine- 15The N crystal.
Embodiment 4
(1) Diethyl Oximinomalonate- 15N's is synthetic: take by weighing a certain amount of Na 15NO 2, diethyl malonate, toluene and water, make Na 15NO 2: the diethyl malonate mol ratio is 0.1: 1, toluene: diethyl malonate is volume ratio 0.2: 1, water: Na 15NO 2Mass ratio is 0.01: 1, adds in the reactor and stirs, and the temperature of reaction system is reduced to 0 ℃, is added dropwise to acetate, acetate in about 1 hour: Na 15NO 2Mol ratio is 0.1: 1; Again temperature is raise 10 ℃, continue to stir 3 hours, reaction finishes the back and adds toluene and water, by extracting and separating obtain containing Diethyl Oximinomalonate- 15The toluene phase of N, through washing dry and underpressure distillation remove toluene obtain Diethyl Oximinomalonate- 15N;
(2) acetamino diethyl malonate- 15N's is synthetic: will (1) middle gained Diethyl Oximinomalonate- 15N and acetate, diacetyl oxide and alumel are according to acetate: Diethyl Oximinomalonate- 15N: diacetyl oxide: the alumel mol ratio is 1: 1: 1: 1, join in the reactor and stir, under 0 ℃, continue reaction 1 hour, solids removed by filtration, and,, add dichloromethane solution with the dissolution of crystals of separating out with the acetate pressure reducing and steaming with the acetate washing leaching cake 3～4 times of heat, with saturated common salt water washing 3～4 times, spend the night with anhydrous sodium sulfate drying, methylene dichloride is steamed remove again, obtain the crystal of white, use acetic acid ethyl dissolution, add sherwood oil, placement is spent the night, with the crystal of separating out filter, drying obtains acetamino diethyl malonate- 15N, with the mother liquor secondary crystal can also the recovery part acetamino diethyl malonate- 15N;
(3) 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N's is synthetic: will (2) middle gained acetamino diethyl malonate- 15N with to methoxybenzyl bromine, toluene, according to the methoxybenzyl bromine: acetamino diethyl malonate- 15N is mol ratio 1: 1, adds in the reactor, and in base catalysis ,-10 ℃ were reacted 1 hour down, obtain muddy solution; Add the 100ml water crystallization, be placed in the refrigerator 24 hours, obtain 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15The N crystal;
(4) DL-tyrosine- 15N's is synthetic: 2-acetylaminohydroxyphenylarsonic acid 2-(to the methoxybenzyl) diethyl malonate that obtains by (3)- 15N add be equivalent to 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 151: 1 times acid of N molar weight under 10 ℃, was reacted 1 hour, and the products therefrom vacuum is steamed deacidification liquid, and solid dissolves with small amount of acid, uses activated carbon decolorizing, regulates pH=5.6, and the solid of separating out is 15N-DL-tyrosine crystal;
(5) DL-tyrosine- 15The purifying of N
The thick DL-tyrosine that obtains by (4)- 15N is made into 0.01～1mol/L solution, is to use activated carbon decolorizing at 3 o'clock in the pH value, regulates pH=5.6, obtain behind the isoelectric point crystallizing DL-tyrosine- 15The N crystal.
The DL-tyrosine that obtains- 15The N crystal, 15The N abundance is 98.4%, and chemical purity is 98.8%, and productive rate is 89.5% (so that 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate-15N), the HPLC collection of illustrative plates is unimodal.

Claims (7)

  1. A DL-tyrosine- 15The N preparation method is characterized in that, with Na 15NO 2For the synthetic DL-tyrosine of isotropic substance nitrogenous source- 15N, this method may further comprise the steps:
    A. Diethyl Oximinomalonate- 15N's is synthetic: take by weighing a certain amount of Na 15NO 2, diethyl malonate, toluene and water, make Na 15NO 2: the diethyl malonate mol ratio is 0.1～20: 1, toluene: diethyl malonate is a volume ratio 0.2～10: 1, and water: Na 15NO 2Mass ratio is 0.01～2: 1, adds in the reactor and stirs, and the temperature of reaction system is reduced to 0～10 ℃, is added dropwise to acetate, acetate in about 1～4 hour: Na 15NO 2Mol ratio is 0.1～15: 1; Again temperature is raise 10～80 ℃, continue to stir 3～15 hours, reaction finishes the back and adds toluene and water, by extracting and separating obtain containing Diethyl Oximinomalonate- 15The toluene phase of N, through washing dry and underpressure distillation remove toluene obtain Diethyl Oximinomalonate- 15N;
    B. acetamino diethyl malonate- 15N's is synthetic: will (a) middle gained Diethyl Oximinomalonate- 15N and acetate, diacetyl oxide and reductive agent are according to acetate: Diethyl Oximinomalonate- 15N: diacetyl oxide: the reductive agent mol ratio is 1～10: 1: 1～10: 1～5, join in the reactor and stir, under 0～120 ℃, continue reaction 1～20 hour, solids removed by filtration, and,, add dichloromethane solution with the dissolution of crystals of separating out with the acetate pressure reducing and steaming with the acetate washing leaching cake 3～4 times of heat, with saturated common salt water washing 3～4 times, spend the night with anhydrous sodium sulfate drying, methylene dichloride is steamed remove again, obtain the crystal of white, use acetic acid ethyl dissolution, add sherwood oil, placement is spent the night, and the crystal of separating out is filtered, drying obtain acetamino diethyl malonate- 15N, with the mother liquor secondary crystal can also the recovery part acetamino diethyl malonate- 15N;
    C.2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15N's is synthetic: will (b) middle gained acetamino diethyl malonate- 15N with to methoxybenzyl bromine, toluene, according to the methoxybenzyl bromine: acetamino diethyl malonate- 15N is a mol ratio 1～15: 1, add in the reactor, and in base catalysis ,-10～50 ℃ were reacted 1～4 hour down, obtain muddy solution; Add 100～150ml water crystallization, be placed in the refrigerator 24～72 hours, obtain 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15The N crystal;
    D.DL-tyrosine- 15N's is synthetic: 2-acetylaminohydroxyphenylarsonic acid 2-(to the methoxybenzyl) diethyl malonate that obtains by (c)- 15N add be equivalent to 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 151～30 times acid of N molar weight under 10～150 ℃, was reacted 1～10 hour, and the products therefrom vacuum is steamed deacidification liquid, and solid dissolves with small amount of acid, uses activated carbon decolorizing, regulates pH=3～6, and the solid of separating out is 15N-DL-tyrosine crystal;
    E.DL-tyrosine- 15The purifying of N: the thick DL-tyrosine that obtains by (d)- 15N is made into 0.01～1mol/L solution, is to use activated carbon decolorizing at 3～8 o'clock in the pH value, regulates pH=4～6, obtain behind the isoelectric point crystallizing DL-tyrosine- 15The N crystal.
  2. 2. a kind of DL-tyrosine according to claim 1- 15The preparation method of N is characterized in that, described acetamino diethyl malonate- 15Go back original reagent in N synthetic and be selected from one or more of zinc, iron, magnesium, nickel, alumel, form of metal is selected from particle, powder or its mixture.
  3. 3. a kind of DL-tyrosine according to claim 1- 15The preparation method of N is characterized in that, described DL-tyrosine- 15Acid is selected from one or more of hydrofluoric acid, hydrochloric acid, Hydrogen bromide, acetate, phosphoric acid in N synthetic.
  4. 4. a kind of DL-tyrosine according to claim 1- 15The preparation method of N is characterized in that, described Diethyl Oximinomalonate- 15The synthetic middle Na of N 15NO 2: the diethyl malonate mol ratio is 0.5～10: 1, acetate: Na 15NO 2Mol ratio is 1～10: 1, toluene: diethyl malonate is a volume ratio 0.5～5: 1, and water: Na 15NO 2Mass ratio is 0.01～1: 1.
  5. 5. a kind of DL-tyrosine according to claim 1- 15The preparation method of N is characterized in that, described 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15In N synthetic to the methoxybenzyl bromine: acetamino diethyl malonate- 15The mol ratio of N is 1～8: 1, and temperature of reaction is-10～30 ℃.
  6. 6. a kind of DL-tyrosine according to claim 1- 15The preparation method of N is characterized in that, described DL-tyrosine- 15The synthetic middle acid of N: 2-acetylaminohydroxyphenylarsonic acid 2-(to methoxybenzyl) diethyl malonate- 15The mol ratio of N is 2～20: 1, and temperature of reaction is 30～100 ℃, and the reaction times is 2～6 hours.
  7. 7. a kind of DL-tyrosine according to claim 1- 15The preparation method of N is characterized in that, described DL-tyrosine- 15The pH value in when decolouring is 3～8 in the purifying of N, and the pH value of isoelectric point crystallizing is 5～6, after obtain DL-tyrosine- 15The N crystal.
CN2006101164678A 2006-09-25 2006-09-25 Method of producing DL-tyrosine -15N Expired - Fee Related CN101153013B (en)

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Title
Baldwin Jack E.等.Synthesis of [15N]-
Baldwin, Jack E.等.Synthesis of [15N]-, [1-13C]-, [3-13C]-, [ring-1,2-13C2]-, and[ring-3,4,5-13C3]-labeled DL-tyrosine..J. Chem. Res., Synop.6.1984,6176-177. *
俞凌翀.利用相转移催化烷基化合成α-氨基酸.北京师范大学学报 1.1983,(1),94-96.
俞凌翀.利用相转移催化烷基化合成α-氨基酸.北京师范大学学报 1.1983,(1),94-96. *
耿愚.非天然氨基酸3-(4-噻唑基)-D L-丙氨酸盐酸盐的合成.氨基酸和生物资源22 2.2000
耿愚.非天然氨基酸3-(4-噻唑基)-D,L-丙氨酸盐酸盐的合成.氨基酸和生物资源22 2.2000,22(2),27-27. *

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