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CN-122011017-A - Synthesis method of carbon-14 marked arginate-ammonium phosphonate

CN122011017ACN 122011017 ACN122011017 ACN 122011017ACN-122011017-A

Abstract

The invention belongs to the field of radiochemical synthesis, and in particular relates to a synthesis method of carbon-14 marked arginate-ammonium phosphonate, which takes carbon-14 marked potassium cyanide as a radioisotope raw material, the carbon-14 marked arginate-ammonium phosphonate is prepared through the steps of substitution, two-step reduction, bromination, phosphorylation, hydrolysis and the like. The carbon-14 marked arginate-ammonium phosphonate prepared by the method can be used as a tracer for tracing plants, animals, soil and water bodies and other aspects, and meanwhile, the method provides a reference for preparing the carbon-14-containing synthetic building blocks.

Inventors

  • LI HUAGUANG
  • XU LINGFENG
  • Jian Caiguang
  • ZOU JIANSHENG
  • YU YUNDONG

Assignees

  • 浙江爱索拓标记医药科技有限公司

Dates

Publication Date
20260512
Application Date
20260326

Claims (10)

  1. 1. A method for synthesizing carbon-14 marked arginate-ammonium phosphonate comprises the following steps: Mixing [ 14 C ] potassium cyanide, N- (tert-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine ester and a polar solvent for substitution reaction to obtain (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) cyanopropionate; The N- (tert-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine ester has a structure shown in a formula I-2: r in the formula I-2 is Bn or C 6 H 5 ; the (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) cyanopropionate has a structure shown in formula I-3: Formula I-3; mixing (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) cyanopropionate, a proton solvent, a first reducing agent and sodium hypophosphite, and performing a first reduction reaction under the condition of H 2 to obtain (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) formylpropionate, wherein the (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) formylpropionate has a structure shown in formula I-4: Formula I-4; Mixing (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) formyl propionate, a first aprotic solvent and a second reducing agent, and performing a second reduction reaction to obtain (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) hydroxybutyrate, wherein the (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) hydroxybutyrate has a structure shown in a formula I-5: Formula I-5; Mixing (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) hydroxybutyrate, a second aprotic solvent, an organic base, triphenylphosphine and carbon tetrabromide, and performing bromination reaction to obtain (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) bromobutyrate, wherein the (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) bromobutyrate has a structure shown in a formula I-6; formula I-6; Mixing (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) bromobutyrate and methyl phosphite ester compounds, and carrying out esterification reaction to obtain (2S) -2- (tert-butoxycarbonyl) amino- [4- (methylethoxy phosphate) - 14 C ] butyrate, wherein the methyl phosphite ester compounds comprise diethyl methylphosphite and/or diisopropyl methylphosphite; the (2S) -2- (tert-butoxycarbonyl) amino- [4- (methylethoxy phosphate) - 14 C ] butanoic acid ester has a structure shown in a formula I-7: R 2 is Et or I-Pr; Mixing the (2S) -2- (tert-butoxycarbonyl) amino- [4- (methylethoxy phosphate) - 14 C ] butanoate, an alcohol solvent and a metal reducing agent, and performing a third reduction reaction under the condition of H 2 to obtain (2S) -2- (tert-butoxycarbonyl) amino- [4- (methylethoxy phosphate) - 14 C ] butanoic acid, wherein the (2S) -2- (tert-butoxycarbonyl) amino- [4- (methylethoxy phosphate) - 14 C ] butanoic acid has a structure shown in a formula I-8: formula I-8; Hydrolyzing the (2S) -2- (tert-butoxycarbonyl) amino- [4- (methylethoxy phosphate) - 14 C ] butyric acid to obtain the carbon-14 marked arginate-ammonium phosphonate; The carbon-14 marked arginate-ammonium phosphonate comprises carbon-14 marked arginate-ammonium phosphonate hydrochloride, carbon-14 marked arginate-ammonium phosphonate sulfate or carbon-14 marked arginate-ammonium phosphonate; the carbon-14 marked arginate-ammonium phosphonate has a structure shown in a formula A: in the formula A, M is hydrochloric acid, phosphoric acid or sulfuric acid; Represents a carbon-14 labeling site.
  2. 2. The method according to claim 1, wherein the N- (t-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine ester comprises one or more of N- (t-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine methyl ester, N- (t-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine ethyl ester, N- (t-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine phenyl ester and N- (t-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine benzyl ester, and the polar solvent comprises one or more of DMSO, DMF and THF.
  3. 3. The synthetic method according to claim 1 or 2, wherein the substitution reaction is carried out at a temperature of 0 to 50 ℃ for a time of 1 to 24 hours.
  4. 4. The method of claim 1, wherein the protic solvent comprises one or more of methanol, ethanol, formic acid, and acetic acid, and the first reducing agent comprises one or more of Pd/C, pd (OH) 2 /C and Raney Ni.
  5. 5. The method according to claim 1 or 4, wherein the temperature of the first reduction reaction is 25 to 80 ℃ and the time is 1 to 12 hours.
  6. 6. The synthesis method according to claim 1, wherein the first aprotic solvent comprises one or more of diethyl ether, isopropyl ether, methyl tertiary ether and THF, the second reducing agent comprises one or more of LAH, sodium borohydride, aluminum isopropoxide and borane tetrahydrofuran, and the temperature of the second reduction reaction is-70-25 ℃ for 1-12 h.
  7. 7. The synthesis method according to claim 1, wherein the second aprotic solvent comprises one or more of chloroform, DCM and THF, the organic base comprises one or more of imidazole, triethylamine, diisopropylamine and DBU, and the bromination reaction is carried out at a temperature of 0-25 ℃ for 1-12 h.
  8. 8. The synthesis method according to claim 1, wherein the methylphosphite compound comprises diethylmethylphosphite and/or diisopropyl methylphosphite, and the esterification reaction is carried out at a temperature of 50-150 ℃ for 1-12 h.
  9. 9. The synthesis method according to claim 1, wherein the third reducing agent comprises Pd/C and/or Pd (OH) 2 /C, and the temperature of the third reducing reaction is 25-50 ℃ and the time is 1-12 h.
  10. 10. The synthesis method according to claim 1, wherein the hydrolysis is performed at a temperature of 50-100 ℃ for a time of 1-12 hours.

Description

Synthesis method of carbon-14 marked arginate-ammonium phosphonate Technical Field The invention belongs to the technical field of radiochemical synthesis, and particularly relates to a synthesis method of carbon-14 marked arginate-ammonium phosphonate. Background In 2006 Japanese company successfully developed single isomer of glufosinate-ammonium (L-glufosinate-ammonium), which has twice as much herbicidal activity as the racemic DL-glufosinate-ammonium mixture, and which is widely used in agricultural production. The action mechanism of the herbicide can inhibit the activity of glutamine synthetase in plants, so that the synthesis of glutamine is blocked, the nitrogen metabolism of normal physiological activities in the plants is further disturbed, ammonium ions in the plants are accumulated, the cell membranes of plant cells are dehydrated due to the change of the concentration of the ions in and out of the membranes, chloroplast is disintegrated, and the biosynthesis of proteins and nucleotides is inhibited, so that photosynthesis is inhibited and can not be normally carried out to provide nutrition required by the metabolism of normal physiological activities of plants, and the plants are dead, so that the weeding effect is achieved. It has the characteristics of high activity, small effective dosage, wide weed killing variety range, rapid weed killing, low toxicity, environmental friendliness and the like. The application amount of the glufosinate per mu is only 50% of that of the glufosinate, and the application cost is basically equivalent to that of the glufosinate per mu. The development and production of the L-glufosinate can greatly reduce the dosage of raw medicines, and has very important effects on improving the economy of products, reducing the dosage of pesticides and relieving the environmental pressure. The isotope tracing technology has the characteristics of tracing, intuitionistic, trace (ultra trace) and accuracy, and the like, can easily reach the detection limit of 10 -12 g or even lower which is difficult to be measured by other chemical analysis methods, and has very important significance in the research of pesticide metabolism. Currently, the studies on the absorption, distribution, transfer, residue and environmental behaviors of the arginate in plants in water and soil are limited to the detection of parent compounds by chromatography or chromatography-mass spectrometry, but the detection of the parent compounds is rarely related to metabolism/degradation products, and the deep study on the metabolic process, environmental behaviors and the like of the arginate is still lacking. In the process of creating international new pesticides, researches on metabolic pathways, action mechanisms, environmental behaviors, homing and the like of the new pesticides mostly use a radioactive isotope tracing technology, and radioactive isotope carbon-14 marked arginate is a tracer necessary for carrying out the tracing research. At present, the preparation of the carbon-14 marked arginate-ammonium has the defect of insufficient chiral purity. Disclosure of Invention In view of the above, the invention provides a method for synthesizing carbon-14 marked arginate-ammonium phosphonate, and the carbon-14 marked arginate-ammonium phosphonate obtained by the method has high yield and high optical purity. The invention provides a synthesis method of carbon-14 marked arginate-ammonium phosphonate, which comprises the following steps: Mixing [ 14 C ] potassium cyanide, N- (tert-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine ester and a polar solvent for substitution reaction to obtain (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) cyanopropionate; The N- (tert-butoxycarbonyl) -O-p-toluenesulfonyl-L-serine ester has a structure shown in a formula I-2: r in the formula I-2 is Bn or C 6H5; the (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) cyanopropionate has a structure shown in formula I-3: Formula I-3; mixing (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) cyanopropionate, a proton solvent, a first reducing agent and sodium hypophosphite, and performing a first reduction reaction under the condition of H 2 to obtain (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) formylpropionate, wherein the (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) formylpropionate has a structure shown in formula I-4: Formula I-4; Mixing (2S) -2- (tert-butoxycarbonyl) amino- (3- 14 C) formyl propionate, a first aprotic solvent and a second reducing agent, and performing a second reduction reaction to obtain (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) hydroxybutyrate, wherein the (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) hydroxybutyrate has a structure shown in a formula I-5: Formula I-5; Mixing (2S) -2- (tert-butoxycarbonyl) amino- (4- 14 C) hydroxybutyrate, a second aprotic solvent, an organic base, triphenylphosphine and carbon tetrabromide, and performing bromination reaction to obtain (2S) -2- (tert-butoxycar