Search

CN-117603094-B - Synthesis method of amino-protected 2-aminomethyl olefine acid derivative

CN117603094BCN 117603094 BCN117603094 BCN 117603094BCN-117603094-B

Abstract

The invention relates to a synthesis method of an amino-protected 2-aminomethyl olefine acid derivative, which comprises the following steps of (1) leading a compound shown as a formula (II) With 2-methyl-2-butene in the presence of a solvent under the action of a catalyst to produce a compound represented by the formula (III) (2) Reacting a compound represented by the formula (III) with an amino protecting agent to produce a compound represented by the formula (I) I.e. the amino-protected 2-aminomethyl enoic acid derivative. The synthesis method disclosed by the invention is simple to operate, few in synthesis steps, few in byproducts and high in product yield, and is more suitable for industrial production.

Inventors

  • WANG MINGZHONG
  • ZHU MINGXIN
  • SU DAO
  • LI JINJIN

Assignees

  • 苏州爱玛特生物科技有限公司

Dates

Publication Date
20260505
Application Date
20231130

Claims (12)

  1. 1. A synthesis method of an amino-protected 2-aminomethyl olefine acid derivative is provided, wherein the structural formula of the amino-protected 2-aminomethyl olefine acid derivative is shown as a formula (I): the synthesis method is characterized by comprising the following steps of: (1) Reacting a compound shown in a formula (II) with 2-methyl-2-butene under the action of a catalyst in the presence of a solvent to generate a compound shown in a formula (III), wherein the catalyst at least comprises a ruthenium catalyst and a Lewis acid catalyst, the Lewis acid catalyst is B (OPh) 3 , the ruthenium catalyst is (1, 3-bis (2, 4, 6-trimethylphenyl) -2-imidazolidinylidene) dichloro (o-isopropoxy benzylidene) ruthenium, and the solvent is ethanol; (2) Reacting a compound shown in a formula (III) with an amino protective agent to generate the compound shown in the formula (I), namely the amino-protected 2-aminomethyl olefine acid derivative; The structural formula of the compound shown in the formula (II) is as follows: the structural formula of the compound shown in the formula (III) is as follows: In the formula (I), R is an amino protecting group, and in the formulas (I), (II) and (III), n is 1-4.
  2. 2. The method for synthesizing an amino-protected 2-aminomethyl olefine acid derivative according to claim 1, wherein the molar ratio of the catalyst to the compound of formula (II) is 0.005-0.05:1, and/or the molar ratio of the 2-methyl-2-butene to the compound of formula (II) is greater than 10.
  3. 3. The method for synthesizing an amino-protected 2-aminomethyl olefine acid derivative according to claim 2, wherein the molar ratio of 2-methyl-2-butene to the compound represented by formula (II) is 10-40:1.
  4. 4. The method for synthesizing the amino-protected 2-aminomethyl olefine acid derivative according to claim 1, wherein in the step (1), the reaction is performed at 15-50 ℃ for 3-15 hours, and/or the step (1) is specifically performed by reacting a compound represented by the formula (II) with 2-methyl-2-butene in the presence of a catalyst and a solvent under an inert gas atmosphere at 15-50 ℃, and after the reaction is completed, filtering, washing with water, and pulping to obtain the compound represented by the formula (III).
  5. 5. The method for synthesizing an amino-protected 2-aminomethyl alkenoic acid derivative according to claim 1, wherein R is selected from Boc and Fmoc, and/or said amino-protecting agent is selected from di-tert-butyl dicarbonate and fluorenylmethoxycarbonyl succinimide.
  6. 6. The method for synthesizing an amino-protected 2-aminomethyl olefine acid derivative according to claim 1, wherein in the step (2), the reaction is performed in the presence of a solvent, the solvent is a mixture of an organic solvent and water, and the organic solvent is one or a combination of a plurality of dioxane, tetrahydrofuran, N-dimethylformamide.
  7. 7. The method for synthesizing an amino-protected 2-aminomethyl olefine acid derivative according to claim 1, wherein in step (2), said reaction is carried out at 15 to 40 ℃, and said reaction is carried out in the presence of a base.
  8. 8. The method for synthesizing an amino-protected 2-aminomethyl acid derivative according to claim 1, wherein when the amino-protecting agent is di-tert-butyl dicarbonate, the step (2) is carried out by adding a compound represented by formula (III), a solvent and a base into a reactor under ice bath conditions, then adding the amino-protecting agent and the base into the reactor, reacting at 15-40 ℃ for 6-10 hours, spinning the solvent, diluting with ethyl acetate in ice bath, acidifying to pH 2-3, extracting, washing with water, merging organic phases, drying and spinning to obtain the amino-protected 2-aminomethyl acid derivative, or When the amino protective agent is fluorenylmethoxycarbonyl succinimide, the specific implementation of the step (2) is that under the ice bath condition, the amino protective agent is dissolved in a solvent and then added into a reactor filled with a compound shown in a formula (III), the solvent and alkali, the reaction is carried out for 6 to 10 hours at 15 to 40 ℃, the mixture is extracted, the pH value is adjusted to 1to 3, the extraction is carried out, the weak acid water washing, the drying and the concentration are carried out, and the amino-protected 2-aminomethyl olefine acid derivative is obtained by recrystallization.
  9. 9. A preparation method of a compound shown in a formula (III) is characterized in that the compound shown in the formula (II) reacts with 2-methyl-2-butene under the action of a catalyst in the presence of a solvent to generate the compound shown in the formula (III), wherein the catalyst at least comprises a ruthenium catalyst, the catalyst also comprises a Lewis acid catalyst, the Lewis acid catalyst is B (OPh) 3 , the ruthenium catalyst is (1, 3-bis (2, 4, 6-trimethylphenyl) -2-imidazolidinylidene) dichloro (o-isopropoxy benzylidene) ruthenium, and the solvent is ethanol; The structural formula of the compound shown in the formula (II) is as follows: the structural formula of the compound shown in the formula (III) is as follows: And n is 1-4.
  10. 10. The method for producing a compound of formula (III) according to claim 9, wherein the molar ratio of the catalyst to the compound of formula (II) is 0.005-0.05:1, and/or the molar ratio of the 2-methyl-2-butene to the compound of formula (II) is greater than 10.
  11. 11. The method for preparing a compound represented by the formula (III) according to claim 9, wherein the molar ratio of the 2-methyl-2-butene to the compound represented by the formula (II) is 10-40:1.
  12. 12. The method for preparing the compound shown in the formula (III) according to claim 9, wherein the solvent is ethanol, and/or the reaction is carried out at 15-50 ℃ for 3-15 h, and/or the method is concretely implemented by reacting the compound shown in the formula (II) with 2-methyl-2-butene in the presence of a catalyst and a solvent under the inert gas atmosphere at 15-50 ℃, filtering, washing with water, and pulping to obtain the compound shown in the formula (III).

Description

Synthesis method of amino-protected 2-aminomethyl olefine acid derivative Technical Field The invention belongs to the technical field of synthesis of organic compounds, and particularly relates to a synthesis method of an amino-protected 2-aminomethyl olefine acid derivative. Background The amino-protected 2-aminomethyl olefine acid derivative belongs to an unnatural amino acid, is an important medical intermediate, and has very wide application in the field of medicinal chemistry, such as adding the substance into bioactive peptide in the research of medicines. The traditional synthesis method of the compound is to take 3-methylbut-2-enoic acid as a starting material, carry out alcoholization firstly, then iodize the 3-methylbut-2-ene into 1-iodine-3-methylbut-2-ene through p-toluenesulfonyl chloride, prepare for the next amino, remove acetyl after the amino acetyl is carried out on the diethyl acetamino malonate, obtain the target amino acid, and then carry out amino protecting group to obtain the target product. The traditional synthesis method has the defects of tedious steps, more loss, low yield and high cost. Disclosure of Invention Aiming at the problems of long steps and low yield of the synthesis method in the prior art, the invention provides an improved synthesis method of an amino-protected 2-aminomethyl olefine acid derivative, which is more suitable for industrial production. In order to achieve the purpose, the invention adopts the following technical scheme: a synthesis method of an amino-protected 2-aminomethyl olefine acid derivative is provided, wherein the structural formula of the amino-protected 2-aminomethyl olefine acid derivative is shown as a formula (I): The synthesis method comprises the following steps: (1) Reacting a compound shown in a formula (II) with 2-methyl-2-butene under the action of a catalyst in the presence of a solvent to generate a compound shown in a formula (III); (2) Reacting a compound shown in a formula (III) with an amino protective agent to generate the compound shown in the formula (I), namely the amino-protected 2-aminomethyl olefine acid derivative; The structural formula of the compound shown in the formula (II) is as follows: the structural formula of the compound shown in the formula (III) is as follows: In the formula (I), R is an amino protecting group, and in the formulas (I), (II) and (III), n is 1-4. Further, n is 1, 2, 3 or 4. In some embodiments, in step (1), the catalyst comprises at least a ruthenium catalyst. In some embodiments, the catalyst further comprises a Lewis acid catalyst that is one or a combination of several of B (OPh) 3, tributylboron (B (C 2H5)3), tributylfluoroborane (BF 3·OEt2). Advantageously, the mass ratio of the ruthenium catalyst to the Lewis acid catalyst is 1:1.5-2.5. In some embodiments, the ruthenium catalyst is one or a combination of (1, 3-dimethylimidazolidin-2-ylidene) (2-isopropoxybenzylidene) ruthenium (VI) chloride, phenylmethylenebis (tricyclohexylphosphorus) ruthenium dichloride. In some embodiments, the molar ratio of the catalyst to the compound of formula (II) is 0.005-0.05:1, and the molar ratio of the 2-methyl-2-butene to the compound of formula (II) is greater than 10. Further, the feeding molar ratio of the 2-methyl-2-butene to the compound shown in the formula (II) is 10-40:1. Further, the feeding molar ratio of the 2-methyl-2-butene to the compound shown in the formula (II) is 15-25:1. In some embodiments, in step (1), the solvent is ethanol. In some embodiments, in step (1), the reaction is performed at 15-50 ℃ for 3-15 hours. Further, the reaction is carried out at 35-45 ℃ for 3-6 hours. In some specific embodiments, the step (1) is specifically implemented by reacting a compound shown in a formula (II) with 2-methyl-2-butene in the presence of a catalyst and a solvent at 15-50 ℃ in an inert gas atmosphere, filtering, washing with water and pulping after the reaction is finished to obtain the compound shown in the formula (I). Further, the beating adopts a mixture of ethyl acetate and n-heptane, and the volume ratio of the ethyl acetate to the n-heptane is 1:5-15. In some embodiments, the R is selected from Boc, fmoc, and the amino protecting agent is selected from di-tert-butyl dicarbonate, fluorenylmethoxycarbonyl succinimide. In some embodiments, in step (2), the reaction is performed in the presence of a solvent that is a mixture of an organic solvent and water, the organic solvent being one or a combination of several of dioxane, tetrahydrofuran, N-Dimethylformamide (DMF). Further, when the amino protective agent is di-tert-butyl dicarbonate, the organic solvent is dioxane, and the volume ratio of dioxane to water is 1-3:1. Further, when the amino protecting agent is fluorenylmethoxycarbonyl succinimide, the organic solvent is tetrahydrofuran. In some embodiments, in step (2), the reaction is performed at 15-40 ℃, and the reaction is performed in the presence of a base. Further, the alkali