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CN-122010781-A - Synthesis method of 1-tert-butyl-3-ethylcarbodiimide

CN122010781ACN 122010781 ACN122010781 ACN 122010781ACN-122010781-A

Abstract

The invention provides a synthesis method of 1-tertiary butyl-3-ethyl carbodiimide. The method has mild reaction conditions, simple steps and environmental friendliness, and can realize high-yield and high-purity synthesis of the target product. The synthesis method comprises the steps of (1) carrying out addition reaction on ethyl isothiocyanate and tert-butylamine in an organic solvent I at a temperature of 30-60 ℃ to obtain ethyl tert-butylthiourea, wherein the organic solvent I is one or more selected from petroleum ether, n-hexane and n-heptane, (2) carrying out oxidation desulfurization reaction on the ethyl tert-butylthiourea and a sodium hypochlorite aqueous solution with a concentration of 10-15 wt% in an organic solvent II at a temperature of 0-10 ℃, removing sulfur generated by the reaction, and purifying feed liquid to obtain 1-tert-butyl-3-ethylcarbodiimide, wherein the organic solvent II is selected from halogenated hydrocarbon.

Inventors

  • CHEN XI
  • YU WEI
  • CHEN DAOXIN
  • ZHAO YIJUN

Assignees

  • 浙江海翔药业股份有限公司
  • 台州金沣医药化工有限公司
  • 浙江海翔川南药业有限公司

Dates

Publication Date
20260512
Application Date
20260120

Claims (11)

  1. 1. A method for synthesizing 1-tertiary butyl-3-ethyl carbodiimide, which is characterized by comprising the following steps: (1) Carrying out addition reaction on ethyl isothiocyanate and tert-butylamine in an organic solvent I at a temperature of 30-60 ℃ to obtain ethyl tert-butylthiourea, wherein the organic solvent I is one or more selected from petroleum ether, n-hexane, n-heptane, n-pentane, isopentane, n-octane and isooctane; (2) Oxidizing and desulfurizing the ethyl tertiary butyl thiourea and a sodium hypochlorite aqueous solution with the concentration of 10-15 wt% in an organic solvent II at the temperature of 0-10 ℃, removing sulfur generated by the reaction, and purifying the feed liquid to obtain 1-tertiary butyl-3-ethylcarbodiimide, wherein the organic solvent II is selected from halogenated hydrocarbons.
  2. 2. The synthesis method according to claim 1, wherein the step (1) specifically comprises the steps of mixing ethyl isothiocyanate and the organic solvent I, heating to 30-35 ℃, adding tert-butylamine, and then carrying out heat preservation reaction at 40-60 ℃; Preferably, the tert-butylamine is fed in a dropwise manner, preferably with a temperature of 40 ℃ or less being controlled during the dropwise addition.
  3. 3. The synthesis method according to claim 1 or 2, wherein in the step (1), after the reaction is completed, the reaction liquid is cooled to 10-15 ℃, then solid-liquid separation is performed, and the obtained solid phase is dried to obtain ethyl tert-butylthiourea; Preferably, the liquid phase obtained by the solid-liquid separation is recycled as the organic solvent I in the step (1).
  4. 4. The synthesis method according to any one of claims 1 to 3, wherein the step (2) specifically comprises the steps of mixing ethyl tertiary butyl thiourea and the organic solvent II, cooling to 0-5 ℃, then dropwise adding the sodium hypochlorite aqueous solution, preferably controlling the temperature to be 0-10 ℃, and after the completion of the dropwise adding, preserving the reaction solution, and testing the starch potassium iodide test paper to turn blue to reach a reaction end point.
  5. 5. The method according to any one of claims 1 to 4, wherein in step (1), the organic solvent I is one or more of petroleum ether, n-hexane, n-heptane, more preferably petroleum ether; And/or, in the step (2), the organic solvent II is one or more of dichloromethane, chloroform, dichloroethane and carbon tetrachloride.
  6. 6. The method according to any one of claims 1 to 5, wherein in step (2), the concentration of the aqueous sodium hypochlorite solution is 10 to 12wt% or 12 to 15wt%, more preferably 12wt%.
  7. 7. The method according to any one of claims 1 to 6, wherein in the step (2), after the reaction, the reaction solution is filtered to remove sulfur generated by the reaction, the filtrate is allowed to stand still and delaminate to obtain an organic layer I and an aqueous layer I, the aqueous layer I is extracted with the organic solvent II, the extracted organic layer II and the organic layer I are combined and then concentrated under reduced pressure to obtain a crude 1-tert-butyl-3-ethylcarbodiimide product, and the crude product is rectified to obtain the 1-tert-butyl-3-ethylcarbodiimide product.
  8. 8. The synthetic method according to any one of claims 1 to 7, wherein in step (1), the ratio of the amounts of the substances of ethyl isothiocyanate and tert-butylamine is 1:1 to 2, preferably 1:1; In the step (2), the mass ratio of the ethyl tertiary butyl thiourea to the sodium hypochlorite aqueous solution is 1:7-9.
  9. 9. The synthetic method according to any one of claims 1 to 8, wherein in the step (2), the oxidative desulfurization reaction is performed without adding a catalyst or an inorganic base.
  10. 10. The synthetic method of any one of claims 1-9, wherein in step (1), the ethyl isothiocyanate is prepared by a method comprising the steps of: (a) Dropwise adding an aqueous ethylamine solution with the concentration of 68-72wt% and dropwise adding carbon disulfide into a mixed solution of alkali liquor and water at the temperature of 10-15 ℃, and then stirring the reaction solution at the temperature of 10-30 ℃; (b) And (C) adding sodium carbonate and cyanuric chloride into the reaction liquid obtained in the step (a), stirring the reaction liquid at 20-40 ℃, monitoring the completion of the reaction, standing for layering, and obtaining the upper layer of ethyl isothiocyanate.
  11. 11. The synthesis method according to claim 10, wherein in the step (a), the alkali solution is an aqueous sodium hydroxide solution with a concentration of 48-52 wt%; and/or in the step (a), the mass ratio of the alkali liquor to the water is 1:4-5, the mass ratio of the ethylamine aqueous solution to the alkali liquor is 1:1-2, and the mass ratio of the carbon disulfide to the ethylamine is 1:0.5-1.1; and/or the ratio of the amount of the cyanuric chloride used in step (b) to the amount of the ethylamine used in step (a) is 1:1 to 3.5; And/or in the step (b), the ratio of the amount of the cyanuric chloride to the amount of the sodium carbonate is 1:1-2.

Description

Synthesis method of 1-tert-butyl-3-ethylcarbodiimide Technical Field The invention relates to the technical field of preparation of 1-tertiary butyl-3-ethyl carbodiimide, in particular to a synthetic method of 1-tertiary butyl-3-ethyl carbodiimide. Background 1-Tert-Butyl-3-ethylcarbodiimide (1-Tert-Butyl-3-ethylcarbodimide, TBEC) is a very useful dehydration condensing agent, which is most characterized by the fact that the urea by-product formed in the reaction has very low solubility in diethyl ether and ethyl acetate and can be removed from the reaction system by simple filtration. This feature gives it unique purification advantages in liquid phase synthesis, especially for those synthetic processes where there is a high requirement for simplicity of the purification step. CN109369459A discloses a method for producing N, N ' -di-tert-butylcarbodiimide by using a thiourea method, which comprises the steps of synthesizing N, N ' -di-tert-butylthiourea in an aqueous medium by using tert-butylamine and carbon disulfide, carrying out suction filtration and drying on the N, N ' -di-tert-butylthiourea, then carrying out primary oxidation, sequentially adding the N, N ' -di-tert-butylthiourea, a flake alkali, a solvent and a catalyst into a reaction kettle, heating to 60-65 ℃, adding an oxidant, reacting for 2 hours at 60-65 ℃, standing for 20-25 minutes, discarding a lower aqueous phase, carrying out secondary oxidation reaction, dropwise adding a quantitative oxidant and a catalyst, reacting for 1 hour at 65 ℃, adding alkali for neutralizing water, separating the aqueous layer, evaporating the solvent, and carrying out reduced pressure rectification to obtain the N, N ' -di-tert-butylcarbodiimide. CN112250600A and CN103382168B also use thiourea method, use hydrogen peroxide and sodium hydrosulfide as the secondary oxidizing agent, the operation is complicated, the technical requirement is high. CN104193654B1 discloses a preparation method of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, which comprises the following steps of (1) reacting N, N' -dimethylpropanamine and carbon disulfide serving as raw materials in an organic solvent at 10-15 ℃ to generate an intermediate 1, (2) reacting the intermediate 1 with ethyl chloroformate in the organic solvent at 10-15 ℃ to prepare an intermediate 2 by using triethylamine as an acid binding agent, (3) reacting the intermediate 2 with ethylamine in the organic solvent at 10-15 ℃ to prepare an intermediate 3, (4) adding a catalyst EDTA or TEBA into the intermediate 3, performing primary oxidation at 20-30 ℃ by using an oxidant to obtain crude 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, extracting and separating to obtain an intermediate 4, and (5) performing salt exchange reaction between the intermediate 4 and hydrochloride to prepare the product 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The process aims at improving the yield of EDC hydrochloride and requires the addition of a phase transfer catalyst in step (4) in the process. JP1996198836A discloses a process for producing 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, wherein it is mentioned that potassium hydroxide is required to be added to a reaction system to facilitate improvement of productivity, and a phase transfer catalyst is required to be added to moderately conduct desulfurization, and oxidation reaction is a three-phase system, and the reaction process has disadvantages of severe heat release, uncontrollable reaction and the like. In the prior art, a new synthesis process is necessary to be developed aiming at the 1-tertiary butyl-3-ethyl carbodiimide, so that the method is favorable for high yield and high purity, and has the characteristics of mild reaction conditions, simple steps, good reaction safety and the like. Disclosure of Invention Aiming at the defects existing in the prior art, the invention provides a synthesis method of 1-tertiary butyl-3-ethyl carbodiimide. The method has mild reaction conditions, simple steps and environmental friendliness, and can realize high-yield and high-purity synthesis of the target product. The invention provides the following technical scheme for achieving the purpose: the invention provides a synthesis method of 1-tertiary butyl-3-ethyl carbodiimide, which comprises the following steps: (1) Carrying out addition reaction on ethyl isothiocyanate and tert-butylamine in an organic solvent I at a temperature of 30-60 ℃ to obtain ethyl tert-butylthiourea, wherein the organic solvent I is one or more selected from petroleum ether, n-hexane, n-heptane, n-pentane, isopentane, n-octane and isooctane; (2) Oxidizing and desulfurizing the ethyl tertiary butyl thiourea and a sodium hypochlorite aqueous solution with the concentration of 10-15 wt% in an organic solvent II at the temperature of 0-10 ℃, removing sulfur generated by the reaction, and purifying the feed liquid to obtain 1-tertiary butyl-3-ethylcarbodiimide, wherein