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Preparation method of 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate

A technology of carbodiimide methyl and p-toluene sulfonate, applied in the preparation of sulfonate, organic chemistry, etc., can solve the problems of high toxicity of raw materials, difficult operation, and low overall repeatability

Active Publication Date: 2021-05-07
SUZHOU HIGHFINE BIOTECH
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Problems solved by technology

[0003] At present, about the preparation method of 1-cyclohexyl-2-(morpholine ethyl) carbodiimide methyl p-toluenesulfonate, there are reports using cyclohexyl isothiocyanate and mercuric oxide as raw materials to prepare, However, the raw materials used in this method are highly toxic, difficult to operate, and the overall reproducibility is not high

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  • Preparation method of 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate
  • Preparation method of 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate
  • Preparation method of 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate

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[0029] The preparation method of 1-cyclohexyl-2-(morpholine ethyl) carbodiimide methyl p-toluenesulfonate according to the embodiment of the present invention comprises:

[0030] Step S1, adding N-(2-aminoethyl)morpholine to the first organic solvent, and then adding cyclohexyl isocyanate dropwise to generate intermediate 1, the chemical structure of intermediate 1 is shown in formula (1) .

[0031]

[0032] Specifically, its reaction formula is as shown in the following formula (3):

[0033]

[0034] Wherein, considering the solubility of each reaction raw material, the ease of recovery, the ease of operation, and the load on the environment, preferably, the first organic solvent is dichloromethane.

[0035] In addition, the molar ratio of N-(2-aminoethyl)morpholine to cyclohexyl isocyanate may preferably be 1:(1˜1.2). By adding cyclohexyl isocyanate slightly higher than the stoichiometric ratio, the reaction can be promoted and the yield can be improved.

[0036] In...

Embodiment 1

[0059] (1) Preparation of intermediate 1

[0060] Take 1L reaction flask and add N-(2-aminoethyl)morpholine (180g, 1.38mol, 1.0eq) and dichloromethane (540mL, 3P), dropwise add cyclohexyl isocyanate (173g, 1.3mol, 1.0eq), The temperature is controlled at 20-25° C., and the reaction is completed after being incubated for 2 hours. The reaction solution was concentrated to remove dichloromethane to obtain a crude product, which was then beaten with petroleum ether to obtain 343 g of CMC-1, with a melting point of 118.1-118.8° C. and a yield of 97.3%.

[0061] (2) Preparation of Intermediate 2

[0062] Take a 2L reaction flask and add triphenylphosphine (421.8g, 1.61mol, 1.2eq) into dichloromethane (1.3L, 5P), and add liquid bromine (257.6g, 1.61mol, 1.2eq) dropwise in an ice-water bath, Control the temperature at 10-20°C; continue to drop triethylamine (406g, 4.02mol, 3.0eq), control the temperature at 10-20°C; continue to dropwise add CMC-1 (343g, 1.34mol, 1.0eq), control the te...

Embodiment 2

[0067] (1) Preparation of Intermediate 1

[0068] Take 2L reaction flask and add N-(2-aminoethyl)morpholine (324g, 2.48mol, 1.0eq) and dichloromethane (1L, 3P), dropwise add cyclohexyl isocyanate (311.4g, 2.48mol, 1.0eq) , the temperature is controlled at 20-25° C., and the reaction is completed after insulated for 2 hours. The reaction solution was concentrated to remove dichloromethane to obtain a crude product, which was then beaten with petroleum ether to obtain 614 g of CMC-1, with a melting point of 118.3-119.1° C. and a yield of 96.8%.

[0069] (2) Preparation of Intermediate 2

[0070] Take a 5L reaction flask and add triphenylphosphine (756g, 2.89mol, 1.2eq) into dichloromethane (3L, 5P), and add liquid bromine (462.4g, 2.89mol, 1.2eq) dropwise in an ice-water bath to control the temperature At 10-20°C; continue to drop triethylamine (727.2g, 7.2mol, 3.0eq), control the temperature at 10-20°C; continue to dropwise add CMC-1 (614g, 2.4mol, 1.0eq), control the tempera...

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Abstract

The invention provides a preparation method of 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate, and the method comprises the following steps: S1, adding N-(2-aminoethyl) morpholine into a first organic solvent, and dropwise adding cyclohexyl isocyanate to generate an intermediate 1; S2, carrying out intramolecular dehydration reaction on the intermediate 1 to obtain an intermediate 2; S3, enabling the intermediate 2 to react with methyl p-toluenesulfonate, so as to generate the 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate. According to the preparation method of the 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate disclosed by the embodiment of the invention, a product with high purity can be smoothly obtained, and the method is good in operability, higher and stable in yield and easily available in raw materials.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate. Background technique [0002] 1-cyclohexyl-2-(morpholinoethyl) carbodiimide methyl p-toluenesulfonate is a condensing agent that can react in water and is used in the field of peptide synthesis. [0003] At present, about the preparation method of 1-cyclohexyl-2-(morpholine ethyl) carbodiimide methyl p-toluenesulfonate, there are reports using cyclohexyl isothiocyanate and mercuric oxide as raw materials to prepare, However, the raw materials used in this method are highly toxic, difficult to operate, and the overall reproducibility is not high. Contents of the invention [0004] In view of this, the present invention provides a kind of preparation of 1-cyclohexyl-2-(morpholine ethyl) carbodiimide methyl p-toluenesulfonate with high safety, easy handling and good reprodu...

Claims

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Application Information

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IPC IPC(8): C07D295/13C07C309/30C07C303/32
CPCC07D295/13C07C309/30C07C303/32
Inventor 王桂春骆浩王子安
Owner SUZHOU HIGHFINE BIOTECH
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