JPS6052698B2 - Method for producing thiourea and urea derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION CH32=〒CH2-S-CH2-℃H2-NH-℃-
/ ＼ 11HN, ..., Nx y------ Imidazole nucleus It is used in basic fields as a thiourea and urea-induced histamine receptor antagonist, and is also used for hyperacidity and gastric acidosis to strongly suppress gastric juice secretion. - It has come to be used as a clinical medicine for the treatment of digital ulcer disease.

Since cimetidine, methyamide and related substances were disclosed in British Patent No. 1338189, numerous manufacturing methods have been proposed. In addition, the superiority of the method of reacting the mercapto group and heterocycle of a mercaptoethylthiourea compound, which is one of the target compounds of the present invention, was disclosed in JP-A-51-125.
074 has been pointed out. In this work, Black et al. gave a detailed description of the specific manufacturing invention of the mercaptoethyl urea compound.They chemically modified the imidazole nucleus as a drug that specifically suppresses the histamine action mediated by the Leur receptor, and specifically inhibited gastric acid secretion caused by histamine. succeeded in developing brimamide that inhibits

[Nature 236386 (1972)] Subsequent research revealed that methyamide (X=5 in formula [I]), which has strong activity, low toxicity, and can be administered orally, and cimetidine (X
=NCN) was developed and JHCH3[I] method is as follows: (1) 2-mercaptoethylamine and alkyl isothiocyanate or isocyanate are reacted to form 1-[2-(N-alkyldithiocarbamoyl)ethyl-3-alkyl]- 2-thiourea and 1-[2-(N
-alkylthiolcarbamoyl)ethyl] - Synthesis method from -3-alkylurea via silver salt (J, Org
, Chem, Vol. 28, 3140 (1963)), (2)2
- Method for ring-opening alkylamino-2-thiazolines with hydrogen sulfide (J, Org, Chem-33, 884 (196
3)) etc. are listed.

Both of these methods have drawbacks such as long synthetic routes and low yields. The present invention is a completely new method compared to these conventional methods, and is an extremely economical method for obtaining a target product in high yield and high purity.

The present invention is produced by reacting ethyleneimine and isothiocyanate or ethyleneimine and isocyanate, and then reacting them with an acid to obtain the formula [wherein R is C1 to C4 lower alkyl, x is sulfur, *where R is C1 to It represents a C4 lower alkyl group, and when ethyleneimine and thioisocyanate are reacted, x becomes sulfur, and when ethyleneimine and isocyanate are reacted, X becomes oxygen.

The product of formula [] is the desired thiourea and urea derivative, and Y can react with the functional group of imidazole and other heterocyclic compounds as shown in formula [1] to form a sulfide bond (-S-). group, specifically a thiol group and chlorine. When Y is a thiol group, HY is hydrogen sulfide, and if it is further oxidized and dimerized with hydrogen peroxide, oxygen in the air, etc., a disulfide group can be obtained. When Y is chlorine, a ring-opening reaction may be performed with hydrochloric acid. The reaction temperature is carried out at room temperature or lower, preferably 0 to 10°C. The solvent is not particularly limited, and examples include single or mixed solvents of aromatic, aliphatic hydrocarbons, cycloaliphatic hydrocarbons, acetone ether, and water.

Preferably, benzene and toluene are used in the formula [formerly], and alcohol and water are preferably used in the formula []. Formula [Old thioisocyanates and cycloadducts of ethyleneimine to isocyanates may be isolated as crystals and subjected to the reaction of formula [], or the ring-opening reaction may be performed directly without isolating the crystals. In both cases, a predetermined object can be obtained.

As mentioned above, the present invention is a method for producing thiourea and urea derivatives represented by ethyleneimine, 8 oxygen, and Y means chlorine or a thiol group.

The compound obtained in the present invention relates to a method for producing thiourea and urea derivatives corresponding to the side chain part of formula [1].The thiourea derivative can be directly used as a material for synthesizing methamide, and both the thiourea and urea derivatives can be produced by various methods. It can be used as a synthetic material for cimetidine.

It is recognized that the method of the present invention relies on the following chemical reaction.

Using isothiocyanate, isocyanate as a starting material,
The present invention provides a method for producing thiourea and urea derivatives that is economically and industrially advantageous, by carrying out the reaction under mild conditions, and in high yield and purity. be.

Examples are shown below.

Example 1 Methyl isothiocyanate 17y was dissolved in 30ml of toluene, and ethyleneimine 10V was dissolved in 20ml of toluene under ice cooling.
Add the solution dissolved in 1 dropwise.

White crystals precipitate at about 30 degrees after dropping, then the temperature is increased to 5℃ for 1 to 2 hours.
The crystals are filtered and dried under reduced pressure. 23.5y of N-aziridinyl-N''-methylthiourea is obtained, melting point 52.
7℃, aziridine ring 97.07%, nitrogen 22.97% (
Theoretical value: 24.1%) 100 ml of ethanol was cooled with a cryogen, and while hydrogen sulfide gas was passed through the mixture, a solution of 23.5 y of the obtained N-azirinidyl-N''-methylthiourea dissolved in 120 ml of ethanol was added dropwise.

The hydrogen sulfide gas was turned off after 10 to 10 minutes after dropping, and after being left overnight, nitrogen gas was aerated to drive out the hydrogen sulfide, and the mixture was concentrated and dried under reduced pressure to form a colorless oily N-(2-mercaptoethyl)-N-
32.6y of methylthiourea is obtained. Nitrogen 19.46% (
Theoretical value 18.65%) Confirmation of substance: Colorless oily N-(2
-mercaptoethyl)-N''-methylthiourea in 250ml of ethanol, then 92.8ml of 10% caustic soda.
t, then 2●4-dinitrochlorobenzene46.
A solution of 4y dissolved in 350 ml of ethanol was added, heated to reflux, filtered under heat, the solution was cooled, and the precipitated crystals were removed.
When reconsolidated with ethanol, N-(2-mercaptoethyl)
A 2●4-dinitrophenyl sulfide derivative of -N''-methylthiourea was obtained.

The melting point and infrared absorption spectrum of this product are reported in J. Or
g. Chem. 2?3140-3144 (1963).

Melting point 159 raw C (literature value 158-1600C) Example 2 Methyl isothiocyanate 17q was dissolved in toluene 30ml, and ethyleneimine 10y was dissolved in toluene 20ml under ice cooling.
Add the solution dissolved in 1 dropwise.

White crystals precipitate at about 3 drops after dropping. One to two hours after precipitation, 50Tn1 of ethanol is added to dissolve the crystals. 100 ml of ethanol is cooled with a cryogen, and the solution is added dropwise while passing hydrogen sulfide gas.

After the dropwise addition, aeration of hydrogen sulfide gas was stopped for 10 to 10 minutes, and after being left overnight, nitrogen gas was aerated to drive out the hydrogen sulfide, and the mixture was concentrated and dried under reduced pressure to form a colorless oily N-(2-mercaptoethyl)- 33.5 N''-methylthiourea are obtained. Nitrogen 18.
17% (theoretical value 18.65%) Example 3 Methyl isothiocyanate 17y was dissolved in 30ml of toluene, and ethyleneimine 10y was dissolved in 20ml of toluene under ice cooling.
Add the solution dissolved in 1 dropwise.

White crystals precipitate at about 3 drops after dropping. After 1 to 2 hours, 50 mt of ethanol is added to dissolve the crystals.

This solution was added dropwise to a solution of 21.5 ml of concentrated hydrochloric acid (36%) and 80 ml of ethanol cooled with a cryogen. After standing overnight, the mixture was concentrated to dryness under reduced pressure, added with 50 ml of ethanol, dispersed, cooled, filtered, and dried under reduced pressure to obtain 32.5 y of white crystals of N-(2-chloroethyl)-N''-methylthiourea.

Melting point 133.2'C1 nitrogen 16.66% (theoretical value 18.
35%) chlorine 22.70% (theoretical value 23.25%) Example 4 22.6 y of n-butyl isocyanate was dissolved in 30 ml of toluene, and the solution was added dropwise to a solution of 9.8 y of ethyleneimine dissolved in 20 ml of toluene under ice cooling.

After 1 to 2 hours, this liquid is cooled with 100 mt of ethanol using a cryogen and added dropwise while aerating hydrogen sulfide gas.

After 10 to 10 minutes of dropping, the hydrogen sulfide gas was stopped, and after being left overnight, nitrogen gas was passed through to drive out the hydrogen sulfide, and the mixture was concentrated to dryness under reduced pressure.
41.1V of butyl urea is obtained. Nitrogen 15.64% (theoretical value 15.9%) Example 5 23.7y of n-butyl isocyanate was added to 30m of toluene.
1, and a solution of 8.8 g of ethyleneimine dissolved in 20 mL of toluene was added dropwise under ice cooling.

After 1 to 2 hours, this liquid was cooled with 100 ml of ethanol as a cryogen, and added dropwise while aerating hydrogen sulfide gas.

After completing the dropwise addition, stop the hydrogen sulfide at 10 to 1 powder, leave it for one night, then blow nitrogen gas to drive out the hydrogen sulfide, and then concentrate to dryness under reduced pressure to obtain a colorless oily N-(2-mercaptoethyl)-N''.
39.9y of -n-butylthiourea is obtained. Nitrogen 14.2
9% (theoretical value: 14.56%) The oily substance obtained above was synthesized and confirmed as a 2●4-dinitrophenyl sulfide derivative using the substance confirmation method of Example 1.

Claims (1)

[Scope of Claims] 1. A formula characterized by reacting ethyleneimine and isothiocyanate or ethyleneimine and isocyanate, and then reacting with an acid ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is C_1 to C_4 , X means sulfur or oxygen, and Y means chlorine or a thiol group. ] A method for producing thiourea and urea derivatives.