JPS61260074A - Production of 1-amidino-4-formylpiperazine - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for medicines in high purity and yield with ready separation and purification, by reacting a 1-formylpiperazine selectively with cyanamide, as necessary, using a mineral acid. CONSTITUTION:A 1-formylpiperazine expressed by formula I (R<1> and R<2> are H or lower alkyl), e.g. 1-formylpiperazine, is reacted with cyanamide in the presence or absence of a mineral acid, e.g. sulfuric acid, in an inert solvent, e.g. water, preferably at 20-80 deg.C normally for 1-3hr to afford the aimed compound expressed by formula II or a mineral acid salt thereof. The molar amount of the compound expressed by formula I to be used is equimolar, as necessary, may be 0.5-2 times based on the cyanamide and the amount of the mineral acid to be used is 0-1 equivalent, preferably 0.3-0.6 equivalent based on the compound expressed by formula I. EFFECT:The aimed compound can be readily separated and purified simply by concentrating the reaction solution of the formed aimed compound, adding methanol thereto and filtering off the aimed compound.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing 1-ashino-4-formylpiperazines or mineral acid salts thereof.

More specifically, the present invention relates to a method for producing 1-amidino-4-formylpiperazines or mineral acid salts thereof by centering 1-formylpiperazines and cyanamide. 1
-Amidino-4-formylpiperazines or mineral acid salts thereof.

It is an extremely important compound as an intermediate for pharmaceutical synthesis.

Problem 1# to be solved by conventional technology and the present invention
A conventional method for producing amidino-4-formylpiperazines or mineral acid salts thereof is to react l-formylpiperazine with a mineral acid salt of ethyl or methylthiomethanimidamide to obtain 1-amidino-4-formylpiperazine. A method (US Pat. No. 4,258,188) is known.

However, this method generates a foul-smelling and toxic mercaptan as a by-product, which is undesirable from the standpoint of pollution, and it is not suitable as an industrial method for producing 1-amidino-4-formylpiperazine or its mineral acid salt. It's not something I should be satisfied with.

As a result of intensive research to develop a manufacturing method to solve the problem, the present invention has finally been completed. , (wherein, R
1, R'' represents a hydrogen atom or a lower alkyl group) by reacting l-formylpiperazines represented by the formula (2) (in which R1, R2
is the same as above) The present invention relates to a method for producing 1-amidino-4-formylpiperazines or mineral acid salts thereof.

1-formylpiperazine, which is a starting material in the present invention, is a compound represented by the general formula (1), and specifically, l-formylpiperazine, 1-formyl-2-methylpiperazine, l-formyl-3 - methylpiperazine,
1-formyl-2,5-dimethylpiperazine, l-formyl-2,6-dimethylpiperazine, l-formyl-2
-ethylpiperazine, 1-formyl-3-ethylpiperazine, and the like.

Examples of mineral acid salts in the present invention include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, carbonates, and the like.

The reaction method of the present invention is to charge a 1-formylpiperazine represented by general formula (1), an inert solvent, and a mineral acid (or unused) into a reaction vessel, and add sialyamide under stirring. 1-amidino-4-formylpiperazines or mineral acid salts thereof are produced in high yield.

Water is usually used as the reaction solvent, but if necessary, lower alcohols such as methanol or ethanol, or inert hydrocarbons such as benzene, toluene or xylene may be used without affecting the reaction.

The reaction temperature in the present invention is not particularly limited as long as it is 0° C. or higher, but the reaction time is preferably 30 minutes or longer in order to alleviate the decomposition of cyanoamide.

The addition time varies depending on the amount of preparation, but is usually 1 to 3 hours.

The amount of l-formylpiperazines used in this reaction is equivalent to the mole of Shear & It is sufficient, but if necessary, it can be used in the range of 0.5 to 2 times the mole without any effect on the reaction. It is not something that will affect you.

The amount of mineral acid used in this reaction can range from θ to equivalents per mole of l-formylpiperazine, but preferably ranges from 0.3 to 0.6 equivalents. In addition, when a mineral acid salt is required, a considerable amount of mineral acid is used.

The 1-amidino-4-formylpiperazines or mineral acid salts produced in the reaction described in the claims of the present invention can be produced by, for example, simply concentrating the reaction solution, adding methanol, and separating it in a furnace. Easily separated and purified from liquids.

X Ri Ni Ri! According to the method of the present invention, 1-amidino-4-formylpiperazines or mineral acid salts thereof can be obtained in high yield based on 1-formylpiperazines as raw materials, and the reaction may be extremely slow. Because it occurs with high selectivity, there are few by-products such as 1,4-diamidinopiperazines (1,4-diamidinopiperazines, etc.). or its mineral acid salt can be obtained, and is extremely advantageous industrially.

EXAMPLES The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 Thermometer, stirrer 2 dropping funnel, reflux condenser (F) (11
Lumylviperazine 2041 (1,79 mol) and water (12:1F) were charged into a 11-piece four-flask. Next, while maintaining the internal temperature of 45 to 50°C, 5096HttrSOa aqueous solution 117F was added dropwise from the dropping funnel, and further, 5096 cyanamide aqueous solution 100F (1.19 mol) was added dropwise over 45 minutes at an internal temperature of 45 to 50°C.

After stirring at the same temperature for 2 hours, the bath temperature was increased to 80°C.
℃, and 100 f of water was distilled off under reduced pressure.

Add methanol 300 to the residue, stir for 20 minutes at an internal temperature of 60°C, filter the reaction product at a temperature of 40 to 50°C, then wash the crystals with methanol 100, and dry l-amidino-4-formyl. Of piperazine! -H1!504 salt 1
97 g (0,961 mol) were obtained. y H2sA of 1-amidino-4-formylpiperazine to cyanamide
The yield of Ja salt was 80.8%.

Example 2 The same operation as in Example 1 was carried out except that the amounts of 50% Hs 504 aqueous solution and methanol used were 1109 and 4009, respectively. -HllSO4 salt 191N was obtained. , (yield 75%) Example 3 1-formyl-2,5 instead of 1-formylpiperazine
- 190 g of 4Hz SO4 salt of 1-formyl-2,5-dimethyl-4-amidinopiperazine was prepared in the same manner as in Example 1 except that 254f of dimethylpiperazine was used.
Total 190 (8% collection)

Claims (1)

[Claims] General formula (1) ▲Mathematical formulas, chemical formulas, tables, etc. in the presence or absence of mineral acids▼(1) (In the formula, R^1 and R^2 are hydrogen atoms or lower General formula (2), which is characterized by reacting cyanamide with 1-formylpiperazines (representing an alkyl group) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(2) (In the formula, R^1, R ^2 is the same as above) A method for producing 1-amidino-4-formylpiperazines or mineral acid salts thereof.