JPS6341385B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing amidine derivatives, and in particular to a method for producing amidine derivatives from carboxylic acids and primary amines.

PRIOR ART Amidine derivatives are extremely important compounds in synthetic chemistry, as many of them not only exhibit physiological activity, but also various useful compounds can be derived from them (S. Patai, ``The Chemistry''). 'Of Amidines and Immediatees', John Willey & Sons, 1975
(S.Patai, “The Chemistry of Amidines and
John Wiley Sons, 1975)).

Conventionally, amidine derivatives are synthesized by reacting an imidochloride obtained by reacting the corresponding amide with a halogenating agent such as phosphorus pentachloride and an amine;
A common method of synthesis was to react the corresponding nitrile with an amine. However, the former method uses a halogenating agent that is difficult to handle, and the imide halide produced also has drawbacks such as high reactivity with moisture. In addition, the latter method has the problem that there are restrictions on the types of nitrile that can be obtained as a starting material compared to carboxylic acids and the like.

DISCLOSURE OF THE INVENTION The present inventors have conducted extensive research to overcome these drawbacks, and as a result, they have found that a carboxylic acid and a primary amine, which are easily available, can be synthesized by reaction of both in the presence of polyphosphoric acid trimethylsilyl ester. It was confirmed that amidine derivatives could be directly produced, and the present invention, which overcomes the drawbacks of the above-mentioned conventional methods, was thereby achieved.

That is, the present invention is a method for producing amidine derivatives in which a carboxylic acid and a primary amine are reacted in the presence of polyphosphoric acid trimethylsilyl ester.

The carboxylic acid of the present invention is a carboxylic acid represented by the general formula () R ¹ CO ₂ H () (R ¹ in the formula represents a monovalent organic group), and the carboxylic acid represented by the above formula () Examples include linear and branched carboxylic acids with 1 to 20 carbon atoms, such as formic acid, acetic acid, butyric acid, isobutyric acid, caproic acid, and decanoic acid; alicyclic acids such as cyclopropanecarboxylic acid, cyclopentanecarboxylic acid, and cyclohexanecarboxylic acid; Formula carboxylic acid, unsaturated carboxylic acid such as crotonic acid, cinnamic acid, aromatic carboxylic acid such as benzoic acid, toluic acid, anisic acid, fluorobenzoic acid, chlorobenzoic acid, nitrobenzoic acid, nicotinic acid, furancarboxylic acid Examples include heterocyclic carboxylic acids such as.

The primary amine of the present invention is a primary amine represented by the general formula () R ² NH ₂ () (R ² in the formula represents a monovalent organic group), and is represented by the above formula (). Primary amines include linear and branched aliphatic amines having 3 to 20 carbon atoms such as butylamine, isobutylamine, hexylamine, and decylamine, alicyclic amines such as cyclohexylamine and cyclooctylamine, aniline, and toluidine. , aromatic amines such as anisidine, fluoroaniline, chloroaniline, and bromoaniline, and heterocyclic amines such as aminopyridine.

The polyphosphoric acid trimethylsilyl ester of the present invention is a compound that can be easily synthesized from, for example, phosphorus pentoxide and hexamethyldisiloxane (for example, Imai et al., Synthesis, 1983, p. 851).
However, the manufacturing method is not limited to this. In addition, polyphosphoric acid trimethylsilyl ester obtained from phosphorus pentoxide and hexamethyldisiloxane is substantially a cyclic and linear tetramer of phosphoric acid represented by the following formulas (A), (B) and (C). It is a mixture consisting of four components: trimethylsilyl ester of pyrophosphoric acid and trimethyl ester of pyrophosphoric acid represented by the following formula (D), and the proportion of each component varies somewhat depending on the preparation conditions, but an example is given below. and prepared in methylene chloride, (A) is
52%, (B) 29%, (C) 15%, (D) 4%
(Yamamoto et al., Chemistry Letters,
(1982, 1225 pages) In the above formula, TMS represents (CH ₃ ) ₃ Si−. The amount of polyphosphoric acid trimethylsilyl ester used in the present invention is 1 to 30% of the amount of carboxylic acid used.
Although the amount is molar equivalent, the amount to be used is 2 to 10 molar equivalents, which is economical and allows the reaction to proceed smoothly.

The amount of primary amine used in the present invention is required to be at least twice the amount of carboxylic acid used, but a large excess of amine deactivates trimethylsilyl polyphosphate and is not economical. In practice it is optimal to use 2 to 3 molar equivalents of amine.

The present invention proceeds without a solvent or in the presence of a solvent. The reaction solvent used in the present invention is limited by the fact that it does not substantially react with polyphosphoric acid trimethylsilyl ester, but includes hydrocarbon solvents such as hexane, octane, and decane, benzene, chlorobenzene, dichlorobenzene, nitrobenzene, and anisole. aromatic solvents, halogenated solvents such as methylene chloride, chloroform, dichloroethane, and tetrachloroethane, and sulfonic solvents such as sulfolane and diphenylsulfone.

In the present invention, the reaction temperature can be selected from 60°C to 250°C, but the reaction at low temperatures is slow and the reaction at high temperatures is not economical. Preference is given to selecting a reaction temperature between 120°C and 180°C.

The reaction time in the present invention is greatly influenced by the types of carboxylic acid and primary amine used and the reaction temperature used, but in any case it is preferable to stir until the maximum yield is obtained. Under normal conditions it is in the range of 10 minutes to 10 hours.

The amidine derivative obtained by the present invention has the general formula () (In the formula, R ¹ and R ² each represent a monovalent organic group.)

EXAMPLES OF THE INVENTION Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Phosphorus pentoxide (5 mmol, 1.42 g) and hexamethyldisiloxane (16 mmol, 2.56 g) were heated under reflux in 3 ml of methylene chloride under a nitrogen stream for 30 minutes. Methylene chloride was distilled from the resulting solution at normal pressure. p-methoxybenzoic acid (1.25 mmol, 190 mg) was added to the obtained distillation residue, and the mixture was heated to 160°C under a nitrogen stream. Furthermore, aniline (2.5 mmol 235 mg) was added and reacted for 5 hours. After cooling the reaction solution to room temperature, it was poured into 200 ml of 1N-NaOH aqueous solution and
A precipitate of N'-diphenyl-p-methoxybenzamidine was obtained. Further, a pure sample was obtained by recrystallization in a water-ethanol system. Yield 87%, mp122.5
°C IR (cm ^-1 ): 1625, 1215, 1105 NMR δppm (CDCl ₃ ): 3.67 (S, 3H), 5.70 (s,
1H) 7.00 (m, 14H) Example 2 N,
N'-diphenylbenzamidine was obtained.

Yield 83% mp149-150℃ IR (cm ^-1 ): 1620, 1215, 1100 NMR δppm (CDCl ₃ ): 5.80 (broads, 1H) 7.12
(m, 15H) Example 3 N,N'-diphenyl-p-chlorobenzamidine was obtained from p-chlorobenzoic acid (1.25 mmol) and aniline (2.5 mmol) in the same manner as in Example 1.

Yield 88% mp156℃ IR (cm ^-1 ): 1625, 1215, 1100 NMR δppm (CDCl ₃ ): 7.08 (m) Example 4 By the same operation as Example 1, p-nitrobenzoic acid (1.25 mmol) and N,N'-diphenyl-p-nitrobenzamidine was obtained from aniline (2.5 mmol).

Yield 84% mp156.5-158.5℃ IR (cm ^-1 ) 1640, 1215, 1100 Example 5 Cyclohexanecarboxylic acid (1.25 mmol) and aniline (2.5 mmol) were prepared in the same manner as in Example 1.
N,N'-diphenylcyclohexanecarboxamidine was obtained.

Yield 81% mp116-117℃ IR (cm ^-1 ): 1635, 1205, 775 NMR δppm (CDCl ₃ ): 0.86-2.90 (m, 11H),
5.80 (S, 1H), 7.12 (m, 10H) Example 6 Hexane-1-carboxylic acid (1.25 mmol) and aniline (2.5 mmol) were prepared in the same manner as in Example 1.
From this, N,N'-diphenylhexane-1-carboxamidine was obtained.

Yield 79% mp97℃ IR (cm ^-1 ): 1630, 1210, 755 Example 7 Using the same procedure as in Example 1, N,
N'-diphenylcinnamamidine was obtained.

Yield 65% mp121.5-122.5℃ IR (cm ^-1 ): 1635, 1210, 750 NMR δppm (CDCl ₃ ): 6.33 (S, 1H), 6.60 (s,
1H), 7.07 (m, 16H) Example 8 N,N'-bis(p-methoxyphenyl) was prepared from benzoic acid (1.25 mmol) and p-anisidine (2.5 mmol) by the same procedure as in Example 1. Benzamidine was obtained.

Yield 88% mp126-128℃ IR (cm ^-1 ): 1625, 1220, 1100 NMR δppm (CDCl ₃ ): 3.63 (s, 6H), 5.70 (s,
1H), 6.88 (m, 13H) Example 9 N,N'-bis(p-toluyl)benzamidine was prepared from benzoic acid (1.25 mmol) and p-toluidine (2.5 mmol) by the same procedure as in Example 1. Obtained.

Yield 87% mp137-137.5℃ IR (cm ^-1 ): 1625, 1220, 1100 NMR δppm (CDCl ₃ ): 2.22 (s, 6H), 0.96 (m,
14H) Example 10 Benzoic acid (1.25 mmol) and p-chloroaniline (2.5 mmol) were prepared in the same manner as in Example 1.
From, N,N'-bis(p-chlorophenyl)
Benzamidine was obtained.

Yield 69% mp146-147℃ IR (cm ^-1 ): 1625, 1220, 1090 Example 11 Phosphorus pentoxide (5 mmol, 1.42 g) and hexamethyldisiloxane (16 mmol, 2.56 g) were mixed in 3 ml of methylene chloride with a nitrogen stream. The mixture was heated under reflux for 30 minutes. Methylene chloride was distilled from the resulting solution at normal pressure. 10 ml of sulfolane was added to the obtained distillation residue and heated to 160°C under a nitrogen stream. Benzoic acid (1.25 mmol) and aniline (2.5 mmol) were added, and the mixture was stirred at 160°C for 5 hours. After cooling the obtained solution to room temperature, 1N−
The mixture was poured into 200 ml of NaOH aqueous solution to obtain a precipitate of N,N'-diphenylbenzamidine, which was recrystallized from a water-ethanol system. Yield: 91% Effects of the Invention As described above, the present invention involves reacting a carboxylic acid represented by the general formula () with a primary amine represented by the general formula () in the presence of polyphosphoric acid trimethylsilyl ester. This made it possible to produce an amidine derivative represented by the general formula () in one step.

According to the present invention, a compound having physiological activity,
This invention is recognized as a novel and useful invention in that it enables mass production of intermediates that can be derived into various useful compounds at low cost.

Claims (1)

[Claims] 1. A method for producing an amidine derivative, which comprises reacting a carboxylic acid and a primary amine in the presence of trimethylsilyl polyphosphate.