JPH0558985A - Production of cyanoguanidine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a potassium channel opening medicine by reacting an aniline derivative with an isocyanide derivative in the presence of a dehydrating agent using a specific catalyst while blowing oxygen gas, etc., into the reaction mixture and reacting the resultant product with cyanamide. CONSTITUTION:An aniline derivative (e.g. 3,5-dichloroaniline) expressed by formula I (R<1> and R<2> are halogen, cyano or nitro) is reacted with an isocyanide derivative (e.g. t-butyl isocyanide) expressed by the formula CN-R<3> (R<3> is 4-7C alkyl having a branched chain at the 1-position) in the presence of a dehydrating agent in an inert organic solvent using nickel chloride, a nickel chloride complex or a zero-valent palladium complex as a catalyst while blowing oxygen gas or dry air into the reaction mixture. Thereby, a carbodiimide derivative expressed by formula II is obtained and then reacted with cyanamide in an aprotic organic solvent to afford the objective compound expressed by formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a cyanoguanidine derivative useful as a medicine. More specifically, the present invention provides compounds of general formula (4) useful as potassium channel openers.

[0002]

[Chemical 3] (In the formula, R ¹ and R ² each independently represent a halogen atom, a cyano group or a nitro group, and R ³ represents an alkyl group having a branched chain at the 1-position and having 4 to 7 carbon atoms.) The present invention relates to a method for producing the cyanoguanidine derivative shown.

[0003]

2. Description of the Related Art As a method for producing a cyanoguanidine derivative, JP-A-3-31250 and JP-A-2-290841 disclose thiourea derivatives, which are then introduced into carbodiimide derivatives and reacted with cyanamide. A method of making the derivative is disclosed. In addition,
2-91057 discloses a method for producing a cyanoguanidine derivative via an N-cyanothiourea derivative.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
In the production methods disclosed in JP-A Nos. 2-290841 and 3-31250, highly toxic thiophosgene is used in the reaction to obtain isothiocyanate as a raw material for thiourea and N-cyanothiourea derivatives. There is a need.
Further, these manufacturing methods have many steps and are complicated in operation.

[0005]

Means for Solving the Problems The present inventors have studied a method for producing a carbodiimide as a synthetic intermediate for the purpose of developing a safe and convenient method for producing a cyanoguanidine derivative. As a general synthetic method of carbodiimides, the
Journal of Organic Chemistry (J.Or
g. Chem.), 40, 2981-2982 (1975), a method of reacting an amine with an isocyanide in the presence of palladium chloride and silver oxide is reported. However, the method described here has room for improvement because it requires the use of expensive silver oxide in stoichiometric amounts as oxidant.

As a result of various studies, the present inventors have found an industrially advantageous method for producing a carbodiimide, and have completed a method for producing a cyanoguanidine derivative which is safe and has a small number of steps. The present invention uses an aniline derivative (1) and an isocyanide derivative (2) in an inert organic solvent, using nickel chloride, a nickel chloride complex or a zero-valent palladium complex as a catalyst, in the presence of a dehydrating agent, oxygen gas or dry air. Is a method for producing a cyanoguanidine derivative (4), which comprises reacting with a cyanamide in an aprotic organic solvent by reacting while blowing the carbodiimide derivative (3).

[0007]

[Chemical 4]

The present invention will be described in detail below. Examples of the aniline derivative (1) used in the present invention include 3,5-dichloroaniline, 3-amino-5-chlorobenzonitrile, 3-chloro-5-nitroaniline and the like.
Examples of the isocyanide derivative (2) include alkyl isocyanide having 4 to 7 carbon atoms, which has a branched chain at the 1-position, such as t-butyl isocyanide and t-pentyl isocyanide.

The reaction for synthesizing the carbodiimide (3) is carried out in the presence of a catalyst and a dehydrating agent in an inert organic solvent such as benzene or toluene, while blowing oxygen gas or dry air into the reaction solution and the compound (1) and the compound. (2) and 70
It is carried out by reacting at ˜150 ° C. for 1 to 4 hours. The amount of the compound (2) used is usually 1.0 to 5.0 mol, preferably 2.5 to 3.0 mol, per 1 mol of the compound (1), and may be added in two or more portions. Good.

As the catalyst, nickel chloride or a phosphine complex of nickel chloride, for example, bis (triphenylphosphine) nickel (II) chloride, bis (tri-n-butylphosphine) nickel (II) chloride, [1,1'-chloride] Bis (diphenylphosphino) ferrocene] nickel (II) can be used. It can also be used as a catalyst by adding nickel chloride and the above phosphine ligand to the reaction system.
A zero-valent palladium complex such as tetrakis (triphenylphosphine) palladium can also be used as the catalyst. These catalysts are usually used in 0.01 to 0.1 equivalent based on the compound (1).

As the dehydrating agent, for example, molecular sieve or anhydrous sodium sulfate can be used. The produced carbodiimide derivative (3) can be easily purified by distillation or column chromatography.

Then, the carbodiimide (3) and cyanamide are reacted in an aprotic organic solvent at 50 ° C. to the boiling point of the solvent for 30 minutes to 72 hours to produce a cyanoguanidine derivative (4). As the aprotic organic solvent used in this reaction, tetrahydrofuran, N, N-dimethylformamide (hereinafter, DM
Abbreviated as F. ), Dimethyl sulfoxide and the like.
Cyanamide is used in the amount of 1 to 10 equivalents based on compound (3). In this reaction, a base such as diisopropylethylamine can be used as a catalyst. The cyanoguanidine derivative produced by the present invention can be separated and purified by a conventional method such as column chromatography and / or recrystallization.

[0013]

INDUSTRIAL APPLICABILITY According to the present invention, the cyanoguanidine derivative (4) useful as a potassium channel opener can be produced safely and in a short process, and is an excellent industrial production method.

[0014]

EXAMPLES The present invention will be described in more detail below with reference to examples and reference examples. Example 1 Nt-Butyl-N'-cyano-N "-(3,5-dic
Production of ( lorophenyl) guanidine: (1) Nt-butyl-N '-(3,5-dichlorophenyl) carbodiimide: To 4.4 g of benzene, 648 mg of 3,5-dichloroaniline, 52 mg of nickel chloride and 1.00 g of anhydrous sodium sulfate were added. Then, 5.7 g of a benzene solution of t-butyl isocyanide (containing 998 mg of t-butyl isocyanide) was added over 1 hour while stirring at a boiling temperature of the solvent by blowing oxygen gas. Further, the mixture was stirred for 20 minutes at the boiling point of the solvent while blowing oxygen gas. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; cyclohexane), Nt-
414 mg of butyl-N '-(3,5-dichlorophenyl) carbodiimide was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 6.94 (2H, d), 7.08 (1
H, t).

(2) Nt-butyl-N'-cyano-
N "-(3,5-dichlorophenyl) guanidine: N-
335 mg of t-butyl-N '-(3,5-dichlorophenyl) carbodiimide, 290 mg of cyanamide and 71 mg of diisopropylethylamine were dissolved in 3.0 ml of DMF and heated at 90-95 ° C.
After stirring with heating for 40 minutes, ethyl acetate and water were added and the layers were separated, and the aqueous layer was extracted with ethyl acetate. After dried over anhydrous magnesium sulfate, purified by silica gel column chromatography (solvent; hexane / ethyl acetate = 10/3),
215 mg of Nt-butyl-N'-cyano-N "-(3,5-dichlorophenyl) guanidine were obtained. Mp 191.0-192.5 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 1.33 (9H, s. ), 7.09 (2H, d), 7.25
(1H, t), 7.39 (1H, bs), 9.29 (1H, bs).

Example 2 N- (3-chloro-5-cyanophenyl) -N'-sia
Preparation of no-N ″ -t-pentylguanidine: (1) N- (3-chloro-5-cyanophenyl) -N ′
-T-pentyl carbodiimide: 6.76 g of a benzene solution of t-pentyl isocyanide (t-pentyl isocyanide 5
Contains 83 mg. ), 763 mg of 3-amino-5-chlorobenzonitrile, 578 mg of tetrakis (triphenylphosphine) palladium and 1.50 g of molecular sieve 4A were added thereto, and the mixture was stirred for 15 minutes at the boiling temperature of the solvent while blowing oxygen gas into the reaction solution. Furthermore, 13.5 g of a benzene solution of t-pentyl isocyanide (t-pentyl isocyanide 1.17 g
including. ) Was added, and the mixture was stirred at the boiling point of the solvent for 2 hours and 45 minutes while blowing oxygen gas. The mixture was allowed to cool to room temperature, the insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; cyclohexane / ethyl acetate = 10/1) and N- (3-chloro-5-
Cyanophenyl) -N'-t-pentylcarbodiimide
675 mg was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t), 1.3
9 (6H, s), 1.65 (2H, q), 7.15 ~ 7.35 (3H, m).

(2) N- (3-chloro-5-cyanophenyl) -N'-cyano-N "-t-pentylguanidine: N- (3-chloro-5-cyanophenyl) -N'-
7.5 g of t-pentylcarbodiimide, 6.5 g of cyanamide and 319 mg of diisopropylethylamine were dissolved in 40 ml of DMF, and the mixture was heated with stirring at 90 to 95 ° C for 2 hours. After cooling to room temperature, the reaction solution was poured into 400 ml of water, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give N- (3-chloro-5).
5.7 g of -cyanophenyl) -N'-cyano-N "-t-pentylguanidine was obtained. Mp 181.0-183.0 ° C ¹ H-NMR (DMSO-d ₆ ) δ: 0.83 (3H, t), 1.29 (6H , s), 1.70
(2H, q), 7.29 (1H, bs), 7.4〜7.5 (2H, m), 7.6〜7.7 (1H, m),
9.43 (1H, bs).

Reference Example The N- (3-chloro-5-cyanophenyl) -N'-t-pentylcarbodiimide described in Example 2 (1) can also be produced by the following method. That is, Example 2 (1)
N-chloride by blowing oxygen gas or dry air using nickel chloride or nickel chloride complex as a catalyst according to
(3-Chloro-5-cyanophenyl) -N'-t-pentylcarbodiimide was prepared. The reaction conditions and the yield (quantified by gas chromatography) are shown in Table 1.

[0019]

[Table 1]

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Claims (1)

[Claims] 1. The following formula (1): (In the formula, R ¹ and R ² each independently represent a halogen atom, a cyano group or a nitro group.), And an aniline derivative represented by the following formula (2) CN—R ³ (2) ³ represents an alkyl group having a branched chain at the 1-position and having 4 to 7 carbon atoms), and a nickel chloride, nickel chloride complex or zero-valent palladium complex as a catalyst in an inert organic solvent. By reacting while blowing oxygen gas or dry air in the presence of a dehydrating agent, the compound of the general formula (3) (In the formula, R ¹ and R ² each independently represent a halogen atom, a cyano group or a nitro group, and R ³ represents an alkyl group having a branched chain at the 1-position and having 4 to 7 carbon atoms.) Obtaining the carbodiimide derivative shown, and then reacting with cyanamide in an aprotic organic solvent, a compound of the general formula (4): (In the formula, R ¹ and R ² each independently represent a halogen atom, a cyano group or a nitro group, and R ³ represents an alkyl group having a branched chain at the 1-position and having 4 to 7 carbon atoms.) A method for producing the indicated cyanoguanidine derivative.