JPH0733729A - Process for producing N-cyano-N'-substituted-aryl carboximidamide compound - Google Patents

Abstract

(57) [Summary] [Object] To provide a novel method for producing an N-cyano-N'-substituted-arylcarboximidamide compound. A method for producing an N-cyano-N'-substituted-arylcarboximidamide compound represented by the following formula (1), wherein an amide compound represented by the following formula (2) is added to a dehydration condensing agent, for example, A production method characterized by treating with acetic anhydride, triethyloxonium tetrafluoroborate, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, and then reacting with cyanamide. [Chemical 1] [Chemical 2] (In the formulas (1) and (2), Ar and R ¹ represent various specific substituents.) This preferred embodiment is represented by the formulas (1) and (2):
2- (or 3 in which Ar may be substituted with an amino group
-Or 4-) pyridyl, and R ¹ is phenyl optionally substituted with a halogen atom. By the above-mentioned production method, the N-cyano-N′-substituted-arylcarboximidamide compound can be easily produced in a shorter step.

Description

Detailed Description of the Invention

<Background of the Invention>

FIELD OF THE INVENTION The present invention relates to a process for producing an N-cyano-N'-substituted-arylcarboximidamide compound.

[0002]

2. Description of the Related Art N-cyano-N'-substituted-arylcarboximidamide compounds have been found to have a K ⁺ channel opening action, a hypotensive action, a coronary vasodilatory action, etc. Kaihei 3-163061, Japanese Unexamined Patent Publication No. Hei 3
-218343, JP-A-4-13342). Generally, as a method for producing an N-cyano-N′-substituted-arylcarboximidamide compound, the following method has been generally known. (I) A nitrile compound represented by the following formula (3) is introduced into a cyanoimidate compound represented by the following formula (4), and then reacted with an amine compound to form N-cyano-N′-substituted-
Method for producing aryl carboximidamide (ja
Null of Organic Chemistry (J. Or
g. Chem. ), 28, 1816, 1963,
JP-A-3-163061, JP-A-3-218343
No. JP-A-4-13342).

[Chemical 5] (In the formula, Ar is an optionally substituted aryl group.)

[Chemical 6] (In the formula, Ar is an optionally substituted aryl group and R ² is a lower alkyl group.) (Ii) An orthoester compound represented by the following formula (5) is represented by the following formula (6). To a cyano imidate compound, which is then reacted with an amine compound to give N-cyano-N '
-Method for producing a substituted-aryl carboximidamide compound (Journal of Organic Chemistry (J. Org. Chem.), 28, 1816,
1963, etc.).

[Chemical 7] (In the formula, Ar is an optionally substituted aryl group, and R ³ is a lower alkyl group.)

[Chemical 8] (In the formula, Ar is an optionally substituted aryl group and R ³ is a lower alkyl group.) (Iii) An amide compound represented by the following formula (7) is represented by the following formula (8). A method for producing an N-cyano-N′-substituted-arylcarboximidamide compound by leading it to a thioamide compound and reacting it with cyanoamide (International Publication WO / 9202514).

[Chemical 9] (In the formula, Ar is an optionally substituted aryl group, and R ⁴ is a lower alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group.)

[Chemical 10] (In the formula, Ar is an optionally substituted aryl group, and R ⁴ is an alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group.)

[0003]

However, the method using a nitrile compound as a raw material requires several steps for converting a carboxylic acid compound into a nitrile compound, and also requires N-cyano-N'-substituted-arylcarboximidamide. The problem is that several steps are required to lead to the compound, and finally multiple steps are required. Further, the method using an orthoester compound as a raw material also requires several steps in order to obtain an orthoester compound from a nitrile compound or a halogenated hydrocarbon, and leads to an N-cyano-N′-substituted-arylcarboximidamide compound. In order to do so, several more steps are required, and finally multiple steps are required, which is a problem. Further, the method using a thioamide compound as a raw material is not satisfactory in yield, and a bad odor during production of the thioamide compound is a problem. From the above, a method for easily producing an N-cyano-N'-substituted-arylcarboximidamide compound in a shorter step has been desired. The present invention aims to provide a manufacturing method which overcomes the above drawbacks.

<Outline of Invention>

Means for Solving the Problems The present inventors have completed the present invention as a result of examining various methods for solving the above problems. That is, the present invention is a method for producing an N-cyano-N′-substituted-arylcarboximidamide compound represented by the following formula (1), wherein an amide compound represented by the following formula (2) is added as a dehydration condensation agent. And then reacting with cyanamide. The present invention relates to a process for producing an N-cyano-N′-substituted-arylcarboximidamide compound represented by the formula (1).

[Chemical 11]

[Chemical 12] [In the formulas (1) and (2), Ar represents a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an alkylamino group,
Substituted with a group selected from dialkylamino group, aralkylamino group, hydroxyalkyl group, acylamino group, alkylsulfoneamino group, bisalkylsulfonylamino group, trifluoromethyl group, lower alkyl group, lower alkoxyl group, nitro group and cyano group. Optionally, phenyl group, 2- (or 3- or 4-) pyridyl group, 2- (or 3-) thienyl group, 2- (or 3-, 4-, 5-, 6-, 7- Or 8-) quinolyl group or 1- (or 3-, 4-, 5-, 6-, 7- or 8-) isoquinolyl group, R ¹ is a lower alkyl group or a hydroxyl group, or a halogen atom, Hydroxyl group, amino group, alkylamino group, trifluoromethyl group, lower alkyl group, lower alkoxyl group and nitro group It is a phenyl group or a 2- (or 3- or 4-) pyridyl group which may be substituted with a group. n is 0, 1, 2, 3 or 4. A preferred embodiment of the above production method is that Ar in the formulas (1) and (2) is a 2- (or 3- or 4-) pyridyl group optionally substituted with an amino group, and R ¹ is a halogen atom. A phenyl group which may be substituted with, and n is 2
Is the case. That is, a preferred embodiment of the present invention is a method for producing an N-cyano-pyridinecarboximidamide compound represented by the following formula (1 ′), wherein
Of an N-cyano-N′-substituted-arylcarboximidamide compound represented by formula (1 ′), characterized in that the amide compound represented by ′ ′) is treated with a dehydration condensation agent and reacted with cyanamide. It is a manufacturing method (however, formula (1 ')
And Ar ′ in (2 ′) is a 2- (or 3- or 4-) pyridyl group optionally substituted with an amino group, R
^{1 'is} a phenyl group which may be substituted by a halogen atom, n' is 2).

[Chemical 13]

[Chemical 14]

<Detailed Description of the Invention> Basic Structure of Related Compounds The compounds prepared by the method of the present invention have the formula (1)
Is an N-cyano-N′-substituted-arylcarboximidamide compound represented by Basic skeleton of this compound (N
-Part other than cyano group) is derived from the amide compound of formula (2). In these formulas (1) and (2), A
r is a phenyl group, a pyridyl group (2-, 3-, or 4
-), Quinolyl group (3-, 4-, 5-, 6-, 7-, or 8-) or isoquinolyl group (3-, 4-, 5-,
6-, 7-, or 8-), or a nuclear substitution product thereof. In that case, the substituent is a halogen atom,
Hydroxyl group, carboxyl group, amino group, alkylamino group, dialkylamino group, aralkylamino group, hydroxyalkyl group, acylamino group, alkylsulfonamino group, bisalkylsulfonylamino group, trifluoromethyl group, lower alkyl group, lower alkoxyl group , A nitro group and a cyano group. Alkylene group-
R ¹ forming the N ′ substituent of the amide compound of formula (2) via (CH ₂ ) n is a phenyl group or a pyridyl group (2
-, 3-, or 4-), or a nuclear substitution product thereof. The substituent in that case is a lower alkyl group or a hydroxyl group, or is selected from a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trifluoromethyl group, a lower alkyl group, a lower alkoxyl group and a nitro group. As described above, a preferred embodiment of the production method of the present invention for deriving the target compound of formula (1) from the amide compound of formula (2) is the target compound of formula (1 ′) from the amide compound of formula (2 ′). Is a production method for deriving the compound. Here, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a chlorine atom. The lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, a methyl group,
An ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, etc., preferably a methyl group or an ethyl group in the case of Ar, and an isopropyl group in the case of R ^1. Or te
An rt-butyl group may be mentioned. The lower alkoxyl group means an alkoxyl group having 1 to 4 carbon atoms, and specific examples thereof include a methoxyl group, an ethoxyl group, a propoxyl group and a butoxyl group, preferably a methoxyl group or an ethoxyl group. The alkyl in the alkylamino group, dialkylamino group, alkylsulfonamino group and bisalkylsulfonylamino group means a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, a methyl group or an ethyl group. , N-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, etc., preferably methyl group or ethyl group. The amide compound represented by the formula (2) can be easily obtained in a high yield by a general amidation method using a carboxylic acid compound represented by the following formula (9) and an amine compound represented by the following formula (10). Can be obtained at
Specifically, for example, condensation by heat, condensation with a condensing agent such as carbonyldiimidazole, carbodiimide, or a method of activating a carboxylic acid into an acid anhydride, an acid chloride or the like and then reacting it with an amine compound can be mentioned (for example, Experimental Chemistry Lecture (4th Edition) Volume 22, 138-151
Page, edited by The Chemical Society of Japan).

[Chemical 15] (In the formula, Ar represents a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an alkylamino group, a dialkylamino group, an aralkylamino group, a hydroxyalkyl group, an acylamino group, an alkylsulfoneamino group, a bisalkylsulfonylamino group, and trifluoromethyl. A group, a lower alkyl group, a lower alkoxyl group, a phenyl group which may be substituted with a group selected from a nitro group and a cyano group,
2- (or 3- or 4-) pyridyl group, 2- (or 3-) thienyl group, 2- (or 3-, 4-, 5
-, 6-, 7- or 8-) quinolyl group or 1-
(Or 3-, 4-, 5-, 6-, 7- or 8-)
It is an isoquinolyl group.

[Chemical 16] (R ¹ is a lower alkyl group or a hydroxyl group, or is substituted with a group selected from a halogen atom, a hydroxyl group, an amino group, an alkylamino group, a trifluoromethyl group, a lower alkyl group, a lower alkoxyl group and a nitro group. Phenyl group or 2- (or 3- or 4-) pyridyl group, where n is 0, 1, 2, 3 or 4.

N-Cyanation The amide compound of the formula (2) is converted to the desired N represented by the formula (1).
The reaction leading to a -cyano-N'-substituted-arylcarboximidamide compound is carried out, for example, by reacting the amide compound of the formula (2) in the presence or absence of a solvent in an amount of 1 to 20 with respect to 1 equivalent of the amide compound. An equivalent amount (preferably 1 to 10 equivalents) of a dehydrating condensing agent such as acetic anhydride, triethyloxonium tetrafluoroborate, sulfuryl chloride, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride (preferably thionyl chloride or phosphorus oxychloride). ) With stirring at a temperature of −20 to 250 ° C. (preferably −10 to 100 ° C.) for 1 to 24 hours (preferably 1 to 10 hours), and then 1 to 50 equivalents (preferably 1 to 1 equivalent) to 1 equivalent of the amide compound. Cyanamide (30 equivalents) is added with or without dilution with a solvent, and a temperature of -20 to 250 ° C (preferably -10 to 100 ° C) is added. In 1 to 48 hours (preferably 5-24 hours) can be carried out by stirring. Examples of the suitable solvent include benzene, chlorobenzene, dichlorobenzene, toluene, xylene, dichloromethane, trichloroethylene, chloroform, dimethylformamide, diethyl ether, petroleum ether, tetrahydrofuran, dioxane, ligroin, etc., preferably toluene, dimethylformamide or Tetrahydrofuran may be mentioned. These solvents can be used alone or in an appropriate mixture as necessary. Further, depending on the kind of the amide compound used, for example, in the case of 5-amino-N- [2- (2-chlorophenyl) ethyl] -3-pyridinecarboxamide, the reaction is carried out in the presence of a base. In some cases, it may be preferable in order to proceed smoothly. Examples of the base in this case include inorganic bases such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate, or organic bases such as trimethylamine, triethylamine, dimethylaniline and pyridine, preferably triethylamine or pyridine. Further, these organic bases can also be used as a solvent.

[0007]

The following examples serve to explain the present invention in more detail, but the present invention is not limited thereto. Reference Example 1 Preparation of 5-amino-N- [2- (2-chlorophenyl) ethyl] -3-pyridinecarboxamide 15 g of 3-amino-5-pyridinecarboxylic acid was dissolved in 10 ml of o-dichlorobenzene to prepare 2- (2 -Chlorophenyl) ethylamine (19.3 ml) was added, and the mixture was allowed to stand at 220 degrees for 6
Stir for hours. 400% 10% aqueous sodium hydroxide solution
1 was added and extracted with 400 ml of chloroform. The extract was dried over sodium sulfate, concentrated to 200 ml, 100 ml of diethyl ether was added, and the precipitated crystals were filtered to give 5-amino-N- [2- (2-chlorophenyl).
Ethyl] -3-pyridinecarboxamide 9.48 g was obtained. NMR (CDCl ₃ ): δ3.09 (t, J = 7.0Hz, 2H), 3.60 ~
3.90 (m, 2H), 6.23 (brs, 1H), 7.10 ~ 7.50 (m, 5H), 8.15 (d, J =
2.9Hz, 1H), 8.20 (d, J = 1.8,1H)

Reference Example 2 Preparation of N- [2- (2-chlorophenyl) ethyl] -3-pyridinecarboxamide 1 g of nicotinic acid chloride hydrochloride was added to 5 m of dichloromethane.
It was dissolved in 1 and 1.9 ml of triethylamine was added, and 2- (2-chlorophenyl) ethylamine 0.87 was added under ice cooling.
ml was added dropwise, and the mixture was stirred at room temperature for 12 hours. Saturated baking soda water 7
5 ml was added and extracted with 100 ml of chloroform, the extract was dried over sodium sulfate and concentrated, and the concentrated residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent to obtain N-.
1.15 g of [2- (2-chlorophenyl) ethyl] -3-pyridinecarboxamide was obtained. NMR (CDCl ₃ ): δ3.11 (t, J = 7.0Hz, 2H), 3.65〜
3.90 (m, 2H), 6.26 (brs, 1H), 7.10 ~ 7.50 (m, 5H), 7.95 ~ 8.
15 (m, 1H), 8.68 (dd, J = 1.5,4.8,1H) 8.88 (d, J = 1.5,1H) Example 1 5-amino-N-cyano-N '[2- (2-chlorophenyl) Production of ethyl] -3-pyridinecarboximidamide (Production of N-cyano-N ′-[2- (2-chlorophenyl) ethyl] -5- (3-aminopyridine) carboximidamide) 5-Amino-N- 5 g of [2- (2-chlorophenyl) ethyl] -3-pyridinecarboxamide was dissolved in 25 ml of tetrohydrofuran, 30 ml of pyridine was added, 12.5 ml of thionyl chloride was added dropwise under ice cooling, and the mixture was stirred for 2 hours under ice cooling. 22 g of cyanamide to 44 m of tetrahydrofuran
It was dissolved in 1 and added dropwise. It returned to room temperature and stirred for 15 hours. After adding 100 ml of water, 250 ml of 10% sodium hydroxide aqueous solution was added, the mixture was extracted twice with 300 ml of ethyl acetate, dried over sodium sulfate and concentrated to 8.1 g.
A residue of was obtained. The residue was dissolved in 20 ml of ethanol, 200 ml of ethyl ether was added, the precipitated impurities were filtered off, and the filtrate was concentrated to obtain 5.42 g. Add 90 ml of ethanol and heat to 50 ° C.
5 ml was added, the mixture was slowly cooled to room temperature, the precipitated crystals were filtered, and N-cyano-N '-[2- (2-chlorophenyl) ethyl] -5- (3-aminopyridine) carboximidamide 2.4 g. Obtained. The physicochemical properties of the obtained compound are shown in Example 2 of Japanese Patent Application No. 4-13342.
In accordance with the data for N-cyano-N '-[2- (2-chlorophenyl) ethyl] -5- (3-aminopyridine) carboximidamide described in.

Example 2 Preparation of N-cyano-N '-[2- (2-chlorophenyl) ethyl] -3-pyridinecarboximidamide N- [2- (2-chlorophenyl) ethyl] -3-pyridinecarboxamide 0 0.88 g was added to 15 ml of pyridine, 0.38 ml of phosphorus oxychloride was added dropwise under ice cooling, the mixture was stirred at room temperature for 2 hours, 0.2 g of cyanoamide was added, and the mixture was stirred at room temperature for 15 hours. After adding 20 ml of water, 50 ml of 10% sodium hydroxide aqueous solution was added, and 60 m of ethyl acetate was added.
After extracting twice with 1, the extract was dried over sodium sulfate and concentrated to obtain 1.1 g of residue. The concentrated residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent to give N-cyano-N'-.
0.6 g of [2- (2-chlorophenyl) ethyl] -3-pyridinecarboximidamide was obtained. The physicochemical properties of the obtained compound are described in N-cyano-N '-[2- (2-
Consistent with the data for chlorophenyl) ethyl] -3-pyridinecarboximidamide.

[0010]

According to the production method of the present invention, N-cyano-
N'-substituted-aryl carboximidamide compound,
It can be easily manufactured in a shorter process.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/47 9454-4C C07C 311/15 7419-4H C07D 213/81 213/82 215/48 217 / 02 217/26 333/38

Claims (2)

[Claims] 1. N-cyano-N'- represented by the following formula (1):
A process for producing a substituted-arylcarboximidamide compound, which comprises treating an amide compound represented by the following formula (2) with a dehydration condensing agent and then reacting it with cyanamide. N-cyano-N'-substituted-
Process for producing aryl carboximidamide compound. [Chemical 1] [Chemical 2] [In the formulas (1) and (2), Ar represents a halogen atom, a hydroxyl group, a carboxyl group, an amino group, an alkylamino group,
Substituted with a group selected from dialkylamino group, aralkylamino group, hydroxyalkyl group, acylamino group, alkylsulfoneamino group, bisalkylsulfonylamino group, trifluoromethyl group, lower alkyl group, lower alkoxyl group, nitro group and cyano group. Optionally, phenyl group, 2- (or 3- or 4-) pyridyl group, 2- (or 3-) thienyl group, 2- (or 3-, 4-, 5-, 6-, 7- Or 8-) quinolyl group or 1- (or 3-, 4-, 5-, 6-, 7- or 8-) isoquinolyl group, R ¹ is a lower alkyl group or a hydroxyl group, or a halogen atom, Hydroxyl group, amino group, alkylamino group, trifluoromethyl group, lower alkyl group, lower alkoxyl group and nitro group It is a phenyl group or a 2- (or 3- or 4-) pyridyl group which may be substituted with a group. n is 0, 1, 2, 3 or 4. ] 2. N-cyano-N 'represented by the following formula (1'):
A process for producing a -substituted-pyridinecarboximidamide compound, which comprises treating an amide compound represented by the following formula (2 ') with a dehydration condensing agent, and then reacting it with cyanamide. ) N-cyano-N'- represented by
A process for producing a substituted-arylcarboximidamide compound. [Chemical 3] [Chemical 4] [In the formulas (1 ′) and (2 ′), Ar ′ is a (2- or 3- or 4-) pyridyl group which may be substituted with an amino group, and R ^{1 ′} is substituted with a halogen atom. Is a good phenyl group. n ′ is 2. ]