HU213117B - Process for producing n-cyano-n`-(4-pyridyl)-o-phenyl-isourea - Google Patents

Abstract

The present invention relates to a novel N-cyano compound of formula (I) for the preparation of pinaN '- (4-pyridyl) -O-phenylisocarbamide (TV). For the preparation of cidyl (I). NCN CH, H - C - NH - CH - 6- II NCN Ah, CH, CH (IV) HU 213117 B Scope of the description: 4 pages (including 1 sheet)

Description

The present invention relates to a process for the preparation of a novel N-cyano-N '(4-pyridyl) -O-phenylisocarbamide of formula (I).

The compound of formula (I) can be used as an intermediate in the preparation of N-cyano-N '(4-pyridyl) -N- (1,2,2-trimethylpropyl) guanidine of formula IV having an antihypertensive activity, known internationally as pinacidil. . Pinacidil is disclosed in U.S. Pat. German Patent Publication No. 4,666,151, but no reference is made to the compound of formula (I) in the anteriority.

It has now been found that the novel compound of formula (I) can be prepared simply and economically by reacting the 4-aminopyridine of formula (II) with the diphenyl N-cyanocarbonimidate of formula (ΙΠ).

The reaction of 4-aminopyridine (II) with diphenyl-N-cyanocarbonimide (III) can be carried out in the presence or absence of an organic solvent by melting the compounds. The organic solvent may be a polar or apolar, protic or aprotic solvent. Preferably, chlorinated hydrocarbons such as dichloromethane or chloroform or ethers such as tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether or 2-methoxyethanol are used as the reaction medium, and the reaction is usually carried out at room temperature to the reflux temperature of the solvent.

In the absence of a solvent, the compounds of formula (II) and (old) are reacted, generally at a temperature of about 100 ° C.

The starting compounds are generally reacted in equimolar amounts or an excess of one of the compounds of formula (ΠΙ) is preferred.

The reaction of the compounds of formula (Π) and (III) takes place relatively quickly, usually between 30 and 180 minutes. After completion of the reaction, the product of formula (I) is usually precipitated from the reaction mixture containing the organic solvent and can be isolated by filtration.

In a melt reaction, the product of formula (I) can be isolated after the addition of an organic solvent. If the product of formula (I) does not precipitate but remains in solution, the solvent is evaporated and the residue is crystallized from a suitable organic solvent.

Both 4-aminopyridine (II) and diphenyl-N-cyanocarbonimidate (ΙΠ) are commercially available.

The process of the invention is extremely easy to carry out and provides a yield of 78%. The process is environmentally friendly since its only by-product, phenol, can be recovered from the mother liquor after isolation of the product after evaporation and can be reused. The compound of formula (I) is reacted with 2-amino-3,3-dimethylbutane to give the pinacidil of formula (IV). The invention is illustrated in detail by the following examples:

Example 1

N-cyano-N '- (4-pyridyl) -O-phenyl-isourea

A mixture of 16.7 g (0.07 mol) of diphenyl N-cyanocarbonimidate, 6.6 g (0.07 mol) of 4-aminopyridine and 35 ml of tetrahydrofuran was heated at 50 ° C for 1 hour. The starting compounds are first dissolved and then the product crystallizes out. The reaction mixture is cooled to 10 ° C, the precipitated crystalline material is filtered off, washed with 2 x 10 ml of cold tetrahydrofuran and then dried at 50 ° C under an infrared lamp. 13 g (78%) of the title compound are obtained, m.p. 164-166 ° C.

Example 2

N-Cyano-N-14-Pyridyl-O-Phenylisocarbamide The procedure of Example 1 was repeated except that the reaction was carried out at 20 ° C for 3 hours instead of 50 ° C. 12.5 g (75%) of the title compound are obtained, m.p. 164-166 ° C.

Example 3

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide The procedure of Example 1 was repeated except that the reaction was carried out at the boiling point of tetrahydrofuran at 66 ° C for 45 minutes instead of 50 ° C. 11.7 g (70%) of the title compound are obtained, m.p. Mp: 164-166 ° C.

Example 4

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide In the same manner as in Example 2, except that 0.0105 moles of diphenyl-N-cyanocarbonimidate were used instead of 0.010 moles (25, 0 g). 12.7 g (76%) of the title compound are obtained, m.p. 164-166 ° C.

Example 5

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide The procedure of Example 3 was repeated except that dichloromethane was used instead of tetrahydrofuran and the reaction was carried out at its boiling point (40 ° C).

1.5 hours. The reaction mixture was evaporated, the residue was stirred with 50 ml of diethyl ether and the precipitated product was filtered off. 10.3 g (62%) of the title compound are obtained, m.p. 164-166 ° C.

Example 6

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide Example 5 was repeated except that dichloroethane was used in place of dichloromethane and the reaction was carried out at reflux for 1 hour. 11.5 g (69%) of the title compound are obtained, m.p. 164-166 ° C.

Example 7

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide The procedure of Example 5 was repeated except that chloroform was used in place of dichloromethane. 10.0 g (60%) of the title compound are obtained, m.p. 164-166 ° C.

The mixture is heated at 110 ° C for 30 minutes. Yield: 8.7 g (52), m.p. 164-166 ° C.

Example 8

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide In the same manner as in Example 3, 50 ml of diethyl ether were used instead of tetrahydrofuran and the reaction was carried out for 1.5 hours. 10.2 g (61%) of the title compound are obtained, m.p. 164-166 ° C.

Example 9

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide In the same manner as in Example 5 except that 20 ml of diethylene glycol dimethyl ether are used instead of dichloromethane and the reaction is carried out for 30 minutes. 100 ° C. 105 g (63%) of the title compound are obtained, m.p. 164-166 ° C.

Example 70

N-Cyano-N '- (4-pyridyl) -O-phenylisocarbamide In the same manner as in Example 5, except that 25 ml of 2-methoxyethanol (methylcellosolve) was used instead of dichloromethane, the reaction was repeated 77. example

N-cyano-N '- (4-pyridyl) -O-phenyl-isourea

Diphenyl N-cyanocarbonimidate (1.67 g, 0.007 mole) was mixed well with 4-aminopyridine (0.66 g, 0.007 mole) and then stirred in an oil bath at 100 ° C for 1 hour. To the cooled melt was added diethyl ether (5 mL) and the precipitated product was filtered off. 10.0 g (60%) of the title compound are obtained.

Claims (1)

A process for the preparation of N-cyano-N '- (4-pyridyl) -O-phenylisocarbamide of formula (I) comprising reacting 4-aminopyridine of formula (Π) with diphenyl-N-cyanocarbonimidate (III).