HUT63406A - Process for producing tetrazolylacryl nitrile derivatives - Google Patents

Description

The present invention relates to a novel 3- (pyridylamino) -

Relates to the preparation of 2- (1H-tetrazol-5-yl) -acrylonitriles. These novel compounds are primarily preferred starting materials for antiallergic and anti-yeast agents.

It is known that 3- (1H-tetrazol-5-yl) -4H-pyrido [j. 2-α-pyrimidin-4-ones have valuable antiallergic and anti-ulcer properties (U.S. Patent Nos. 4,122,274 and 4,457,732), which are prepared from 3-cyano-4H-pyrido [1,2-a] pyrimidin-4-one or ethyl Reaction of N-cyano-3- (2-pyridylamino) acrylates with sodium azide in the presence of aluminum chloride is carried out in mild to moderate yields. A further method of preparing these compounds is the cyclization of ethyl 3- (2-pyridylamino) -N-2- (1H-tetrazol-5-yl) acrylates in polyphosphoric acid (U.S. Patent No. 4,474,953). A disadvantage of the latter process is that, in addition to the ring closure, the alkylation of the tetrazole ring also takes place partially under the reaction conditions.

The present invention is based on the discovery that 3- (1H-tetrazol-5-yl) -4H-pyrido [1,2-a] pyrimidin-4-one of formula (II) can be prepared in a simple manner and in good yield. ring closure of 3- (2-pyridylamino) -2- (1H-tetrazol-5-yl) acrylonitrile.

The present invention relates to a process for the preparation of compounds of the formula I, their geometric isomers, their tautomers and their hydrates

R is hydrogen, (C 1 -C 4) alkyl, halogen, hydroxy, nitro, carboxyl, (C 2 -C 5) alkoxycarbonyl or (C 7 -C 12) aralkoxy;

R 1 is hydrogen, C 1-4 alkyl, or halogen;

R 4 is hydrogen, C 1-4 alkyl, or

C 6 -C 10 aryl).

As used herein, the term "C 1-4 alkyl group, alone or in combination, for example alkoxy, is intended to include straight or branched chain aliphatic saturated C 1-4 hydrocarbon groups (e.g., methyl, ethyl, n-propylisopropyl, tert-butyl). -group). The term C 6 -C 10 aryl as used herein refers to phenyl or naphthyl optionally substituted with C 1 -C 4 alkyl. The term C 7-12 aralkoxy, as used herein, optionally means phenylalkoxy or naphthylalkoxy having C 1-4 alkyl.

The present invention also relates to the preparation of geometric isomers and tautomers of the compounds of formula (I). The structure of the geometric isomers is shown in formulas IA and IB. The structure of tautomers is illustrated in Reaction Schemes A and B.

According to the process of the present invention, (I)

- the novel compounds of formula 3, their geometric isomers and their tautomers, are prepared by:

a) 3-Cyano-4] pyrido- [1,2-a] pyrimidin-4-imine of formula (III) (wherein R 1, R 4 and R 4 are as defined above) with ammonium chloride and reacting in the presence of a solvent at a temperature of from 0 to 150 ° C, or

(b) reacting a compound of formula (IV) (wherein R, R 4 · and R 4 are as defined above) with an alkali azide in the presence of ammonium chloride and a solvent at a temperature of 0 to 150 ° C; or

c) a 2-aminopyridine of formula (V) (wherein R and R ^ are as defined above) with an orthoester of formula VI (wherein R ^ is as defined above, R 1-4 is C 1 -C 4 alkyl); and reacting with 2- (1H-tetrazol-5-yl) acetonitrile in the presence of anhydride and Lewis acid, or ^;

d) reacting a 2-aminopyridine of formula (V) wherein R and R 3 are as defined above with a compound of formula VII (wherein R 1 and r 3 are as defined above).

Preferably, the alkali azide is sodium azide.

If desired, dipolar aprotic solvents such as dimethylformamide are preferably used as the solvent.

The compound of formula I formed in the reaction (wherein R, R ¹ and R ² are as defined above) is either precipitated immediately from the reaction mixture or is added to a different solvent mixture. The product can be recovered from the reaction mixture by filtration or after removal of the solvent (e.g. by distillation).

The resulting compounds of Formula I (wherein R, R ¹ and R ² are as defined above) may be purified by conventional techniques (e.g., recrystallization, chromatography).

The starting compounds of formula (III) or (IV) (wherein R, R 1 and R ² are as defined above) are known in the literature or may be prepared analogously thereto. · _

The starting compounds of formula (V) and (VI) (wherein R 1, R ² and R ⁵ are as defined above) are commercially available, while the compound of formula VII (wherein R ² and R 1 are as defined above) are commercially available. 1) may be prepared in an analogous manner to alkoxymethylenemalononitrile known in the art.

The following examples further illustrate the process without limiting the invention to the examples.

- 5 EXAMPLES

Example 1

18.98 g (0.1115 mole) of 4-imino-4H-pyrido [1,2a-a] pyrimidine-3-carbonitrile with 7.25 g (0.1115 mole) of sodium azide and 6.1 g (0.1115 mole). ammonium chloride was stirred in 100 ml of dimethylformamide for 1 hour at 80 ° C. The dark red reaction mixture was poured into 300 ml of ice water at 80 ° C and then acidified to pH 3 with 35 ml of 10% hydrochloric acid. The precipitated material is suction filtered and washed with water. 21.34 g (89.8%) of 3- (2-pyridylamino) -2- (1H-tetrazol-5-yl) acrylonitrile are obtained, which is dissolved in ethanol, clarified with activated carbon and diluted with an equal volume of alcohol. Crystalline at 294-295 ° C.

Elemental analysis using the formula CgHyNy:

Calculated: C, 50.70; H, 3.31%; N, 45.99%; Found: C, 50.92; H, 3.18%; N, 46.09%.

Example 2

46.05 g (0.25 mol) of 9-methyl-4-imino-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile with 16.25 g (0.25 mol) of sodium azide and 13.37 g of 0.25 mol) of ammonium chloride was stirred in 250 ml of dimethylformamide for 1 hour at 80 ° C. The reaction mixture was cooled to 30 ° C, poured into 750 mL of ice water and then acidified to pH 5-6 with 17 mL of 96% acetic acid. The precipitated material is suction filtered and washed with water. 51.2 g

6 - (90.1%) of 3 - [(3-methyl-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile was obtained containing 1.25 moles of crystalline water. Crystalline at 322 ° C.

Elemental analysis based on the formula 1.25 H2O:

Found: C, 48.10%; H, 4.64%; N, 39.26%;

Found: C, 48.37; H, 4.55%; N, 39.65%.

Example 3

18.4 g (0.1 mole) of (£ (6-methyl-2-pyridyl) amino) methylene] propanedonitrile with 6.5 g (0.1 mole) of sodium azide and 5.4 g (0.1 mole) of ammonium Chloride was stirred in 100 ml of dimethylformamide for 1 hour at 80 DEG C. The yellow reaction mixture was poured into 350 ml of water and acidified to pH 3 with 20 ml of 10% hydrochloric acid, and the finely divided crystalline material was suction filtered and washed with water. 92 g (92.2%) of 3 - [(6-methyl-2-pyridyl) -arphino] -2- (1H-tetrazol-5-yl) -acrylonitrile are obtained, which is a crystal decomposed at 251 ° C.

Elemental analysis using the formula:

Calculated: C, 52.86; H, 3.99%; N, 43.15%;

Found: C, 52.86; H, 3.87%; N, 42.46%.

Example 4

6.26 g (0.0316 mol) of (1 - [(6-methyl-2-pyridyl) amino] ethylidene) -propanedonitrile, 2.10 g (0.0316 mol) of sodium azide and 1.71 g (0.0316 mol) of ammonium CH 2 Cl 2 in DMF (ml) for 3 hours at 80 ° C. Pour the light yellow reaction mixture into 100 mL of water. The crystalline material which precipitates during cooling is suctioned off on a sintered glass filter and washed with water.

4.65 g (61.0%) of N-methyl-3- (6-methyl-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile are obtained, which is recrystallized from dimethylformamide at 238-240 ° C. Crystalline at C. Elemental analysis using the formula:

Calculated: C, 54.76; H, 4.60%; N, 40.64%;

Found: C, 54.2; H, 4.88%; N, 40.21%.

Example 5

15 mg (0.074 mol) of 7-chloro-4-imino-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile with 4.81 g (0.074 mol) of sodium azide and 3.95 g (0.074 mol) of ammonium chloride 75 The reaction mixture was stirred in 110 ml of dimethylformamide at 110 ° C for 1.5 hours. The reaction mixture was poured into 225 ml of water / The crystalline material which precipitated on cooling was filtered off with suction and washed with water. 12.13 g (66.2%) of 3 - [(5-chloro-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile are obtained, which is recrystallized from 50% ethanol to give 318-320. Crystalline at ° C.

Elemental analysis of Ο ^ Η ^ ΝγΟΙ 3H _? Using the formula 0:

Calculated: C, 35.8; H, 4.0%; N, 32.5%; Cl, 11.77%; Found: C, 35.26%; H, 3.60%; N, 32.05%; Cl, 11.63%.

Example 6

5.53 g (0.03 mol) of 7-methyl-4-imino-4H-pyrido [1,2-a] pyrid ····

8 midin-3-carbonitrile with 1.95 g (0.03 mol) of sodium azide and

1.6 g (0.03 mol) of ammonium chloride were stirred in 60 ml of dimethylformamide for 1 hour at 100 ° C. The light brown reaction mixture was cooled to 30 ° C, poured into ice water (180 ml) and acidified to pH 2-3 with 5 ml of 1: 1 hydrochloric acid. The precipitated material is suction filtered and washed with water. 5.46 g (80.1%) of 3 - [(5-methyl-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile are obtained, which is a crystal decomposed at 307 ° C.

Elemental analysis for C ^ HH ^ NyN: requires: C, 52.86; H, 3.99%; N, 43.15%; Found: C, 52.57; H, 3.90%; N, 43.20%;

Example 7

5.53 g (0.03 mol) of 8-methyl-4-imino-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile with 1.95 g (0.03 mol) of sodium azide and

1.6 g (0.03 mol) of ammonium chloride were stirred in 60 ml of dimethylformamide for 2 hours at 100 ° C. The reaction mixture was poured into water (180 ml) at room temperature and the orange-red solution was acidified to pH 3-4 with 8 ml of 1: 1 hydrochloric acid. The precipitated material is suction filtered and washed with water. 5.97 g (87.5%) of 3 - [(4-methyl-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile are obtained, which is crystallized from dimethylformamide at 289-290 ° C. crystal on.

Elemental analysis based on the formula ^c 10 ^h 9 ⁿ 7. ·

- 9 calculated: C, 52.86%; H, 3.99%; N, 43.15%;

found:

C, 52.96%; H, 3.95%; N, 43.37%.

Example 8

5.95 g (0.03 mol) of (4,6-dimethyl-2-pyridyl) -aminomethylene-propanedonitrile with 1.95 g (0.03 mol) of sodium azide and

After stirring at 100 ^DEG C for 3 hours in 60 ml of dimethylformamide 1,6g (0.03 mol) of ammonium chloride. The reaction mixture was poured into 180 ml of water at 60 ° C and acidified to pH 5 with 10 ml of 10% hydrochloric acid. The finely divided crystalline material is filtered off with suction and washed with water.

6.47 g (89.4%) of 3 - [(4,6-dimethyl-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile are obtained, which is crystallized at 238-239 ° C. . . Elemental analysis for C ₁₁ H ₁₁ M ₇ . 1/2 H 2 O: Calculated: C, 52.79; H, 4.83%; N, 39.18%; Found: C, 52.65%; H, 4.83%; N, 39.15%.

Example 9

5.58 g (0.03 mol) of 9-hydroxy-4-imino-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile were treated with 1.95 g (0.03 mol) of sodium azide and 1.60 g of g (0.03 mol) in ammonium chloride (60 ml) was stirred in dimethylformamide for 3 hours at 100 ° C. The reaction mixture was poured into water (180 ml) at room temperature and acidified to pH 3 with 13 ml of 10% hydrochloric acid. The precipitated material is suction filtered and washed with water.

··· «* · · · ♦♦ ·· ···· · · · · · ···

10.52 g (94.9%) of 3- [3- (3-hydroxy-2-pyridyl) amino] -2- (1H-tetrazol-5-yl) acrylonitrile are obtained, which decomposes at 258-259 ° C. crystal.

Elemental Analysis C9H7N7Q. Based 1/3 H ₂ 0: Calcd; C, 45.96%; H, 3.28%; N, 41.68%;

Found: C, 45.97; H, 3.00%; N, 42.17%.

Example 10

2.76 g (0.01 mol) of 9-benzyloxy-4-imino-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile 0.65 g (0.01 mol) of sodium azide and 0.53 g (0.01 mol) of ammonium chloride was stirred in 20 ml of dimethylformamide for 1 hour at 100 ° C. The lemon yellow reaction mixture was cooled to room temperature, poured into water (60 mL) and acidified to pH 3 with 5 mL of 10% hydrochloric acid. The precipitated material is filtered off with suction and washed with water. -

2.77 g (87%) of 3- _[> (3-benzyloxy-2-pyridyl) amino-2- (lH · - tetrazol-5-yl) acrylonitrile is obtained, which decomposed 246-248 ° C crystals.

Elemental analysis using the formula C ^ H ^ NyO ·.

Calculated: C, 60.2%; H, 4.10%; N, 30.72%;

Found: C, 60.14; H, 4.10%; N, 31.04%.

Example 11

4.35 g (0.015 mol) of 9-benzyloxy-2-methyl-4-imino-4H-pyrido [1,2-a] pyrimidine-3-carbonitrile, 0.975 g (0.015 mol) · * · ♦ ··

- 11 ml of sodium azide and 0.8 g (0.015 mol) of ammonium chloride were stirred in 30 ml of dimethylformamide for 1 hour at 100 ° C.

The reaction mixture was cooled to room temperature, poured into 90 ml of water and then acidified with 3 ml of 10% hydrochloric acid. The precipitated material is suction filtered and washed with water. 2.75 g (55%) of 3-methyl-3 - [(3-benzyloxy-2-pyridyl) -amino] -2- (1H-tetrazol-5-yl) -acrylonitrile are obtained, which is refluxed in 20 times abs. Crystalline at ° C.

Elemental analysis using the formula:

Found: C, 61.25%; H 4.54% f N 29.41%; Found: C, 61.39; H, 4.39%; N, 29.94%.

Claims (6)

Claims A process for the preparation of compounds of the formula I, their geometric isomers, their tautomers and their hydrates, wherein R is hydrogen, (C 1 -C 4) alkyl, halogen, hydroxy, nitro, carboxyl, (C 2 -C 5) alkoxycarbonyl or (C 7 -C 12) aralkoxy, R 1 is hydrogen, C 1 -C 4 alkyl or halogen, R 4 is hydrogen, C 1 -C 4 alkyl or C 6 -C 10 aryl, characterized in that a) an ammonium salt of a 3-cyano-4H-pyrido [1,2-a] pyrimidin-4-imine of formula (III) wherein R, R * * and R 4 are as defined herein; with alkali azide in the presence of chloride, or (b) reacting a compound of formula (IV) wherein R, R 1 · and R ³ are as defined herein with ammonium chloride in the presence of ammonium chloride; or c) a 2-aminopyridine of formula (V) wherein R and R 1 · are as defined above for an orthoester of formula (VI) - wherein R ³ is as defined above and R ³ * · ···· 4 · * 4 · · -C 1-4 alkyl and 2- (1H-tetrazol-5-yl) acetonitrile, or d) a 2-aminopyridine of formula (V) wherein R and R R are as defined in the above formula - with a compound of formula (VII) wherein R ^ is as defined in process (c) - with. Processes a) and b) according to claim 1, characterized in that the alkali azide is sodium azide. Processes a) and b) according to claim 1, characterized in that the reaction is carried out in a solvent medium. 4. A process according to claim 3, wherein the solvent is dimethylformamide. Processes a) and b) according to claim 1, characterized in that the reaction is carried out at a temperature of from 0 to 150 ° C. Compounds of the formula I, their geometric isomers, their tautomers and their hydrates, wherein R, R 1 and R are as defined in claim 1.