JP3252483B2 - Method for producing tricyclic triazolo derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a tricyclic triazolo derivative which is useful as an intermediate for producing pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art The present inventors have proposed an antihistamine effect and anti-P
As a result of searching for a drug having an AF action, as an example, in PCT / JP92 / 00523,
The following general formula (IV)

Embedded image [Wherein, R ⁴ is hydrogen, lower alkyl, or carbon number 3 to
5 represents cycloalkyl, R ⁵ and R ⁶ each represent hydrogen, lower alkyl, lower alkoxy or halogen, W represents C ＝ O, CR ⁷ R ⁸ (R ⁷ and R ⁸ represent hydrogen and lower alkyl, respectively) A represents 1 to 5 carbon atoms.
Represents a saturated or unsaturated alkylene, and may contain a hetero atom. l represents 0 to 2, n represents 1 to 3,
Represents a single bond or a double bond, Y represents N or C, Z is C (B) Ar ¹ Ar ² (B is hydrogen, hydroxy or methoxy, Ar ¹ and Ar ² are each
Hydrogen, representing substituted or unsubstituted aryl), CAR
¹ Ar ² (Ar ¹ and Ar ² are the same as above), O-CHA
r ¹ Ar ² (Ar ¹ and Ar ² are the same as described above) or a condensed aromatic ring].
[4,3-a] It has been reported that a quinoxaline derivative is a compound having both actions, and a synthetic intermediate thereof represented by the following general formula (III):

Embedded image (Wherein R ¹ and R ² each represent hydrogen, lower alkyl, lower alkoxy, or halogen, and R ³ represents hydrogen, lower alkyl, cycloalkyl having 3 to 5 carbon atoms, or substituted or unsubstituted aryl. The method for producing the tricyclic triazolo derivative represented by the following formula is also exemplified.

[0003]

SUMMARY OF THE INVENTION However, PCT
/ II / JP92 / 00523.
The method for producing the tricyclic triazolo derivative of I) is not satisfactory because a sulfur compound having a strong toxicity and a bad smell is used and a special reactor is required.

[0004]

Means for Solving the Problems To overcome these drawbacks, the present inventors have made intensive studies, and as a result, have found that the general formula (I)
The present inventors have found a novel method for synthesizing the tricyclic triazolo derivative of II) and completed the present invention. That is, the present invention relates to a compound represented by the general formula (I):

Embedded image (Wherein R ¹ and R ² each represent hydrogen, lower alkyl, lower alkoxy or halogen); and an orthophenylenediamine derivative represented by the general formula (II):

Embedded image (Wherein R ³ represents hydrogen, lower alkyl, cycloalkyl having 3 to 5 carbon atoms, or substituted or unsubstituted aryl) 2- (chloromethyl) -1,3,4-oxadiazo By reacting the compound with the following general formula (II)
I)

Embedded image (Wherein R ¹ , R ² , and R ³ have the same meanings as described above).

The orthophenylenediamine derivative (I) used in the present invention includes, for example, orthophenylenediamine, 4,5-dimethylorthophenylenediamine, 4,5-
Examples include dimethoxyorthophenylenediamine and 4,5-dichloroorthophenylenediamine.

[0006] The 2- (chloromethyl) -1,3,3
As the 4-oxadiazol derivative (II), for example, 2-
(Chloromethyl) -5-methyl-1,3,4-oxadiazol,
2- (chloromethyl) -5-ethyl-1,3,4-oxadiazo-
2- (chloromethyl) -5-propyl-1,3,4-oxadiazol, 2- (chloromethyl) -5-isopropyl-1,3,4-oxadiazol, 2- (chloromethyl) -5-butyl-1,3,4-
Oxadiazol, 2- (chloromethyl) -5-phenyl-1,3,
4-oxadiazol and the like.

The tricyclic triazolo derivative (III) which is the object of the present invention includes 4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, 1-methyl-4,5 -Dihydro
[1,2,4] triazolo [4,3-a] quinoxaline, 1,6,7-trimethyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, 1-methyl -6,7-dichloro-4,5-dihydro [1,
2,4] triazolo [4,3-a] quinoxaline, 1-methyl-6,7-
Dimethoxy-4,5-dihydro [1,2,4] triazolo [4,3-a]
Quinoxaline, 1-ethyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, 1-propyl-4,5-dihydro
[1,2,4] triazolo [4,3-a] quinoxaline, 1-isopropyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline, 1-phenyl-4,5 -Dihydro [1,2,4] triazolo
[4,3-a] quinoxaline, 1- (2-furyl) -4,5-dihydro
[1,2,4] triazolo [4,3-a] quinoxaline and 1- (2-thienyl) -4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline .

The base used in the present invention includes potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like, and preferably potassium carbonate and sodium carbonate.

The reaction solvent used in the present invention includes, for example, methanol, ethanol, propanol and butanol.
, Pentanol, hexanole, 2-ethoxyethanol
Lower alcohols such as dimethylformamide,
Examples include amides such as dimethylacetamide.

In the present invention, the orthophenylenediamine derivative is preferably used in an amount of 1 to 4 times the molar amount of the 2- (chloromethyl) -1,3,4-oxadiazol derivative.
It is desirable to use 1.5 to 3 times mol. The amount of the base to be used is not particularly limited, but is 2- (chloromethyl) -1,3,
It is preferable to use 1.1 to 2 times mol of the 4-oxadiazol derivative.

The reaction temperature ranges from 0 ° C. to the boiling point of the solvent, preferably from 50 ° C. to 100 ° C., and the reaction time varies depending on the solvent used and the reaction temperature, but ranges from 1 to 60 hours.

By using the tricyclic triazolo derivative (III) obtained in the present invention, PCT / JP92 / 0
0523, antihistamine, anti-P
A 4,5-dihydrotriazolo [4,3-a] quinoxaline derivative (IV) having an AF function can be easily produced.

[0013]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Reference Example 1 1-acetyl-2-chloroacetylhydrazine

Embedded image Acetohydrazide 99.97 g (1.35 mol), sodium carbonate 8
4.65 g (0.799 mol) was dissolved in water and cooled to 0 ° C. After 161.72 g (1.43 mol) of chloroacetyl chloride was added dropwise over 2 hours, the mixture was stirred at room temperature for 1 hour. The precipitated crystals were separated by filtration and recrystallized from 500 ml of ethanol-water (2: 1) to give the title compound.
25 g were obtained.

Colorless crystals mp: 154-157 ° C IR (KBr) cm ^-1 : 3202,3058,3032,1640-1570,1504,1375,12
^{76,1241,1141,1004,930,785,723,632,565,472 1 HNMR (CD3OD) δ:} 4.12 (2H, s), 2.00 (3H, s)

Reference Example 2 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol

Embedded image 17.75 g (0.118 mol) of 1-acetyl-2-chloroacetylhydrazine was added to 58 g (0.38 mol) of phosphorus oxychloride, and the mixture was stirred at 110 ° C. for 30 minutes. After distilling off excess phosphorus oxychloride under slightly reduced pressure, distillation was performed under reduced pressure at 1 mmHg. The fraction was dissolved in ether, washed with a 10% aqueous sodium carbonate solution and saturated saline, and dried over magnesium sulfate. After distilling off the ether, distillation under reduced pressure was performed to obtain 6.93 g of the title compound.

Colorless liquid bp: 63-64 ° C./0.3 mmHg IR (Neat) cm ^-1 : 3028,1591,1572,1435,1396,1357,1272,12
^{28,1054,1000,980,959 768,752,677,625 1 HNMR (CDCl3) δ} : 4.68 (2H, s), 2.57 (3H, s)

Reference Example 3 2- (chloromethyl) -5-ethyl-1,3,4-oxadiazol

Embedded image The same reaction as in Reference Example 1 was performed except that propionylhydrazine was used instead of acetohydrazide, and then the same reaction was performed as in Reference Example 2 except that 1-propionyl-2-chloroacetylhydrazine was used instead of 1-acetyl-2-chloroacetohydrazine. The title compound was obtained by carrying out a similar reaction.

Colorless liquid bp: 58-59 ° C./0.02 mmHg IR (neat) cm ^-1 : 2988,1589,1568,1460,1433,1388,1216,11
^{93,1027,1006,988,760,663 1 HNMR (CDCl3) δ:} 4.68 (2H, s), 2.91 (2H, q, J = 7.5Hz), 1.40
(3H, t, J = 7.5Hz)

Reference Example 4 2- (chloromethyl) -5-propyl-1,3,4-oxadiazo-
Le

Embedded image The same reaction as in Reference Example 1 was performed except that butyrylhydrazine was used instead of acetohydrazide, and then Reference Example 2 was performed except that 1-butyryl-2-chloroacetylhydrazine was used instead of 1-acetyl-2-chloroacetohydrazine. The title compound was obtained by carrying out the same reaction as in.

Colorless liquid bp: 70-72 ° C / 0.4 mmHg IR (neat) cm ^-1 : 2972,2940,2880,1586,1568,1464,1433,13
^{81,1241,1189,1027,984,754 1 HNMR (CDCl3) δ:} 4.68 (2H, s), 2.86 (2H, t, J = 7.5Hz), 2.1-
1.6 (1H, m), 1.04 (3H, t, J = 7.5Hz)

Reference Example 5 2- (chloromethyl) -5-isopropyl-1,3,4-oxadiazol

Embedded image The same reaction as in Reference Example 1 except that isobutyrylhydrazine was used instead of acetohydrazide, and then Reference Example except that 1-isobutyryl-2-chloroacetylhydrazine was used instead of 1-acetyl-2-chloroacetohydrazine. The title compound was obtained by carrying out the same reaction as in 2.

The colorless liquid bp: 53-54 ℃ / 0.2mmHg IR ( neat) cm -1: 2980,1586,1564,1369,1152,1025,752,659 1 HNMR (CDCl3) δ: 4.68 (2H, s), 3.21 (1H, quint, J = 7Hz), 1.
41 (6H, d, J = 7.0Hz)

Reference Example 6 2- (chloromethyl) -5-phenyl-1,3,4-oxadiazo-
Le

Embedded image 8.87 g (65.2 mmol) of benzoylhydrazine and 11.34 g (71.8 mmol) of ethyliminochloroacetate hydrochloride in ethanol
It was added to 100 ml and refluxed for 4 hours. After cooling, add water,
The precipitated crystals were separated by filtration to obtain 9.96 g of the title compound.

Colorless crystals mp: 118-120 ° C IR (KBr) cm ^-1 : 3030,2974,1576,1553,1487,1452,1247,11
66,1071,781,760,745 708 ¹ H NMR (CDCl3) δ: 8.2-8.0 (2H, m), 7.6-7.4 (3H, m), 4.78 (2
H, s)

EXAMPLE 1 1-Methyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline (1)

Embedded image 2.23 g (20.6 mmol) of O-phenylenediamine, potassium carbonate
While 2.43 g (17.6 mmol) was suspended in 30 ml of n-butanol, 1.55 g (11.7 mmol) of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol was added dropwise. . After refluxing for 46 hours,
Upon cooling, the inorganic salts were filtered off. The solvent was distilled off and recrystallized from acetone to obtain 0.94 g of the title compound.

The pale yellow crystals mp: 181-183 ℃ IR (KBr) cm -1: 3230,1562,1510,1499,1431 1 HNMR (CDCl3) δ: 7.50-6.82 (4H, m), 4.58 (2H, d , J = 1.8),
4.18 (1H, brs), 2.78 (3H, s) MS (EI): 186 (M +, base peak), 144,118

Example 2 1-ethyl-4,5-dihydro [1,2,4] triazolo [4,3-a] quinoxaline (2)

Embedded image Example 1 except that 2- (chloromethyl) -5-ethyl-1,3,4-oxadiazol was used instead of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol The title compound was obtained by carrying out the same reaction as in.

Pale yellow crystal mp: 147-151 ° C IR (KBr) cm ^-1 : 3264,1562,1522,1499,1437,1315,745,420
^{cm -1 1 HNMR (CDCl3) δ} : 7.43 (1H, m), 7.3-6.8 (3H, m), 4.57 (2H,
d, J = 1.8), 4.16 (1H, brs), 3.12 (2H, q, J = 7.5), 1.51 (3H, t, J
= 7.3) MS (EI): 200 (M +, base peak), 144,118

Example 3 1-propyl-4,5-dihydro [1,2,4] triazolo [4,3-a]
Quinoxaline (3)

Embedded image Example 1 except that 2- (chloromethyl) -5-propyl-1,3,4-oxadiazol was used instead of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol The title compound was obtained by carrying out the same reaction as in.

Pale yellow crystal mp: 116-120 ° C IR (KBr) cm ^-1 : 3242,2970,1615,1562,1524,1502,1460,14
^{31,1299,750,420 1 HNMR (CDCl3) δ:} 7.42 (1H, d, J = 7.9), 7.3-6.8 (3H, m), 4.5
7 (2H, d, J = 1.8), 4.16 (1H, brs), 1.91 (2H, t, J = 7.4), 2.2-1.
7 (2H, m), 1.10 (3H, t, J = 7.3) MS (EI): 214 (M +, base peak), 144,118

Example 4 1-Isopropyl-4,5-dihydro [1,2,4] triazolo [4,3
-a] Quinoxaline (4)

Embedded image 2- (chloromethyl) -5-isopropyl-1,3,4- instead of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol
The title compound was obtained by performing the same reaction as in Example 1 except that oxadiazol was used.

Pale yellow crystal mp: 126-129 ° C IR (KBr) cm ^-1 : 3254,2974,1562,1524,1508,1460,1431,13
^{25,1301,1278,745 1 HNMR (CDCl3) δ:} 7.47 (1H, d, J = 7.5), 7.3-6.8 (3H, m), 4.5
5 (2H, d, J = 1.8), 4.32 (1H, brs), 3.7-3.2 (1H, m), 1.51 (6H,
s) MS (EI): 214 (M +, base peak), 144,118

Example 5 1-phenyl-4,5-dihydro [1,2,4] triazolo [4,3-a]
Quinoxaline (5)

Embedded image Example 1 except that 2- (chloromethyl) -5-phenyl-1,3,4-oxadiazol was used instead of 2- (chloromethyl) -5-methyl-1,3,4-oxadiazol The title compound was obtained by carrying out the same reaction as in.

[0035] Colorless crystals mp: 136-141 ℃ IR (KBr) cm -1: 1510,1468,1423,756,702 1 HNMR (CDCl3) δ: 7.7-7.4 (5H, m), 7.2-6.5 (4H, m) , 4.64 (2
H, s) MS: 248 (M +, base peak), 144,118

[0036]

According to the present invention, the tricyclic triazolo derivative (III) useful as an intermediate for the production of medicines, agricultural chemicals, etc.
Can be easily and efficiently produced without using a sulfur compound having a strong toxicity and a bad smell.

Claims (1)

(57) [Claims] 1. A compound represented by the following general formula (I) in the presence of a base: (Wherein R ¹ and R ² each represent hydrogen, lower alkyl, lower alkoxy, or halogen), and an orthophenylenediamine derivative represented by the general formula (II): (Wherein R ³ represents hydrogen, lower alkyl, cycloalkyl having 3 to 5 carbon atoms, or substituted or unsubstituted aryl) 2- (chloromethyl) -1,3,4-oxadiazo And reacting the compound with the following general formula (III): (Wherein R ¹ , R ² and R ³ have the same meanings as described above).