JPH0285260A - Production of imidazole derivative - Google Patents

Abstract

PURPOSE: To advantageously obtain an imidazole derivative by reacting, e.g. a compound such as N,N'-dicyano-N"-[2-(5-methylimidazol-4-ylmethylthio) ethyl]guanidine with a compound such as methylamine.

CONSTITUTION: A compound of formula I [wherein R¹ is lower alkyl; R² and R³ are each lower alkylene; X¹ is a halogen, mercapto, cyanamido, a nitrogen- containing 5-membered aromatic heterocyclic-N-yl group, or a group of formula II (wherein Z is hydroxyl or alkyl; n is 1 or 2)] is reacted with a compound of formula III (wherein R⁴ is lower alkyl) in a solvent such as methanol usually under cooling or at a temperature up to room temperature to obtain a compound of formula IV. Further, when a compound of formula I wherein X¹ is a halogen, a sulfino-group or a sulfo-group is used as the starting material, it is preferred to carry out the reaction in the presence of a base such as triethylamine, pyridine, etc. Also, when a compound of formula I wherein X¹ is a mercapto group is used as the starting material, it is preferred to carry out the reaction in the presence of a compound of a heavy metal such as mercury, etc.

COPYRIGHT: (C)1990,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION This invention is based on the general formula (wherein R1 and R4 are lower alkyl Ml" and R
No. 3 relates to a novel method for producing imidazole derivatives or salts thereof, in which the lower alkylene groups are represented by different colors, and the formula is as follows.

[In the formula, R1, n*, R3 and R4 have the same meanings as before, and xl is a halogen, a mercapto group, a nitrogen-containing 5-membered aromatic complex ring -N-yl group, or a group of the formula 5-(0)n- Z (where Z is a hydroquine group or an alkyl group, n is 1 or 2
The method of the present invention is carried out by reacting compound (II) with compound (1).

In the starting compound (11), the lower alkyl group represented by R' may be a linear or branched group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, etc. Examples of lower alkylene groups represented by R' and R3 include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 2-
Linear or branched alkylene groups such as methyltrimethylene and 2,2-dimethyltrimethylene are mentioned,
The lower alkylene groups of R1 and R3 may be the same or different.

Examples of the lower alkyl group represented by R4 in the other raw material compound (1) include the same groups as the lower alkyl group of R1 described above. Further, the halogen represented by xi includes chlorine, bromo, iodo, etc., and the nitrogen-containing n5-membered aromatic complex -N~yl group includes 1-pyrazolyl,! −
imidazolyl, 1-pyrrolyl, 1,2,3-triazol-1-yl, 3,5-tumethyl-1-pyrazolyl, 1
．． 2゜4-triazol-4-yl etc., formula-5(0)
Groups represented by nZ include sulfino group, sulfo group,
Alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl, tertiary butylsulfinyl, pentylsulfinyl, hexylsulfinyl, and methylsulfonyl;
Examples include alkylsulfonyl groups such as ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tertiary butylsulfonyl, pendelsulfonyl, and hexylsulfonyl.

This reaction is usually carried out in a solvent, such as alcohols such as methanol, ethanol, propatool, butanol, isopropyl alcohol, acetonitrile,
Examples include methylene chloride, dimethylformamide, dimethylsulfoxide, nooxane, and tetrahydrofuran. The reaction temperature is usually carried out under cooling or at room temperature.

In addition, in the above general formula (In), xl is halogen,
When using a compound with a sulfino group or a sulfo group as a raw material, triethylamine, pyridine,
N-methylaniline, 1,5-diazabicyclo[5,4
,0]-5-undecene or the like, and when a compound in which xl is a mercapto group in the general formula (III) is used as a raw material, Preferably, the reaction is carried out in the presence of a heavy metal compound such as mercury, silver or lead. In addition, the raw material compound (
Among III), compounds in which Xl is a sulfino group or a sulfo group can also be used in the form of a salt, and such salts include alkali metal salts such as sodium and potassium salts,
Representative examples include 1,5-diazabicyclo[5,4,0L-5 undecene salt and the like.

Imidazole derivative (1) produced by the method of this invention
) can be isolated from the reaction mixture and purified by a conventional method, and the free compound (1) may be converted into a desired salt such as a hydrochloride by a conventional method.

Incidentally, all of the raw material compounds used in the method of the present invention can be produced by the methods described in the Examples or by methods similar thereto.

Next, the method of the present invention will be explained using examples.

Example 1 (1) Cyanamide (18,59) and N-cyanoS-methyl-N'-[2-(5-methylimidazol-4-ylmethylthio)edyl]isothiourea (lO,7
6 g) of sodium metal (1,019) was added to an ethanol solution (+2010
WC) and adjusted to pl-145 with 10% hydrochloric acid, and then cooled in a water bath for 1 hour. Filter the precipitate, wash with water,
Upon drying, the crude product (7439) is obtained. When this product is recrystallized from a mixture of ethanol and water (ll), the mp18
3-186°C NN-Anno-N”-[2-(5-
Methylimidazol-4-ylmethylthio)ethyl]guaninone (5,179) is obtained. Yield 49.2%.

Elemental analysis C,, I-1,3N7S Calculated value: C45,61,1-14,98,N37.2
4. S12.18 experimental value C45,59,H4,99N
36.51 S12.17[1e(Nunoyor) νmax: 3330.3110.2660,2170
．． 1575, 1518.14351378134813
101230867ca'NMR(DMSOda+D
to) δ: 2.32 (3H, s), 2.4-2.7 (211,
m).

3.26 (2H,L, J = 71(z)3.83
(21(,s), 8.77(IH,5) (2) N,N'-Zineano-N''-[2(5-methylimidazol-4-ylmethylthio)ethyl]guaninone (5
27ff9) in an ethanol solution of methylamine (40%
, 3.1 g) and stirred at room temperature for 47 hours. The reaction solution was concentrated under reduced pressure, and the residue was pulverized with acetonitrile. Undissolved starting material is filtered off and the filtrate is concentrated under reduced pressure.

The residue is chromatographed on 7 silica gel and eluted with a mixture of acetonitrile and methanol (11+). The eluate was concentrated under reduced pressure, and the concentrated solution was subjected to silica gel thin layer chromatography [developing solvent: 28% ethyl acetate and methanol.
A mixture of aqueous ammonia (10.I:1)] and recrystallized from acetonitrile yielded mp135-137.
Obtain N''-noanor N-methyl N'-[2-(5-methylimidazol-4-ylmethylthio)ethyl]guaninone (1,0x9) at °C.

Example 2 (1) A solution of 2-(5-methylimidazol-.1-ylmethylthio)ethyl isothionoanate (prepared from its hydrochloride) (4,17y) in chloro (20 m
Q) with noanamide (1,05y) and 1,5-noazahinculo[5,4,03-5-undecene (3809
) to the chlorolum solution (50ffC) and stirred overnight. After concentrating the reaction solution, the residue was dissolved in water (30ffQ), washed with ether, treated with activated carbon, and adjusted to pI-15 with 10% hydrochloric acid under water cooling. The precipitate was collected by filtration. , washed with water and dried, N of mp158-161℃
-cyano-N”[2-(5-methylimidazole-4-
ylmethylthio)ethylcothiourea monohydrate (3,5
711).

Elemental analysis Ce H13N 5S 2・I-1, 0 calculated value: C39,54,115,53,N25.62. S
23.46 Experimental value C39,71,I! 5.44.
N2569. S 22.73In (Nunoyol) vmax: 3400327031302760265
0.2190.165215401470.14301
381.1362, 1278.12371217120
511Q31088967831cm'NMR(DM
SO-d, +-D, O) 62.32 (311, s), 2.4-2.8 (21-1
m) 3.0-3.67(2+-(1m), 3.87(2
H,s)8.9. '3(IH,5) (2) The monohydrate (765ffg) of N-cyano-N'-[2-(5medylimidazol-4-ylmethylthio)ethylthiourine obtained above Methylene chloride solution (7
After introducing dry hydrogen chloride gas into i12) for several minutes while cooling with water, phosphorus pentachloride (1,259) is added and stirred at room temperature for 3 hours. After concentrating the reaction mixture containing N''-noanorN-[1-(5methylimidazol-4-ylmethylthio)ethyl]chloropolmaminone and diluting the concentrate with methylene chloride (5-shoulder Q), - Cool to 5° C. Add methylamine in ethanol (40%, 15II
Add C) below 30°C and stir at room temperature for 20 hours. Filter the reaction mixture and concentrate the filtrate. Dilute the concentrate with acetonitrile and filter again. d and the liquid were concentrated to dryness, and the residue was subjected to column chromatography [silica gel
acetonitrile-methanol (4:1)] and further thin layer chromatography [silica gel, developing solvent: ethyl acetate-methanol-28% aqueous ammonia (10:1:
1)] and then recrystallized from acetonitrile to obtain N''-cyano-
N-methyl-N'-[2-(5methylimidazole-
4-ylmethylthio)edyl]guanidine (10,4m
l? ). Yield 1.5%.

Patent Applicant: SmithKline Corporation Procedures Official Document (Method) 1. Indication of the Case 1999 Patent Application No. 114018 2. Invention 9
Name: Process for producing imidazole derivatives 3, relationship with the amended case Name of patent applicant: SmithKline Corporation 4, agent

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a lower alkyl group, R^2 and R^3
is a lower alkylene group, n means a group represented by 1 or 2, respectively] Compounds represented by the general formula R^4-NH_2 (wherein R^4 means a lower alkyl group) to obtain the imidazole derivative represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^2, R^3 and R^4 have the same meanings as before) Characteristic method for producing imidazole derivatives.