CS208770B2 - Method of making the quanidine derivatives - Google Patents

Abstract

Prodn. of guanidine derivs. of formula (I) comprises reacting a mercaptan deriv. of formula Het-(CH2)m-SM (III) is reacted with a guanidine of formula (IV). In the formulae, Het is opt. substd. 5- or 6-membered heterocyclic residue with 1 or 2 N-atoms; m is 1,2,3 or 4; R1 is H or 1-4C alkyl; R2 is CN or NO2; M is H or alkali metal; and Y is 2-oxo-3-oxazolidinyl, ethyleneimino or 2-haloethylamino. The intermediates 4-methyl-5-mercaptomethyl-imidazole and 1-(N-methyl-N'-cyano-carboxamido) -azinidine are also new. (I) are histamine H2 receptor blockers useful against gastric ulcers.

Description

. The invention relates to a process for the preparation of a guanidine derivative of the formula II.

^ NHCH.

(II)

This known substance has therapeutic properties, especially against gastric ulcers, by blocking histamine H2 receptors.

Methods for making this known compound are described in DE 2 344 779 and 2 344 833. However, these known methods make it difficult to obtain a product of the purity required for its use.

SUMMARY OF THE INVENTION The present invention provides a novel process for the preparation of this known compound which provides the final product in high yield and high purity.

The process according to the invention consists in reacting a compound of the formula III,

(lil) where

M · represents a hydrogen or alkali metal atom, with a compound of formula IV, (NH-CIH 3)

Y — C (IV) \ N — Ch-N where *

Y denotes residues a,. b or c

(b) or

Hal-CH2-CH2-NH- (c) wherein

Hal denotes a halogen atom.

The group Y represents a structure with an electrophilic carbon in the beta position to the nitrogen atom.

The product of the invention N-methyl-N'-cyano-N '- [2- ((4-methyl-5-imidazolyl] methylthio) ethyl] guanidine is preferably obtained by reacting 4-methyl-5-mercaptomethylimidazole hydrochloride with N- ( This reaction is carried out in an aqueous solution under an inert atmosphere, preferably NaOH is added under a stream of nitrogen, and an inert atmosphere is maintained throughout the reaction. quality.

The compounds of formulas III and IV are novel compounds obtained as described in Examples 1-4. 4-Methyl-5-mercaptomethylimidazole is prepared in three reaction steps.

The starting product is ethoxydithioformyl-2,3-diketobutane, which is converted to 4-methyl-5- (ethoxydithioformyl) imidazole, which is converted to 4-methyl-5-mercaptomethyimidazole.

The following examples describe several methods for preparing the compound of the invention as well as intermediates. These embodiments do not limit the invention in any way.

Example 1

Ethoxydithiophenyl-2,3-diketobutane

To a solution of 74.4 g of potassium ethylxanthogenate in 200 ml of ice-cooled methanol, 76.7 g of 1-bromobutane-2,3-dione are added dropwise with stirring. After 16 hours, the insoluble potassium bromide was removed by filtration and the solvent was removed under reduced pressure. The residue was extracted with petroleum ether, the solution was filtered and the solvent was evaporated. The liquid residue 97.7 g has a boiling point of 98-100 ° C at 13.3 Pa. Yield 98%.

C7H10O3S1 (206)

Calculated:

C 40.77, H 4.85, S 31.06,

Found:

% C, 40.83;% H, 4.96;% S, 31.05%.

IC (film):

1710, 1660, 1440, 1350, 1230, 1200, 1150, 1110, 1060, 1035, 930, 845, 760 ст ^'1.

Example 2

4-Methyl-5- (ethoxydithioformyl) imidazole

A solution of 13.2 g of ethoxydithioformyl-2,3-diketobutane, 1.66 g of hexamethylenetetramine, 32 grams of ammonium acetate in 200 ml of concentrated acetic acid was heated at 50 ° C for 7 hours. The solvent was evaporated under reduced pressure, the residue was taken up in chloroform. After filtration, the solution was extracted twice with a solution of 15 ml of 12 N hydrochloric acid in 250 ml of water. The aqueous phase was neutralized with sodium bicarbonate, then extracted with chloroform. The organic solution was dried over anhydrous sodium sulfate. The residue after evaporation of the solvent is a crystalline solid which is recrystallized from acetone and has a melting point of 139-141 ° C. Yield 57%.

C8H12N2OS1 (216)

Calculated:

% C, 44.44;% H, 5.55;% N, 12.96.

Found:

C 44.48, H 5.63, N 12.99, S. 29.62.

IR (nujol):

1610, 1410, 1280, 1260, 1220, 1110, 1045, 960, 850, 820, 740, 670 cm @ -1.

Example 3

3.1. 4-Methyl-5-mercaptomethylimidazole hydrochloride (hydrochloride of compound III where M = H)

A solution of 8.7 g of 4-methyl-5- (ethoxy-dithiofornyl) -imidazole in 100 ml of 12N hydrochloric acid is heated to reflux for 6 hours under a nitrogen atmosphere, the solvent is removed under reduced pressure and the solid residue is recrystallized from 2-butanol. After recrystallization from 2-butanol, m.p. 208 DEG-210 DEG C. Yield 90%.

G5H8N2S. HCl (164.5)

Calculated:

C, 36.47; H, 5.47; S, 19.45; Cl, 21.58.

Found:

36.69% C, 5.63% H, 19.41% S, 21.43% oCl.

IR (nujol):

3070, 2700, 2620, 1625, 1520, 1310, 1270, 1220, 1180, 1095, 980, 940, 920, 830, 730 cm ^-1 .

3.2. 4-Methyl-5-mercaptomethylimidazole hydrochloride (hydrochloride of compound III where M = H)

To a solution of 4-methyl-5-chloromethylimidazole hydrochloride (16.5 g) in ethanol (70 ml) was added potassium ethylxanthogenate (29.6 g) and refluxed for 3 hours. The residue was evaporated and boiled with 100 ml of 12N hydrochloric acid under a stream of nitrogen for 6 hours. The solvent was removed under reduced pressure and the cold solid residue was crystallized from 2-butanol. Recrystallization from 2-butanol gave the product, m.p. 208-210 ° C. Yield 80%.

CsHsNžS. HCl (164.5)

Calculated:

C, 36.47; H, 5.47; N, 17.02; S, 19.45; Cl, 21.58.

Found:

C 36.69, H 5.63, N 16.99, S 19.41, Cl 21.43.

1P (nujol):

3070, 2700, 2620, 1625, 1520, 1310, 1270, 1220, 1180, 1095, 980, 940, 920, 830, 730 cm @ -1.

Example 1 a d 4

4.1. 1- (N-methyl-N‘-cyanocarboxamidino) aziridine (1V, where Y = b)

3.1 g of N-cyano-N, S-dimethylisothiourea are dissolved in a solution of 15.8 g of chlormercuriaziridine ligand (1: 1) in 60 ml of dimethylformamide and maintained at 55 DEG C. for 5 hours and then filtered. The solvent was evaporated under reduced pressure. The residue was treated with an aqueous solution containing 184.4 mmol ethylenediaminotetraacetic acid and 737.6 mmol sodium hydroxide. This solution was extracted six times with chloroform. The solvent evaporation residue was crystallized from tetrahydrofuran, then recrystallized from ethyl acetate. M.p. 133-135 ° C. Yield 70%.

CsHeNj '(124)

Calculated:

48.38 O / o C, 6.45 Vo 11, 45.16% N.

Found:

% C, 48.20;% H, 6.48;

1C (nujol):

3220, 3100, 3050, 2160, 1580, 1540, 1410, 1270, 1190, 1160, 1090, 1060, 1030, 945, 855, 850, 820, 735 cm ^-1 .

4.2. N-Methylthiocarbamoylaziridine

To a solution of 7.3 g of methylthioisocyanate in ml of dry ether was added dropwise at -15 ° C 4.3 g of ethyleneimine in 25 ml of ether. After 30 minutes, the ether was removed to give a crystalline product, m.p. 46 ° C. Titration with perchloric acid showed a purity of 99.8%. Yield 98%.

1Č:

3140, 3030, 1535, 1440, 1365, 1335, 1190, 1075—1060,1010, 850, 740 on- '.

4.3. 1- (N-Methyl-N‘-cyanocarboxamidino) aziridine (1V, Y = b)

4.64 g of N-methylthiocarbamoylaziridine are dissolved in a mixture of 50 ml of acetonitrile and 50 ml of dimethylformamide, and 15.82 g of cyanamide Pb are added and the mixture is heated under reflux for 7 hours. Then the sulfide Pb 'and excess cyanamide Pb are filtered off. The solvents were removed by distillation and the residue was taken up in ether. The solvent evaporation residue was crystallized from tetrahydrofuran and then recrystallized from ethyl acetate. M.p. 133-135 ° C. Yield 65%.

C5H8N4

Calculated:

% C, 48.38;% H, 6.45;

Found:

% C, 48.20;% H, 6.48;

1P (nujol):

3220, 3100, 3050, 2160, 1580, 1540, 1410, 1270, 1190, 1160, 1090, 1030, 945, 930, 885, 850, 820, 723 cm -1.

Example 5

N-Methyl-N-cyano-N '- (2 - ((4-methyl-5-imidazolyl) methylthioethyl) guanidine (11)

To a solution of 16.45 g of 4-methyl-5-mercaptomethylimidazole hydrochloride and 12.4 g of N- (N'H-methyl-N'-cyanoamidino) aziridine in 100 ml of distilled water was added 4.4 g of sodium hydroxide under a nitrogen atmosphere. wherein the inert atmosphere is maintained throughout the reaction. After 20 hours at room temperature, a crystalline product is isolated which, after recrystallization from acetonitrile, has a melting point of 142-143 ° C.

CioHieNeS (252)

Calculated:

% C, 47.60;% H, 6.35;% N, 33.33;

12.69% S.

Found:

% C, 47.53;% H, 6.48;% N, 33.28.

12.72% S.

IR (nujol):

3270, 3100, 2160, 1610, 1580, 1490, 1400, 1300, 1280, 1235, 1205, 1070, 950, 840, 800, 760, 680, 670 ^cm-first

Example 6

6.1. 4-Methyl-5-mercaptomethylimidazole (Compound III)

To a solution of 4-methyl-5-chloromethylimidazole hydrochloride (16.5 g) in methanol (70 ml) was added potassium ethylxanthogenate (29.6 g) and the reaction mixture was refluxed for three hours. Dilute hydrochloric acid was added to the residue and refluxed for 5 hours. The residue was neutralized and extracted with tetrahydrofuran. Titration with perchloric acid showed a purity of 99.5%.

Found:

C, 46.7; H, 6.1; N, 21.9.

Company ID:

3100, 1660, 930, 680 cm @ -1.

6.2. N- (2-Hydroxyethyl) -N‘-methylthiourea

To a solution of 6.1 ethanolamine in 25 mL of tetrahydrofuran (THF) was added 7.3 g of methylthioisocyanate. After three hours the solvent was evaporated and the residue was crystallized from tetrahydrofuran ether.

Mp 69-70 ° C.

Company ID:

3300, 3200, 1570, 1510, 1245, 1070, 1050, 730 cm @ -1.

6.3. N- (2-Hydroxyethyl) -N‘-methyl-N'-cyanoguanidine

To a solution of 4.0 g of N- (2-hydroxyethyl) -N‘-methylthiourea in a mixture of 50 ml of acetonitrile and 50 ml of dimethylformamide was added 8.89 grams of lead cyanamide, and the suspension was heated to reflux to acetonitrile. After 4 hours the lead sulfide was removed and the solvent was evaporated. Titration with perchloric acid showed a purity of 99.3%.

Company ID:

3300, 3200, 2150, 1650, 1245, 1080, 1050, 730 cm-.

6.4. 1- (N-Methyl-N‘-cyanoamidino) -2-oxazolidinone (IV, Y = a)

To 18.3 g of N- (2-hydroxyethyl) -N‘-methyl-N'-cyanoguanidine, 13 g of ethyl carbonate and 0.80 g of sodium ethylate are added. At 140 degrees Celsius, the ethanol formed in the reaction mixture is continuously distilled off. After 4.5 hours the product is isolated as an oil. Titration with perchloric acid shows purity

99.3%.

Company ID:

3200, 2150, 1730 cm ^-1 .

6.5. N-Methyl-N‘-cyano-N '- [2 ((4-methyl-5-imidazolyl) methylmercapto-ethyl) guanidine (Compound II)

13 g of 1- (N-Methyl-N-cyanoamidino) -2-oxazolidinone in 50 ml of ethanol are added to 16 g

4-methyl-5-methylmercaptoimidazole in the form of sodium mercaptide. The reaction mixture was refluxed for 18 hours, neutralized, the solvent was removed and the residue crystallized from acetonitrile-ether. M.p. 141-142 ° C.

Example 1 a d 7

7.1. N-Methylthiocarbamylaziridine

To a solution of 7.3 g of methylthioisocyanate in 25 ml of ether (anhydrous) was added dropwise at -15 DEG C. 4.3 g of ethyleneimine in 25 ml of ether. After 30 minutes, the ether was removed to give a crystalline solid, mp 46 ° C. Titration with perchloric acid showed a purity of 99.8%.

Company ID:

3140, 3030, 1535, 1440, 1365, 1335, 1190, 1075-1060, 1010, 850, 740 cm ^1st

7.2.1- (N-Methyl-N'-cyanocarboxamidino) -azir ^! din (substance IV, Y = b)

4.64 g of N-methylthiocarbamylaziridine are dissolved in a mixture of 50 ml of acetonitrile and 50 ml of dimethylformamide, to which 5.82 g of lead cyanamide are added over 7 hours under reflux, the lead sulphide and excess lead cyanamide are filtered off. The solvents were removed by distillation and the residue was taken up in ether. Evaporation gave an oil. Titration with perchloric acid showed a purity of 99.6%.

Company ID:

3170, 2170, 1610, 1250, 1020 cm -1.

7.3. N-Methyl-N-cyano-N '- [2 {(4-methyl-5-imidazolyl) methylmercapto-ethyl] guanidine (Compound II)

13.0 g of 4-methyl-5-methyl-208770 mercaptoimidazole were added to a solution of 2.40 g of 1- (N-methyl-N'-cyanocarboxamidinoyaziridine in 25 ml of tetrahydrofuran) and the reaction mixture was heated under reflux for 6 hours. It was evaporated and the residue was crystallized from acetonitrile-ether, m.p. 141-142 ° C.

Example 8

8.1. N- (2-bromoethyl) -N ^{<-methylthiomočovina}

To a suspension of 19 g of bromoethylamine hydrobromide in 80 ml of tetrahydrofuran, 10.1 g of triethylamine and 7.5 grams of methyl isothiocyanate are added under stirring. After 3 hours the insoluble triethylamine hydrobromide was removed and the thiourea was isolated as an oil. Titration with perchloric acid showed a purity of 99.3%.

IC:

3200, 1570, 1510, 55 cm ^-1 .

8.2. N- (2-Bromoethyl) -N‘-methyl-N'-cyanoguanidine (IV, Y = c)

To a solution of 18 g of N- (2-bromoethyl) -N‘-methylthiourea in a mixture of 200 ml of acetonitrile and 200 ml of dimethylformamide, 29 g of lead cyanamide is added and the mixture is refluxed with acetonitrile. After 6 hours, the lead sulfide was separated and the solvent was evaporated to give an oil. Titration with perchloric acid showed a purity of 99.7%.

16:

3200, 2150, 1650, 1085, 560 cm ^-1 .

8.3. N-Methyl-N‘-cyano-N '- [2 ((4-methyl-54-imidazolyl) methylmercapto-ethyl) guanidine (Compound II)

К solution of 10 g of 4-methyl-5-methylmercaptoimidazole (as sodium mercaptide) in 50 mL of ethanol was added 21 g of N- (2-bromoethyl) -N'-methyl-N ^with cyanoguanidine, and the reaction mixture was heated for 5 hours under reflux condenser. After removal of sodium bromide, the product crystallized from acetonitrile-ether and had a melting point. M.p. 141-142 ° C.

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of a guanidine derivative of the formula II, NHCl CH 2 S-CH 2 CH 2 NH-C ⁶ zz The process of claim 1, wherein the hydrochloride of a compound of formula III is reacted in an aqueous solution under a nitrogen atmosphere wherein: M is hydrogen or an alkali metal, with a compound of formula IV, NH — СНз / Y — С (IV) \ N — ON where Y denotes residues a, b or c, οΓΊλ- ΟΥ O (a) (b) or Hal-CH 2 -CH ₂ -NH- (C) wherein Hal denotes a halogen atom.