KR870001157B1 - Process for the preparation of guanidinothiazole compounds - Google Patents

Abstract

Guanidinothiazole compds. (I), useful as medicaments, esp. a gastric secretion inhibitor, are prepd. by the reaction of II and III. Thus, the mixture of 16.8g amidinothiourea and 75ml aceton is reacted with 18g 1,3-dichloroaceton to give 26.53g 2-guanidino -4- chloromethylthiazolyhydrochloride (m.p.=191-193 deg. c).

Description

Method for preparing guanidino thiazole compound

The present invention relates to a novel process for preparing guanidino thiazole derivatives represented by the following structural formula (I).

Compounds of formula (I), which are the target compounds of the present invention, are guanidino thiazole derivatives useful as gastric acid secretion inhibitors, and known compounds are prepared in Belgium Patents 882,071, British Patents 2,052,478 and 2,055,800, French Patent Nos. 2,450,827, German Patent Nos. 2,951,675 and 3,008,056, Japanese Patent Publication Nos. 80-118, 476, 81-05, 469 and 81-22, 770 and Domestic Patent Publications 83-2478 And the like.

Known preparation methods are described as 3- (2-aminothiazole-4- by reacting with chloro propionitrile using S- (2-aminothiazol-4-yl-methyl) isothiourea polyhydrochloride as starting material. Mono-methylthio) propionitrile is prepared and then reacted with benzoyl isocyanate and 3- [2- (benzoyl thioureido) -thiazol-4-yl methylthio] propionitrile obtained at 50 ° C. After stirring for 5 hours in potassium solution, 3- (2-thioureido thiazol-4-yl methylthio) propionitrile was obtained, which was subjected to methiation with iodomethyl to give 3- [2- (S-methyl-iso Thioureido) thiazol-4-yl methylthio] propionitrile hydro iodide.

The reaction was carried out in methanol containing ammonium to give 3- (2-guanidinothiazol-4-yl methylthio) propionitrile. The reaction was carried out for 20 hours after passing hydrogen chloride gas through anhydrous methanol and anhydrous chloroform solution. -3 [(2-guanidinothiazol-4-yl) methylthio] propion imidate is obtained and reacted with sulfamide to give the compound of formula (I).

If this is expressed as a reaction scheme, it is as follows.

The preparation method as described above requires a complex process of four steps (formula (III) -formula) to introduce guanidino groups from the compound of formula (III), and the overall reaction process is long, resulting in low yield. It is economical.

The present invention has the advantage of simply introducing a guanidino group in a high yield because it is easy to prepare a compound of the structural formula (Ⅸ) in order to compensate for this disadvantage of the prior art,

It is the specificity of the present invention that the target compound of formula (I) can be obtained in high yield by a simple process by quantitatively reacting the compound of formula (VII) with the compound of formula (VII), which is newly synthesized, in an equimolar ratio. .

The present invention is described in detail as follows.

The compound of formula (VII) can be prepared in high yield simply by reacting amidinothiourea and 1,3-dichloro acetone in an acetone solvent in an animal ratio,

The compound of formula (VII) was passed through hydrogen chloride gas with stirring in 3,3'-dithio dipropion nitrile and anhydrous methanol anhydrous chloroform solvent to prepare dimethyl 3,3'-dithio dipropion imidate polyhydrochloride. Thereafter, sulfamide may be reacted to prepare an N-sulfamoyl derivative, which may be prepared by breaking a disulfide bond using potassium triisopropoxyborohydride in a detrahydrofuran solvent.

N-sulfamoyl-3- [92-guanidinothiazol-4-yl) methylthio] propionamidine was reacted by reacting the compound of formula (VII) and the compound of formula (IV) with anhydrous methane in a solvent. That is, the compounding compound of structural formula (I) which is a target compound can be obtained in high yield.

Hereinafter, the present invention will be described in detail with reference to Examples.

Example 1

16.8 g of amidinothiourea is added to 75 ml of acetone and stirred, while 18 g of acetone solution containing 1,3-dichloroacetone is added thereto, followed by stirring until white crystals are formed.

When crystals start to form, stop stirring, leave overnight, filter and wash with acetone to afford 26.53 g of 2-guanidino-4-chloro methylthiazole hydrochloride.

Melting Point: 191-193 ℃

Elemental Analysis: C ₅ H ₈ Cl ₂ N ₄ S

Example 2

To 5 ml of anhydrous chloroform, 1.3 g of 3,3'-dithio dipropion nitrile and 0.53 ml of anhydrous methanol were added, and 0.5 g of hydrogen chloride gas was passed while stirring at 0 ° C. After washing with anhydrous chloroform and drying, 1.80 g of dimethyl 3,3'-dithio dipropion imidate dihydrochloride is obtained.

Melting Point: 174-176 ℃

Elemental Analysis: C ₈ H ₁₈ Cl ₂ N ₂ O ₂ S ₂

NMR (d ₆ -DMSO) δ2.8 (m, 8H, -CH ₂ CH _2- )

δ 3.7 (s, 6H, -OCH ₃ )

δ 6.7 (broad, 2H, = NH)

cm^-11658 (C=N)IR

cm ^-1 1658 (C = N)

Example 3

15 g of dimethyl-3,3'-dithio propion imidate dihydrochloride and 9.4 g of sulfamide are added to 70 ml of anhydrous methanol and 20 ml of triethylamine, and the mixture is refluxed for 5 hours, filtered and the filtrate is blown under reduced pressure. Send to obtain 13.78 g of 3,3'-dithio di-N-sulfamoyl-dipropion amidine.

Elemental Analysis: C ₆ H ₁₆ N ₆ O ₄ S ₄

NMR (d ₆ -DMSO) δ2.7 (m, 8H, -CH ₂ CH _2- )

cm^-1

IR

cm ^-1

Example 4

5.0 g of 3,3'-dithio-di-N-sulfamoyl-di-propionamidine was added to 12 ml of tetrahydrofuran, and 5.8% of potassium triisopropoxyborohydride was dissolved in 18 ml of tetrahydrofuran. After the solution was added, the mixture was stirred for 4 hours at room temperature, the mixture was adjusted to pH 6-6.9 with slightly acidic acid with dilute sulfuric acid, extracted with ethyl ether, and blown off under reduced pressure to give 3-mecapto-N-sulfamoyl-propion amidine 4.52 get g

Elemental Analysis: C ₃ H ₉ N ₃ O ₂ S ₂

NMR (d ₆ -DMSO) δ 2.4 (m, 2H, -S-CH ₂ C H _2- )

NMR (d ₆ -DMSO) δ3.1 (m, 2H, -S- C H ₂ CH _2- )

cm^-11,320, 1,160(SO₂)IR

cm ^-1 1,320, 1,160 (SO ₂ )

Example 5

To 30 mL of anhydrous methanol and 9.5 mL of triethylamine solution, 6.8 g of 2-guanidino-4-chloromethylazole hydrochloride and 5.48 g of 3-mecapto-N-sulchamoyl-propionamidine were added thereto at room temperature. After stirring for an hour, the filtrate was filtered and the filtrate was blown out under reduced pressure, dissolved in chloroform, washed with sodium hydrogencarbonate solution, the chloroform was separated and the solvent was blown out to send 9.3 g of N-sulfamoyl-3-[(2-guanidino- Thiazol-4-yl) methylthio] propion amidine.

Melting Point: 162-164 ℃

Elemental analysis: C ₈ H ₁₅ M ₇ O ₂ S ₃

NMR (d ₆ -DMSO) δ 2.50 (m, 2H, -S-CH ₂ CH _2- )

δ 2.65 (m, 2H, -S-CH ₂ -CH ₂ )

)δ 3.60 (s, 2H,

)

)δ6.45 (s, 1H,

)

Claims (1)

The compound of formula (I) was reacted by reacting compound 2-guanidino-4-chloromethyl thiazole hydrochloride of formula (VII) with compound 3-mecapto-N-sulfamoyl-propionamidine of formula (VII). How to manufacture.