JPH0141634B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a new method for synthesizing 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole. The gist of the present invention is to provide guanylthiourea with the general formula [In the formula, A represents a reactive group and R represents a protective group. ] 2-Guanidino-
2-guanidino-
4-[2-(formamido)ethylthiomethyl]
The point is to obtain thiazole. The method of the present invention is shown by the following reaction formula. [In the formula, A and R each have the same meanings as above. ] In the above definition, reactive groups include halogen (e.g., chlorine, bromine, iodine), sulfonyloxy groups (e.g., tosyloxy, mesyloxy), and protective groups include 1-3 aryl-substituted methyl groups (e.g., trityl, benzhydryl). , p-methoxybenzyl). The target substance () exhibits an antagonistic effect on histamine H ₂ and is useful in the treatment of gastric ulcers [US Patent Application No. 144,946]. However, existing industrial production methods are not necessarily satisfactory. In the ring-closing reaction of the method of the present invention, guanylthiourea and ketone () are mixed in a suitable solvent (for example, acetone,
dioxane, dimethylformamide, dimethyl sulfoxide, etc.) by heating at 20 to 200°C, preferably around the boiling point of the solvent used. If necessary, a base such as triethylamine or pyridine may be added. The deprotection reaction of the N-protecting group is then carried out using a suitable deprotecting agent (e.g. trifluoroacetic acid, 85% sulfuric acid, 90%
% phosphoric acid, etc.) at 0°C to 50°C, preferably at room temperature. The raw material () is easily synthesized from cystamine as shown in the reaction formula below: [In the formula, A and R have the same meanings as above. ] The method of the present invention proceeds with good yields in both steps, and is suitable as a method for industrially synthesizing the target substance (2). Examples and reference examples of the method of the present invention are shown below. Example 1 133 guanylthiourea in a solution consisting of 448 mg of N-formyl-N-trityl-2-(3-chloroacetonylthio)ethylamine and 12 ml of acetone.
mg and reflux for 18 hours. The reaction solution was concentrated under reduced pressure to obtain crude 2-guanidino-4-[2-(N-tritylformamido)ethylthiomethyl]thiazole. Dissolve this in 3 ml of trifluoroacetic acid and stir for 30 minutes. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in methanol, made basic with triethylamine, and concentrated under reduced pressure. The resulting oil was subjected to column chromatography on silica gel using ethyl acetate/methanol (4:1, v/
v), and the eluate was concentrated to obtain 239 mg of 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole as an oil. NMR (CD ₃ OD), δ 3.73 (s, 2H), 6.85 (s,
1H), 7.97 (s, 1H) Maleate, melting point 146-148℃ Elemental analysis C ₈ H ₁₃ N ₅ OS ₂・C ₄ H ₄ O ₄ Calculated value C, 38.39; H, 4.56; N, 18.66; S, 17.08 (%) Experimental value C, 38.58; H, 4.47; N, 18.45; S, 16.74 (%) Example 2 After adding about 1/5 amount of a solution consisting of 3.4 g of N-formyl-N-tritylcysteamine and 80 ml of acetone to a suspension consisting of 1.8 g of potassium carbonate and 90 ml of acetone at -15°C, 1,3-di A solution consisting of 1.9 g of chloracetone and 20 ml of acetone is added all at once. Next, the remaining N-formyl-N-tritylcysteamine solution was added dropwise over 20 minutes at -7 to -5°C, and the mixture was gradually warmed to room temperature and stirred for 4 hours. After removing the precipitate, 1.7 g of guanylthiourea was added to the resulting solution containing N-formyl-N-trityl-2-(3-chloroacetonylthio)ethylamine, and the mixture was refluxed for 16.5 hours. The reaction solution was concentrated under reduced pressure to obtain crude 2-guanidino-4-[2-(N
8.9 g of -tritylformamide)ethylthiomethyl]thiazole are obtained. Add this to trifluoroacetic acid
Dissolve in 20 ml and stir at room temperature for 20 minutes. The reaction solution is concentrated to dryness under reduced pressure, the residue is dissolved in 50 ml of methanol, made basic with triethylamine, and concentrated under reduced pressure. The residue is subjected to column chromatography on silica gel, eluting with ethyl acetate and then ethyl acetate/methanol (4:1, v/v). The eluate was concentrated to obtain 1.855 g of 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole as an oil. Example 3 After adding 9.6 g of N-formyl-N-tritylcysteamine to a suspension of 5.0 g of potassium carbonate and 200 ml of acetone at -20°C in an amount of about 1/5 of the solution of 220 ml of acetone, 1,3-di A solution consisting of 6.0 g of chloracetone and 40 ml of acetone is added all at once. While returning the reaction solution to room temperature, the remaining N-formyl-N-tritylcystamine solution was gradually added dropwise, and the mixture was stirred for 2 hours. After removing the precipitate, the obtained N-formyl-N-trityl-2-
Add 4.8 g of guanylthiourea to the solution containing (3-chloroacetonylthio)ethylamine and reflux for 22 hours. The reaction solution was concentrated under reduced pressure, and 500 ml of a saturated aqueous sodium bicarbonate solution and 5 ml of methanol were added to the residue. Take the precipitated crystals and chloroform-
Distribute in water. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off to obtain 18.1 g of 2-guanidino-4-[2-(N-trimethylformamido)ethylthiomethyl]thiazole. Melting point 255℃ or higher (decomposition) (recrystallized from methanol). NMR (d ₆ - DMSO), δ 6.87 (br, s, 4H),
7.27 (br, s, 16H), 8.38 (s, 1H) Elemental analysis C ₂₇ H ₂₇ N ₅ As OS ₂ Calculated value C, 64.64; H, 5.43; N, 13.96; S, 12.78 (%) Experimental value C, 64.56; H, 5.53; N, 13.76; S, 12.54 (%) 2-guanidino-4-[2-(N-tritylformamide)ethylthiomethyl]thiazole 3.5
Add 9 ml of 85% sulfuric acid to the mixture and stir at room temperature for 20 minutes. The reaction solution is neutralized by pouring into saturated sodium bicarbonate solution and shaken with ethyl acetate. The aqueous layer is concentrated under reduced pressure, and the residue is extracted with methanol. The solvent was distilled off from the methanol extract, and the residue was subjected to column chromatography using silica gel and eluted with ethyl acetate-methanol (4:1, v/v).
The eluate was concentrated and 2-guanidino-
4-[2-(formamido)ethylthiomethyl]
Obtain 481 mg of thiazole. Maleate salt, melting point 146
~148℃. Example 4 Using 90% phosphoric acid as the deprotecting agent, Example 3
The reaction (b) was carried out to obtain 2-guanidino-
4-[2-(formamido)ethylthiomethyl]
Get thiazole. Reference example 1

【formula】

[Formula] a Metallic sodium 1.2g and ethanol 100ml
5.63 g of cystamine dihydrochloride was added to the solution consisting of, and stirred at 50-60°C for 1 hour. Ethanol was distilled off under reduced pressure, and 50 ml of ethyl formate was added to the residue.
Reflux for an hour. After cooling, add 50ml of methanol to the reaction solution.
was added to remove the precipitated sodium chloride,
Concentrate the liquid under reduced pressure. The residue was subjected to column chromatography using silica gel and ethyl acetate/
Elute with methanol (10:1, v/v).
Concentrate the eluate and extract N,N'- as a colorless oil.
2.9 g of diformylcystamine is obtained. NMR (CD ₃ OD), δ 2.83 (t, J=6PH,
2H), (3.53(t, J=6Hz, 2H), 7.98
(s, 1H) b Cystamine dihydrochloride 5.5g and ethyl formate
Add 10 g of triethylamine to the 60 ml suspension and reflux for 5 hours. After cooling, remove the precipitate and concentrate the liquid under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate/methanol (10:1, v/v). Concentrate the eluate and extract N as an oil.
3.6 g of N'-diformylcystamine is obtained. Reference example 2 100 mg of triethylamine is added to a suspension consisting of 65 mg of N,N'-diformylcystamine, 192 mg of trityl chloride and 4 ml of dry acetonitrile, and the mixture is stirred at room temperature for 3 hours. Take the precipitated crystals,
Wash with a small amount of acetonitrile, water, and dry to obtain 175 mg of N,N'-diformyl-N,N'-ditrimethylcystamine. Melting point: 217-218°C (chloroform-ethanol). Elemental analysis C ₄₄ H ₄₀ N ₂ O ₂ S ₂ Calculated value C, 76.26; H, 5.82; N, 4.04; S, 9.26 (%) Experimental value C, 76.38; H, 5.66; N, 3.89; S, 9.11 (%) Reference example 3 5 ml of water and 1.7 g of tributylphosphine to a solution of 3.4 g of N,N'-diformyl-N,N'-ditritylcystamine and 50 ml of methylene chloride.
were added successively and the mixture was refluxed for 1 hour with stirring. After cooling, the organic layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to give a melting point of 165~
2.735 g of N-formyl-N-tritylcysteamine is obtained as crystals at 167°C. Yield 93%. Elemental analysis C ₂₂ H ₂₁ as NOS Calculated value C, 76.04; H, 6.09; N, 4.03; S, 9.23 (%) Experimental value C, 76.09; H, 5.95; N, 3.82; S, 9.36 (%) IR, ν ^Nujol _nax 1656cm ^-1 Reference example 4 Cystamine dihydrochloride 22g and ethyl formate 300g
50 g of triethylamine are added to the suspension consisting of 1 ml and refluxed for 6 hours. Distill 150ml of ethyl formate at normal pressure, add 150ml of freshly distilled ethyl formate,
Reflux for 2 hours. After cooling, remove the white precipitate,
Concentrate the liquid. The residue is dissolved in ethyl acetate/acetonitrile (1:1, v/v) and insoluble materials are removed. Concentrate the liquid under reduced pressure to obtain N,N′- as an oily substance.
24.9 g of diformylcystamine is obtained. Dissolve this in 250ml of dry acetonitrile and add trityl chloride.
Add 54.2 g and 21 g of triethylamine, and stir at room temperature for 6 hours. The precipitated crystals were collected, washed with ethanol, and converted into N,N'-diformyl-N,
N′-ditritylcystamine is obtained. This was dissolved in 300 ml of methylene chloride, 50 ml of water and 15.3 g of tributylphosphine were added, and the mixture was heated and stirred for 1 hour. After cooling, the organic layer was separated and dried with anhydrous sodium sulfate.
Concentrate under reduced pressure. Wash the residue with ethanol and
45 g of formyl-N-tritylcysteamine is obtained. Melting point 165-167℃. Reference example 5 Add 1,3-dichloroacetone to a suspension of 500 mg of potassium carbonate and 20 ml of acetone at -5°C.
231 mg of N-formyl-N-tritylcysteamine was added thereto, and with vigorous stirring, a solution consisting of 575 mg of N-formyl-N-tritylcysteamine and 30 ml of acetone was added dropwise over 30 minutes, followed by stirring at 0° C. for 30 minutes. Remove the precipitate and concentrate the liquid under reduced pressure. Dissolve the residue in chloroform, wash with water,
Dry with anhydrous sodium sulfate and concentrate. The resulting oil was subjected to column chromatography on silica gel and eluted with benzene/ethyl acetate (10:1, v/v). The eluate was concentrated and N-
448 mg of formyl-N-trityl-2-(3-chloroacetonitrile)ethylamine is obtained. NMR (CDCl ₃ ), δ 3.25 (s, 2H), 4.13 (s,
2H), 7.23 (d, 15H), 8.38 (s, 1H)

Claims (1)

[Claims] 1 2-guanidino-4-[2-(formamide) characterized by treating 2-guanidino-4-[2-(N-protected formamide)ethylthiomethyl]thiazole with a deprotecting agent. ) New synthesis method for ethylthiomethyl]thiazole. 2 General formula for guanylthiourea [In the formula, A represents a reactive group and R represents a protective group. ] 2-Guanidino-
2-guanidino-4-[2-(formamido)ethylthio] characterized in that 4-[2-(N-protected formamido)ethylthiomethyl]thiazole is produced and then the product is treated with a deprotecting agent. A new synthesis method for methyl]thiazole.