JPS5872573A - Novel synthetic method for 2-guanidino-4-(2-(formamide) ethylthiomethyl)thiazole - Google Patents

Abstract

PURPOSE:2-Guanidino-4-[2-(N-protected formamide)ethylthiomethyl]thiazole is treated with an appropriate deprotecting agent to produce the titled compound used as a remedy for gastric ulcer in high yield. CONSTITUTION:The reaction of guanylthiourea with a compound of formula I(A is reactive group; R is protecting group) gives 2-guanidino-4-[2-(N-protected formamide)ethylthiomethyl]thiazole of formula II and the product is treated with a deprotecting agent such as trifluoroacetic acid, 85% sulfuric acid or 90% phosphoric acid to give 2-guanidino-4-[2-(fromamide)ethylthiomethyl]thiazole of formula III. USE:A drug showing an antagonistic action on himstamine H2.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new method for synthesizing amido)ethylthiomethylcutiazole.

The gist of the invention is as follows. to guanylthiourea general formula %formula%() [During the ceremony. A is a reactive group. Each R represents a protecting group.

] 2-guanidino-q-(
:x-(N-protected formamido)ethylthiomethyl)thiazole (n) is produced. The product is then treated with a deprotecting agent to obtain 2-guanidino-g-C2-Cformamido)ethylthiomethylcutiazole.

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, zero-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) are exemplified.

Target substance (1) exhibits an antagonistic effect on histamine salts and is useful for the treatment of gastric ulcers [US Patent Application No. 114'
No. 914]. However, existing industrial production methods are not necessarily satisfactory.

The ring-closing reaction of the method of the present invention involves guanylthiourea and ketone (
ill) in a suitable solvent (e.g., acetone, dioxane, dimethylpolamide, dimethyl sulfoxide, etc.)
It is carried out by heating to a temperature of 20 to 20 θ°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 (eg, trifluoroacetic acid M, I!% sulfuric acid.

90% phosphoric acid, etc.), θ6c~! 06c, preferably carried out at room temperature.

Raw material (1) is easily synthesized from 7stamine as shown in the following reaction formula: [wherein 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 an industrial synthesis method for the target substance (1).

Examples and reference examples of the method of the present invention are shown below.

Example 1 Guanylthiourea/33Mg is added to a solution consisting of N-formyl-N-trityl-2-(3-chloroacetonylthio)ethylamine talrIIg and acetone/2ml and refluxed for 7f hours. The reaction solution was concentrated under reduced pressure to obtain crude 2
-guanidino-'l-C2-(N-tritylformamido)ethylthiomethylfuthiazole is obtained. This was dissolved in 3 ml of trifluoroacetic acid and stirred for 3θ minutes. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in methanol.
Make basic with triethylamine and concentrate under reduced pressure. The resulting oil was subjected to column chromatography using phosphoric acid gel and ethyl acetate/methanol 1:/.

-), the eluate was concentrated, and the 2-
Guanidino-cou[λ-(formamido)ethylthiomethylfuthiazole 2391111 is obtained.

NMR (CDJOD), δ 3.73 ([1,,2H
).

413 (8, /H).

797 (B, /H) Maleate, melting point / guza °C elemental analysis C,
Calculated value as H, 3N, O8, ・C, H40 c, 3
ZaJ9iH, HirojI! ,iN,/Noro Otsu;S,/701
r (%) Experimental value C, 313; I:H, '1. '17. N, /l
ri3rS, /1. ．． 7 g (%) (margin below c) Example: Into a suspension consisting of potassium carbonate l♂f and acetone 90 ml -/at 3'C, a solution consisting of N-formyl-N-tritylcysteamine 3 g f and acetone 10 ml was added. After adding approximately 1.9% of 13-dichloroacetone,
Add a solution consisting of g and 20xl of acetone all at once. Then, the remaining N-formyl-N-
) Add the richlensteamine solution dropwise over a period of 20 minutes, gradually return to room temperature, and stir for a period of time. The precipitate was removed, and guanylthiourea/7II was added to the obtained P solution containing N-formyl-N-)lithyl-2-(3-chloroacetonylthio)ethylamine, and refluxed for /f hours. Reaction. The liquid was concentrated under reduced pressure to obtain crude 2-guanidino-g-C2-(N-).
lythylformamide)ethylthiomethyl]thiazole 1
Get 91/. This was dissolved in 20 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in methanol. Dissolve in Oml, make basic with triethylamine, and concentrate under reduced pressure. The residue was subjected to column chromatography on silica gel and ethyl acetate.

Next, elute with ethyl theacetate/methanol (Q:/, v/). Concentrate the eluate to obtain 2-geanidino'l-C2-(formamido)ethylthiomethylcutiazole 1rssy as an oil.

Example 3 After adding 9 t of N-formyl-N-tritylcysteamine (/) to a suspension consisting of 200 ml of potassium carbonate and 200 ml of acetone at -20''C, approximately the amount of a solution consisting of 220 ml of acetone was added. , 13-dichloroacetone Og and acetone'l0sl are added all at once.While the reaction solution is being returned to room temperature, the remaining N-formyl-N-tritylcystamine solution is gradually added dropwise.
Stir for an hour. The precipitate was removed and the resulting N-formyl-N-)-lythyl-2-(3-chloroacetonylthio)
Add guanylthiourea lA♂f to P solution containing ethylamine.

Reflux for 22 hours. The reaction solution was concentrated under reduced pressure, and the residue was a saturated aqueous sodium hydrogen carbonate solution! ;00ml 1-methanol 3m
Add l. The precipitated crystals are collected and distributed between chloroform and water. The organic layer is dried over anhydrous sodium sulfate and the solvent is distilled off to obtain 2-guanidino-hiro-[2-(N-1-lythylformamido)ethylthiomethylcutiazole/l/1/. Melting point 2! ;3;"C or higher (decomposition) (recrystallized from methanol).

NMR (d-DMSO), δ otonoa (br, s
, 4/H).

727 (br, 8./Otsu H).

! 37 (8, /H) Elemental analysis cA7N, os2 calculation value C, 6hiro64 H, mag 3', N, /3.9t
.

S, /17J' (%) Experimental value C,41Aj6i H,3J3 iN, /3
．． 76 iS, /, 2.51%) b) Trt 2-guanidino-g C2-(N-tritylporumamido)ethylthiomethythyl]thiazo-J, add 9 ml of tS% sulfuric acid to 3 sg, and stir at room temperature for 2θ minutes. do. 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 is distilled off from the methanol extract,
The residue was subjected to column chromatography on silica gel, and ethyl acetate-methanol (44:/, v/v
').

Concentrate the eluate and extract Kogeanidino #-C as an oil.
2-(formamido)ethylthiomethane]thiazole'It/η is obtained. Maleate salt, melting point /IA ~ /lI
l°c.

Example Hiro Using 90% phosphoric acid as the deprotecting agent, Example 3(b)
The reaction was carried out to give 2-guanidono+-C2 with similar yield.
-(formamido)ethyl-rethiomethyl]thiazole is obtained.

a) Adding cystane dihydrochloride it, 31 to a solution consisting of metallic sodium 12f/and ethanol lOθ,
The mixture was stirred for 1 hour at a temperature of 0 to 0. Ethanol was distilled off under reduced pressure, and 0 ml of ethyl formate was added to the residue.

Kojiki reflux. After cooling, add 1 Oml of methanol to the reaction solution to remove the precipitated sodium chloride, and concentrate the P solution under reduced pressure. The residue was subjected to column chromatography on silica gel using ethyl acetate/methanol (10:/,
Elute at v/v, ). Concentrate the eluate to obtain 2.91 N,N'-diformylcystamine as a colorless oil.

NMR (CDjOD), δ Qr3(t, J=6Hz
, 2H).

3.3; 3 (t, J=gHz, , 2H)
.

'Z91 (s, /H) b) Nstamine dihydrochloride jjjg and ethyl formate 1.0
Add 10f of triethylamine to the suspension consisting of ml,
Reflux for 5 hours. After cooling, the precipitate was removed from the oven.

Concentrate the P solution under reduced pressure. The residue was subjected to column chromatography on silica gel and ethyl acetate/methanol (1
Elute at 0:/, v/). Concentrate the eluate to obtain N,N'-diformylcystamine 3f as an oil.

Reference Example 2 N,N'-diformylcystamine 4jllllf, trityl chloride/92111f/ and dry acetonitrile l
Add triethylamine 700119 to a suspension consisting of sodium bicarbonate.

Stir at room temperature for 3 hours. Count the number of crystals that precipitate.

Wash with a small amount of acetonitrile, water, dry, and
N'-diformyl-N, N'-ditritylcystamine/7! ; obtain III. Melting point 277-2/r"c (chloroform-ethanol).

Elemental analysis Calculated value as C□H,,NyuOyuSyu・c
, 7 Otsu, 24iH, Ma♂2jN, 1A0117S, 92
1. C%) Experimental value c, 7 JJ'; H, J: 44; N, JJ'; S, 9 // (%) Reference example 3 N, N-diformyl-N, N-ditritylcystamine 3
．． 'll and methylene chloride! ;Jml of water and 179 ml of tributylphosphine are sequentially added to the solution consisting of Oxl, and the mixture is refluxed for 1 hour while 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 16j~lOtsu7@
N-formyl-N-)lythylcysteamine as crystals of C2. ．． Get 7331. Yield 93%.

Elemental analysis C2UH,, Calculated value as NO8 C,7t,θ＆iH,4,C9iN,
lAθ3; 8.923 (%) Experimental value C, 76,09, H, 3;: N, 3. The 2
;8,937. (%) IR,, Nu J O' t 6s t cMax Reference example ψ Cystamine dihydrochloride 229 and ethyl formate J and 3θOs
Add triethyl J raremin jθf to the suspension consisting of
Reflux for 6 hours. Formic acid ethi Jshi/! Distill 0*1 at normal pressure, add 130ml of freshly distilled ethyl formic acid,
Reflux for 2 hours. After cooling, remove the white precipitate and concentrate the P solution. The residue was diluted with ethyl acetate/ethyl nitrile (/:
/, v/v) I and insoluble materials are removed.

Concentrate solution F under reduced pressure to obtain N as an oil.

N'-diformylcystamine 21A9 fl is obtained. Dry this with acetonitrile J2! ;0xli dissolved, trityl chloride jlA 2g and triethyl chloride JlA 2/f
/ and stirred at room temperature for 6 hours. The precipitated crystals were collected in a furnace and washed with ethanol to give N, N'-diform ε
Roux N,N-ditritylcystamine is obtained. This was dissolved in 3θOml of methylene chloride, water, SO and tributylphosphine/i31 were added, and the mixture was heated and stirred for 7 hours. After cooling, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is washed with ethanol to obtain N-,formyl-N-tritylcysteaming sy. Melting point l Otsuj~/Otsu7
°C0 Reference Example 5 13-dichloroacetone 23/
llf/ and N-formyl-N with vigorous stirring.
,-) Lythyl cysteamine, f73; A solution consisting of H1 and 30 ml of acetone was added dropwise over 30 minutes and stirred at θ°C for 30 minutes. Remove the precipitate.

Concentrate the furnace liquid under reduced pressure. The residue is dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and concentrated. The resulting oil is subjected to column chromatography on silica gel, eluting with benzene/ethyl acetate (70:t, v/)&t. The eluate was concentrated to obtain N-formyl-N-)lithium-2-(3-chloroacetonylthio)ethylamine g+♂q4 as an oily substance.

NMfL(CDCA), δ 3yuj(s, 2H)
.

1A/J (s, 2H).

723(d, /3H').

ZaJ, 5' ('8./H)

Claims (2)

[Claims] (1) 2-guanidino-4 characterized by treating 2-guanidinoder C2-(N-protected formamide)ethylthiomethyl]thiazole with a deprotecting agent! -(2-(
A new synthesis method for thiazole (formamide)ethylthiomethyazole. (2) Guanylthiourea has the general formula % (% formula %) [In the formula, A represents a reactive group and R represents a protective group, respectively. ] 2-guanidino-+-C by reacting the compound represented by
2-guanidino-4!, characterized in that 2-(N-protected formamido)ethylthiomethylcutiazole is produced and then the product is treated with a deprotecting agent. -C2-(
A new synthesis method for (formamide) ethylthiazole.