2-Guanidino-4-hydroxymethylthiazole and derivatives thereof

A compound of the formula: ##STR1## wherein R is hydrogen, C.sub.1 -C.sub.5 alkanoyl or substituted sulfonyl, which is useful as a synthetic intermediate to 2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole, histamine H.sub.2 receptor antagonist.

The present invention relates to 2-guanidino-4-hydroxymethylthiazole and 
derivatives thereof. More particularly, this invention relates to a 
compound of the formula: 
##STR2## 
in which R is hydrogen, C.sub.1 -C.sub.5 alkanoyl or substituted sulfonyl, 
which is useful as a synthetic intermediate to 
2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole, histamine H.sub.2 
receptor antagonist. [U.S. patent application Ser. No. 256,918]. 
In the formula (I), the C.sub.1 -C.sub.5 alkanoyl includes illustratively 
formyl, acetyl, propionyl, butyryl and valeryl, with the acetyl group 
being preferred. The substituted sulfonyl includes illustratively C.sub.1 
-C.sub.5 alkanesulfonyl such as methanesulfonyl, ethanesulfonyl, 
propanesulfonyl, butanesulfonyl and pentanesulfonyl, preferably 
methanesulfonyl (mesyl) and C.sub.6 -C.sub.8 arenesulfonyl such as 
benzenesulfonyl, toluenesulfonyl, or xylenesulfonyl, preferably 
4-toluenesulfonyl (tosyl). 
Said compound of the formula (I) can be prepared by the following scheme: 
##STR3## 
(in which R.sup.1 is C.sub.1 -C.sub.5 alkanoyl, R.sup.2 is C.sub.1 
-C.sub.5 alkyl, R.sup.3 is C.sub.1 -C.sub.5 alkyl or C.sub.6 -C.sub.8 
aryl, and X, X.sup.1 and Y are each halogen (e.g. chlorine, bromine, 
etc.)). 
Route A 
2-Guanidino-4-(alkanoyloxymethyl)thiazole (Ia) is prepared by reacting 
1-alkanoyloxy-3-halo-2-propanone (II) with guanylthiourea in an inert 
solvent such as acetone, dimethylformamide, dimethylsulfoxide, or 
pyridine. The reaction may be performed at room temperature or under 
heating up to 100.degree. C., preferably 20.degree. to 70.degree. C. 
Then the above product (Ia) is subjected to hydrolysis with an inorganic 
base such as an alkali metal hydroxide (e.g. sodium hydroxide, potassium 
hydroxide), alkali an metal hydrogencarbonate (e.g. potassium 
hydrogencarbonate, sodium hydrogencarbonate) or an alkali metal carbonate 
(e.g. potassium carbonate, sodium carbonate). The reaction may be 
performed at room temperature (about 15.degree. to 20.degree. C.) or under 
heating up to 100.degree. C. in a solvent such as methanol, ethanol, 
dioxane, acetone, dimethylsulfoxide or water or a mixed solvent thereof. 
Thus 2-guanidino-4-hydroxymethylthiazole (Ib) is prepared in a good yield. 
The starting 1-alkanoyloxy-3-halo-2-propanone (II) is prepared by reacting 
epihalohydrin with an alkanoic acid to give 
1-alkanoyloxy-3-halo-2-propanol and oxidizing the resulting propanol with 
a Jones reagent. 
Route B 
2-Guanidino-4-alkoxycarbonylthiazole (IV) is prepared by reacting alkyl 
3-halopyruvate (III) with guanylthiourea in a solvent. The reaction is 
performed under heating about 50.degree. to 120.degree. C., preferably 
about 65.degree. to 95.degree. C. in a solvent such as methanol, ethanol, 
dimethylformamide, dimethylsulfoxide, pyridine or hexamethylphosphoric 
triamide. 
Then the above product (IV) is reduced with an aluminum hydride compound 
such as lithium aluminum hydride, sodium bis(methoxyethoxy)aluminum 
hydride, lithium bis(methoxyethoxy)aluminum hydride or the like. The 
reaction is performed at room temperature to the boiling point of the 
solvent used in an appropriate solvent such as tetrahydrofuran, dioxane, 
diglyme, toluene or the like. Thus 2-guanidino-4-hydroxymethylthiazole 
(Ib) is prepared in a good yield. 
The above product (Ib) is converted into 2-guanidino-4-(substituted 
sulfonyloxymethyl)thiazole (Ic) by reacting the compound (Ib) with an 
alkanesulfonyl or arenesulfonyl halide (V) in the presence of a base such 
as pyridine or triethylamine. The reaction may be performed in a solvent 
such as acetone, toluene, dimethylformamide, dimethylsulfoxide, or 
hexamethylphosphoric triamide at room temperature. 
The product (I), namely 2-guanidino-4-hydroxymethylthiazole (Ib) and 
derivatives thereof (Ia) and (Ic) are useful as synthetic intermediates to 
2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole, histamine H.sub.2 
receptor antagonist [U.S.patent application Ser. No. 256,918]. For 
example, said H.sub.2 antagonist is prepared by reacting 
2-guanidino-4-hydroxymethylthiazole (Ib) with N,N'-diformylcystamine in 
the presence of a phosphorus compound such as tributylphosphine, 
triphenylphosphine or methylphenylaminotriphenylphosphonium iodide 
[J.Org.Chem., 28, 483 (1963)]. This reaction may be performed under 
cooling or heating (0.degree. to 100.degree. C.), preferably at room 
temperature in a protic solvent such as pyridine, dimethylformamide or the 
like.

Presently preferred and practical embodiments of the present invention are 
illustratively shown in the following examples. 
EXAMPLE 1 
Preparation of 2-guanidino-4-acetoxymethylthiazole hydrochloride: 
(1) A suspension of epichlorhydrin (27.8 g) and sodium acetate (12.3 g) in 
acetic acid (36 g) is heated at 50.degree.-55.degree. C. for 8 hours. The 
reaction mixture is allowed to stand overnight and concentrated in vacuum. 
The residue is neutralized with aqueous sodium hydrogencarbonate and 
shaken with ether. The ethereal layer is dried over anhydrous sodium 
sulfate and concentrated in vacuum. The residue is distilled in vacuum to 
give 1-acetoxy-3-chloro-2-propanol (30 g) as an oil boiling at 
115.degree.-116.degree. C./13 mm Hg. The yield is 65.4%. 
(2) To a solution of 1-acetoxy-3-chloro-2-propanol (15.3 g) in acetone (250 
ml) is dropwise added Jones reagent (37.4 ml) containing chromic anhydride 
(10.39 g) and conc. sulfuric acid (10.18 ml) in 1 hour, and the resultant 
mixture is stirred at room temperature for 3 hours. The reaction mixture 
is mixed with isopropanol (10 ml) and the insoluble material is filtered 
off. The organic layer is concentrated in vacuum, and the residue is 
distilled to give 1-acetoxy-3-chloro-2-propanone (9 g) as an oil boiling 
at 102.degree.-104.degree. C./15 mm Hg. The yield is 60.0%. 
NMR (CDCl.sub.3), .delta.2.17 (s, 3H), 4.13 (s, 2H), 4.87 (s, 2H). 
[Heese, et al., Ber. 48, 1986 (1915)]. 
(3) A suspension of 1-acetoxy-3-chloro-2-propanone (4.52 g) and 
guanylthiourea (3.55 g) in acetone (100 ml) is stirred at room temperature 
for 64 hours. The precipitated crystals are filtered to give 
2-guanidino-4-acetoxymethylthiazole hydrochloride hemihydrate (6.2 g) as 
crystals melting at 170.degree.-172.degree. C. 
EXAMPLE 2 
Preparation of 2-guanidino-4-hydroxymethylthiazole: 
(1) A suspension of guanylthiourea (2.36 g) and ethyl 3-bromopyruvate (4.8 
g) in dry ethanol (50 ml) is refluxed under stirring for 2.5 hours. The 
reaction mixture is concentrated in vacuum to dryness, and the residue is 
dissolved in water (about 100 ml). The aqueous solution is washed with 
ethyl acetate and made alkaline with 5% sodium hydrogencarbonate solution. 
The precipitated crystals are filtered, washed with water and dried to 
give 2-guanidino-4-ethoxycarbonylthiazole (3.6 g) as crystals. The yield 
is 84%. 
NMR (d.sub.6 -DMSO), .delta.1.28 (t, 3H, J=7 Hz), 4.23 (q, 2H, J=7 Hz), 
6.93 (br. s, 4H), 7.55 (s, 1H). 
(2) To a suspension of lithium aluminum hydride (0.5 g) in dry 
tetrahydrofuran (260 ml) is portionwise added 
2-guanidino-4-ethoxycarbonylthiazole (3.6 g) at 0.degree. C. with stirring 
in half an hour, and the resultant mixture is refluxed under stirring for 
4 hours. Ethyl acetate and water are added to the reaction mixture for 
decomposing excess lithium aluminum hydride. The organic layer is 
separated and the residual layer is extracted with methanol. The 
methanolic extract is combined with the organic layer, dried over 
anhydrous sodium sulfate and concentrated in vacuum. The residue is 
chromatographed on a column of silica gel, which is eluted with ethyl 
acetate:methanol (4:1, v/v). The eluate is concentrated in vacuum to give 
2-guanidino-4-hydroxymethylthiazole (1.8 g) as crystals melting at 
163.degree.-165.degree. C. The yield is 62.2%. 
NMR (CD.sub.3 OD), .delta.4.48 (s, 2H), 6.57 (s, 1H). 
EXAMPLE 3 
Preparation of 4-guanidino-2-hydroxymethylthiazole: 
To a solution of sodium hydroxide (2 g) in methanol (100 ml) is added 
2-guanidino-4-acetoxymethylthiazole hydrochloride hemihydrate (6.15 g), 
and the resultant mixture is stirred at room temperature for half an hour. 
The insoluble material is filtered off, and the filtrate is concentrated 
in vacuum. The residue is chromatographed on a column of silica gel, which 
is eluted with methanol:ethyl acetate (1:4, v/v). The eluate is 
concentrated to give 2-guanidino-4-hydroxymethylthiazole (3.5 g) as 
crystals melting at 163.degree. to 165.degree. C. The yield is 82.9%. 
Anal. Calcd. for C.sub.5 H.sub.8 N.sub.4 OS: C, 34.87; H, 4.68; N, 32.54; 
S, 18.62 (%). Found: C, 34.88; H, 4.58; N, 32.13; S, 18.51 (%). 
EXAMPLE 4 
Preparation of 2-guanidino-4-hydroxymethylthiazole: 
Using potassium carbonate (6.6 g) and methanol (90 ml), the reaction is 
performed as in Example 3, whereby 2-guanidino-4-hydroxymethylthiazole 
(7.2 g) is obtained from 2-quanidino-4-acetoxymethylthiazole hydrochloride 
hemihydrate (12.4 g). The yield is 87.2%. 
EXAMPLE 5 
Preparation of 2-guanidino-4-(4-toluenesulfonyloxymethyl)thiazole: 
To a solution of 2-guanidino-4-hydroxymethylthiazole (0.69 g) in pyridine 
(5 ml) is gradually added 4-toluenesulfonyl chloride (0.763 g), and the 
resultant mixture is stirred at room temperature for 4 hours. The 
resultant mixture is concentrated in vacuum, and the residue is 
chromatographed on a column of silica gel, which is eluted with methanol. 
The eluate is concentrated in vacuum to give 
2-guanidino-4-(4-toluenesulfonyloxymethyl)thiazole (0.6 g) as an oil. The 
yield is 45.8%. 
NMR (CD.sub.3 OD), .delta.2.33 (s, 3H), 5.87 (s, 2H), 7.62 (s, 1H), 
7.17-7.66 (ABq, J=8 Hz, 4H), 
IR .nu..sub.max.sup.film 1170, 1220 cm.sup.-1. 
EXAMPLE 6 
To a solution of 2-guanidino-4-hydroxymethylthiazole (0.86 g) in pyridine 
(6 ml) is gradually added methanesulfonyl chloride (0.6 g) under ice 
cooling, and the resultant mixture is stirred at room temperature for 2 
hours. The reaction mixture is concentrated in vacuum, and the residual 
oil is chromatographed on a column of silica gel, which is eluted with 
methanol. The eluate is concentrated in vacuum to give 
2-guanidino-4-(methanesulfonyloxymethyl)thiazole (1.2 g) as an oil. The 
yield is 96%. 
NMR (CD.sub.3 OD), .delta.2.70 (s, 3H), 5.83 (s, 2H), 7.57 (s, 1H). 
IR .nu..sub.max.sup.film 1170, 1220 cm.sup.-1. 
REFERENTIAL EXAMPLE 
A mixture of 2-guanidino-4-hydroxymethylthiazole (0.517 g), 
N,N'-diformylcystamine (1.87 g), tributylphosphine (1.82 g) and pyridine 
(1.5 ml) is stirred at room temperature for 8 hours. The reaction mixture 
is allowed to stand overnight and concentrated in vacuum and treated with 
maleic acid. The residue is chromatographed on a column of silica gel, 
which is eluted with methanol:ethyl acetate (1:4, v/v). The eluate is 
concentrated in vacuum to give 
2-guanidino-4-[2-(formamido)ethylthiomethyl]thiazole maleate (0.81 g) as 
crystals melting at 146.degree.-148.degree. C. The yield is 71.7%.