4-[[(2-Aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine

Brown Liquid

2-AMINOETHANETHIOL hydrochloride (cysteamine hydrochloride, 520 G, 4.5 mol) is suspended in water (500 ml). This suspension is cooled to 5 C and sodium hydroxide solution (45 percent w/w, 870 ml; 14.7 mol) is added into it at 5-10 C. Into this suspension, hydroxylamine sulphate (100 g; 0.6 mol) is added and stirred. A solution OF 4-CHLOROMETHYL-2- DIMETHYLAMINOMETHYLTHIAZOLE hydrochloride (1000 G ; 4.43 mol) dissolved in water (1250 ml) is prepared separately. This solution is added into the said suspension below 10 C and the reaction continued at 10 C for another 1 h. The completion of the reaction is determined by qualitative HPLC. The reaction mixture is then diluted with water (2000 ml), heated to 40-45o C and extracted with toluene (2 x 2000 ml). The toluene extract is treated with activated carbon at 40-45o C for 30 min. Activated carbon is removed by filtration through HYFLO bed and evaporated toluene from the filtrate under reduced pressure at 60 C to obtain 910 g of the product. Yield = 88 percent.Separately, 105 g of 2- (N, N-dimethylamino) -4-thiazolemethanol and 71.5 g of cysteamine hydrochloride were weighed, mixing, Then dissolved in 210 mL of 48percent hydrobromic acid solution, Warmed to reflux temperature, After the reaction of the raw material is completed, a potassium hydroxide solution with a concentration of 50percent is added to the reaction system to adjust the pH of the system to 12, Then extracted six times with toluene, Each 250mL, The combined organic phase, Off to prepare the formula V;The yield of this process was 94.6percentPurity 99.5percent;2-AMINOETHANETHIOL hydrochloride (cysteamine hydrochloride, 520 G, 4.5 mol) is suspended in water (500 ml). This suspension is cooled to 5 C and sodium hydroxide solution (45 percent w/w, 870 ml; 14.7 mol) is added into it at 5-10 C. Into this suspension, hydroxylamine sulphate (100 g; 0.6 mol) is added and stirred. A solution OF 4-CHLOROMETHYL-2- DIMETHYLAMINOMETHYLTHIAZOLE hydrochloride (1000 G ; 4.43 mol) dissolved in water (1250 ml) is prepared separately. This solution is added into the said suspension below 10 C and the reaction continued at 10 C for another 1 h. The completion of the reaction is determined by qualitative HPLC. The reaction mixture is then diluted with water (2000 ml), heated to 40-45o C and extracted with toluene (2 x 2000 ml). The toluene extract is treated with activated carbon at 40-45o C for 30 min. Activated carbon is removed by filtration through HYFLO bed and evaporated toluene from the filtrate under reduced pressure at 60 C to obtain 910 g of the product. Yield = 88 percent.Preparation of 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-4-pyrimidinethione Following the procedure of Example 12, a mixture of 1.11 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.24 g. of 2-methylthio-5-(3-pyridyl)methyl-4-pyrimidinethione in 15 ml. of pyridine was refluxed for 2 days. The desired reaction product was purified by gradient elution high pressure liquid chromatography over silica using an ethyl acetate/ethanol/ammonium hydroxide solvent system as the eluant. Fractions shown by tlc to contain 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-4-pyrimidinethione free base were combined and the solvent removed by evaporation.Preparation of 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methoxy-4-pyrimidone A reaction mixture was prepared from 1.26 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.36 g. of 2-methylthio-5-(3-pyridyl)methoxy-4-pyrimidone in 20 ml. of pyridine. The reaction mixture was heated to reflux temperature for about 2 days. The pyridine was then removed by evaporation in vacuo and the resulting residue subjected to high pressure liquid chromatography over silica. Fractions shown by tlc to contain the desired compound were combined and the combined fractions rechromatographed on a silica preparative plate using 3percent ammoniated ethanol as the solvent. 2-[2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methoxy-4-pyrimidone free base thus obtained was converted to the trihydrochloride salt by standard procedures. Recrystallization of the crude trihydrochloride salt from ethanol yielded 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methoxy-4-pyrimidone trihydrochloride melting at 183°-185° C. Analysis Calculated: C, 42.11; H, 5.02; N, 15.51: Found: C, 42.35; H, 5.11; N, 15.71.Preparation of 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-4-pyrimidone. A reaction mixture prepared from 1.24 g. of 2-nitroamino-5-(3-pyridyl)methyl-4-pyrimidone, 1.14 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 6 ml. of anhydrous ethanol was refluxed for about 1 day under a nitrogen atmosphere. The volatile constitutents were removed by evaporation to yield an oily residue. Water was added and the aqueous layer extracted with ether and with ethyl acetate. The organic extracts were combined, dried and evaporated to dryness to yield 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-4-pyrimidone as a residue which was crystallized from ether. Recrystallization from an ethanol-ether solvent mixture yielded 2-[2-(2-dimethylaminomethyle-4-thiazolylmethylthio)ethyl]amino-5-(3-pyridyl)methyl-4-pyrimidone melting at 122°-123° C.; yield=0.68 g. Analysis Calculated: C, 54.78; H, 5.81; N, 20.17: Found: C, 54.94; H, 5.65; N, 19.91.Following the procedure of Example 1, a reaction mixture was prepared from 1.62 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine, 1.73 g. of 2-nitroamino-5-(2-pyridyl)methyl-4-pyrimidone and 20 ml. of ethanol. The reaction mixture was heated at refluxing temperature for about 21 hours. The solvents were removed in vacuo and the residue purified by high pressure liquid gradient elution chromatography (silica-ethanol/ethyl acetate/ammonium hydroxide). Fractions containing 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-amino-5-(2-pyridyl)methyl-4-pyrimidone (as determined by TLC) were combined and the solvents removed from the combined fractions by evaporation. The resulting crystalline residue was dissolved in ethanol and a slight excess of 5N aqueous hydrochloric acid added. The reaction mixture was evaporated to dryness and the resulting crystalline residue recrystallized from a mixture of methanol and ethanol to yield 1.2 g. of 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(2-pyridyl)methyl-4-pyrimidone trihydrochloride melting at 205°-207° C. Analysis Calculated: C, 43.39; H, 5.17; N, 15.98: Found: C, 43.11; H, 5.21; N, 16.01.Preparation 3 Preparation of 2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethylamine A reaction mixture was prepared from 18.8 g. of 2-dimethylaminomethyl-4-thiazolemethanol, 12.8 g. of 2-aminoethanethiol hydrochloride (cysteamine hydrochloride) and 160 ml. of 48percent aqueous hydrobromic acid. The reaction mixture was stirred at about 100° C. for about 11 hours. The volatile constituents were removed in vacuo on a rotary evaporator. Water was added and the volatile constituents again removed by evaporation. The resulting residue, comprising 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction, was dissolved in ethanol. The ethanol was evaporated and the resulting residue again dissolved in ethanol. Evaporation of the ethanol yielded a hygroscopic residue which was recrystallized from a methanol-ethyl acetate solvent mixture. 2-(2-Dimethylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide thus prepared had the following physical characteristics: Analysis calculated: C, 22.80; H, 4.25; Br, 50.56; N, 8.86; S, 13.53. Found: C, 23.02; H, 4.31; Br, 50.64; N, 8.80; S, 13.60. The nmr spectrum in DMSOd6 (TMS internal standard) gave the following signals (delta): 2.55-3.2 (multiplet, 4H), 2.84 (singlet 6H), 3.92 (singlet, 2H), 4.74 (singlet, 2H), 7.2-7.7 (broad, 1H), 7.94 (singlet, 1H), 7.92 (broad, 3H), 10.22 (broad, 1H).EXAMPLE 4 Preparation of N-2-propynyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N-cyanoguanidine A solution was prepared from 3.07 g. of dimethyl cyanodithioimidocarbonate and 35 ml. of ethanol. A second solution containing 4.62 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine in 50 ml. of ethanol was added in dropwise fashion with stirring to the first solution over a period of about 1.5 hours. The resulting reaction mixture was stirred for an additional 20 hours after which time the volatile constituents were removed in a rotary evaporator. Chromatography of the residue over silica by gradient elution using ethyl acetate containing increasing quantities of methanol as the eluant yielded fractions containing methyl N-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N'-cyanocarbamidothioate, formed in the above reaction. These fractions were combined and the solvent removed from the combined fractions in a rotary evaporator. The residue weighed 4.8 g. and, after recrystallization from carbon tetrachloride, melted at about 75°-77° C. Analysis Calculated: C, 43.74; H, 5.81; N, 21.25; S, 29.19 Found: C, 43.46; H, 5.71; N, 20.98 S, 29.15 1.32 Grams of the above thioester and 1.98 g of redistilled propargylamine dissolved in 6 ml. of anhydrous methanol, and the solution stirred at reflux temperature under a positive nitrogen pressure for 5 hours, an additional gram of propargylamine was added and the reaction mixture refluxed for an additional 6 hours. The solvent and excess amine were then removed by evaporation on a rotary evaporator. The residue was purified by gradient elution high pressure liquid chromatography (silica-ethyl acetate-methanol). Fractions containing N-2-propynyl-N'-2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl-N-cyanoguanidine formed in the above reaction as shown by TLC were combined to yield 0.96 g. of a glassy residue upon evaporation of the solvent. Rf =0.33 (silica, 5:95 NH4 OH; ethanol). Mass spectrum; m/e 337. The nmr spectrum in CDCl3 (TMS internal standard) shows the following signals (delta): 2.33 (singlet, 6H); 2.28 (multiplet, 1H); 2.73 (triplet, 2H); 3.43 (doublet of triplets, 2H); 3.72 (singlet, 2H); 3.80 (singlet, 2H); 4.0 (multiplet, 2H); 6.36 (multiplet, 1H); 6.63 (multiplet, 1H); 7.01 (singlet, 1H).Preparation 2

Nizatidine intermediate.

Molecular Weight:231.4
XLogP3:0.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:6
Exact Mass:231.08638990
Monoisotopic Mass:231.08638990
Topological Polar Surface Area:95.7
Heavy Atom Count:14
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes