2-aminoethanethiol;hydrochloride

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of cysteamine hydrochloride (5.68 g) in water (20 ml) was added to a suspension of N-cyano-N,S-dimethylisothiourea (6.46 g) in ethanol (100 ml). A solution of sodium hydroxide (4.0 g) in water (20 ml) was added to the mixture and the suspension was heated under reflux for one hour. The resulting clear solution was concentrated to remove ethanol, a little more water was added and the alkaline aqueous solution was extracted with ethyl acetate. The aqueous solution was adjusted to pH4 with hydrochloric acid and extracted with ethyl acetate. This latter organic extract was dried and evaporated to give N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.12 g) as a colourless oil. In order to characterise this product a solution of 2,4-dinitrochlorobenzene (7.7 g) in 95% ethanol (50 ml) was added to a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (6.0 g) in 95% ethanol. The mixture was refluxed for one hour and cooled. The resulting crystalline solid (7.73 g) was collected and was triturated with a large volume of ether and was recrystallised from acetonitrile to afford N-cyano-N'-methyl-N"-[S-(2,4-dinitrophenyl)-2-mercaptoethyl]guanidine, m.p. 210°-211° C. the suspension was heated under reflux for one hour The resulting clear solution was concentrated to remove ethanol a little more water was added the alkaline aqueous solution was extracted with ethyl acetate extracted with ethyl acetate This latter organic extract was dried evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cysteamine hydrochloride (4.5 g) was added to a cooled solution of potassium-t-butoxide (8.98 g) in dry dimethylformamide (125 ml). The mixture was stirred for 20 min and [5-[4-(dimethylamino)butyl]-2-furanyl]methyl ethanoate (9.6 g) was added. The reaction was heated at 90° for 4 hr, poured onto an ice-water mixture and extracted with chloroform. Distillation of the organic extract gave a yellow oil which after column chromatography on silica, using methanol/0.880 ammonia (9:1) as eluent, and a further distillation afforded a colourless oil b.p. 140°/0.05 mm Hg. Found: C, 60.81; H, 9.86; N, 10.44, Calc. for C13H24N2OS: C, 60.91; H, 9.44; N, 10.93%. The reaction was heated at 90° for 4 hr extracted with chloroform Distillation of the organic extract gave a yellow oil which after column chromatography on silica a further distillation

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1 equivalent of cysteamine hydrochloride and 1 equivalent of triphenylmethanol are dissolved in glacial acetic acid at 60° and treated with stirring with 1.1 equivalents of BF3 etherate. The mixture is stirred for one hour and worked up in the customary manner and Trt-cysteamine hydrochloride (“C”) is obtained. treated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Equimolar quantities of 2-methoxymethyl(1,3,4)thiadiazole and cysteamine hydrochloride were refluxed under nitrogen for 42 hours in a three-fold excess of hydrobromic acid (48%). The mixture was evaporated to dryness and the residue was dissolved in water. The solution was adjusted to pH 11 by the addition of IRA 400(OH-) and applied to a column of CG50(H+) which was eluted with dilute acetic acid. The eluate was evaporated to give 2-(2-(1,3,4)thiadiazolylmethythio)ethylamine as an oil. The mixture was evaporated to dryness the residue was dissolved in water The solution was adjusted to pH 11 by the addition of IRA 400(OH-) was eluted with dilute acetic acid The eluate was evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Cysteamine hydrochloride (3.75 g) was added to a stirred solution of sodium ethoxide (prepared from 2.83 g sodium) in ethanol (200 ml) and the mixture was cooled to less than 10°. 2-Chloromethyl-4-dimethylaminomethylpyridine dihydrochloride (7.3 g) was added portionwise and the solution was stirred for 1 hour. Water (200 ml) was added, the pH was adjusted to ca. 4 with hydrochloric acid and the volume was reduced to ca. 100 ml. The solution was extracted with chloroform, the aqueous phase was basified to pH 12 and extracted with chloroform to give 2-[4-dimethylaminomethyl-2-pyridylmethylthio)ethylamine (4.7 g) as an oil. the mixture was cooled to less than 10° The solution was extracted with chloroform extracted with chloroform

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (50% w/w dispersion in oil; 0.114 g.) was added portionwise to ethanol (2 ml.). To the resulting solution was added 2-aminoethanethiol hydrochloride (0.134 g.) and the mixture stirred at room temperature. 2-[2-(2,2,2-Trifluoroethyl)guanidino]-6-chloropyrazine (0.1 g.) was added and the mixture heated under reflux on a steam bath for 22 hours. The mixture was cooled, evaporated, water added and extracted with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and the filtrate evaporated to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[(2-aminoethyl)thio]pyrazine as a gum (0.16 g.) which was used without further purification. the mixture heated under reflux on a steam bath for 22 hours The mixture was cooled evaporated water added extracted with ethyl acetate The extracts were dried over magnesium sulphate filtered the filtrate evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-chloromethyl-3-carboethoxy-4-(m-nitrophenyl) -5-nitro-6-methyl-1,4-dihydropyridine (1.5 g) in EtOH (15 ml) is added dropwise at 0° C. under N2 atmosphere to a solution of cysteamine hydrochloride (0.9 g) and sodium hydroxide (0.32 g) in EtOH (45 ml). After two hours the solution is acidified (pH≃4) with AcOH, evaporated under reduced pressure and the residue is dissolved in water (50 ml) and extracted with Et2O (2×20 ml). The ethereal extractions are discarded, the water layer is made basic with NaHCO3 and extracted with AcOEt (2×20 ml); the organic phase is washed with water (3×10 ml), dried (Na2SO4), added to a solution of fumaric acid (0.45 g) in MeOH (15 ml), and evaporated to dryness. The residue is crystallized from AcOEt to give 1.9 g of 2-[(2-aminoethyl)thio]methyl-3-carboethoxy-4-(m-nitrophenyl)-5-nitro-6-methyl-1,4-dihydropyridine fumarate (C18H22N4O6S.C4H4O4), m.p. 182°-185° C. (pH≃4) with AcOH, evaporated under reduced pressure the residue is dissolved in water (50 ml) extracted with Et2O (2×20 ml) The ethereal extractions extracted with AcOEt (2×20 ml) the organic phase is washed with water (3×10 ml) dried (Na2SO4) added to a solution of fumaric acid (0.45 g) in MeOH (15 ml) evaporated to dryness The residue is crystallized from AcOEt

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the aqueous phase from Example 14 above was added 27 g. of 2-aminoethanethiol, hydrochloride. The mixture was heated and stirred, until the pot temperature reached 120°. The mixture was held at that temperature for 6 hours, and was then allowed to cool to 60°. To the residue was added 80 ml. of deionized water, and the mixture was allowed to cool to ambient temperature and stand for some days. Eighty ml. of dichloromethane was then added, and the pH of the mixture was adjusted to 6.1 by the addition of 9 ml. of 50% sodium hydroxide. The aqueous layer was extracted twice with 40 ml. portions of dichloromethane, and the aqueous layer was then mixed with 80 ml. of dichloromethane and the pH was adjusted to 12.6 by the addition of 40 ml. of 50% sodium hydroxide. The aqueous layer of the resulting mixture was extracted twice with 40 ml. of dichloromethane, and the two aqueous layers were combined, filtered and evaporated under vacuum to obtain 31.5 g. of the desired product, which was found to be 74.7% pure by the analytical method described in Preparation 1 above. The mixture was heated reached 120° to cool to 60° To the residue was added 80 ml stand for some days the pH of the mixture was adjusted to 6.1 by the addition of 9 ml The aqueous layer was extracted twice with 40 ml portions of dichloromethane, and the aqueous layer was then mixed with 80 ml of dichloromethane and the pH was adjusted to 12.6 by the addition of 40 ml The aqueous layer of the resulting mixture was extracted twice with 40 ml filtered evaporated under vacuum to obtain 31.5 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To the solution from Example 13 above was added 56.7 g. of 2-aminoethanethiol, hydrochloride. The mixture was then heated and stirred, and distilled. The distillation was stopped when the pot temperature reached 133°, after 22 ml. of organic and 115 ml. of aqueous distillate had been received. To the residue remaining in the distillation flask was added 100 ml. of deionized water, 100 ml. of dichloromethane, and 100 ml. of 50% aqueous sodium hydroxide, dropwise with ice bath cooling. The mixture was then filtered, and the filter cake was washed with dichloromethane. The aqueous layer of the filtrate was extracted twice with 100 ml. portions of dichloromethane, and then the organic layers were combined, dried over sodium sulfate and filtered. The filtrate was evaporated to dryness under vacuum to obtain 97.7 g. of the desired product, which was identified as being 79.8% pure by gas chromatography, using a 2 mm. by 6-foot column of Gaschrom-Q (Applied Science Co.) containing 10% of OV-210 (Ohio Valley Chemical Co.) using 25 ml./min. of helium as the carrier at 170° isothermal. The mixture was then heated distilled The distillation reached 133° was added 100 ml of 50% aqueous sodium hydroxide, dropwise with ice bath cooling The mixture was then filtered the filter cake was washed with dichloromethane The aqueous layer of the filtrate was extracted twice with 100 ml dried over sodium sulfate filtered The filtrate was evaporated to dryness under vacuum to obtain 97.7 g

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the above procedure, 10.1 millimoles of 2-(methylaminomethyl)-4-thiazolemethanol dihydrochloride, 1.15 g. of cysteamine hydrochloride and 15 ml. of 48% aqueous hydrobromic acid were stirred at about 100° C. for about 7.5 hours. Water and hydrobromic acid were removed on a rotary evaporator and the resulting residue comprising 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine trihydrobromide formed in the above reaction was dissolved in water and the water removed by evaporation. The residue was again taken up in water and the water removed by evaporation. The residue was then dissolved in a small volume of water and a solution of 5.5 g. of potassium carbonate in 15 ml. of water was added. The resulting alkaline solution was evaporated to dryness. The resulting residue, comprising the free base of 2-(2-methylaminomethyl-4-thiazolylmethylthio)ethylamine, was slurried with ethanol and the ethanol separated and removed by evaporation. The residue was twice slurried with isopropanol. The residue was next extracted with boiling isopropanol several times and the combined isopropanol extracts combined and filtered. Removal of the isopropanol yielded a yellow oil. The yellow oil was dissolved in chloroform and the chloroform solution filtered. Chloroform was evaporated from the filtrate to yield 1.59 g. of a yellow oil comprising 2-(2methylaminomethyl-4-thiazolylmethylthio)ethylamine. The compound had the following physical characteristics: Water and hydrobromic acid were removed on a rotary evaporator

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 17.0 g (0.15 mol) of cysteaminium chloride and 19.8 g (0.3 mol) of potassium hydroxide are boiled for 3 hours on a water separator in 180 ml of toluene. 24.6 g (0.1 mol) of 2-chlorothioxanthone and 180 mol of dimethylpropyl-eneurea are added to the evaporated residue, and the mixture is stirred for 20 hours at 100° C. The reaction mixture is poured into 1 l of 2N hydrochloric acid and the aqueous phase is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 10 and extracted with ethyl acetate. Work-up of the organic phase gives 24.0 g of the analytically pure compound IIIb. the aqueous phase is extracted with ethyl acetate extracted with ethyl acetate gives 24.0 g of the analytically pure compound IIIb

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the procedure of Example 3, a reaction mixture consisting of 6.4 g. of ethyl 2-(dimethylaminomethyl)-5-methyl-4-thiazolemethanol, 4.2 g. of cysteamine hydrochloride and 30 ml. of 48% aqueous hydrobromic acid was maintained at a temperature of about 100° C. under a nitrogen atmosphere for about 4 hours. The reaction mixture was cooled and the volatile constituents removed in vacuo. The resulting dark residue was twice trituated with ethanol and the ethanol removed by evaporation to remove residual HBr. The residue was then treated with 50 ml. of 5 N aqueous sodium hydroxide. The alkaline layer was continuously extracted with ether over an 18 hour period. The ether extract was dried and the ether removed therefrom in vacuo to provide 2-([2-(dimethylaminomethyl)-5-methyl-4-thiazolyl]methylthio)ethylamine prepared in the above reaction. The compound was a brown oil having the following physical characteristics: yield=1.38 g. The reaction mixture was cooled the volatile constituents removed in vacuo the ethanol removed by evaporation to remove residual HBr The residue was then treated with 50 ml The alkaline layer was continuously extracted with ether over an 18 hour period The ether extract was dried the ether removed