methyl carbamimidate;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound III is synthesized according to the procedure of Pfeiderer (Pfeilderer, W. (1957) Chem. Ber., 90:2272-2276) as follows. 12.2 g of o-methylisourea hydrochloride (110.6 mmol), 11.81 mL methylcyanoacetate (134 mmol), 12.45 g of sodium methoxide (230.5 mmol) and 80 mL of methanol are placed in a 250 mL round bottom flask. The suspension is stirred and refluxed for 5 hours at 68°-70° C. After cooling at room temperatute, the suspension is filtered through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL), and the NaCl on the filter is washed with methanol. The filtrate is filtered by gravity through a Whatman™ no. 1 paper in a 500 mL round bottom flask, and the solvent is evaporated under reduced pressure with a rotary evaporator at 50° C. The residue is solubilized with warm distilled water, and the product is precipitatedd by acidification to pH 3-4 with glacial acetic acid. After 2 hours (or overnight) at room temperature, the suspension is filtered under vacuum through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL). The product is washed with water, acetone, and dried. The product is recrystallized with water as the solvent and using charcoal for decolorizing (activated carbon, NoritrA<100 mesh, decolorizing). The yield is 76%. refluxed for 5 hours at 68°-70° C After cooling at room temperatute the suspension is filtered through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL) the NaCl on the filter is washed with methanol The filtrate is filtered by gravity through a Whatman™ no 1 paper in a 500 mL round bottom flask, and the solvent is evaporated under reduced pressure with a rotary evaporator at 50° C with warm distilled water the suspension is filtered under vacuum through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL) The product is washed with water, acetone dried The product is recrystallized with water as the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 110.5 parts of O-methylisourea hydrochloride in 475 parts of water is adjusted with 8.9 parts of 50% NaOH solution to pH 6. After raising the pH to 9, 114.5 parts of methyl chloroformate is added, while maintaining the pH at 9 by the simultaneous addition of 175.3 parts of 50% NaOH solution. The resulting reaction mass is then extracted 5 times with 134 parts methylene chloride, and the combined extracts are then dried by removing the dissolved water by azeotropic distillation. The resulting methylene chloride solution shows by gas chromatographic analysis the presence of 121.0 parts (92.2% yield) of methyl N-[(amino) (methoxy)methylene]carbamate. One half of the above methylene chloride solution is gradually added to 45 parts of neat phosgene at 0° C within 10 minutes. Initally, gummy solids are formed, which gradually dissolve, as a white crystalline solid precipitates. After holding the temperature to 0° C for 30 minutes, 51.7 parts of solids are isolated by filtration. The filtrate is then evaporated to produce 23.5 parts of residue, which is almost completely soluble in water, and represents (based on equation (I) and the starting 0-methylisourea hydrochloride) a 89.3% yield of crude dimethyl N,N'-{[(2,4-dioxo-1,3-diazetidine)-1,3-diyl]-bis[(methoxy)methylidyne]}biscarbamate. is added while maintaining the pH at 9 The resulting reaction mass is then extracted 5 times with 134 parts methylene chloride the combined extracts are then dried by removing the dissolved water by azeotropic distillation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound III is synthesized according to the procedure of Pfeiderer (Pfeilderer, W. (1957) Chem. Ber., 90:2272-2276) as follows. 12.2 g of o-methylisourea hydrochloride (110.6 mmol), 11.81 mL methylcyanoacetate (134 mmol), 12.45 g of sodium methoxide (230.5 mmol) and 80 mL of methanol are placed in a 250 mL round bottom flask. The suspension is stirred and refluxed for 5 hours at 68°-70° C. After cooling at room temperatute, the suspension is filtered through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL), and the NaCl on the filter is washed with methanol. The filtrate is filtered by gravity through a Whatman™ no. 1 paper in a 500 mL round bottom flask, and the solvent is evaporated under reduced pressure with a rotary evaporator at 50° C. The residue is solubilized with warm distilled water, and the product is precipitatedd by acidification to pH 3-4 with glacial acetic acid. After 2 hours (or overnight) at room temperature, the suspension is filtered under vacuum through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL). The product is washed with water, acetone, and dried. The product is recrystallized with water as the solvent and using charcoal for decolorizing (activated carbon, NoritrA<100 mesh, decolorizing). The yield is 76%. refluxed for 5 hours at 68°-70° C After cooling at room temperatute the suspension is filtered through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL) the NaCl on the filter is washed with methanol The filtrate is filtered by gravity through a Whatman™ no 1 paper in a 500 mL round bottom flask, and the solvent is evaporated under reduced pressure with a rotary evaporator at 50° C with warm distilled water the suspension is filtered under vacuum through a sintered glass funnel (Pyrex, 40-60 ASTM, 60 mL) The product is washed with water, acetone dried The product is recrystallized with water as the solvent

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction of sarcosine with O-methylisourea hydrochloride, described by E. Schutte in Hoppe-Seylers Z. Physiol. Chemie 279 (1943) 52-59, affords creatine in a yield of only 21%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction of sarcosine with O-methylisourea hydrochloride, described by E. Schutte in Hoppe-Seylers Z. Physiol. Chemie 279 (1943) 52-59, affords creatine in a yield of only 21%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction of sarcosine with O-methylisourea hydrochloride, described by E. Schutte in Hoppe-Seylers Z. Physiol. Chemie 279 (1943) 52-59, affords creatine in a yield of only 21%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a sealed tube O-methylisourea hydrochloride (3.0 g, 27 mmol) and dimethyl malonate (3.1 mL, 27 mmol) were dissolved in 30% w/v solution of sodium methoxide in methanol. The reaction mixture was refluxed for four hours before being allowed to cool to ambient temperature overnight. The resultant white precipitate was filtered and dried in vacuo yielding 4.2 g (quantitative yield) of the title compound. The reaction mixture was refluxed for four hours The resultant white precipitate was filtered dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere 3.10 mL (27.0 mmol) dimethylmalonate, 3.00 g (27.1 mmol) o-methylisourea hydrochloride and 15.0 mL (80.8 mmol) sodium methoxide solution (30%) were refluxed for 1.25 h with stirring. The reaction mixture was cooled. The precipitate formed was suction filtered, washed and dried. The reaction mixture was cooled The precipitate formed filtered washed dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under a nitrogen atmosphere, MTBE (3 ml) was added to 60% sodium hydride (0.10 g). Methyl-N-tert-butoxycarbonyl-glycinate (0.39 g, 2.05 mmol) and methyl formate (0.31 g, 5.13 mmol) were dissolved in MTBE (2 ml) in an ice bath and the solution was added dropwise over 1 hr. After overnight stirring at normal temperature, the precipitate was collected by filtration and the crystal and O-methylisourea hydrochloride (0.22 g, 2.05 mmol) were stirred overnight at 40° C. in methanol. The reaction mixture was analyzed by HPLC. As a result, 2-methoxy-6-oxo-5-tert-butoxycarbonylamino-1,6-dihydropyrimidine (0.21 g, 0.88 mmol, yield 43%) was contained. the solution was added dropwise over 1 hr the precipitate was collected by filtration

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene (10 ml) was added to methyl-N-benzyloxycarbonyl-glycinate (1.50 g, 6.73 mmol) and tert-butoxybisdimethylaminomethane (1.83 ml, 8.91 mmol) and the mixture was stirred overnight at 70° C. The mixture was then washed with saturated brine and concentrated under reduced pressure. MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was separated and the organic layer was washed with saturated brine. A solution (1.23 g, 6.39 mmol) of 28% sodium methoxide in methanol was added dropwise and the mixture was concentrated under reduced pressure. Acetonitrile was added and O-methylisourea hydrochloride (0.72 g, 6.50 mmol) was added. The mixture was stirred overnight at 70° C. and concentrated. Water (5 ml) was added and the mixture was stirred for 1 hr. The precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-benzyloxycarbonylamino-1,6-dihydropyrimidine (1.43 g, 5.20 mmol). The property values were the same as in Example 3. The mixture was then washed with saturated brine concentrated under reduced pressure MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath the mixture was stirred at room temperature for 2 hr Thereafter, the mixture was separated the organic layer was washed with saturated brine the mixture was concentrated under reduced pressure Acetonitrile was added The mixture was stirred overnight at 70° C. concentrated Water (5 ml) was added the mixture was stirred for 1 hr The precipitate was collected by filtration and vacuum dried

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene (10 ml) was added to N-benzyloxycarbonyl-glycine methyl ester (1.50 g, 6.73 mmol) and tert-butoxybisdimethylaminomethane (1.83 ml, 8.91 mmol) and the mixture was stirred overnight at 70° C. The mixture was washed with saturated brine and concentrated under reduced pressure. MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was separated and the organic layer was washed with saturated brine. A solution (1.23 g, 6.39 mmol) of 28% sodium methoxide in methanol was added drop-wise and the mixture was concentrated under reduced pressure. The solvent was substituted by acetonitrile and O-methylisourea hydrochloride (0.72 g, 6.50 mmol) was added. The mixture was stirred overnight at 70° C. and concentrated. Water (5 ml) was added and the mixture was stirred for 1 hr. The precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-benzyloxycarbonylamino-1,6-dihydropyrimidine (1.43 g, 5.20 mmol). The mixture was washed with saturated brine concentrated under reduced pressure MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath the mixture was stirred at room temperature for 2 hr Thereafter, the mixture was separated the organic layer was washed with saturated brine the mixture was concentrated under reduced pressure was added The mixture was stirred overnight at 70° C. concentrated Water (5 ml) was added the mixture was stirred for 1 hr The precipitate was collected by filtration and vacuum dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The reaction of sarcosine with O-methylisourea hydrochloride, described by E. Schutte in Hoppe-Seylers Z. Physiol. Chemie 279 (1943) 52-59, affords creatine in a yield of only 21%.