6,7-dichloro-3,5-dihydro-1H-imidazo[2,1-b]quinazolin-2-one

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

実験手順: To a mixture of 15 ml of ethylene glycol and 2 ml (0.02 moles) of cc. hydrochloric acid, warmed to 120° C., 2.50 g (0.01 mole) of (2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetonitrile are added, and the solution is stirred at the same temperature for 20 minutes. Then it is cooled to room temperature and made neutral with 10% potassium carbonate solution. The separated crystals are filtered off. Thus 2.72 g (97.1%) of crude 6,7-dichloro-1,5dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 97.2%), which is dissolved in a hot mixture of 15 ml of methanol and 16 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.76 moles/1000 ml) and allowed to crystallize. Then it is cooled, the separated product is filtered off and washed with a slight amount of ethanol. The separated crystals are filtered off

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

実験手順: To a solution of 10 ml of ethylene glycol in 0.5 ml (0.005 moles) of cc. hydrochloric acid, warmed to 120° C., 0.28 g (0.001 mole) of (2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetonitrile are added, and the solution is stirred at the same temperature for 20 minutes. Then it is cooled to room temperature and made neutral with 10% potassium carbonate solution. The separated crystals are filtered off. Thus 0.27 g (96.4%) of crude 6,7-dichloro-1, 5-dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 96.3%), which is dissolved in a hot mixture of 7 ml of methanol and 6 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.76 moles/1000 ml) and allowed to crystallize. Then it is cooled, the separated product is filtered off and washed with a slight amount of ethanol. The separated crystals are filtered off

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

実験手順: To a solution of 10 ml of ethylene glycol in 0.5 ml (0.005 moles) of cc. hydrochloric acid, warmed to 120° C., 0.28 g (0.001 mole) of (2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetonitrile are added, and the solution is stirred at the same temperature for 20 minutes. Then it is cooled to room temperature and made neutral with 10% potassium carbonate solution. The separated crystals are filtered off. Thus 0.27 g (96.4%) of crude 6,7-dichloro-1, 5-dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 96.3%), which is dissolved in a hot mixture of 7 ml of methanol and 6 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.76 moles/1000 ml) and allowed to crystallize. Then it is cooled, the separated product is filtered off and washed with a slight amount of ethanol. The separated crystals are filtered off

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

実験手順: To a solution of 150 ml of ethylene glycol and 15 ml (0.15 moles) of cc. hydrochloric acid 24.5 g (0.075 moles) of ethyl-(2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetate are added in small portions, within about 10 minutes, at 115° C., and the mixture is kept at the same temperature for further 20 minutes. Then it is cooled to room temperature and made neutral by the dropwise addition of 10% potassium carbonate solution. The separated crystals are filtered off. Thus 17.75 g (93.0%) of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 99.5%), which is dissolved in a hot mixture of 150 ml of methanol and 150 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.75 moles/1000 ml). The mixture is then cooled, the separated product is filtered off and washed with a slight amount of ethanol. The separated crystals are filtered off

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

実験手順: To a solution of 150 ml of ethylene glycol and 15 ml (0.15 moles) of cc. hydrochloric acid 24.5 g (0.075 moles) of ethyl-(2-cyanoimino-5,6-dichloro-1,2,3,4-tetrahydroquinazolin-3-yl) acetate are added in small portions, within about 10 minutes, at 115° C., and the mixture is kept at the same temperature for further 20 minutes. Then it is cooled to room temperature and made neutral by the dropwise addition of 10% potassium carbonate solution. The separated crystals are filtered off. Thus 17.75 g (93.0%) of 6,7-dichloro-1,5-dihydroimidazo[2,1-b]quinazolin-2[3H]-one base are obtained (m.p.>300° C., HPLC content: 99.5%), which is dissolved in a hot mixture of 150 ml of methanol and 150 ml of cc. ethanolic hydrogen chloride (hydrogen chloride content: 0.75 moles/1000 ml). The mixture is then cooled, the separated product is filtered off and washed with a slight amount of ethanol. The separated crystals are filtered off

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

実験手順: Anagrelide is an imidazoquinazoline that is sparingly soluble in dimethylsulfoxide and N,N-dimethylformamide and very slightly soluble in water. Anagrelide is insoluble in diethyl ether or n-heptane. Anagrelide can be made using any of the processes known in the art (e.g., see U.S. Pat. Nos. 3,932,407; 4,146,718; 4,208,521; 4,357,330; Re 31,617; 5,801,245, and 6,388,073 and WO/2002/008228). Commercially, as discussed in U.S. Pat. No. 5,801,245, anagrelide has been prepared as the hydrochloride monohydrate from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide (CNBr) in an aprotic solvent to give the iminoquinazoline intermediate, which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base. For example, anagrelide can be prepared as shown in Scheme I below, by treating ethyl 2-(6-amino-2,3-dichlorobenzyl-amino)acetate with CNBr in toluene under reflux to produce ethyl 2-(5,6-dichloro-2-imino-1,2-dihydroquinazolin-3(4H)-yl)acetate, which, when treated with triethylamine in ethanol under reflux, yields anagrelide free base. The free base can be converted to anagrelide hydrochloride monohydrate by appropriate treatment with HCl. The CAS® Registry Number for anagrelide monohydrochloride is 58579-51-4. under reflux

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

実験手順: Anagrelide is an imidazoquinazoline that is sparingly soluble in dimethylsulfoxide and N,N-dimethylformamide and very slightly soluble in water. Anagrelide is insoluble in diethyl ether or n-heptane. Anagrelide can be made using any of the processes known in the art (e.g., see U.S. Pat. Nos. 3,932,407; 4,146,718; 4,208,521; 4,357,330; Re 31,617; 5,801,245, and 6,388,073 and WO/2002/008228). Commercially, as discussed in U.S. Pat. No. 5,801,245, anagrelide has been prepared as the hydrochloride monohydrate from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide (CNBr) in an aprotic solvent to give the iminoquinazoline intermediate, which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base. For example, anagrelide can be prepared as shown in Scheme I below, by treating ethyl 2-(6-amino-2,3-dichlorobenzyl-amino)acetate with CNBr in toluene under reflux to produce ethyl 2-(5,6-dichloro-2-imino-1,2-dihydroquinazolin-3(4H)-yl)acetate, which, when treated with triethylamine in ethanol under reflux, yields anagrelide free base. The free base can be converted to anagrelide hydrochloride monohydrate by appropriate treatment with HCl. The CAS® Registry Number for anagrelide monohydrochloride is 58579-51-4. under reflux

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

実験手順: 6,7-Dichloro-1,5-dihydroimidazo[2,1-b]-quinazolin-2(3H)-one (94.0 g, 0.367 mol) was added to 2.82 liters of boiling methanol. To the suspension was added 77 ml. (0.92 mol) of concentrated hydrochloric acid. A nearly complete solution resulted. Darco G-60 was added, the mixture was boiled for ca. 3 minutes and then filtered. The filtrate was reheated to boiling to effect solution, then cooled slightly, and 1.9 liters of ether added cautiously. The mixture was stirred at ambient temperature for 2 hours and the solid was filtered off. (Crop A). To the suspension was added 77 ml A nearly complete solution resulted filtered cooled slightly 1.9 liters of ether added cautiously the solid was filtered off

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

実験手順: 6,7-Dichloro-1,5-dihydroimidazo[2,1-b]-quinazolin-2(3H)-one (94.0 g, 0.367 mol) was added to 2.82 liters of boiling methanol. To the suspension was added 77 ml. (0.92 mol) of concentrated hydrochloric acid. A nearly complete solution resulted. Darco G-60 was added, the mixture was boiled for ca. 3 minutes and then filtered. The filtrate was reheated to boiling to effect solution, then cooled slightly, and 1.9 liters of ether added cautiously. The mixture was stirred at ambient temperature for 2 hours and the solid was filtered off. (Crop A). To the suspension was added 77 ml A nearly complete solution resulted filtered cooled slightly 1.9 liters of ether added cautiously the solid was filtered off

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

実験手順: Anagrelide is an imidazoquinazoline that is sparingly soluble in dimethylsulfoxide and N,N-dimethylformamide and very slightly soluble in water. Anagrelide is insoluble in diethyl ether or n-heptane. Anagrelide can be made using any of the processes known in the art (e.g., see U.S. Pat. Nos. 3,932,407; 4,146,718; 4,208,521; 4,357,330; Re 31,617; 5,801,245, and 6,388,073 and WO/2002/008228). Commercially, as discussed in U.S. Pat. No. 5,801,245, anagrelide has been prepared as the hydrochloride monohydrate from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide (CNBr) in an aprotic solvent to give the iminoquinazoline intermediate, which is isolated and then reacted with a base in a hot solution of alcohol to form anagrelide base. For example, anagrelide can be prepared as shown in Scheme I below, by treating ethyl 2-(6-amino-2,3-dichlorobenzyl-amino)acetate with CNBr in toluene under reflux to produce ethyl 2-(5,6-dichloro-2-imino-1,2-dihydroquinazolin-3(4H)-yl)acetate, which, when treated with triethylamine in ethanol under reflux, yields anagrelide free base. The free base can be converted to anagrelide hydrochloride monohydrate by appropriate treatment with HCl. The CAS® Registry Number for anagrelide monohydrochloride is 58579-51-4. under reflux

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

実験手順: Commercially, as discussed in U.S. Pat. No. 5,801,245 and as shown in FIG. 1, Anagrelide has been prepared as the hydrochloride monohydrate (compound IV) from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent to give the iminoquinazoline intermediate (compound II) which is isolated and then reacted with a base in a hot solution of alcohol to form Anagrelide base (compound III).

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

実験手順: Commercially, as discussed in U.S. Pat. No. 5,801,245 and as shown in FIG. 1, Anagrelide has been prepared as the hydrochloride monohydrate (compound IV) from the intermediate, ethyl N-(6-amino-2,3-dichlorobenzyl)glycine (compound I) by reaction with cyanogen bromide in hot alcohol solution, or, preferentially, by reaction with cyanogen bromide in an aprotic solvent to give the iminoquinazoline intermediate (compound II) which is isolated and then reacted with a base in a hot solution of alcohol to form Anagrelide base (compound III).