ethyl 2-[(6-amino-2,3-dichlorophenyl)methylamino]acetate

反応条件: temp:0.00; pressure:0.00; stir:

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: A solution of cyanogen bromide (89.6 g, 0.85 mol) in toluene (1.6 liters) was poured into a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester (231 g, 0.834 mol) in toluene (1.6 liters). The temperature rose quickly from 18° to 31°. The mixture was slowly (1 hour) heated to reflux and refluxed for 12 hours. The mixture was cooled to room temperature and filtered, the product being washed with toluene both by decantation and on the filter. The residue was washed with ether and then dried under pump vacuum (0.5-1 mm Hg) over P2O5. A yield of 290 g (91%) of the title product was obtained as a brown powder. When heated this powder decomposed over a wide temperature range: 200°-300°. rose quickly from 18° to 31° (1 hour) heated to reflux refluxed for 12 hours filtered the product being washed with toluene both by decantation The residue was washed with ether dried under pump vacuum (0.5-1 mm Hg) over P2O5

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

実験手順: A solution of cyanogen bromide (0.53 gm. 5 mmol) in toluene (10 ml.) was added to a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester (1.39 gm, 5 mmol) in toluene (10 ml.) and stirred at room temperature. There was an almost immediate precipitate. Stirring was continued for 30 minutes, and the reaction mixture was then heated to reflux and refluxed for 18 hours. After cooling, the solid was filtered off, washed with toluene and dried to give 1.81 gm (94.5%) of the title product. A portion of the product was recrystallized from ethanol, washed with ethanol and ether, and dried in vacuo at 78° to give an analytical sample as golden crystals. Stirring the reaction mixture was then heated to reflux refluxed for 18 hours After cooling the solid was filtered off washed with toluene dried

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

実験手順: A solution of cyanogen bromide (0.53 gm. 5 mmol) in toluene (10 ml.) was added to a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester (1.39 gm, 5 mmol) in toluene (10 ml.) and stirred at room temperature. There was an almost immediate precipitate. Stirring was continued for 30 minutes, and the reaction mixture was then heated to reflux and refluxed for 18 hours. After cooling, the solid was filtered off, washed with toluene and dried to give 1.81 gm (94.5%) of the title product. A portion of the product was recrystallized from ethanol, washed with ethanol and ether, and dried in vacuo at 78° to give an analytical sample as golden crystals. Stirring the reaction mixture was then heated to reflux refluxed for 18 hours After cooling the solid was filtered off washed with toluene dried

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

実験手順: A solution of cyanogen bromide (3.2 g, 0.030 mol) in 100 ml. 2-methoxyethanol was added to a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester (8.2 g, 0.030 mol) in 250 ml. 2-methoxyethanol. The solution was stirred at room temperature for 1 hour, heated at reflux for 22 hours, and cooled. The precipitate was filtered off, washed with ether and air dried to give 3.11 gms. of the crude title product (31% yield as the hydrobromide salt). Recrystallization from ethanolic HCl gave the pure title product in 71% recovery (22% overall yield); m.p. >250°. heated at reflux for 22 hours cooled The precipitate was filtered off washed with ether and air dried to give 3.11 gms Recrystallization from ethanolic HCl

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

実験手順: A solution of 6-amino-2,3-dichlorobenzyl alcohol (10.0 g., 0.0521 mol) in 250 ml. of boiling benzene was treated with a slow-stream of dry hydrogen chloride for 0.5 hour. The finely divided suspension was cooled slightly, thionyl chloride (12.4 g, 0.104 mol) was added in one portion, and reflux was continued for 2.5 hours. The solution was evaporated in vacuo to remove excess thionyl chloride and hydrogen chloride, and the residue was redissolved in 250 ml. benzene. This solution was added over 1 hour to a reluxing mixture of glycine ethyl ester hydrochloride (29.1 g, 0.208 mol) and triethylamine (31.6 g, 0.313 mol) in 600 ml. CH2Cl2. Reflux was continued for 1 hour, the mixture was allowed to stand overnight and was then extracted with 1N HCl. The extract was washed with CH2Cl2 and ether, made slightly alkaline with concentrated NH4OH and extracted with ether. After drying (K2CO3) and evaporation there remained 8.3 g (58%) of the title product as a light yellow oil which crystallized. The analytical sample was obtained from Skellysolve B as white needles, mp. 60°-61° C. The finely divided suspension was cooled slightly reflux The solution was evaporated in vacuo to remove excess thionyl chloride and hydrogen chloride the residue was redissolved in 250 ml Reflux was continued for 1 hour to stand overnight was then extracted with 1N HCl The extract was washed with CH2Cl2 and ether extracted with ether After drying (K2CO3) and evaporation there remained 8.3 g (58%) of the title product as a light yellow oil which crystallized The analytical sample was obtained from Skellysolve B as white needles, mp. 60°-61° C.

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

実験手順: A solution of 6-amino-2,3-dichlorobenzyl alcohol (10.0 g., 0.0521 mol) in 250 ml. of boiling benzene was treated with a slow-stream of dry hydrogen chloride for 0.5 hour. The finely divided suspension was cooled slightly, thionyl chloride (12.4 g, 0.104 mol) was added in one portion, and reflux was continued for 2.5 hours. The solution was evaporated in vacuo to remove excess thionyl chloride and hydrogen chloride, and the residue was redissolved in 250 ml. benzene. This solution was added over 1 hour to a reluxing mixture of glycine ethyl ester hydrochloride (29.1 g, 0.208 mol) and triethylamine (31.6 g, 0.313 mol) in 600 ml. CH2Cl2. Reflux was continued for 1 hour, the mixture was allowed to stand overnight and was then extracted with 1N HCl. The extract was washed with CH2Cl2 and ether, made slightly alkaline with concentrated NH4OH and extracted with ether. After drying (K2CO3) and evaporation there remained 8.3 g (58%) of the title product as a light yellow oil which crystallized. The analytical sample was obtained from Skellysolve B as white needles, mp. 60°-61° C. The finely divided suspension was cooled slightly reflux The solution was evaporated in vacuo to remove excess thionyl chloride and hydrogen chloride the residue was redissolved in 250 ml Reflux was continued for 1 hour to stand overnight was then extracted with 1N HCl The extract was washed with CH2Cl2 and ether extracted with ether After drying (K2CO3) and evaporation there remained 8.3 g (58%) of the title product as a light yellow oil which crystallized The analytical sample was obtained from Skellysolve B as white needles, mp. 60°-61° C.

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:

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

実験手順: A mixture of N-(2-amino-5,6-dichlorobenzyl)glycine ethyl ester (2.77 g, 0.01 mole) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (2.01 g, 0.01 mole) in absolute ethanol (30 ml) was heated at reflux for 24 hours. The mixture was filtered and the product was washed successively with ethanol, acetone and ether to yield the title compound (1.02 g, 40%); identical (ir, nmr) with authentic material prepared by a prior art procedure. was heated at reflux for 24 hours The mixture was filtered the product was washed successively with ethanol, acetone and ether