hydroxyurea

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

Procedure: To a solution of NaOH (0.015 g) dissolved in water (0.410 mL) was added hydroxyurea (0.008 g, 0.100 mmol). The resulting mixture was stirred for 30 minutes before the dropwise addition of methyl 2,3-dibromo-5-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylheptanoate, 85a, (0.064 g, 0.110 mmol) in MeOH (0.150 mL). The solution was stirred for 6 hours before the addition of AcOH (0.031 mL). The residue was purified by reverse phase preparative HPLC to afford the desired product: 1H NMR (300 MHz, MeOD) δ 8.57 (dd, J=9.7, 2.8 Hz, 1H), 8.16 (d, J=5.5 Hz, 2H), 8.00 (d, J=4.1 Hz, 1H), 5.68 (s, 1H), 3.03 (ddd, J=27.4, 15.4, 12.3 Hz, 2H), 1.10 (d, J=3.3 Hz, 11H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.15 minutes (M+H) 416.04. The residue was purified by reverse phase preparative HPLC

Conditions: temp:1.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.261 mol (19.85 g) hydroxy urea have been dissolved in 390 ml 1 M HCl and 0.235 mol (51.77 g) 1,1,3,3-tetraethoxypropane were added dropwise under ice cooling, with the internal temperature being maintained at 1-2° C. The solution was thawed in an ice bath to room temperature and stirred over night, then evaporated to dryness. The residue was suspended with 250 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying, 24.5 g of crude product were obtained. The crude product was recrystallized with 460 ml of methanol from the boiling heat, cooled in an ice/ethanol bath, filtered off and dried. The mother liquor was concentrated on a rotary evaporator until again product started to precipitate, then a second fraction was crystallized similarly. After drying 11.8 g (1. fraction) and 5.9 g (2. fraction) the title compound were obtained. The solution was thawed in an ice bath to room temperature evaporated to dryness the mixture was cooled in an ice/ethanol bath the solid filtered off washed with a little ice-cold acetone After drying

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

Procedure: Trifluoroacetoacetonitrile (5.12 g, 0.030 mole), hydroxyurea (2.51 g, 0.033 mole) and methanol were heated under reflux for 150 hours to give the title compound (0.50 g, 11.0%). under reflux for 150 hours

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

Procedure: 16 g (58 mmol) of 4-hydroxycyclophosphamide and 5.2 g (68 mmol) of hydroxyurea were dissolved in 160 ml of water, acidified with trichloracetic acid (pH 3-4) and left to stand for 20 hours at 0° C. in a refrigerator. The crystal sludge was then drawn off by suction, washed with water, dried over P2O5 under high vacuum and recrystallized from methanol/chloroform. left washed with water dried over P2O5 under high vacuum recrystallized from methanol/chloroform

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

Procedure: 15 g (54 mmol) of 4-hydroxycyclophosphamide (that is to say 2-[bis-(2-chloroethyl)-amino]-4-hydroxytetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.4 g (58 mmol) of hydroxyurea were dissolved in 70 ml of DMF, acidified with trichloroacetic acid (pH 3-4) and left for 20 hours at 0° C. in a refrigerator. The resultant crystal sludge was diluted with 70 ml of ethyl acetate and after 2 hours was drawn off by suction, washed, dried and recrystallized from methanol. washed dried recrystallized from methanol

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

Procedure: 15 g (54 mmol) of 4-hydroxycyclophosphamide (that is to say 2-[bis-(2-chloroethyl)-amino]-4-hydroxytetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide) and 4.4 g (58 mmol) of hydroxyurea were dissolved in 70 ml of DMF, acidified with trichloroacetic acid (pH 3-4) and left for 20 hours at 0° C. in a refrigerator. The resultant crystal sludge was diluted with 70 ml of ethyl acetate and after 2 hours was drawn off by suction, washed, dried and recrystallized from methanol. washed dried recrystallized from methanol

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

Procedure: To a solution of NaOH (0.015 g) dissolved in water (0.410 mL) was added hydroxyurea (0.008 g, 0.100 mmol). The resulting mixture was stirred for 30 minutes before the dropwise addition of methyl 2,3-dibromo-5-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-6,6-dimethylheptanoate, 85a, (0.064 g, 0.110 mmol) in MeOH (0.150 mL). The solution was stirred for 6 hours before the addition of AcOH (0.031 mL). The residue was purified by reverse phase preparative HPLC to afford the desired product: 1H NMR (300 MHz, MeOD) δ 8.57 (dd, J=9.7, 2.8 Hz, 1H), 8.16 (d, J=5.5 Hz, 2H), 8.00 (d, J=4.1 Hz, 1H), 5.68 (s, 1H), 3.03 (ddd, J=27.4, 15.4, 12.3 Hz, 2H), 1.10 (d, J=3.3 Hz, 11H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=2.15 minutes (M+H) 416.04. The residue was purified by reverse phase preparative HPLC

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

Procedure: Prepared according to Synthesis 1985, 1100. To a stirred solution of N-hydroxyurea (3.80 g, 50 mmol) and 1,5-diazabicyclo[5.4.0]undec-5-ene (8.37 g, 55 mmol) in methanol (50 mL) with cooling (ice bath) was added dimethyl ethyne dicarboxylate (7.11 g, 50 mmol) dropwise over 20 min. A dark red colour appeared then dissipated with each drop added, until finally a deep orange/red clear solution had formed. After an additional 20 min the mixture was concentrated to give a red oil which was then acidified with cooling in an ice/water bath to pH 1 with HCl (conc.). The resulting yellow mixture was extracted with diethyl ether (3×40 mL) then the aqueous phase was saturated with brine and extracted with ether (2×50 mL). The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated to afford the title compound (2.89 g, 40%) as white crystals after recrystallisation from chloroform. MS: m/e=143.8 [M+H]+. Prepared according to Synthesis 1985, 1100 added until finally a deep orange/red clear solution had formed After an additional 20 min the mixture was concentrated to give a red oil which The resulting yellow mixture was extracted with diethyl ether (3×40 mL) extracted with ether (2×50 mL) The combined organic layers were then washed with water and brine dried over sodium sulfate filtered evaporated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, hydroxyurea was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give N-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyloxy}urea in 32% yield, m.p. 84°-85° C.

Conditions: temp:-7.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The synthesis of the precursor 4,4-dimethoxy-3-methylbutan-2-one was performed in analogy to E. E. Royals and K. C. Brannock (J. Am. Chem., 1953, 75, 2050-2053) and yielded a mixture of 58% of the desired precursor, 24% of the byproduct 1,1-dimethoxy-pentan-3-one and about 18% elimination product. 102 g of this mixture (0.405 mol of 4,4-dimethoxy-3-methylbutan-2-one) were dissolved in 30 ml of methanol and added dropwise to 0.698 mol of N-hydroxyurea in 400 ml of 2M HCl, while the internal temperature was maintained at −10 to −4° C. The solution was thawed to room temperature, stirred for 1 h, and then evaporated to dryness. The residue was slurried with 200 ml of acetone, the solid filtered off and washed with little ice-cold acetone. After drying, the crude product was heated with 150 ml of ethanol to boiling, filtered hot, concentrated to 50 ml and cooled to −18° C. The precipitated solid was filtered off, washed with little ethanol and dried. 20 g of this solid was again recrystallized from 100 ml of ethanol, and finally 10 g (12% yield) of the title compound were obtained (content of 85% the title compound and 13% ammonium chloride). Brannock (J. Am. Chem., 1953, 75, 2050-2053) and yielded was thawed to room temperature evaporated to dryness the solid filtered off washed with little ice-cold acetone After drying the crude product was heated with 150 ml of ethanol filtered hot concentrated to 50 ml cooled to −18° C The precipitated solid was filtered off washed with little ethanol dried 20 g of this solid was again recrystallized from 100 ml of ethanol

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.12 mol (9.13 g) hydroxy urea were dissolved in 50 ml 2 M HCl, 20 ml of methanol were added and 0.10 mol (11.41 g) 2,4-hexanedione were added dropwise under cooling by approximately −15° C. Further 30 ml of water and 10 ml of methanol were added. The two-phase reaction mixture was allowed to warm up slowly to room temperature and was stirred at room temperature for further 2 h, then evaporated until dryness. The residue was suspended with 50 ml of acetone, the mixture was cooled in an ice/ethanol bath, the solid filtered off and washed with a little ice-cold acetone. After drying 7.88 g crude product were obtained which were recrystallized from 45 ml ethanol wherefrom first an insoluble salt compound was hot filtered off and the product was subsequently recrystallized from the filtrate at −18° C. 3.0 g product were obtained which were again recrystallized from 28 ml ethanol. Finally 2.26 g of the title compound were obtained. The two-phase reaction mixture to warm up slowly to room temperature evaporated until dryness the mixture was cooled in an ice/ethanol bath the solid filtered off washed with a little ice-cold acetone After drying 7.88 g crude product were obtained which were recrystallized from 45 ml ethanol wherefrom first an insoluble salt compound was hot filtered off the product was subsequently recrystallized from the filtrate at −18° C

Conditions: temp:-6.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 0.388 mol (25.9 g) hydroxy urea were dissolved in 195 ml 2 M HCl, 80 ml of methanol were added and 0.388 mol (56.7 g) of 1,1-dimethoxypentane-3-on (62% content in product mixture) were added dropwise under cooling with the internal temperature being maintained at −6 to −7° C. The solution was thawed to room temperature in an ice bath and stirred for 1 h, then evaporated until dryness. The residue was suspended with 100 ml of acetone, the mixture was cooled to below 0° C. in an ice/ethanol bath, the solid filtered off and washed with little ice-cold acetone. After drying 32.6 g crude product were obtained. The crude product was heated until boiling with 200 ml ethanol, hot filtered and slowly cooled to −18° C. The precipitated solid was filtered off, washed with a little amount of ethanol and dried. 11.7 g of the title compound were obtained. under cooling with the internal temperature The solution was thawed to room temperature in an ice bath evaporated until dryness the mixture was cooled to below 0° C. in an ice/ethanol bath the solid filtered off washed with little ice-cold acetone After drying 32.6 g crude product were obtained hot filtered slowly cooled to −18° C The precipitated solid was filtered off washed with a little amount of ethanol dried