tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate

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

実験手順: The title compound was prepared as a solid according to the method of Example 81 using the product of Example 112 step i) and (R)-2-(hydroxymethyl)-piperazine-1-carboxylic acid, tert-butyl ester.

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

実験手順: A mixture of the product of Example 75 step i) (300 mg), (R)-2-(hydroxymethyl)piperazine-1-carboxylic acid, tert-butyl ester (465 mg) and sodium triacetoxyborohydride (608 mg) in dichloromethane (20 mL) was stirred under nitrogen for 16 hours. The reaction was partitioned between dichloromethane and water, the organics were then collected and concentrated to dryness. The residue was purified by HPLC to give the title compound (230 mg) as a solid. The reaction was partitioned between dichloromethane and water the organics were then collected concentrated to dryness The residue was purified by HPLC

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

実験手順: To a solution of tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (0.479 g) and triethylamine (0.618 mL) in THF (6 mL) was added dropwise a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 0.715 g) in THF (10 mL). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure before adding water and extracting into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure. Trituration with ethyl acetate gave the subtitle compound (0.855 g). The resulting solution was concentrated under reduced pressure before adding water extracting into ethyl acetate The combined organics were dried (MgSO4) filtered evaporated under reduced pressure

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

実験手順: (R)-t-Butyl 2-(hydroxymethyl)piperazine-1-carboxylate (1.15 g, 5.32 mmol), t-butylchlorodimethylsilane (0.882 g, 5.85 mmol), and imidazole (0.796 g, 11.7 mmol) were stirred in dichloromethane (3 mL) for three days. The solution was added to aqueous K2CO3 (30 mL) and extracted with dichloromethane (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Silica gel chromatography (gradient elution hexanes/0-50% ethyl acetate) afforded compound 308 as a colorless oil (1.06 g, 60%). extracted with dichloromethane (3×30 mL) The combined organics were dried (MgSO4) evaporated to give a yellow oil Silica gel chromatography (gradient elution hexanes/0-50% ethyl acetate)

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

実験手順: 4-(5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-{1-[2-Chloro-4-(1-hydroxy-1-methyl-ethyl)-benzyl]-1H-indazol-5-ylmethylene}-2-ethylsulfanyl-thiazol-4-one and 2-(R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.

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

実験手順: 4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-cyano-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-5-(2-ethylsulfanyl-4-oxo-4H-thiazol-5-ylidenemethyl)-1H-indazole-3-carbonitrile and 2-(R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.

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

実験手順: 4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.

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

実験手順: 4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R)—Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.

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

実験手順: To a 250 mL flask was added 5-(bromoacetyl)-4-fluoro-2-methoxybenzonitrile (2.00 g, 7.35 mmol), (R)—N-Boc-2-hydroxymethyl-piperazine (3.18 g, 14.7 mmol), DIEA (2.57 mL, 14.7 mmol) and THF (50 mL) and stirred at rt for 1 h; LC analysis of the reaction mixture indicated completion of the reaction. The solution was treated with EtOAc (100 mL), washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The residue was then purified over silica gel with the solvent systems of 5% MeOH in DCM to furnish the desired product. LC/MS: [(M+1)]+=408. completion of the reaction washed with brine dried (Na2SO4) filtered concentrated to dryness The residue was then purified over silica gel with the solvent systems of 5% MeOH in DCM

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

実験手順: (2R)2-Hydroxymethyl-4-{5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.

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

実験手順: (2R)2-Hydroxymethyl-4-{5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.

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

実験手順: (2R)-2-Hydroxymethyl-4-(5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-{1-[4-(1-hydroxy-1-methyl-ethyl)-2-trifluoromethyl-benzyl]-1H-indazol-5-ylmethylene}-thiazol-4-one and (2R)2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.