Hydrochloric Acid → HCID 22240472, compound

HRID 892300Notes

Reaction equation

HRID 892300 reaction equation
[NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]#[N:20])[CH:13]=2)[N:5]=1)=[O:3].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N=[C:31]=[N:32][CH:33]([CH3:35])[CH3:34])(C)C.Cl>CN(C=O)C>[C:19]([C:14]1[CH:13]=[C:12]([N:6]2[C:7]([C:9]([N:21]3[C:22]4[C:24](=[CH:23][CH:35]=[C:33]([N:32]5[CH2:31][CH2:9][CH2:7][CH2:8][CH2:4][C:2]5=[O:3])[CH:34]=4)[CH2:25][CH2:26]3)=[O:11])=[CH:8][C:4]([C:2]([NH2:1])=[O:3])=[N:5]2)[CH:17]=[CH:16][C:15]=1[F:18])#[N:20]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 12734DiisopropylcarbodiimideHCID 21936836HCID 21936836, compound

Product 1

HCID 22240472HCID 22240472, compoundYield 29%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Part A. To tert-butyl-6-nitro-1H-indole-1-carboxylate (3.80 g, 14 mmol), prepared according to Part F of Example 14 using 6-nitro-1H-indole as starting material, was added 150 mL of MeOH and 150 mL of EtOAc. The solution was covered with a stream of N2, and 10 wt % Pd/C (100 mg) was added in one portion. The mixture was subjected to a hydrogen atmosphere (50 psi) for 14 h and was then filtered and concentrated. Analysis (LC/MS) of the resulting brown residue (3.34 g, 100%) showed it to be a 20:80 mixture of tert-butyl 6-amino-1-indolinecarboxylate: tert-butyl-6-amino-1H-indole-1-carboxylate. LC/MS (ESI+): 233.1 (indole M+H)+, 235.1 (indoline M+H)+. Part B. To the mixture from Part A (400 mg, 1.7 mmol) was added 6-bromohexanoyl chloride (0.26 mL, 1.7 mmol) and 15 mL of THF. Potassium tert-butoxide (1.90 mL, 1.9 mmol; 1.0 M in THF) was added and the cloudy mixture was stirred for 10 min. A second 1.90- mL portion of potassium tert-butoxide was added and the reaction was maintained at rt for 1 h. The reaction was then poured into 1N HCl (70 mL), and the aqueous layer was washed with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by radial chromatography to give a mixture of tert-butyl 6-(2-oxohexahydro-1H-azepin-1-yl)-1-indolinecarboxylate and tert-butyl 6-(2-oxohexahydro-1H-azepin-1-yl)-1H-indole-1-carboxylate (340 mg, 60%) as a red oil. LC/MS (ESI+): 329.3 (indole M+H)+, 331.2 (indoline M+H)+. Part C. To the product from Part B was added 5 mL of trifluoroacetic acid and NaBH3CN (260 mg, 4.1 mmol). After 2 h, an additional 100 mg-portion of borohydride was added. The mixture was stirred for 14 h, and another 100 mg-portion was added. After maintaining the reaction at rt under N2 for 24 h, the mixture was concentrated and poured into 1N NaOH (25 mL). The aqueous layer was washed with EtOAc (3×25 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by radial chromatography (5% MeOH in CH2Cl2) to afford solely 1-(2,3-dihydro-1H-indol-5-yl)hexahydro-2H-azepin-2-one as a yellow foam (90 mg, 38%). 1H NMR (CDCl3) δ 7.24 (d, 1H), 7.17 (s, 1H), 7.06 (m, 1H), 3.60–3.85 (m, 2H), 3.45 (m, 1H), 3.18 (m, 2H), 2.97 (m, 1H), 2.69 (br s, 2H), 1.82 (br s, 6H). Part D. To the product from Part C (90 mg, 0.39 mmol), was added 3-(aminocarbonyl)-1-(3-cyano-4-fluorophenyl)-1H-pyrazole-5-carboxylic acid (89 mg, 0.33 mmol), 3.0 mL of pyridine and 1.0 mL of DMF. 1,3-Diisopropylcarbodiimide (0.056 mL, 0.36 mmol) was added, and the resulting solution was stirred for 14 h. The red mixture was poured into 1N aqueous HCl (70 mL) and washed with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. Concentration of the filtrate and purification of the resulting residue by preparative LC/MS (C18 reverse phase, eluted with 0.05% TFA in CH3CN/H2O) gave 1-(3-cyano-4-fluorophenyl)-5-{[6-(2-oxohexahydro-1H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide (67, 29% mg) as a white foam. LC/MS (ESI+): 487.2 (M+H)+. Part E. To the product from Part D (67 mg, 0.11 mmol) was added 6.3 mL of DMF and 2.5 mL of H2O. Potassium carbonate (95 g, 0.69 mmol) and acetohydroxamic acid (26 mg, 0.34 mmol) were added, and the resulting mixture was warmed to 50° C. under an N2 atmosphere. After 2 h, the reaction was cooled to rt and poured into EtOAc (50 mL). The organic layer was washed with H2O (2×15 mL), brine, and dried over Na2SO4. Filtration and concentration afforded a brown oily residue that was purified by preparative LC/MS (C18 reverse phase, eluted with 0.05% TFA in CH3CN/H2O) to afford 1-(3-amino-1,2-benzisoxazol-5-yl)-5-{[6-(2-oxohexahydro-1-H-azepin-1-yl)-2,3-dihydro-1H-indol-1-yl]carbonyl}-1H-pyrazole-3-carboxamide trifluoroacetate (33 mg, 40%) as a white solid. LC/MS (ESI+): 500.2 (M+H-TFA)+.

Workup

  1. washwashed with EtOAc (3×50 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. customConcentration of the filtrate and purification of the resulting residue by preparative LC/MS (C18 reverse phase
  6. washeluted with 0.05% TFA in CH3CN/H2O)

Sources & evidence

ORD record
ord-916769c608dd4a63a7aea7ef87cea3c4
Source dataset
uspto-grants-2006_02
Patent number
US07005435B2

Reaction notes

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