Methane → HCID 67263894, compound

HRID 1687223Notes

Reaction equation

HRID 1687223 reaction equation
[F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:20])[C:14]([N+:16]([O-])=O)=[CH:15][C:8]=2[CH2:7][CH2:6]1.C.O>CO.[Pd]>[NH2:16][C:14]1[C:13]([O:19][CH3:20])=[CH:12][C:9]2[CH2:10][CH2:11][N:5]([CH2:4][C@H:3]([OH:21])[C:2]([F:1])([F:22])[F:23])[CH2:6][CH2:7][C:8]=2[CH:15]=1

Participants

6

Reactant 3

HCID 297MethaneHCID 962WaterHCID 67264126HCID 67264126, compound

Product 1

HCID 67263894HCID 67263894, compoundYield 93%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalyst2×HCID 887MethanolSolvent

Procedure

(S)-1,1,1-Trifluoro-3-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol (316 mg, 0.95 mmol) was dissolved in 10 mL methanol, 10% Pd/C, 50% wet (5:45:50, Palladium:carbon black:Water, 0.105 g) was added and the mixture was stirred under an atmosphere of Hydrogen (balloon) overnight. Filtration through Celite with methanol afforded (S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (268 mg, 93%), which was used without further purification. (S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (88 mg, 0.29 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (101 mg, 0.298 mmol), and 10-Camphorsulfonic acid (0.10 g, 0.43 mmol) in 2-Methoxyethanol (4 mL) were heated in a microwave vial at 120° C. for a total of 4 h. The light brown solution was diluted with 3 mL satd. bicarbonate solution, resulting in a suspension, which was added to 12 mL satd. bicarbonate solution which was thoroughly mixed and then filtered to afford the product in ˜80% purity by HPLC (93 mg). Trituration from ether gave an oil, so the material wash purified by RP-HPLC (10-30% acetonitrile:water) followed by formation of the free base with Macroporous carbonate resin to afford N-((1R,2R)-2-{5-Chloro-2-[8-methoxy-3-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide as off white solids (81 mg, 46%). m.p.=122-127° C.; LCMS (m/e) 608 (M+1); 1H-NMR (CD3OD, 400 MHz) δ 7.94 (s, 1H), 7.58 (s, 1H), 7.1-7.3 (m, 3H), 7.04 (s, 1H), 4.70 (m, 1H), 3.94 (m, 1H), 3.89 (s, 3H), 3.4-3.7 (m, 6H), 3.25 (m, 4H), 2.95 (s, 3H), 2.32 (s, 1H), 2.14 (m, 2H), 1.82 (m, 2H), 1.2-1.6 (m, 5H).

Workup

  1. filtrationFiltration through Celite with methanol

Sources & evidence

ORD record
ord-dcaff28198bd40cbb638a5c75fa42d15
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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