HCID 67264088, compound → HCID 67264830, compound

HRID 1041482Notes

Reaction equation

HRID 1041482 reaction equation
C(N1C2C=C(N)C(OC)=CC=2CN(CC)CC1)C.OC(C(F)(F)F)=O.[Cl:26][C:27]1[C:28]([NH:51][C@@H:52]2[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]2[NH:58][S:59]([CH3:62])(=[O:61])=[O:60])=[N:29][C:30]([NH:33][C:34]2[C:35]([O:49][CH3:50])=[CH:36][C:37]3[CH2:43][N:42]([CH2:44][CH3:45])[CH2:41][CH2:40][N:39]([CH2:46][CH3:47])[C:38]=3[CH:48]=2)=[N:31][CH:32]=1>>[Cl:26][C:27]1[C:28]([NH:51][C@@H:52]2[CH2:57][CH2:56][CH2:55][CH2:54][C@H:53]2[NH:58][S:59]([CH3:62])(=[O:60])=[O:61])=[N:29][C:30]([NH:33][C:34]2[C:35]([O:49][CH3:50])=[CH:36][C:37]3[CH2:43][N:42]([CH2:44][CH3:45])[CH2:41][CH2:40][N:39]([CH2:46][CH3:47])[C:38]=3[CH:48]=2)=[N:31][CH:32]=1

Participants

3

Reactant 2

HCID 67264088HCID 67264088, compound2×HCID 86634045HCID 86634045, compound

Product 1

HCID 67264830HCID 67264830, compoundYield 8%

Procedure

Into a round bottom flask, 8-amino-1,4-diethyl-7-methoxy-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.30 g, 0.0011 mol), 1,4-dioxane (10.0 mL, 0.128 mol) and 2.00 M of borane-dimethyl sulfide complex in toluene (4.56 mL) were added and heated to reflux overnight. The solvent was removed under vacuum. 6N HCl (5 mL) was added and heated to reflux for one hour. The mixture was cooled to room temperature. 50% NaOH was added to pH 12. The aqueous was extracted with DCM (3×100 mL) The organic was separated, washed with Brine, and dried over magnesium sulfate. The solid was filtered and washed with EtOAc. The solvent was removed under vacuum. The product was isolated via ISCO column chromatography with DCM and NH3 in methanol as eluant (0 to 15% NH3 in methanol). The collected fractions afforded 1,4-diethyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine as an off white solid (0.10 mg, 30%). 1,4-diethyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine was converted to 1,4-diethyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine was converted to N-{(1R,2R)-2-[5-Chloro-2-(1,4-diethyl-7-methoxy-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide TFA salt as described in Example 787. The product was purified via Gilson HPLC to give of lyophilized solid (14 mg, 8%). 1H-NMR (DMSO-D6, 400 MHz) δ 9.52 (bs, 1H), 8.35 (bs, 1H), 8.08 (s, 1H), 7.83 (bs, 1H), 7.35 (bs, 1H), 7.22 (s, 1H), 7.10-7.18 (m, 1H), 4.15-4.28 (m, 1H), 3.83-3.94 (m, 1H), 3.85 (s, 3H), 2.92-3.40 (m, 8H) 2.98 (s, 3H), 1.80-2.08 (m, 2H), 1.60-1.75 (m, 2H), 1.40-1.52 (m, 2H), 1.10-1.30 (complex m, 10H). LC/MS (ESI+) 572.36.

Workup

  1. customThe product was purified via Gilson HPLC

Sources & evidence

ORD record
ord-6cc74f827d6842debeffaf3037f2a24c
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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