Methanol → HCID 66830703, compound

HRID 1687774Notes

Reaction equation

HRID 1687774 reaction equation
[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[C:34]1(C)C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[CH3:34][O:28][C:27](=[O:29])[C:26]1[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=1[NH:24][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)[N:4]=1

Participants

6

Reactant 4

HCID 887MethanolHCID 1140TolueneHCID 167693TrimethylsilyldiazomethaneHCID 67263901HCID 67263901, compound

Product 1

HCID 66830703HCID 66830703, compoundYield 21.6%

Reagents, catalysts & solvents 1

HCID 8058HexaneSolvent

Procedure

2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester (1.168 g, 2.355 mmol) was dissolved in tetrahydrofuran (117 mL, 1440 mmol). Lithium hydroxide (67.7 mg, 2.82 mmol) dissolved in water (23.4 mL, 1.30 mol) was added and the reaction was stirred for 48 hours. The reaction was concentrated under reduced pressure and azetroped twice with toluene. The reaction was then further dried under high vacuum to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid. 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid (1.55 g, 3.31 mmol) was placed in toluene (40.0 mL, 376 mmol) and methanol (10.0 mL, 247 mmol). 2.00 M of Trimethylsilyldiazomethane in hexane (4.50 mL) was added and the reaction was stirred overnight. The reaction was quenched with acetic acid and then concentrated under reduced pressure. The residue was taken up in DCM (50 mL) and washed with sat. NaHCO3 (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid methyl ester as a pale yellow solid (344 mg, 21%). m.p.=152-156° C.; LCMS (m/e) 482 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.13 (s, 1H), 8.86 (d, 1H, J=8.6 Hz), 8.14 (s, 1H), 8.09 (d, 1H, J=8.0 Hz), 7.55-7.46 (m, 1H), 7.35 (s, 1H), 7.30-7.22 (m, 1H), 7.14-7.02 (m, 2H), 6.92 (s, 1H), 3.99 (s, 3H), 3.56 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.98-2.89 (m, 4H), 2.80-2.71 (m, 6H).

Workup

  1. customThe reaction was quenched with acetic acid
  2. concentrationconcentrated under reduced pressure
  3. washwashed with sat. NaHCO3 (50 mL)
  4. dry with materialThe organic layer was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customPurification by amine
  8. customcapped silica gel chromatography

Sources & evidence

ORD record
ord-4566ba41d5b04e8983bc175c7e084a8e
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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