3-(Chloromethyl)pyridazine → 7,7-Dimethyl-2-{6-[(6-methylpyridazin-3-yl)amino]-2,3-dihydro-4h-1,4-benzoxazin-4-yl}-5,6,7,8-tetrahydro-4h-[1,3]thiazolo[5,4-c]azepin-4-one acetate salt

HRID 417941Notes

Reaction equation

HRID 417941 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:23])[NH:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=4[N:20]=3)[C:6]=2[CH:24]=1.Cl[CH2:26][C:27]1[N:28]=[N:29][CH:30]=[CH:31][CH:32]=1.CC(C)([O-:36])C.[Na+]>C1(C)C=CC=CC=1>[C:14]([OH:23])(=[O:36])[CH3:13].[CH3:21][C:17]1([CH3:22])[CH2:16][NH:15][C:14](=[O:23])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:24]=[C:2]([NH:1][C:30]5[N:29]=[N:28][C:27]([CH3:26])=[CH:32][CH:31]=5)[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:20][C:19]=2[CH2:18]1

Participants

5

Reactant 3

HCID 142397123-(Chloromethyl)pyridazineHCID 23676156Sodium t-butoxideHCID 666484122-(6-Amino-2,3-dihydro-4h-1,4-benzoxazin-4-yl)-7,7-dimethyl-5,6,7,8-tetrahydro-4h-[1,3]thiazolo[5,4-c]azepin-4-one

Product 1

HCID 666484257,7-Dimethyl-2-{6-[(6-methylpyridazin-3-yl)amino]-2,3-dihydro-4h-1,4-benzoxazin-4-yl}-5,6,7,8-tetrahydro-4h-[1,3]thiazolo[5,4-c]azepin-4-one acetate saltYield 19.4%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

A mixture of Example 69 (100 mg, 0.29 mmol), chloromethylpyridazine (20 mg, 0.29 mmol), sodium tert-butoxide (80 mg, 0.8 mmol) and dichloro(1,1′-bis(di-tert-butylphosphino)ferrocene)palladium (10 mg, catalytic) in toluene (5 mL) was heated to 120° C. under microwave irradiation for 2 h. It was cooled to r.t., concentrated in vacuo and purified by prep HPLC to give the title compound (14 mg, 9%) as an off-white solid. δH (CD3OD/CDCl3) 1.11 (6H, s), 2.02 (3H, s), 2.54 (3H, s), 2.85 (2H, s), 3.12 (2H, s), 4.09-4.17 (2H, m), 4.29-4.35 (2H, m), 6.94 (1H, d, J 8.9 Hz), 7.10-7.30 (3H, m), 7.99 (1H, s). LCMS (ES+) 437 (M+H)+.

Workup

  1. concentrationconcentrated in vacuo
  2. custompurified by prep HPLC

Sources & evidence

ORD record
ord-7bdf040597524ea6bd2da7971d4a3aa3
Source dataset
uspto-grants-2012_01
Patent number
US08093238B2

Reaction notes

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