p-Toluenesulfonic acid monohydrate → HCID 57955658, compound

HRID 1880958Notes

Reaction equation

Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C@@:9]([F:16])([CH:14]=[CH2:15])[CH2:8][N:7]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH:17]1([N:7]2[CH2:8][C@:9]([F:16])([CH:14]=[CH2:15])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:33]([O:34][CH3:35])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([F:36])[CH:25]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18]1

Participants

Conditions

Temperature: 95 °C

Procedure

A mixture of (R)-2-chloro-9-cyclopentyl-7-fluoro-5-methyl-7-vinyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (1.0 g, 3.086 mmol), and methyl 4-amino-2-fluoro-5-methoxybenzoate (3.07 g, 15.43 mmol) was dissolved in dioxane (20 ml), and p-toluenesulfonic acid, monohydrate (2.99 g, 15.74 mmol) was added. The mixture was stirred at 95° C. for 24-48 h. The final compound was purified by reverse phase HPLC to give 400 mg product as white solid (40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.82 (m, 4 H) 1.93-1.98 (m, 4 H) 3.29 (s, 3 H) 3.51 (br. s., 2 H) 3.61 (m, 3 H), 3.86 (m, 3 H) 3.94 (s, 3 H) 4.88 (t, J=8.08 Hz, 1 H) 5.30-5.47 (m, 2 H) 6.01 (ddd, J=17.43, 12.63, 10.86 Hz, 1 H) 7.41-7.57 (m, 1 H) 7.82 (s, 1 H) 8.12 (s, 1 H) 8.31 (d, J=8.08 Hz, 1 H). [M+H] calc'd for C24H27F2N5O4, 488; found 488.

Workup

customThe final compound was purified by reverse phase HPLC

Sources & evidence

ORD record: ord-ffb5a4e0805a4c4f9106f0700b34061d
Source dataset: uspto-grants-2012_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08318727B2

Reaction notes

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