Hydrochloric Acid → 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid

HRID 1881024Notes

Reaction equation

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

Participants

Conditions

Temperature: 53 °C

Procedure

A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (2.542 kg, 8.05 mol), 3-methoxy-4-aminobenzoic acid (1.50 kg) in t-butyl alcohol (23 L) and heat to about 53° C. Add conc. HCl (951 g) over about 10 minutes, heat to 80° C. and stir for 60 hours. The temperature was adjusted to 15° C. and stirred for 40 hours to give a solid which was collected by filtration, rinsed with isopropyl alcohol/water (1:1, 2×2.5 L) and dried under a stream of nitrogen for about 1.5 hours, then in a vacuum oven at 40° C. for 4 days to give 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid.

Workup

temperatureheat to 80° C.
customwas adjusted to 15° C.
stirringstirred for 40 hours
customto give a solid which
filtrationwas collected by filtration
washrinsed with isopropyl alcohol/water (1:1, 2×2.5 L)
customdried under a stream of nitrogen for about 1.5 hours

Sources & evidence

ORD record: ord-c686e9d991514ddeaec595e6adab357f
Source dataset: uspto-grants-2012_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08318727B2

Reaction notes

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