Hydrochloric Acid → Lumacaftor

HRID 870797Notes

Reaction equation

[F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](C(C)(C)C)=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([O-:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.Cl>CC#N>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1

Participants

Conditions

Temperature: 45 °C

Procedure

To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) was added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture was heated to 45±5° C. After stirring for 24 to 48 hours, the reaction was complete, and the mixture was allowed to cool to ambient temperature. Water (1.33 vol) was added and the mixture stirred. The solid was collected by filtration, washed with water (2×0.3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (less than 1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl as an off-white solid.

Workup

temperatureto cool to ambient temperature
stirringthe mixture stirred
filtrationThe solid was collected by filtration
washwashed with water (2×0.3 vol)
custompartially dried on the
filtrationfilter under vacuum
dry with materialThe solid was dried to a constant weight (less than 1% difference) in a vacuum oven at 60° C. with a slight N2

Sources & evidence

ORD record: ord-e7b48851e09b4bf0ae2db18a1634ff8b
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08969574B2

Reaction notes

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