Hydrochloric Acid → HCID 178422169, compound

HRID 2095707Notes

Reaction equation

Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH:20]([F:22])[F:21])=[CH:17][CH:16]=[C:15]([F:23])[C:14]=3[Cl:24])[CH3:12])=[CH:9][N:8](C(OC(C)(C)C)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][C:33]1[N:37]([C@H:38]2[CH2:43][CH2:42][C@H:41]([C:44]([O:46]CC)=O)[CH2:40][CH2:39]2)[N:36]=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].O.Cl.O.[OH-].[Li+].C(Cl)Cl.[NH4+].[Cl-].C[N:71](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:24][C:14]1[C:15]([F:23])=[CH:16][CH:17]=[C:18]([O:19][CH:20]([F:22])[F:21])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[N:36][N:37]([C@H:38]4[CH2:43][CH2:42][C@H:41]([C:44]([NH2:71])=[O:46])[CH2:40][CH2:39]4)[C:33]=3[CH3:32])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]

Participants

Conditions

Temperature: 45 °C

Procedure

A mixture of tert-butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (70.0 mg, 0.135 mmol), ethyl trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexane-carboxylate (97.6 mg, 0.269 mmol), Pd(PPh3)4 (7.78 mg, 0.00673 mmol), potassium fluoride (23.5 mg, 0.404 mmol) and 4:1 dioxane:H2O (5 mL, 50 mmol) was heated in a microwave reactor at 95° C. for 30 min. The material was extracted with DCM and water, and the organic layer was dry-loaded onto silica gel for column chromatography, eluting with 1-2% MeOH/DCM. The fractions containing the intermediate were concentrated in vacuo, and redissolved in MeOH. 12 M of HCl in H2O (0.4 mL, 5 mmol) was added, and the solution was heated to 45° C. for 1 h to remove BOC group. Lithium hydroxide monohydrate (56.5 mg, 1.35 mmol) was added to bring to pH=12, and the solution was heated to 40° C. for 2 h to hydrolyze the ester. The material was concentrated in vacuo and transferred to a separatory funnel with DCM and water. The aqueous layer was added 2 M HCl to bring to pH=6, and the material was extracted. The organic layer was concentrated in vacuo, redissolved in DCM (10 mL, 200 mmol), and NH4Cl (72.0 mg, 1.35 mmol), TBTU (64.9 mg, 0.202 mmol) and DIPEA (0.0704 mL, 0.404 mmol) were added at rt. The solution was stirred for 20 min, then extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 2-5% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.65-1.78 (m, 2H), 1.84 (d, J=7.3 Hz, 3H), 1.94-2.08 (m, 6H), 2.22 (s, 3H), 2.35 (tt, J=12.3, 3.3 Hz, 1H), 4.21 (m, J=10.0, 10.0, 5.2, 5.1 Hz, 1H), 5.10 (q, J=7.0 Hz, 1H), 6.44 (br. s., 1H), 7.08-7.16 (m, 1H), 7.16-7.21 (m, 1H), 7.37 (d, J=1.8 Hz, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.48 (s, 1H), 8.13 (d, J=2.0 Hz, 1H). MS (ES+): m/z=546.16/548.16 (100/50) [MH+]. HPLC: tR=1.40 min (polar—3 min, UPLC-ACQUITY).

Workup

extractionThe material was extracted with DCM and water
washeluting with 1-2% MeOH/DCM
additionThe fractions containing the intermediate
concentrationwere concentrated in vacuo
dissolutionredissolved in MeOH
customto remove BOC group
temperaturethe solution was heated to 40° C. for 2 h
concentrationThe material was concentrated in vacuo
customtransferred to a separatory funnel with DCM and water
additionThe aqueous layer was added 2 M HCl
extractionthe material was extracted
concentrationThe organic layer was concentrated in vacuo
extractionextracted with DCM and water
customThe organic layer was purified via column chromatography
washeluting with 2-5% (7N NH3 in MeOH)/DCM
additionThe fractions containing the pure product
concentrationwere concentrated in vacuo

Sources & evidence

ORD record: ord-d9c41b7a996f44f9a0ed282a6e5c6e6c
Source dataset: uspto-grants-2013_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08445510B2

Reaction notes

Loading…