Hydrochloric Acid → (2R)-3-[4-(3-{(1S)-1-[2-Chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethyl-1H-pyrazol-1-yl]propane-1,2-diol

HRID 2095696Notes

Reaction equation

HRID 2095696 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.CC1(C)[O:37][C@H:36]([CH2:38][N:39]2[C:43]([CH3:44])=[C:42](B3OC(C)(C)C(C)(C)O3)[C:41]([CH3:54])=[N:40]2)[CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].O.Cl>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:42]3[C:41]([CH3:54])=[N:40][N:39]([CH2:38][C@@H:36]([OH:37])[CH2:35][OH:34])[C:43]=3[CH3:44])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 962Water2×HCID 11430Potassium CarbonateHCID 67003931tert-Butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 670044181-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Product 1

HCID 54674208(2R)-3-[4-(3-{(1S)-1-[2-Chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethyl-1H-pyrazol-1-yl]propane-1,2-diol

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
40 °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 (10.0 mg, 0.0192 mmol), 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12.9 mg, 0.0385 mmol), Pd(PPh3)4 (1.1 mg, 0.00096 mmol), K2CO3 (7.98 mg, 0.00577 mmol) and 4:1 dioxane:H2O (0.7 mL, 8 mmol) was heated in a microwave reactor at 100° C. for 45 min. 12 M of HCl in H2O (0.04 mL, 0.5 mmol) was added, and the solution was heated to 40° C. for 20 min. The solution was used directly for HPLC purification, and 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=1.84 (d, J=7.3 Hz, 3H), 2.04 (s, 3H), 2.17 (s, 3H), 3.50-3.61 (m, 2H), 3.96-4.10 (m, 2H), 4.13-4.19 (m, 1H), 5.07-5.15 (m, 1H), 6.43 (br. s., 1H), 7.12 (dd, J=9.2, 4.4 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.41 (d, J=1.3 Hz, 1H), 7.96-8.04 (m, 1H). MS (ES+): m/z=509.15/511.15 (100/50) [MH+]. HPLC: tR=1.33 min (polar—3 min, UPLC-ACQUITY).

Workup

  1. customThe solution was used directly for HPLC purification
  2. additionthe fractions containing the pure product
  3. concentrationwere concentrated in vacuo

Sources & evidence

ORD record
ord-e52e4cc92c4e4c6b86bc0434160cc32c
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

Loading…