Hydrochloric Acid → Hydrochloric Acid

HRID 2095717Notes

Reaction equation

HRID 2095717 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)[CH:41]=[N:40]2)[CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].O.[ClH:62].CCOCC>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:21])[F:22])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:42]3[CH:41]=[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].[ClH:62]

Participants

10

Reactant 6

HCID 313Hydrochloric Acid2×HCID 962Water2×HCID 3283Diethyl EtherHCID 11430Potassium CarbonateHCID 67003931tert-Butyl 5-bromo-3-{(1S)-1-[2-chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridine-1-carboxylateHCID 670040821-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Product 2

HCID 313Hydrochloric AcidHCID 54673762(2R)-3-[4-(3-{(1S)-1-[2-Chloro-6-(difluoromethoxy)-3-fluorophenyl]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-5-methyl-1H-pyrazol-1-yl]propane-1,2-diol

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

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 (50.0 mg, 0.0962 mmol), 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (46.50 mg, 0.1443 mmol), Pd(PPh3)4 (5.558 mg, 0.004810 mmol), K2CO3 (39.89 mg, 0.2886 mmol) and 4:1 dioxane:H2O (2 mL, 20 mmol) was heated to 95° C. for 2 h. The solution was cooled to rt, and 12 M of HCl in H2O (0.08017 mL, 0.9620 mmol) was added. The material was concentrated in vacuo, and extracted with DCM and sat. NaHCO3. The organic layer was dry-loaded onto silica gel and purified via column chromatography, eluting with 3-6% (7N NH3 in MeOH)/DCM. The fractions containing the pure product were concentrated in vacuo, redissolved in MeOH, and 2.0 M of HCl in Et2O (0.4810 mL, 0.9620 mmol) was added at rt. The solution was concentrated in vacuo to afford the title compound as an HCl salt. 1H NMR (400 MHz, CD3OD): δ=1.85 (d, J=7.1 Hz, 3H), 2.27 (s, 3H), 3.52-3.63 (m, 2H), 4.00-4.08 (m, 1H), 4.11-4.19 (m, 1H), 4.26 (dd, J=14.1, 4.3 Hz, 1H), 5.12 (q, J=7.2 Hz, 1H), 6.44 (br. s., 1H), 7.14 (dd, J=8.8, 4.5 Hz, 1H), 7.20 (t, J=8.7 Hz, 1H), 7.37-7.43 (m, 2H), 7.52 (s, 1H), 8.16 (d, J=2.0 Hz, 1H). MS (ES+): m/z=495.11/497.11 (100/50) [MH+]. HPLC: tR=1.29 min (polar—3 min, UPLC-ACQUITY).

Workup

  1. concentrationThe material was concentrated in vacuo
  2. extractionextracted with DCM and sat. NaHCO3
  3. custompurified via column chromatography
  4. washeluting with 3-6% (7N NH3 in MeOH)/DCM
  5. additionThe fractions containing the pure product
  6. concentrationwere concentrated in vacuo
  7. dissolutionredissolved in MeOH
  8. concentrationThe solution was concentrated in vacuo

Sources & evidence

ORD record
ord-0ba8418bffbf42648709c119706e9012
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

Loading…