Hydrochloric Acid → Hydrochloric Acid

HRID 2095700Notes

Reaction equation

HRID 2095700 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 670045381-[[(4S)-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 54674209(2S)-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 (45.0 mg, 0.0866 mmol), 1-{[(4S)-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 (41.85 mg, 0.1299 mmol), Pd(PPh3)4 (5.002 mg, 0.004329 mmol), K2CO3 (35.90 mg, 0.2597 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 (0.072 mL, 0.87 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 2-4% (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 (0.4329 mL, 0.8658 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=7.3 Hz, 3H), 2.27 (s, 3H), 3.50-3.63 (m, 2H), 4.00-4.09 (m, 1H), 4.15 (dd, J=14.1, 7.6 Hz, 1H), 4.25 (dd, J=14.3, 4.4 Hz, 1H), 5.12 (q, J=7.1 Hz, 1H), 6.44 (br. s., 1H), 7.14 (dd, J=8.7, 4.4 Hz, 1H), 7.20 (t, J=8.7 Hz, 1H), 7.35-7.45 (m, 2H), 7.52 (s, 1H), 8.16 (d, J=2.0 Hz, 1H). MS (ES+): m/z=494.99/496.98 (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 2-4% (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-6aad50277d6b445ea09874b14a02c5bc
Source dataset
uspto-grants-2013_05
Patent number
US08445510B2

Reaction notes

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