Hydrochloric Acid → 3-(5-Chloro-8-fluoroisoquinolin-3-yl)-5-((S)-1-pyrrolidin-3-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride

HRID 1926314Notes

Reaction equation

HRID 1926314 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=[N:14]2)[CH2:9]1)=O)(C)(C)C.Br[C:28]1[CH:29]=[C:30]([C:35]2[N:36]=[CH:37][C:38]3[C:43]([CH:44]=2)=[C:42]([Cl:45])[CH:41]=[CH:40][C:39]=3[F:46])[C:31]([NH2:34])=[N:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[ClH:53]>C(Cl)Cl.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.COCCOC.O>[ClH:45].[ClH:53].[ClH:45].[Cl:45][C:42]1[CH:41]=[CH:40][C:39]([F:46])=[C:38]2[C:43]=1[CH:44]=[C:35]([C:30]1[C:31]([NH2:34])=[N:32][CH:33]=[C:28]([C:16]3[CH:15]=[N:14][N:13]([C@H:10]4[CH2:11][CH2:12][NH:8][CH2:9]4)[CH:17]=3)[CH:29]=1)[N:36]=[CH:37]2

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 57812584(S)-(1-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)-1H-pyrazol-4-yl)boronic acid pinacol esterHCID 675207675-Bromo-3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine

Product 1

HCID 675212803-(5-Chloro-8-fluoroisoquinolin-3-yl)-5-((S)-1-pyrrolidin-3-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 18180031Water 1,2-dimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of (S)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.0804 g, 0.221 mmol), 5-bromo-3-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-2-ylamine (0.065 g, 0.18 mmol), potassium carbonate (0.0815 g, 0.590 mmol), and Pd(PPh3)4 (0.015 g, 0.013 mmol) in previously degassed DME/Water (4:1) (2.05 mL) was placed in a microwave tube and evacuated and charged with N2 (2×). The reaction mixture was heated in the microwave reactor to 100° C. for 45 min. The reaction mixture was diluted with EtOAc and washed with H2O (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo to give a brown oil. This material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3] resulting in (R)-3-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester, MS (ES+): m/z=508.9/510.8 (76/24) [MH+]. This compound was dissolved in DCM (2.0 mL) and charged with 1.0 M of HCl in Et2O (1.1 mL) and stirred at 40° C. for 5 then at rt for an additional 16 h. The solid that formed was filtered off and washed with diethyl ether (3×), yielding the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.23-2.36 (m, 1H), 2.39-2.49 (m, 1H), 3.33-3.48 (m, 1H), 3.51-3.62 (m, 2H), 3.62-3.82 (m, 2H), 5.14-5.28 (m, 1H), 7.66 (t, J=9.2 Hz, 1H), 8.11 (dd, J=8.4, 4.8 Hz, 1H), 8.17 (s, 1H), 8.47 (d, J=1.8 Hz, 1H), 8.54 (d, J=11.7 Hz, 2H), 8.67 (br. s., 1H), 9.41 (br. s., 1H), 9.54 (br. s., 1H), 9.68 (s, 1H). MS (ES+): m/z=408.88/410.77 (76/24) [MH+]. HPLC: tR=1.84 min (ZQ2, polar—5 min).

Workup

  1. customevacuated
  2. additioncharged with N2 (2×)
  3. additionThe reaction mixture was diluted with EtOAc
  4. washwashed with H2O (2×), brine (2×)
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give a brown oil
  9. customThis material was purified by chromatography on silica gel [eluting with 1% MeOH in CHCl3]
  10. customresulting in (R)-3-{4-[6-Amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester
  11. customThe solid that formed
  12. filtrationwas filtered off
  13. washwashed with diethyl ether (3×)

Sources & evidence

ORD record
ord-4935a05ebea347e49578d62eb4047af9
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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