Pyridine → HCID 67520457, compound

HRID 1926442Notes

Reaction equation

HRID 1926442 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37][NH:36]1.N1C=CC=CC=1.C(Cl)Cl>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([N:36]4[CH2:37][CH2:38][C:39]5[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:35]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 4

HCID 1049PyridineHCID 6344DichloromethaneHCID 70461,2,3,4-TetrahydroisoquinolineHCID 534879604-[4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-3-yl]pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 67520457HCID 67520457, compound

Procedure

A mixture of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB4) (93.9 mg, 0.200 mmol), 1,2,3,4-tetrahydroisoquinoline (53.3 mg, 0.400 mmol), cupric acetate (36.3 mg, 0.200 mmol), pyridine (32 μL, 0.40 mmol) and DCM (5 mL, 80 mmol) was stirred at rt under an atmosphere of air (Reaction A). Another reaction was set up with the same amount of above reagents, and 4 Å molecular sieves (53 mg, 264 mg/mmol SM) was added (Reaction B). After stirring overnight at rt, the same amount of molecular sieve as in reaction B was added to reaction A. After stirring at rt for 7 h, both reaction mixtures were combined, washed with EDTA solution (2%, 3×30 ml), water (30 ml) and brine (30 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a dark-blue solid. Purification by prep. TLC eluting with 5% MeOH/DCM gave 4-{4-[6-amino-5-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as brown oil; MS(ES+): m/z=475.12 [MH+]. This brown oil was dissolved in MeOH (10 mL), 1.0 M of HCl in Et2O (10 mL) was added, and the solution was stirred at rt for 3 d. The solvent was removed; the residue was dissolved in DMSO and purified by Gilson HPLC to give the title compound as light-brown oil. 1H NMR (400 MHz, DMSO-d6): δ=1.99-2.11 (m, 2H), 2.12-2.19 (m, 2H), 2.89-2.99 (m, 2H), 3.00-3.05 (m, 2H), 3.12-3.18 (m, 2H), 3.26-3.33 (m, 2H), 4.10 (s, 2H), 4.33-4.43 (m, 1H), 5.51 (brs, 2H), 7.13-7.19 (m, 4H), 7.47 (d, J=2.0 Hz, 1H), 7.82 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 8.13 (s, 1H), 8.30 (brs, 2H). MS(ES+): m/z=375.17 (42) [MH+]. HPLC: tR=1.73 min (ZQ2, polar—5 min).

Workup

  1. customReaction A)
  2. additionwas added
  3. custom(Reaction B)
  4. stirringAfter stirring overnight at rt
  5. customthe same amount of molecular sieve as in reaction B
  6. additionwas added to reaction A
  7. stirringAfter stirring at rt for 7 h
  8. customboth reaction mixtures
  9. washwashed with EDTA solution (2%, 3×30 ml), water (30 ml) and brine (30 ml)
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customto give a dark-blue solid
  14. customPurification by prep
  15. washTLC eluting with 5% MeOH/DCM

Sources & evidence

ORD record
ord-382c6623cfb84bad98aea4528dc520a2
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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