Tetrahydrofuran → 1-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-3'-hydroxymethyl-1'H-[1,4']bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate salt

HRID 60680Notes

Reaction equation

HRID 60680 reaction equation
[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:51][O:52][Si](C(C)C)(C(C)C)C(C)C)=[N:43][N:44]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C[O:84]CC1>>[CH:51]([OH:52])=[O:84].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[C:42]([CH2:51][OH:52])=[N:43][N:44]([CH2:46][CH2:47][N:48]([CH3:50])[CH3:49])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]

Participants

4

Reactant 3

HCID 8028TetrahydrofuranHCID 2724141Tetrabutylammonium FluorideHCID 1231771221-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-3'-triisopropylsilanyloxymethyl-1'H-[1,4']bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea

Product 1

HCID 863429461-[3-tert-Butyl-1'-(2-dimethylamino-ethyl)-3'-hydroxymethyl-1'H-[1,4']bipyrazolyl-5-yl]-3-{(1S,4R)-4-[3-((S)-2-methyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea formate saltYield 32%

Conditions

Temperature
50 °C

Procedure

A solution of Intermediate 74k (76 mg, 0.088 mmol) in THF (0.44 mL) was treated with tetrabutylammonium fluoride (1M in THF, 0.44 mL, 0.44 mmol) and the mixture was heated to 50° C. for 5 h. The mixture was evaporated in vacuo and the residue was partitioned between DCM and a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-9% [2M NH3 in MeOH] in DCM. Further purification by HPLC in 3 portions (Method 6, 30-60% MeCN in H2O, 0.1% HCO2H over 25 min) gave a colourless glass that was triturated with ether. The solid was collected by filtration, washed with ether and dried at 50° C. in vacuo to give the title compound (20 mg, 32%). LCMS (Method 5): Rt 3.47 min, m/z 710.5 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.3 Hz), 1.25 (9H, s), 1.44-1.57 (2H, m), 1.61-1.74 (2H, m), 1.74-1.92 (3H, m), 1.92-2.02 (1H, m), 2.01-2.16 (2H, m), 2.18 (6H, s), 2.68 (2H, t, J=6.8 Hz), 2.87-2.95 (1H, m), 3.16 (1H, dt, J=12.0, 4.1 Hz, partially obscured by water), 3.27-3.36 (11, m, obscured by water), 4.16 (2H, t, J=7.0 Hz), 4.31 (2H, s), 4.80-4.88 (1H, m), 4.92-5.11 (0.3H, br s), 5.53 (1H, t, J=4.3 Hz), 6.30 (1H, s), 7.14-7.22 (2H, m), 7.25-7.40 (41H, m), 7.64 (1H, d, J=10.0 Hz), 7.70 (1H, d, J=1.6 Hz), 8.00 (1H, s), 8.07 (1H, s), 8.19 (1H, s).

Workup

  1. customThe mixture was evaporated in vacuo
  2. customthe residue was partitioned between DCM
  3. customThe layers were separated
  4. extractionthe aqueous layer was then extracted with DCM (2×)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. customevaporated in vacuo
  9. customThe residue was purified by FCC
  10. customFurther purification by HPLC in 3 portions (Method 6, 30-60% MeCN in H2O, 0.1% HCO2H over 25 min)
  11. customgave a colourless glass that
  12. customwas triturated with ether
  13. filtrationThe solid was collected by filtration
  14. washwashed with ether
  15. customdried at 50° C. in vacuo

Sources & evidence

ORD record
ord-1dbce7366e3b4b878839174710d2e9eb
Source dataset
uspto-grants-2016_09
Patent number
US09440974B2

Reaction notes

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