Water → (S)-(1-(6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol dihydrochloride

HRID 57998

Reaction equation

HRID 57998 reaction equation
[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[Cl:8][C:9]1[N:14]=[C:13]([C:15]2[N:20]=[CH:19][C:18]3[CH:21]=[N:22][N:23]([C:24]4[N:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]5)[CH:27]=[CH:26][CH:25]=4)[C:17]=3[CH:16]=2)[CH:12]=[N:11][CH:10]=1.[F-].[Cs+].O>CS(C)=O>[ClH:8].[ClH:8].[N:30]1([C:28]2[N:29]=[C:24]([N:23]3[C:17]4[CH:16]=[C:15]([C:13]5[N:14]=[C:9]([N:1]6[CH2:5][CH2:4][CH2:3][C@H:2]6[CH2:6][OH:7])[CH:10]=[N:11][CH:12]=5)[N:20]=[CH:19][C:18]=4[CH:21]=[N:22]3)[CH:25]=[CH:26][CH:27]=2)[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1

Participants

6

Reactant 4

HCID 962WaterHCID 25953Cesium fluorideHCID 640091L-ProlinolHCID 86707183tert-butyl 4-(6-(6-(6-chloropyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate

Product 1

HCID 86707185(S)-(1-(6-(1-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol dihydrochloride

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
105 °C

Procedure

A mixture of 3-5 eq. of (S)-pyrrolidin-2-ylmethanol, 1 eq. of tert-butyl 4-(6-(6-(6-chloropyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperazine-1-carboxylate, 6-10 eq of cesium fluoride in DMSO was heated at 105° C. for 12-24 hours. The mixture was mixed with water and extracted with ethyl acetate. The organic extracts were washed with water, brine, dried over sodium sulfate and concentrated in vacuum. The crude products were purified on a silica gel column eluting with gradient of ethyl acetate in heptane or DCM. The Boc group was deprotected with 4 M HCl in dioxane in methanol. The crude product was collected by filtration, dissolved in water and lyophilized to give 280. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 9.31-9.19 (m, 2H), 9.10 (s, 1H), 8.80 (s, 1H), 8.73 (s, 1H), 8.19 (s, 1H), 7.89 (t, J=8.1 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 4.21 (d, J=6.0 Hz, 1H), 3.93 (t, J=5.3 Hz, 4H), 3.58 (m, 1H), 3.49 (m, 2H), 3.22 (d, J=5.4 Hz, 4H), 2.06 (m, 4H). MS (ESI) m/z: 458.3.

Workup

  1. extractionextracted with ethyl acetate
  2. washThe organic extracts were washed with water, brine
  3. dry with materialdried over sodium sulfate
  4. concentrationconcentrated in vacuum
  5. customThe crude products were purified on a silica gel column
  6. washeluting with gradient of ethyl acetate in heptane or DCM
  7. filtrationThe crude product was collected by filtration
  8. dissolutiondissolved in water

Sources & evidence

ORD record
ord-ee71eea13f904307891ff7f453a0464c
Source dataset
uspto-grants-2016_09
Patent number
US09434725B2

Linked notes

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