Tetrabutylammonium Fluoride → (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(2,3-difluoro-6-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate

HRID 921181Notes

Reaction equation

HRID 921181 reaction equation
C([O:8][C:9]1[C:14]([CH2:15][CH:16]=[CH:17][C:18]2[CH:70]=[C:21]3[N:22]=[C:23]([CH3:69])[C:24]([C@H:58]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[C:25]([N:26]4[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([O:40][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)[CH3:39])([CH3:32])[CH2:28][CH2:27]4)[N:20]3[N:19]=2)=[C:13]([F:71])[C:12]([F:72])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(O)C.C1COCC1.[Pd]>[C:65]([O:64][C@@H:58]([C:24]1[C:23]([CH3:69])=[N:22][C:21]2[N:20]([N:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:14]3[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([F:72])[C:13]=3[F:71])[CH:70]=2)[C:25]=1[N:26]1[CH2:31][CH2:30][C:29]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][C@H:38]([OH:40])[CH3:39])([CH3:32])[CH2:28][CH2:27]1)[C:59]([O:61][CH2:62][CH3:63])=[O:60])([CH3:66])([CH3:67])[CH3:68]

Participants

7

Reactant 3

HCID 2724141Tetrabutylammonium FluorideHCID 131734920(S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetateHCID 178418361HCID 178418361, compound

Product 1

HCID 118318838(S)-ethyl 2-(tert-butoxy)-2-(2-(3-(2,3-difluoro-6-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetateYield 45.6%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (114 mg, 0.114 mmol) in Ethanol (4 mL) was added 10% Pd—C (24 mg, 0.022 mmol) and the resulting mixture was stirred under balloon hydrogen atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered through a pad of celite, concentrated and dried under high vac. The residue was then treated with 1M TBAF (0.849 mL, 0.849 mmol) in THF (4 mL) for 16 h. Mixture was then concentrated and purified by Biotage (5-70% EtOAc/hexane) to afford (S)-ethyl 2-(tert-butoxy)-2-(2-(3-(2,3-difluoro-6-hydroxyphenyl)propyl)-7-(4-(((R)-5-hydroxyhexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (35 mg, 0.052 mmol, 30% yield) as thick paste. 1H NMR (400 MHz, CDCl3) δ 6.90 (q, J=9.0 Hz, 1H), 6.59 (d, J=10.0 Hz, 1H), 6.36 (s, 1H), 5.91 (br. s., 1H), 4.32-4.15 (m, 2H), 3.85 (d, J=6.3 Hz, 2H), 3.44 (br. s., 3H), 2.94 (br. s., 1H), 2.89-2.71 (m, 4H), 2.63 (s, 3H), 2.15-2.04 (m, 2H), 2.04-1.94 (m, 2H), 1.90 (d, J=6.8 Hz, 2H), 1.75 (d, J=7.3 Hz, 1H), 1.57-1.44 (m, 6H), 1.38-1.27 (m, 12H), 0.94-0.87 (m, 6H). LCMS (M+H)=675.4.

Workup

  1. customcompletion of reaction
  2. filtrationMixture was then filtered through a pad of celite
  3. concentrationconcentrated
  4. customdried under high vac
  5. concentrationMixture was then concentrated
  6. custompurified by Biotage (5-70% EtOAc/hexane)

Sources & evidence

ORD record
ord-1a7ec97b41ae4ec0a061b533b2ba2fbc
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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