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

HRID 921173Notes

Reaction equation

HRID 921173 reaction equation
C([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH:19][C:20]1[CH:72]=[C:23]2[N:24]=[C:25]([CH3:71])[C:26]([C@H:60]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[C:61]([O:63][CH2:64][CH3:65])=[O:62])=[C:27]([N:28]3[CH2:33][CH2:32][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si:43]([C:56]([CH3:59])([CH3:58])[CH3:57])([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH3:41])([CH3:34])[CH2:30][CH2:29]3)[N:22]2[N:21]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:67]([O:66][C@@H:60]([C:26]1[C:25]([CH3:71])=[N:24][C:23]2[N:22]([N:21]=[C:20]([CH2:19][CH2:18][CH2:17][C:10]3[CH:11]=[C:12]([F:16])[CH:13]=[C:14]([F:15])[C:9]=3[OH:8])[CH:72]=2)[C:27]=1[N:28]1[CH2:29][CH2:30][C:31]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][C@H:40]([O:42][Si:43]([C:56]([CH3:59])([CH3:57])[CH3:58])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH3:41])([CH3:34])[CH2:32][CH2:33]1)[C:61]([O:63][CH2:64][CH3:65])=[O:62])([CH3:68])([CH3:69])[CH3:70]

Participants

5

Reactant 2

HCID 131734917(S)-ethyl 2-(2-(3-(2-(benzyloxy)-3,5-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 131734918(S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(3,5-difluoro-2-hydroxyphenyl)propyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetateYield 81%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

To a solution of (S)-ethyl 2-(2-(3-(2-(benzyloxy)-3,5-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 (190 mg, 0.190 mmol) in Ethanol (4 mL) was added 10% Pd—C (40.4 mg, 0.038 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 to afford (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-(3-(3,5-difluoro-2-hydroxyphenyl)propyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (140 mg, 0.153 mmol, 81% yield) as thick paste. Used as is in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J=7.3 Hz, 4H), 7.45-7.34 (m, 6H), 6.75-6.63 (m, 2H), 6.34 (s, 1H), 5.90 (br. s., 1H), 4.33-4.10 (m, 3H), 3.95-3.79 (m, 1H), 3.35 (br. s., 2H), 2.92-2.76 (m, 3H), 2.73 (br. s., 1H), 2.61 (s, 3H), 2.16-2.04 (m, 3H), 1.92 (br. s., 1H), 1.87 (br. s., 1H), 1.53-1.46 (m, 3H), 1.45-1.26 (m, 9H), 1.24 (s, 9H), 1.07 (s, 9H). LCMS (M+H)=913.9.

Workup

  1. customcompletion of reaction
  2. filtrationMixture was then filtered through a pad of celite
  3. concentrationconcentrated
  4. customdried under high vac

Sources & evidence

ORD record
ord-c4590528ee734af794f4c23078a3595c
Source dataset
uspto-grants-2016_03
Patent number
US09273067B2

Reaction notes

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