Lithium hydroxide, monohydrate → (S)-2-(7-(4-(Allyloxy)-4-methylpiperidin-1-yl)-2-(4'-fluoro-2'-((S)-pent-4-en-2-yloxy)-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid

HRID 1400768Notes

Reaction equation

HRID 1400768 reaction equation
C([O:3][C:4](=[O:51])[C@H:5]([C:11]1[C:12]([CH3:50])=[N:13][C:14]2[N:15]([N:28]=[C:29]([C:31]3[CH:32]=[C:33]([C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:34]=[CH:35][CH:36]=3)[CH:30]=2)[C:16]=1[N:17]1[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=[CH2:27])([CH3:23])[CH2:19][CH2:18]1)[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])C.O[Li].O>CO.O>[CH2:25]([O:24][C:20]1([CH3:23])[CH2:19][CH2:18][N:17]([C:16]2[N:15]3[N:28]=[C:29]([C:31]4[CH:32]=[C:33]([C:37]5[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=5[O:44][C@H:45]([CH2:47][CH:48]=[CH2:49])[CH3:46])[CH:34]=[CH:35][CH:36]=4)[CH:30]=[C:14]3[N:13]=[C:12]([CH3:50])[C:11]=2[C@H:5]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:4]([OH:51])=[O:3])[CH2:22][CH2:21]1)[CH:26]=[CH2:27]

Participants

5

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 86710820(S)-Ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4'-fluoro-2'-((S)-pent-4-en-2-yloxy)-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate

Product 1

HCID 86710821(S)-2-(7-(4-(Allyloxy)-4-methylpiperidin-1-yl)-2-(4'-fluoro-2'-((S)-pent-4-en-2-yloxy)-[1,1'-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acidYield 23%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of (S)-ethyl-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (32 mg, 0.048 mmol, 1 equiv) in MeOH (1.0 mL) and water (0.1 mL) was added LiOH.H2O (60 mg, 1.43 mmol, 30 equiv). The reaction was heated to 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was then filtered and purified via preparative HPLC with the following conditions: Column. XBridge Phenyl, 19×mm, 5-1 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Product (7 mg, 23%) isolated. 1H NMR (600 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.52 (t, J=7.7 Hz, 1H), 7.36-7.30 (m, 2H), 7.10 (d, J=11.6 Hz, 1H), 7.04 (s, 1H), 6.88-6.81 (m, 1H), 6.31 (d, J=6.1 Hz, 1H), 5.58 (s, 1H), 4.66-4.60 (m, 1H), 4.53 (q, J=7.0 Hz, 1H), 4.37 (t, J=12.1 Hz, 1H), 3.64-3.55 (m, 4H), 2.88 (br. s., 1H), 2.53 (s, 3H), 2.40-2.32 (m, 1H), 2.31-2.24 (m, 1H), 1.96-1.59 (m, 4H), 1.32 (s, 3H), 1.16 (s, 9H), 1.13 (d, J=6.1 Hz, 3H). LCMS (M+1)=643.5.

Workup

  1. temperatureUpon cooling to ambient temperature
  2. filtrationthe reaction was then filtered
  3. custompurified via preparative HPLC with the following conditions
  4. customa 5-minute hold

Sources & evidence

ORD record
ord-111bb07e01844c5c9e0d2315e5062c9e
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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