Sodium borohydride → Methyl (2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate

HRID 1400743Notes

Reaction equation

HRID 1400743 reaction equation
[CH2:1]([O:4][C:5]1([CH3:50])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:34]([CH2:36][CH:37]=[CH2:38])[CH3:35])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:7][CH2:6]1)C=C.[BH4-].[Na+]>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.CCOC(C)=O>[C:46]([O:45][C@@H:40]([C:12]1[C:13]([CH3:39])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:50])([O:4][CH2:1][CH2:38][CH2:37][CH2:36][C@H:34]([CH3:35])[O:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:47])[CH3:49]

Participants

6

Reactant 2

HCID 4311764Sodium borohydrideHCID 86710799(S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5'-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 86710798Methyl (2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate

Reagents, catalysts & solvents 3

HCID 178425456HCID 178425456, compoundCatalystHCID 111,2-DichloroethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-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 (0.17 g, 0.25 mmol, 1 equiv) in DCE (50 mL) was heated to 80° C. The Hoyveda Grubbs 2nd generation catalyst (31 mg, 0.05 mmol, 0.2 equiv) was added. The pale green brown solution was stirred for 1.5 h and then allowed to cool to ambient temperature. The reaction was concentrated in vacuo. The dark residue was then taken up in MeOH (5 mL) and NaBH4 (13 mg, 0.35 mmol, 1.4 equiv) was added. After stirring 30 min, the reaction was diluted with EtOAc and washed with water. The EtOAc layer was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc in hexane) to provide the product as a colorless film (62 mg, 38%). 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.80 (s, 1H), 7.51 (s, 1H), 7.39-7.31 (m, 1H), 7.09 (s, 1H), 7.05-6.87 (m, 3H), 5.93-5.82 (m, 1H), 4.68-4.42 (m, 2H), 4.27-4.17 (m, 1H), 3.84-3.68 (m, J=3.5 Hz, 4H), 3.56-3.22 (m, 2H), 3.03-2.85 (m, 1H), 2.62 (br. s., 3H), 2.02-1.70 (m, J=12.8 Hz, 10H), 1.26-1.21 (m, 12H), 1.15 (d, J=6.0 Hz, 3H). LCMS (M+1)=659.45.

Workup

  1. concentrationThe reaction was concentrated in vacuo
  2. stirringAfter stirring 30 min
  3. washwashed with water
  4. dry with materialThe EtOAc layer was dried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by flash column chromatography (0-100% EtOAc in hexane)
  7. customto provide the product as a colorless film (62 mg, 38%)

Sources & evidence

ORD record
ord-b277454634ce4e1b8ffed4bd81b9eba7
Source dataset
uspto-grants-2014_12
Patent number
US08906929B2

Reaction notes

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