Water → HCID 86709990, compound

HRID 920627Notes

Reaction equation

HRID 920627 reaction equation
C([Sn](CCCC)(CCCC)[C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.C([Li])CCC.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C@:43]([CH:45]=[O:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1.O>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]3[CH:37]=[C:38]4[C:43]([C@H:45]([C:6]5[N:7]=[CH:8][CH:9]=[CH:10][N:11]=5)[OH:46])([CH2:44][C:35]=3[CH:34]=[N:33]2)[CH2:42][N:41]([S:47]([C:50]2[CH:51]=[C:52]([CH3:56])[CH:53]=[CH:54][CH:55]=2)(=[O:49])=[O:48])[CH2:40][CH2:39]4)=[CH:28][CH:27]=1

Participants

6

Reactant 4

HCID 962WaterHCID 27632512-(Tributylstannyl)pyrimidineHCID 86709989HCID 86709989, compoundHCID 178418339Butyllithium

Product 1

HCID 86709990HCID 86709990, compoundYield 31.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of 2-(tributylstannyl)pyrimidine (428 μl, 1.351 mmol) in dry tetrahydrofuran (5 mL) was added butyllithium (2.5 M in hexanes) (554 μl, 1.384 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 1.5 hours. A solution of (R)-1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-carbaldehyde (200 mg, 0.443 mmol) in dry tetrahydrofuran (5 mL) was added dropwise and the reaction mixture was stirred for 1.5 hours at −78° C. Water (25 mL) was added and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was partitioned between acetonitrile (25 mL) and hexanes (15 mL). The hexane layer was discarded. The acetonitrile layer was concentrated in vacuo to give a pale orange oil. The crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane) to afford (R)-(1-(4-fluorophenyl)-6-(m-tolylsulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyrimidin-2-yl)methanol (75 mg) as a colourless oil. LCMS (Method F, ES-API): RT 2.27 min, m+H=532.2.

Workup

  1. stirringthe reaction mixture was stirred for 1.5 hours at −78° C
  2. extractionthe aqueous layer was extracted with ethyl acetate (2×30 mL)
  3. washThe combined organic layers were washed with brine (30 mL)
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe residue was partitioned between acetonitrile (25 mL) and hexanes (15 mL)
  8. concentrationThe acetonitrile layer was concentrated in vacuo
  9. customto give a pale orange oil
  10. customThe crude product was purified by chromatography on silica gel (gradient: 0-100% ethyl acetate in isohexane)

Sources & evidence

ORD record
ord-557005ee5332487e856da8b0fcf4ac8a
Source dataset
uspto-grants-2016_03
Patent number
US09273047B2

Reaction notes

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