Diisopropylethylamine → 5-((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one

HRID 1747737Notes

Reaction equation

HRID 1747737 reaction equation
C(OC([N:8]1[C@@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:22]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH2:31][NH:32][CH2:33][CH2:34][C:29]=2[C:28](=[O:35])[O:27]1)[CH:23]([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[OH:21][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([C:18]([N:32]3[CH2:33][CH2:34][C:29]4[C:28](=[O:35])[O:27][C:26]([CH2:22][CH:23]([CH3:24])[CH3:25])([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]=4[CH2:31]3)=[O:20])[NH:8][CH2:9]2)=[CH:14][CH:13]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 7015829(3R)-2-((tert-butoxy)carbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acidHCID 896147743-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one

Product 1

HCID 896158615-((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-oneYield 67%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (R)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (102 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and the crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes). The purified fractions were re-dissolved in dichloromethane (5 mL), cooled to 0° C. and stirred with TFA (1 mL) for 5 hours at room temperature. The reaction mixture was concentrated to dryness, re-dissolved in dichloromethane (20 mL), washed with sat. NaHCO3 solution (5 mL), brine (5 mL), dried (MgSO4), and concentrated to provide 5-((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (55 mg, 67%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.58-1.88 (m, 2H), 2.25-2.54 (m, 5H), 2.65-2.97 (m, 2H), 3.52 (d, J=6.40 Hz, 1H), 3.75-3.95 (m, 2H), 3.98-4.11 (m, 3H), 4.56-4.86 (m, 1H), 6.51 (s, 1H), 6.59-6.73 (m, 1H), 6.95 (t, J=8.48 Hz, 1H), 7.28-7.45 (m, 5H); MS m/z 447 (M+H)+.

Workup

  1. concentrationThe reaction mixture was concentrated to dryness
  2. customthe crude reaction mixture
  3. concentrationwas concentrated
  4. custompurified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes)
  5. dissolutionThe purified fractions were re-dissolved in dichloromethane (5 mL)
  6. temperaturecooled to 0° C.
  7. stirringstirred with TFA (1 mL) for 5 hours at room temperature
  8. concentrationThe reaction mixture was concentrated to dryness
  9. dissolutionre-dissolved in dichloromethane (20 mL)
  10. washwashed with sat. NaHCO3 solution (5 mL), brine (5 mL)
  11. dry with materialdried (MgSO4)
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-dd5dd7b5d68844da93b8539684a38b41
Source dataset
uspto-grants-2015_10
Patent number
US09150582B2

Reaction notes

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