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

HRID 1747736Notes

Reaction equation

HRID 1747736 reaction equation
C1C2C(COC([N:18]3[C@H:27]([C:28](O)=[O:29])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][NH:41][CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33].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>[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][N:41]([C:28]([C@@H:27]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][NH:18]3)=[O:29])[CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 978341Fmoc-L-Tic-OHHCID 896147743-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one

Product 1

HCID 716104413-isobutyl-3-phenyl-5-((S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-oneYield 68.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (147 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, re-dissolved in 20% piperidine in DMF (5 mL), and stirred at room temperature for 1 hour. The crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-3-phenyl-5-((S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (54 mg, 68%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.59-1.74 (m, 1H), 1.75-1.88 (m, 1H), 2.26-2.52 (m, 3H), 2.71-2.85 (m, 1H), 2.87-3.10 (m, 1H), 3.37-3.72 (m, 2H), 3.76-3.99 (m, 2H), 4.00-4.15 (m, 3H), 4.62-4.86 (m, 1H), 7.01-7.22 (m, 4H), 7.28-7.45 (m, 5H); MS m/z 431 (M+H)+, 429 (M−H)−.

Workup

  1. concentrationThe reaction mixture was concentrated to dryness
  2. dissolutionre-dissolved in 20% piperidine in DMF (5 mL)
  3. stirringstirred at room temperature for 1 hour
  4. customThe crude reaction mixture
  5. concentrationwas concentrated
  6. custompurified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-15b08c79e3ed40f48502c237a05ebbfe
Source dataset
uspto-grants-2015_10
Patent number
US09150582B2

Reaction notes

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