1,2-Dichloroethane → HCID 58813120, compound

HRID 1391716Notes

Reaction equation

HRID 1391716 reaction equation
[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH2:29])[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=[CH2:3].[O:31]=[C:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH:37]([CH2:41][CH:42]=[CH2:43])[C:38](O)=[O:39].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:30])[C@@H:19]([NH:29][C:38](=[O:39])[C@@H:37]([N:33]2[CH2:34][CH2:35][CH2:36][C:32]2=[O:31])[CH2:41][CH:42]=[CH2:43])[CH2:20][C:21]2[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=2)[CH2:6]1)[CH:2]=[CH2:3]

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 588131062-(2-Oxopyrrolidin-1-yl)pent-4-enoic acidHCID 59676141HCID 59676141, compound

Product 1

HCID 58813120HCID 58813120, compoundYield 28%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

Step I (1): A mixture of (2R,3S)-1-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol (73 mg, 0.183 mmol) from stepE(2), 2-(2-oxopyrrolidin-1-yl)pent-4-enoic acid (35 mg, 0.192 mmol) from stepA(2), EDC (35 mg, 0.183 mmol), HOBt (25 mg, 0.192 mmol), DIEA (0.155 mL, 0.870 mmol) in 3 mL of DMF were stirred at room temperature for 18 h. The crude product was purified using reverse phase preparatory HPLC to provide two diastereomers. The fractions containing products were neutralized with solid NaHCO3 prior to concentration in vacuo. Water was added to the solid residues, the aqueous mixtures were extracted with EtOAc, the organic layers were dried over Na2SO4, filtered and concentrated in vacuo to provide 28.4 mg (28% yield) of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(2-oxopyrrolidin-1-yl)pent-4-enamide (diastereomer A, first to elute) and 38.6 mg (38% yield) of (R)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-(2-oxopyrrolidin-1-yl)pent-4-enamide (diastereomer B, second to elute). Data for diastereomer A: LC-MS (M+H)+=584.37, HRMS (M+H)+=584.2927; 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.24 Hz, 1H), 6.91 (d, J=2.14 Hz, 1H), 6.83 (dd, J=8.24, 2.44 Hz, 1H), 6.65-6.80 (m, J=6.10, 6.10 Hz, 2H), 6.54-6.68 (m, 2H), 5.85-6.06 (m, 1H), 5.51-5.72 (m, 1H), 5.31 (dd, J=17.24, 1.68 Hz, 1H), 5.18 (dd, J=10.38, 1.53 Hz, 1H), 4.94-5.12 (m, 2H), 4.77 (dd, J=6.26, 4.43 Hz, 1H), 4.52 (dd, J=9.00, 6.56 Hz, 1H), 3.96-4.24 (m, 4H), 3.79 (s, 3H), 3.39-3.59 (m, 1H), 3.03-3.35 (m, 2H), 2.75-2.93 (m, 2H), 2.46-2.76 (m, 4H), 2.20-2.40 (m, 2H), 2.07-2.22 (m, 1H), 1.79-1.96 (m, 2H), 1.66-1.81 (m, 1H). Data for diasteomer B: LC-MS (M+H)+=584.97; HRMS (M+H)+=584.2955; 1H NMR (500 MHz, CDCl3) δ 7.29 (d, J=8.54 Hz, 1H), 6.97-7.13 (m, 1H), 6.89-6.97 (m, 1H), 6.83 (dd, J=8.39, 2.29 Hz, 1H), 6.73 (m, 2H), 6.57-6.67 (m, 1H), 5.80-6.05 (m, 1H), 5.41-5.59 (m, 1H), 5.24-5.39 (m, 1H), 5.17 (d, J=10.38 Hz, 1H), 4.88-5.10 (m, 2H), 4.67-4.84 (m, 1H), 4.35 (dd, J=8.55, 7.02 Hz, 1H), 3.96-4.23 (m, 4H), 3.70-3.87 (m, 3H), 3.50-3.64 (m, 1H), 3.24-3.45 (m, 2H), 3.00 (dd, J=14.19, 4.12 Hz, 1H), 2.80 (dd, J=12.21, 3.36 Hz, 1H), 2.54-2.76 (m, 3H), 2.39-2.55 (m, 1H), 2.19-2.43 (m, 3H), 1.75-1.99 (m, 3H).

Workup

  1. customThe crude product was purified
  2. customto provide two diastereomers
  3. additionThe fractions containing products
  4. concentrationto concentration in vacuo
  5. additionWater was added to the solid residues
  6. extractionthe aqueous mixtures were extracted with EtOAc
  7. dry with materialthe organic layers were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-aa916fb057b84bee90eb8f4c860d73e3
Source dataset
uspto-grants-2008_03
Patent number
US07338974B2

Reaction notes

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