1,2-Dichloroethane → 1306760-88-2

HRID 1809511Notes

Reaction equation

HRID 1809511 reaction equation
C(OC([N:8]([C@H:13]1[C:21]2[C:16](=[C:17]([C:22]3[N:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[C:29]([C:37]#[N:38])[CH:28]=4)[O:24][N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)[CH2:9][C:10]([OH:12])=O)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:51].[CH3:53][NH:54][CH3:55]>CN(C=O)C.O>[ClH:51].[C:37]([C:29]1[CH:28]=[C:27]([C:25]2[O:24][N:23]=[C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:16]=3[CH2:15][CH2:14][C@H:13]4[NH:8][CH2:9][C:10]([N:54]([CH3:55])[CH3:53])=[O:12])[N:26]=2)[CH:32]=[CH:31][C:30]=1[O:33][CH:34]([CH3:35])[CH3:36])#[N:38]

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 674DimethylamineHCID 757711-HydroxybenzotriazoleHCID 86655195HCID 86655195, compound

Product 1

HCID 672006061306760-88-2Yield 74%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

Prepared using General Procedure 10. To 4.9 g (9.5 mmol) of (R)-2-(tert-butoxycarbonyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid INT-25 in DMF (20 mL) was added HOBt (4.4 g, 28.5 mmol) and EDC (5.5 g, 28.5 mmol) and the reaction mixture was stirred at room temperature for 30 min. Dimethylamine (2.0N in THF, 14.25 mL, 28.5 mmol) was added and the reaction was stirred at room temperature for 2 h. The reaction mixture was poured into water (300 mL) and the precipitate was filtered. The solid was thoroughly washed with water (200 mL). The solid was dissolved in DCM with 5% MeOH, dried over MgSO4 and filtered. 4M HCl in dioxane was added and the mixture was heated to 50° C. After 1 h, the solvent was removed under reduced pressure and the solid residue was recrystallized from 120 mL MeOH/120 mL Et2O/70 mL hexane/10 mL of IPA mixture to provide 3.37 g (74%) of (R)-2-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)-N,N-dimethylacetamide hydrochloride 90 as a white powder. LCMS-ESI (m/z) calculated for C25H27N5O3: 445.5; found 446.2 [M+H]+, tR=2.52 min. Elemental analysis of C25H28N5O3Cl*H2O: C calc.=60.05%; found=59.68%; H calc.=6.05%; found=6.45%; N calc.=14.01%; found=13.91%; Cl calc.=7.09; found=6.98%. 1H NMR (400 MHz, DMSO) δ 9.44 (s, 2H), 8.53 (d, J=2.3 Hz, 1H), 8.41 (dd, J=9.0, 2.3 Hz, 1H), 8.16 (d, J=7.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.62-7.52 (m, 2H), 5.05-4.92 (m, 1H), 4.88 (dd, J=7.0, 4.2 Hz, 1H), 4.11 (d, J=16.1 Hz, 1H), 4.02 (d, J=16.0 Hz, 1H), 3.51 (ddd, J=17.2, 8.2, 6.6 Hz, 1H), 3.25 (ddd, J=17.4, 8.8, 5.0 Hz, 1H), 2.97 (s, 3H), 2.91 (s, 3H), 2.60-2.51 (m, 1H), 2.33 (dq, J=9.0, 4.9 Hz, 1H), 1.39 (d, J=6.0 Hz, 6H). 13C NMR (101 MHz, DMSO) δ 173.33, 167.95, 164.97, 162.56, 144.68, 139.16, 134.61, 133.85, 129.43, 128.70, 127.63, 122.90, 115.87, 115.24, 114.92, 102.48, 72.54, 61.28, 44.84, 35.77, 34.98, 31.52, 27.68, 21.45. Chiral HPLC of the free base: (R)-2-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)-N,N-dimethylacetamide was eluted using 15% i-PrOH in hexanes plus 0.3% DEA: 98.5% ee, tR=41.19 min. (S)-2-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylamino)-N,N-dimethyl-acetamide 91 can be obtained in an analogous fashion from (S)-2-(tert-butoxycarbonyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid. tR for (S)-enantiomer=34.35 min. An alternative route is described below.

Workup

  1. customPrepared
  2. stirringthe reaction was stirred at room temperature for 2 h
  3. filtrationthe precipitate was filtered
  4. washThe solid was thoroughly washed with water (200 mL)
  5. dissolutionThe solid was dissolved in DCM with 5% MeOH
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. addition4M HCl in dioxane was added
  9. temperaturethe mixture was heated to 50° C
  10. waitAfter 1 h
  11. customthe solvent was removed under reduced pressure
  12. customthe solid residue was recrystallized from 120 mL MeOH/120 mL Et2O/70 mL hexane/10 mL of IPA mixture

Sources & evidence

ORD record
ord-a2aa35470eae4b1e82ac9952a1291890
Source dataset
uspto-grants-2013_01
Patent number
US08362048B2

Reaction notes

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