1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → N-(2-hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide

HRID 1190675Notes

Reaction equation

HRID 1190675 reaction equation
O[C:2]([C:4](F)(F)F)=[O:3].[CH:8]([N:11]1[C:15]([C:16]2[S:17][C:18]3[CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:33][N:32]([CH2:34][C:35]([OH:37])=O)[CH2:31]5)[CH:27]=[CH:26][C:23]=4[C:24]=3[N:25]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C[CH2:39][N:40]=C=NCCCN(C)C.[CH:49]1C=CC2N(O)N=NC=2C=1.NCC(C)(O)C.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:3][C:2]([CH3:4])([CH3:49])[CH2:39][NH:40][C:35](=[O:37])[CH2:34][N:32]1[CH2:33][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:25]=[C:16]([C:15]5[N:11]([CH:8]([CH3:9])[CH3:10])[N:12]=[CH:13][N:14]=5)[S:17][C:18]=4[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31]1

Participants

8

Reactant 6

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide2×HCID 757711-Hydroxybenzotriazole2×HCID 81531Diisopropylethylamine2×HCID 951022-Propanol, 1-amino-2-methyl-2×HCID 516892Sodium BicarbonateHCID 131729946{3-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid TFA salt

Product 1

HCID 67050528N-(2-hydroxy-2-methyl-propyl)-2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamideYield 44.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

A solution of {3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetic acid TFA salt (228 mg, 0.42 mmol), EDCI (97 mg, 0.50 mmol) and HOBT (68 mg, 0.50 mmol) in THF (3 mL) was stirred for 20 minutes. 1-Amino-2-methyl-propan-2-ol (42 mg, 0.47 mmol) and diisopropylethylamine (0.18 mL, 1.05 mmol) in THF (2 mL) were added and the reaction mixture was stirred at RT for 18 hours. Another portion of 1-amino-2-methyl-propan-2-ol, EDCI, HOBT, DIPEA and THF (1.5 mL) was added and the reaction mixture was warmed at 45° C. for 3 hours. Aqueous saturated sodium bicarbonate solution was added and the mixture was extracted with DCM (×2). The combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-10% MeOH in DCM) to give 472 as a white solid (92 mg, 44%). LCMS: RT=3.14 min, [M+H]+=497. 1H NMR δ (ppm) (DMSO-d6): 8.26 (1H, d, J=8.18 Hz), 8.06 (1H, s), 7.44 (1H, t, J=6.04 Hz), 7.19 (1H, dd, J=8.24, 1.80 Hz), 7.01 (1H, d, J=1.75 Hz), 5.82-5.74 (1H, m), 4.51 (1H, s), 4.32 (2H, t, J=5.03 Hz), 3.73-3.60 (3H, m), 3.39 (2H, t, J=5.06 Hz), 3.26-3.16 (2H, m), 3.10 (2H, s), 3.02 (2H, d, J=6.03 Hz), 1.50 (6H, d, J=6.59 Hz), 1.01 (6H, s)

Workup

  1. temperaturethe reaction mixture was warmed at 45° C. for 3 hours
  2. extractionthe mixture was extracted with DCM (×2)
  3. dry with materialThe combined organic extracts were dried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customthe residue purified by flash chromatography (SiO2, 0-10% MeOH in DCM)

Sources & evidence

ORD record
ord-b164b568aa2d4d5f8c710294a2f4f9c5
Source dataset
uspto-grants-2014_03
Patent number
US08673952B2

Reaction notes

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