Diisopropylethylamine → N-(2-amino-5-(oxetan-3-yl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide

HRID 511669Notes

Reaction equation

HRID 511669 reaction equation
[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][N:22]([CH3:32])[CH:23]2[CH2:26][CH:25]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:24]2)[O:12]1.[O:33]1[CH2:36][CH:35]([C:37]2[CH:38]=[C:39]([NH2:44])[C:40]([NH2:43])=[CH:41][CH:42]=2)[CH2:34]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[NH2:43][C:40]1[CH:41]=[CH:42][C:37]([CH:35]2[CH2:34][O:33][CH2:36]2)=[CH:38][C:39]=1[NH:44][C:29](=[O:30])[CH2:28][CH2:27][CH:25]1[CH2:26][CH:23]([N:22]([CH2:21][C@@H:13]2[C@@H:14]3[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]3)[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH2:1])[O:12]2)[CH3:32])[CH2:24]1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 677751233-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acidHCID 677761524-(Oxetan-3-YL)benzene-1,2-diamine

Product 1

HCID 67775354N-(2-amino-5-(oxetan-3-yl)phenyl)-3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamideYield 82%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
15 °C

Procedure

A suspension of the above crude 3-(3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid and 4-(oxetan-3-yl)benzene-1,2-diamine (0.135 g, 0.822 mmol) in methylene chloride (8.0 mL) was treated with N,N-diisopropylethylamine (0.716 mL, 4.11 mmol) and cooled to −5° C. (ice/brine). N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate [HATU] (0.469 g, 1.23 mmol) was added and the reaction mixture was stirred for 5.25 h, warming to 15° C.; HPLC/LC MS indicated complete conversion. The reaction mixture was concentrated in vacuo and diluted with CH2Cl2 (15 mL) and water (7.5 mL). The separated aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a brown-purple semi-opaque oil/foam. Purification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2) afforded both amide regioisomers of the title compound (0.45 g, 82%) as a semi-opaque pink foam: MS (ESI+) for C30H40N8O5 m/z 593.3 (M+H)+; MS (ESI−) for C30H40N8O5 m/z 591.3 (M−H)− and 637.4 (M+HCO2)−; HPLC purity 90% (ret. time, 2.097 min).

Workup

  1. concentrationThe reaction mixture was concentrated in vacuo
  2. additiondiluted with CH2Cl2 (15 mL) and water (7.5 mL)
  3. extractionThe separated aqueous layer was extracted with CH2Cl2 (2×10 mL)
  4. dry with materialThe combined organics were dried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. customto afford a brown-purple semi-opaque oil/foam
  7. customPurification by column chromatography (2×8 cm silica; 0-5% 7 N methanolic NH3/CH2Cl2)

Sources & evidence

ORD record
ord-b46bda07b86e48b1b242dea4fcf57fd7
Source dataset
uspto-grants-2015_08
Patent number
US09096634B2

Reaction notes

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