3-Hydroxy-2,2-dimethylpropionic acid → 2,2-dimethyl-3-(2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol

HRID 272003Notes

Reaction equation

HRID 272003 reaction equation
Cl.Cl.Cl.[CH3:4][C:5]1[N:9]([CH:10]2[CH2:16][C@H:15]3[N:17]([CH2:18][CH2:19][C:20]4([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[O:25][CH2:24][CH2:23][NH:22][CH2:21]4)[C@H:12]([CH2:13][CH2:14]3)[CH2:11]2)[C:8]2[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=2[N:6]=1.[OH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39](O)=[O:40].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[CH3:42][C:38]([CH3:43])([C:37]([N:22]1[CH2:23][CH2:24][O:25][C:20]([CH2:19][CH2:18][N:17]2[C@H:12]3[CH2:13][CH2:14][C@@H:15]2[CH2:16][CH:10]([N:9]2[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[N:6]=[C:5]2[CH3:4])[CH2:11]3)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21]1)=[O:36])[CH2:39][OH:40]

Participants

7

Reactant 4

HCID 785483-Hydroxy-2,2-dimethylpropionic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 689336682-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihydrochloride

Product 1

HCID 598359752,2-dimethyl-3-(2-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-olYield 55.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

To a stirred solution of 2-methyl-1-{(1R,5S)-8-[2-(2-phenylmorpholin-2-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole trihyrdochloride (59.3 mg, 0.10 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (18 mg, 0.15 mmol), and diisopropylethylamine (70 μL, 0.40 mmol) in 1 mL DMF was added HATU (57 mg, 0.15 mmol). The resulting mixture was stirred at ambient temperature for 24 h and then diluted with methylene chloride and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), concentrated by evaporation, and purified by chromatography (5% (2M NH3/MeOH) in CHCl3) to afford 2,2-dimethyl-3-(2-{2-[(1R,5S)-3(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-2-phenylmorpholin-4-yl)-3-oxopropan-1-ol (29.3 mg. 55%) as amorphous solid. 1H NMR (400 MHz, CDCl3), δ 7.65 (m, 1H), 7.44-7.26 (m, 6H), 7.19-7.10 (m, 2H), 4.80 (br., 1H), 4.69 (m, 1H), 3.75-3.37 (m, 8H), 3.35-3.16 (m, 3H), 2.58 (s, 3H), 2.46-2.34 (m, 2H), 2.13-1.84 (m, 8H), 1.68-1.59 (m, 2H), 1.23 (s, 3H), 1.02 (s, 3H); ESI-MS 531 (M+H), 553 (M+Na).

Workup

  1. washwashed with saturated aqueous NaHCO3
  2. dry with materialThe organic phase was dried (Na2SO4)
  3. concentrationconcentrated by evaporation
  4. custompurified by chromatography (5% (2M NH3/MeOH) in CHCl3)

Sources & evidence

ORD record
ord-97430bd3866444c99b387961f305abca
Source dataset
uspto-grants-2008_11
Patent number
US07452992B2

Reaction notes

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