Benzimidazole → (4-(3-(Azetidin-3-YL)pyridin-2-yloxy)phenyl)(1H-benzo[D]imidazol-2-YL)methanone

HRID 410288Notes

Reaction equation

HRID 410288 reaction equation
C(OC(OC(C)C)[N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1)(C)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.N1C2C=CC=CC=2NC=1.[Li].C([O:41][C:42]([C:44]1[CH:67]=[CH:66][C:47]([O:48][C:49]2[C:54]([CH:55]3[CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56]3)=[CH:53][CH:52]=[CH:51][N:50]=2)=[CH:46][CH:45]=1)=O)C.N1C2C=CC=CC=2NC=1>C1COCC1>[NH:57]1[CH2:58][CH:55]([C:54]2[C:49]([O:48][C:47]3[CH:66]=[CH:67][C:44]([C:42]([C:7]4[NH:6][C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[N:8]=4)=[O:41])=[CH:45][CH:46]=3)=[N:50][CH:51]=[CH:52][CH:53]=2)[CH2:56]1

Participants

7

Reactant 5

HCID 5798BenzimidazoleHCID 2733832Lithium HexamethyldisilazideHCID 59327019Tert-butyl 3-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)azetidine-1-carboxylateHCID 593513441-(diisopropoxymethyl)-1H-benzo[d]imidazoleHCID 66986428Lithium benzoimidazole

Product 1

HCID 59327242(4-(3-(Azetidin-3-YL)pyridin-2-yloxy)phenyl)(1H-benzo[D]imidazol-2-YL)methanone

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 1-(diisopropoxymethyl)-1H-benzo[d]imidazole (318 mg, 1.280 mmol) in THF (5 mL) at 0° C. is added LiHMDS (0.753 mL, 0.753 mmol) over 1 min. The reaction was stirred 5 min., then 3.5 mL of the 6 mL solution (1.0 theoretical equivalent of the lithium benzoimidazole) was added to a solution of tert-butyl 3-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)azetidine-1-carboxylate (300 mg, 0.753 mmol) in THF (3 mL) at 0° C. The reaction was stirred at 0° C. 30 min. LCMS showed only 5% conversion. The remaining solution of benzoimidazole was added and the reaction stirred 1 h at 0° C. LCMS shows 2:1 ratio of starting material to desired product. The reaction was quenched with 2 N HCl (15 mL) and warmed to rt and stirred overnight. The aqueous layer was neutralized with solid Na2CO3 and the aqueous layer extracted with CH2Cl2 (2×25 mL). The combined organic fractions were washed with saturated NaCl, dried (MgSO4), and concentrated. The crude material was then taken up in MeOH (3 mL) and 4.0 M HCl in dioxane was added. The reaction was stirred at rt 2 h, then concentrated to give the crude amine hydrochloride, which was taken on to the next step without purification.

Workup

  1. stirringThe reaction was stirred at 0° C
  2. custom30 min
  3. stirringthe reaction stirred 1 h at 0° C

Sources & evidence

ORD record
ord-2c0ff77dc96244689190f8d7fafdee28
Source dataset
uspto-grants-2014_06
Patent number
US08759532B2

Reaction notes

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