Tetrahydrofuran → HCID 71227776, compound

HRID 715505Notes

Reaction equation

HRID 715505 reaction equation
[NH2:1][CH2:2][C@:3]1([OH:21])[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:4]1.C1C[O:25][CH2:24]C1>>[O:25]=[C:24]1[NH:1][CH2:2][C@@:3]2([CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[C:14]4[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH2:4]2)[O:21]1

Participants

3

Reactant 2

HCID 8028TetrahydrofuranHCID 71227749HCID 71227749, compound

Product 1

HCID 71227776HCID 71227776, compoundYield 97%

Conditions

Temperature
160 °C

Procedure

A suspension of 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (760 mg, 2.84 mmol) in MeOH (8 mL) was treated with 7M ammonia in MeOH (1.429 mL, 10.00 mmol) in a 20 mL microwave vial. The vial was sealed and heated in a microwave at 100° C. for 3 h. The reaction mixture was cooled to RT and blown down to dryness with nitrogen for 24 h to give crude 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile which was used without further purification. A solution of 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (808 mg, 2.84 mmol) in THF (24 mL) was sealed under nitrogen in three 20 mL microwave vials and heated with microwave at 160° C. for 3 h. The combined reaction mixture was then concentrated to dryness and 50 mL of water was added. The solid was then filtered and washed with 2×10 mL of water. The solid was air-dried under house vacuum overnight. The compound was purified under normal phase flash column chromatography (ISCO CombiFlash Rf, 120 g silica column, MeOH/DCM 0-10%) to give 1-{[(5S,7S)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an off-white solid (856 mg, 97% yield). The aromatic region of the NMR spectra showed that the product contained less than 8% of the cis-diastereomer. MS (m/z) 311.1 (M+H+).

Workup

  1. customwas used without further purification
  2. customThe combined reaction mixture
  3. concentrationwas then concentrated to dryness and 50 mL of water
  4. additionwas added
  5. filtrationThe solid was then filtered
  6. washwashed with 2×10 mL of water
  7. customThe solid was air-dried under house vacuum overnight
  8. customThe compound was purified under normal phase flash column chromatography (ISCO CombiFlash Rf, 120 g silica column, MeOH/DCM 0-10%)

Sources & evidence

ORD record
ord-46de1d13d64f4533b0e4c3c054a556d5
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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