Cyclobutanone → 7-Methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid ((S)-1-cyclobutyl-pyrrolidin-2-ylmethyl)-isoquinolin-3-ylmethyl-amide

HRID 2220719Notes

Reaction equation

HRID 2220719 reaction equation
[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][N:12]([CH2:28][C@@H:29]2[CH2:33][CH2:32][CH2:31][NH:30]2)[C:13]([C:15]2[CH:25]=[C:24]([O:26][CH3:27])[C:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=2)=[O:14])[N:2]=1.[C:34]1(=O)[CH2:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:34]1([N:30]2[CH2:31][CH2:32][CH2:33][C@H:29]2[CH2:28][N:12]([CH2:11][C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:13]([C:15]2[CH:25]=[C:24]([O:26][CH3:27])[C:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[CH:16]=2)=[O:14])[CH2:37][CH2:36][CH2:35]1

Participants

5

Reactant 3

HCID 14496CyclobutanoneHCID 5049666Sodium triacetoxyborohydrideHCID 586221577-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid isoquinolin-3-ylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amide

Product 1

HCID 586222517-Methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid ((S)-1-cyclobutyl-pyrrolidin-2-ylmethyl)-isoquinolin-3-ylmethyl-amideYield 60.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

In 1 mL dichloromethane was dissolved 40 mg (0.089 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid isoquinolin-3-ylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amide, to this solution was added 20 mg (0.25 mmol) of cyclobutanone and 53 mg (0.25 mmol) of sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and purified using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min. Fractions containing pure product were evaporated, the residue was dissolved in dichloromethane, washed with aqueous sodium bicarbonate, dried with anhydrous magnesium sulfate and evaporated in vacuum to yield 27 mg of the product as the free base as a pale yellow solid. LC-MSD, m/z for C30H35N3O4 [M+H]+: 502.7. 1H NMR (400 MHz, CDCl3): δ 1.4-2.0 (m, 9 H), 1.7 (s, 6 H), 2.3-2.4 (m, 1 H), 2.8-3.5 (m, 5 H), 3.7 (bs, 3 H), 3.8-4.0 (m, 1 H), 4.9-5.1 (m, 2 H), 6.6 (s, 1 H), 6.7-6.9 (m, 1 H), 7.5 (bs, 1 H), 7.5-7.6 (m, 1 H), 7.6-7.7 (m, 1 H), 7.8-7.9 (m, 1 H), 7.9-8.0 (m, 1 H), 9.2 (s, 1 H).

Workup

  1. customAfter overnight the reaction was quenched with aqueous sodium bicarbonate
  2. custompurified
  3. customin 40 min
  4. additionFractions containing pure product
  5. customwere evaporated
  6. dissolutionthe residue was dissolved in dichloromethane
  7. washwashed with aqueous sodium bicarbonate
  8. dry with materialdried with anhydrous magnesium sulfate
  9. customevaporated in vacuum

Sources & evidence

ORD record
ord-ce5483942aa546ccbaef5ca69c266584
Source dataset
uspto-grants-2008_08
Patent number
US07417062B2

Reaction notes

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