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

HRID 2220711Notes

Reaction equation

HRID 2220711 reaction equation
C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[C:40]2[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=2[CH:38]=[C:37]([C:46](Cl)=[O:47])[CH:36]=1.[C:49]1(=O)[CH2:52]C[CH2:50]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:6]1([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][N:14]([CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C:46]([C:37]2[CH:36]=[C:35]([O:34][CH3:33])[C:40]3[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=3[CH:38]=2)=[O:47])[CH2:52][CH2:49][CH2:50]1

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 14496CyclobutanoneHCID 5049666Sodium triacetoxyborohydrideHCID 59772986(S)-2-{[(Naphthalen-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl esterHCID 714100777-Methoxy-2,2-dimethyl-2H-1,3-benzodioxole-5-carbonyl chloride

Product 1

HCID 586222137-Methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid ((S)-1-cyclobutyl-pyrrolidin-2-ylmethyl)-naphthalen-2-ylmethyl-amide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Experimental conditions analogous Example 58, from 0.35 g (1.01 mmol) of (S)-2-{[(naphthalen-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, 169 μL (1.21 mmol) of triethylamine, and 0.27 g (1.12 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride. The crude mixture was filtered through silica and the compound was deprotected in 10 mL 10% trifluoroacetic acid/dichloromethane in 1.5 hours. The reaction mixture was treated with aqueous sodium bicarbonate, and extracted with dichloromethane. The crude material was dissolved in 10 mL of dichloromethane, to this mixture was added 0.21 g (3.0 mmol) of cyclobutanone and 0.636 g (3.0 mmol) of sodium triacetoxyborohydride. After overnight the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate. The organic layer was separated, the residue was purified using flash chromatography (7N ammonia in methanol, 0-3% in dichloromethane), gave 76 mg of off white solid as a free base. LC-MSD, m/z for C31H36N2O4 [M+H]+: 501.7. 1H NMR (400 MHz, CDCl3/HCl): δ 1.7 (s, 6 H), 1.9-2.7 (m, 10 H), 2.8-3.0 (m, 1 H), 3.5-3.7 (m, 1 H), 3.8 (s, 3 H), 3.8-4.0 (m, 4 H), 4.9-5.0 (m, 1 H), 5.2-53 (m, 1 H), 6.7 (s, 1H), 6.8 (s, 1 H), 7.2-7.3 (m, 1H), 7.4-7.5 (m, 2 H), 7.7 (s, 1 H), 7.8-7.9 (m, 3 H), 12.2-12.3 (m, 1 H).

Workup

  1. filtrationThe crude mixture was filtered through silica
  2. additionThe reaction mixture was treated with aqueous sodium bicarbonate
  3. extractionextracted with dichloromethane
  4. dissolutionThe crude material was dissolved in 10 mL of dichloromethane, to this mixture
  5. customAfter overnight the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate
  6. customThe organic layer was separated
  7. customthe residue was purified
  8. customgave 76 mg of off white solid as a free base

Sources & evidence

ORD record
ord-c07e49fcfa41463e8b3644b4d5a64ff6
Source dataset
uspto-grants-2008_08
Patent number
US07417062B2

Reaction notes

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