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

HRID 2220713Notes

Reaction equation

HRID 2220713 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[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[C:39]2[O:40][C:41]([CH3:44])([CH3:43])[O:42][C:38]=2[CH:37]=[C:36]([C:45](Cl)=[O:46])[CH:35]=1.[C:48]1(=O)[CH2:51]C[CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[S:20]1[C:16]([CH2:15][N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH:6]2[CH2:51][CH2:48][CH2:49]2)[C:45]([C:36]2[CH:35]=[C:34]([O:33][CH3:32])[C:39]3[O:40][C:41]([CH3:44])([CH3:43])[O:42][C:38]=3[CH:37]=2)=[O:46])=[CH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]1=2

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 14496CyclobutanoneHCID 5049666Sodium triacetoxyborohydrideHCID 58622178(S)-2-{[(Benzo[b]thiophen-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 586221367-Methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid benzo[b]thiophen-2-ylmethyl-((S)-1-cyclobutyl-pyrrolidin-2-ylmethyl)-amideYield 21.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Experimental conditions were analogous to Example 58, from 0.29 g (0.84 mmol) of (S)-2-{[(benzo[b]thiophen-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, 141 μL (1.01 mmol) of triethylamine, and 0.22 mg (0.92 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride. The crude mixture was filtered through silica and the Boc-deprotection was conducted in 10 mL 10% trifluoroacetic acid/dichloromethane in 2 hours, followed by aqueous sodium bicarbonate quench. The crude material from organic layer was alkylated in 5 mL dichloromethane, with 0.2 g (2.5 mmol) of cyclobutanone and 0.53 mg (2.5 mmol) of sodium triacetoxyborohydride. After 2 days the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate. The residue from the organic layer was purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min., gave 92 mg of off-white solid as the free base. LC-MSD, m/z for C29H34N2O4S [M+H]+: 507.6. 1H NMR (400 MHz, CDCl3): δ 1.5-3.5 (m, 16 H), 1.7 (s, 6 H), 3.8 (bs, 3 H), 5.0 (bs, 2 H), 6.6 (s, 1 H), 6.7 (s, 1 H), 7.2 (bs, 1 H), 7.3-7.4 (m, 2 H), 7.7-7.8 (m, 1 H), 7.8-7.9 (m, 1 H).

Workup

  1. filtrationThe crude mixture was filtered through silica
  2. customquench
  3. customAfter 2 days the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate
  4. customThe residue from the organic layer was purified
  5. customin 50 min.

Sources & evidence

ORD record
ord-fb788f3af0654a74bef1602f4f6b452f
Source dataset
uspto-grants-2008_08
Patent number
US07417062B2

Reaction notes

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