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

HRID 2220709Notes

Reaction equation

HRID 2220709 reaction equation
FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][NH:21][CH2:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[CH:27]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:39][O:40][C:41]1[C:46]2[O:47][C:48]([CH3:51])([CH3:50])[O:49][C:45]=2[CH:44]=[C:43]([C:52](Cl)=[O:53])[CH:42]=1.[C:55]1(=O)[CH2:58]C[CH2:56]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[CH:27]=[C:23]1[CH2:22][N:21]([CH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:15]1[CH:13]1[CH2:58][CH2:55][CH2:56]1)[C:52]([C:43]1[CH:42]=[C:41]([O:40][CH3:39])[C:46]2[O:47][C:48]([CH3:51])([CH3:50])[O:49][C:45]=2[CH:44]=1)=[O:53]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 14496CyclobutanoneHCID 5049666Sodium triacetoxyborohydrideHCID 69311018(s)-2-{[(Benzofuran-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetic acid saltHCID 714100777-Methoxy-2,2-dimethyl-2H-1,3-benzodioxole-5-carbonyl chloride

Product 1

HCID 586222117-Methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carboxylic acid benzofuran-2-ylmethyl-((S)-1-cyclobutyl-pyrrolidin-2-ylmethyl)-amide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Experimental conditions analogous to Example 15, from 0.27 g (0.62 mmol) of (S)-2-{[(benzofuran-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester trifluoroacetic acid salt, was dissolved 1 mL dichloromethane, 216 μL (1.55 mmol) of triethylamine, and 0.16 g (0.68 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride were added to this mixture. The crude mixture was filtered through silica and the Boc-deprotection was conducted in 4 mL 10% trifluoroacetic acid/dichloromethane in 2 hours, followed by aqueous sodium bicarbonate quench and submitting the crude material to reductive amination reaction in dichloromethane using 0.24 g (3.1 mmol) of cyclobutanone and 0.657 g (3.1 mmol) of sodium triacetoxyborohydride. After 5 hours the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate. The residue from the organic layer was purified using flash chromatography (7N ammonia in methanol, 0-3% in dichloromethane), gave 49 mg off-white solid as a free base solid. LC-MSD, m/z for C29H34N2O5 [M+H]+: 491.2. 1H NMR (400 MHz, CDCl3/HCl): δ 1.7 (s, 6 H), 1.8-2.1 (m, 6 H), 2.1-2.2 (m, 1 H), 2.3-2.4 (m, 1 H), 2.5-2.7 (m, 2 H), 2.8-2.9 (m, 1 H), 3.5-3.7 (m, 1 H), 3.7-3.9 (m, 3 H), 3.9 (s, 3 H), 4.0-4.1 (m, 1 H), 4.8-5.0 (m, 2 H), 6.8 (s, 1H), 6.9 (s, 1 H), 7.0 (s, 1 H), 7.2-7.3 (m, 2H), 7.4-7.5 (m, 1 H), 7.5-7.6 (m, 1 H), 12.0-12.1 (bs, 1 H).

Workup

  1. additionwere added to this mixture
  2. filtrationThe crude mixture was filtered through silica
  3. customquench
  4. customAfter 5 hours the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate
  5. customThe residue from the organic layer was purified

Sources & evidence

ORD record
ord-adcda486fae84d5a898379c30310b75c
Source dataset
uspto-grants-2008_08
Patent number
US07417062B2

Reaction notes

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