Triethylamine → tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate

HRID 590744Notes

Reaction equation

HRID 590744 reaction equation
Cl.[C:2]([NH:5][C@:6]1([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)[CH2:9][NH:8][CH2:7]1)(=[O:4])[CH3:3].CCN(CC)CC.[Cl:37][C:38]1[CH:47]=[C:46]2[C:41]([CH2:42][CH:43]([CH:55]=O)[N:44]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:45]2)=[CH:40][CH:39]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:2]([NH:5][C@:6]1([C:23](=[O:24])[NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:10]([CH2:11][CH2:12][CH2:13][B:14]2[O:18][C:17]([CH3:19])([CH3:20])[C:16]([CH3:21])([CH3:22])[O:15]2)[CH2:9][N:8]([CH2:55][CH:43]2[CH2:42][C:41]3[C:46](=[CH:47][C:38]([Cl:37])=[CH:39][CH:40]=3)[CH2:45][N:44]2[C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:7]1)(=[O:4])[CH3:3]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 67517412(3R,4S)-3-acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochlorideHCID 86665792HCID 86665792, compound

Product 1

HCID 69669687tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylateYield 84%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A stirred mixture of (3R,4S)-3-acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochloride (226 mg, 0.524 mmol) and Et3N (0.110 mL, 0.786 mmol) in methylene chloride (2.5 mL) was treated with a solution of tert-butyl 7-chloro-3-formyl-3,4-dihydroisoquinoline-2(1 H)-carboxylate (155 mg, 0.524 mmol) in methylene chloride (2.5 mL). After stirring for 20 min, sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and stirring was continued for 1 h. The resulting mixture was carefully quenched with saturated aqueous NaHCO3 (5 mL), diluted with saturated aqueous sodium chloride (15 mL) and extracted with methylene chloride (4×15 mL). The combined organic phase was dried over Na2SO4 and concentrated. Purification by silica gel chromatography (40 g column, 2-4% MeOH in ethyl acetate) gave tert-butyl 3-({(3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidin-1-yl}methyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (296 mg, 84%, mixture of diastereomers) as a clear gum. LC-MS gives ESI+ MS found for C35H56BClN4O6 m/z 675.4 (M+H).

Workup

  1. stirringstirring
  2. waitwas continued for 1 h
  3. customThe resulting mixture was carefully quenched with saturated aqueous NaHCO3 (5 mL)
  4. additiondiluted with saturated aqueous sodium chloride (15 mL)
  5. extractionextracted with methylene chloride (4×15 mL)
  6. dry with materialThe combined organic phase was dried over Na2SO4
  7. concentrationconcentrated
  8. customPurification by silica gel chromatography (40 g column, 2-4% MeOH in ethyl acetate)

Sources & evidence

ORD record
ord-d5edad61b4054455978fd6aafbb22f15
Source dataset
uspto-grants-2016_01
Patent number
US09233985B2

Reaction notes

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