Sodium Hydroxide → tert-Butyl (R)-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

HRID 2205090Notes

Reaction equation

HRID 2205090 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([NH2:11])[CH2:6][CH2:5]2.Cl[CH2:13][C:14]1([CH:27]=O)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([N:11]1[CH2:13][C:14]3([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[CH2:27]1)[CH2:6][CH2:5]2

Participants

8

Reactant 4

HCID 14798Sodium HydroxideHCID 5003444Sodium cyanoborohydrideHCID 28206722(1R)-5-Bromo-2,3-dihydro-1H-inden-1-amineHCID 53392200Tert-butyl 4-(chloromethyl)-4-formylpiperidine-1-carboxylate

Product 1

HCID 53392276tert-Butyl (R)-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylateYield 100.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine (1835 g, 8.66 mol) in anhydrous methanol (24 L) was added tert-butyl 4-(chloromethyl)-4-formylpiperidine-1-carboxylate (2310 g, 8.83 mol). The mixture was stirred at 50° C. for 16 h, and cooled to rt. Sodium cyanoborohydride (1000 g, 15.9 mol) in THF (15 L) was added via a syringe pump over 2 hours. The mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath. The reaction was cooled to 20° C. and transferred via a cannula into a vessel containing 24 L of 2.5M sodium hydroxide, and 30 L of DCM. The layers were separated and the aqueous layer was extracted with DCM (2×5 L). The aqueous layer was treated to destruct residual sodium cyanoborohydride. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The crude material was slurried in MTBE (7 L) by stirring at 40° C. for 1 h and at rt for 1 h. The solid was filtered, and washed with MTBE (2×500 mL) and dried under vacuum oven at 50° C. to give the title product as a white crystals (3657 g, 90%). MS (ES+) 422.3 (M+H)+. 1H NMR (CDCl3) δ 1.44 (s, 9H), 1.67 (dd, 4H), 1.84-1.93 (m, 1H), 2.07-2.16 (m, 1H), 2.72-2.81 (m, 1H), 2.95-3.15 (m, 5H), 3.31 (dd, 4H), 3.85 (br s, 1H), 7.12 (d, 1H), 7.28 (br s, 1H), 7.35 (br s, 1H). [α]D20=+39.6 deg (c=1.06 mg/mL, MeOH).

Workup

  1. temperaturecooled to rt
  2. stirringThe mixture was stirred at 60° C. for 24 hours under nitrogen with a vent into a bleach bath
  3. temperatureThe reaction was cooled to 20° C.
  4. customtransferred via a cannula into a vessel
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with DCM (2×5 L)
  7. additionThe aqueous layer was treated
  8. dry with materialThe combined organic layers were dried (MgSO4)
  9. concentrationconcentrated under reduced pressure
  10. stirringby stirring at 40° C. for 1 h and at rt for 1 h
  11. filtrationThe solid was filtered
  12. washwashed with MTBE (2×500 mL)
  13. customdried under vacuum oven at 50° C.

Sources & evidence

ORD record
ord-ecd9a774c93f4cb38dd034fe23fd88ba
Source dataset
uspto-grants-2016_06
Patent number
US09370516B2

Reaction notes

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