1,2-Dichloroethane → (+/-)-tert-Butyl 6-(1-cyanocyclopropanecarbonyl)-6-azaspiro[3.4]octan-8-ylcarbamate

HRID 877840Notes

Reaction equation

HRID 877840 reaction equation
[CH2:1]1[C:4]2([CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][NH:6][CH2:5]2)[CH2:3][CH2:2]1.[C:17]([C:19]1([C:22](O)=[O:23])[CH2:21][CH2:20]1)#[N:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:17]([C:19]1([C:22]([N:6]2[CH2:7][CH:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:4]3([CH2:1][CH2:2][CH2:3]3)[CH2:5]2)=[O:23])[CH2:21][CH2:20]1)#[N:18]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27332591-Cyanocyclopropanecarboxylic acidHCID 19354273tert-butyl N-{6-azaspiro[3.4]octan-8-yl}carbamate

Product 1

HCID 68350497(+/-)-tert-Butyl 6-(1-cyanocyclopropanecarbonyl)-6-azaspiro[3.4]octan-8-ylcarbamateYield 76.4%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

A solution of (+/−)-tert-butyl 6-azaspiro[3.4]octan-8-ylcarbamate (from Step 1 of Example 318, 0.177 g, 0.783 mmol), 1-cyanocyclopropanecarboxylic acid (0.104 g, 0.939 mmol), EDC (0.300 g, 1.565 mmol), HOBT (0.144 g, 0.939 mmol), and Hunig's Base (0.547 mL, 3.13 mmol) in DMA (7.67 mL) was stirred @ r. t. under N2 for 16 hrs. +/−MS analysis after 16 hrs indicated that the reaction had proceeded essentially to completion and no starting material was detected. The volatiles were removed under high vacuum. EtOAc, THF, and 10% aq LiCl solution were added. The layers were separated, the organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine, dried over Na2SO4, and concentrated under vacuum to yield 0.223 g of the crude product as an orange viscous semi-solid. Flash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane:EtOAc yielded 0.191 g of the title compound as a pale yellow solid. +/−MS: m/e 320.3 (M+H). 318.5 (M−H), 220.2 (M+H-Boc), 264.2 (M+H-isobutylene). This material was used in the next step without further purification.

Workup

  1. wait+/−MS analysis after 16 hrs indicated that the reaction
  2. customThe volatiles were removed under high vacuum
  3. additionEtOAc, THF, and 10% aq LiCl solution were added
  4. customThe layers were separated
  5. washthe organic layer was washed with 10% aq LiCl solution, 1N HCl (3×), sat. aq NaHCO3 solution (3×), brine
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated under vacuum
  8. customto yield 0.223 g of the crude product as an orange viscous semi-solid
  9. washFlash chromatography on silica gel (Teledyne-Isco RediSep Rf 4 g column), eluting with 100 mL of 75:25 hexane

Sources & evidence

ORD record
ord-2c9238665a844a1da01df7605e38016d
Source dataset
uspto-grants-2015_03
Patent number
US08987268B2

Reaction notes

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