Dimethylamine, hydrochloride → (-)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N,N-dimethylacetamide

HRID 1525910Notes

Reaction equation

HRID 1525910 reaction equation
[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:14][CH2:13][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16](O)=[O:17])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1.Cl.[CH3:38][N:39](C)[CH2:40]CCN=C=NCC.Cl.CNC>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]2[CH2:9][C:8]3([CH2:10][CH2:11][N:12]([CH:15]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:34]=[C:33]6[C:28]([CH:29]=[CH:30][CH:31]=[N:32]6)=[CH:27][CH:26]=5)=[CH:21][C:20]=4[F:35])[C:16]([N:39]([CH3:40])[CH3:38])=[O:17])[CH2:13][CH2:14]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 10473Dimethylamine, hydrochlorideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride2×HCID 712709422-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetic acid

Product 1

HCID 71270859(-)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N,N-dimethylacetamideYield 31.6%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

A solution of 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetic acid (0.153 mmol) in dichloromethane (1 mL) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.230 mmol) and 4-(dimethylamino)pyridine (0.766 mmol). This mixture was stirred at room temperature for 10 min at which point dimethylamine hydrochloride (0.306 mmol) was added. The reaction vessel was sealed and the reaction was stirred at room temperature overnight. At this point an additional portion of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.230 mmol) was added. The reaction vessel was sealed and the reaction was stirred at room temperature overnight. The resulting reaction mixture was concentrated to dryness under a stream of nitrogen. Purification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chromegachiral CC4, methanol) and lyophilization from water (w/25% acetonitrile) afforded the title compound as a solid (25 mg, 30%). MS(ES)+ m/e 517.4 [M+H]+, >99% ee, αD=−69 deg (c=0.01, methanol).

Workup

  1. additionwas added
  2. customThe reaction vessel was sealed
  3. customThe reaction vessel was sealed
  4. stirringthe reaction was stirred at room temperature overnight
  5. customThe resulting reaction mixture
  6. concentrationwas concentrated to dryness under a stream of nitrogen
  7. customPurification of the residue by reverse phase HPLC (20-65% acetonitrile/water with 0.1% NH4OH)

Sources & evidence

ORD record
ord-a59d5f00eb3d4edea29c1fdddae09c05
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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