Ammonium Bromide → 2-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetamide

HRID 1525873Notes

Reaction equation

HRID 1525873 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]([OH:18])=O)[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:3][CH2:2]1.Cl.C[N:39](C)CCCN=C=NCC.[Br-].[NH4+]>ClCCl.CN(C)C1C=CN=CC=1>[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]([NH2:39])=[O:18])[CH2:11][CH2:10]3)[O:7][CH2:6][C:5]2=[O:36])[CH2:2][CH2:3]1

Participants

6

Reactant 3

HCID 25514Ammonium BromideHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 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 712707212-(4-Cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetamideYield 37.4%

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 (0.257 mmol) in dichloromethane (2 mL) was treated with N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.386 mmol) and 4-(dimethylamino)pyridine (1.030 mmol) at room temperature. This mixture was stirred for ten minutes at which point ammonium bromide (0.309 mmol) was added. The reaction was allowed to stir at room temperature overnight. The reaction was then concentrated to dryness under a stream of nitrogen. The resulting crude product was purified by reverse phase HPLC (10-40% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ˜10 with 30% w/v aq ammonium hydroxide. This mixture was concentrated to a minimal volume in vacuo and was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Lyophilization from water afforded the title product as a white solid (47 mg, 35%). MS(ES)+ m/e 489.5 [M+H]+.

Workup

  1. additionwas added
  2. concentrationThe reaction was then concentrated to dryness under a stream of nitrogen
  3. customThe resulting crude product was purified by reverse phase HPLC (10-40% acetonitrile with 0.1% TFA/water with 0.1% TFA)
  4. additionFractions containing the desired product
  5. concentrationThis mixture was concentrated to a minimal volume in vacuo
  6. extractionwas extracted three times with dichloromethane
  7. dry with materialThe combined organic layers were dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-911ac55738a246ea961efc9601fe5c1b
Source dataset
uspto-grants-2015_07
Patent number
US09084794B2

Reaction notes

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