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Dimethylformamide → N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-1,3-dihydroxycyclopentanecarboxamide

HRID 1160613
Notes
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Reaction equation

HRID 1160613 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH2:16])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1.C1C=CC2N([OH:34])N=NC=2C=1.CCN=C=NC[CH2:41][CH2:42]N(C)C.C(N([CH2:51][CH3:52])CC)C.[C:53](=[O:56])(O)[O-].[Na+].CN([CH:61]=[O:62])C>C(Cl)(Cl)Cl.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[C:5]([C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)=[C:6]([C:8]2[CH:9]=[C:10]([F:17])[C:11]([C@H:14]([NH:16][C:61]([C:53]3([OH:56])[CH2:52][CH2:51][CH:42]([OH:34])[CH2:41]3)=[O:62])[CH3:15])=[N:12][CH:13]=2)[CH:7]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 6

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 68714852((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)amine

Product

1
HCID 57608300N-((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)-1,3-dihydroxycyclopentanecarboxamide

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 6212ChloroformSolvent

Procedure

The above acid (300 mg, 1.15 mmol) and the compound of Reference Example 4 (491 mg, 1.27 mmol) were dissolved in 2 mL of DMF. HOBT (31 mg, 0.23 mmol) and EDCI (254 mg, 1.33 mmol) were added, and the mixture was made basic with triethylamine (117 mg, 1.15 mmol). After 1.5 hours at ambient temperature, 5 mL of water and 5 mL of 10% sodium bicarbonate were added, and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in 10 mL of THF and 10 mL of 1 N HCl was added. The reaction mixture was stirred at ambient temperature for 1 hour, and then the pH of the reaction was adjusted to 8.5 by addition of saturated aqueous sodium bicarbonate solution. Extraction with EtOAc followed by washing of the combined extracts with brine and drying over sodium sulfate afforded crude product. Chromatography on silica gel eluting with 1 to 2% methanol in chloroform afforded the title compound as a racemic mixture of cis and trans isomers, which gave a proton NMR spectrum consistent with theory and a mass ion (ES+) of 479.2 for M+H+: 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H), 7.35 (d, J=9 Hz, 1H), 7.26 (m, 2H), 5.44 (m, 1H), 4.35 (s, 3H), 2.43-1.82 (m, 6H), 1.46 (d, J=7 Hz, 3H).

Workup

  1. extractionthe mixture was extracted with EtOAc
  2. washThe combined organic layers were washed with water and brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. dissolutionThe residue was dissolved in 10 mL of THF
  7. addition10 mL of 1 N HCl was added
  8. additionthe pH of the reaction was adjusted to 8.5 by addition of saturated aqueous sodium bicarbonate solution
  9. extractionExtraction with EtOAc
  10. washby washing of the combined extracts with brine
  11. dry with materialdrying over sodium sulfate
  12. customafforded crude product

Sources & evidence

ORD record
ord-810cadf953ab459da4d568dcb84d21c0
Source dataset
uspto-grants-2010_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07816380B2

Reaction notes

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