Methanesulfonyl chloride → Avacopan metabolite M1

HRID 2273871Notes

Reaction equation

HRID 2273871 reaction equation
CS(Cl)(=O)=O.[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([OH:26])=O)[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[CH:48]=1>C(Cl)Cl>[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:56])([F:57])[F:58])[CH:48]=4)=[O:26])[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1

Participants

6

Reactant 4

HCID 31297Methanesulfonyl chlorideHCID 81531Diisopropylethylamine2×HCID 58506538(2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)piperidine-3-carboxylic acidHCID 59134957(4-Amino-2-(trifluoromethyl)phenyl)methanol

Product 1

HCID 58506551Avacopan metabolite M1Yield 61%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Step b) Methanesulfonyl chloride (378 mg, 3.3 mmol) was added to a solution of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid prepared above (1.4 g, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) in dry CH2Cl2 (25 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred for an additional 15 minutes, then [4-amino-2-(trifluoromethyl)phenyl]methanol (631 mg, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) were added sequentially. The reaction mixture was allowed to attain room temperature over a period of 30 minutes. When TLC and LCMS indicated completion of the reaction, excess solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in dichloromethane) to get the desired compound (1.2 g) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 9.50 (bs, 0.6H), 9.38 (bs, 0.4H), 7.75-7.70 (m, 1H), 7.50-7.33 (m, 3H), 7.24-7.19 (m, 2H), 7.06-6.90 (m, 2H), 6.67-6.55 (m, 3H), 4.77-4.76 (m, 2H), 3.78-3.66 (m, 1H), 3.32-3.00 (m, 3H), 2.44-1.45 (m, 17H). MS: (ES) m/z 598 (M+H+).

Workup

  1. waitto attain room temperature over a period of 30 minutes
  2. customcompletion of the reaction, excess solvent
  3. customwas removed under reduced pressure
  4. customThe residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in dichloromethane)

Sources & evidence

ORD record
ord-e16bb86fdbf24088a90a316b54fc1fbd
Source dataset
uspto-grants-2015_09
Patent number
US09126939B2

Reaction notes

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