Methanol → Trifluoroacetic acid

HRID 2406249Notes

Reaction equation

HRID 2406249 reaction equation
[CH3:1][CH:2]1[CH2:7][CH:6]([N:8]2[CH2:13][CH2:12][N:11]3[C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:29][CH2:30][N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)=[C:23]([S:45]([C:48]([F:51])([F:50])[F:49])(=[O:47])=[O:46])[CH:22]=4)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]3[CH2:9]2)[CH2:5][CH2:4][NH:3]1.[Cl:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[C:60]([CH:65]=[O:66])=[CH:61][CH:62]=[CH:63][CH:64]=2)=[CH:55][CH:54]=1.C([BH3-])#N.[Na+].[CH3:71][OH:72]>[Cl-].[Zn+2].[Cl-]>[Cl:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[CH2:65][N:3]2[CH2:4][CH2:5][CH:6]([N:8]3[CH2:13][CH2:12][N:11]4[C:14]([NH:17][S:18]([C:21]5[CH:26]=[CH:25][C:24]([NH:27][C@@H:28]([CH2:37][S:38][C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH2:29][CH2:30][N:31]6[CH2:32][CH2:33][O:34][CH2:35][CH2:36]6)=[C:23]([S:45]([C:48]([F:51])([F:49])[F:50])(=[O:47])=[O:46])[CH:22]=5)(=[O:20])=[O:19])=[N:15][N:16]=[C:10]4[CH2:9]3)[CH2:7][CH:2]2[CH3:1])=[CH:57][CH:58]=1.[C:71]([OH:66])([C:48]([F:51])([F:50])[F:49])=[O:72]

Participants

7

Reactant 4

HCID 887MethanolHCID 13936894'-Chlorobiphenyl-2-carbaldehydeHCID 5003444Sodium cyanoborohydrideHCID 67980541HCID 67980541, compound

Product 2

HCID 6422Trifluoroacetic acidYield 18%HCID 86667201HCID 86667201, compound

Reagents, catalysts & solvents 1

HCID 3007855ZincchlorideCatalyst

Procedure

To a vial containing N-[7-(2-methyl-piperidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl]-4-((R)-3-morpholin-4-yl-1-phenylsulfanylmethyl-propylamino)-3-trifluoro methanesulfonyl-benzenesulfonamide (20 mg, 0.026 mmol), 4′-chloro-biphenyl-2-carbaldehyde (16.82 mg, 0.078 mmol) and zinc chloride (3.53 mg, 0.034 mol) was added methanol (1 mL) under nitrogen and the mixture was stirred for 10 minutes. Sodium cyanoborohydride (13.01 mg, 0.207 mmol) was then added, and the reaction was stirred at ambient temperature for 14 hours. The reaction mixture was then concentrated and partitioned between ethyl acetate and 2 M NaOH. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with 1M NaOH, dried under Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified via HPLC (0.1% TFA Modifier in water in MeCN) to afford the title compound as a TFA salt (5 mg, 18% yield).

Workup

  1. stirringthe reaction was stirred at ambient temperature for 14 hours
  2. concentrationThe reaction mixture was then concentrated
  3. custompartitioned between ethyl acetate and 2 M NaOH
  4. extractionThe aqueous layer was extracted three times with EtOAc
  5. washThe combined organic layers were washed with 1M NaOH
  6. customdried under Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude material was purified via HPLC (0.1% TFA Modifier in water in MeCN)

Sources & evidence

ORD record
ord-8ff4f92e0319485c8e98ee90ae7e1f81
Source dataset
uspto-grants-2014_08
Patent number
US08809352B2

Reaction notes

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