Hydrochloric Acid → Azd-4320

HRID 1476337Notes

Reaction equation

HRID 1476337 reaction equation
[Si]([O:8][CH2:9][CH2:10][N:11]([CH3:70])[CH2:12][CH2:13][C@@H:14]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34](=[O:62])[C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][CH2:45][CH:44]([C@H:47]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[C:55]4[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=4)[OH:48])[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:32])=[O:31])=[CH:26][C:25]=1[S:63]([C:66]([F:69])([F:68])[F:67])(=[O:65])=[O:64])[CH2:15][S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C(C)(C)C)(C)C.Cl>O1CCOCC1.CO>[Cl:61][C:58]1[CH:59]=[CH:60][C:55]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=2[C@H:47]([OH:48])[CH:44]2[CH2:43][CH2:42][N:41]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([NH:33][S:30]([C:27]4[CH:28]=[CH:29][C:24]([NH:23][C@H:14]([CH2:13][CH2:12][N:11]([CH2:10][CH2:9][OH:8])[CH3:70])[CH2:15][S:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:25]([S:63]([C:66]([F:67])([F:68])[F:69])(=[O:64])=[O:65])[CH:26]=4)(=[O:31])=[O:32])=[O:62])=[CH:36][CH:37]=3)[CH2:46][CH2:45]2)=[CH:56][CH:57]=1

Participants

5

Reactant 2

HCID 313Hydrochloric Acid2×HCID 86661870N-(4-((R)-4-((2-(tert-butyldimethylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4'-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide2×

Product 1

HCID 86661883Azd-4320Yield 80.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of N-(4-((R)-4-((2-(tert-butyldimethylsilyloxy)ethyl)(methyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzamide (INTERMEDIATE 34, 2.96 g, 2.51 mmol) in dioxane (5.03 ml) and methanol (5.03 ml) was added slowly HCl (4M in dioxane, 15.08 ml, 60.33 mmol). Approximately half way through addition, a slight exotherm was noted, and the reaction was cooled to 0° C. Addition of hydrochloric acid in dioxane (4M) continued, and once complete, the ice bath was removed. The resulting yellow solution was allowed to warm to r.t. and stirred for 3 min before being concentrated under reduced pressure to half volume and diluted with ethyl acetate. The resulting mixture was washed with sodium bicarbonate (saturated, aqueous) and sodium chloride (saturated, aqueous) before being dried over sodium sulfate, filtered, and concentrated. Upon concentration, a thick oily residue precipitated out of solution and this material was redissolved in acetone before being reconcentrated to a beige film. This film was dissolved in 10% methanol in ethyl acetate and purified by column chromatography (ISCO, 330 g SiO2, isocratic 15% methanol in ethyl acetate for 30 min) to afford the title compound (1.90 g, yield: 80%).

Workup

  1. additionApproximately half way through addition
  2. customonce complete, the ice bath was removed
  3. temperatureto warm to r.t.
  4. concentrationbefore being concentrated under reduced pressure to half volume
  5. additiondiluted with ethyl acetate
  6. washThe resulting mixture was washed with sodium bicarbonate (saturated, aqueous) and sodium chloride (saturated, aqueous)
  7. dry with materialbefore being dried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. concentrationUpon concentration
  11. customa thick oily residue precipitated out of solution
  12. dissolutionthis material was redissolved in acetone
  13. dissolutionThis film was dissolved in 10% methanol in ethyl acetate
  14. custompurified by column chromatography (ISCO, 330 g SiO2, isocratic 15% methanol in ethyl acetate for 30 min)

Sources & evidence

ORD record
ord-76a60debf4fa454887cd0332a02da960
Source dataset
uspto-grants-2015_04
Patent number
US09018381B2

Reaction notes

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