Hydrochloric Acid → HCID 57761194, compound

HRID 230948Notes

Reaction equation

HRID 230948 reaction equation
C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[CH:17]=[C:16]([N:28]3[CH2:33][CH2:32][N:31]([C:34]4[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1[CH2:50][CH2:49]OCC1>>[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([N:28]3[CH2:29][CH2:30][N:31]([C:34]4[C:39]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:19]=2)[CH:25]=[CH:24][C:23]=1[F:26].[Cl:27][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]([N:28]3[CH2:29][CH2:30][N:31]([C:34]4[C:39]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:37]=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[N:15]=[C:14]([CH:11]3[CH2:10][CH2:9][N:8]([CH2:6][CH2:49][CH3:50])[CH2:13][CH2:12]3)[N:19]=2)[CH:25]=[CH:24][C:23]=1[F:26]

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 312751,4-Dioxane2×HCID 57761677HCID 57761677, compound

Product 2

HCID 57761194HCID 57761194, compoundHCID 57761923HCID 57761923, compound

Procedure

To a solution of 4-{4-(3-chloro-4-fluoro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-piperidine-1-carboxylic acid tert-butyl ester (97 mg, 0.157 mmol) in dioxane, add 0.5 mL of HCl in dioxane (4M) and stir at room temperature for 2 hours. Concentrate the solution under reduced pressure and wash the residue with dry ether. Discard the ether wash, add additional ether and stir for one hour to give a pale yellow suspension. Collect the solid to afford 4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as the HCl salt. Prepare the freebase by partitioning between EtOAc and 10% NaOH solution. Dry (Na2SO4) and evaporate the EtOAc layer. Dissolve the free base in dichloroethane and add propionaldehyde (0.09 mmol) and sodium triacetoxyborohydride (22 mg, 010 mmol) followed by one drop of HOAc. Stir the mixture for one hour, dilute with DCM and wash with 10% NaOH (1×). Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Chromatograph the residue on a 2 mm preparative TLC plate (5% MeOH(1 N NH3)/DCM eluent) to give 4-(3-chloro-4-fluoro-phenyl)-2-(1-propyl-piperidin-4-yl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine. 1H NMR (CDCl3): δ 0.93 (t, 3H), 1.59 (m, 2H), 2.05 (m, 6H), 2.37 (m, 2H), 2.75 (m, 1H), 3.08)m, 2H), 3.40 (m, 4H), 3.88 (m, 4H), 6.69 (s, 1H), 7.06 (m, 1H), 7.21 (t, 1H), 7.86-7.93 (m, 2H), 8.08 (d, 1H), 8.47 (m, 1H).

Workup

  1. concentrationConcentrate the solution under reduced pressure
  2. washwash the residue with dry ether
  3. washwash
  4. additionadd additional ether
  5. stirringstir for one hour
  6. customto give a pale yellow suspension
  7. customCollect the solid

Sources & evidence

ORD record
ord-b0e8b456d09243b3b77e48dd51d2680b
Source dataset
uspto-grants-2009_07
Patent number
US07566712B2

Reaction notes

Loading…