Boron Trichloride → HCID 87058761, compound

HRID 1972453Notes

Reaction equation

HRID 1972453 reaction equation
Cl.Cl.Cl.C([O:11][CH:12]1[CH2:18][CH:17]2[N:19]([CH2:20][C@H:21]3[CH2:26][NH:25][CH2:24][CH2:23][NH:22]3)[CH:13]1[CH2:14][O:15][CH2:16]2)C1C=CC=CC=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33].Cl[C:37]1[N:42]=[CH:41][C:40]([C:43]([OH:52])([C:48]([F:51])([F:50])[F:49])[C:44]([F:47])([F:46])[F:45])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C.B(Cl)(Cl)Cl>O.CO.C(Cl)Cl.O1CCOCC1>[F:47][C:44]([F:45])([F:46])[C:43]([C:40]1[CH:41]=[N:42][C:37]([N:22]2[CH2:23][CH2:24][N:25]([S:32]([C:28]3[S:27][CH:31]=[CH:30][N:29]=3)(=[O:34])=[O:33])[CH2:26][C@@H:21]2[CH2:20][N:19]2[CH:13]3[CH:12]([OH:11])[CH2:18][CH:17]2[CH2:16][O:15][CH2:14]3)=[N:38][CH:39]=1)([OH:52])[C:48]([F:51])([F:50])[F:49]

Participants

10

Reactant 5

HCID 25135Boron TrichlorideHCID 81531DiisopropylethylamineHCID 115792352-Thiazolesulfonyl chlorideHCID 66582472HCID 66582472, compoundHCID 866703482-(2-Chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol2×

Product 1

HCID 87058761HCID 87058761, compoundYield 10.5%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

A 100-mL round-bottomed was charged with 6-(benzyloxy)-8-((2R)-2-piperazinylmethyl)-3-oxa-8-azabicyclo[3.2.1]octane tris-hydrochloride (0.400 g, 0.937 mmol, Example 79, Step 2), 10 mL of CH2Cl2, and thiazole-2-sulfonyl chloride (0.210 g, 1.031 mmol, Bioorg. Med. Chem., 2006, 14, 6628). The mixture was diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4), filtered, and concentrated to give an oil. Purification via column chromatography on silica gel (0 to 10% MeOH in CH2Cl2, delivered the intermediate amine. To this was added 2-(2-chloropyrimidin-5-yl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.066 g, 0.23 mmol, Intermediate D), 2 mL of dioxane, and Hünig's base (0.049 mL, 0.281 mmol). The mixture was heated at 85° C. for 12 h then cooled to room temperature and purified by column chromatography on silica gel (0 to 50% EtOAc in hexanes) to give the intermediate benzyl protected alcohol. To this was added 4 mL of CH2Cl2 and BCl3 (1M in CH2Cl2, 0.937 mL, 0.937 mmol, Sigma-Aldrich, St. Louis, Mo.). After 30 min at room temperature, 5 mL of MeOH was added and the mixture was concentrated and purified by column chromatography on silica gel (0 to 10% MeOH in CH2Cl2) to give 8-(((S)-1-(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyrimidin-2-yl)-4-(thiazol-2-ylsulfonyl)piperazin-2-yl)methyl)-3-oxa-8-azabicyclo[3.2.1]octan-6-ol (0.015 g) as a mixture of two isomers.

Workup

  1. extractionextracted with EtOAc
  2. dry with materialThe combined organics were dried (MgSO4)
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customto give an oil
  6. customPurification via column chromatography on silica gel (0 to 10% MeOH in CH2Cl2
  7. temperaturethen cooled to room temperature
  8. custompurified by column chromatography on silica gel (0 to 50% EtOAc in hexanes)
  9. customto give the intermediate benzyl
  10. concentrationthe mixture was concentrated
  11. custompurified by column chromatography on silica gel (0 to 10% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-66d1a4cec6af48708297579e635aa926
Source dataset
uspto-grants-2013_04
Patent number
US08431563B2

Reaction notes

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