Ethanolamine → methanesulfonic acid 8-fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-yl ester

HRID 1513942Notes

Reaction equation

HRID 1513942 reaction equation
C1(C(C2C=CC=CC=2)([C@@H]2CCCN2)O)C=CC=CC=1.B.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:43](=O)[C:44]3[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][N:53]4[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]4)=[CH:46][CH:45]=3)=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[C:33]([O:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:32]=[CH:31]3)=[C:24]([S:60]C)[CH:23]=1.C(CN)O.[Cl-].[NH4+].C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[F:21][C:22]1[CH:23]=[C:24]2[C:25](=[CH:26][CH:27]=1)[C:28]1[C:29](=[C:30]3[C:35](=[CH:36][CH:37]=1)[CH:34]=[C:33]([O:38][S:39]([CH3:42])(=[O:40])=[O:41])[CH:32]=[CH:31]3)[CH:43]([C:44]1[CH:45]=[CH:46][C:47]([O:50][CH2:51][CH2:52][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)=[CH:48][CH:49]=1)[S:60]2

Participants

10

Reactant 8

HCID 700EthanolamineHCID 6331Borane2×HCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 31297Methanesulfonyl chloride2×HCID 516892Sodium BicarbonateHCID 27248992-Pyrrolidinemethanol, alpha,alpha-diphenyl-, (S)-HCID 11238709Methanesulfonic acid 6-(4-fluoro-2-methylsulfanyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester

Product 1

HCID 11249977methanesulfonic acid 8-fluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-yl esterYield 88.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
45 °C

Procedure

Charge a flask with (s)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (380 mg, 1.5 mmol), dissolve with 1M borane in THF (60 mL, 60 mmol), purge with nitrogen and heat to 45° C. Dissolve methanesulfonic acid 6-(4-fluoro-2-methylsulfanyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (9.0 g, 15.1 mmol) in dry THF (80 mL) and add to the borane solution via syringe pump over 2 hours. After the addition is complete, add ethanolamine (18.2 mL, 300 mmol) and stir at 45° C. for 3 hours. Pour the reaction into saturated aqueous ammonium chloride and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate to a beige foam. Dissolve the crude foam in dry THF (150 mL). Add triethylamine (12.4 mL, 90 mmol) and methanesulfonyl chloride (7.0 mL, 90 mmol) and heat to reflux under nitrogen. Add more methanesulfonyl chloride (0.45 mL, 5.8 mmol) after 2 hours to drive the reaction to completion. Pour the reaction into saturated aqueous sodium bicarbonate and extract twice with methylene chloride. Dry the combined organic layers with sodium sulfate, filter and concentrate. Purify the residue on silica gel (0% to 4% methanol in methylene chloride) to yield 7.5 g (88%) of the title compound. HPLC Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 25 to 95% B, Purity@254 nm)=2.96 min (100%); mass spectrum (ion spray): m/z=564.3 (M+H).

Workup

  1. custompurge with nitrogen
  2. additionAfter the addition
  3. additionPour
  4. extractionextract with methylene chloride
  5. dry with materialDry over sodium sulfate
  6. filtrationfilter
  7. concentrationconcentrate to a beige foam
  8. dissolutionDissolve the crude foam in dry THF (150 mL)
  9. temperatureto reflux under nitrogen
  10. customthe reaction to completion
  11. additionPour
  12. extractionextract twice with methylene chloride
  13. dry with materialDry the combined organic layers with sodium sulfate
  14. filtrationfilter
  15. concentrationconcentrate
  16. customPurify the residue on silica gel (0% to 4% methanol in methylene chloride)

Sources & evidence

ORD record
ord-92ba206267a5437dbfe0cbe273e0c9fe
Source dataset
uspto-grants-2012_07
Patent number
US08217032B2

Reaction notes

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