Methanesulfonic Acid → Luminespib mesylate anhydrous

HRID 1695557Notes

Reaction equation

HRID 1695557 reaction equation
[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:33])=[CH:26][C:25]=2[OH:34])[O:8][N:7]=1)=[O:5])[CH3:2].[CH3:35][S:36]([OH:39])(=[O:38])=[O:37]>CC(C)=O.O>[S:36]([OH:39])(=[O:38])(=[O:37])[CH3:35].[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][CH:12]=2)=[C:9]([C:24]2[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[C:27]([OH:33])=[CH:26][C:25]=2[OH:34])[O:8][N:7]=1)=[O:5])[CH3:2]

Participants

5

Reactant 2

HCID 6395Methanesulfonic AcidHCID 135539077Luminespib

Product 1

HCID 135565057Luminespib mesylate anhydrousYield 86.1%

Reagents, catalysts & solvents 2

HCID 180AcetoneSolventHCID 962WaterSolvent

Conditions

Temperature
35 °C

Procedure

A stirred suspension of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (7.76 g, 15 mmol, containing about 9 wt % TBME) in acetone (15 ml) is warmed to 35° C. To the mixture is added a solution of methanesulfonic acid (1.43 g, 14.85 mmol) in water (3.33 g) over 20 min. After 15 min, the solution is warmed to 45° C. and clear filtered into a warm flask (about 45° C.). The filter is rinsed with acetone/water 9:1 (v/v, 12 ml). The 45° C. warm filtrate is diluted with acetone (53 ml) over 30 min and seeded with 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide methanesulfonic acid salt (4 mg) whereupon crystallization begins. After 1 h at 45° C. acetone (30 ml) is added. The suspension is stirred at 45° C. for 1 h before it is cooled to 24° C. over 90 min. TBME (20 ml) is added, and the suspension is stirred at about 24° C. for 15 h. Two more portions of TBME (20 ml each) are added followed by 2 h stirring each time. Thereafter, the suspension is cooled to 0-5° C. and stirred for 3 h before it is filtered. The filter cake is washed with acetone/tert-butyl methyl ether 3:1 (v/v) and dried under reduced pressure at 50° C. for about 17 h to give 7.18 g (85%) of the title compound as a white, crystalline powder.

Workup

  1. temperaturethe solution is warmed to 45° C.
  2. filtrationclear filtered into a warm flask (about 45° C.)
  3. washThe filter is rinsed with acetone/water 9:1 (v/v, 12 ml)
  4. temperatureThe 45° C. warm filtrate
  5. additionis diluted with acetone (53 ml) over 30 min
  6. customseeded with 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide methanesulfonic acid salt (4 mg) whereupon crystallization
  7. additionAfter 1 h at 45° C. acetone (30 ml) is added
  8. temperatureis cooled to 24° C. over 90 min
  9. additionTBME (20 ml) is added
  10. stirringthe suspension is stirred at about 24° C. for 15 h
  11. additionTwo more portions of TBME (20 ml each) are added
  12. waitfollowed by 2 h
  13. stirringstirring each time
  14. temperatureThereafter, the suspension is cooled to 0-5° C.
  15. stirringstirred for 3 h before it
  16. filtrationis filtered
  17. washThe filter cake is washed with acetone/tert-butyl methyl ether 3:1 (v/v)
  18. customdried under reduced pressure at 50° C. for about 17 h

Sources & evidence

ORD record
ord-fd6ff2bd9ae647448aaac9c89993af66
Source dataset
uspto-grants-2012_04
Patent number
US08163747B2

Reaction notes

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