Methanesulfonic Acid → Milategrast mesylate

HRID 32279Notes

Reaction equation

HRID 32279 reaction equation
[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH3:27][S:28]([OH:31])(=[O:30])=[O:29]>C(C(C)=O)C>[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].[CH:1]1([CH2:4][N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH2:22]3)[CH2:9][CH2:10]2)[CH2:3][CH2:2]1

Participants

4

Reactant 2

HCID 6395Methanesulfonic AcidHCID 11302685859217-52-0

Product 1

HCID 11633798Milategrast mesylate

Reagents, catalysts & solvents 1

HCID 6569Methyl Ethyl KetoneSolvent2×

Conditions

Temperature
81 °C

Procedure

A mixture of 1-cyclopropylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (277.0 g, 781.2 mmol) and methyl ethyl ketone (2493 mL) was stirred while heating at an external temperature of 81° C. Methanesulfonic acid (76.58 g, 796.8 mmol) was then added dropwise thereto over a period of 3 minutes, to form a thoroughly dissolved state. After heating and stirring for 7 minutes at an external temperature of 81° C., the external temperature was gradually lowered and stirring was continued until the internal temperature reached 37° C. The reaction suspension containing the produced precipitate was transferred to another flask using methyl ethyl ketone (100 mL). The suspension was then concentrated under reduced pressure over a period of 1 hour and 20 minutes at an external temperature of 21° C. It was then dried under reduced pressure for 30 minutes at an external temperature of 40° C. for solidification of the flask contents, to give a crude solid product of the title compound. After adding a mixed solvent of ethyl acetate (1662 mL) and heptane (1108 mL) to this crude solid product, the resulting suspension was stirred for 1 hour at an external temperature of 65° C. The suspension was then further stirred while gradually lowering the external temperature, and after the external temperature reached 45° C., stirring was continued for 14 hours at an external temperature of room temperature. The obtained suspension was filtered and the precipitated solid was collected. The solid was washed with a mixed solvent of ethyl acetate (330 mL) and heptane (220 mL) and aircured by aspiration for 4 hours at room temperature. The obtained crystals were dried for 6 hours at 70° C. in a warm-air drier to give 335.9 g of the title compound as colorless (white) powdery crystals.

Workup

  1. customto form a thoroughly dissolved state
  2. temperatureAfter heating
  3. stirringstirring for 7 minutes at an external temperature of 81° C.
  4. stirringstirring
  5. customreached 37° C
  6. additionThe reaction suspension containing the produced precipitate
  7. customwas transferred to another flask
  8. concentrationThe suspension was then concentrated under reduced pressure over a period of 1 hour and 20 minutes at an external temperature of 21° C
  9. customIt was then dried under reduced pressure for 30 minutes at an external temperature of 40° C. for solidification of the flask contents

Sources & evidence

ORD record
ord-118603c8f74b40bd81f11d21a11546f0
Source dataset
uspto-grants-2008_09
Patent number
US07425554B2

Reaction notes

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