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Mycophenolate mofetil impurity

A technology of mycophenolate mofetil and morpholine, applied in the field of mycophenolate mofetil and mycophenolate mofetil impurities

Inactive Publication Date: 2007-01-31
TEVA GYOGYSZERGYAR RESVENYTARSASAG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthetic method to prepare the esters results in various impurities

Method used

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  • Mycophenolate mofetil impurity
  • Mycophenolate mofetil impurity
  • Mycophenolate mofetil impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0103] Embodiment 1: the preparation of N-(2-methylsulfonylethyl)morpholine

[0104] Charge 5.2 g of N-(2-hydroxyethyl)morpholine, 25 ml of DCM and 5.5 ml of triethylamine with a magnetic bar and top with CaCl 2 tube in a 150ml single neck round bottom flask. The mixture was stirred and cooled in an ice-water bath while 3.1 ml of methanesulfonyl chloride were added over 5 minutes. The reaction mixture was stirred overnight, then quenched in 20 ml of water. Extract the aqueous phase with two 25 ml portions of DCM, combine the organic extracts, wash with 20 ml brine, MgSO 4 Drying and concentration under reduced pressure afforded 4.1 g of crude mesylate, which was purified by TLC.

Embodiment 2

[0105] Embodiment 2: the preparation of compound 1

[0106] 6.21 g of mycophenolate mofetil (14.3 mmol) and 20 ml of anhydrous DMF were charged into a 150 ml two necked round bottom flask equipped with a magnetic stirrer and nitrogen inlet tube. To the stirred solution was added stepwise 570 mg of sodium hydride (60% in mineral oil) over 10 minutes and the resulting mixture was stirred at room temperature for 25 minutes. To the reaction mixture was added the methanesulfonyl derivative, 2.92 g (14 mmol) in 4 ml DMF. The reaction mixture was heated in an oil bath at 50°C for 14 hours, then allowed to cool to room temperature, diluted with 50 ml of water and extracted with three 20 ml portions of ethyl acetate. The combined organic extracts were washed with brine (20ml), dried and concentrated under reduced pressure to afford 7g (89%) of a pale yellow viscous liquid as pure product (analysis by TLC). Further purification was possible by column chromatography on silica gel eluti...

Embodiment 3

[0107] Embodiment 3: the preparation of compound 1

[0108] The acidic washes (5 L) obtained from the production of crude MMF were combined and neutralized with solid sodium bicarbonate. Isobutyl acetate (1 L) and charcoal (10 g) were added, filtered and the phases were separated. The organic phase was evaporated to 300ml. Water (300ml) was added and the pH was adjusted to 4-4.5 using acetic acid. After separation of the phases, the aqueous phase was neutralized with solid sodium bicarbonate and extracted with isobutyl acetate (200ml). The organic phase was dried over sodium sulfate and evaporated to dryness. The purity of the residue (0.81 g brown oil) was 77a% compound 1.

[0109] The residue was chromatographed on a silica gel column (eluent: acetone) to give a syrupy product compound 1 (560 mg, purity: 95a%).

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Abstract

Provided is an impurity of mycophenolate mofetil, processes for its preparation and its use as a reference.

Description

[0001] This application claims the benefit of the following U.S. Provisional Patent Applications: 60 / 566,056, filed April 27, 2004; 60 / 572,985, filed May 20, 2004; 589,400, 60 / 638,478 filed 23 December 2004, 60 / 639,151 filed 22 December 2004, 60 / 642,867 filed 10 January 2005, 15 March 2005 Serial No. 60 / 661,485 filed on , the entire contents of which are hereby incorporated by reference in their entirety. field of invention [0002] The present invention relates to (E)-6-(1,3-dihydro-4-[2-(4-morpholinyl)ethoxy]-6-methoxy-7-methyl-3-oxo- 2-(4-morpholinyl)ethyl isobenzofuran-5-yl)-4-methyl-hex-4-enoate (compound 1), an impurity of mycophenolate mofetil, which Methods of preparation and isolation and use as reference markers. The present invention also relates to mycophenolate mofetil with a small amount of Compound 1, and an HPLC method for its identification. Background of the invention [0003] Mycophenolic acid, chemical name 6-[4-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/88C07B41/12C07B63/00
Inventor S·莫尔纳A·埃森斯塔德特T·塔马斯J·哈科B·科斯茨亚
Owner TEVA GYOGYSZERGYAR RESVENYTARSASAG
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