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Process for preparing atazanavir bisulfate and novel forms

A technology of atazanavir and bisulfate, applied in the field of preparing HIV protease inhibitor atazanavir bisulfate

Active Publication Date: 2009-10-28
BRISTOL MYERS SQUIBB HLDG IRELAND UNLTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Preferred C-mode substances

Method used

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  • Process for preparing atazanavir bisulfate and novel forms
  • Process for preparing atazanavir bisulfate and novel forms
  • Process for preparing atazanavir bisulfate and novel forms

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis{[N-(methoxycarbonyl)-L-tert-leucyl]amino}-4-( S)-Hydroxy-6-phenyl-2-azahexane, bisulfate (Form A) (Atazanavir bisulfate-Form A)

[0177]

[0178] (1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis[tert-butoxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2 -Azahexane.3HCl (triamine.3HCl salt))

[0179] The protected triamine 1-[4-(pyridin-2-yl)phenyl]-5(S)-2,5-bis[tert-butoxycarbonyl)amino]-4(S)-hydroxyl-6 -Phenyl-2-azahexane

[0180]

[0181] (100g, 0.178mol) and CH 2 Cl 2 (500 mL; 5 mL / g protected triamine feed) (its preparation is described in Z. Xu et al., Process Research and Development for an Efficient Synthesis of the HIV Protease Inhibitor BMS-232, 632, Organic Process Research and Development, 6 , 323-328 (2002)) into a 1000 mL 3-necked round bottom flask equipped with a mechanical stirrer, nitrogen inlet, and temperature sensor, and the resulting slurry was stirred while maintaining the temperature at about 5 to about 22°C.

...

Embodiment 2

[0230] Atazanavir bisulfate-C pattern substance

[0231] Method A:

[0232] Atazanavir bisulfate Form A crystals (prepared as described in Example 1) (25.33 g) were suspended in 200 mL of water, and the mixture was mechanically stirred to give a viscous gel, which was dried.

[0233] The dry mixture was triturated with a spatula to obtain the Pattern C material. The powder X-ray diffraction pattern of the C-mode material is as follows Figure 6 show.

[0234] Method B:

[0235] Wet granulate the atazanavir bisulfate Form A crystals with sufficient water (approximately 40% w / w) in a suitable mixer-granulator. Dry the wet mass in an oven. The product is sieved to size using a suitable sieve. The X-ray diffraction pattern of the obtained product and Figure 6 Concordance with the C-mode species shown.

[0236] The characteristics of the differential scanning calorimetry thermogram of C mode are as follows: Figure 7 It is shown that there is generally an endotherm in the...

Embodiment 3

[0239] Atazanavir Bisulfate-Form E3 (Triethanol Solvate)

[0240] In a 100mL 3-necked round-bottomed flask equipped with a mechanical stirrer, a temperature sensor and a pressure-balanced addition funnel, atazanavir free base (prepared according to Part C in Example 1) (3.0g, 4.26mmol) was dried at 200 Slurry was made in proof ethanol (20.25 mL, 6.75 mL / g free base).

[0241] Concentrated H 2 SO 4 (0.25 mL, 0.46 g, 4.69 mmol, 1.1 eq.) was added to the atazanavir free base slurry maintained at 20-25 °C. The resulting solution (KF 0.2 to 1.0% water) was polish filtered (Whatman #1 paper), the filter was rinsed with 2.25 mL of absolute ethanol, and the rinse was added to the filtered solution. The solution was heated to 37°C, seeded with 10 mg of amorphous atazanavir bisulfate derived from Form E3 crystals (by exposing Form E3 crystals to ambient temperature), and the mixture was stirred for 15 minutes. Heptane (380 mL, 8.25 mL / g free base) was added over 1 hour. The resulting...

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Abstract

A process is provided for preparing the HIV protease inhibitor atazanavir bisulfate wherein a solution of atazanavir free base is reacted with concentrated sulfuric acid in an amount to react with less than about 15% by weight of the free base, seeds of Form A crystals of atazanavir bisulfate are added to the reaction mixture, and as crystals of the bisulfate form, additional concentrated sulfuric acid is added in multiple stages at increasing rates according to a cubic equation, to effect formation of Form A crystals of atazanavir bisulfate. A process is also provided for preparing atazanavir bisulfate as Pattern C material. A novel form of atazanavir bisulfate is also provided which is Form E3 which is a highly crystalline triethanolate solvate of the bisulfate salt from ethanol.

Description

[0001] This application is a divisional application submitted based on the application date of May 3, 2005, application number 200580022550.2, and the title of the invention "Method for preparing atazanavir bisulfate and new form". [0002] Reference to other applications [0003] This application claims priority to US Provisional Application Nos. 60 / 568,043, filed May 4, 2004, and 60 / 607,533, filed September 7, 2004, the disclosures of which are incorporated herein by reference. technical field [0004] The present invention relates to a process for the preparation of the HIV protease inhibitor atazanavir bisulphate and new forms thereof. Background technique [0005] awarded No. 5,849,911 of U.S. Patent No. 911 discloses a series of azapeptide HIV protease inhibitors (including atazanavir), and its structure is [0006] [0007] in [0008] R 1 is lower alkoxycarbonyl, [0009] R 2 is secondary or tertiary lower alkyl or lower alkylthio-lower alkyl, [0010] R ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/42A61K31/4418A61P31/18
Inventor S·金B·T·罗茨M·F·马利J·Z·古古塔斯M·达维多维奇S·K·斯里瓦斯塔瓦
Owner BRISTOL MYERS SQUIBB HLDG IRELAND UNLTD
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