Preparation method of atazanavir hydrosulfate crystal form H1

A technology of bisulfate and atazanavir is applied in the field of preparation of atazanavir bisulfate crystal form H1, can solve the problems of high methanol content, low yield and the like, and achieves high chromatographic purity, high yield, good repeatability

Active Publication Date: 2017-11-24
SHANGHAI VIWIT PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The problem to be solved by the present invention is to provide a kind of atazanavir hydrogen sulfate crystal form H1 in order to overcome the defects of low yield and high methanol content in the existing preparation method of atazanavir hydrogen sulfate salt form H1 preparation method

Method used

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  • Preparation method of atazanavir hydrosulfate crystal form H1
  • Preparation method of atazanavir hydrosulfate crystal form H1
  • Preparation method of atazanavir hydrosulfate crystal form H1

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preparation example Construction

[0032] The preparation method used in Comparative Example 1 in the examples of the present invention is the preparation method of atazanavir crystal form H1 disclosed in patent WO2010079497.

[0033] In the drawings of the present invention figure 2 and Figure 4 XRPD and DSC charts of atazanavir bisulfate crystalline form H1 disclosed in the cited patent WO2010079497.

[0034] The powder X-diffraction testing instrument model involved in the present invention is: German Bruker D8 advance; testing conditions: Voltage, Current is 40Kv, 40mA, Stand-End Position is 0-40°2θ, Increment is 0.02°2θ, Time per step 0.5s, detection environment: 26°C, humidity 44%RH.

[0035] The model of the differential scanning calorimeter involved in the present invention is: TA Q200; the test method: Equlibrate at 20°C, Ramp at 10.0°C / min to 250.0°C, N 2 The flow rate is 40mL / min, the aluminum pan is covered. Testing environment: 25°C, humidity 55%RH.

[0036] Methanol detection method of the ...

Embodiment 1

[0037] Example 1: Preparation of Atazanavir Hydrogen Sulfate Form H1

[0038] A mixed solution of 30 g of methanol, 450 g of ethyl acetate and 30 g of butanone was added to 100 g of atazanavir hydrogen sulfate crystal form A, stirred at room temperature for 12 h, filtered, and the solid was washed with 30 g of butanone. The obtained product was vacuum-dried at 50-55°C for 8.0 hours to obtain an off-white solid. Yield: 96.5%, HPLC purity: 98.86%, methanol content: 0.13%. See XRPD figure 1 , see DSC image 3 .

Embodiment 2

[0039] Example 2: Preparation of Atazanavir Hydrogen Sulfate Form H1

[0040] A mixed solution of 50 g of methanol, 500 g of ethyl acetate and 50 g of butanone was added to 100 g of atazanavir hydrogen sulfate crystal form A, stirred at room temperature for 12 h, filtered, and the solid was washed with 3.0 g of butanone. The obtained product was vacuum-dried at 50-55°C for 8.0 hours to obtain an off-white solid. Yield: 95.3%, HPLC purity: 99.13%, methanol content: 0.15%. XRPD with figure 1 Consistent, DSC same image 3 unanimous.

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Abstract

The invention discloses a preparation method of an atazanavir hydrosulfate crystal form H1. The preparation method comprises the following steps: mixing atazanavir hydrosulfate with a solvent, and stirring to obtain the atazanavir hydrosulfate crystal form H1, wherein the solvent is a mixed solvent of methanol, butanone and ethyl acetate. The preparation method of an atazanavir hydrosulfate crystal form H1 disclosed by the invention has the advantages of high repeatability, easiness in operation and high yield; the methanol content in the product meets the requirements for medicinal use, and the chromatographic purity is high; thus, the product is more applicable to medicament and suitable for industrial production and has a potential market value.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of atazanavir bisulfate crystal form H1. Background technique [0002] Atazanavir sulfate, trade name Reyataz, is a drug developed by Bristol-Myers Squibb for the treatment of HIV-1 infection. The pharmaceutical preparation is in the form of capsules, which was launched in the United States in 2003 and entered the Chinese market in 2011. [0003] The Chinese chemical name of atazanavir bisulfate is (3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo -9-(Benzyl)-6-[[4-(2-pyrimidine)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl hydrogensulfate Salt, the structure is as follows: [0004] [0005] Various crystal forms of atazanavir hydrogen sulfate have been reported at this stage: WO9936404 discloses atazanavir hydrogen sulfate salt crystal form I (crystal form A) and crystal form II for the first time; WO200510...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/42
CPCC07B2200/13C07D213/42
Inventor 蔡明君魏彦君刘金飞李玉源徐兴华罗宾尹超邢艳平
Owner SHANGHAI VIWIT PHARMA CO LTD
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