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Vonoprazan salts and crystal forms, and preparation method and application thereof

A technology of crystal form and salt crystal, applied in Vonorazan salt, preparation of anti-gastric acid secretion drugs, crystal form and its preparation, which can solve the problems of difficulty in sterility assurance and high production cost

Inactive Publication Date: 2018-03-06
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the freeze-dried powder injection is conducive to improving stability, it involves relatively high production costs and relatively high difficulty in aseptic assurance.

Method used

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  • Vonoprazan salts and crystal forms, and preparation method and application thereof
  • Vonoprazan salts and crystal forms, and preparation method and application thereof
  • Vonoprazan salts and crystal forms, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0366] Example 1: Preparation of Vonorazan Dihydrochloride (Formula III) and Form A thereof

[0367] Dissolve 3.00 g (8.69 mmol) of Vonorazan in 6 ml of ethanol, and 1.59 g (15.64 mmol, 1.8 eq) of concentrated hydrochloric acid (containing 36% hydrogen chloride) in 3 ml of ethanol. At 40-45°C, the hydrochloric acid ethanol solution was added dropwise to the Vonorazan ethanol solution, and then 20 ml of ethyl acetate was added dropwise. Cool to about 5°C. Filtration and washing with ethyl acetate gave Vonorazan dihydrochloride.

[0368] The content of vonorazan was determined by HPLC to be consistent with vonorazan dihydrochloride.

[0369] The powder X-ray diffraction pattern of measured Vonorazan dihydrochloride is shown in figure 1 , the measured value is as follows (take the measured value corresponding to the diffraction peak with a relative intensity greater than 2% within the range of 2θ angle 4°-40°, the measured values ​​of 2θ and d are rounded to three decimal pla...

Embodiment 2

[0374] Example 2: Preparation of Vonorazan Dihydrochloride (Formula III) and Form B thereof

[0375] Dissolve 3.00 g (8.69 mmol) of Vonorazan in 6 ml of ethanol, and 1.59 g (15.64 mmol, 1.8 eq) of concentrated hydrochloric acid (containing 36% hydrogen chloride) in 3 ml of ethanol. At 40-45°C, add the above hydrochloric acid ethanol solution dropwise to the Vonorazan ethanol solution, and then slowly add 20 ml of ethyl acetate dropwise. Cool to about 5°C. Filtrate, wash with ethyl acetate, and dry under reduced pressure at 40-45°C to obtain Divornorazan dihydrochloride.

[0376] 1 H NMR (400MHz, DMSO-d 6 )δ: 2.477-2.517(m, 4.3H, with DMSO-d 6 Solvent peak overlap), 3.972-4.000(t,2H), 5.393(br.,2H), 6.634-6.639(d,1H), 7.072-7.114(m,1H), 7.212-7.258(m,2H),7.510 -7.568(m,1H),7.617-7.651(m,1H),7.875-7.879(m,1H),7.914-7.945(m,1H),8.571-8.576(d,1H),8.888-8.904(dd, 1H),9.446-9.456(br.,2H).

[0377] The content of vonorazan was determined by HPLC to be consistent with vonorazan...

Embodiment 3

[0383] Embodiment 3: Preparation of Vonorazan Dihydrobromide (Formula IV) and Form A thereof

[0384] Dissolve 3.00 g (8.69 mmol) of Vonorazan in 6 ml of ethanol, and 2.78 g (16.51 mmol, 1.9 eq) of hydrobromic acid (containing 48% hydrogen bromide) in 3 ml of ethanol. At 45-50° C., the hydrobromic acid ethanol solution was added dropwise to the Vonorazan ethanol solution, and then 20 ml of acetone was added dropwise. Cool to about 10°C. Filter, wash with acetone, and dry under reduced pressure at 45-50°C to obtain Dihydrobromide of Vonorazan.

[0385] 1 H NMR (400MHz, DMSO-d 6 )δ:2.540-2.567(t,3H),4.020-4.049(t,2H),4.744(br.,2H),6.551-6.555(d,1H),7.087-7.128(m,1H),7.220-7.261 (m,2H),7.519-7.558(m,1H),7.628-7.663(m,1H),7.844-7.849(m,1H),7.886-7.917(m,1H),8.579-8.584(d,1H) ,8.799(br.,2H),8.899-8.915(dd,1H).

[0386] The content of vonorazan was determined by HPLC to be consistent with vonorazan dihydrobromide.

[0387] The powder X-ray diffraction pattern of measured Vono...

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Abstract

The invention relates to vonoprazan dihydrochloride, vonoprazan dihydrobromide, vonoprazan disulfate, vonoprazan nitrate, vonoprazan diphosphate, vonoprazan sulfonate, vonoprazan 1,4-hemibutanedisulfonate, vonoprazan 1,4-butanedisulfonate, vonoprazan 2-isethionate, vonoprazan L-tartrate and free alkali of vonoprazan, and crystal forms thereof. The salts and the crystal forms are simple to prepare,and the crystal forms are easy to control and has good dissolvability and stability. The invention further relates to preparation methods for the salts and the crystal forms, injections containing the salts, and application of the salts and the crystal forms to preparation of drugs used for treating and / or preventing diseases related to gastric acid.

Description

technical field [0001] The present invention relates to the fields of organic chemistry and pharmacy, in particular to Vonorazan salts, crystal forms and preparation methods thereof, pharmaceutical compositions containing Vonorazan salts and crystal forms, and the preparation of these salts and crystal forms for anti-inflammatory drugs. Use in gastric acid secretory medicines. Background technique [0002] Vonoprazan, English common name: vonoprazan, chemical name: 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N- Methylmethylamine, the structural formula is as shown in formula I. Developed by Takeda Pharmaceutical Company, Vonorazan is the world's first reversible potassium ion competitive acid blocker (P-CAB), which competitively inhibits the proton pump (H + , K + -ATPase) in K + And work. In February 2015, Vonorazan was approved for marketing in Japan. The salt form on the market is a fumarate salt as shown in formula II, and the dosage form on the m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07C309/04C07C309/05C07C303/32C07C309/30C07C309/08C07C51/41C07C59/255A61K31/4439A61P1/04A61K9/08
Inventor 陈大峰彭丹程鹤冯文华罗杰
Owner SICHUAN HAISCO PHARMA CO LTD
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