Olodaterol hydrochloride crystalline form B and preparation method thereof

A technology of olodaterol hydrochloride and crystal form, which is applied in the field of medicine, can solve the problems of affecting the efficacy of drugs, difficulties in quality control and preparation work, and inability to obtain stable crystalline products, so as to improve bioavailability, stability, and solubility Improved effect

Pending Publication Date: 2018-12-14
SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, the inventors found that according to the above method, olodaterol hydrochloride is very easy to absorb moisture and turn into an oily substance during suction filtration, and a stable crystalline product cannot be obtained, which has caused great difficulties for subsequent quality control and preparation work.
[0009] As we all know, for the same drug, the solubility, stability, fluidity, compressibility, bioavailability and other aspects of physical and chemical properties may vary greatly between different crystal forms, thus affecting the efficacy of the drug

Method used

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  • Olodaterol hydrochloride crystalline form B and preparation method thereof
  • Olodaterol hydrochloride crystalline form B and preparation method thereof
  • Olodaterol hydrochloride crystalline form B and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] The preparation of embodiment 1 olodaterol hydrochloride crystal form B

[0066] 1) Preparation of 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one

[0067] 100.6 g (0.3 mol) of 6-benzyloxy-8-((R)-2-chloro-1-hydroxy-ethyl-4H-benzo[1,4]-oxazin-3-one and 2LDMF were added Put it into the reaction bottle, stir, cool down in an ice bath, and drop to 0°C, add 400ml of 2N sodium hydroxide aqueous solution, keep it at 0-5°C for four hours, pour the reaction solution into ice water, stir at 0-5°C for 1 hour, Filtration and vacuum drying of the filter cake at 50°C yielded 86g of off-white solid. Yield 96%, purity HPLC: 96.5%.

[0068] 2) 6-Benzyloxy-8-{(R)-1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl The preparation of base}-4H-benzo[1,4]oxazin-3-one

[0069] 52.5g (0.178mol) of 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one prepared in step 1), 63g (0.351 mol) 2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamine and 500ml of isopropanol were adde...

Embodiment 2

[0083] The preparation of embodiment 2 olodaterol hydrochloride crystal form B

[0084] Add 5 g of the crude product of olodaterol hydrochloride obtained in Example 1, 50 ml of isopropanol and 5 ml of methanol into the reaction flask, stir, heat up to 50-55 ° C, dissolve, keep stirring for half an hour, cool down to 30 ° C, add The seed crystals prepared in Example 1 were incubated and stirred at 25-30°C for 2 hours, filtered, and the filter cake was vacuum-dried at 50°C to obtain 4.6 g of off-white solid, yield: 92%, purity: 99.7%.

[0085] Adopt Bruker D8 Advance X-ray diffractometer, the product of this embodiment obtains and figure 1 Basically consistent X-ray diffraction pattern (pattern omitted).

[0086] According to the "Chinese Pharmacopoeia" (2005 edition) two appendix XIX J drug hygroscopicity test guidelines to test, measure the hygroscopicity of the olodaterol hydrochloride crystal form B prepared in this example, the result hygroscopicity weight gain 0.33%. M...

Embodiment 3

[0087] The preparation of embodiment 3 olodaterol hydrochloride crystal form B

[0088] Add 4.3 g of the crude product of olodaterol hydrochloride obtained in Example 1, 60 ml of isopropanol and 4 ml of methanol into the reaction flask, stir, heat up to 50-55° C. to dissolve, keep stirring for half an hour, and cool down to 30° C. Add seed crystals, keep stirring at 25-30°C for 2 hours, filter, and vacuum-dry the filter cake at 50°C to obtain 3.8g of off-white solid, yield: 88%, purity: 99.3%.

[0089] Adopt Bruker D8 Advance X-ray diffractometer, the product of this embodiment obtains and figure 1 Basically consistent X-ray diffraction pattern (pattern omitted).

[0090] According to the "Chinese Pharmacopoeia" (2005 edition) two appendix XIX J drug hygroscopicity test guidelines to test, measure the hygroscopicity of the olodaterol hydrochloride crystal form B prepared in this example, the result hygroscopicity weight gain 0.25%. Measured at room temperature, the solubil...

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PUM

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Abstract

The invention relates to a crystalline form B of a long-acting beta 2 adrenergic agonist drug olodaterol hydrochloride and a preparation method thereof, and a pharmaceutical composition containing thecrystalline form B, wherein the crystalline form is characterized by an X-ray diffraction pattern characteristic absorption peak thereof. Compared with the prior art, the crystalline form B of olodaterol hydrochloride provided by the invention is not easy to absorb moisture, remarkably improves stability and is convenient for product quality control; the preparation process is simple, which is beneficial to the cost control in industrial production and has high economic value.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a new crystal form of olodaterol hydrochloride and a preparation method thereof. Background technique [0002] Odaterol hydrochloride, systematic name: 6-hydroxy-8-{(1R)-1-hydroxy-2-{[2-(4-methoxyphenyl)-1,1-dimethylethyl ]amino}ethyl}-4H-benzo[1,4]oxazin-3-one hydrochloride (6-Hydroxy-8-{(1R)-1-hydroxy-2-{[2-(4- methoxyphenyl)-1,1-dimethyl-ethyl]amino}ethyl}-4H-[1,4]-benzoxazin-3-one,,hydrochloride), molecular formula: C 21 h 27 ClN 2 o 5 , molecular weight: 386.44, CAS registration number: 868049-49-4, structural formula as shown in 1 [0003] [0004] Odaterol hydrochloride is a long-acting beta 2 Receptor agonist for patients with chronic obstructive pulmonary disease (COPD). [0005] Publication number CN101817800A (published on September 1, 2010) describes the 6-hydroxyl-8-{1-hydroxyl-2-{[2-(4-methoxy phenyl)-1,1-dimethylethyl]amino}ethyl}-4H-benzo[1,4]oxazin-...

Claims

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Application Information

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IPC IPC(8): C07D265/36A61P11/00A61K31/538
CPCA61P11/00C07D265/36C07B2200/13
Inventor 俞雄张袁伟袁西伦
Owner SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD
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