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Crystal form C of olodaterol hydrochloride 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 inability to obtain stable crystalline products, affect the efficacy of drugs, and difficulties in quality control and preparation work, and achieve improved stability, improved drug efficacy, and improved solubility Effect

Active Publication Date: 2018-11-16
SHANGHAI FANGYU HEALTH PHARMA TECH CO LTD +1
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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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  • Crystal form C of olodaterol hydrochloride and preparation method thereof
  • Crystal form C of olodaterol hydrochloride and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1 Preparation of olodaterol hydrochloride crystal form C

[0064] 1) Preparation of 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one

[0065] 100.6g (0.3mol) of 6-benzyloxy-8-((R)-2-chloro-1-hydroxyl-ethyl-4H-benzo[1,4]-oxazin-3-one and 2L of Add DMF into the reaction flask, stir, cool down in an ice bath, and drop to 0°C, add 400ml of 2N aqueous sodium hydroxide solution, keep it at 0-5°C for four hours, pour the reaction solution into ice water, and stir at 0-5°C After 1 hour, filter and vacuum-dry the filter cake at 50° C. to obtain 86 g of off-white solid. Yield 96%, purity HPLC: 96.5%.

[0066] 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

[0067] 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 added to the reaction ...

Embodiment 2

[0078] Example 2 Preparation of olodaterol hydrochloride crystal form C

[0079] Add 6 g of the crude product of olodaterol hydrochloride obtained in Example 1, 45 ml of isopropanol and 3 ml of methanol into the reaction flask, stir, heat up to 45-50° C. to dissolve, keep stirring for half an hour, cool down to 20° C., 20° C. Stir at ~25°C for 24 hours, filter, and vacuum-dry the filter cake at 50°C to obtain 5.4 g of off-white solid, yield: 90%, purity: 99.4%.

[0080] Adopt Bruker D8Advance X-ray diffractometer, the product of present embodiment obtains and figure 1 Basically consistent X-ray diffraction pattern (pattern omitted).

[0081] According to the "Chinese Pharmacopoeia" (2005 edition) two appendix XIX J drug hygroscopicity test guidelines, the hygroscopicity of the olodaterol hydrochloride crystal form C prepared in this example was measured, and the hygroscopicity weight gain was 0.23%. Measured at room temperature, the solubility of crystal C in water is 1050...

Embodiment 3

[0082] Example 3 Preparation of olodaterol hydrochloride crystal form C

[0083] Add 5.3 g of the crude product of olodaterol hydrochloride obtained in Example 1, 70 ml of isopropanol and 10 ml of methanol into the reaction flask, stir, heat up to 45-50° C. to dissolve, keep stirring for half an hour, and cool down to 25° C. Stir at 20-25°C for 15 hours, filter, and vacuum-dry the filter cake at 50°C to obtain 4.8 g of off-white solid, yield: 91%, purity: 99.3%.

[0084] Adopt Bruker D8Advance X-ray diffractometer, the product of present embodiment obtains and figure 1 Basically consistent X-ray diffraction pattern (pattern omitted).

[0085] According to the "Chinese Pharmacopoeia" (2005 edition) two appendix XIX J drug hygroscopicity test guidelines, the hygroscopicity of the olodaterol hydrochloride crystal form C prepared in this example was measured, and the hygroscopicity weight gain was 0.21%. Measured at room temperature, the solubility of crystal C in water is 105...

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Abstract

The invention relates to a crystal form C of a long-acting beta2 adrenergic agonist olodaterol hydrochloride and a preparation method thereof and a pharmaceutical composition containing the crystal form C. The crystal form is represented by the characteristic absorption peak of X-ray diffraction pattern. In comparison with the prior art, the crystal form C of olodaterol hydrochloride is not easy to absorb moisture, stability is remarkably raised, and the quality of the product is convenient to control; and the preparation technology is simple, is beneficial to cost control in the 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-3...

Claims

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Application Information

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