CN105566246A - Mirabegron compound - Google Patents
Mirabegron compound Download PDFInfo
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- CN105566246A CN105566246A CN201410628819.2A CN201410628819A CN105566246A CN 105566246 A CN105566246 A CN 105566246A CN 201410628819 A CN201410628819 A CN 201410628819A CN 105566246 A CN105566246 A CN 105566246A
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- Prior art keywords
- mirabegron
- compound
- preparation
- compound crystal
- composition
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- 229960001551 mirabegron Drugs 0.000 title claims abstract description 44
- -1 Mirabegron compound Chemical class 0.000 title claims abstract description 25
- 239000013078 crystal Substances 0.000 claims abstract description 20
- PBAPPPCECJKMCM-IBGZPJMESA-N mirabegron Chemical compound S1C(N)=NC(CC(=O)NC=2C=CC(CCNC[C@H](O)C=3C=CC=CC=3)=CC=2)=C1 PBAPPPCECJKMCM-IBGZPJMESA-N 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 239000003814 drug Substances 0.000 claims abstract description 8
- 206010020853 Hypertonic bladder Diseases 0.000 claims abstract description 7
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims abstract description 7
- 208000020629 overactive bladder Diseases 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 7
- ZMBWDDDYLYNBHS-UHFFFAOYSA-N acetic acid;propan-2-one;hydrate Chemical compound O.CC(C)=O.CC(O)=O ZMBWDDDYLYNBHS-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 229910016523 CuKa Inorganic materials 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000005259 measurement Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 1
- 239000000843 powder Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000126 substance Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940120393 myrbetriq Drugs 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention belongs to the technical field of medicines and particularly relates to a Mirabegron compound and a preparation method thereof. A Mirabegron crystal obtained by the method has the advantages of being high in purity and good in stability. The invention further relates to application of the Mirabegron compound to preparation of a drug for treating overactive bladder.
Description
Technical field
The invention belongs to medical art, be specifically related to Mirabegron compound and preparation method thereof, the invention still further relates to the application used in this Mirabegron composition treatment overactive bladder medicine.
Background technology
Mirabegron (Myrbetriq, Mirabegron) is that FDA (Food and Drug Adminstration) (FDA) ratifies on June 28th, 2012 and is used for the treatment of the medicine of overactive bladder (OAB).
Structural formula is as follows:
In research process, repeat the method for prior art, the Mirabegron impurity number obtained is more, and total impurities is higher.The Mirabegron that the present invention obtains, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability.
Summary of the invention
One object of the present invention, discloses a kind of Mirabegron compound crystal.
Another object of the present invention, discloses the preparation method of Mirabegron compound crystal.
Another object of the present invention, discloses the pharmaceutical composition of Mirabegron.
The compound crystal that the invention also discloses Mirabegron is manufacturing the application in treatment overactive bladder medicine.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of Mirabegron compound, this Mirabegron compound crystal, adopt D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: CuKa target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value as follows,
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Another object of the present invention, discloses the preparation method of Mirabegron compound crystal,
Bibliographical information, Mirabegron has multiple preparation method, and because its process for purification is different, fusing point has relatively big difference; Quantity and the total amount of impurity are larger.The present inventor is by a large amount of experiments, explore refining solvent and the relationship between quality of Mirabegron crystal obtained, by Mirabegron is dissolved in acetone-acetic acid-heated in water solution, then add and lower the temperature stage by stage, obtain the preparation method of Mirabegron compound crystal of the present invention.Astoundingly, the advantage that has of this Mirabegron compound crystal: purity is high, and maximum contaminant is less than 1 ‰; Good stability.
This preparation method screens from a large amount of single or mixed solvents, does not have method to instruct and draws.The partial solvent of testing has, water; Methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, propylene glycol etc.; The ketone reagent such as acetone; The ethers such as ether and diisopropyl ether reagent; Ester class, as ethyl acetate, methyl acetate, isopropyl acetate, butylacetate, ethyl butyrate, methyl-butyrate etc.; Acetonitrile; Methylene dichloride, trichloromethane, hexane, heptane, toluene, tetrahydrofuran (THF), DMF etc.Use the single of them or mixed solvent, mixed solvent can be two kinds, three kinds or four kinds of solvent, and in mixed solvent, the ratio of all kinds of SOLVENTS is different.
Specifically comprise the following steps: that Mirabegron adds in the mixed solution of 2-3 times of (weight or measurement (WM) ratio) acetone-acetic acid-water=5-9:0.5-1:1-2, be heated to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3-4 hour, 10 DEG C-15 DEG C, then be incubated 3-4 hour, crystallization, filter, namely drying obtains above-mentioned Mirabegron compound crystal.
Mirabegron used, according to the method synthesis that existing document provides, the chemical structure of the Mirabegron of synthesis is through proton nmr spectra, and ultimate analysis, proves that chemical structure is correct.
Another object of the present invention, provides the composition comprising the Mirabegron that Mirabegron compound crystal and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 50%(weight of composition).
Present invention also offers Mirabegron compound crystal and manufacture the application in treatment overactive bladder medicine.
stability test
The chemical stability of contriver to Mirabegron compound crystal of the present invention is studied, investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), high humidity (92.5%, RH) inspection target is outward appearance, content and related substance (optical isomer).
Outward appearance, content is without remarkable change.
Result: from 0-10 days under high light, high temperature, super-humid conditions, outward appearance, optical isomer, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Mirabegron used in the present invention, according to the method synthesis that existing document provides, its chemical structure is through proton nmr spectra, ultimate analysis confirmation.
embodiment 1
In the 3000ml reaction flask that stirring, thermometer, condenser are housed, add acetone-acetic acid-water (5:0.5:1) mixed solution of 200 grams of Mirabegrons and 400ml, start stirring, heat temperature raising is heated to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3 hours, 10 DEG C-15 DEG C, then be incubated 3 hours, crystallization, filter, namely drying obtains above-mentioned Mirabegron compound crystal, 172.6 grams.Purity 99.94%, optical isomer 0.05%.
embodiment 2
In the 3000ml reaction flask that stirring, thermometer, condenser are housed, add acetone-acetic acid-water (9:1:2) mixed solution of 200 grams of Mirabegrons and 600ml, start stirring, heat temperature raising is heated to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3 hours, 10 DEG C-15 DEG C, then be incubated 3 hours, crystallization, filter, namely drying obtains above-mentioned Mirabegron compound crystal, 172 grams.Purity 99.90%, optical isomer 0.06%.
Claims (6)
1. Mirabegron compound shown in formula I,
（Ⅰ）
The crystal of described Mirabegron compound, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and D value,
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of Mirabegron compound crystal described in claim 1, by Mirabegron being dissolved in acetone-acetic acid-heated in water solution, then cooling obtains stage by stage.
3. the preparation method of Mirabegron compound crystal described in claim 2, it is characterized in that comprising the following steps: that Mirabegron adds in the mixed solution of 2-3 times of (weight or measurement (WM) ratio) acetone-acetic acid-water=5-9:0.5-1:1-2, be heated to 50 DEG C-55 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3-4 hour, 10 DEG C-15 DEG C, be incubated 3-4 hour again, crystallization, filter, namely drying obtains above-mentioned Mirabegron compound crystal.
4. the composition of the Mirabegron formed containing Mirabegron compound crystal described in claim 1 and one or more pharmaceutically acceptable carriers.
5. composition according to claim 4, is characterized in that said composition is for the preparation of oral preparations.
6. the application of Mirabegron compound described in claim 1 in the medicine manufacturing treatment overactive bladder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410628819.2A CN105566246A (en) | 2014-11-11 | 2014-11-11 | Mirabegron compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410628819.2A CN105566246A (en) | 2014-11-11 | 2014-11-11 | Mirabegron compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105566246A true CN105566246A (en) | 2016-05-11 |
Family
ID=55876945
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410628819.2A Pending CN105566246A (en) | 2014-11-11 | 2014-11-11 | Mirabegron compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105566246A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112745276A (en) * | 2019-10-31 | 2021-05-04 | 四川国为制药有限公司 | Crystallization method of mirabegron |
-
2014
- 2014-11-11 CN CN201410628819.2A patent/CN105566246A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112745276A (en) * | 2019-10-31 | 2021-05-04 | 四川国为制药有限公司 | Crystallization method of mirabegron |
| CN112745276B (en) * | 2019-10-31 | 2023-10-03 | 四川国为制药有限公司 | Crystallization method of milbegron |
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Legal Events
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| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160511 |