CN105646247A - Fesoterodine compound - Google Patents

Abstract

The invention belongs to the technical field of medicines and particularly relates to a fesoterodine compound and a preparation method therefor. A fesoterodine crystal prepared by the preparation method has the advantages of high purity and good stability. The invention also relates to an application of the fesoterodine compound in the preparation of drugs for treating overactive bladder.

Description

A kind of fesoterodine compound

Technical field

The invention belongs to medical art, be specifically related to fesoterodine compound and its preparation method, the present invention also relates to the application used in this kind of fesoterodine composition treatment overactive bladder medicine.

Background technology

Fumaric acid fesoterodine (fesoterodinefumarate/Toviaz) is an overactive bladder treatment new drug of Pfizer company exploitation, obtains U.S. FDA approval in October, 2008. Fumaric acid fesoterodine belongs to prodrug, is 5-hydroxymethyl tolterodine (5-HMT) through rapid hydrolysis in blood after oral, and the latter is also the active metabolite of tolterodine.

The Chinese another name of fesoterodine: isopropylformic acid 2-[(1R)-3-(diisopropylaminoethyl)-1-phenyl propyl]-4-(hydroxymethyl) phenyl ester.

Structural formula is as follows:

In research process, repeating the method for prior art, the fesoterodine impurity number obtained is more, and total impurities is higher. The fesoterodine that the present invention obtains, the advantage having: purity height, maximum contaminant is less than 1 ��; Good stability.

Summary of the invention

One object of the present invention, discloses a kind of fesoterodine compound crystal.

Another object of the present invention, discloses the preparation method of fesoterodine compound crystal.

Another object of the present invention, discloses the pharmaceutical composition of fesoterodine.

The invention also discloses the compound crystal of fesoterodine in the application manufactured in treatment overactive bladder medicine.

Now content of the present invention is specifically described by object in conjunction with the present invention.

The present invention provides a kind of fesoterodine compound, this fesoterodine compound crystal, adopts 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 ��) and D value are as follows,

In the present invention, the mensuration of 2 �� values uses light source, and precision is �� 0.2 ��, therefore represents above-mentioned got value and has allowed certain reasonably limit of error, and its limit of error is �� 0.2 ��.

Another object of the present invention, discloses the preparation method of fesoterodine compound crystal,

Document is reported, fesoterodine 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 bigger. The present inventor is by a large amount of experiments, explore the relationship between quality of refining solvent with the fesoterodine crystal obtained, by fesoterodine is dissolved in alcohol, acetic acid heated in water solution, then add and lower the temperature stage by stage, obtain the preparation method of fesoterodine compound crystal of the present invention. Wondrously, the advantage that this fesoterodine compound crystal has: purity height, maximum contaminant is less than 1 ��; Good stability.

This preparation method screens from a large amount of single or mixed solvents, it does not have method can be instructed and be drawn.The partial solvent tested has, water; Methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, propylene glycol etc.; The ketone class reagent such as acetone; The ether class reagent such as ether and diisopropyl ether; Ester class, such as ethyl acetate, methyl acetate, isopropyl acetate, butylacetate, ethyl butyrate, methyl-butyrate etc.; Acetonitrile; Methylene dichloride, trichloromethane, hexane, heptane, toluene, tetrahydrofuran (THF), DMF etc. Using the single of them or mixed solvent, mixed solvent can be two kinds, and three kinds or four kinds of solvent mixing, in mixed solvent, the ratio of all kinds of SOLVENTS is different.

Specifically comprise the following steps: in the mixed solution that fesoterodine adds 5-7 times of (weightmeasurement ratio) alcohol, acetic acid water=4-6:0.5-1:1-2, it is heated to 40 DEG C-45 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3-4 hour, 10 DEG C-15 DEG C, then it is incubated 3-4 hour, crystallization, filtering, namely drying obtains above-mentioned fesoterodine compound crystal.

Fesoterodine used, according to the method synthesis that existing document provides, the chemical structure of the fesoterodine of synthesis is through proton nmr spectra, and ultimate analysis, proves that chemical structure is correct.

Another object of the present invention, it provides comprise the composition of the fesoterodine of fesoterodine compound crystal and one or more pharmaceutically acceptable carriers composition.

The 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 arbitrarily 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 fesoterodine compound crystal in the application manufactured in treatment overactive bladder medicine.

Stability test

The chemical stability of the fesoterodine compound crystal of the present invention has been studied by contriver, investigation condition is high temperature (60 DEG C �� 2 DEG C), strong illumination (4500Lx �� 500lx), high by wet (92.5%, RH) inspection target is outward appearance, content and have 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.

Fesoterodine 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, adding ethanol-acetic acid-water (4:0.5:1) mixed solution of 200 grams of fesoterodines and 1200ml, start stirring, heat temperature raising is heated to 40 DEG C-45 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3 hours, 10 DEG C-15 DEG C, then it is incubated 3 hours, crystallization, filtering, namely drying obtains above-mentioned fesoterodine 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, adding ethanol-acetic acid-water (6:1:2) mixed solution of 200 grams of fesoterodines and 1400ml, start stirring, heat temperature raising is heated to 40 DEG C-45 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3 hours, 10 DEG C-15 DEG C, then it is incubated 3 hours, crystallization, filtering, namely drying obtains above-mentioned fesoterodine compound crystal, 172 grams. Purity 99.90%, optical isomer 0.06%.

Claims (6)

1. fesoterodine compound shown in formula I,

(I)

The crystal of described fesoterodine compound, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 �� diffraction angle and D value,

The error of 2 �� diffraction angle is �� 0.2.

2. the preparation method of fesoterodine compound crystal described in claim 1, by being dissolved in alcohol, acetic acid heated in water solution by fesoterodine, then cooling obtains stage by stage.

3. the preparation method of fesoterodine compound crystal described in claim 2, it is characterized in that in the mixed solution comprising the following steps: that fesoterodine adds 5-7 times of (weightmeasurement ratio) alcohol, acetic acid water=4-6:0.5-1:1-2, it is heated to 40 DEG C-45 DEG C, filtered while hot, filtrate 30 DEG C-35 DEG C insulation 3-4 hour, 10 DEG C-15 DEG C, it is incubated 3-4 hour again, crystallization, filters, and namely drying obtains above-mentioned fesoterodine compound crystal.

4. the composition of the fesoterodine formed containing fesoterodine compound crystal described in claim 1 and one or more pharmaceutically acceptable carriers.

5. composition according to claim 4, it is characterised in that said composition is for the preparation of oral preparations.

6. fesoterodine compound described in claim 1 is in the application manufactured in treatment overactive bladder medicine.