KR20180023419A - Novel salt of (r)-(1-methylpyrrolidin -3-yl)methyl(3'-chloro-4'-fluoro-[1,1'-biphenyl]-2-yl)carbamate and crystalline forms thereof - Google Patents

Abstract

The present invention relates to novel salt of (R)-(1-methylpyrrolidin -3-yl)methyl(3′-chloro-4′-fluoro-[1,1′-biphenyl]-2-yl)carbamate and a crystalline form thereof. Additionally, the novel salt of (R)-(1-methylpyrrolidin -3-yl)methyl(3′-chloro-4′-fluoro-[1,1′-biphenyl]-2-yl)carbamate and the crystalline form thereof according to an embodiment of the present invention have remarkably improved stability, hygroscopicity and solubility.

Description

(3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate of the general formula (I) CARBAMATE AND CRYSTALLINE FORMS THEREOF (3'-CHLORO-4'-FLUORO- [1,1'-BIPHENYL] -2-YL) CARBAMATE AND CRYSTALLINE FORMS THEREOF}

The present invention relates to a novel (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] Salts and crystalline forms thereof.

Muscarinic receptors are found throughout the body from the human brain to the salivary glands, which are members of G-protein coupled receptors and are subdivided into five subtypes, from M1 to M5. Of these, the M1, M2, and M3 receptors have been extensively characterized for their pharmacological properties in animal and human tissues. Muscarinic M1 receptors are mainly expressed in the cerebral cortex and are involved in the regulation of high levels of cognitive function. M2 receptors are predominant in the heart and bladder smooth muscle and are involved in heart rate modulation. M3 receptors are widely expressed in many peripheral tissues and are known to be involved in gastrointestinal and urinary tract stimulation and salivation. The M4 and M5 receptors are present in the brain, and the M4 receptors are mainly involved in exercise, but little is known about the role of M5 receptors.

In general, muscarinic receptor antagonists are useful in the treatment of a variety of diseases, such as chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, Spasmodic colitis, chronic cystitis Alzheimer ' s disease, senile dementia, glaucoma, schizophrenia, gastroesophageal reflux disease, cardiac arrhythmia, arrhythmia, and hyper salvation syndromes. Drugs Future, 1997, 22 (2) 135-137, Drugs Future, 1996, 21 (11), 1105-1108, 1997, Drugs Future, 1997, 22 (7), 733-737).

It is also known that M2 and M3 are dominant among the muscarinic receptor subtypes in the human bladder, and they play a role in controlling the bladder contraction mechanism. The M2 receptor is more than three times more abundant in the bladder than the M3 receptor, but it plays a role in inhibiting bladder relaxation through the beta receptor rather than directly involved in the bladder contraction. The receptors that play a major role in bladder contraction are the M3 receptor . Thus, the selective antagonist of the M3 receptor exhibits an excellent inhibitory effect on muscarinic bladder contraction, while at the same time inhibiting salivation, thereby inducing edema.

Korean Patent Laid-Open Publication No. 2015-0014673 discloses that (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate.

(A)

On the other hand, in order to be considered as a candidate substance for development as a drug, a compound must possess not only desirable biological properties but also properties enabling its use in the production of pharmaceutical compositions. In particular such compounds should form stable, preferably crystalline solids that are readily prepared and formulated.

However, the compound of formula (A) is not suitable for development as a pharmaceutical agent as a foam or an oil compound, and has a disadvantage that handling is not easy industrially. Thus, the present inventors have found that (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- [1,1'-biphenyl] -2-yl) carbamate and its crystal polymorphism. As a result, it was found that (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate and a crystal form thereof were completed.

Korean Patent Publication No. 2015-0014673

It is an object of the present invention to provide a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- Biphenyl] -2-yl) carbamate and crystal forms thereof.

In order to achieve the above object, the inventors of the present invention have found that (R) - (1-methylpyrrolidone) having improved stability of the product, (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate and its crystalline form.

Hereinafter, the present invention will be described in detail.

Whenever a component is referred to as "comprising ", it is understood that it may include other components as well, without departing from the other components unless specifically stated otherwise.

The present invention relates to (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- Yl) carbamate oxalate.

[Chemical Formula 1]

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate The salt is crystalline. Specifically, the oxalate salt of the present invention may exist in crystalline form I to crystalline form VIII, and the present invention provides crystalline Form I to crystalline Form VIII.

The term "crystalline" as used herein means a crystalline solid, i.e., a crystalline solid that is not a solvate, that does not contain a molar ratio of solvent molecules substantially fixed in the crystal lattice.

Crystal form I

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] Crystal form I is provided.

In one embodiment of the invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ The crystalline Form I of the carbamate oxalate salt is characterized in that the X-ray powder diffraction pattern has three diffractograms selected from the group consisting of diffraction angle 2θ of 13.402 ± 0.2 °, 14.300 ± 0.2 °, 18.519 ± 0.2 °, 19.577 ± 0.2 ° and 21.499 ± 0.2 ° Or more.

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ ) Crystal Form I of the carbamate oxalate comprises diffraction peaks at diffraction angle 2? Of the X-ray powder diffraction pattern of 13.402 ± 0.2 °, 14.300 ± 0.2 °, 18.519 ± 0.2 °, 19.577 ± 0.2 ° and 21.499 ± 0.2 °.

In another embodiment, the present invention provides a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ 2-yl) carbamate oxalate has an X-ray powder diffraction pattern of 7.182 0.2, 8.379 0.2, 8.679 0.2, 11.180 0.2, 16.320 0.2, 16.659 0.2, 17.321 0.2 20.632 ± 0.2 °, 22.180 ± 0.2 °, 22.922 ± 0.2 °, 23.339 ± 0.2 °, 24.019 ± 0.2 °, 24.297 ± 0.2 °, 24.699 ± 0.2 °, 25.441 ± 0.2 °, 27.239 ± 0.2 And a diffraction angle 2 &thetas; of 29.880 +/- 0.2 DEG.

In another embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ -2-yl) carbamate oxalate can be substantially the same as the peak position of FIG. 1 in the X-ray powder diffraction pattern.

In another embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Crystalline form I of the carbamate oxalate salt has an onset of 121.85 ° C (± 0.5 ° C) and a temperature of 126.96 ° C (± 0.5 ° C) in a differential scanning calorimetry (DSC) analysis at a heating rate of 20 ° C / And has an endothermic peak. More preferably, the DSC endothermic peak can substantially coincide with that shown in Fig.

Crystal form II

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] To provide crystal form II.

In one embodiment of the present invention, there is provided a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ The crystalline Form II of carbamate oxalate is characterized in that the X-ray powder diffraction pattern has three diffractograms selected from the group consisting of 13.439 ± 0.2 °, 14.481 ± 0.2 °, 18.501 ± 0.2 °, 21.779 ± 0.2 ° and 23.358 ± 0.2 ° diffraction angle 2θ Or more.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Crystalline Form II of carbamate oxalate includes diffraction peaks at diffraction angle 2? Of 13.439 ± 0.2 °, 14.481 ± 0.2 °, 18.501 ± 0.2 °, 21.779 ± 0.2 ° and 23.358 ± 0.2 °.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate crystal form II has an X-ray powder diffraction pattern of 8.360 + -0.2, 11.340 + 0.2, 16.401 + 0.2, 16.739 + 0.2, 17.360 + 0.2, 17.938 + 0.2, 22.179 + 0.2 , At least one diffraction peak selected from the group consisting of diffraction angles 2θ of 24.299 ± 0.2 °, 24.641 ± 0.2 °, 25.500 ± 0.2 °, 26.422 ± 0.2 °, 27.260 ± 0.2 °, 28.201 ± 0.2 ° and 29.878 ± 0.2 ° .

In another embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ -2-yl) carbamate oxalate, the peak position of the X-ray powder diffraction pattern may substantially coincide with the peak position of FIG.

In another embodiment of the present invention, the crystalline form II is a crystalline form of the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- -Biphenyl] -2-yl) carbamate oxalate has an onset temperature of 127.39 ° C (± 0.5 ° C) and a temperature of 130.20 ° C (-10 ° C) in a differential scanning calorimetry (DSC) analysis at a heating rate of 20 ° C / ± 0.5 ° C.). More preferably, the DSC endothermic peak can substantially coincide with that shown in Fig.

Crystal form III

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] To provide crystal form III.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate is characterized in that the X-ray powder diffraction pattern is selected from the group consisting of diffraction angle 2? Of 10.720 ± 0.2 °, 11.018 ± 0.2 °, 14.239 ± 0.2 °, 17.880 ± 0.2 ° and 21.440 ± 0.2 ° Or more diffraction peaks.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Crystalline Form III of carbamate oxalate contains diffraction peaks at diffraction angle 2? Of the X-ray powder diffraction pattern of 10.720 占 0.2 占 11.018 占 0.2 占 14.239 占 0.2 占 17.880 占 0.2 占 and 21.440 占 0.2 占.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- Crystalline Form III of carbamate oxalate has an X-ray powder diffraction pattern of 8.700 0.2, 13.098 0.2, 14.959, 0.2 0.2, 15.382 0.2, 16.701 0.2, 17.309 0.2, 18.680 0.2 Diffraction angles 2 &thetas; &thetas;, 19.561 +/- 0.2 DEG, 20.560 +/- 0.2 DEG, 22.042 +/- 0.2 DEG, 22.762 +/- 0.2 DEG, 23.940 +/- 0.2 DEG, 24.141 +/- 0.2 DEG, 26.855 +/- 0.2 DEG, 27.379 +/- 0.2 DEG, ≪ / RTI > and at least one diffraction peak selected from the group consisting of < RTI ID = 0.0 >

In another embodiment of the present invention there is provided a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ -Yl) carbamate oxalate, the peak position of the X-ray powder diffraction pattern may substantially coincide with the peak position of FIG.

In another embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ 2-yl) carbamate oxalate salt crystals had an onset of 123.68 ° C (± 0.5 ° C) and a temperature of 128.37 ° C (± 0.5 ° C) in a differential scanning calorimetry (DSC) analysis at a heating rate of 20 ° C / And has an endothermic peak. More preferably, the DSC endothermic peak can substantially coincide with that shown in Fig.

Crystalline form IV

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] Crystal form IV.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate crystal form IV is characterized in that the X-ray powder diffraction pattern has a diffraction angle? Of 3 from a group consisting of diffraction angle 2? Of 16.642 ± 0.2 °, 17.839 ± 0.2 °, 20.981 ± 0.2 °, 21.580 ± 0.2 ° and 22.701 ± 0.2 ° Or more diffraction peaks.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Crystalline Form IV of carbamate oxalate includes diffraction peaks at diffraction angle 2 &thetas; of the X-ray powder pattern of 16.642 0.2, 17.839 0.2, 20.981 0.2, 21.580 0.2 and 22.701 0.2.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate crystal form IV shows that the X-ray powder diffraction pattern is 8.355 ± 0.2 °, 11.415 ± 0.2 °, 13.419 ± 0.2 °, 13.956 ± 0.2 °, 15.619 ± 0.2 °, 18.579 ± 0.2 °, 23.219 ± 0.2 ° , 24.720 占 0.2 占 26.478 占 0.2 占 27.195 占 0.2 占 28.143 占 0.2 占 and 29.172 占 0.2 占 The diffraction angle 2θ is further comprised of one or more diffraction peaks selected from the group consisting of:

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate, the peak position of the X-ray powder diffraction pattern may substantially coincide with the peak position of FIG.

In another embodiment of the present invention, the crystalline Form IV is prepared by reacting the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- 2-yl) carbamate oxalate salt crystals have an onset of 120.60 ° C (± 0.5 ° C) and a temperature of 126.88 ° C (± 0.5 ° C) in a differential scanning calorimetry (DSC) analysis at a heating rate of 20 ° C / Lt; 0 > C). More preferably, the DSC endothermic peak may substantially coincide with that shown in Fig.

Crystal form V

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] Crystal form V is provided.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate crystal form V is characterized in that the X-ray powder diffraction pattern has three or more diffraction peaks selected from the group consisting of diffraction angle 2 &thetas; 10.925 +/- 0.2 DEG, 14.200 +/- 0.2 DEG, 20.559 +/- 0.2 DEG and 21.396 +/- 0.2 DEG .

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ ) Crystal Form V of carbamate oxalate contains diffraction peaks at diffraction angle 2 &thetas;, where the X-ray powder diffraction pattern is 10.925 +/- 0.2 DEG, 14.200 +/- 0.2 DEG, 20.559 +/- 0.2 DEG and 21.396 +/- 0.2 DEG.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- - yl) carbamate oxalate crystal form V has an X-ray powder diffraction pattern with diffraction angles 2θ of 7.049 ± 0.2 °, 8.592 ± 0.2 °, 16.081 ± 0.2 °, 17.226 ± 0.2 °, 17.840 ± 0.2 ° and 19.565 ± 0.2 ° And at least one diffraction peak selected from the group consisting of

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Crystal form V of a) carbamate oxalate can substantially match the peak position of the X-ray powder diffraction pattern with the peak position of FIG.

Crystal form VI

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] Crystal form VI.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate crystal form VI is characterized in that the X-ray powder diffraction pattern has three or more diffraction peaks selected from the group consisting of diffraction angle 2? Of 10.127 ± 0.2 °, 10.893 ± 0.2 °, 11.751 ± 0.2 ° and 17.978 ± 0.2 ° .

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ ) ≪ / RTI > crystal form VI of carbamate oxalate contains diffraction peaks at diffraction angle 2 &thetas;, where the X-ray powder diffraction pattern is 10.127 +/- 0.2 DEG, 10.893 +/- 0.2 DEG, 11.751 +/- 0.2 DEG and 17.978 +/- 0.2 DEG.

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ ) Crystal form VI of carbamate oxalate is characterized in that the X-ray powder diffraction pattern is one or more selected from the group consisting of 7.150 0.2, And further includes a diffraction peak.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate, the peak position of the X-ray powder diffraction pattern may substantially coincide with the peak position of FIG.

Crystal form VII

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] To provide crystalline Form VII.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate crystal form VII is characterized in that the X-ray powder diffraction pattern has three or more diffraction peaks selected from the group consisting of the diffraction angle 2? Of 8.169 ± 0.2 °, 8.847 ± 0.2 °, 11.071 ± 0.2 ° and 13.156 ± 0.2 ° .

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Yl) carbamate oxalate includes X-ray powder diffraction patterns having diffraction peaks at diffraction angle 2? Of 8.169 0.2, 8.847 0.2, 11.071 0.2 and 13.156 0.2.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate is characterized in that the X-ray powder diffraction pattern is characterized by a diffraction angle 2 &thetas; of from 13.3454 +/- 0.2 DEG, 14.220 +/- 0.2 DEG, 15.828 +/- 0.2 DEG, 16.486 +/- 0.2 DEG and 17.186 +/- 0.2 DEG diffraction angle 2 & And more than two diffraction peaks. Specifically, a crystalline form of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] VII can have the peak position of the X-ray powder diffraction pattern substantially coincident with the peak position of FIG.

Crystal form VIII

The present invention relates to the use of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] To provide crystalline Form VIII.

In one embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- -Yl) carbamate oxalate crystals comprise at least three diffraction peaks selected from the group consisting of diffraction angle 2? Of the linear powder diffraction pattern of 8.903 ± 0.2 °, 13.090 ± 0.2 °, 14.347 ± 0.2 ° and 15.871 ± 0.2 ° do.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Yl) carbamate oxalate includes diffraction peaks at a diffraction angle 2? Of 8.903 ± 0.2 °, 13.090 ± 0.2 °, 14.347 ± 0.2 ° and 15.871 ± 0.2 ° in the X-ray powder diffraction pattern.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ The crystalline form VIII of the carbamate oxalate salt is one in which the X-ray powder diffraction pattern is one selected from the group consisting of diffraction angle 2? Of 6.720 ± 0.2 °, 10.646 ± 0.2 °, 11.683 ± 0.2 °, 13.490 ± 0.2 ° and 17.941 ± 0.2 ° Or more. Specifically, a solution of the above (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate Crystal form VIII can have the peak position of the X-ray powder diffraction pattern substantially coincident with the peak position of FIG.

Method for preparing crystal form I to crystal form VIII

The present invention relates to a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- In acetone; Adding oxalic acid to the solution and stirring; And (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- Phenyl] -2-yl) carbamate oxalate < / RTI >

In another embodiment of the present invention, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ -2-yl) carbamate oxalate as an organic solvent.

More particularly, the present invention relates to a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ The step of recrystallizing oxalate crystal form I with one or more solvents selected from the group consisting of an alcohol solvent, an ether solvent, an ester solvent, a ketone solvent, a halogenated hydrocarbon solvent, a nitrile solvent and a hydrocarbon solvent (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate There is provided a process for producing any one of the salt crystal form II to VIII.

More specifically, the present invention relates to a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- Carbamate oxalate crystalline form I in dichloromethane; Acetone; Heptane; Methyl ethyl ketone; Acetonitrile; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, 1'-biphenyl] -2-yl) carbamate oxalate crystals II.

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ In the process for producing the carbamate oxalate crystal type II, the step of recrystallizing with the recrystallization solvent may further include a step of adding a recrystallization solvent and centrifugation.

The present invention also relates to a process for preparing (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [ Mate oxalate crystalline form I in ethanol; Methyl-t-butyl ether; Heptane; 1,4-dioxane; Isopropyl acetate; Dichloromethane; Isopropanol; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, 1'-biphenyl] -2-yl) carbamate oxalate crystal Form III.

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ The step of recrystallizing with the recrystallization solvent in the production method of the carbamate oxalate crystal type III may further include a step of adding a recrystallization solvent, stirring, and then centrifuging.

The present invention also relates to a process for preparing (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [ (3'-chloro-4'-fluoro-[1 < RTI ID = 0.0 > , 1'-biphenyl] -2-yl) carbamate oxalate crystal form IV.

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ In the process for producing the carbamate oxalate crystal type IV, the step of recrystallizing with the recrystallization solvent may further include a step of adding a recrystallization solvent and centrifugation.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1 '-Biphenyl] -2-yl) carbamate oxalate salt crystal form V.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ ) ≪ / RTI > (3 ' -chloro-4 ' - fluoro- [ -Biphenyl] -2-yl) carbamate oxalate < / RTI >

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Yl) carbamate oxalate crystal form II in ethanol; benzene; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, Apos; -biphenyl] -2-yl) carbamate oxalate < / RTI >

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ The step of recrystallizing from the recrystallization solvent in the production method of the carbamate oxalate crystal type VII may include the step of sequentially adding the recrystallization solvent.

In another embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Yl) carbamate oxalate crystal form II in ethanol; benzene; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, Apos; -biphenyl] -2-yl) carbamate oxalate crystal form VIII.

In one embodiment, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ In the process for preparing the carbamate oxalate crystal form VIII, the recrystallization with the recrystallization solvent may include the step of sequentially adding the recrystallization solvent.

The kind of the solvent, the temperature at the time of dissolution, the humidity, the order of the solvent to be introduced when two or more solvents are used, the drying temperature, and the like can be controlled according to the type of the crystal form to be obtained.

 (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate salt.

In another embodiment of the present invention, the above-mentioned (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ -2-yl) carbamate oxalate as an active ingredient.

The above (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] And specifically (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate Oxalate I to VIII.

In the present invention, the muscarinic M3 receptor antagonist may be used for the treatment of chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic a disease such as diarrhea, colitis, chronic cystitis, Alzheimer disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, Hyper salivation syndromes may be compositions for the prevention or treatment of diseases selected from the group consisting of enuresis, neurogenic urinary frequency, neurogenic bladder, unstable bladder, bladder spasm and frequency.

In one embodiment of the present invention, the muscarinic M3 antagonist is selected from the group consisting of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- -Biphenyl] -2-yl) carbamate oxalate, one or more of the active ingredients exhibiting the same or similar function may be further contained.

In addition, in one embodiment of the present invention, in addition to the above-described effective ingredients for administration, the present invention is further prepared by incorporating one or more pharmaceutically acceptable carriers, and pharmaceutically acceptable carriers include saline, sterilized A buffered saline solution, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and one or more of these components may be mixed and used. If necessary, other conventional additives such as an antioxidant, a buffer, and a bacteriostatic agent may be added . In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Further, it can be suitably formulated according to each disease or ingredient according to a suitable method in the art or using a method disclosed in Remington's Pharmaceutical Science, Merck Publishing Company, Easton PA.

In the present invention, the pharmaceutical composition can be administered orally or parenterally in the form of injections, suppositories, transdermal preparations, inhalants or intravesical administration.

In addition, when the muscarinic M3 receptor antagonist of the present invention is used for oral administration, (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- , 1'-biphenyl] -2-yl) carbamate oxalate may be contained in the formulation in an amount of 0.1 wt% to 95 wt%.

The present invention also relates to a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ There is provided a method of treating or alleviating a disease caused by a decrease in the muscarinic M3 receptor effect by administering a muscarinic M3 receptor antagonist containing carbamate oxalate as an active ingredient to a mammal including a mammal requiring a muscarinic M3 receptor antagonistic effect do.

The muscarinic M3 receptor antagonists of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the prevention and treatment of diseases caused by degradation of muscarinic M3 receptor effect .

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate Oxalate can be prepared by reacting (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [ It is a crystalline form that has a relatively high melting point, low hygroscopicity, and allows rapid elution as compared with a salt form, and is well suited for formulation. In addition, it is excellent in storage stability, has excellent mechanical stability and fluidity, and is uniformly distributed in particles, and thus is very suitable as an agate.

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro- 4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate salt can be produced with high yield and is suitable for industrial production.

Also, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) These crystalline polymorphs are the properties of a compound of several compounds and the occurrence of different crystal forms of a single compound. These crystalline polymorphs are recognized as different solids sharing the same molecular formula and have inherent physicochemical properties such as solubility, melting point and X-ray powder diffraction pattern, and the stability of active drug , Solubility and the like, thereby improving the stability and efficacy of the drug.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a schematic diagram of a process for the preparation of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ X-ray powder diffraction (XPRD) of crystalline Form I is shown.
Figure 2 is a graphical representation of the reaction of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- The results of the differential scanning calorimetry method of crystal form I are shown.
Figure 3 shows the synthesis of (R) - (1-methylpyrrolidin-3-yl) methyl (3'- chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate The results of nuclear magnetic resonance of crystalline Form I are shown.
Figure 4 is a graphical representation of the reaction of (R) - (1-methylpyrrolidin-3-yl) methyl (3'- chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate citrate X-ray powder diffraction (XPRD) results.
Figure 5 is a graphical representation of the reaction of (R) - (1-methylpyrrolidin-3-yl) methyl (3'- chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate citrate The results of differential scanning calorimetry are shown.
Figure 6 is a graphical representation of the reaction of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate citrate Nuclear magnetic resonance results.
Figure 7 is a graph showing the effect of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] X-ray powder diffraction (XPRD) results.
8 is a graph showing the effect of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate phosphate The results of differential scanning calorimetry are shown.
FIG. 9 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate phosphate Nuclear magnetic resonance results.
FIG. 10 is a graph showing the results of the reaction of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- X-ray powder diffraction (XPRD) of crystalline Form II.
11 is a schematic diagram illustrating the synthesis of (R) - (1-methylpyrrolidin-3-yl) methyl (3'- chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate And the result of differential scanning calorimetry of crystal form II.
12 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate X-ray powder diffraction (XPRD) of crystalline Form III is shown.
FIG. 13 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- And the result of the differential scanning calorimetry method of crystal form III.
14 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) of crystalline Form IV.
FIG. 15 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate And the result of the differential scanning calorimetry of crystalline type IV.
Figure 16 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate X-ray powder diffraction (XPRD) of crystalline V is shown.
FIG. 17 is a graph showing the results of a comparison between (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- X-ray powder diffraction (XPRD) results of crystalline Form VI.
FIG. 18 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- X-ray powder diffraction (XPRD) results of crystalline Form VII.
19 is a graph showing the activity of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- X-ray powder diffraction (XPRD) of crystalline Form VIII.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Measurement method>

The following measurement method is commonly applied to each embodiment according to the present invention.

1. X-ray powder diffraction

The X-ray powder diffraction pattern was obtained using a BRUKER D8 ADVANCE model with CuKα irradiation at 1.54178 Å (40 kV, 40 mA) as a solid state detector. The analysis was carried out with a 0.02 ° step size over the range of 3 ° to 50 ° at 2θ angle.

2. Thermal analysis

Differential scanning calorimetry (DSC) was performed using METTLER TOLEDO DSC1. A sample of about 1-10 mg was weighed and placed in a capped aluminum pan. The samples were evaluated using a linear heating ramp at 30 ° C to 350 ° C at 10 ° C / min or 20 ° C / min.

3. Nuclear magnetic resonance (NMR)

Nuclear magnetic resonance (NMR) analysis was performed using Varian oxford 400 MHz and Agilent 600 MHz.

4. Liquid chromatography ( HPLC )

- Detector: Ultraviolet absorption spectrophotometer (detection wavelength: 244 nm)

- Column: Waters, XBridge C18, 4.6 * 150 mm, 5 um

- Column temperature: 40 ° C

- Flow rate: 1.0 mL / min

- Injection volume: 10 uL

- Mobile phase buffer: 0.01 M (NH ₄ ) HCO ₃ solution is prepared and adjusted to pH 10.5 with ammonia water.

Mobile phase A: buffer: acetonitrile = 8: 2

Mobile phase B: Acetonitrile

Sample solution: 1.0 mg / mL in 50% methanol

Mobile phase condition

< Comparative Example  1 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate Citrate  Produce

Fluoro - [l, r-biphenyl] -2-yl) carbamate The free base (0.5 g) was added to a solution of (3-chloro-4'- ) Was added to the reaction part, and then acetone (5 mL) was added thereto to dissolve it. Then, 0.27 g of citric acid was dissolved in acetone (5 mL) and then added to the reaction part. After stirring at room temperature for 1 hour, the reaction product was concentrated. To the concentrate, methyl-t-butyl ether (40 mL) was added to the reaction mixture and stirred at 0 ° C for 12 hours. The resulting solid was filtered, vacuum-dried at room temperature for 4 hours and analyzed by HPLC to find a relative purity of 97.7% To give the title compound. The X-ray powder diffraction (XPRD) pattern thereof is shown in Fig. 4, the differential scanning calorimetry (DSC) results are shown in Fig. 5, and the nuclear magnetic resonance (NMR) analysis results are shown in Fig.

< Comparative Example  2 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate phosphate

(1'-biphenyl) -2-yl) carbamate The free base (1.0 g) was added to a solution of (3-chloro-4'- ) Was added to the reaction part, and then acetone (10 mL) was added to dissolve the phosphoric acid (0.49 g) into the reaction part. After adding methyl-t-butyl ether (100 mL) at 0 ° C to the reaction mixture and stirring at 0 ° C for 14 hours, the resulting solid was filtered, vacuum-dried at room temperature for 2 hours and analyzed by HPLC to obtain a purity of 98.4% To give the title compound. The X-ray powder diffraction (XPRD) pattern thereof is shown in Fig. 7, the differential scanning calorimetry (DSC) results are shown in Fig. 8, and the nuclear magnetic resonance (NMR) analysis results are shown in Fig.

< Example  1 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

Fluoro - [l, r-biphenyl] -2-yl) carbamate The free base (0.5 g) was added to a solution of (3-chloro-4'- ) Was added to the reaction part, and acetone (5 mL) was added thereto to dissolve it. Then, oxalic acid (0.16 g) was dissolved in acetone (5 mL) and the mixture was stirred at room temperature for 1 hour. Methyl-t-butyl ether (20 mL) was added to the reaction portion and stirred for 6 hours. The resulting solid was filtered, and then dried under vacuum at room temperature for 6 hours and analyzed by HPLC to obtain the title compound having a relative purity of 99.3%. The X-ray powder diffraction (XPRD) pattern thereof is shown in Fig. 1, the differential scanning calorimetry (DSC) results are shown in Fig. 2, and the nuclear magnetic resonance (NMR) analysis results are shown in Fig.

< Example  2 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [ To obtain a crystal form I compound of mate oxalate. The X-ray powder diffraction (XPRD) pattern thereof is shown in Fig. 1, the differential scanning calorimetry (DSC) results are shown in Fig. 2, and the nuclear magnetic resonance (NMR) analysis results are shown in Fig.

< Example  3 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(I) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 50 mg) was added to dichloromethane (1 mL), stirred at room temperature for 3 days, centrifuged and centrifuged Lt; 0 &gt; C to prepare crystalline Form II. The X-ray powder diffraction (XPRD) pattern thereof is shown in Fig. 10, and the results of differential scanning calorimetry (DSC) are shown in Fig.

< Example  4 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(I) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 40 mg) was dissolved in acetone (2 mL) and then heptane (2 mL) was added. The mixture was stirred at room temperature for 24 hours, centrifuged and dried at 40 DEG C to prepare crystalline Form II.

< Example  5> (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(I) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 50 mg) was added to acetone (0.6 mL) and completely dissolved at 60 占 폚. After dissolution, the crystals were cooled to room temperature and the resulting crystals were centrifuged and dried at 40 ° C to prepare crystalline Form II.

< Example  6 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

Crystalline Form II was prepared in the same manner as in Example 5 using methylethylketone instead of acetone.

< Example  7 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

Crystalline Form II was prepared in the same manner as in Example 5, except that acetonitrile was used instead of acetone.

< Example  8 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

Crystalline Form II was prepared in the same manner as in Example 3, except that acetone was used instead of dichloromethane.

< Example  9> (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(I) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 40 mg) was dissolved in ethanol (1 mL) and then methyl-t-butyl ether (2 mL) was added. The mixture was stirred at room temperature for 1 hour, centrifuged and dried at 40 DEG C to prepare crystalline Form III. The X-ray powder diffraction (XPRD) pattern thereof is shown in Fig. 12, and the differential scanning calorimetry (DSC) results are shown in Fig.

< Example  10> (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(I) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 40 mg) was dissolved in ethanol (1 mL), and then heptane (1 mL) was added. The mixture was stirred at room temperature for 1 hour, centrifuged and dried at 40 DEG C to prepare crystalline Form III.

< Example  11> (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(I) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 40 mg) was dissolved in 1,4-dioxane (1.7 mL), followed by the addition of isopropyl acetate (15.3 mL). The mixture was stirred at room temperature for 24 hours, centrifuged and dried at 40 DEG C to prepare crystalline Form III.

< Example  12 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(I) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 40 mg) was dissolved in dichloromethane (2 mL), followed by the addition of isopropyl acetate (2 mL). The mixture was stirred at room temperature for 1 hour, centrifuged and dried at 40 DEG C to prepare crystalline Form III.

< Example  13 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

Crystalline Form III was prepared in the same manner as in Example 5 using isopropanol instead of acetone.

< Example  14> (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

Crystalline Form IV was prepared in the same manner as in Example 5 using 1,4-dioxane instead of acetone. The X-ray powder diffraction (XPRD) pattern thereof is shown in Fig. 14, and the results of differential scanning calorimetry (DSC) are shown in Fig.

< Example  15> (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(II) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 1.1139 g) was dissolved in butanol (100 mL) at a humidity of 31%, followed by heating and dissolving with stirring to 45 캜. The undissolved crystals were filtered and the filtrate was stored at room temperature. When the solvent evaporated and crystals were formed, the solution was transferred to a silica gel desiccator and allowed to stand for about one month to be completely dried to obtain (R) - (1-methylpyrrolidin-3- yl) methyl (3'-chloro-4'- [1,1'-biphenyl] -2-yl) carbamate oxalate was prepared. Its X-ray powder diffraction (XPRD) pattern is shown in Fig.

< Example  16 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(II) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 2.2356 g) was dissolved in methanol (100 mL), and the solution was heated and dissolved with stirring to 45 ° C. The undissolved crystals were filtered and the filtrate was stored in the freezer (-20 ° C) for about 3 months. Thereafter, the mixture was transferred to a silica gel desiccator at room temperature, left to stand for about 9 months, and dried to obtain (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- -Biphenyl] -2-yl) carbamate oxalate as a white solid. Its X-ray powder diffraction (XPRD) pattern is shown in Fig.

< Example  17> (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(II) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 0.5154 g) was dissolved in ethanol (20 mL), and the solution was heated and dissolved with stirring to 45 ° C. Benzene (38 mL) was added, followed by 3 times benzene (30 mL). The undissolved crystals were immediately filtered by filtration and the filtrate was stored at room temperature. Thereafter, the mixture was transferred to a silica gel desiccator at room temperature and allowed to stand for about 2 weeks to be dried to obtain (R) - (1-methylpyrrolidin-3- yl) methyl (3'-chloro-4'- -Biphenyl] -2-yl) carbamate oxalate salt was prepared. Its X-ray powder diffraction (XPRD) pattern is shown in Fig.

< Example  18 > (R) - (1-methylpyrrolidin-3-yl) methyl (3'- Chloro -4'- Fluoro - [1,1'-biphenyl] -2-yl) carbamate oxalate

(II) of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2- yl) carbamate oxalate 0.5519 g) was dissolved in ethanol (20 mL), and the solution was heated and dissolved with stirring to 45 ° C. After benzene (128 mL) was added all at once, the solution was immediately filtered to remove undissolved crystals, and the filtrate was stored at room temperature. Thereafter, the mixture was transferred to a silica gel desiccator at room temperature and allowed to stand for about 2 weeks to be dried to obtain (R) - (1-methylpyrrolidin-3- yl) methyl (3'-chloro-4'- -Biphenyl] -2-yl) carbamate oxalate salt was prepared. Its X-ray powder diffraction (XPRD) pattern is shown in Fig.

< Experimental Example  1> Severe stability in solid state

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) Carbamate oxalate and (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [ Yl) carbamate citrate and (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'-biphenyl ] -2-yl) carbamate phosphate, severe test (severe condition: 60 (Relative humidity) (%) / property of the product obtained is shown in Table 1.

Oxalate Citrate phosphate Early 1 week 2 weeks Early 1 week 2 weeks Early 1 week 2 weeks 60 ° C 99.3 /
solid 99.3 /
solid 99.4 /
solid 97.7 /
solid 97.8 /
Dissolution 97.9 /
Dissolution 98.4 /
solid 98.4 /
Dissolution 98.4 /
Dissolution RH 90% 99.3 /
solid 99.4 /
solid 97.7 /
Dissolution 97.7 /
Dissolution 98.4 /
Dissolution 98.4 /
Dissolution

As shown in Table 1 above, (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Carbamate oxalate, (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate phosphate Although there is no change in purity in the severe condition, the amount of the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ 2-yl) carbamate oxalate is maintained in an insoluble state, the hygroscopicity is low and it is confirmed that it is suitable for formulation because of its excellent storage stability.

< Experimental Example  2> Acceleration stability in solid state

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) Carbamate oxalate and (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [ Biphenyl] -2-yl) carbamate citrate and (R) - (1 -methylpyrrolidin-3- yl) methyl (3'-chloro-4'- fluoro- [ ] -2-yl) carbamate phosphate was subjected to an accelerated test (acceleration condition: 40 ° C / RH 75%), and the analysis results are shown in Table 2.

Test period salt Relative purity (%) Appearance Early Oxalate 99.3 solid Citrate 97.7 solid phosphate 98.4 solid 1 week Oxalate 99.3 solid Citrate 97.7 solid phosphate 98.3 Dissolution 2 weeks Oxalate 99.3 solid Citrate 97.6 solid phosphate 98.3 Dissolution 3 weeks Oxalate 99.3 solid Citrate 97.7 Dissolution phosphate 98.4 Dissolution 4 weeks Oxalate 99.3 solid Citrate 97.7 Dissolution phosphate 98.4 Dissolution

Chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) methyl) thiophene as shown in Table 2 above. Carbamate oxalate, (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate phosphate Is a physicochemical unfavorable salt due to the dissolution of citrate and phosphate even though there is no change in purity as in the case of the severe test under accelerated conditions.

Thus, the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate The oxalate has a normal stability in production, is easy to handle, and can be confirmed to be useful for mass production.

< Experimental Example  3> Acceleration and harsh stability of crystal form I, II and III

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2- ) Carbamate oxalate crystal form I and (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- Yl) carbamate oxalate crystal form II and (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- (Acceleration condition: 40 占 폚 / RH 75%) and a severe test (severe condition: 60 占 폚) were carried out, Table 3 shows the results.

Crystal form Relative purity (%) Crystal form I Crystal form II Crystal form III Crystal form I Crystal form II Crystal form III Early Crystal form I Crystal form II Crystal form III 99.66 99.87 99.81 60 ℃ 1 week Crystal form I Crystal form II Crystal form III 99.71 99.85 99.82 40 ℃ / RH 75% 1 week Crystal form I Crystal form II Crystal form III 99.55 99.83 99.79 60 ℃ 3 weeks Crystal form I Crystal form II Crystal form III 99.61 99.79 99.79 40 ° C / RH 75% 3 weeks Crystal form I Crystal form II Crystal form III 99.60 99.81 99.80

As shown in Table 3, it was found that both of them were stable under accelerated and severe conditions between crystal form I, II and III. It can be seen that the crystal form remains unchanged and the original crystal form is maintained.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the spirit or scope of the invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (31)

(R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [ Mate oxalate.
[Chemical Formula 1]

The method according to claim 1, wherein said (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- The carbamate oxalate salt is a crystalline (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ Yl) carbamate oxalate. Wherein the X-ray powder diffraction pattern comprises three or more diffraction peaks selected from the group consisting of diffraction angle 2? Of 13.402 ± 0.2 °, 14.300 ± 0.2 °, 18.519 ± 0.2 °, 19.577 ± 0.2 ° and 21.499 ± 0.2 ° ( R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate. 5. The method of claim 3, wherein the X-ray powder diffraction pattern is at least one of the following: 7.182 0.2, 8.379 0.2, 8.679 0.2, 11.180 0.2, 16.320 0.2, 16.659 0.2, 17.321 0.2, 17.861 0.2 20.632 ± 0.2 °, 22.180 ± 0.2 °, 22.922 ± 0.2 °, 23.339 ± 0.2 °, 24.019 ± 0.2 °, 24.297 ± 0.2 °, 24.699 ± 0.2 °, 25.441 ± 0.2 °, 27.239 ± 0.2 ° and 29.880 ± 0.2 (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1 ' -biphenyl] -2-yl) carbamate oxalate. 4. The method according to claim 3, wherein when the temperature raising rate is 20 ° C / min, the specimen has an onset temperature of 121.85 ° C (± 0.5 ° C) and an endothermic peak of 126.96 ° C (± 0.5 ° C) The crystalline form I of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] . (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate The free base was dissolved in acetone Dissolving; Adding oxalic acid to the solution and stirring; And (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- Phenyl] -2-yl) carbamate oxalate &lt; / RTI &gt; Wherein the X-ray powder diffraction pattern comprises three or more diffraction peaks selected from the group consisting of diffraction angle 2? Of 13.439 ± 0.2 °, 14.481 ± 0.2 °, 18.501 ± 0.2 °, 21.779 ± 0.2 ° and 23.358 ± 0.2 ° ( R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate salt II. 8. The method of claim 7, wherein the X-ray powder diffraction pattern is 8.360 +/- 0.2, 11.340 +/- 0.2, 16.401 +/- 0.2, 16.739 +/- 0.2, 17.360 +/- 0.2, 17.938 +/- 0.2, 22.179 +/- 0.2, Further comprising at least one diffraction peak selected from the group consisting of diffraction angles 2θ of 24.641 ± 0.2 °, 25.500 ± 0.2 °, 26.422 ± 0.2 °, 27.260 ± 0.2 °, 28.201 ± 0.2 ° and 29.878 ± 0.2 ° The crystalline form II of the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate . The method according to claim 7, wherein when the temperature raising rate is 20 占 폚 / min, an endothermic peak having an onset temperature of 127.39 占 폚 (± 0.5 占 폚) and 130.20 占 폚 (占 0.5 占 폚) in a differential scanning calorimetry (DSC) The crystalline form II of the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate . Crystalline form I of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate Dichloromethane; Acetone; Heptane; Methyl ethyl ketone; Acetonitrile; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, Apos; -biphenyl] -2-yl) carbamate oxalate crystal Form II. Wherein the X-ray powder diffraction pattern comprises three or more diffraction peaks selected from the group consisting of 10.720 占 0.2 占 11.018 占 0.2 占 14.239 占 0.2 占 17.880 占 0.2 占 and 21.440 占 0.2 占 diffraction angle 2? R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate. 13. The method of claim 11, wherein the X-ray powder diffraction pattern is at least one of the following: X-ray powder diffraction pattern of 8.700 +/- 0.2 deg., 13.098 +/- 0.2 deg., 14.959 +/- 0.2 deg., 15.382 +/- 0.2 deg., 16.701 +/- 0.2 deg., 17.309 +/- 0.2 deg. From the group consisting of diffraction angles 2? Of 0.2 °, 20.560 ± 0.2 °, 22.042 ± 0.2 °, 22.762 ± 0.2 °, 23.940 ± 0.2 °, 24.141 ± 0.2 °, 26.855 ± 0.2 °, 27.379 ± 0.2 ° and 29.006 ± 0.2 ° (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate &lt; / RTI &gt; 12. The method according to claim 11, wherein when the temperature raising rate is 20 占 폚 / min, DSC analysis has an onset temperature of 123.68 占 폚 (± 0.5 占 폚) and an endothermic peak of 128.37 占 폚 (占 0.5 占 폚) The crystalline form III of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate . Crystalline form I of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate ethanol; Methyl-t-butyl ether; Heptane; 1,4-dioxane; Isopropyl acetate; Dichloromethane; Isopropanol; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, Apos; -biphenyl] -2-yl) carbamate oxalate &lt; / RTI &gt; Wherein the X-ray powder diffraction pattern comprises three or more diffraction peaks selected from the group consisting of 16.642 ± 0.2 °, 17.839 ± 0.2 °, 20.981 ± 0.2 °, 21.580 ± 0.2 ° and 22.701 ± 0.2 ° diffraction angle 2θ R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate IV. 16. The method of claim 15, wherein the X-ray powder diffraction pattern is at least one of 8.355 + -0.2, 11.415 + 0.2, 13.419 + 0.2, 13.956 + 0.2, 15.619 + 0.2, 18.579 + 0.2, 23.219 + 0.2, (R) - (1-methylpiperazin-1-yl) -propane, which further comprises one or more diffraction peaks selected from the group consisting of diffraction angles 2 &amp;thetas;, 26.478 +/- 0.2 DEG, 27.195 +/- 0.2 DEG, 28.143 +/- 0.2 DEG and 29.172 +/- 0.2 DEG, (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate IV. 16. The method according to claim 15, wherein when the temperature raising rate is 20 캜 / minute, the specimen having an endothermic peak of 120.60 캜 (± 0.5 캜) and 126.88 캜 (± 0.5 캜) in a differential scanning calorimetry (DSC) The crystalline form IV of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] . Crystalline form I of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'-biphenyl ] -2-yl) carbamate oxalate salt crystal form IV. Wherein the X-ray powder diffraction pattern comprises at least three diffraction peaks selected from the group consisting of diffraction angles 2 &amp;thetas; of 10.925 +/- 0.2 DEG, 14.200 +/- 0.2 DEG, 20.559 +/- 0.2 DEG and 21.396 +/- 0.2 DEG, -Methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate. The method according to claim 19, wherein the amount of the (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [ The crystal form V of the carbamate oxalate salt was determined from the group consisting of diffraction angle 2? Of X-ray powder diffraction pattern of 7.049 ± 0.2 °, 8.592 ± 0.2 °, 16.081 ± 0.2 °, 17.226 ± 0.2 °, 17.840 ± 0.2 ° and 19.565 ± 0.2 ° (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] -2-yl) carbamate oxalate &lt; / RTI &gt; The crystalline form II of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1,1'- biphenyl] -2-yl Process for the preparation of carbamate oxalate crystal form. Wherein the X-ray powder diffraction pattern comprises three or more diffraction peaks selected from the group consisting of 10.127 0.2, 10.893 0.2, 11.751 0.2, and 17.978 0.2, -Methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate. 23. The method of claim 22, wherein the X-ray powder diffraction pattern comprises one or more diffraction peaks selected from the group consisting of 7.150 0.2, 14.362 0.2, 14.654 0.2, 15.251 0.2 and 16.360 0.2, (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbazole Crystalline form of mate oxalate VI. The crystalline form II of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] Methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) ) Carbamate oxalate crystal form VI. Wherein the X-ray powder diffraction pattern comprises at least three diffraction peaks selected from the group consisting of the diffraction angles 2 &amp;thetas; of 8.169 +/- 0.2 DEG, 8.847 +/- 0.2 DEG, 11.071 +/- 0.2 DEG and 13.156 +/- 0.2 DEG. -Methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate VII. 26. The method of claim 25, wherein the X-ray powder diffraction pattern is one or more diffraction peaks selected from the group consisting of diffraction angle 2 &amp;thetas; of 13.3454 +/- 0.2 DEG, 14.220 +/- 0.2 DEG, 15.828 +/- 0.2 DEG, 16.486 +/- 0.2 DEG and 17.186 +/- 0.2 DEG (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbazole Crystalline Form of Mate Oxalate VII. The crystalline form II of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] ethanol; benzene; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, Apos; -biphenyl] -2-yl) carbamate oxalate &lt; / RTI &gt; (R) - (1), wherein the X-ray powder diffraction pattern comprises at least three diffraction peaks selected from the group consisting of diffraction angles 2? Of 8.903 占 0.2 占 13.090 占 0.2 占 14.347 占 0.2 占 and 15.871 占 0.2 占-Methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbamate oxalate. 29. The method of claim 28, wherein the X-ray powder diffraction pattern comprises one or more diffraction peaks selected from the group consisting of diffraction angle 2 &amp;thetas; of 6.720 +/- 0.2 deg., 10.646 +/- 0.2 deg., 11.683 +/- 0.2 deg., 13.490 deg. (3'-chloro-4'-fluoro- [1,1'-biphenyl] -2-yl) carbazole Crystalline form of mate oxalate VIII. The crystalline form II of (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [1,1'- biphenyl] ethanol; benzene; (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'-fluoro- [l, Apos; -biphenyl] -2-yl) carbamate oxalate &lt; / RTI &gt; The method of any one of claims 1 to 5, 7 to 9, 11 to 13, 15 to 17, 19, 20, 22, 23, 25 (R) - (1-methylpyrrolidin-3-yl) methyl (3'-chloro-4'- fluoro- [1 Chronic obstructive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence (including urinary incontinence), urinary incontinence, urinary incontinence, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, Alzheimer disease, senile dementia, glaucoma, schizophrenia, reflux esophagitis, gastroesophagial reflux disease, cardiac arrhythmia, hyper salivation syndromes, nocturnal enuresis, neurogenic urinary frequency, neurogenic bladder, unstable bladder, bladder spasm and urinary frequency Muscarinic M3 receptor antagonists for the prevention or treatment of diseases selected from the group eojin.

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