Crystal form of sofpironium bromide and its preparation method

Abstract

To provide a crystalline form of sofpironium bromide which has superior stability without the hygroscopic property, and can be suitably used as a raw material of medicaments.SOLUTION: The invention provides: a cocrystal containing the 1'R-diastereomer and the 1'S-diastereomer of sofpironium bromide at the ratio of 1:3 (Form CO); a crystal mixture (for example, Form B) containing the Form CO and a crystalline form of the 1'R-diastereomer (Form MN); and a method for preparing sofpironium bromide, which is suitable for manufacture of the crystal mixture. Form CO and a crystalline form of sofpironium bromide containing Form CO (for example, Form B) have superior stability without the hygroscopic property, and accordingly can be suitably used as a raw material of medicaments.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a crystalline form of sofpironium bromide, high purity sofpironium bromide, and a method for producing the same. [Background technology]

[0002] It is preferable that pharmaceutical active ingredients are obtained industrially in a highly pure and physicochemically stable form, and from the viewpoint of handling and storage, it is particularly preferable that they are obtained in a physicochemically stable crystalline form.

[0003] Acetylcholine is known as a major neurotransmitter in the body and has a variety of actions, one of which is the sweating action caused by the activation of sweat glands. Anticholinergic agents inhibit the action of acetylcholine and are therefore useful as therapeutic agents for hyperhidrosis. BBI-4000 (sofpironium bromide) is known as an anticholinergic agent useful for the treatment of hyperhidrosis (Patent Document 1).

[0004] Sofpironium bromide has the following formula (I): [ka] The compound is a quaternary ammonium salt represented by the formula (BBI-4000, (2R,3'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-(ethoxycarbonylmethyl)-1'-methylpyrrolidinium bromide). In sofpironium bromide, the configurations at the 2- and 3'-positions are each specified as R configuration, but the configuration of the quaternary nitrogen moiety at the 1'-position is not specified.

[0005] More specifically, sofpironium bromide has the following formula (Ia): [ka] (2R,3'R,1'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-(ethoxycarbonylmethyl)-1'-methylpyrrolidinium bromide represented by the following formula (hereinafter, in this specification, the 1'R-diastereomer is also referred to as "compound (Ia)"), The following formula (Ib): [ka] and (2R,3'R,1'S)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-(ethoxycarbonylmethyl)-1'-methylpyrrolidinium bromide represented by the following formula (hereinafter, in this specification, the 1'S-diastereomer is also referred to as "compound (Ib)").

[0006] Non-Patent Document 1 and Patent Document 2 disclose methods for producing compound (I), compound (Ia), and compound (Ib), which are represented by the following formula (II): [ka] The present invention discloses a method for isolating compounds (Ia) and (Ib) by subjecting an amine compound represented by the following formula ((2R,3'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1'-methylpyrrolidine (hereinafter, in this specification, the above amine compound is also referred to as "compound (II)" or "(2R,3'R)-CPMA-MP") represented by the following formula (2):

[0007] Compound (I) obtained by this manufacturing method is a crude product, and although Non-Patent Document 1 does not mention the content ratio of compound (Ia) and compound (Ib) in crude compound (I), compound (Ia) is obtained in a yield of 19% (isolated yield) and compound (Ib) is obtained in a yield of 28% (isolated yield) by column chromatography. However, despite being purified by column chromatography, the purity of compound (Ia) and compound (Ib) obtained by this manufacturing method is low, and there is no description regarding their properties or crystal form. Therefore, compound (I), compound (Ia) and compound (Ib) obtained by this manufacturing method are considered not to have a suitable profile as a drug substance for pharmaceuticals.

[0008] Patent Document 3 describes a method in which compound (II) and methyl bromoacetate are N-alkylated in acetonitrile, and then a methylene chloride solution of the resulting crude compound (I) is added to diethyl ether to obtain a precipitate. However, it is doubtful whether compound (I) can be produced by reacting compound (II) with methyl bromoacetate. Even if compound (I) could be produced, Patent Document 3 does not describe the properties of the above precipitate of compound (I), nor does it describe the crystal form or purity of compound (I). Furthermore, in the production method described in Patent Document 3, the step of obtaining a precipitate is repeated three times, but a method that requires such an operation is not industrially applicable, and the methylene chloride and diethyl ether used are not industrially suitable solvents. From these points, it is difficult to say that the above precipitate of compound (I) described in Patent Document 3 has physicochemical properties and characteristics suitable for use as a drug substance for pharmaceuticals, and it is difficult to industrially produce compound (I) using this production method.

[0009] In each of the above-mentioned prior art documents, sofpironium bromide is produced as a mixture of compound (I), i.e., diastereomers (epimers), because the stereochemistry at the 1'-position cannot be controlled in the N-alkylation reaction. In addition, none of the documents discloses or suggests the crystal form of sofpironium bromide, high purity sofpironium bromide, or a method for producing the same.

[0010] In general, there are few cases where a drug substance is a mixture of diastereomers, and there are almost no known general methods or examples for obtaining a crystal form having a profile suitable for use as a drug substance. In the above-mentioned prior art documents, sofpironium bromide is produced as a mixture of diastereomers, but there is no disclosure or suggestion of its crystal form. Furthermore, these documents do not disclose or suggest at all the crystal form of sofpironium bromide having a profile suitable for use as a drug substance, or the manufacturing method for obtaining it. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Pharmazie (2006), 61(2), 90-96 [Patent documents]

[0012] [Patent Document 1] International Publication No. 2015 / 138776 [Patent Document 2] International Publication No. 2007 / 058971 [Patent Document 3] International Publication No. 2018 / 026869 Summary of the Invention [Problem to be solved by the invention]

[0013] It is preferable that pharmaceutical raw materials are supplied in a stable crystalline form, but at the same time, they must be supplied in a simple and industrially applicable manner. The above-mentioned prior art documents do not disclose any crystalline form of sofpironium bromide, nor do they suggest its existence. Therefore, it is completely impossible to predict whether the crystalline form of sofpironium bromide is obtained as a single crystal or as a mixture of several crystalline forms.

[0014] In view of the above background, one of the problems to be solved by the present invention is to provide sofpironium bromide having an optimal profile as a drug substance for pharmaceuticals. Another problem to be solved by the present invention is to provide a crystalline form of sofpironium bromide having an optimal profile as a drug substance for pharmaceuticals.

[0015] Another problem to be solved by the present invention is to provide high-purity sofpironium bromide, and in particular to provide a physicochemically stable crystalline form of high-purity sofpironium bromide. Still another problem to be solved by the present invention is to provide an industrially applicable method for producing the above-mentioned sofpironium bromide (including its crystalline form). [Means for solving the problem]

[0016] In view of the above problems, the present inventors have conducted extensive and intensive studies in order to provide a crystalline form of sofpironium bromide having an optimal profile as a drug substance for pharmaceuticals.

[0017] The present inventors have confirmed that in the production of sofpironium bromide, even if the conditions of the N-alkylation reaction are changed in various ways, the obtained sofpironium bromide always contains compound (Ia) and compound (Ib), and the content ratio thereof is within a certain range. For example, in one embodiment of the present invention, the content ratio of compound (Ia) to compound (Ib) in compound (I) obtained by the N-alkylation reaction is 50:50 to 10:90, and in a typical embodiment of the present invention, it is 40:60 to 25:75.

[0018] As described above, in the method of reacting compound (II) with ethyl bromoacetate (N-alkylation reaction), sofpironium bromide containing compound (Ia) and compound (Ib) is always obtained regardless of the manufacturing conditions. Therefore, the present inventors considered that, when supplying compound (I) as a drug substance for a drug, it is industrially unrealistic to separate compound (Ia) and compound (Ib) and supply them, and that it is essential to obtain the drug substance as a crystalline form of compound (I), which is a mixture of diastereomers (epimers), and use it as a raw material for a drug from the viewpoint of manufacturing costs and stable supply of a drug.

[0019] The present inventors have been studying a method for providing a stable crystalline form of sofpironium bromide and for producing the crystalline form by industrially applicable means, and have succeeded for the first time in obtaining a crystalline form of compound (I) by adding ethyl bromoacetate that is not diluted with any solvent to a solution of compound (II) containing at least ethyl acetate as a solvent (hereinafter, the crystalline form of compound (I) obtained by this production method is referred to as "Form A").

[0020] Next, the present inventors examined the profile of Form A in detail. The present inventors separated compound (Ia) and compound (Ib) from compound (I) by silica gel chromatography, and then succeeded in obtaining each of them in a crystalline form using a mixed solvent of methyl t-butyl ether and ethyl acetate (hereinafter, the crystals of compound (Ia) obtained by the above method are referred to as "Form MN", and the crystals of compound (Ib) obtained by the above method are referred to as "Form MJ").

[0021] As a result of detailed investigation, the inventors have demonstrated that Form MN is an extremely stable crystalline form and has a suitable profile as an active pharmaceutical ingredient for pharmaceuticals, whereas Form MJ undergoes a crystalline transition under humid conditions. The present inventors have further clarified that Form A contains compound (Ia) and compound (Ib), and at the same time, Form A is a crystalline mixture of Form MN and Form MJ.

[0022] However, Form A undergoes crystal transformation under humid conditions and is not optimal as a drug substance for pharmaceuticals. Therefore, the present inventors conducted further research to find a crystal form with a profile more suitable for use as a drug substance for pharmaceuticals.

[0023] Incidentally, compound (I) contains compound (Ia) and compound (Ib) in any ratio. However, in the crystallization of compound (I), it was completely unpredictable how the content ratio of compound (Ia) to compound (Ib) and the production method (crystallization method) would affect the crystalline form of the product compound (I).

[0024] Therefore, the present inventors prepared a large number of compounds (I) containing compounds (Ia) and (Ib) at various content ratios, and investigated the effect of the content ratio on the crystal morphology of compound (I). As a result, it was surprisingly found that under certain manufacturing conditions (crystallization conditions), a new crystalline form other than Form MN or Form MJ was produced. As a result of the investigation, it was confirmed that the crystalline form has a cocrystal structure containing compound (Ia) and compound (Ib) in a ratio of 1:3 (hereinafter, the cocrystal is referred to as "Form CO"). And even more surprisingly, it was confirmed that Form CO has extremely excellent properties as a drug substance for pharmaceuticals.

[0025] The present inventors have studied the method for producing Form CO in detail and have found that the step of adding methyl t-butyl ether dropwise over a long period of time and / or the step of stirring a suspension of a crystalline form of Compound (I) in a solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether over a long period of time are extremely important in the production of Form CO.

[0026] The present inventors believed that a crystalline form of Compound (I) containing Form CO would be excellent as an active ingredient for pharmaceuticals, and further investigated its production method. As a result, the present inventors have succeeded in obtaining a crystalline form of compound (I) including Form CO by preparing a solvent including at least one solvent selected from ethyl acetate and methyl t-butyl ether and a suspension including a crystalline form of compound (I) and stirring the suspension for one hour or more (hereinafter, the crystalline form of compound (I) obtained by this method is referred to as "Form B").

[0027] The present inventors have conducted extensive research to clarify the properties of Form B, 13 Analysis was performed using C nuclear magnetic resonance spectroscopy and powder X-ray crystal structure analysis. As a result, it was revealed that Form B is a crystalline mixture of Form MN and Form CO. As a result of further investigation, the present inventors have revealed that Form B is a crystalline form with an optimal profile as a drug substance for pharmaceuticals.

[0028] Furthermore, it has become clear that the production method of the present invention can provide high-purity sofpironium bromide (including the crystalline form of sofpironium bromide), and the present invention has been completed.

[0029] As described above, the present inventors have newly created Form CO (a cocrystal containing Compound (Ia) and Compound (Ib) in a ratio of 1:3), which cannot be obtained as a single crystal form by simply processing Compound (I), and have clarified that Form CO is stable, non-hygroscopic, and has an excellent profile as a drug substance. It has also been clarified that the crystalline form of Compound (I), which is a crystalline mixture containing Form CO (e.g., Form B), is highly stable and has an extremely excellent profile as a drug substance. Furthermore, the production method of the present invention makes it possible to obtain a highly stable crystalline form of sofpironium bromide with high purity on an industrial scale.

[0030] That is, the present inventors have completed the following invention. [1] Formula (Ia): [ka] Compound (Ia) represented by the formula: Formula (Ib): [ka] A cocrystal containing compound (Ib) represented by the formula (Ib) in a ratio of 1:3. Formula (I): [ka] The crystalline form of compound (I) (sofpironium bromide) represented by the formula:

[0031] [2] The crystalline form (Form CO) of [1], characterized in that in a powder X-ray diffraction spectrum, the crystalline form (Form CO) has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.6±0.2°, 11.0±0.2°, and 22.2±0.2°. [3] A crystalline form of compound (I), comprising the crystalline form according to [1] or [2] and containing compound (Ia) and compound (Ib) in any ratio.

[0032] [4] A crystalline form of compound (I), which is a crystalline mixture containing the crystalline form according to [1] or [2] and also containing a crystalline form of compound (Ia). [5] A crystalline form of Compound (I), which is a crystalline mixture containing the crystalline form according to [1] or [2] and a crystalline form of Compound (Ia) (Form MN) characterized by having peaks at diffraction angles represented by 2θ in a powder X-ray diffraction spectrum of 7.1±0.2°, 21.4±0.2°, 22.3±0.2°, and 24.5±0.2°.

[0033] [6] A crystalline form (Form B) of Compound (I) characterized by having peaks at diffraction angles represented by 2θ in a powder X-ray diffraction spectrum of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2°.

[0034] [7] A method for producing a crystalline form of compound (I) according to any one of [1] to [6], comprising the steps of: Step C: preparing a suspension of compound (I) in a solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); A manufacturing method comprising:

[0035] [8] A method for producing a crystalline form of compound (I) according to any one of [1] to [6], comprising the steps of: Step A: In a solvent, Formula (II): [ka] reacting compound (II) represented by the formula: with ethyl bromoacetate to prepare a reaction solution containing compound (I); Step B: filtering the reaction solution to obtain a crystalline form of compound (I); Step C': preparing a suspension of the crystalline form of Compound (I) in a solvent comprising at least one solvent selected from ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least one hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); A manufacturing method comprising:

[0036] [9] The content of compound (I) is calculated based on the following formula (III): [ka] The content of compound (III) represented by the formula (I) is 0.5 w / w% or less.

[0037]

[10] The content of compound (I) is calculated based on the following formula (IV): [ka] The content of compound (IV) represented by the formula (I) is 0.5 w / w% or less.

[0038]

[11] The content of compound (I) is calculated based on the following formula (V): [ka] The content of compound (V) represented by the formula (I) is 0.5 w / w% or less.

[0039]

[12] A crystalline form of compound (I), in which the contents of compound (III), compound (IV), and compound (V) are each 0.5 w / w% or less relative to the content of compound (I), and the purity of compound (I) is 98.0 w / w% or more.

[13] A crystalline form of compound (I), in which the contents of compound (III), compound (IV), and compound (V) are each 0.5 w / w% or less relative to the content of compound (I), the total content of impurities is 2.0 w / w% or less, and the purity of compound (I) is 98.0 w / w% or more.

[14] A crystalline form of compound (I), in which the contents of compound (III), compound (IV), and compound (V) are each 0.15 w / w% or less relative to the content of compound (I), the total content of impurities is 1.0 w / w% or less, and the purity of compound (I) is 99.0 w / w% or more.

[15] The crystalline form of compound (I) according to any one of [9] to

[14] , wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 20:80.

[0040]

[16] A pharmaceutical composition for the treatment and / or prevention of diseases associated with the action of acetylcholine, prepared by mixing a crystalline form of compound (I) as described in any one of [1] to [6] or any one of [9] to

[15] with a pharma- ceutical acceptable carrier.

[17] A pharmaceutical composition for the treatment and / or prevention of hyperhidrosis, prepared by mixing a crystalline form of compound (I) as described in any one of [1] to [6] or any one of [9] to

[15] with a pharma- ceutical acceptable carrier.

[18] A pharmaceutical composition for the treatment and / or prevention of primary axillary hyperhidrosis or primary palmar hyperhidrosis, prepared by mixing a crystalline form of compound (I) as described in any one of [1] to [6] or any one of [9] to

[15] with a pharma- ceutical acceptable carrier.

[0041]

[19] An anticholinergic agent prepared by mixing a crystalline form of compound (I) described in any one of [1] to [6] or any one of [9] to

[15] with a pharma- ceutically acceptable carrier.

[20] A method for treating and / or preventing a disease associated with the action of acetylcholine, comprising administering to a mammal, including a human, a pharmaceutical composition prepared by mixing a crystalline form of compound (I) described in any one of [1] to [6], or any one of [9] to

[15] , with a pharma- ceutical acceptable carrier.

[21] A method for treating and / or preventing hyperhidrosis, comprising the step of administering to a mammal, including a human, a pharmaceutical composition prepared by mixing a crystalline form of compound (I) described in any one of [1] to [6], or any one of [9] to

[15] , with a pharma- ceutically acceptable carrier.

[22] A method for treating and / or preventing primary axillary hyperhidrosis or primary palmar hyperhidrosis, comprising the step of administering to a mammal, including a human, a pharmaceutical composition prepared by mixing a crystalline form of compound (I) described in any one of [1] to [6], or any one of [9] to

[15] , with a pharma- ceutical acceptable carrier.

[0042]

[23] Use of a crystalline form of compound (I) as described in any one of [1] to [6] or any one of [9] to

[15] for the manufacture of an anticholinergic agent.

[24] Use of a crystalline form of compound (I) as described in any one of [1] to [6] or any one of [9] to

[15] for the manufacture of a pharmaceutical composition for use in the treatment of a disease associated with the action of acetylcholine.

[25] Use of a crystalline form of compound (I) as described in any one of [1] to [6] or any one of [9] to

[15] for the manufacture of a pharmaceutical composition for use in the treatment of hyperhidrosis.

[26] Use of a crystalline form of compound (I) as described in any one of [1] to [6] or any one of [9] to

[15] for the manufacture of a pharmaceutical composition for use in the treatment of primary axillary hyperhidrosis or primary palmar hyperhidrosis.

[0043] The present invention also includes the following inventions. [2a] The crystalline form (Form CO) of [1], characterized in that in a powder X-ray diffraction spectrum, the crystalline form (Form CO) has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.6±0.1°, 11.0±0.1°, and 22.2±0.1°.

[0044] [3a] A crystalline form of compound (I), comprising the crystalline form (Form CO) described in [2a] and containing compound (Ia) and compound (Ib) in any ratio. [3b] The crystalline form according to [3] or [3a], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 99:1 to 1:99. [3c] The crystalline form according to [3] or [3a], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 90:10 to 10:90. [3d] The crystalline form according to [3] or [3a], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 50:50 to 10:90. [3e] The crystalline form according to [3] or [3a], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 20:80. [3f] The crystalline form according to [3] or [3a], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 25:75. [3g] The crystalline form according to [3] or [3a], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 30:70.

[0045] [4a] A crystalline form of compound (I), which is a crystalline mixture comprising the crystalline form of any one of [3a] to [3g] and at least one of the crystalline forms of compound (Ia). [4b] A crystalline form of compound (I) which contains at least the crystalline form described in [1], [2] or [2a], and does not contain a crystalline form consisting of compound (Ib) alone. [4c] A crystalline form of compound (I) according to any one of [3a] to [3g], which does not contain a crystalline form consisting only of compound (Ib). [4d] A crystalline form of compound (I), which is a crystalline mixture containing the crystalline form according to [1], [2] or [2a] and a crystalline form of compound (Ia), and which does not contain a crystalline form consisting only of compound (Ib). [4e] A crystalline form of compound (I) according to any one of [3a] to [3g], which is a crystalline mixture containing a crystalline form of compound (Ia) and does not contain a crystalline form consisting only of compound (Ib). [4f] A crystalline form of compound (I) according to any one of [3a] to [3g], which is a crystalline mixture containing the crystalline form according to [1], [2] or [2a] and a crystalline form of compound (Ia), and which does not contain a crystalline form consisting only of compound (Ib).

[0046] [5a] A crystalline form of Compound (I), which is a crystalline mixture containing the crystalline form according to [1], [2] or [2a] and a crystalline form of Compound (Ia) (Form MN) characterized by having peaks at diffraction angles represented by 2θ of 7.1±0.1°, 21.4±0.1°, 22.3±0.1°, and 24.5±0.1° in a powder X-ray diffraction spectrum. [5b] A crystalline form of Compound (I), which is a crystalline mixture containing a crystalline form of Compound (Ia) (Form MN) according to any one of [3a] to [3g], characterized in that the crystalline form has peaks at diffraction angles represented by 2θ in a powder X-ray diffraction spectrum of 7.1±0.1°, 21.4±0.1°, 22.3±0.1°, and 24.5±0.1°.

[0047] [6a] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 99:1 to 1:99. [6b] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 90:10 to 10:90. [6c] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 50:50 to 10:90.

[0048] [6d] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 40:60 to 20:80. [6e] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 40:60 to 25:75. [6f] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 40:60 to 30:70.

[0049] [6g] A crystalline form (Form B) of Compound (I), characterized in that in a powder X-ray diffraction spectrum, the crystalline form (Form B) of Compound (I) has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1°. [6h] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 99:1 to 1:99. [6i] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 90:10 to 10:90.

[0050] [6j] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 50:50 to 10:90. [6k] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 40:60 to 20:80. [6l] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 40:60 to 25:75. [6m] A crystalline form of compound (I), characterized in that it has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1° in a powder X-ray diffraction spectrum, and contains compound (Ia) and compound (Ib) in a content ratio of 40:60 to 30:70. [6o] A crystalline form of compound (I), comprising the crystalline form according to [1] and characterized in that in a powder X-ray diffraction spectrum, the crystalline form has peaks at diffraction angles represented by 2θ of 5.9±0.2°, 7.2±0.2°, 7.7±0.2°, 11.1±0.2°, 22.3±0.2°, and 24.6±0.2°. [6p] A crystalline form of compound (I), comprising the crystalline form described in [1] and characterized in that in a powder X-ray diffraction spectrum, the crystalline form has peaks at diffraction angles represented by 2θ of 5.9±0.1°, 7.2±0.1°, 7.7±0.1°, 11.1±0.1°, 22.3±0.1°, and 24.6±0.1°.

[0051] [7a] A method for producing a crystalline form of compound (I) according to any one of [1] to [6], a crystalline form of compound (I) according to any one of [2a] to [6p], or a compound (I) according to any one of [9] to

[15] , comprising: Step C: preparing a suspension of compound (I) in a solvent containing at least ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour; Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); A manufacturing method comprising: [8a] A method for producing compound (I) according to any one of [9] to

[15] , comprising the steps of: Step A': In a solvent containing ethyl acetate, Formula (II): [ka] reacting compound (II) represented by the formula: with ethyl bromoacetate to prepare a reaction solution containing compound (I); Step B: filtering the reaction solution to obtain a crystalline form of compound (I); A manufacturing method comprising:

[0052] [8b] A method for producing a crystalline form of compound (I) according to any one of [1] to [6], a crystalline form of compound (I) according to any one of [2a] to [6p], or a compound (I) according to any one of [9] to

[15] , comprising: The process is as follows: Step A': In a solvent containing ethyl acetate, Formula (II): [ka] reacting compound (II) represented by the formula: with ethyl bromoacetate to prepare a reaction solution containing compound (I); Step B: filtering the reaction solution to obtain a crystalline form of compound (I); Step C': preparing a suspension of said crystalline form of compound (I) in a solvent containing at least ethyl acetate and methyl t-butyl ether and stirring the suspension for at least 1 hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); A manufacturing method comprising:

[0053] [9a] The content of compound (I) is calculated based on the following formula (III): [ka] The compound (I), wherein the content of compound (III) represented by the following formula (I) is 0.5 w / w% or less.

[0054] [10a] The content of compound (I) is calculated based on the following formula (IV): [ka] The compound (I), wherein the content of compound (IV) represented by the following formula (I) is 0.5 w / w% or less.

[0055] [11a] The content of compound (I) is calculated based on the following formula (V): [ka] The compound (I), wherein the content of the compound (V) represented by the following formula (I) is 0.5 w / w% or less.

[0056] [12a] Compound (I), in which the contents of compound (III), compound (IV), and compound (V) are each 0.5 w / w% or less relative to the content of compound (I), and the purity of compound (I) is 98.0 w / w% or more. [13a] Compound (I), in which the contents of compound (III), compound (IV), and compound (V) are each 0.5 w / w% or less, the total content of impurities is 2.0 w / w% or less, and the purity of compound (I) is 98.0 w / w% or more, relative to the content of compound (I). [14a] Compound (I), in which the contents of compound (III), compound (IV), and compound (V) are each 0.15 w / w% or less relative to the content of compound (I), the total content of impurities is 1.0 w / w% or less, and the purity of compound (I) is 99.0 w / w% or more. [15a] Compound (I) according to any one of [9a] to [14a], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 20:80.

[0057] [16a] A pharmaceutical composition for treating and / or preventing diseases associated with the action of acetylcholine, comprising compound (I) according to any one of [9a] to [15a] as an active ingredient. [17a] A pharmaceutical composition for treating and / or preventing hyperhidrosis, comprising compound (I) according to any one of [9a] to [15a] as an active ingredient. [18a] A pharmaceutical composition for the treatment and / or prevention of primary axillary hyperhidrosis or primary palmar hyperhidrosis, comprising compound (I) according to any one of [9a] to [15a] as an active ingredient.

[0058] [19a] An anticholinergic agent comprising, as an active ingredient, compound (I) according to any one of [9a] to [15a]. [20a] A method for treating and / or preventing a disease associated with the action of acetylcholine, comprising the step of administering to a mammal, including a human, a therapeutically and / or prophylactically effective amount of compound (I) described in any one of [9a] to [15a]. [21a] A method for treating and / or preventing hyperhidrosis, comprising the step of administering to a mammal, including a human, a therapeutically and / or prophylactically effective amount of compound (I) described in any one of [9a] to [15a]. [22a] A method for treating and / or preventing primary axillary hyperhidrosis or primary palmar hyperhidrosis, comprising the step of administering to a mammal, including a human, a therapeutically and / or prophylactically effective amount of compound (I) described in any one of [9a] to [15a].

[0059] [23a] Use of compound (I) according to any one of [9a] to [15a] for the manufacture of an anticholinergic agent. [24a] Use of compound (I) as described in any one of [9a] to [15a] for the preparation of a pharmaceutical composition for use in the treatment of diseases associated with the action of acetylcholine. [25a] Use of compound (I) as described in any one of [9a] to [15a] for the manufacture of a pharmaceutical composition for use in the treatment of hyperhidrosis. [26a] Use of compound (I) as described in any one of [9a] to [15a] for the manufacture of a pharmaceutical composition for use in the treatment of primary axillary hyperhidrosis or primary palmar hyperhidrosis.

[0060] Furthermore, the present invention also includes the following inventions. [9b] The content of compound (I) is represented by the following formula (III): [ka] The crystalline form of compound (I) according to any one of [1] to [6], wherein the content of compound (III) represented by the formula:

[0061] [10b] The content of compound (I) is calculated based on the following formula (IV): [ka] The crystalline form of compound (I) according to any one of [1] to [6], wherein the content of compound (IV) represented by the formula:

[0062] [11b] The content of compound (I) is calculated based on the following formula (V): [ka] The crystalline form of compound (I) according to any one of [1] to [6], wherein the content of compound (V) represented by the formula:

[0063] [12b] A crystalline form of compound (I) according to any one of [1] to [6], wherein the contents of compound (III), compound (IV), and compound (V) are each 0.5 w / w% or less relative to the content of compound (I), and the purity of compound (I) is 98.0 w / w% or more. [13b] A crystalline form of compound (I) according to any one of [1] to [6], wherein the contents of compound (III), compound (IV), and compound (V) are each 0.5 w / w% or less relative to the content of compound (I), the total content of impurities is 2.0 w / w% or less, and the purity of compound (I) is 98.0 w / w% or more. [14b] A crystalline form of compound (I) according to any one of [1] to [6], wherein the contents of compound (III), compound (IV), and compound (V) are each 0.15 w / w% or less relative to the content of compound (I), the total content of impurities is 1.0 w / w% or less, and the purity of compound (I) is 99.0 w / w% or more. [15b] A crystalline form of compound (I) according to any one of [9b] ​​to [14b], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 99:1 to 1:99.

[0064] [15c] A crystalline form of compound (I) according to any one of [9b] ​​to [14b], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 50:50 to 10:90. [15d] A crystalline form of compound (I) according to any one of [9b] ​​to [14b], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 20:80. [15e] A crystalline form of compound (I) according to any one of [9b] ​​to [14b], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 25:75. [15f] A crystalline form of compound (I) according to any one of [9b] ​​to [14b], wherein compound (Ia) and compound (Ib) are contained in a content ratio of 40:60 to 30:70. Effect of the Invention

[0065] Form CO, which is one embodiment of the crystalline form of sofpironium bromide of the present invention, is non-hygroscopic and highly stable, and therefore can be used as an active pharmaceutical ingredient for pharmaceuticals. Form B, which is another embodiment of the crystalline form of sofpironium bromide of the present invention, is a crystalline form that includes Form CO and Form MN, and is suitable as an active pharmaceutical ingredient for pharmaceuticals because it is non-hygroscopic and highly stable. The method for producing a crystalline mixture of sofpironium bromide (e.g., Form B) of the present invention can be carried out by a simple operation suitable for an industrial scale, and can produce a crystalline mixture of sofpironium bromide of high purity in high yield. [Brief description of the drawings]

[0066] [Figure 1] 1 is a powder X-ray diffraction spectrum of the crystalline form (Form MN) of compound (Ia) prepared in Preparation Example 4. [Diagram 2] 1 is a powder X-ray diffraction spectrum of the crystalline form (Form MJ) of compound (Ib) prepared in Preparation Example 5. [Diagram 3] 1 is a powder X-ray diffraction spectrum of the crystalline form (Form CO) of sofpironium bromide prepared in Example 6. [Figure 4] 1 is a solid-state 13C nuclear magnetic resonance spectrum of the crystalline form (Form B) of sofpironium bromide prepared in Example 3. [Diagram 5] 1 is a solid-state 13C nuclear magnetic resonance spectrum of the crystalline form (Form MN) of sofpironium bromide prepared in Preparation Example 4. [Figure 6] 1 is a solid-state 13C nuclear magnetic resonance spectrum of the crystalline form (Form MJ) of sofpironium bromide prepared in Preparation Example 5. [Figure 7] 1 is a solid-state 13C nuclear magnetic resonance spectrum of the crystalline form (Form CO) of sofpironium bromide prepared in Example 6. [Figure 8] FIG. 5 is an enlarged view of the solid-state 13C nuclear magnetic resonance spectrum shown in FIG. 4 from 110 to 190 ppm. [Figure 9] 1 is a powder X-ray diffraction spectrum of the crystalline form (Form A) of sofpironium bromide prepared in Example 1. [Figure 10] 1 is a powder X-ray diffraction spectrum of the crystalline form (Form B) of sofpironium bromide prepared in Example 3. [Figure 11] 1 is a powder X-ray diffraction spectrum of the crystalline form (Form B) of sofpironium bromide prepared in Example 5. [Figure 12] 1 is a differential scanning calorimetry (DSC) chart of the crystalline form (Form A) of sofpironium bromide prepared in Example 1. [Figure 13] 1 is a differential scanning calorimetry (DSC) chart of the crystalline form (Form B) of sofpironium bromide prepared in Example 3. [Figure 14] 1 is a differential scanning calorimetry (DSC) chart of the crystal form (Form MN) of sofpironium bromide prepared in Preparation Example 4. [Figure 15] 1 is a differential scanning calorimetry (DSC) chart of the crystal form (Form MJ) of sofpironium bromide produced in Production Example 5. [Figure 16] 1 is a differential scanning calorimetry (DSC) chart of the crystalline form (Form CO) of sofpironium bromide prepared in Example 6. [Figure 17] 1 is an infrared absorption spectrum of the crystalline form (Form A) of sofpironium bromide prepared in Example 1. [Figure 18] 1 is an infrared absorption spectrum of the crystalline form (Form B) of sofpironium bromide prepared in Example 3. [Figure 19] 1 is an infrared absorption spectrum of the crystal form (Form MN) of sofpironium bromide prepared in Preparation Example 4. [Figure 20] 1 is an infrared absorption spectrum of the crystalline form (Form MJ) of sofpironium bromide prepared in Preparation Example 5. [Figure 21] 1 is an infrared absorption spectrum of the crystalline form (Form CO) of sofpironium bromide prepared in Example 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] The present invention will be described in detail below. In the present specification, compound (I) refers to a mixture of compound (Ia) and compound (Ib). The content ratio of compound (Ia) to compound (Ib) (hereinafter, unless otherwise specified, the content ratio refers to the weight ratio) is not particularly limited, and the content ratio can be, for example, in the range of 99:1 to 1:99.

[0068] In the present specification, the content ratio of compound (Ia) to compound (Ib) contained in the drug substance, solution, suspension, formulation, or crystalline form of compound (I) is preferably 50:50 to 10:90, more preferably 45:55 to 20:80, and even more preferably 40:60 to 20:80. In another embodiment of the present invention, a preferred content ratio of compound (Ia) to compound (Ib) contained in compound (I) is 40:60 to 25:75. In another embodiment of the present invention, another preferable content ratio of compound (Ia) and compound (Ib) contained in compound (I) is 40:60 to 30:70. In this specification, unless otherwise specified, a numerical range includes the maximum and minimum values ​​defined in the range. For example, "1 to 99" means a range of 1 or more and 99 or less.

[0069] As used herein, the term "crystalline form" refers to solids in which the constituent components (molecules) form a three-dimensional repeating structure called a crystal lattice, and mixtures of such solids, and is distinguished from amorphous solids which do not have such a repeating structure.

[0070] In the present specification, the term "crystal form" includes a cocrystal in which a plurality of components (preferably several, more preferably two, types of organic compound molecules) are present in a single crystal lattice, and a mixture of a plurality of single crystals. Therefore, when a crystal form is prepared from a mixture containing two or more compounds, the crystal form may be, for example, a single crystal consisting of only a single compound, a mixture of a plurality of crystal polymorphs of a single compound, a single cocrystal consisting of a plurality of compounds, a mixture of crystals containing a plurality of such crystals, and the like. As used herein, the term "crystal mixture" refers to a mixture of multiple crystals of one crystal form.

[0071] Generally, the crystalline form of a low molecular weight compound such as sofpironium bromide often has a peak near a specific diffraction angle (2θ) in the powder X-ray diffraction spectrum, and is a solid 13 C nuclear magnetic resonance spectrum (solid 13 It has a peak at a specific chemical shift value in C-NMR measurement, a specific endothermic peak in differential scanning calorimetry (DSC) measurement, and an absorption band at a specific wavelength in infrared absorption spectroscopy (IR) measurement. However, depending on the properties or quality of each crystal form, these instrumental analyses may not be performed properly.

[0072] In this specification, unless otherwise specified, the analysis by X-ray diffraction refers to a powder X-ray diffraction spectrum, and can be performed according to a conventional method such as the "Powder X-ray Diffraction Measurement Method" described in the Japanese Pharmacopoeia (17th edition). Note that, in the case of the same crystal form, the diffraction angle 2θ usually coincides within a range of ±0.2° or ±0.1°. In this specification, the peak value of the diffraction angle 2θ means that at least the peak is present. For example, "in the powder X-ray diffraction spectrum, the diffraction angle represented by 2θ is 5.9±0.2°, 7.6±0.2°, 11.0±0.2°, and 22.2±0.2° peaks" means that at least 5.9±0.2°, 7.6±0.2°, 11.0±0.2°, and 22.2±0.2° peaks are present, and other peaks may be observed. In addition, the peak intensities of 5.9±0.2°, 7.6±0.2°, 11.0±0.2°, and 22.2±0.2° are not particularly limited as long as they are distinguishable from others.

[0073] In the powder X-ray diffraction spectrum of the present specification, the sample obtained in the production process was directly measured after only powderization without pretreatment such as grinding, sieving, etc. However, the sample may be pretreated as necessary.

[0074] In this specification, solid 13 C nuclear magnetic resonance spectrum (solid 13 Unless otherwise specified, the C-NMR measurements are performed by CP / MAS. 13 C. 15 It is widely used to measure nuclei with low natural abundance, such as N, and by utilizing the cross polarization (cross relaxation) (CP) method and magic angle spinning (MAS) the chemical shift can be observed in the same way as in the solution spectrum.

[0075] In this specification, the analysis by differential scanning calorimetry (DSC) can be performed according to a conventional method such as the "thermal analysis method" described in the Japanese Pharmacopoeia (17th edition). In this specification, the "endothermic peak" refers to the temperature at the peak apex, which may vary somewhat depending on the measurement conditions. The range of measurement error that may occur varies somewhat depending on the measurement conditions and the test substance, but may be, for example, within a range of ±5°C, or within a range of ±2°C. In other words, if the crystal form is the same, the "endothermic peak" will match within a range of ±5°C or ±2°C.

[0076] In this specification, the analysis by infrared absorption spectrum can be performed according to a conventional method such as the "Infrared Absorption Spectroscopy Method" described in the Japanese Pharmacopoeia (17th edition). Note that the wave number and intensity at which absorption is observed may vary slightly depending on the measurement conditions, etc. Absorption band (cm -1 ) The range of measurement error that may occur is usually within ±0.5% or ±5cm -1 In this case, if the crystal form is the same, the absorption band (cm -1 ) is within the range of ±0.5% or ±5cm -1 Matches within the range.

[0077] Next, the crystal forms of Compound (I), Compound (Ia), and Compound (Ib) described in the present specification will be described in detail.

[0078] Compound (I) is a mixture of compound (Ia) and compound (Ib). Furthermore, as shown in the test examples described later, the crystal form of compound (I) varies depending on the content ratio and the production method (e.g., crystallization method).

[0079] Form CO is one of the crystal forms of compound (I), and is a cocrystal in which compound (Ia) and compound (Ib) exist in a ratio of 1:3. Compound (Ia) and compound (Ib) are epimers, and generally, cases in which such two epimers form a single cocrystal are extremely rare, and there have been almost no reported cases.

[0080] Form CO is thermally stable, does not undergo crystal transition, especially under humid conditions, and is an extremely stable crystalline form. Form CO is a white solid, non-hygroscopic, and easy to handle, such as by filtering from a suspension. Because of the above properties, Form CO is one of the preferred crystal forms of Compound (I).

[0081] Form CO can be produced, for example, by using compound (I) having a ratio of compound (Ia) and compound (Ib) of 1:3 as a raw material, through the following steps: Step C: preparing a suspension of compound (I) in a solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); However, the method for producing Form CO is not limited to the above specific method.

[0082] Since compound (I) is a mixture of compound (Ia) and compound (Ib) mixed in any ratio, it is usually difficult to obtain only Form CO even if a crystalline form is produced using compound (I) as a raw material by the above-mentioned production method, and a crystalline mixture of Form CO and other crystalline forms is obtained.

[0083] Since Form CO has an extremely excellent profile as a drug substance, a crystalline form of Compound (I) containing a large amount of Form CO has a suitable profile as a drug substance for drugs. For example, a crystalline form of Compound (I) containing 50% or more of Form CO by weight in Compound (I) is preferred, a crystalline form of Compound (I) containing 60% or more of Form CO is more preferred, and a crystalline form of Compound (I) containing 80% or more of Form CO is even more preferred.

[0084] Form MN is a crystalline form of compound (Ia). Form MN is thermally stable, and does not undergo crystal transition, particularly under humid conditions, making it an extremely stable crystalline form. Form MN is non-hygroscopic, a white solid, and easy to handle, such as by filtration from a suspension. Due to the above properties, Form MN has an excellent profile as an active pharmaceutical ingredient.

[0085] Form MJ is a crystalline form of compound (Ib). Form MJ is a white solid and is an easy-to-handle crystalline form, such as by filtering from a suspension. However, Form MJ undergoes crystal transition under humid conditions, and there are many crystalline polymorphs. Due to the above properties, it is difficult to say that Form MJ has an optimal profile as an active pharmaceutical ingredient.

[0086] Form A is one of the crystal forms of compound (I). Form A is a crystal mixture consisting of Form MN and Form MJ. Since compound (Ia) in compound (I) forms Form MN, and compound (Ib) in compound (I) forms Form MJ, the content ratio of Form MN and Form MJ constituting Form A depends on the content ratio of compound (Ia) and compound (Ib). For example, when the content ratio of compound (Ia) and compound (Ib) is 1:2, the content ratio of Form MN and Form MJ is also about 1:2. Form A is a crystalline form that contains Form MJ. Therefore, Form A undergoes crystal transition under humid conditions, and it is difficult to say that this is an optimal profile for use as an active pharmaceutical ingredient in pharmaceuticals.

[0087] Form B is one of the crystalline forms of Compound (I). Form B is a crystalline mixture consisting of Form CO and Form MN. The content ratio (weight ratio) of Form CO and Form MN constituting Form B is 99:1 to 50:50, preferably 96:4 to 60:40, and more preferably 92:8 to 80:20. The content ratio of Form CO and Form MN in Form B is determined depending on the content ratio of compound (Ia) and compound (Ib) contained in compound (I) used as a raw material. For example, when the content ratio of compound (Ia) and compound (Ib) is 1:2, the content ratio of Form CO and Form MN in Form B is approximately 89:11.

[0088] As mentioned above, Form CO and Form MN have excellent profiles as pharmaceutical active ingredients, and Form B, which is a mixture of them, has an optimal profile as a pharmaceutical active ingredient. That is, Form B is thermally stable, does not undergo crystal transition, especially under humid conditions, and is an extremely stable crystalline form. Furthermore, Form B is non-hygroscopic, is a white solid, and is easy to handle, such as by filtration from a suspension. Form B, which does not contain Form MJ, is a particularly preferred embodiment.

[0089] Form B is produced by applying the above-mentioned method for producing Form CO. Form B, which is substantially free of Form MJ, is produced by applying the above-mentioned method for producing Form CO using compound (I) having a compound (Ia) content of 25% or more as a raw material. Furthermore, by applying the production method of the present invention, high-purity Form B can be produced on an industrial scale.

[0090] Because of the above characteristics and properties, Form B is a preferred crystalline form for industrially producing and providing a crystalline form of sofpironium bromide, and Form B not containing Form MJ is a particularly preferred crystalline form.

[0091] As used herein, the term "crystalline form of Compound (I)" includes the above-mentioned crystalline forms and mixtures thereof, for example, a mixture of Form MJ and Form MN (e.g., Form A), a mixture of Form CO and Form MN (e.g., Form B), and a mixture of Form CO and Form MJ. As used herein, the term "crystalline form of compound (Ia)" refers to a crystalline form consisting essentially of compound (Ia) (e.g., Form MN). As used herein, the term "crystalline form of compound (Ib)" refers to a crystalline form consisting essentially of compound (Ib) (e.g., Form MJ). As used herein, the term "crystalline form of the present invention" refers to crystalline forms of Compound (I) including Form CO, for example Form B. In the present invention, a preferred crystalline form of Compound (I) is a crystalline form containing Form CO, a more preferred crystalline form of Compound (I) is a crystalline mixture containing Form CO and Form MN, and a further preferred crystalline form of Compound (I) is a crystalline mixture containing Form CO and Form MN, and is substantially free of Form MJ.

[0092] Next, the details of each step described in [7] above regarding the method for producing sofpironium bromide, which is one embodiment of the present invention, will be explained. By applying the production method of the present invention, the crystalline form of the present invention (e.g., Form B) can be obtained with high purity. In addition, this production method can be applied on an industrial scale.

[0093] In one embodiment of the present invention, the production method of the present invention comprises the steps of: Step C: preparing a suspension of compound (I) in a solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); Includes.

[0094] In the above step C, the compound (I) used as the raw material is preferably, but not limited to, a crystalline form of sofpironium bromide. Moreover, the step C includes both a recrystallization step and a suspension washing step. After preparing the solution of compound (I), recrystallization may be carried out or suspension washing may simply be carried out.

[0095] The "solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether" in step C refers to any one of a solvent containing only ethyl acetate, a solvent containing only methyl t-butyl ether, a mixed solvent of ethyl acetate and methyl t-butyl ether, a mixed solvent of ethyl acetate or methyl t-butyl ether with other solvents, a mixed solvent of ethyl acetate or methyl t-butyl ether with other solvents, and the like.

[0096] A preferred solvent for step C is any one of a solvent containing only ethyl acetate, a mixed solvent of ethyl acetate and acetonitrile, a mixed solvent of ethyl acetate and methyl t-butyl ether, and a mixed solvent of ethyl acetate, acetonitrile, and methyl t-butyl ether. A more preferred solvent is a mixed solvent of ethyl acetate, methyl t-butyl ether, and acetonitrile.

[0097] The amount of the solvent containing at least one solvent selected from the above-mentioned ethyl acetate and methyl t-butyl ether is not particularly limited, but is preferably 3 to 40 times the volume (L) of the weight (Kg) of compound (I), more preferably 5 to 30 times the volume (L), even more preferably 8 to 20 times the volume (L), and even more preferably 10 to 15 times the volume (L).

[0098] In this specification, the terms "suspension" and "slurry" refer to a dispersion system in which solid particles exist in a liquid, and the two terms are used synonymously. In step C, the stirring time refers to the time during which the suspension of compound (I) is stirred, specifically, the time from when solid particles of compound (I) are generated in the solution to when stirring is completed. For example, when seed crystals are added to the solution of compound (I), the stirring time refers to the time from when the seed crystals are added to when stirring is completed. In addition, when ethyl acetate or methyl t-butyl ether is added to the solution of compound (I) without adding seed crystals (including when added dropwise), the stirring time in step C refers to the time from when solid particles of compound (I) are generated in the solution to when stirring is completed. In addition, when the solution of compound (I) is not used in step C (i.e., when only suspension washing is performed), the stirring time in step C refers to the time from when compound (I) is mixed with a solvent containing ethyl acetate or methyl t-butyl ether to when stirring is completed.

[0099] The stirring time in step C is 1 hour or more, preferably 2 hours or more, more preferably 3 hours or more, and even more preferably 4 hours or more. In another embodiment of the present invention, the stirring time in step C is preferably 1 hour or more and 72 hours or less, more preferably 1 hour or more and 48 hours or less, and even more preferably 1 hour or more and 24 hours or less. When ethyl acetate or methyl t-butyl ether is added dropwise, the addition time is not particularly limited, but is preferably 30 minutes or more, more preferably 1 hour or more, even more preferably 3 hours or more, and even more preferably 4 hours or more and 72 hours or less.

[0100] In another embodiment of the present invention, the production method of the present invention further comprises the steps of: Step C-1: dissolving compound (I) in a solvent containing acetonitrile to obtain a solution of compound (I); and Step C-2: mixing the solution of compound (I) with a poor solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether to prepare a suspension of compound (I), and stirring the suspension for one hour or more; may include.

[0101] In the above step C-1, compound (I) is preferably completely dissolved in a solvent containing acetonitrile. "Completely dissolved" means that compound (I) is dissolved to such an extent that it cannot be observed with the naked eye, and a colorless or colored clear solution of compound (I) is usually obtained.

[0102] In step C-1, the "solvent containing acetonitrile" includes a solvent containing only acetonitrile and a mixed solvent of acetonitrile and another solvent. A preferred "solvent containing acetonitrile" is a mixed solvent of acetonitrile and ethyl acetate. When a mixed solvent of acetonitrile and ethyl acetate is used, the ratio can be appropriately changed within a range of 99:1 to 1:99, but is preferably within a range of 90:10 to 10:90, and more preferably within a range of 60:40 to 40:60. In addition, other solvents may be added to the mixed solvent of acetonitrile and ethyl acetate as appropriate.

[0103] In addition, when a mixed solvent of acetonitrile and ethyl acetate is used as the "solvent containing acetonitrile", ethyl acetate may be added stepwise as necessary to obtain an acetonitrile solution of compound (I). For example, compound (I) may be dissolved in acetonitrile and then ethyl acetate may be added, or compound (I) may be dissolved in a mixed solvent of acetonitrile and ethyl acetate and then ethyl acetate may be further added.

[0104] In step C-1, the solution of compound (I) may be heated as appropriate in order to completely dissolve compound (I) in the "solvent containing acetonitrile". For example, compound (I) may be suspended in a mixed solvent of acetonitrile and ethyl acetate, and then heated to completely dissolve compound (I).

[0105] In step C-1, the volume of the "solvent containing acetonitrile" is not particularly limited as long as it can dissolve compound (I), but for example, a volume (L) of the solvent can be used that is 2 to 10 times the volume (kg) of the crystalline form of compound (I) used as a raw material. The preferred amount of the solvent (L) is 3 to 8 times, more preferably 4 to 5 times, the crystalline form of compound (I) (kg).

[0106] Step C-2 is a step of mixing the solution of compound (I) with a poor solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether to prepare a suspension of compound (I), and stirring the suspension for one hour or more. The start and end points of the stirring time in step C-2 are the same as the start and end points of the stirring time in step C described above.

[0107] In one embodiment of the present invention, step C-2 comprises: Step C-2(a): adding a poor solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether to the solution of compound (I) to prepare a suspension of compound (I), and stirring the suspension for one hour or more; or Step C-2(b): adding the solution of compound (I) to a poor solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether to prepare a suspension of compound (I), and stirring the suspension for at least one hour; That's fine too.

[0108] The poor solvent in step C-2 (hereinafter including the case of step C-2(a) or step C-2(b)) is a solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether. Any of a solvent containing only ethyl acetate, a solvent containing only methyl t-butyl ether, a mixed solvent of ethyl acetate and methyl t-butyl ether, a mixed solvent of ethyl acetate or methyl t-butyl ether with another solvent, and a mixed solvent of ethyl acetate and methyl t-butyl ether with another solvent is preferable. More preferable poor solvents are any of a solvent containing only ethyl acetate, a solvent containing only methyl t-butyl ether, and a mixed solvent of ethyl acetate and methyl t-butyl ether.

[0109] In step C-2, the volume of the poor solvent used is not particularly limited, but for example, a volume (L) of the solvent containing acetonitrile added in step C-1 that is 1.0 to 2.5 times the volume (L) of the solvent can be used. The volume (L) of the poor solvent is preferably 1.0 to 2.0 times, more preferably 1.0 to 1.5 times.

[0110] Step C-2 is preferably step C-2(a). That is, the poor solvent is added to the solution of compound (I) to mix them. In this case, the poor solvent is preferably added stepwise or dropwise. For example, after the poor solvent is added in an amount of 0.1 to 0.25 times the volume of the solvent containing acetonitrile added in step C-1, the remaining poor solvent may be added. When the poor solvent is added dropwise, it is preferable to add it dropwise over a certain period of time or more. When the poor solvent is added dropwise, the drop time is not particularly limited, but is preferably 30 minutes or more, more preferably 1 hour or more, even more preferably 3 hours or more, and even more preferably 4 hours or more and 72 hours or less. In this case, the poor solvent may be added after the solution of compound (I) is heated. After the poor solvent is added, the solution may be gradually cooled as necessary.

[0111] Step D is a step of filtering the suspension of compound (I) produced in step C to obtain a crystalline form of compound (I). The crystalline form of Compound (I) obtained in Step D is, for example, Form B, and includes Form CO.

[0112] In one embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained via step C and step D is 99:1 to 1:99. In another embodiment of the present invention, the content ratio of compound (Ia) to compound (Ib) in compound (I) of the present invention obtained through step C and step D is 90:10 to 10:90. In another embodiment of the present invention, the content ratio of compound (Ia) to compound (Ib) in compound (I) of the present invention obtained through step C and step D is 50:50 to 10:90. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained via step C and step D is 40:60 to 20:80. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained via step C and step D is 40:60 to 25:75. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained through step C and step D is 40:60 to 30:70.

[0113] Next, the details of each step described in [8] above regarding the method for producing sofpironium bromide, which is another embodiment of the present invention, will be described. By applying the production method of the present invention, the crystal form of sofpironium bromide of the present invention (e.g., Form B) can be obtained in high purity via the crystal form (e.g., Form A). In addition, this production method can be applied on an industrial scale.

[0114] In another embodiment of the present invention, the process of the present invention comprises the steps of: Step A: In a solvent, Formula (II): [ka] reacting compound (II) represented by the formula: with ethyl bromoacetate to prepare a reaction solution containing compound (I); Step B: filtering the reaction solution to obtain a crystalline form of compound (I); Step C': preparing a suspension of the crystalline form of Compound (I) in a solvent comprising at least one solvent selected from ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least one hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); Includes.

[0115] Compound (I) can be produced by reacting compound (II) with ethyl bromoacetate. However, the production method disclosed in Non-Patent Document 1 and the like uses only acetonitrile as a solvent, and as described above, cannot be applied to industrial production.

[0116] In step A, by using an appropriate solvent, the resulting sofpironium bromide can be precipitated in a crystalline form in the reaction solution. Therefore, in the next step B, the crystalline form of sofpironium bromide can be obtained simply by filtering the reaction solution, so the production method of the present invention is industrially suitable. In this specification, when simply referring to "step A", it also includes a step equivalent to step A or a step similar to step A, for example, step A', etc. Similarly, below, step C includes step C', etc.

[0117] The "solvent" used in step A is not particularly limited as long as it allows the resulting sofpironium bromide to precipitate in a crystalline form in the reaction solution. A preferred solvent used in step A is a solvent containing ethyl acetate, and a more preferred solvent is a solvent containing only ethyl acetate.

[0118] The amount of the solvent in step A is not particularly limited as long as the reaction proceeds. A preferred amount of the solvent is 3 to 40 times (L) the weight (Kg) of compound (II), more preferably 5 to 20 times (L), even more preferably 8 to 16 times (L), and even more preferably 11 to 13 times (L).

[0119] The reaction temperature in step A is not particularly limited as long as the reaction proceeds. For example, the reaction temperature in step A may be from room temperature to 80° C. or less. According to one embodiment of the present invention, the reaction temperature in step A is preferably 50° C. or more and 60° C. or less. The reaction time in step A is not particularly limited as long as the reaction proceeds, but is preferably in the range of 0.5 to 72 hours, more preferably 1 to 24 hours.

[0120] The equivalent amount of ethyl bromoacetate used in step A is not particularly limited as long as the reaction proceeds, but is preferably 1.0 to 30 equivalents relative to compound (II), more preferably 1.0 to 5.0 equivalents, even more preferably 1.0 to 2.0 equivalents, still more preferably 1.0 to 1.5 equivalents, and particularly preferably 1.0 to 1.1 equivalents. As an embodiment of step A, a bromoethyl acetate solution in which bromoethyl acetate is dissolved in a solvent in advance may be used. For example, a solution of bromoethyl acetate in ethyl acetate may be added to a separately prepared solution of compound (II). The amount of solvent, reaction temperature, reaction time, and equivalent amount of bromoethyl acetate in this embodiment are not particularly limited as long as the reaction proceeds, but are preferably in accordance with the above values.

[0121] After step A and before step B, the reaction solution may be heated or cooled to precipitate a crystalline form of sofpironim bromide. For example, the reaction solution may be heated to 40° C. or higher and 80° C. or lower, stirred for a certain period of time, and then slowly cooled to room temperature. The time required for cooling is not particularly limited as long as a crystalline form can be obtained in good yield and with high purity, but it is preferable to slowly cool the reaction solution to room temperature over, for example, one hour or more.

[0122] Step B is a step of filtering the reaction solution obtained in step A to obtain a crystalline form of compound (I). The crystalline form of compound (I) obtained in step B includes, but is not limited to, Form A. The crystalline form of compound (I) obtained through steps A and B is of high purity.

[0123] In one embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained via step A and step B is 99:1 to 1:99. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained through step A and step B is 90:10 to 10:90. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained via step A and step B is 50:50 to 10:90. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained through step A and step B is 40:60 to 20:80. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained through step A and step B is 40:60 to 25:75. In another embodiment of the present invention, the content ratio of compound (Ia) and compound (Ib) in compound (I) of the present invention obtained through step A and step B is 40:60 to 30:70.

[0124] Form A is a mixture of Form MN and Form MJ crystals, but crystal transitions may occur. Therefore, it is desirable to obtain a crystal form (e.g., Form B) with a profile more suitable for use as a pharmaceutical drug substance.

[0125] In another embodiment of the present invention, a crystalline form of sofpironium bromide having a profile more suitable as a pharmaceutical active ingredient (e.g., Form B) is obtained by carrying out Steps A and B, followed by Steps C' and D. The definitions of the terms used in step C' of the production method of the present invention described in [8] etc. are the same as those in step C described in [7]. The definitions of the terms used in step D of the production method of the present invention described in [8] etc. are the same as those in step D described in [7].

[0126] Next, the purity and impurities of the compound (I) of the present invention will be described. Compound (I) of the present invention (including the crystalline form of the present invention) has extremely few impurities and is highly pure, and therefore has a quality suitable for use as a drug substance for pharmaceuticals. In this specification, the term "impurities" refers to substances contained in drug substances or formulations other than chemical substances defined as drug substances or pharmaceutical additives, and includes related substances, reaction products, decomposition products, etc.

[0127] In this specification, "compound (I) of the present invention" refers to high-purity compound (I) obtained by the above-mentioned production method of the crystalline form of the present invention (e.g., [8a], [8b]), and includes the crystalline form of the present invention. In the present specification, "high purity compound (I)" refers to compound (I) having a purity of 98.0 w / w% or more. For example, in one embodiment of the present invention, "high purity compound (I)" refers to compound (I) having a purity of 99.0 w / w% or more, and in another embodiment of the present invention, "high purity compound (I)" refers to compound (I) having a purity of 99.5 w / w% or more.

[0128] The content of each impurity contained in the compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less, based on the content of the compound (I). Therefore, the content of each impurity contained in the pharmaceutical composition using the compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less, based on the content of the compound (I).

[0129] The total content of impurities contained in the compound (I) of the present invention is 4.0 w / w% or less, preferably 2.0 w / w% or less, more preferably 1.0 w / w% or less, based on the content of compound (I). Therefore, the total content of impurities contained in a pharmaceutical composition using the compound (I) of the present invention is 4.0 w / w% or less, preferably 2.0 w / w% or less, more preferably 1.0 w / w% or less, based on the content of compound (I).

[0130] As used herein, the term "impurities" includes, but is not limited to, the following compounds: 1) The following formula (III): [ka] Compound (III) represented by the formula:

[0131] Compound (III) is a compound obtained by hydrolysis of the ethyl ester of compound (I), and is a mixture of epimers at the 1'-position. The content of compound (III) contained in compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less. Therefore, the content of compound (III) contained in a pharmaceutical composition using compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less, based on the content of compound (I).

[0132] 2) The following formula (IV): [ka] Compound (IV) represented by the formula:

[0133] Compound (IV) can be produced when bromoacetic acid is contained as a contaminant in the ethyl bromoacetate used in the above-mentioned step A. The content of compound (IV) contained in compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less. Therefore, the content of compound (IV) contained in a pharmaceutical composition using compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less, based on the content of compound (I).

[0134] 3) The following formula (V): [ka] Compound (V) represented by the formula:

[0135] Compound (V) is a compound obtained by hydrolysis of the cyclopentylmandelic acid ester of compound (I). The content of compound (V) contained in compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less. Therefore, the content of compound (V) contained in a pharmaceutical composition using compound (I) of the present invention is 0.5 w / w% or less, preferably 0.15 w / w% or less, based on the content of compound (I).

[0136] The total content of compound (III), compound (IV) and compound (V) contained in compound (I) of the present invention is 4.0 w / w% or less, preferably 2.0 w / w% or less, more preferably 1.0 w / w% or less. Therefore, the total content of compound (III), compound (IV) and compound (V) contained in a pharmaceutical composition using compound (I) of the present invention is 4.0 w / w% or less, preferably 2.0 w / w% or less, more preferably 1.0 w / w% or less, based on the content of compound (I).

[0137] As described in [8a], the compound (I) of the present invention (i.e., high-purity compound (I)) can be produced by a production method including steps A and B. As described in [8b], steps A and B may be followed by steps C' and D.

[0138] The above-mentioned impurities, Compound (III), Compound (IV), and Compound (V), are useful as indicators for producing high-purity Compound (I) (including the crystalline form of Compound (I) of the present invention).

[0139] The present invention includes a pharmaceutical composition (hereinafter also referred to as the pharmaceutical composition of the present invention) using the compound (I) of the present invention (including the crystalline form of the present invention) as an active ingredient. The pharmaceutical composition of the present invention is not particularly limited, but is preferably a topical application preparation. When the pharmaceutical composition of the present invention is a preparation for external application, it can be produced according to a standard method, for example, in accordance with the preparation described in Patent Document 1.

[0140] The pharmaceutical composition of the present invention is not particularly limited, but is preferably a medicine used for treating hyperhidrosis, more preferably a medicine used for treating primary axillary hyperhidrosis or primary palmar hyperhidrosis. However, since compound (I) has an anticholinergic effect, the pharmaceutical composition of the present invention can be used as a medicine for treating various diseases related to the action of acetylcholine. EXAMPLES

[0141] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0142] In each of the crystalline forms described herein, the solid 13 The chemical shift value of the C nuclear magnetic resonance spectrum, the characteristic diffraction angle by powder X-ray diffraction, the characteristic endothermic peak by DSC measurement, and the characteristic absorption band by IR measurement may vary depending on the measurement conditions. Therefore, the measured values ​​of the crystal form in this specification may have errors.

[0143] Production Example 1 <Production method of crude (R)-cyclopentylmandelic acid (compound (V), (R)-CPMA)> DL-Cyclopentylmandelic acid (CPMA) (66.0 g, 0.30 mol) was dissolved in acetonitrile (1300 mL) at 50°C. L-Tyrosine methyl ester (70.2 g, 0.36 mol) was added. The inlet was washed with acetonitrile (66 mL), stirred under reflux, and then gradually cooled to room temperature while stirring, and the precipitate was filtered. The filtrate was washed with acetonitrile, and the obtained filtrate and washings were combined and concentrated, and then water (292 mL) was added to the residue to dissolve it. The obtained aqueous solution was cooled with water, and dilute sulfuric acid was added until the pH of the aqueous layer was about 1, and then extracted with methyl t-butyl ether. The organic layer was dried with magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off, and the obtained solid was dried to obtain crude (R)-CPMA (yield: 32.3 g, yield: 49%, optical purity: 96.8%ee) as a pale yellow solid.

[0144] The optical purity of crude (R)-CPMA was measured by high performance liquid chromatography (HPLC) under the following conditions. <Optical purity measurement of (R)-CPMA> 1)Analysis conditions Detector: UV spectrophotometer (measurement wavelength: 220 nm) Column: AD-RH (inner diameter 4.6 mm, length 15 cm, particle size 5.0 μm) Column temperature: constant temperature around 30℃ Flow rate: 0.9 mL / min Injection volume: 10 μL Mobile phase: Water / acetonitrile / formic acid mixture (600:400:1) 2) Preparation of sample solution Approximately 10 mg of each sample was weighed out, and 10 mL of acetonitrile was added to prepare a sample solution.

[0145] Production Example 2: Production method for (R)-cyclopentylmandelic acid (compound (V), (R)-CPMA) The crude (R)-CPMA (31.9 g, 145 mmol) produced in Production Example 1 was suspended in toluene (140 mL), and (R)-phenylethylamine (20.7 g, 171 mmol) was added. The reaction solution was stirred under reflux, and then n-heptane (140 mL) was added to the reaction solution. The reaction solution was further stirred under reflux. The reaction solution was stirred while gradually cooling to room temperature, and then the precipitate was filtered. The precipitate was washed with n-heptane and dried. The dried precipitate was suspended in a mixture of toluene (127 mL) and n-heptane (127 mL). The suspension was turned into a solution under reflux, and then stirred while gradually cooling to room temperature. The precipitate was filtered, washed with n-heptane, and then dried. Methyl t-butyl ether (171 mL) and water (79 mL) were added to the dried precipitate and stirred. Dilute sulfuric acid was added until the solid was dissolved. The resulting solution was stirred, and then the organic layer was separated and the aqueous layer was extracted with methyl t-butyl ether. The organic layers were combined and extracted with a sodium hydrogen carbonate solution. For washing, the aqueous layer was extracted with methyl t-butyl ether, and then dilute sulfuric acid was added until the aqueous layer became acidic to form a suspension. The resulting suspension was extracted with methyl t-butyl ether, and the organic layer was washed with water and then dried with magnesium sulfate. After filtering off the magnesium sulfate, the solvent was distilled off, and the resulting solid was dried to obtain (R)-CPMA (yield: 22.7 g, yield: 71%, optical purity: >99.9% ee) as a pale yellow solid. The optical purity was measured in the same manner as in Production Example 1.

[0146] Production Example 3: Production method for (2R,3'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1'-methylpyrrolidine (compound (II), (2R,3'R)-CPMA-MP) After stirring a solution of (R)-CPMA (5.0 g, 23 mmol) and 1,1'-carbonyldiimidazole (CDI) (4.8 g, 30 mmol) produced in Production Example 2 in toluene (60 mL) at 5°C, the reaction solution was degassed under reduced pressure and replaced with argon. At room temperature, sodium t-butoxide (0.4 g, 5 mmol) and (R)-1-methyl-3-pyrrolidinol ((R)-MP) (2.5 g, 25 mmol) were suspended in toluene (30 mL) in a separate container and the temperature was adjusted to 40°C. The above reaction solution of (R)-CPMA and CDI was added dropwise to the resulting solution, and the resulting solution was stirred. After stirring while gradually cooling the reaction solution to room temperature, water was added and the aqueous layer was removed. The organic layer was washed with water again, dilute sulfuric acid was added until the pH of the aqueous layer was 2, and the organic layer was removed. The resulting aqueous layer was extracted with toluene for washing, and an aqueous potassium carbonate solution was added until the pH of the aqueous layer was 9, followed by extraction with ethyl acetate. The aqueous layer was re-extracted with ethyl acetate, and the organic layers were collected and washed with water. The organic layer was then concentrated to give (2R,3'R)-CPMA-MP (yield: 6.4 g, 93%) as a colorless oil.

[0147] Production Example 4 <Production method for the crystal form (Form MN) of compound (Ia)> The diastereomers of sofpironium bromide (approximately 900 mg) were separated by silica gel column chromatography using a 2-channel parallel purification apparatus Purif-Rp2. Two Presep (registered trademark) (Luer Lock) silica gel (HC-N) type L were connected, and the mobile phase shown in Table 1 was used.

[0148] Table 1 Preparation conditions [Table 1]

[0149] The first peak was compound (Ia). The fraction concentrate (g) of the first peak was dissolved in 2 volumes (mL) of acetonitrile at 40°C, and 10 volumes (mL) of methyl t-butyl ether / ethyl acetate mixed solution (3 / 2) was added and stirred to crystallize compound (Ia). Further, 8 volumes (mL) of methyl t-butyl ether / ethyl acetate mixed solution (3 / 2) was added to prepare a suspension. The suspension was stirred while being gradually cooled to room temperature. The precipitate was collected by filtration and washed twice with 2 volumes (mL) of methyl t-butyl ether / ethyl acetate mixed solution (3 / 2). The obtained solid was dried to obtain the crystalline form (Form MN) of compound (Ia) as a white solid (recovery rate 90%). The recovery rate represents the weight of the obtained crystalline solid divided by the weight of the fraction concentrate.

[0150] Production Example 5 <Production method of crystalline form (Form MJ) of compound (Ib)> The second peak obtained by the fractionation in Production Example 4 was compound (Ib). The fraction concentrate (g) of the second peak was dissolved in 2 volumes (mL) of acetonitrile at 40°C, and 10 volumes (mL) of a methyl t-butyl ether / ethyl acetate mixture (3 / 2) was added and stirred to crystallize compound (Ib). Further, 8 volumes (mL) of a methyl t-butyl ether / ethyl acetate mixture (3 / 2) was added to prepare a suspension. The suspension was stirred for 4 hours while being gradually cooled to room temperature. The precipitate was collected by filtration and washed twice with 2 volumes (mL) of a methyl t-butyl ether / ethyl acetate mixture (3 / 2). The obtained solid was dried under reduced pressure at 40°C for 11 hours to obtain the crystalline form (Form MJ) of compound (Ib) as a white solid (recovery rate 88%). The definition of the recovery rate is the same as that in Production Example 4.

[0151] Production Example 6 <Study of crystal morphology by crystallization method 1 using sofpironium bromide having various content ratios of compound (Ia) and compound (Ib)> Sofpironium bromide (3.7 g) and compound (Ia) (0.3 g) in a content ratio of compound (Ia) and compound (Ib) of 1:2 were suspended in acetonitrile (11.6 mL) and ethyl acetate (6.6 mL) and heated to form a solution. Ethyl acetate (11.0 mL) was added, and the mixture was cooled to 40°C, after which methyl t-butyl ether (1.2 mL) and seed crystals (Form A, 2.0 mg) were added. Methyl t-butyl ether (25.2 mL) was added all at once to the suspension, and the mixture was stirred at room temperature and further stirred at 5°C. The solid was filtered, washed with ethyl acetate, and dried to obtain sofpironium bromide (3.8 g) as a white solid with a content of compound (Ib) of 60% (actual area percentage measured by HPLC: 58.9%).

[0152] By a similar production method (crystallization method 1), sofpironium bromide having a compound (Ib) content of 80% (actual area percentage measured by HPLC: 80.8%) was prepared (Production Example 6-2).

[0153] Production Example 7 <Study of crystal morphology by crystallization method 2 using sofpironium bromide having various content ratios of compound (Ia) and compound (Ib)> Sofpironium bromide (3.7 g) and compound (Ia) (0.3 g) in a content ratio of compound (Ia) and compound (Ib) of 1:2 were suspended in acetonitrile (11.6 mL) and ethyl acetate (6.6 mL) and heated to form a solution. Ethyl acetate (11.0 mL) was added, and the mixture was cooled to 40°C, after which methyl t-butyl ether (1.2 mL) and seed crystals (Form A, 2.0 mg) were added and stirred. Methyl t-butyl ether (25.2 mL) was added dropwise over 5 hours and stirred at room temperature. After stirring at 5°C, the solid was filtered, washed with ethyl acetate, and dried to obtain sofpironium bromide (3.2 g) as a white solid with a content of compound (Ib) of 60% (actual area percentage measured by HPLC: 59.3%).

[0154] Similarly, sofpironium bromide having a compound (Ib) content of 70%, 75%, and 80% was prepared (Production Example 7-2 (actual area percentage measured by HPLC: 70.3%), Production Example 7-3 (actual area percentage measured by HPLC: 75.3%), Production Example 7-4 (actual area percentage measured by HPLC: 79.6%)).

[0155] Example 1 <Method for producing crystalline form (Form A) of sofpironium bromide> At room temperature, (2R,3'R)-CPMA-MP (2.7 g, 9 mmol) was dissolved in ethyl acetate (33 mL), and ethyl bromoacetate (0.08 g, 0.5 mmol) was added. After confirming the precipitation of sofpironium bromide, ethyl bromoacetate (1.5 g, 9 mmol) was added and stirred. The mixture was then heated to 52°C and stirred, and gradually cooled to room temperature, after which the solid was filtered off. The obtained solid was washed with ethyl acetate and dried to obtain the crystalline form of sofpironium bromide (Form A, yield: 4.1 g, 86.6%) as a white solid.

[0156] Example 2 <Method for producing crystalline form (Form B) of sofpironium bromide> At room temperature, sofpironium bromide Form A (5.0 g, 11 mmol) was suspended in a mixture of acetonitrile (14.5 mL) and ethyl acetate (8.3 mL) and heated to 50°C to obtain a solution. Ethyl acetate (13.8 mL) was added, and methyl t-butyl ether (33.0 mL) was added dropwise to the obtained solution over 5 hours. The obtained suspension was stirred, gradually cooled to 5°C, and further stirred. The solid was filtered, washed with ethyl acetate, and dried to obtain the crystalline form of sofpironium bromide (Form B, yield: 4.8 g, recovery rate: 97%) as a white solid. The crystal form was confirmed to be Form B by powder X-ray diffraction spectroscopy.

[0157] Example 3 <Another method for producing the crystalline form (Form B) of sofpironium bromide> At room temperature, sofpironium bromide of Form A (5.6 g, 12 mmol) was suspended in a mixture of acetonitrile (16.3 mL) and ethyl acetate (9.2 mL) and heated to 50°C to obtain a solution. After adding ethyl acetate (15.4 mL) and cooling to 40°C, methyl t-butyl ether (1.7 mL) and sofpironium bromide of Form B were added as seed crystals (2.8 mg, 0.006 mmol) to the obtained solution, and after confirming the precipitation of sofpironium bromide in crystalline form, methyl t-butyl ether (35.3 mL) was added dropwise over 5 hours and stirred while gradually cooling to room temperature. The reaction solution was cooled to 5°C and further stirred. The obtained solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure at 40°C for 11 hours to obtain sofpironium bromide in crystalline form (Form B, yield: 5.4 g, recovery rate: 96%) as a white solid. The crystal form was confirmed to be Form B by powder X-ray diffraction spectrum and other spectra.

[0158] Example 4 <Another method for producing the crystalline form (Form B) of sofpironium bromide> Ethyl bromoacetate (92 kg) and ethyl acetate (29 kg) were mixed to obtain an ethyl bromoacetate solution. Separately, (2R,3'R)-CPMA-MP (159 kg) was dissolved in ethyl acetate (1722 kg), and then ethyl bromoacetate solution (6 kg) was added to confirm the precipitation of sofpironium bromide. Ethyl bromoacetate solution (115 kg) was further added and stirred. After that, the mixture was heated to 50°C and stirred, and then slowly cooled to room temperature, and the solid was filtered. The obtained solid was washed with ethyl acetate and dried to obtain the crystalline form of sofpironium bromide (222 kg) as a white solid.

[0159] The obtained sofpironium bromide (222 kg) was suspended in a mixture of acetonitrile (443 kg) and ethyl acetate (290 kg) at room temperature and heated to 55°C, after which activated carbon (7 kg) was added and stirred. The solid matter was removed by filtration, and the solid matter was washed with a mixture of acetonitrile (61 kg) and ethyl acetate (40 kg). The washing liquid and the filtrate were combined, and then ethyl acetate (550 kg) was added and cooled to 40°C. To the obtained solution, methyl t-butyl ether (49 kg) and sofpironium bromide of Form B (1.1 kg) were added as seed crystals.

[0160] The resulting suspension was heated to 50°C, and methyl t-butyl ether (1035 kg) was added dropwise over 5 hours. The resulting suspension was stirred while being gradually cooled to 5°C. Acetonitrile (17 kg), ethyl acetate (32 kg) and methyl t-butyl ether (39 kg) were added to the suspension, and the solid was filtered off. The resulting solid was washed with ethyl acetate and then dried to obtain a crystalline form of sofpironium bromide (Form B, yield: 200 kg, two-step yield: 90.1%) as a white solid. The crystal form was confirmed to be Form B by powder X-ray diffraction spectroscopy.

[0161] Example 5 <Another method for producing the crystalline form (Form B) of sofpironium bromide> Step 1: Resolution of α-cyclopentylmandelic acid α-Cyclopentylmandelic acid (22.8 kg, 103.5 mol) was dissolved in acetonitrile at 80°C. L-Tyrosine methyl ester (22.2 kg) was added to the solution, and the mixture was heated to reflux for 70 minutes. The mixture was cooled to room temperature, and the precipitate (the salt of (S)-α-cyclopentylmandelic acid and L-tyrosine methyl ester) was collected and discarded. The mother liquor was concentrated under reduced pressure to approximately 46 L, and the salt of (R)-α-cyclopentylmandelic acid and L-tyrosine methyl ester was precipitated as a thick slurry. The slurry was then diluted with water, concentrated hydrochloric acid was added, and extracted with ethyl acetate. The organic layer was washed with brine and solvent-exchanged with heptane at 75°C. After adding seed crystals and cooling to 0°C, the solid was collected by filtration. Finally, the precipitate was washed with heptane and dried to give 8.5 kg, 37% yield of the desired (R)-α-cyclopentylmandelic acid as an off-white solid. Step 2: Mitsunobu reaction and N-alkylation To a stirred solution of (R)-α-cyclopentylmandelic acid (8.5 kg, 38.6 mol), triphenylphosphine (10.1 kg), and (S)-1-methyl-3-pyrrolidinol (3.7 kg) in anhydrous 2-methyltetrahydrofuran (2-Me THF) was added diisopropyl azodicarboxylate (DIAD) (7.8 kg) over 1-1.5 hours at 5° C. After stirring at ambient temperature for 1 hour, the mixture was diluted with methyl t-butyl ether (MTBE) and cooled to 0° C. to obtain a precipitate of triphenylphosphine, which was filtered. The filtrate containing the product was solvent-substituted with acetonitrile (40 kg, approximately 50.9 L), ethyl bromoacetate (9.7 kg) was added, and the mixture was stirred at 20° C. for 4 hours to obtain a crude BBI-4000 solution. This solution was treated with a Cuno carbon cartridge, and MTBE was added to the sofpironium bromide solution after carbon treatment, and seeded to obtain 13.95 kg (77% yield) of sofpironium bromide solid after filtration and drying.

[0162] Sofpironium bromide (13.9 kg) was dissolved in acetonitrile (33.4 kg, ca. 42.7 L) at 60°C and cooled to 30°C. The clear solution was passed through a Cuno carbon cartridge, filtered, seeded with MTBE (80 kg, ca. 108 L) and stirred for 7 h. The precipitate was collected by filtration, washed with a mixture of acetonitrile (7 kg, ca. 8.91 L) and MTBE (25 kg, ca. 33.7 L), and dried under reduced pressure to give 11.6 kg of a white solid (mp 144-146°C, HPLC purity 99.8%). The crystal form was confirmed to be Form B by powder X-ray diffraction spectroscopy.

[0163] Example 6 <Method for producing the crystalline form (Form CO) of Compound (I)> Compound (Ia) (50 mg) and compound (Ib) (150 mg) obtained in Preparation Examples 4 and 5 were suspended in a mixture of acetonitrile (0.58 mL), ethyl acetate (0.88 mL) and methyl t-butyl ether (0.06 mL) and heated to 50° C. The suspension was stirred at 50° C. for 15 hours, and then stirred while gradually cooling to room temperature. The precipitate was collected by filtration, washed twice with ethyl acetate (2 mL), and then dried to obtain a crystalline form of compound (I) (Form CO, yield: 121 mg, recovery rate: 61%) as a white solid. The obtained crystalline form of compound (I) contained compound (Ia) and compound (Ib) in a ratio of 1:3. The crystal form was confirmed to be Form CO by powder X-ray diffraction spectroscopy and other spectroscopy.

[0164] Reference Example 1: Method for producing (2R,3'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-methyl-1'-carboxymethylpyrrolidinium inner salt (compound (III)) [ka]

[0165] Sofpironium bromide (15 g, 3.2 mmol) was dissolved in aqueous sodium hydroxide (0.1 mol / L, 318 mL) and stirred at room temperature for 3.5 hours. The resulting solution was freeze-dried, and the residue was extracted with dichloromethane. The resulting dichloromethane solution was concentrated, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol = 90 / 10) to obtain a white solid of compound (III) (yield: 5.4 g, 47%).

[0166] Reference Example 2: <Production method of (2R,3'R)-3'-(2-cyclopentyl-2-hydroxy-2-phenylacetyl)-1'-methyl-1'-ethoxycarbonylmethoxycarbonylmethyl-pyrrolidinium bromide (compound (IV))> [ka]

[0167] At room temperature, (2R,3'R)-CPMA-MP (4.3 g, 14 mol) was dissolved in ethyl acetate (50 mL), and 2-ethoxy-2-oxyethyl 2-bromoacetate (3.7 g, 16.4 mmol) was added. The reaction solution was stirred for 16 hours, and the reaction solution was concentrated. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / ethanol) to obtain a crude viscous white solid of compound (IV) (yield: 6.3 g). The obtained crude compound (IV) was dissolved in acetonitrile (10 mL), ethyl acetate (15 mL) was added, and the mixture was heated to 50°C. The solution was cooled to 40°C, and methyl t-butyl ether (100 mL) was added to obtain a suspension. The suspension was gradually cooled to room temperature, and the precipitate was collected by filtration. The precipitate was washed with methyl t-butyl ether and then dried at 50° C. under reduced pressure for 5 hours to obtain compound (IV) (white solid) (yield: 5.8 g, two-step yield: 78%). 1 H-NMR (400 MHz, CDCl 3)δ:1.25-1.73(9H,m),2.11-2.27(1H,m),2.43(2H,s),2.80-3.08(2H ,m),3.15(1H,s),3.69(2H,s),3.91-4.02(1H,m),4.12-4.56(6H,m),4 .65-4.77(2H,m),4.77-4.96(1.33H,m),5.28-5.45(0.67H,m),5.52- 5.61(1H,m),7.20-7.30(1H,m),7.30-7.39(2H,m),7.54-7.62(2H,m).

[0168] Test Example 1-1 <Powder X-ray diffraction measurement of the crystal form of sofpironium bromide produced by crystallization method 1> Sofpironium bromide is a mixture of diastereomers (compound (Ia) and compound (Ib)), but it was unclear how the ratio of the diastereomers affects the crystal morphology and physicochemical properties of the mixture. Therefore, for each diastereomer and various sofpironium bromides having different content ratios of compound (Ia) and compound (Ib) (sofpironium bromides having a compound (Ib) content of 60%, 70%, 75% or 80%), recrystallization (crystallization method 1 or crystallization method 2) was carried out using a mixed solvent of acetonitrile / ethyl acetate / methyl t-butyl ether, and various instrumental analyses were carried out.

[0169] In Test Example 1-1, the crystal forms obtained in Production Example 4 (Form MN), Production Example 5 (Form MJ), Production Example 6, and Production Example 6-2 were subjected to powder X-ray diffraction measurement according to the following method. Note that, in general, if the crystal forms are the same, the diffraction angle 2θ coincides within the range of ±0.2° or ±0.1°.

[0170] Approximately 0.1 g of each sample was packed into a glass sample plate. The sample plate was attached to a standard sample holder, and the diffraction pattern was measured under the following conditions using a powder X-ray diffraction measuring device (Rigaku Corporation: RINT2200Ultima II / PC). Separately, an angle standard silicon powder was measured.

[0171] [Table 2]

[0172] Figure 1 shows the diffraction pattern of the crystalline form (Form MN) of compound (Ia). The characteristic diffraction angles are shown in the table below.

[0173] [Table 3]

[0174] Figure 2 shows the diffraction pattern of the crystalline form (Form MJ) of compound (Ib). The characteristic diffraction angles are shown in the table below.

[0175] [Table 4]

[0176] The peak at a diffraction angle of 2θ = 7.1° for Form MN and the peak at a diffraction angle of 2θ = 6.7° for Form MJ were strong and characteristic peaks for each crystal form. Therefore, it was revealed that the presence of Form MN and Form MJ in various crystal forms of sofpironium bromide can be confirmed by observing the peaks at 2θ = 7.1 ± 0.1° and 2θ = 6.7 ± 0.1°.

[0177] Next, Table 5 shows characteristic peaks in each crystal form tested in the above Test Example 1-1. [Table 5] *: If a peak was observed at the corresponding diffraction angle, enter "Yes." A blank space indicates that the peak was not clearly observed.

[0178] In both sofpironium bromide with a compound (Ib) content of 60% and 80%, a peak at a diffraction angle 2θ=7.1±0.1° characteristic of Form MN and a peak at a diffraction angle 2θ=6.7±0.1° characteristic of Form MJ were observed. Since the respective peak intensities varied relatively according to the diastereomeric ratio, it is considered that the sofpironium bromide produced by the above crystallization method 1 (Production Example 6 and Production Example 6-2) is a mixture of Form MN and Form MJ.

[0179] Test Example 1-2 <Powder X-ray diffraction measurement of the crystal form of sofpironium bromide produced by crystallization method 2> In Test Example 1-2, the crystal forms obtained in Production Example 4 (Form MN), Production Example 5 (Form MJ), Production Example 7, Production Example 7-2, Production Example 7-3, and Production Example 7-4 were measured by powder X-ray diffraction in the same manner as in Test Example 1-1. Characteristic peaks in each measurement are shown in Table 6.

[0180] [Table 6] *: If a peak was observed at the corresponding diffraction angle, enter "Yes." A blank space indicates that the peak was not clearly observed.

[0181] In the sofpironium bromide of Production Example 7 and Production Example 7-2, a peak at 2θ=7.1±0.1° characteristic of the crystal form (Form MN) of compound (Ia) was confirmed. Since the peak at 2θ=7.1±0.1° is a peak characteristic of Form MN, the sofpironium bromide of Production Example 7 and Production Example 7-2 contains Form MN. On the other hand, in the sofpironium bromide of Production Example 7 and Production Example 7-2, a peak at 2θ=5.9±0.1° and a peak at 2θ=7.6±0.1° were observed. Since these peaks are not strongly detected in either the crystal form of Form MN or Form MJ, the sofpironium bromide of Production Example 7 and Production Example 7-2 is considered to contain a crystal form other than Form MN and Form MJ.

[0182] In the sofpironium bromide of Production Example 7-3 (containing 75% compound (Ib)), the peaks characteristic of Form MN (2θ=7.1±0.1°) and Form MJ (2θ=6.7±0.1°) were not observed. On the other hand, peaks at 2θ=5.8±0.1° and 2θ=7.6±0.1° were observed. From this, it was considered that the sofpironium bromide of Production Example 7-3 is a new crystalline form of sofpironium bromide, and is a new cocrystal (Form CO) in which the content ratio of compound (Ia) and compound (Ib) is 1:3.

[0183] In sofpironium bromide of Production Example 7-4 (content of compound (Ib) 80%), a peak of Form CO and a peak thought to be derived from the crystal form of compound (Ib) were observed, but a peak characterizing Form MN (2θ=7.1±0.1°) was not observed (data not shown in the table).

[0184] Next, the powder X-ray diffraction patterns of the crystalline form of sofpironium bromide prepared in Example 6 and the crystalline form of sofpironium bromide prepared in Production Example 7-3 were compared. Figure 3 is the diffraction pattern of Form CO prepared in Example 6. The characteristic diffraction angles are shown in Table 7.

[0185] [Table 7]

[0186] The crystal form of Example 6 and the crystal form of Production Example 7-3 were compared by powder X-ray diffraction, and the diffraction patterns of both were identical. That is, the presence of a cocrystal (Form CO) composed of 25% of compound (Ia) and 75% of compound (Ib) was confirmed.

[0187] Since the sofpironium bromide of Production Example 7 and Production Example 7-2 show a mixture of peaks derived from Form CO and peaks derived from Form MN, it is considered to be a mixture of crystals of Form CO and Form MN. On the other hand, in Test Example 1-1 (Production Example 6 and Production Example 6-2), Form CO was not observed, which indicates that the selection of production method (e.g., recrystallization method) conditions is extremely important in producing Form CO. Specifically, it has been found that in the preparation of Form CO, the step of dripping methyl t-butyl ether for a long period of time (e.g., for 4 hours or more) and / or the step of stirring a suspension of sofpironium bromide in methyl t-butyl ether in a solvent for a long period of time (e.g., 13 hours) are important.

[0188] Test Example 2 <Solids of each crystal form 13 C nuclear magnetic resonance spectrum (solid 13 C-NMR) measurement> Each sample of Form B, Form MN, Form MJ and Form CO was filled into a 4 mmφ zirconia rotor, and solid samples were measured under the following conditions using polydimethylsiloxane as a reference substance. 13 C nuclear magnetic resonance spectra were measured.

[0189] <Solid 13 C Nuclear Magnetic Resonance Spectroscopy Measurement Conditions [Table 8]

[0190] The results are shown in Figures 4 to 8. FIG. 4 shows a solid of the crystalline form (Form B) of Compound (I). 13 C nuclear magnetic resonance spectrum. Characteristic peaks are shown in Table 9.

[0191] [Table 9]

[0192] The Form B used in this test had a content ratio of compound (Ia) and compound (Ib) of 33:67.

[0193] FIG. 5 shows a solid of the crystalline form (Form MN) of compound (Ia). 13 C nuclear magnetic resonance spectrum. Characteristic peaks are shown in Table 10.

[0194] [Table 10]

[0195] FIG. 6 shows the solid state of the crystalline form (Form MJ) of compound (Ib). 13 C nuclear magnetic resonance spectrum. Characteristic peaks are shown in Table 11.

[0196] [Table 11]

[0197] FIG. 7 shows a solid of the crystalline form (Form CO) of Compound (I). 13 C nuclear magnetic resonance spectrum. Characteristic peaks are shown in Table 12.

[0198] [Table 12]

[0199] Figure 4 shows the solid form of Form B. 13 The C nuclear magnetic resonance spectrum was very complex, with many peaks observed. However, as shown in Table 13, the spectrum characteristic of Form B observed around 140 ppm coincides with the spectra characteristic of Form CO and Form MN, confirming that the crystalline form of Form B is a mixture of Form CO and Form MN.

[0200] [Table 13] *: If a peak was observed at the corresponding chemical shift value, enter "Yes." A blank space indicates that the peak was not observed.

[0201] solid 13 C nuclear magnetic resonance spectroscopy (CP / MAS) is a method for detecting cross polarization. 1 The magnetization of H nuclei 13 Transfer to nucleus C and measure. 1 The magnetization of H nucleus is 13 The efficiency of transfer to the C nucleus is 13 C nucleus and 1 It depends on the position of the H nucleus, molecular mobility, etc. 13 The integrated data in C nuclear magnetic resonance spectroscopy (CP / MAS) is not quantitative, and the abundance ratio of compounds cannot be directly calculated from the integrated intensity ratio of peaks. However, in a similar environment 13 The CP efficiency is thought to be similar between C nuclei, and the abundance ratio of the crystal forms can be estimated from the signal intensity as a guideline.

[0202] According to Test Example 1, Form CO is a cocrystal in which the content ratio of compound (Ia) and compound (Ib) is 1:3. Therefore, the content ratio of Form CO and Form MN in Form B, which has a compound (Ib) content of 67%, is theoretically 89:11. Figure 8 shows the solid form of Form B. 13 An enlarged view of the C nuclear magnetic resonance spectrum shows integral data for both the peaks derived from Form CO and Form MN. For example, at around 140 ppm, the ratio of the peak area derived from Form CO to the peak area derived from Form MN was 4.6:0.6 (approximately 88:12). These results indicate that the crystalline form of Form B is a mixture of Forms CO and MN.

[0203] Test Example 3 <Purity test of each crystal form (related substances)> Purity measurements of the crystalline forms obtained in the above examples were carried out using high performance liquid chromatography (HPLC) under the following conditions.

[0204] 1)Analysis conditions Detector: UV spectrophotometer (measurement wavelength: 220 nm) Column: Luna (2) C18 (inner diameter 4.6 mm, length 15 cm, particle size 3.0 μm) Column temperature: constant temperature around 50℃ Flow rate: 1.2 mL / min Injection volume: 15 μL Mobile phase A: Water: Methanol: Acetonitrile: Trifluoroacetic acid = 700: 200: 100: 1 Mobile phase B: methanol:acetonitrile:water:trifluoroacetic acid = 6500:2500:1000:7 Delivery of mobile phase: The mixing ratio of mobile phase A and mobile phase B was changed as follows to control the concentration gradient.

[0205] [Table 14]

[0206] 2) Preparation of sample solution Approximately 30 mg of each sample was weighed out, and 10 mL of a mixture of water / acetonitrile / trifluoroacetic acid (500:500:1) was added to prepare a sample solution.

[0207] When the relative retention time of compound (Ib) was taken as 1, the relative retention time of compound (Ia) was 0.9, the relative retention times of the impurity compound (III) were 0.6 and 0.7, the relative retention time of compound (IV) was 1.2, and the relative retention time of compound (V) was 1.3.

[0208] The purity of each of the crystal forms obtained in Example 1 (Form A), Example 3 (Form B) and Example 6 (Form CO) was 99.5 w / w% or more, and the impurities of Compound (III), Compound (IV) and Compound (V) were all 0.5 w / w% or less. Furthermore, the peaks of impurities other than Compound (III), Compound (IV) and Compound (V) were below the quantification limit. Therefore, it was revealed that the compound (I) of the present invention (including the crystalline form of compound (I)) produced by the above production method is of high purity.

[0209] Test Example 4 <form AとForm Bの粉末X線回折パターン解析> According to the method described in Test Example 1-1, the powder X-ray diffraction patterns of Form A and Form B were measured. Usually, if the crystal form is the same, the diffraction angle 2θ will match within the range of ±0.2° or ±0.1°. The results are shown in Figures 9 to 11.

[0210] Figure 9 is a diffraction pattern of the crystalline form of Compound (I) (Form A). Characteristic diffraction angles are shown in Table 15.

[0211] [Table 15]

[0212] In the powder X-ray diffraction pattern analysis of the crystalline form of Form A, a peak at a diffraction angle 2θ=7.1±0.1° characteristic of Form MN and a peak at a diffraction angle 2θ=6.7±0.1° characteristic of Form MJ were observed. Therefore, Form A is a mixture of crystals of Form MN and Form MJ. The content ratio of compound (Ia) and compound (Ib) contained in Form A used in this test was within the range of 40:60 to 25:75.

[0213] Figure 10 is a diffraction pattern of the crystalline form (Form B) of Compound (I). Characteristic diffraction angles are shown in Table 16.

[0214] [Table 16]

[0215] Powder X-ray diffraction pattern analysis of the crystalline form of Form B showed both a peak at a diffraction angle of 2θ=7.1±0.1° characteristic of Form MN and diffraction angles of 2θ=5.9±0.1° and 2θ=7.6±0.1° characteristic of Form CO. Therefore, Form B is a mixture of crystals of Form MN and Form CO. The content ratio of compound (Ia) and compound (Ib) contained in Form B used in this test was within the range of 40:60 to 25:75.

[0216] Test Example 5 <Thermal analysis (DSC) of each crystal form> According to the thermal analysis method of the Japanese Pharmacopoeia (17th edition), about 5-6 mg of each sample was weighed into an aluminum pan (with a drop lid) and measured under a nitrogen gas flow (50 mL per minute) at a heating rate of 2°C per minute in the range of 30°C to 230°C. α-alumina was used as the reference material. Alternatively, in accordance with the thermal analysis method of the Japanese Pharmacopoeia (17th edition), approximately 1-2 mg of each sample was weighed into an aluminum pan (simple hermetic type) and measured under a nitrogen gas flow (50 mL per minute) at a heating rate of 2°C per minute in the range of 30°C to 165°C. α-alumina was used as the reference material. The results are shown in Figures 12 to 16.

[0217] [Table 17]

[0218] The endothermic peak of Form A was lower than those of Form MN and Form MJ. The endothermic peak of Form B was lower than those of Form MN and Form CO. In general, the melting point of a compound containing impurities is lower than that of the pure substance. In the case of Form A and Form B, Form MN, Form MJ, and Form CO behave like impurities to each other, which is thought to be why the endothermic peaks of Form A and Form B are lower than those of Form MN, Form MJ, and Form CO. The content ratio of compound (Ia) to compound (Ib) contained in Form A and Form B used in this test was within the range of 40:60 to 25:75.

[0219] Test Example 6 <Infrared absorption spectrum (IR) measurement of each crystal form> Each sample was analyzed according to the potassium bromide tablet method of infrared absorption spectroscopy in the Japanese Pharmacopoeia (17th revision). The results are shown in Figures 17 to 21.

[0220] 17 is an IR chart of the crystalline form (Form A) of Compound (I). Characteristic peaks are shown in Table 18.

[0221] [Table 18]

[0222] 18 is an IR chart of the crystalline form (Form B) of Compound (I). Characteristic peaks are shown in Table 19.

[0223] [Table 19]

[0224] Figure 19 is an IR chart of the crystalline form (Form MN) of compound (Ia). Characteristic peaks are shown in Table 20.

[0225] [Table 20]

[0226] Figure 20 is an IR chart of the crystalline form (Form MJ) of compound (Ib). Characteristic peaks are shown in Table 21.

[0227] [Table 21]

[0228] Figure 21 is an IR chart of the crystalline form (Form CO) of Compound (I). Characteristic peaks are shown in Table 22.

[0229] [Table 22]

[0230] The content ratio of compound (Ia) to compound (Ib) contained in Form A and Form B used in this test was within the range of 40:60 to 25:75.

[0231] Test Example 7 <Hygroscopicity and stability test of each crystal form (dynamic vapor sorption: DVS)> Each sample was dried under reduced pressure (in the presence of silica gel, 40°C, 1 hour), and approximately 20 mg was weighed into a sample pan. The sorption-desorption isotherm (0-95% RH) was measured using a dynamic water vapor sorption measuring device under the following conditions.

[0232] <Pre-drying conditions for equipment> [Table 23]

[0233] <Sorption-desorption isotherm measurement conditions> [Table 24]

[0234] [Table 25] *: In the column for hygroscopicity, "Yes" indicates that the weight increase after the test was more than 3%, and "No" indicates that the weight increase after the test was 3% or less. **: In the crystal transformation column, "Yes" indicates that a change in crystal morphology occurred after the test, and "No" indicates that the crystal morphology remained the same after the test as before the test.

[0235] From the results of Test Example 7, none of the crystal forms were hygroscopic. However, when Form A and Form MJ were cycled from 0% RH to 95% RH and back to 0% RH, crystal transition was observed. On the other hand, Form B, Form MN, and Form CO did not show crystal transition under the same humidification conditions. From these results, it was found that Form MN and Form CO did not undergo crystal transition under humid conditions and are stable crystalline forms. Since Form B is a crystalline form that contains Form MN and Form CO, it was found to be a crystalline form with a more suitable profile as an active pharmaceutical ingredient. The content ratio of compound (Ia) to compound (Ib) contained in Form A and Form B used in this test was within the range of 40:60 to 25:75.

[0236] Test Example 8 Form B was stored at 25°C±2°C / 93% RH for 4 weeks, and its properties, purity, and crystal morphology were observed from the start. The results are shown in the table below. The purity test was carried out in the same manner as in Test Example 3. In this test, the term "impurities" includes the above-mentioned compounds (III), (IV), and (V), as well as other related substances, decomposition products, impurities, and contaminants. The crystal form was determined by the powder X-ray diffraction pattern.

[0237] [Table 26] *: Below the limit of quantification (<0.03%)

[0238] From the results of Test Example 8, Form B did not change in properties, purity, or crystal form even after storage at 25°C ± 2°C / 93% RH for 4 weeks. Therefore, it was revealed that Form B is a stable crystal form under humid conditions and is an excellent crystal form as a pharmaceutical bulk. Similarly, it was revealed that Form MN and Form CO, which constitute Form B, are also excellent crystal forms as pharmaceutical bulks. The content ratio of compound (Ia) and compound (Ib) contained in Form B used in this test was within the range of 40:60 to 25:75.

[0239] Test Example 9 The stability of Form A and Form B was compared. Each sample of Form A and Form B was stored for 4 weeks at 60±2°C in the dark. The results are shown in the table below. In the table, each value of the purity test represents the percentage (%) of impurities contained in compound (I). Specifically, each value represents the percentage (%) of all peak areas other than the peaks of compound (Ia) and compound (Ib) when analyzed under the analytical conditions of Test Example 3.

[0240] As shown in Test Example 7, Form A undergoes crystal transition under humid conditions. The crystal form after crystal transition was designated as "Form A (after crystal transition)" and the stability was measured in the same manner. In this test, the term "impurities" includes the above-mentioned compounds (III), (IV), and (V), as well as other related substances, decomposition products, impurities, and contaminants. The numerical value of the isomer ratio represents the value obtained by dividing the peak area of ​​compound (Ia) by the sum of the peak areas of compounds (Ia) and (Ib) when analyzed under the analytical conditions of Test Example 3. The content ratio of compound (Ia) to compound (Ib) contained in Form A and Form B used in this test was within the range of 40:60 to 25:75.

[0241] [Table 27] *: Below the limit of quantification (<0.03%)

[0242] As shown in the table above, the purity of both Form A and Form B was 99.9% or more at the start and after 4 weeks, and impurities did not increase even after 4 weeks. In addition, no significant change was observed in the isomer ratio of Compound (Ia) and Compound (Ib) during the test period. On the other hand, in Form A (after crystal transition), no increase in impurities was observed, but 0.03% of an impurity (compound (III)) was confirmed from the beginning. As a result of Test Examples 7 to 9, it was revealed that although both Form A and Form B were stable crystals, Form A underwent crystal transformation under humid conditions, resulting in the inclusion of a small amount of impurities. On the other hand, it was revealed that Form B did not experience such a phenomenon, was stable, and had a profile more suitable for use as a drug substance.

[0243] From the above results, it was revealed that the crystalline forms of sofpironium bromide of the present invention, including Form CO (e.g., Form B), are non-hygroscopic, highly pure, and physicochemically stable crystalline forms, and therefore have an optimal profile as an active pharmaceutical ingredient for pharmaceuticals. [Industrial Applicability]

[0244] The crystalline form of sofpironium bromide of the present invention is physicochemically stable and has a profile suitable for use as an active pharmaceutical ingredient in pharmaceuticals. Furthermore, the sofpironium bromide obtained by the production method of the present invention has high purity and can be produced easily on an industrial scale.< / form>

Claims

1. Formula (Ia): 【Chemistry 1】 Compound (Ia) represented by the formula: Formula (Ib): 【Chemistry 2】 A cocrystal containing compound (Ib) represented by the formula (Ib) in a ratio of 1:

3. Formula (I): 【Chemistry 3】 A method for producing a crystalline form of compound (I) (sofpironium bromide) represented by the formula: Step C: preparing a suspension of compound (I) in a solvent containing at least one solvent selected from ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least 1 hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); A manufacturing method comprising:

2. A method for producing a crystalline form of compound (I) represented by formula (I), which is a co-crystal containing compound (Ia) represented by formula (Ia) and compound (Ib) represented by formula (Ib) in a ratio of 1:3 according to claim 1, comprising the steps of: Step A: In a solvent, Formula (II): 【Chemistry 4】 reacting compound (II) represented by the formula: with ethyl bromoacetate to prepare a reaction solution containing compound (I); Step B: filtering the reaction solution to obtain a crystalline form of compound (I); Step C': preparing a suspension of the crystalline form of compound (I) in a solvent comprising at least one solvent selected from ethyl acetate and methyl t-butyl ether, and stirring the suspension for at least one hour; and Step D: filtering the suspension of compound (I) to obtain a crystalline form of compound (I); A manufacturing method comprising:

3. The compound (I) represented by formula (I), which is a cocrystal containing a compound (Ia) represented by formula (Ia) and a compound (Ib) represented by formula (Ib) according to claim 1 in a ratio of 1:3, is represented by the following formula (III) relative to the content of the compound (I) containing a crystalline form of the compound (I): 【Chemistry 5】 The content of compound (III) represented by the formula (I) is 0.5 w / w% or less.

4. The compound (I) represented by formula (I), which is a cocrystal containing a compound (Ia) represented by formula (Ia) and a compound (Ib) represented by formula (Ib) according to claim 1 in a ratio of 1:3, is represented by the following formula (IV): 【Chemistry 6】 The content of compound (IV) represented by the formula (I) is 0.5 w / w% or less.

5. The compound (I) represented by formula (I), which is a cocrystal containing a compound (Ia) represented by formula (Ia) and a compound (Ib) represented by formula (Ib) according to claim 1 in a ratio of 1:3, is represented by the following formula (V): 【Chemistry 7】 The content of compound (V) represented by the formula (I) is 0.5 w / w% or less.

6. The compound (I) represented by formula (I), which is a cocrystal containing a compound (Ia) represented by formula (Ia) and a compound (Ib) represented by formula (Ib) according to claim 1 in a ratio of 1:3, is represented by the following formula (III) relative to the content of the compound (I) containing a crystalline form of the compound (I): 【Chemistry 8】 and a compound represented by the following formula (IV): 【Chemistry 9】 and a compound represented by the following formula (V): 【Chemistry 10】 and the purity of compound (I) is 98.0 w / w% or more.

7. The compound (I) represented by formula (I), which is a cocrystal containing a compound (Ia) represented by formula (Ia) and a compound (Ib) represented by formula (Ib) according to claim 1 in a ratio of 1:3, is represented by the following formula (III) relative to the content of the compound (I) containing a crystalline form of the compound (I): 【Chemistry 11】 and a compound represented by the following formula (IV): 【Chemistry 12】 and a compound represented by the following formula (V): 【Chemistry 13】 is 0.5 w / w% or less, the total content of impurities is 2.0 w / w% or less, and the purity of compound (I) is 98.0 w / w% or more.

8. The compound (I) represented by formula (I), which is a cocrystal containing a compound (Ia) represented by formula (Ia) and a compound (Ib) represented by formula (Ib) according to claim 1 in a ratio of 1:3, is represented by the following formula (III): 【Chemistry 14】 and a compound represented by the following formula (IV): 【Chemistry 15】 and a compound represented by the following formula (V): 【Chemistry 16】 is 0.15 w / w% or less, the total content of impurities is 1.0 w / w% or less, and the purity of compound (I) is 99.0 w / w% or more.

9. A pharmaceutical composition for the treatment and / or prevention of diseases associated with the action of acetylcholine, prepared by a process comprising mixing a crystalline form of compound (I) according to any one of claims 3 to 8 with a pharma- ceutically acceptable carrier.

10. A pharmaceutical composition for the treatment and / or prevention of hyperhidrosis, prepared by a process comprising the step of mixing a crystalline form of compound (I) according to any one of claims 3 to 8 with a pharma- ceutically acceptable carrier.

11. A pharmaceutical composition for the treatment and / or prevention of primary axillary hyperhidrosis or primary palmar hyperhidrosis, prepared by a process comprising the step of mixing a crystalline form of compound (I) according to any one of claims 3 to 8 with a pharma- ceutically acceptable carrier.

12. A method for preparing a pharmaceutical composition for the treatment and / or prevention of diseases associated with the action of acetylcholine, comprising mixing a crystalline form of compound (I) as defined in any one of claims 3 to 8 with a pharma- ceutically acceptable carrier.

13. A method for preparing a pharmaceutical composition for the treatment and / or prevention of hyperhidrosis, comprising the step of mixing a crystalline form of compound (I) according to any one of claims 3 to 8 with a pharma- ceutically acceptable carrier.

14. A method for preparing a pharmaceutical composition for the treatment and / or prevention of primary axillary hyperhidrosis or primary palmar hyperhidrosis, comprising mixing a crystalline form of compound (I) according to any one of claims 3 to 8 with a pharma- ceutically acceptable carrier.

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