Amorphous evocalcet, production intermediate thereof, and method for producing same

Abstract

The present invention addresses the problem of providing a highly safe, efficient, and / or economical method for producing: an amorphous evocalcet which has an activating effect on the calcium-sensing receptor (CaSR) and is useful as a medicine, particularly as a prophylactic or therapeutic agent for hyperparathyroidism or the like; and a production intermediate thereof. The present invention provides a method for producing amorphous 4-(3S-(1R-(1-naphthyl) ethylamino) pyrrolidin-1-yl) phenylacetic acid represented by formula (8) by neutralizing an ester hydrolysate of a compound represented by formula (7) in a buffer. Preferably, the compound represented by formula (7) is obtained using an intermediate represented by formula (3) of the present invention.

Description

Amorphous evocalcet and its manufacturing intermediates, and methods for producing them.

[0001] This invention relates to a novel method for producing amorphous evocalcet and its intermediates. This application claims priority based on Japanese Patent Application No. 2025-052265, filed in Japan on March 26, 2025, the contents of which are incorporated herein by reference.

[0002] Evocalcet (chemical name: 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid), which has calcium-sensitive receptor (CaSR) activating activity, is known to be useful as a preventive or therapeutic agent for hyperparathyroidism and other conditions (Patent Document 1). The preferred form of the evocalcet pharmaceutical raw material is the free form, and furthermore, there are two types of crystal forms of the free form (crystals characterized by diffraction peaks at 17.3°±0.2° and 22.6°±0.2° as diffraction angles represented by 2Θ in the powder X-ray diffraction pattern are called type A crystals, and crystals characterized by diffraction peaks at 15.9°±0.2° and 21.4°±0.2° are called type B crystals, and in this specification, they are referred to as "type A crystals" and "type B crystals," respectively), and it has been reported that type A crystals are the most stable crystals (Patent Document 2).

[0003] On the other hand, while Patent Document 2 reports on the dihydrochloride salt and the free amorphous form of evocalcet, both are manufactured in a form containing organic solvents. Therefore, it is difficult to apply these amorphous forms as pharmaceuticals in their current form.

[0004] Furthermore, as shown below (excerpted from Patent Document 2), the manufacturing method does not involve directly isolating the amorphous material from the reaction solution obtained by hydrolyzing the precursor ester (6), but rather involves isolating the crystals of the evocalcet-free material (A) and producing the amorphous material from those crystals.

[0005] Furthermore, Patent Document 2 also describes an industrial method for producing evocalcet, and as an improvement over conventional methods, as shown in the figure above, a 2-nitrobenzenesulfonyl group (Ns) is introduced to the hydroxyl group of compound (1) to convert it to a sulfonic acid ester (2), and then an N-alkylation reaction is performed to produce an intermediate (3).

[0006] As an example different from the amorphous materials described above, Patent Document 3 discloses a method for producing an amorphous solid dispersion of evocalcet. In this method, the amorphous solid dispersion is not produced using amorphous evocalcet, but rather using crystals as the raw material.

[0007] International Public Access WO2005 / 115975, International Public Access WO2015 / 034031, International Public Access WO2024 / 023845

[0008] Guidelines on Residual Solvents in Pharmaceuticals (Notification No. 307 from the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, dated March 30, 1998, addressed to the Directors of Health Departments (Bureaus) of Each Prefecture) Theodora W. Greene, Peter GM Wuts, "Protective Groups in Organic Synthesis" 4th ed., John Wiley & Sons, Inc., 2007 Guidelines on Impurities in Active Pharmaceutical Ingredients in New Active Ingredient-Containing Pharmaceuticals (Notification No. 1216001 from the Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, dated December 16, 2002, addressed to the Directors of Health Departments (Bureaus) of Each Prefecture)

[0009] The only reported manufacturing methods for amorphous evocalcet-free compounds are those containing (or retaining) organic solvents (Reference Examples 1-3 of Patent Document 2). Therefore, there has been a challenge in utilizing amorphous evocalcet-free compounds as pharmaceuticals. Furthermore, to solve this problem, the development of a manufacturing method for amorphous evocalcet-free compounds that are substantially free of organic solvents, or contain only enough organic solvents to be usable in pharmaceuticals, is desirable. However, there is also the challenge of developing a simple manufacturing method suitable for pharmaceutical manufacturing (mass production). Moreover, there is a desire for the development of a manufacturing method for amorphous evocalcet-free compounds that is safer, more economical, and / or more efficient.

[0010] The present inventors conducted diligent studies to solve the above problems and have found a method for producing an amorphous form of evocalcet-free material (hereinafter also referred to as "amorphous form of evocalcet" or "amorphous evocalcet") in a highly reproducible and simple manner, in which the residual solvent is below the concentration limit value of the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guidelines on residual solvents: Q3C (see Non-Patent Document 1 for specific residual solvent limit values, etc.), preferably one-tenth or less of the concentration limit value. Furthermore, the inventors have found a method for producing evocalcet that utilizes a halogen-substituted benzenesulfonyl group instead of a 2-nitrobenzenesulfonyl group as a production intermediate, thereby completing the present invention.

[0011] In this specification, residual solvents refer to volatile organic chemical substances used or generated in the manufacturing process of active pharmaceutical ingredients or pharmaceutical additives, or in the manufacturing process of pharmaceutical preparations. Unless otherwise specified, individual residual solvents (volatile organic chemical substances) are simply referred to as "residual solvents."

[0012] In other words, the first aspect of the present invention is the manufacturing method as shown below. <1> Formula (7): (In the formula, Pro ２represents a protecting group for a carboxyl group.) characterized in that after hydrolyzing a compound represented by the formula or a salt thereof, neutralization is carried out with a buffer, formula (8): A method for producing an amorphous form of the compound (evocalcet) represented by the formula.

[0013] <2> Formula (5): After treating the compound represented by the formula or a salt thereof with a base as necessary, the resulting product is reacted with a compound represented by formula (6): (wherein X ３ represents a halogen atom, and Pro ２ represents a protecting group for a carboxyl group.) the compound represented by the formula is reacted in the presence of a palladium catalyst, a base and a ligand to obtain the compound represented by the above formula (7) or a salt thereof, the production method according to <1> above, further comprising the step of: the production method according to <1> above, further comprising the step of obtaining the compound represented by the formula or a salt thereof.

[0014] <3> Formula (1): (wherein Pro １ represents a protecting group for an amino group.) the compound represented by the formula is reacted with a compound represented by formula (2): (wherein X １ and X ２ are both halogen atoms, or when one is a halogen atom, the other is a hydrogen atom.) the compound represented by the formula is reacted to obtain a compound represented by formula (3): (wherein X １ , X ２ and Pro １ has the same meaning as defined above.) the compound represented by the formula is obtained, which is reacted with 1R-(1-naphthyl)ethylamine in the presence of a base to obtain a compound represented by formula (4): (wherein Pro １ has the same meaning as defined above.) the compound represented by the formula is obtained, which is deprotected to obtain the compound represented by formula (5) or a salt thereof, which is treated with a base as necessary, and then reacted with a compound represented by formula (6): the compound represented by the formula or a salt thereof, which after being treated with a base as necessary, is reacted with a compound represented by formula (6): (wherein X ３ represents a halogen atom, and Pro ２ represents a protecting group for a carboxyl group.) by reacting the compound represented by the formula in the presence of a palladium catalyst, a base and a ligand, to obtain the compound represented by formula (7): (wherein Pro２ has the same meaning as defined above. ), which is characterized in that after hydrolysis, neutralization is performed with a buffer, and represented by formula (8): A method for producing an amorphous form of the compound (evocalcet) represented by .

[0015] <4> The production method according to any one of <1> to <3>, wherein the buffer is a buffer adjusted to pH 5.5 to 6.4.

[0016] <5> The production method according to any one of <1> to <4>, characterized in that an ester hydrolysis reaction solution of the compound represented by formula (7) is added to the buffer.

[0017] <6> The production method according to any one of <1> to <5>, wherein the amorphous form of the compound (evocalcet) represented by formula (8) has substantially no peaks at diffraction angles represented by 2Θ of 15.9°, 17.3°, 21.4° and 22.6° in a powder X-ray diffraction pattern.

[0018] <7> The production method according to any one of <1> to <6>, wherein the amorphous form of the compound (evocalcet) represented by formula (8) has a total residual solvent content of 5000 ppm or less.

[0019] <8> The production method according to any one of <1> to <7>, wherein the amorphous form of the compound (evocalcet) represented by formula (8) has residual solvents not exceeding the ICH Q3C concentration limits.

[0020] The second aspect of the present invention is an amorphous compound as shown below. <9> Formula (8): An amorphous form of the compound (evocalcet) represented by the above, having a total residual solvent content of 5000 ppm or less.

[0021] <10> The compound according to <9>, wherein the compound substantially has no peaks at diffraction angles represented by 2Θ of 15.9°, 17.3°, 21.4° and 22.6° in a powder X-ray diffraction pattern.

[0022] <11> The compound according to <9> or <10>, wherein the residual solvent content does not exceed the ICH Q3C concentration limits.

[0023] The third aspect of the present invention is a pharmaceutical or pharmaceutical composition as described below: <12> A pharmaceutical containing the compound described in any of <9> to <11> above. <13> A pharmaceutical composition containing the compound described in any of <9> to <11> above.

[0024] The fourth aspect of the present invention is the compound shown below. <14> Formula (3): (In the formula, X １ and X ２ Both are halogen atoms, or if one is a halogen atom, the other is a hydrogen atom. １ The symbol indicates a protecting group for the amino group. ) A compound represented by ).

[0025] The fifth aspect of the present invention is a method for producing an amorphous compound as shown below. <15> A solution obtained by dissolving evocalcet-free crystals in an alkaline aqueous solution, followed by neutralization with a buffer, characterized by formula (8): A method for producing an amorphous compound (evocalcet) represented by [formula].

[0026] <16> The manufacturing method according to <15>, characterized in that a water-soluble organic solvent is added when the crystal is dissolved in the alkaline aqueous solution.

[0027] <17> The manufacturing method according to <15> or <16>, wherein the buffer is a buffer prepared to a pH of 5.5 to 6.4.

[0028] <18> The manufacturing method according to any one of <15> to <17>, characterized in that a solution in which the crystal is dissolved is added to the buffer.

[0029] <19> The method for producing the amorphous compound (evocalcet) according to any one of <15> to <18>, wherein the amorphous compound (evocalcet) substantially does not have peaks at 15.9°, 17.3°, 21.4°, and 22.6° as diffraction angles represented by 2Θ in the powder X-ray diffraction pattern.

[0030] <20> The method for producing the amorphous compound (evocalcet) according to any one of <15> to <19>, wherein the total residual solvent content of the amorphous compound (evocalcet) is 5000 ppm or less.

[0031] <21> The method for producing the amorphous compound (evocalcet) according to any one of <15> to <20>, wherein the residual solvent is below the ICH Q3C concentration limit.

[0032] The present invention makes it possible to produce amorphous evocalcet-free compounds that can serve as highly safe pharmaceutical active pharmaceutical ingredients, with residual solvent levels below the ICH Q3C concentration limit, preferably one-tenth or less of the concentration limit. Furthermore, it provides a method for producing amorphous evocalcet-free compounds and evocalcet production intermediates that are highly economical and / or efficient.

[0033] Amorphous powder X-ray pattern of compound 8 obtained in Example 1 (powder X-ray analysis results)

[0034] A. Manufacturing method In the present invention, Pro in general formulas (1), (3), and (4) １ "Amino group protecting groups" refer to the amino group protecting groups of amino acids that are commonly used in the field of peptide synthesis. Examples include the t-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, allyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, and trimethylsilylethyloxycarbonyl group. Among these, the t-butoxycarbonyl group is preferred.

[0035] X in general formulas (2), (3), and (6) １ ~X ３ In this context, "halogen atoms" include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms. Among these, chlorine atoms are preferred in (2) and (3), and bromine atoms are preferred in (6). In general formulas (6) and (7), Pro ２The "carboxyl group protecting group" refers to, for example, linear or branched lower alkyl groups with 1 to 6 carbon atoms, benzyl groups, or allyl groups. Examples of linear or branched lower alkyl groups with 1 to 6 carbon atoms include methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, isobutyl groups, s-butyl groups, t-butyl groups, pentyl groups, or hexyl groups. ２ The "carboxyl group protecting group" is preferably a methyl group, an ethyl group, an isopropyl group, or a benzyl group, with the ethyl group being particularly preferred.

[0036] According to the present invention, the halogen-substituted benzenesulfonyl protected compound (3) and the amorphous evocalcet-free compound (8), which are manufacturing intermediates, can be produced by the following route. The definitions of the symbols in the formulas are as described above. Manufacturing Route

[0037] <Step 1> The sulfonic acid ester (3) can be produced from the alcohol (1) by a sulfonic acid esterification method using sulfonyl chloride (2) and a base.

[0038] For the alcohol (1), a commercially available product can be used, or commercially available (-)-3-pyrrolidinol can be used as a raw material and the introduction and deprotection of the protecting group described in Non-Patent Document 2 can be carried out by conventional methods. The sulfonyl chloride (2) is a halobenzenesulfonyl chloride, for example, 4-chlorobenzenesulfonyl chloride.

[0039] The sulfonic acid esterification reaction can be carried out using, for example, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethyl acetate, diethyl ether (ether), tetrahydrofuran (THF), 1,4-dioxane, acetone, methylene chloride, chloroform, acetonitrile, propionitrile, benzene, toluene, or xylene as the reaction solvent. As the base, an inorganic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, or tripotassium phosphate, or an organic base such as triethylamine or diisopropylethylamine can be used. The reaction can be carried out in the presence of the organic solvent at a reaction temperature of 0°C to room temperature.

[0040] Triethylamine is preferred as the base for the sulfonic acid esterification, and THF, 1,4-dioxane, acetonitrile, or propionitrile are preferred solvents, with acetonitrile being particularly preferred. The amount of sulfonyl chloride (2) used in the reaction is 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, and more preferably 1.0 to 1.1 equivalents, relative to alcohol (1). The amount of base used is 1.0 to 2.0 equivalents, preferably 1.0 to 1.7 equivalents, and more preferably 1.1 to 1.4 equivalents, relative to compound (1).

[0041] Furthermore, the compound (3) obtained in this process can be used in the next process without isolation or purification.

[0042] <Step 2> Aminopyrrolidine (4) can be obtained from sulfonic acid ester (3) by the N-alkylation reaction of 1R-(1-naphthyl)ethylamine. The sulfonic acid ester (3) is preferably 2-chlorobenzenesulfonyl, 4-chlorobenzenesulfonyl, or 2,4-dichlorobenzenesulfonyl, and is particularly preferably 4-chlorobenzenesulfonyl.

[0043] The N-alkylation reaction can be carried out using, for example, DMF, DMSO, ethyl acetate, ether, THF, 1,4-dioxane, acetone, methylene chloride, chloroform, acetonitrile, propionitrile, benzene, toluene, or xylene as the reaction solvent, and as the base, an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, or tripotassium phosphate, or an organic base such as triethylamine or diisopropylethylamine can be used, and the reaction can be carried out at a reaction temperature of 70°C to 130°C.

[0044] The base for the N-alkylation reaction is preferably potassium carbonate, sodium carbonate, or tripotassium phosphate, with tripotassium phosphate being particularly preferred. The reaction temperature is preferably 100 to 120°C, particularly preferably 105 to 115°C, and it is especially preferable to add water to the reaction system.

[0045] The amount of 1R-(1-naphthyl)ethylamine used in the N-alkylation reaction is 1.0 to 1.5 equivalents, preferably 1.0 to 1.25 equivalents, and more preferably 1.05 equivalents, relative to compound (1). The amount of base used varies depending on the base used, but is generally 0.5 to 2.0 equivalents, although in the case of tripotassium phosphate, it is preferably 1.0 equivalent. The amount of water added is 1.0 to 3.0 equivalents, preferably 1.0 to 2.0 equivalents, and more preferably 2.0 equivalents.

[0046] Furthermore, the compound (4) obtained in this process can be used in the next process without isolation or purification.

[0047] <Step 3> The conversion from compound (4) to compound (5) is achieved by the deprotection reaction of the amino group described in Non-Patent Document 2.

[0048] The deprotection reaction of the amino group is carried out by each protecting group (Pro 1The deprotection can be carried out by a method appropriate to the characteristics of the amino group. For example, in the case of the benzyloxycarbonyl group, it is typically carried out by catalytic hydrogen reduction, and in the case of the 9-fluorenylmethyloxycarbonyl group, as one embodiment, it can be carried out by base treatment using piperidine. In the case of the t-butoxycarbonyl group, which is a preferred protecting group among the protecting groups of the amino group, the deprotection reaction can be carried out using an acid such as trifluoroacetic acid, hydrochloric acid, hydrochloric acid-containing methanol, hydrochloric acid-containing ethyl acetate, hydrochloric acid-containing 1,4-dioxane, methanesulfonic acid, acetyl chloride, or trimethylsilyl chloride. The reaction solvent used for the deprotection reaction of the amino group is, for example, methanol, ethanol, isopropanol, DMF, DMSO, THF, 1,4-dioxane, acetone, acetonitrile, or propionitrile, and the reaction can be carried out at a temperature of 0°C to 100°C. Preferred reaction solvents are methanol, ethanol, isopropanol, or THF, with isopropanol being particularly preferred. The acid is preferably trifluoroacetic acid, hydrochloric acid, or acetyl chloride, with acetyl chloride being particularly preferred. The preferred reaction temperature is room temperature to 80°C, and particularly preferably 50 to 70°C.

[0049] <Step 4> Compound (7) can be obtained by a Buchwald-Hartwig amination reaction of compound (5) and compound (6) using a palladium (Pd) catalyst.

[0050] The aforementioned Buchwald-Hartwig amination reaction can use, for example, DMF, DMSO, ethyl acetate, ether, THF, 1,4-dioxane, acetone, methylene chloride, chloroform, acetonitrile, propionitrile, benzene, toluene, xylene, ethanol, or butanol as the reaction solvent, and palladium chloride (PdCl ２ ), palladium acetate (Pd(OAc) ２ ), dichlorobis(triphenylphosphine)palladium (PdCl ２ (PPh ３ ) ２ ), (dichloro[1,1'-bis(diphenylphosphin)ferrocene]palladium(PdCl)２ (dppf)), tetrakis(triphenylphosphine)palladium (Pd(PPh ３ ) ４ ), or tris(dibenzylideneacetone)palladium (Pd ２ (dba) ３ Pd catalysts such as ) can be used, and the procedure can be carried out in the presence of the Pd catalyst by adding potassium carbonate, sodium carbonate, cesium carbonate, or sodium t-butoxide as a base.

[0051] The Buchwald-Hartwig amination reaction may be carried out in the presence of a ligand, for example, tris(o-tolyl)phosphine (P(o-tol) ３ ), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (S-PHOS), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS), or 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) can be used.

[0052] The halogen atom of compound (6) is preferably a bromine atom, and the amount used in the reaction is 1.0 to 2.0 equivalents, preferably 1.0 to 1.5 equivalents, and more preferably 1.0 to 1.1 equivalents relative to compound (5). The amount of palladium catalyst used is 0.005 to 0.1 equivalents, preferably 0.005 to 0.05 equivalents, and more preferably 0.01 to 0.02 equivalents relative to compound (5). The amount of ligand used is 0.005 to 0.5 equivalents, preferably 0.005 to 0.3 equivalents, and more preferably 0.01 to 0.2 equivalents relative to compound (5). The amount of base used is 0.5 to 5 equivalents, preferably 1.0 to 4.0 equivalents, and more preferably 1.4 to 3.0 equivalents relative to compound (5). The reaction can be carried out at a temperature of 50°C to 150°C. The preferred temperature range is 70°C to 130°C, and the more preferred range is 90°C to 110°C.

[0053] Furthermore, if compound (5) has formed a salt with an acid, compound (7) can also be obtained by treating compound (5) with a base to convert it to a free form, and then reacting it with compound (6).

[0054] Compound (7) obtained from compound (5) is used in the fifth step. The reaction solution for compound (7) may be used as is, or the treated product of the reaction solution (for example, washed with an organic solvent) may be used, or compound (7) may be isolated and used. For example, compound (7) or a salt thereof can be isolated as crystals, washed with an organic solvent (for example, toluene), and used in the fifth step.

[0055] <Step 5> Amorphous evocalcet (8) can be obtained by carrying out an alkaline hydrolysis reaction of the ester of the compound of formula (7), followed by neutralizing the resulting alkali salt with an acid, or by carrying out an acid hydrolysis reaction, followed by neutralizing the resulting acid addition salt with an alkali. In particular, the method of neutralizing the alkali salt obtained after carrying out the alkaline hydrolysis reaction with an acid is more preferable.

[0056] The alkaline hydrolysis reaction of the compound of formula (7) can be carried out using, for example, a water-soluble organic solvent (e.g., DMF, DMSO, THF, 1,4-dioxane, acetone, acetonitrile, methanol, ethanol, or butanol) as the reaction solvent, with the addition of an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide, and at a reaction temperature of 0°C to 80°C. The acid hydrolysis reaction can also be carried out using the same solvent, but instead of an alkaline aqueous solution such as an aqueous solution of sodium hydroxide, hydrochloric acid, hydrobromic acid, hydroiodic acid, or trifluoroacetic acid can be added, and at a reaction temperature of 0°C to 80°C.

[0057] Amorphous compound (8) can be obtained by neutralizing the reaction solution obtained after hydrolysis of the compound of formula (7) with a buffer prepared to a pH of 5.5 to 6.4. The reaction solution obtained after hydrolysis of the compound of formula (7) that is neutralized with the buffer may be the reaction solution itself after hydrolysis, or it may be a processed product of the reaction solution (for example, washed with an organic solvent), but preferably it may be the reaction solution itself after hydrolysis.

[0058] The buffer is preferably a buffer that exhibits buffering capacity at pH 5.5 to 6.4, more preferably a buffer that exhibits buffering capacity at pH 5.8 to 6.2, and for example, a so-called Good buffer can be used, and in one embodiment, a phosphate buffer can be used. The buffer concentration may be in the range of 25 to 150 mM, preferably in the range of 50 to 120 mM, more preferably in the range of 90 to 110 mM, and most preferably 100 mM.

[0059] When performing the neutralization, it is preferable to maintain the buffer temperature below 30°C, more preferably below 25°C, more preferably below 15°C, and even more preferably below 10°C. For example, the rate at which the reaction solution (7) is added to the buffer (e.g., the dropping rate) can be adjusted to maintain the buffer temperature. The neutralization reaction is carried out by dropping the reaction solution into the buffer, and the temperature of the reaction solution being added can be in the range of 15°C to 60°C, more preferably between 20°C and 50°C, and more preferably between 25°C and 45°C.

[0060] Amorphous evocalcet (8) precipitates in the buffer, and can be obtained by filtering it off. The amorphous evocalcet (8) obtained by filtering can be washed with water and then dried. Drying can be carried out by any method, but it can be done by freeze-drying.

[0061] <Reference Form> Furthermore, the evocalcet-free crystals can also be converted into amorphous evocalcet (8) by referring to the "fifth step" described above. As evocalcet-free crystals, for example, type A crystals or type B crystals are known (see Patent Document 2 mentioned above). In other words, the amorphous form of evocalcet (8) can also be produced by dissolving the evocalcet-free crystals in an alkaline aqueous solution (such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, or an aqueous solution of lithium hydroxide), or by dissolving them in a solution of an alkaline aqueous solution and a water-soluble organic solvent (for example, DMF, DMSO, THF, 1,4-dioxane, acetone, acetonitrile, methanol, ethanol, or butanol), and then neutralizing the resulting solution with the buffer described in the "fifth step" described above. The neutralization conditions with the buffer can be the same as those in the "fifth step" described above.

[0062] B. Amorphous Compound (8) (Amorphous Evocalcet) The amorphous compound (8) can be obtained by the method described in "A. Manufacturing Method" above. The amorphous compound (8) in this specification preferably refers to an amorphous form showing the powder X-ray pattern shown in Figure 1. Furthermore, the amorphous compound (8) in this specification preferably "substantially does not contain A-type and B-type crystals of evocalcet". For example, when the amorphous compound (8) in a drug-containing composition is measured by powder X-ray diffraction, it is preferable that no characteristic crystal peaks of either A-type or B-type crystals are found, or that the crystal peaks of such crystals are substantially absent. For example, the amorphous compound (8) in this specification preferably substantially does not have peaks at 15.9°, 17.3°, 21.4°, and 22.6° as diffraction angles represented by 2θ in the powder X-ray diffraction pattern. The powder X-ray diffraction patterns of evocalcet type A and type B crystals are disclosed in the aforementioned Patent Document 2.

[0063] The total amount of residual solvent of the amorphous compound (8) (hereinafter referred to as "total residual solvent") is 5000 ppm or less, preferably 500 ppm or less, more preferably 200 ppm, and more preferably 100 ppm or less. The amount of residual solvent of the amorphous compound (8) can be measured by gas chromatography, referring to [Test Example 1] described below.

[0064] Furthermore, of the total residual solvent of the amorphous compound (8), the individual residual solvents are preferably below the ICH Q3C concentration limit, and more preferably below one-tenth of the concentration limit. Alternatively, the organic solvents listed in Class 1 of ICH Q3C that may be contained in the residual solvent of the obtained amorphous compound (8) are preferably below the detection limit. Alternatively, the organic solvents listed in Class 2 of ICH Q3C that may be contained in the residual solvent of the obtained amorphous compound (8) are preferably below one-tenth of the concentration limit of each organic solvent, and more preferably below one-hundredth. Alternatively, the organic solvents listed in Class 3 of ICH Q3C that may be contained in the residual solvent of the obtained amorphous compound (8) are preferably 500 ppm or less, and more preferably 50 ppm or less.

[0065] In this specification, "residual solvents below the ICH Q3C concentration limit" means that the organic solvents remaining in the active pharmaceutical ingredient, excipients, and formulations are below the toxicologically acceptable limit specified in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines for Residual Solvents in Pharmaceuticals (Q3C). Specifically, Non-Patent Literature 1 classifies residual solvents into classes 1 to 3, with class 1 solvents being those that should be avoided in the manufacture of pharmaceuticals, class 2 solvents being those whose residual amounts in pharmaceuticals should be regulated, and class 3 solvents being low-toxicity solvents. As of 2024, ICH Q3C specifies limit values ​​for five types of solvents as class 1 residual solvents, 32 types of solvents as class 2 residual solvents, and 27 types of solvents as class 3 residual solvents. In the present invention, an amorphous form of evocalcet-free material that is substantially free of organic solvents (residual solvents) or contains only an amount of organic solvents (residual solvents) that can be used in pharmaceuticals means, for example, that the concentration of each of the Class 1 to 3 residual solvents contained in the amorphous form of evocalcet-free material of the present invention is below each limit value.

[0066] The amorphous form of compound (8) (amorphous evocalcet) of the present invention substantially does not contain A-type or B-type crystals, and furthermore, the residual solvent is at such a low concentration that it can be used as a high-quality pharmaceutical active pharmaceutical ingredient with excellent safety. Moreover, the amorphous form of compound (8) maintains its storage state without showing any clear changes in quality over time in terms of crystal form (properties) or purity, and is fully usable as a pharmaceutical active pharmaceutical ingredient. The amorphous form of compound (8) can be stored, for example, under refrigerated conditions. According to the manufacturing method of the present invention, the amorphous material can be directly isolated and purified from the solution obtained by hydrolysis of the ester, and large-scale synthesis is possible. Furthermore, the amorphous material can also be produced from A-type or B-type crystals of the evocalcet-free form.

[0067] C. Pharmaceuticals or Pharmaceutical Compositions The amorphous evocalcet of the present invention can be used as a pharmaceutical. Amorphous evocalcet is a useful pharmaceutical for the prevention or treatment of various diseases in which improvement of the pathological condition is expected by activation of CaSR and / or suppression of PTH production (and / or reduction of blood PTH levels via these). Examples of such diseases include hyperparathyroidism (primary hyperparathyroidism, secondary hyperparathyroidism, and ectopic hyperparathyroidism, etc.).

[0068] When the amorphous compound (8) of the present invention (i.e., amorphous evocalcet) is used as an active ingredient in pharmaceutical applications, amorphous evocalcet can be included as an active ingredient in a pharmaceutical composition (e.g., a formulation). A pharmaceutical composition containing amorphous evocalcet can be used as a conventional pharmaceutical preparation (tablets, granules, capsules, powders, solutions, suspensions, emulsions, injections, intravenous infusions, etc.) by including inert additives depending on the method of administration. Examples of carriers for a pharmaceutical composition containing amorphous evocalcet include binders (such as gum arabic, gelatin, sorbitol, and polyvinylpyrrolidone), excipients (such as lactose, sugar, corn starch, and sorbitol), lubricants (such as magnesium stearate, talc, and polyethylene glycol), and disintegrants (such as potato starch), which are generally acceptable in pharmaceuticals. When a pharmaceutical composition containing amorphous evocalcet is made into an injection or intravenous infusion, it can be formulated using distilled water for injection, physiological saline, glucose aqueous solution, etc.

[0069] The method of administering the pharmaceutical composition containing amorphous evocalcet of the present invention is not particularly limited, and general oral or parenteral methods (intravenous, intramuscular, subcutaneous, transdermal, transnasal, transmucosal, enteral, etc.) can be applied.

[0070] When using the amorphous evocalcet of the present invention for pharmaceutical purposes, the dosage should be appropriately set within a range of an effective amount sufficient to produce the therapeutic effect, depending on the potency and properties of the active ingredient compound. The dosage will vary depending on the administration method, the patient's age, weight, and condition, but a general dosage, for example, should be set to an appropriate amount within the range of 0.001 to 300 mg / kg per day.

[0071] The present invention will be further described below with reference to examples, but the present invention is not limited thereto.

[0072] [Example 1] Production of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) (Step 1)

[0073] A mixture of compound 1-1 (50.0 g, 267 mmol), trimethylamine hydrochloride (4.67 g, 48.9 mmol), acetonitrile (142 g), and triethylamine (34.3 g, 339 mmol) was mixed with 4-chlorobenzenesulfonyl chloride (59.5 g, 282 mmol) in toluene (216 mL) at 0–5°C. The dropping vessel was then washed with acetonitrile (17.1 g), and the washings were poured into the reaction mixture. After stirring the reaction mixture at 7°C for 3 hours, water (54 mL) was added to the reaction mixture at below 5°C, and then a solution of water (87 mL) and concentrated hydrochloric acid (10.1 g) was added dropwise. After raising the reaction mixture to room temperature, it was separated. The separated organic layer was washed with water (163 mL), and this washing procedure was repeated. The organic layer was concentrated under reduced pressure to 120 mL, then toluene (150 mL) was added to the residue, and the mixture was concentrated again under reduced pressure to 120 mL to obtain a toluene solution of compound 2 (120 mL). This solution was used directly in the next step (step 2).

[0074] Compound 3-1 (t-butyl(R)-3-(((4-chlorophenyl)sulfonyl)oxy)pyrrolidine-1-carboxylate) was obtained as a colorless crystal by column purification after concentration to dryness, without adding toluene to the vacuum concentrate. The 1H-NMR data of the obtained crystal is shown. 1 H-NMR (400 MHz, CDCl3) δ(ppm)=7.85(2H,d,J=8.8Hz), 7.55(2H,d,J=8.4Hz), 5.09(1H,m), 3.54-3.38(4H,m), 2.19-1.99(2H,m), 1.44(9H,s)

[0075] The following compounds were obtained by reacting compound 1 with 2-chlorobenzenesulfonyl chloride, 3-chlorobenzenesulfonyl chloride, and 2,4-dichlorobenzenesulfonyl chloride using the same procedure as in step 1, followed by concentration and drying of the extract and column purification to obtain the following compounds: 3-2 (t-butyl(R)-3-(((2-chlorophenyl)sulfonyl)oxy)pyrrolidine-1-carboxylate), 3-3 (t-butyl(R)-3-(((3-chlorophenyl)sulfonyl)oxy)pyrrolidine-1-carboxylate), and 3-4 (t-butyl(R)-3-(((2,4-dichlorophenyl)sulfonyl)oxy)pyrrolidine-1-carboxylate).

[0076] Properties: colorless oil 1 H-NMR (400 MHz, CDCl3) δ(ppm)=8.10(1H,d,J=7.6Hz), 7.58(2H,s), 7.49-7.42(1H,m), 5.19(1H,m), 3.64(1H,d,J=13.2Hz), 3.55-3.47(3H,m), 2.30-2.17(1H,m), 2.09-2.01(1H,m), 1.44(9H,s)

[0077] Properties: Colorless crystal 1 H-NMR (400 MHz, CDCl3) δ(ppm)=7.91(1H,s), 7.80(1H,d,J=7.6Hz), 7.65(1H,d,J=7.6Hz), 7.52(1H,t,J=8.0Hz), 5.11(1H,m), 3.55-3.39(4H,m), 2.19-2.03(2H,m), 1.44(9H,s)

[0078] Properties: white crystal 1 H-NMR (400 MHz, CDCl3) δ(ppm)=8.03(1H,d,J=8.4Hz), 7.59(1H,s), 7.44(1H,d,J=8.4Hz), 5.20(1H,m), 3.64(1H,d,J=13.2Hz), 3.56-3.48(3H,m), 2.30-2.19(1H,m), 2.10-2.03(1H,m), 1.45(9H,s)

[0079] (Step 2)

[0080] To a toluene solution (120 mL) of compound 3-1 obtained in step 1, a solution of 1R-(1-naphthyl)ethylamine (48.0 g, 280 mmol) in acetonitrile (76.5 g) was added at room temperature. The dropping vessel was washed with acetonitrile (15.1 g), and the washings were poured into the reaction mixture. After adding tripotassium phosphate (56.7 g, 267 mmol) to the reaction mixture, a solution of water (9.62 g, 534 mmol) and acetonitrile (30.2 g) was added dropwise. After partially removing the solvent from the reaction system under atmospheric pressure until the reaction temperature reached 110°C, the reaction was continued at 105–115°C for a further 14 hours. The reaction mixture was cooled to 50°C, water (389 mL) and ethyl acetate (182 mL) were added to the reaction mixture, and after stirring for 10 minutes, the organic layer was separated. Water (193 mL) and tripotassium phosphate (11.0 g) were added to the obtained organic layer and stirred, after which the organic layer was separated. Water (193 mL) was added to the organic layer and stirred, and after liquid-liquid separation, the obtained organic layer was transferred to a separate container, the container was washed with ethyl acetate (39 mL), and the washings were poured into a separate container. The organic layer transferred to the separate container was concentrated under reduced pressure to 200 mL. Toluene (200 mL) was added to the residue, and the extract was concentrated under reduced pressure to 200 mL to obtain a toluene solution (200 mL) of compound 4-1. This solution was used as is in the next step (step 3).

[0081] (Step 3)

[0082] To 299 mL of isopropanol cooled to below 5°C, 100.5 g, 1.28 mol of acetyl chloride was added dropwise. The dropping vessel was then washed with 13 mL of isopropanol, and the washings were poured into the reaction mixture. The reaction mixture was stirred at 0–10°C for 1 hour, after which a solution of compound 4-1 obtained in step 2, which had been mixed with 152 mL of isopropanol, was added dropwise. The dropping vessel was then washed again with 62 mL of isopropanol, and the washings were poured into the reaction mixture. The reaction mixture was heated to 55–60°C and reacted at that temperature for 17 hours. The reaction mixture was slowly cooled to room temperature over 2 hours under stirring, and then stirred at room temperature for a further 3 hours. After filtering out the precipitated crude crystals, the filtered crude crystals were washed with 207 mL of isopropanol. The crude crystals obtained were suspended in isopropanol (727 mL) and stirred at 70–80°C for 1 hour. After cooling the suspension to room temperature, it was stirred again at room temperature for 15 hours. Insoluble crystals were filtered off, and the filtered crystals were washed twice with isopropanol (136 mL). The obtained crystals were vacuum-dried at 50°C to obtain the target compound 5-1 (71.0 g, yield 71.2%, HPLC 100% area 99.8%) as white crystals. The 1H-NMR data of the obtained crystals is shown. 1 H-NMR (400 MHz, DMSO-d6) δ(ppm)=10.40(1H,br-s), 9.92(1H,br-s), 9.30-8.97(2H,br-d), 8.33(1H,d,J=8.8Hz), 8.04-7.95(3H,m), 7.67-7.59(3H,m), 5.41(1H,s), 3.80-3.73(2H,overlapped with IPA peak), 3.64-3.24(3H,overlapped with H2O peak), 3.12(1H,m), 2.32(1H,m), 2.14(1H,m), 1.71(3H,d,J=6.4Hz), 1.04(6H,d,J=6.0Hz,IPA)

[0083] (Step 4)

[0084] Compound 5-1 (20.0 g) obtained in step 3, toluene (100 mL), and 4N sodium hydroxide aqueous solution (40 mL) were mixed and stirred at room temperature for 30 minutes. The reaction mixture was separated, water (30 mL) was added to the organic layer and stirred, and then separated again. The separated organic layer was concentrated to 80 mL. To this concentrate, cesium carbonate (24.8 g, 76.2 mmol), palladium(II) acetate (0.12 g, 0.54 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos, 0.57 g, 1.20 mmol), water (0.26 g), and ethyl 4-bromophenyl (13.24 g, 54.5 mmol) in toluene (8 mL) solution were added at room temperature. The dropping vessel was washed with toluene (12 mL), the washings were added, and the reaction system was purged with nitrogen. The temperature was then raised to 95–105°C, and the reaction was carried out at that temperature for 22 hours. After cooling to room temperature, water (160 mL) was added and the mixture was stirred for 10 minutes.

[0085] Insoluble matter in the reaction mixture was removed by Celite filtration. The Celite was washed with toluene (40 mL), and the filtrate was separated. 7% saline solution (93 mL) was added to the separated organic layer under stirring, and then separated again. Ethylenediamine (0.18 g, 3.00 mmol) and activated carbon / purified white heron (4.00 g) were added to the separated organic layer, and after stirring at room temperature for 2 hours, ethyl acetate (70 mL) was added. The reaction mixture was filtered using Celite / silica precoat, and the Celite / silica precoat was washed with a mixture of toluene (80 mL) and ethyl acetate (60 mL). The filtrate was concentrated to 100 mL, then toluene (100 mL) was added and it was concentrated again to 170 mL. A mixture of concentrated hydrochloric acid (5.23 g) and ethanol (26 mL) was added to the concentrate, and the hydrochloric acid solution was washed with t-butyl methyl ether (21 mL). To this solution, t-butyl methyl ether (234 mL) was added dropwise over 1 hour at room temperature, and the mixture was stirred for another hour at the same temperature. The precipitated crystals were filtered off, washed with t-butyl methyl ether (120 mL), and dried to obtain the target compound 7-1 as white crystals (20.08 g, yield: 85.4%, HPLC 100% surface area 99.2%). If necessary, the obtained crystals can be re-slurred using toluene. The 1H-NMR data of the obtained crystals is shown. 1 H-NMR (400 MHz, DMSO-d6) δ(ppm)=9.65(1H,br-s), 9.42(1H,br-s), 8.38(1H,d,J=8.8Hz), 8.04(2H,m), 7.91(1H,d,J=7.6Hz), 7.69-7.62(3H,m), 7.07(2H,d,J=8.8Hz), 6.50(2H,d,J=8.8Hz), 5.43(1H,m), 4.02(2H,q,J=6.8Hz), 3.90(1H,m), 3.51-3.21(5H,overlapped with H2O peak), 3.16(1H,m), 2.28(2H,m), 1.73(3H,d,J=6.4Hz), 1.16(3H,t,J=7.2Hz)

[0086] (Step 5)

[0087] A solution of sodium hydroxide (0.81 g, 20.3 mmol) and water (8.6 mL) was mixed with ethanol (6.9 mL) and heated to 50°C. While stirring at the same temperature, compound 7-1 (3.00 g) was added to the solution in five portions at 3-minute intervals. The reaction mixture was heated to 60°C and stirred for 1 hour. Then, water (10 mL) and activated carbon / purified Shirasagi (0.30 g) were added and stirred at room temperature for 1 hour. The activated carbon / purified Shirasagi was filtered, and the activated carbon was washed with a mixture of water (2.1 mL), sodium hydroxide (45 mg), and ethanol (2.3 mL). Sodium erythorbate monohydrate (45.4 mg, 0.21 mmol) was added to the filtrate, and the mixture was heated to 45°C to obtain the crystallization solution.

[0088] In a separate container, water (500 mL), disodium hydrogen phosphate (425 mg), and sodium dihydrogen phosphate (5.70 g) were mixed to prepare a sodium phosphate buffer. After confirming that the pH of the buffer was 5.6 to 6.0, 200 mL of the buffer was purged with reduced-pressure nitrogen to reduce the dissolved oxygen concentration to 1.0 ppm or less. After cooling the obtained buffer to 2 to 5°C, the crystallizing solution was added dropwise using a cannula, and the cannula was washed with a mixture of water (0.7 mL), sodium hydroxide (0.015 g), and ethanol (0.8 mL), and the washings were poured into the buffer. After stirring the buffer at 2 to 7°C for 5 minutes, the precipitated solid was filtered off and washed twice with water (60 mL) cooled to 5 to 10°C. The filtered solid was frozen at -60°C for 2 hours, followed by freeze-drying for 2 days to obtain the target compound 8:4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) (2.29 g, yield: 89.4%, HPLC 100% surface area 99.8%) as a white amorphous material. The 1H-NMR data of the obtained crystals is shown. 1H-NMR (400 MHz, DMSO-d6) δ(ppm)=8.30(1H,d,J=6.8Hz), 7.93-7.91(1H,m), 7.79(1H,d,J=8.4Hz), 7.73(1H,d,J=6.8Hz), 7.53-7.48(3H,m), 6.99(2H,d,J=8.8Hz), 6.36(2H,d,J=8.8Hz), 4.73(1H,q,J=6.4Hz), 3.73-3.29(5H,overlapped with H2O peak), 3.10(1H,m), 2.96(1H,m), 2.03(1H,m), 1.89(1H,m), 1.39 (3H,d,J=6.8Hz)

[0089] [Examples 2-7] Production of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) The temperature of the crystallization solution (referred to as the dropping temperature in Table 1) in step 5 of Example 1, the concentration of the sodium phosphate buffer, and the internal temperature were changed to the conditions shown in Table 1, and 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) was produced in the same manner as in Example 1. The results are shown in Table 1. In Examples 4-7, the aqueous layer was sequentially washed with toluene and heptane after the hydrolysis reaction, and then the aqueous layer was treated with activated carbon / purified Shirasagi.

[0090] [Example 8] Production of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) using MES buffer, a Good buffer. Step 5 of Example 1 above was changed to the following procedure. Ethanol (3.4 mL) was added to a solution of sodium hydroxide (0.41 g, 10.1 mmol) and water (4.3 mL), and the temperature was raised to 50°C. Compound 7-1 (1.5 g) was added to this solution in five portions at 3-minute intervals while stirring at the same temperature. The reaction mixture was raised to 60°C and stirred for 1 hour, then water (5 mL) and activated carbon / purified Shirasagi (0.15 g) were added, and the mixture was stirred at room temperature for 1 hour. The activated carbon / purified Shirasagi was filtered, and the activated carbon was washed with a mixture of water (1.1 mL), sodium hydroxide (23 mg), and ethanol (1.1 mL). Sodium erythorbate monohydrate (22.15 mg, 0.10 mmol) was added to the filtrate, and the mixture was heated to 45°C to obtain the crystallization solution. In a separate container, water (1000 mL), 2-morpholinoethanesulfonic acid (21.538 g), and sodium hydroxide (1.708 g) were mixed to prepare the MES buffer solution. After confirming that the pH of the buffer solution was 5.6 to 6.0, the buffer solution (100 mL) was purged with reduced pressure nitrogen to reduce the dissolved oxygen concentration to 1.0 ppm or less. After cooling the obtained buffer solution to 2 to 5°C, the crystallization solution was added dropwise using a cannula, and the cannula was washed with a mixture of water (0.4 mL), sodium hydroxide (0.008 g), and ethanol (0.4 mL), and the washings were poured into the buffer solution. After stirring the buffer solution at 2–7°C for 5 minutes, the precipitated solid was filtered and washed twice with 30 mL of water cooled to 5–10°C. The filtered solid was frozen at -60°C for 2 hours and then freeze-dried for 2 days to obtain the target compound 8:4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) (0.69 g, yield: 68.8%) as a white amorphous material.

[0091] [Example 9] Production of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) from evocalcet-free form A crystals Ethanol (3.4 mL) was added to a solution of sodium hydroxide (0.41 g, 10.1 mmol) and water (4.3 mL), and the temperature was raised to 50°C. While stirring at the same temperature, 1.5 g of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (form A crystals) was added to this solution. The reaction mixture was raised to 60°C and stirred for 1 hour, then water (5 mL) and activated carbon / purified Shirasagi (0.15 g) were added, and the mixture was stirred at room temperature for 1 hour. The activated carbon / purified Shirasagi was filtered, and the activated carbon was washed with a mixture of water (1.1 mL), sodium hydroxide (23 mg), and ethanol (1.1 mL). Sodium erythorbate monohydrate (22.15 mg, 0.10 mmol) was added to the filtrate, and the mixture was heated to 45°C to obtain the crystallization solution. In a separate container, water (500 mL), disodium hydrogen phosphate (425 mg), and sodium dihydrogen phosphate (5.70 g) were mixed to prepare a sodium phosphate buffer. After confirming that the pH of the buffer was 5.6 to 6.0, 100 mL of the buffer was purged with reduced-pressure nitrogen to reduce the dissolved oxygen concentration to 1.0 ppm or less. After cooling the obtained buffer to 2 to 5°C, the crystallization solution was added dropwise using a cannula, and then in a separate container, water (10 mL), sodium hydroxide (0.3 g), and ethanol (10 mL) were mixed to prepare a mixture. The cannula was washed with the mixture (0.9 mL), and the washings were poured into the buffer. After stirring the buffer solution at 2–7°C for 5 minutes, the precipitated solid was filtered and washed twice with 30 mL of water cooled to 5–10°C. The filtered solid was frozen at -60°C for 2 hours and then freeze-dried for 1 day to obtain the target compound 8:4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) (1.23 g, yield: 82%) as a white amorphous material.

[0092] [Example 10] Production of 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) from evocalcet-free B-type crystals Ethanol (1.1 mL) was added to a solution of sodium hydroxide (0.14 g, 3.38 mmol) and water (1.4 mL), and the temperature was raised to 50°C. While stirring at the same temperature, 4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (B-type crystals) (0.5 g) was added to this solution. The reaction mixture was raised to 60°C and stirred for 1 hour, then water (1.7 mL) and activated carbon / purified Shirasagi (0.05 g) were added, and the mixture was stirred at room temperature for 1 hour. The activated carbon / purified Shirasagi was filtered, and the activated carbon was washed with a mixture of water (0.4 mL), sodium hydroxide (8 mg), and ethanol (0.4 mL). Sodium erythorbate monohydrate (7.38 mg, 0.03 mmol) was added to the filtrate, and the mixture was heated to 45°C to prepare the crystallization solution. In a separate container, water (500 mL), disodium hydrogen phosphate (425 mg), and sodium dihydrogen phosphate (5.70 g) were mixed to prepare a sodium phosphate buffer. After confirming that the pH of the buffer was 5.6 to 6.0, the buffer (33 mL) was purged with reduced-pressure nitrogen to reduce the dissolved oxygen concentration to 1.0 ppm or less. After cooling the obtained buffer to 2 to 5°C, the crystallization solution was added dropwise using a cannula, and then in a separate container, water (10 mL), sodium hydroxide (0.3 g), and ethanol (10 mL) were mixed to prepare a mixture. The cannula was washed with the mixture (0.25 mL), and the washings were poured into the buffer. After stirring the buffer solution at 2–7°C for 5 minutes, the precipitated solid was filtered and washed twice with 10 mL of water cooled to 5–10°C. The filtered solid was frozen at -60°C for 2 hours and then freeze-dried for 1 day to obtain the target compound 8:4-(3S-(1R-(1-naphthyl)ethylamino)pyrrolidine-1-yl)phenylacetic acid (amorphous) (49 mg, yield: 10%) as a cream-colored amorphous material.

[0093] [Test Example 1-1] Residual Solvent Measurement Results (GC); The residual solvent concentration of compound 8 obtained in Example 1 was measured using gas chromatography (GC). The measurement was performed using a sample that had been stored in a sealed state at -21°C for two weeks. The measurement conditions, the residual solvent to be measured, the concentration limit value of the residual solvent (see Non-Patent Literature 1), and the measured values ​​are as follows. The GC measurement conditions are as follows: • Apparatus: Agilent 7890B (main unit), Agilent 7697A (headspace) • Column: Agilent DB-624 (length 60 m, inner diameter 0.25 µm, film thickness 1.4 µm) • Operating conditions: Injection volume: 1 mL Injection method: Split ratio 1:20 Injection port temperature: 250°C Carrier gas: Helium, linear velocity 15 cm / s Detector: FID, 250°C

[0094] The amount of residual solvent in compound 8 obtained in Examples 2-7 can also be measured using the same procedure as in Test Example 1-1, and it can be confirmed that it is below the ICH Q3C concentration limit.

[0095] [Test Example 1-2] Residual Solvent Measurement Results (GC); The residual solvent concentration of compound 8 obtained in Examples 8-10 was measured using gas chromatography (GC). The measurement conditions were the same as in [Test Example 1-1]. The measurement results are shown in the table below. Class 1 benzene can also be measured in the same manner as in [Test Example 1-1], and it can be confirmed that it is below the ICH Q3C concentration limit.

[0096] [Test Example 2] Powder X-ray diffraction: The white amorphous material of compound 8 obtained in Example 1 was analyzed by powder X-ray diffraction. The obtained powder X-ray diffraction pattern is shown in Figure 1. Compound 8 obtained in Examples 2 to 10 also showed a similar powder X-ray diffraction pattern.

[0097] X-ray diffraction analysis conditions and equipment: D2 PHASER (Brker) Operating conditions: X-ray tube: Anode: Copper, Tube voltage: 30kV, Tube current: 10mA Sampling width: 0.020° Measurement range: 2 θ = 3 to 40°

[0098] [Test Example 3] Stability Test Results The stability of compound 8 obtained in Example 1 was evaluated by (1) whether its amorphous state was maintained and (2) whether the purity of the amorphous state was maintained. (1) Confirmation of maintenance of amorphous state The evaluation method for the maintenance of amorphous state followed the method of Test Example 2. The sample used was compound 8 that had been stored at -21°C for 5 days after synthesis. The first day of the test was taken as day 0, and the samples were stored under refrigerated conditions (2-8°C) from day 0 to day 14. The results are shown in Table 4, and it was confirmed that the amorphous state was maintained even after 14 days. (2) Confirmation of purity of amorphous state The purity of the amorphous state was measured by HPLC. The measurement conditions were as follows, based on the guidelines described in Non-Patent Document 3. (HPLC measurement conditions) ・Apparatus: LC-20 Prominence (Shimadzu Corporation) ・Detector: UV 257 nm, spectral measurement range 200-400 nm ・Column temperature: 40°C ・Column: InertSustainC18 (5 μm, 4.6 x 100 mm, GL Sciences) ・Operating conditions Mobile phase A: 0.1% trifluoroacetic acid aqueous solution Mobile phase B: Acetonitrile The sample used was compound 8, which was synthesized and stored at -21°C for 5 days. The first day of the test was designated as day 0, and samples were tested from day 0 to day 14 under storage conditions: refrigerated (2-8°C). The results are shown in Table 4. The purity of amorphous evocalcet can be considered to have not changed between day 0 and day 14, and it was confirmed that no organic impurities (decomposition products) were generated during the storage process.

[0099] As described above, refrigerated storage maintained the amorphous form and no deterioration in quality was observed.

[0100] The present invention provides a method for producing amorphous evocalcet or its intermediates for production that is excellent in terms of safety, efficiency, and / or cost-effectiveness.

Claims

1. Formula (7): (In the formula, Pro ２ The compound represented by (8) or a salt thereof is hydrolyzed and then neutralized with a buffer, characterized by the following: A method for producing an amorphous compound (evocalcet) represented by [formula].

2. Formula (5): After treating the compound represented by formula (6) or a salt thereof with a base as needed, formula (6): (In the formula, X ３ This indicates a halogen atom, Pro ２ The compound represented by () shows a protecting group for the carboxyl group. The compound is reacted with a palladium catalyst, a base and a ligand, and the above formula (7): The manufacturing method according to claim 1, further comprising the step of obtaining a compound represented by or a salt thereof.

3. Formula (1): (wherein Pro １ represents an amino-protecting group) with a compound represented by formula (2): (wherein X １ and X ２ are both halogen atoms, or when one is a halogen atom, the other represents a hydrogen atom), to obtain a compound represented by formula (3): (wherein X １ , X ２ and Pro １ have the same meanings as defined above; the obtained compound is reacted with 1R-(1-naphthyl)ethylamine in the presence of a base to obtain a compound represented by formula (4): (wherein Pro １ has the same meaning as defined above), the obtained compound is deprotected to obtain a compound represented by formula (5) or a salt thereof; after optionally treating with a base, the product is reacted with a compound represented by formula (6): (wherein X ３ represents a halogen atom, and Pro ２ represents a carboxyl-protecting group) in the presence of a palladium catalyst, a base and a ligand, to obtain a compound represented by formula (7) or a salt thereof: (wherein Pro ２ has the same meaning as defined above), followed by hydrolysis and neutralization with a buffer, which is a method for producing amorphous evocalcet represented by formula (8): ​ 4. The manufacturing method according to any one of claims 1 to 3, wherein the buffer is a buffer prepared to a pH of 5.5 to 6.

4.

5. The manufacturing method according to any one of claims 1 to 3, characterized in that the ester hydrolysis reaction solution of the compound represented by formula (7) is added to the buffer.

6. The method for producing the amorphous compound (evocalcet) represented by formula (8) according to any one of claims 1 to 3, wherein the powder X-ray diffraction pattern substantially does not have peaks at 15.9°, 17.3°, 21.4°, and 22.6° as diffraction angles represented by 2Θ.

7. The method for producing the amorphous compound (evocalcet) represented by formula (8) according to any one of claims 1 to 3, wherein the total residual solvent content is 5000 ppm or less.

8. The method for producing the amorphous compound (evocalcet) represented by formula (8) according to any one of claims 1 to 3, wherein the residual solvent is less than or equal to the ICH Q3C concentration limit.

9. Formula (8): A compound in amorphous form (evocalcet) represented by [formula], having a total residual solvent content of 5000 ppm or less.

10. The compound according to claim 9, wherein the powder X-ray diffraction pattern substantially does not have peaks at 15.9°, 17.3°, 21.4°, and 22.6° as diffraction angles represented by 2Θ.

11. The compound according to claim 9 or 10, wherein the residual solvent is below the ICH Q3C concentration limit.

12. A pharmaceutical product containing the compound described in claim 9 or 10.

13. A pharmaceutical composition containing the compound described in claim 9 or 10.

14. Formula (3): (In the formula, X １ and X ２ Both are halogen atoms, or if one is a halogen atom, the other is a hydrogen atom. １ The symbol indicates a protecting group for the amino group. ) A compound represented by ).

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