JP2011105685A - Crystal of phenethylamine compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a crystal of (1R)-2-[(4-aminophenethyl)amino]-1-phenylethan-1-ol monohydrochloride (compound A) having suitable properties in industrial production. <P>SOLUTION: With respect to the crystal of compound A, the formed crystal unexpectedly varies in accordance with the difference in detailed production conditions and the compound A exhibits crystal polymorphism, and furthermore a crystal (type II crystal) different from the type I crystal of compound A is found. This type II crystal particularly excels in flowability and electrification and has suitable properties in industrial production. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

The present invention relates to crystals of (1R) -2-[(4-aminophenethyl) amino] -1-phenylethane-1-ol monohydrochloride (hereinafter referred to as “Compound A”) and a process for producing the same.

Compound A is 2- (2-amino-1,3-thiazol-4-yl) -N- (4), which is known as an active ingredient of pharmaceutical intermediates, particularly therapeutic agents for diabetes and overactive bladder. -{2-[(2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide or a pharmaceutically acceptable salt thereof (Patent Document 1 and Patent Document 2) Compound.
Conventionally, as a method for obtaining a crystal of Compound A, Compound A was obtained by the method described in Preparation Example Step 3 in Patent Document 2, the method described in Reference Example 3 in Patent Document 3 and its alternative method, that is, reaction. Thereafter, a method of dissolving in methanol and adding diisopropyl ether or a method of adding ethyl acetate as a crystallization solvent is known. However, there is no disclosure or suggestion that Compound A exhibits a crystalline polymorph.
In addition to the above document, there is Patent Document 4 which discloses (1R) -2-[(4-aminophenethyl) amino] -1-phenylethane-1-ol as a synthesis intermediate of the example compounds. A is neither disclosed nor suggested.

International Publication No. WO 99/20607 Pamphlet International Publication No. WO 2004/041276 Pamphlet International Publication No. WO 03/037881 Pamphlet International Publication No. WO 02/06258 Pamphlet

Provided is a crystal of Compound A having suitable properties in industrial production.

In the industrial production of pharmaceuticals, it is required to ensure uniform quality and a stable supply of pharmaceuticals. For this reason, unforeseen circumstances such as clogging of powder in the production line, alteration in the remaining solidified layer, and static electricity In order to avoid fires and the like, not only the drug itself but also the intermediate of the drug has properties suitable for industrial production, especially fluidity, chargeability, stability, etc., and is an easy-to-handle form. It will be necessary. However, since the type I crystal of compound A obtained by the same production method as that described in the alternative method of Reference Example 3 of Patent Document 3 has low fluidity and high chargeability, There were problems with its use in industrial production.
Under such circumstances, the present inventors have conducted intensive research on the provision of crystals of Compound A. As a result, unexpectedly, crystals produced due to the difference in the detailed production conditions fluctuated, and Compound A has a crystalline polymorph. In addition, a Type II crystal of Compound A was found. The present inventors have completed the present invention by discovering that the type II crystal of Compound A is particularly excellent in fluidity and chargeability and has suitable properties in industrial production.
That is, the present invention relates to a type II crystal of compound A having suitable properties in industrial production and a method for producing the same.

Since the type II crystal of the compound A of the present invention is particularly excellent in fluidity and chargeability and has suitable properties in industrial production, it is effective as an intermediate for the manufacture of pharmaceuticals, in particular, a therapeutic agent for diabetes and overactive bladder. 2- (2-amino-1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl] amino} ethyl) known as component Phenyl] acetamide or a pharmaceutically acceptable salt thereof is a very useful form when using Compound A as an intermediate in the industrial production.

FIG. 1 shows a powder X-ray diffraction pattern of a Type II crystal of Compound A produced by a method similar to that described in Example 2. FIG. 2 shows a DSC chart of a type II crystal of compound A produced by a method similar to that described in Example 2. FIG. 3 shows an IR chart of a type II crystal of compound A produced by a method similar to that described in Example 2. FIG. 4 shows a powder X-ray diffraction pattern of a type I crystal of Compound A produced by the same method as described in Reference Example 6. FIG. 5 shows a DSC chart of a type I crystal of Compound A produced by the same method as described in Reference Example 6. FIG. 6 shows an IR chart of a type I crystal of Compound A produced by the same method as described in Reference Example 6. FIG. 7 shows (1R) -2-[(4-aminophenethyl) amino] -1-phenylethan-1-ol monohydrochloride derived from type II crystals of compound A produced by the method described in Reference Example 4. 1 shows a powder X-ray diffraction pattern of a salt monohydrate (type II hydrate). FIG. 8 shows (1R) -2-[(4-aminophenethyl) amino] -1-phenylethan-1-ol monohydrochloride derived from Form II crystals of Compound A produced by the method described in Reference Example 4 The DSC chart of a salt monohydrate (type II hydrate) is shown. FIG. 9 shows (1R) -2-[(4-aminophenethyl) amino] -1-phenylethan-1-ol monohydrochloride derived from Form I crystals of Compound A produced by the method described in Reference Example 7. 1 shows a powder X-ray diffraction pattern of salt monohydrate (type I hydrate). FIG. 10 shows (1R) -2-[(4-aminophenethyl) amino] -1-phenylethan-1-ol monohydrochloride derived from Form I crystal of Compound A produced by the method described in Reference Example 7. 1 shows a DSC chart of a salt monohydrate (type I hydrate). FIG. 11 shows a powder X-ray diffraction pattern of compound A type III crystal produced by the method described in Reference Example 8. FIG. 12 shows a DSC chart of a type III crystal of compound A produced by the method described in Reference Example 8.

Hereinafter, the present invention will be described in detail.
The type II crystal of the compound A of the present invention (hereinafter referred to as type II crystal) has good stability, and has better fluidity than the type I crystal of compound A (hereinafter referred to as type I crystal). Since it has low chargeability, it is a form of Compound A suitable for use in the industrial production of pharmaceuticals.
In addition, type I crystals and type II crystals are monohydrate ((1R) -2-[(4-aminophenethyl) amino] -1-phenylethan-1-ol monohydrochloride, respectively, in a high humidity environment. Salt monohydrate), but the monohydrate derived from the type I crystal (hereinafter referred to as type I hydrate) is dehydrated by heating to be different from the crystals of type I and type II ( Hereinafter, it was confirmed that the monohydrate derived from the type II crystal (hereinafter referred to as type II hydrate) returned to the original type II crystal upon dehydration by heating.
Furthermore, when the type III crystal was stored at room temperature, it was confirmed by powder X-ray diffraction, DSC analysis and IR measurement that a part of the type III crystal was transferred to the type II crystal.
From the above, the type II crystal of the present invention is considered to be a suitable form of compound A from the viewpoint of storage management of compound A in industrial production.
Each crystal is distinguished by powder X-ray diffraction measurement, DSC analysis, and / or IR measurement (see FIGS. 1 to 12).

The analysis results of the type II crystal of the present invention are shown below.
[1] DSC analysis shows a heat absorption peak around 135 ° C.
[2] It has peaks in the vicinity of 2θ (°) = 10.10, 20.04, 21.72, 23.48, 26.82, 27.80 and 31.72 by powder X-ray diffraction.
[3] IR measurement 3330cm- ¹ , 3166cm- ¹ , 2857cm- ¹ , 2684cm- ¹ , 2619cm- ¹ , 2464cm- ¹ , 1611cm- ¹ , 1580cm- ¹ , 1516cm- ¹ , 1254cm- ¹ , 1105cm- ¹ , It has infrared absorption peaks in the vicinity of 824 cm ⁻¹ , 757 cm ⁻¹ and 695 cm ⁻¹ .

The measurement conditions for the above analysis are as follows.
DSC analysis uses TA Instruments Q-200 for about 5 mg of sample under conditions of room temperature to 180 ° C (heating rate: 5 ° C / min), N2 (flow rate: 50 ml / min), aluminum sample pan. It was measured.
Measurement of powder X-ray diffraction using RINT-Ultima III, tube: Cu, tube current: 40 mA, tube voltage: 40 kV, sampling width: 0.020 °, scanning speed: 3 ° / min, wavelength: 1.54056Å Measurement diffraction angle range (2θ): Measured under conditions of 3 to 40 ° or 5 to 40 °.
IR measurement, using a Perkin Elmer Spectrum One, resolution 4 cm ^-1, scan number 10 times, in terms of wavenumber 4000 to 400 ^-1, was measured by KBr method.
However, powder X-ray diffraction is important for determining the identity of crystals because of the nature of the data, the crystal lattice spacing and the overall pattern are important, and the relative intensity depends on the crystal growth direction, particle size, and measurement conditions. Since it can change, it should not be interpreted strictly.
In addition, in the description of “near”, in consideration of various errors during measurement, in DSC analysis, it means ± 3 ° C. as one embodiment, ± 2 ° C. as another embodiment, and in powder X-ray diffraction, In some embodiments, it means ± 2 °, and in another embodiment, ± 1 °. In IR measurement, some embodiments mean ± 1.5 cm ⁻¹ , and other embodiments mean ± 1.0 cm ⁻¹ . To do.

(Production method)
Compound A can be produced, for example, by the method described in the alternative method of Reference Example 3 of Patent Document 3.
In some embodiments, the type II crystal of the present invention has a sufficiently high concentration of a compound A methanol solution, in another embodiment, an over-dissolved methanol solution of compound A, and in another embodiment, a compound A The methanol solution of Compound A prepared so that the total amount is 1.7 to 2.2 times (w / w) relative to the amount, and in another embodiment, the methanol solution of the reaction mixture containing Compound A is added to the amount of Compound A. In order to suppress the rapid precipitation of crystals at the initial stage of crystallization in a solution concentrated until the total amount becomes 1.7 to 2.2 times (w / w), ethyl acetate at 30 to 40 ° C. A small amount, as another embodiment, 0.5 to 3 times (w / w) the amount of methanol in the solution, and as another embodiment, 0.8 to 2 times (w / w) Can do.
Moreover, after adding ethyl acetate, the seed crystal of type II crystal is added, and further, an appropriate amount of ethyl acetate is added, whereby the type II crystal of the present invention can be produced efficiently and reproducibly.

なお、核磁気共鳴スペクトル（NMR）は、ジメチルスルホキシド-d₆中で、内部標準としてテトラメチルシラン（TMS）を使用し、日本電子製 JNM-AL400を用いて測定した。また、元素分析は、YANACO MT-6 又は Elementar Vario EL III を用いて測定した。 Hereinafter, the present invention will be specifically described by way of examples. However, these examples do not limit the scope of the present invention, and can be appropriately changed by a method obvious to those skilled in the art. For example, in crystallization, conditions such as solvent, stirring speed, temperature, solution dropping order and concentration are appropriately changed for the purpose of controlling the amount of impurities, improving crystallinity and yield, and shortening the process time. You can also. The raw material compounds can be produced by the methods described in Patent Documents 1 to 3 and the methods described in Reference Examples 1 to 3 below. The synthesis routes of Reference Examples and Examples are shown below.
Furthermore, type II hydrate as reference example 4, type II crystal obtained by heating type II hydrate as reference example 5, type I crystal as reference example 6, type I hydrate as reference example 7 Reference Example 8 shows a method for producing a type III crystal.
Further, as Reference Example 9 and Reference Example 10, (R) -2- (2-aminothiazol-4-yl) -4 ′-[2-] described in Patent Document 3 using the type II crystal of the present invention was used. [(2-Hydroxy-2-phenylethyl) amino] ethyl] acetic acid anilide (2- (2-amino-1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2 The production method of α-type crystals of -hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide) is shown.

By nuclear magnetic resonance spectra (NMR), in dimethyl sulfoxide -d _6, using tetramethylsilane (TMS) as an internal standard, was measured using a JEOL JNM-AL400. Elemental analysis was performed using YANACO MT-6 or Elementar Vario EL III.

(Reference Example 1)
48.5 kg of 4-nitrophenethylamine monohydrochloride, 170 kg of N, N-dimethylformamide, 32.0 kg of (R) -mandelic acid and 21.3 kg of triethylamine, 28.5 kg of hydroxybenztriazole and [3- (dimethylamino) propyl] 42.3 kg of (ethyl) carbodiimide monohydrochloride was added, and the mixture was stirred at 30 ° C. for 2 hours. 804 kg of water and 379 kg of ethyl acetate were added to the reaction solution, and the mixture was stirred and allowed to stand for liquid separation. To the aqueous layer was added 190 kg of ethyl acetate, and the mixture was stirred and allowed to stand for liquid separation. The organic layers were combined, washed with 434 kg of 1M hydrochloric acid, washed with 425 kg of a 20% aqueous potassium carbonate solution, washed with 426 kg of water, and the organic layer was concentrated under reduced pressure. To the concentrated residue, 308 kg of toluene was added, dissolved by heating, cooled to 10 ° C. or lower and precipitated. The crystals were filtered and washed with 64 kg of toluene. By vacuum drying, 60.6 kg of (2R) -2-hydroxy-N- (4-nitrophenethyl) -2-phenylacetamide was obtained as pale yellow crystals.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 2.88 (2H, t, J = 7.2 Hz), 3.31-3.47 (2H, m), 4.86 (1H, d, J = 4.4 Hz), 6.13-6.14 (1H, m), 7.23-7.33 (5H, m), 7.40 (2H, d, J = 8.0Hz), 8.06-8.10 (3H, m)

(Reference Example 2)
4-Nitrophenethylamine monohydrochloride 180.0 kg, N, N-dimethylformamide 720 kg, (R) -mandelic acid 136.5 kg and triethylamine 89.9 kg, hydroxybenzotriazole 120.0 kg and [3- (dimethylamino) propyl] 179 kg of (ethyl) carbodiimide monohydrochloride was added and stirred at 30 ° C. for 2 hours. To the reaction solution, 1010 L of water and 18.0 g of (2R) -2-hydroxy-N- (4-nitrophenethyl) -2-phenylacetamide crystals obtained in Reference Example 1 were added at 30 ° C. for precipitation. Thereafter, 1550 L of water and 270 kg of 33% aqueous potassium carbonate solution were added, and the mixture was stirred at 20 ° C. The crystals were filtered and washed with 540 L of water. Vacuum drying gave (2R) -2-hydroxy-N- (4-nitrophenethyl) -2-phenylacetamide (254.4 kg) as pale yellow crystals.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 2.88 (2H, t, J = 6.8 Hz), 3.31-3.47 (2H, m), 4.86 (1H, d, J = 4.8 Hz), 6.13-6.15 (1H, m), 7.23-7.33 (5H, m), 7.40 (2H, d, J = 8.4Hz), 8.06-8.10 (3H, m)

(Reference Example 3)
A mixture of sodium borohydride (40.0 kg) and tetrahydrofuran (1280 kg) was cooled, and 1,3-dimethyl-2-imidazolidinone (257 kg) obtained in Reference Example 2 (2R) -2-hydroxy-N- (4-nitrophenethyl) A mixture of 254.1 kg of crystals of -2-phenylacetamide and 676 kg of tetrahydrofuran was added at 10 ° C. or lower, and then 293 kg of 47% boron trifluoride tetrahydrofuran complex was added dropwise at 15 ° C. or lower. Thereafter, the temperature was raised to 65 ° C. and stirred for 4 hours. The reaction mixture was cooled, and 130 L of methanol and 211 kg of 35% hydrochloric acid were added at 10 ° C. or lower. After stirring at 65 ° C. for 30 minutes, the mixture was concentrated under reduced pressure. 450 L of water and 1271 kg of 30% aqueous potassium carbonate solution were added, and the mixture was extracted with 1140 kg of ethyl acetate. The organic layer was washed twice with 500 L of water and concentrated under reduced pressure. To the residue, 2000 kg of isopropanol was added and dissolved at 40 ° C., 88.6 kg of 35% hydrochloric acid was added to crystallize, and the mixture was stirred at 5 ° C. The crystals were filtered and washed with 360 kg of isopropanol to obtain 270.8 kg of wet crystals of (1R) -2-[(4-nitrophenethyl) amino] -1-phenylethane-1-ol monohydrochloride.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 3.01-3.07 (1H, m), 3.17-3.29 (5H, m), 5.03-5.05 (1H, m), 6.23 (1H, d, J = 4.0Hz), 7.29-7.33 (1H, m), 7.37-7.43 (4H, m), 7.57 (2H, d, J = 8.8Hz), 8.21 (2H, d, J = 8.8Hz), 9.07 ( 1H, br), 9.56 (1H, br)

Example 1
Methanol 450mL, (1R) -2-[(4-nitrophenethyl) amino] -1-phenylethane-1-ol monohydrochloride 150g, wet 10% palladium-carbon 3.07g under hydrogen atmosphere, hydrogen absorption stopped Stir until The reaction solution was filtered, and the filtrate was divided into 5 parts, and one of them was concentrated under reduced pressure until the total amount became 53.8 mL. To this concentrated filtrate was added 25.5 mL of ethyl acetate at 30 ° C., and the precipitated crystals were filtered to obtain type II crystals.

(Example 2)
Methanol 770 L, (1R) -2-[(4-nitrophenethyl) amino] -1-phenylethane-1-ol monohydrochloride wet crystals 270.8 kg obtained in Reference Example 3, 270.8 kg wet 10% palladium-carbon 5.33 kg Was stirred in a hydrogen atmosphere until hydrogen absorption stopped. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure until the total amount became 400 L. After adding 186 kg of ethyl acetate to the concentrated filtrate at 39 ° C., 250 g of type II crystals obtained in Example 1 were added at 35 ° C. Thereafter, 1640 kg of ethyl acetate was added and cooled to 20 ° C. The crystals were filtered and washed with 457 kg of ethyl acetate. Vacuum drying gave 217.59 kg of type II crystals.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 2.79-2.91 (2H, m), 2.97-3.15 (4H, m), 5.03-5.06 (3H, m), 6.22 (1H, d, J = 4.0Hz), 6.54 (2H, d, J = 8.4Hz), 6.89 (2H, d, J = 8.4Hz), 7.28-7.42 (5H, m), 9.23 (2H, br)
Elemental analysis Theoretical value C: 65.63%, H: 7.23%, N: 9.57%, Cl: 12.11% Measured value C: 65.45%, H: 7.20%, N: 9.61%, Cl: 12.34%

(Reference Example 4)
About 1 g of the type II crystal obtained in Example 2 was accurately weighed and placed in a glass weighing bottle previously weighed so that the layer thickness was 5 mm or less. The balance bottle was placed in a desiccator and allowed to coexist with a saturated aqueous solution of potassium nitrate and left in a thermostatic chamber at 25 ° C. The weight of the balance bottle after standing is measured as appropriate to calculate the amount of moisture absorption. When the moisture absorption exceeded about 5.8% and the weight was almost unchanged, a type II hydrate was obtained.

(Reference Example 5)
About 0.5 g of type II hydrate obtained in Reference Example 4 was accurately weighed and placed in a glass balance bottle so that the layer thickness was 5 mm or less. The balance bottle was placed in an incubator at 80 ° C. and dried by heating for 30 minutes to obtain type II crystals.

(Reference Example 6)
Methanol 240L, (1R) -2-[(4-nitrophenethyl) amino] -1-phenylethan-1-ol monohydrochloride 40.0kg, wet 10% palladium-carbon 1.66kg absorbs hydrogen under hydrogen atmosphere Stir until stopped. The reaction solution is filtered to obtain a filtrate. The same reaction operation was performed, the two filtrates were combined, and then 1280 L of ethyl acetate was added intermittently while concentrating methanol to form a slurry. The crystals were filtered and washed with ethyl acetate. Vacuum drying gave 69.06 kg of type I crystals.
The manufacturing method of Reference Example 6 is the same as the manufacturing method described in the alternative method of Reference Example 3 of Patent Document 3. In addition, when it manufactures with the manufacturing method similar to the reference example 6, a II type crystal may be obtained.

(Reference Example 7)
About 1 g of type I crystal was precisely weighed and placed in a glass weighing bottle previously weighed so that the layer thickness was 5 mm or less. The balance bottle was placed in a desiccator and allowed to coexist with a saturated aqueous solution of potassium nitrate or potassium chloride and left in a constant temperature room at 25 ° C. The weight of the balance bottle after standing is measured as appropriate to calculate the amount of moisture absorption. When the moisture absorption exceeded about 5.8% and the weight was almost unchanged, type I hydrate was obtained.

(Reference Example 8)
About 0.5 g of Type I hydrate obtained in Reference Example 7 was accurately weighed and placed in a glass balance bottle so that the layer thickness was 5 mm or less. This balance bottle was placed in an incubator at 80 ° C. and dried by heating for 30 minutes to obtain a type III crystal.

(Reference Example 9)
Water 4356L, 38% hydrochloric acid 28L, (2-amino-1,3-thiazol-4-yl) acetic acid 180.95 kg and (1R) -2-[(4-aminophenethyl) amino] -1 obtained in Example 2 -Phenylethane-1-ol monohydrochloride crystals (Type II crystals) [3- (Dimethylamino) propyl] (ethyl) carbodiimide monohydrochloride 241.20 kg and water 331 L were added to a 335.00 kg mixture and stirred for 1 hour. . After adding 38 L of 38% hydrochloric acid and 335 L of water, crystallization was performed with a mixed solution of 1372 L of water and 316 L of 25% aqueous sodium hydroxide solution. The crystals are filtered, washed with water 4206L, 2- (2-amino-1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl Crude wet crystals of [amino} ethyl) phenyl] acetamide were obtained. After drying this crude wet crystal, 54 mL of water and 36 mL of ethanol were added to 10 g of the crude crystal, heated and dissolved at about 80 ° C., and then slowly cooled to 20 ° C. The crystals are filtered and dried to give 2- (2-amino-1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl] amino} There were obtained 9.03 g of α-type crystals of ethyl) phenyl] acetamide.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 1.60 (1H, brs), 2.62-2.68 (4H, m), 2.70-2.79 (2H, m), 3.44 (2H, s), 4.58 -4.60 (1H, m), 5.21 (1H, d, J = 3.6Hz), 6.29 (1H, s), 6.89 (2H, s), 7.12 (2H, d, J = 8.0Hz), 7.19-7.23 ( 1H, m), 7.27-7.32 (4H, m), 7.49 (2H, d, J = 8.0Hz), 9.99 (1H, s)

(Reference Example 10)
Water 4356L, 38% hydrochloric acid 28L, (2-amino-1,3-thiazol-4-yl) acetic acid 180.95 kg and (1R) -2-[(4-aminophenethyl) amino] -1 obtained in Example 2 -Phenylethane-1-ol monohydrochloride crystals (Type II crystals) [3- (Dimethylamino) propyl] (ethyl) carbodiimide monohydrochloride 241.20 kg and water 331 L were added to a 335.00 kg mixture and stirred for 1 hour. . After adding 38 L of 38% hydrochloric acid and 335 L of water, crystallization was performed with a mixed solution of 1372 L of water and 316 L of 25% aqueous sodium hydroxide solution. The crystals are filtered, washed with water 4206L, 2- (2-amino-1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl Crude wet crystals of [amino} ethyl) phenyl] acetamide were obtained. To this crude wet crystal, 822 L of water and 1282 L of ethanol were added, dissolved by heating at about 80 ° C. and then cooled. At 65 ° C., 2- (2-amino-1,3-thiazol-4-yl obtained in Reference Example 9 was obtained. 2.1 kg of α-type crystals of) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide were added. Then, it cooled to 20 degreeC. The crystals are filtered and dried to give 2- (2-amino-1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl] amino} 387.58 kg of α-type crystals of ethyl) phenyl] acetamide were obtained.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ (ppm) = 1.60 (1H, brs), 2.62-2.65 (4H, m), 2.70-2.80 (2H, m), 3.45 (2H, s), 4.60 (1H, br), 5.22 (1H, d, J = 3.6Hz), 6.30 (1H, s), 6.90 (2H, s), 7.11 (2H, d, J = 8.4Hz), 7.19-7.23 (1H, m), 7.27-7.33 (4H, m), 7.49 (2H, d, J = 8.8Hz), 9.99 (1H, s)

As shown in Reference Example 9 and Reference Example 10, 2- (2-amino-), which is known as an active ingredient of a therapeutic agent for diabetes and overactive bladder, using type II crystals of the present invention in industrial production. 1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide or a pharmaceutically acceptable salt thereof It was confirmed that can be manufactured satisfactorily.

ＩＩ型結晶のゆるめかさ密度はＩ型結晶よりも約4.7倍大きく、ＩＩ型結晶の比容積はＩ型結晶の1/4〜1/5程度であることが確認された。また、これらのデータを表２に示すCarrの流動性指数（Chemical Engineering, Jan. 18 （1965）、166頁）から評価すると、Ｉ型結晶は安息角、圧縮度ともに「非常に悪い」に分類される。一方、ＩＩ型結晶の安息角は「まあ良好」、圧縮度は「最も良好」に評価され、Ｉ型結晶と比較して、粉体の流動性の優れた結晶であった。また、ＩＩ型結晶は、上記の流動性の改善により、工業的生産での化合物Ａの製造や使用において、乾燥機や仕込みコンテナなどの各系からの排出が、Ｉ型結晶と比較して、非常に容易であることが確認された。 The effects of the type II crystal of the present invention are shown below.
(Test Example 1) Confirmation of fluidity In order to confirm the fluidity of type I crystals and type II crystals, powder characteristics were measured using a Powder tester (HOSOKAWA MICRON CORPORATION MODEL PT-S). The angle of repose was measured by dropping a powder having a sieve opening of 710 μm on a φ40 mm table, and the collapse angle was measured by forming an angle of repose and then applying the impact three times to collapse. The loose bulk density and the hard bulk density were measured by filling a 100 cc cup with a powder that passed through a sieve opening of 710 μm and measuring it, and tapping was performed 180 times with a stroke of 18 mm at the measurement of the solid bulk density. The results are shown in Table 1.

It was confirmed that the loose bulk density of type II crystals was about 4.7 times larger than type I crystals, and the specific volume of type II crystals was about 1/4 to 1/5 that of type I crystals. Moreover, when these data are evaluated from Carr's fluidity index shown in Table 2 (Chemical Engineering, Jan. 18 (1965), p. 166), type I crystals are classified as “very bad” in both angle of repose and degree of compression. Is done. On the other hand, the angle of repose of the type II crystal was evaluated as “good”, and the degree of compression was evaluated as “best”. The crystal was superior in powder flowability as compared with the type I crystal. In addition, due to the improvement in fluidity described above, the type II crystal is less discharged from each system such as a dryer and a charging container in the production and use of compound A in industrial production, compared to the type I crystal, It was confirmed that it was very easy.

ＩＩ型結晶の静電電荷量は、Ｉ型結晶の1/15であり、Ｉ型結晶と比較して、顕著に帯電しにくいことが確認された。 (Test Example 2) Confirmation of chargeability In order to confirm the chargeability of type I and type II crystals, electrostatic charge meter (Kasuga Electric KQ-431B), electrostatic voltmeter (Nihon STATEC SV-511), super insulation The electrostatic characteristics were measured using a meter (Toa DKK SM-8220). The results are shown in Table 3. Each measurement was performed under the following conditions.
<Measurement conditions>
1) Faraday cage (electrostatic charge meter [Kasuga Denki KQ-431B] set in the bottom of the stainless steel tube by dropping 2 to 10g of electrostatic charge into a 1 inch inner diameter, 1050mm long vertical stainless steel tube ]), And the amount of charge per unit weight was measured.
2) Electrostatic voltage drops 10g of powder into a vertical stainless steel tube with an inner diameter of 1 inch and a length of 1050mm, and is received by a paper plate set at the bottom of the stainless steel tube to static electricity (voltage) of the powder on the paper plate. Measured with an electric voltmeter [NIPPON STATEC SV-511].
3) The specific resistance was measured by filling a powder sample measuring electrode with powder and applying a voltage of 100 V with a superinsulator [Toa DKK SM-8220].

The amount of electrostatic charge of the type II crystal was 1/15 of that of the type I crystal, and it was confirmed that it was significantly less charged than the type I crystal.

  From the above results, compared to type I crystals, type II crystals are much less susceptible to powder clogging, alteration in the remaining solidified layer, fire due to static electricity, etc. in the production line during industrial production. It can be said.

Since the type II crystal of the present invention is particularly excellent in fluidity and chargeability and has suitable properties in industrial production, it is known as an active ingredient of pharmaceutical production intermediates, particularly therapeutic agents for diabetes and overactive bladder. 2- (2-amino-1,3-thiazol-4-yl) -N- (4- {2-[(2R) -2-hydroxy-2-phenylethyl] amino} ethyl) phenyl] acetamide Or it is a very useful form at the time of using the compound A as a manufacturing intermediate in the industrial production of the pharmaceutically acceptable salt.

Claims (6)

(1R) -2-[(4-Aminophenethyl) amino] -1-phenylethan-1-ol monohydrochloride having a heat absorption peak at around 135 ° C by DSC analysis (heating rate: 5 ° C / min) Crystal. (1R) -2-[(4-aminophenethyl) amino] -1 having peaks in the vicinity of 2θ (°) = 10.10, 20.04, 21.72, 23.48, 27.80 and 31.72 by powder X-ray diffraction (tube: Cu) -Phenylethane-1-ol monohydrochloride crystals. IR measurement (KBr method) 3330cm ⁻¹ , 3166cm ⁻¹ , 2857cm ⁻¹ , 2684cm ⁻¹ , 2619cm ⁻¹ , 2464cm ⁻¹ , 1611cm ⁻¹ , 1580cm ⁻¹ , 1516cm ⁻¹ , 1254cm ⁻¹ , 1105cm ⁻¹ Of (1R) -2-[(4-aminophenethyl) amino] -1-phenylethan-1-ol monohydrochloride having infrared absorption peaks around 824 cm ⁻¹ , 757 cm ⁻¹ and 695 cm ⁻¹ . The crystal according to claim 1, which has peaks in the vicinity of 2θ (°) = 10.10, 20.04, 21.72, 23.48, 27.80 and 31.72 by powder X-ray diffraction (tube sphere: Cu). IR measurement (KBr method) 3330cm ⁻¹ , 3166cm ⁻¹ , 2857cm ⁻¹ , 2684cm ⁻¹ , 2619cm ⁻¹ , 2464cm ⁻¹ , 1611cm ⁻¹ , 1580cm ⁻¹ , 1516cm ⁻¹ , 1254cm ⁻¹ , 1105cm ⁻¹ , 824 cm ⁻¹ , 757 cm ⁻¹ and 695 cm ⁻¹ near the infrared absorption peak. IR measurement (KBr method) 3330cm ⁻¹ , 3166cm ⁻¹ , 2857cm ⁻¹ , 2684cm ⁻¹ , 2619cm ⁻¹ , 2464cm ⁻¹ , 1611cm ⁻¹ , 1580cm ⁻¹ , 1516cm ⁻¹ , 1254cm ⁻¹ , 1105cm ⁻¹ , 824 cm ⁻¹ , 757 cm ⁻¹ and 695 cm ⁻¹ near the infrared absorption peak.

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