JP2000212138A - Crystal polymorphism of aminoethylphenoxyacetic acid derivative dihydrate - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a crystal polymorphism of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid dihydrate having strong β2-adrenergic receptor stimulation action and β3-adrenergic receptor stimulation action and useful e.g. as a pain remission agent and a lithagogue for lithangiuria. SOLUTION: This crystal polymorphism gives a powder X-ray diffraction pattern having strong diffraction peaks at the diffraction angles (2θ+0.1) of 3.4, 10.2, 13.7, 17.1 and 20.7 deg.. It can be produced by dissolving 2-[4-[2-[[(1S,2R)-2- hydroxy-2-(4hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy] acetic acid in a mixture of water and methanol (at a volume ratio of 1:3 to 1:4), concentrating under reduced pressure and drying the precipitated crystal under reduced pressure at room temperature to 40 deg.C for several hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel aminoethylphenoxyacetic acid derivative dihydrate crystal polymorph useful as a pharmaceutical.

More specifically, the present invention has a potent β ₂ -adrenoceptor stimulating action and β ₃ -adrenoceptor stimulating action, and is useful as an agent for relieving pain in urolithiasis and calculi. Na, expression

[0003]

Embedded image

An aminoethylphenoxyacetic acid derivative represented by the following formula (chemical name: 2- [4- [2-[[(1S, 2R)-
2-hydroxy-2- (4-hydroxyphenyl) -1
-Methylethyl] amino] ethyl] phenoxy] acetic acid)
The present invention relates to a polymorph of dihydrate (α-form dihydrate crystal).

[0005]

2. Description of the Related Art 2- [4- [2-[[(1S, 2R)-
2-hydroxy-2- (4-hydroxyphenyl) -1
-Methylethyl] amino] ethyl] phenoxy] acetic acid and its hydrate are novel compounds that have not been described in the literature, and their physical properties and pharmacological activities are not known at all.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have found that 2-
[4- [2-[[(1S, 2R) -2-hydroxy-2
Studies on-(4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrate revealed that 2- [4- [2-[[(1S, 2R) -2-
Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrate has several types of crystal polymorphs, and the obtained crystals are different due to differences in production methods and production conditions. It has been found that a certain quality cannot be obtained, for example, the types of polymorphs are different, and anhydrides and other hydrates are mixed.

[0007] Usually, compounds having crystal polymorphs have different properties depending on the crystal polymorphs, so that even the same compound may exhibit completely different effects. In particular, it is known that there is a difference in solubility, dissolution rate, stability, etc. in pharmaceuticals, and even when the same compound is used, the intended effect cannot be obtained due to a difference in crystal polymorphism. Or produce a different effect than expected,
This can lead to unexpected situations. Therefore, there is a need to provide a compound of the same quality that can always expect a certain effect. Therefore, when a compound having a crystalline polymorph is used as a drug, it is necessary to stably provide a compound having a certain crystallinity in order to ensure uniform quality and certain effects required as a drug. In addition, a stable polymorph that can maintain the same quality in storage is desired.

As described above, 2- [4- [2-[[(1
(S, 2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrate is a compound having several types of crystalline polymorphs. A plurality of polymorphs including an anhydride may be mixed. In addition, some polymorphs vary depending on the external environment during storage, and may not have a certain quality. Therefore, in order to ensure a certain effect and quality, which are indispensable requirements for pharmaceuticals, we have found a stable crystalline polymorph of the compound and established a manufacturing method to always obtain the crystalline polymorph constantly. I was eager to do it.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The inventors of the present invention have proposed 2- [4- [2-
[[(1S, 2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid hydrate was intensively studied, and as a result, 2 − [4- [2-[[(1S, 2
R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate can be produced with a certain quality according to the following method. The present inventors have found that the crystalline polymorph of the present invention is excellent in moisture resistance and the like and is extremely useful as a pharmaceutical, and have accomplished the present invention.

The present invention relates to a powder X-ray diffraction pattern with a diffraction angle (2θ ± 0.1 degrees) of 3.4, 10.2, 1
Novel 2- [4- [2-[[(1S, 2R) -2-] showing strong diffraction peaks at 3.7, 17.1 and 20.7 degrees
The present invention relates to a crystalline polymorph of hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate (α-form dihydrate crystal). Further, the polymorph of the present invention is excellent in moisture resistance and is desirable for storage.

The crystalline polymorph of the present invention is 2- [4- [2-
[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is mixed with a mixed solvent of water and methanol (at a volume ratio of 1: 3 to 1: After dissolving in 4), it can be manufactured by concentrating or leaving under reduced pressure while avoiding high temperature, collecting precipitated crystals by filtration, and drying under reduced pressure at room temperature to 40 ° C for several hours. The ratio and the amount of the solvent used can be appropriately adjusted depending on the amount to be treated and the like. The drying time can be appropriately adjusted depending on the amount, state and drying temperature of the compound.

The contents of the present invention will be described in detail with reference to the following Reference Examples, Examples, Comparative Examples and Test Examples. The melting points of various polymorphs are determined by Rigaku Co., Ltd., differential thermogravimetry (TG / DTA) Thermo plus TG81.
The temperature was measured at a heating rate of 10 ° C./min using No. 20 and indicated by the extrapolated melting onset temperature. In addition, powder X-ray diffraction data of various crystal polymorphs was obtained from Rigaku's X-ray diffractometer RINT1400.
Using CuKα radiation (1.541 °).

Reference Example 1 Ethyl 2- [4- (2-hydroxyethyl) phenoxy] acetate To a solution of 4- (2-hydroxyethyl) phenol (5 g) in acetone (45 mL) at room temperature was added anhydrous potassium carbonate (6.5 mL).
g) was added and stirred for 30 minutes. Ethyl bromoacetate (4.4 mL) was added dropwise to the mixture at an internal temperature of 40 to 45 ° C, and the mixture was further stirred at 40 ° C for 8 hours. The insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give 2- [4
-(2-Hydroxyethyl) phenoxy] ethyl acetate (5.8 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (3H, t, J = 7.1 Hz), 2.32 (1H, br), 2.76 (2H, t, J =
5.8Hz), 3.84 (2H, m), 4.24 (2H, q, J = 7.1Hz), 4.57 (2H
H, s), 6.88 (2H, d, J = 7.8Hz), 7.12 (2H, d, J = 7.8Hz)

Reference Example 2 Ethyl 2- [4- (2-methanesulfonyloxyethyl) phenoxy] acetate To a solution of ethyl 2- [4- (2-hydroxyethyl) phenoxy] acetate (7.3 g) in ethyl acetate (22 mL). Under a nitrogen stream, triethylamine (5.9 mL) was added at room temperature and stirred. Methanesulfonyl chloride (2.8 mL) was added dropwise to the mixture at an internal temperature of 0 to 15 ° C, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, ethyl acetate (8.6 mL) and 2-propanol (23 mL) were added to the residue, dissolved by heating, cooled to room temperature, and the precipitated crystals were collected by filtration Ethyl-[4- (2-methanesulfonyloxyethyl) phenoxy] acetate (7.2 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (3H, t, J = 7.1 Hz), 2.84 (3H, s), 2.99 (2H, t, J =
6.9Hz), 4.26 (2H, q, J = 7.1Hz), 4.37 (2H, t, J = 6.9H
z), 4.60 (2H, s), 6.87 (2H, d, J = 8.7Hz), 7.15 (2H, d,
J = 8.7Hz)

Reference Example 3 Ethyl phosphorus 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetate Acid salt (1R, 2S) -2-amino-1- (4-hydroxyphenyl) propan-1-ol (8.8 g), 2- [4-
A mixture of (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate (15.9 g), diisopropylamine (11 mL) and N, N-dimethylacetamide (61 mL) was stirred at 75 ° C. for 3.5 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, a mixed solution of ethyl acetate / toluene (9/1) and water were added, the aqueous layer was separated, and the aqueous layer was mixed with a mixed solution of ethyl acetate / toluene (9/1). Extracted. The organic layers were combined, washed with water and 18% brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. After adding ethyl acetate (14 mL) and ethanol (92 mL) to the residue, a 16% phosphoric acid-ethanol solution (32 g) was added dropwise at room temperature with stirring.
The precipitated crystals were collected by filtration, and 2- [4- [2-[[(1
(S, 2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (12.4 g) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 0.89 (3H, d, J = 6.6Hz), 1.23 (3H, t, J = 7.1Hz), 2.80-
3.15 (5H, m), 4.16 (2H, q, J = 7.1Hz), 4.73 (2H, s), 4.
92 (1H, br s), 6.71 (2H, d, J = 8.6Hz), 6.85 (2H, d, J =
8.6Hz), 7.13 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6H
z), 7.92 (4H, br)

Reference Example 4 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (anhydrous α Form crystals) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate ( 62.0 g) in a 2 mol / L aqueous sodium hydroxide solution (3
93 mL), and the mixture was heated to 40 ° C. with stirring to dissolve. 4 mol / L phosphoric acid aqueous solution at an internal temperature of 40 to 46 ° C (115 mL)
After stirring at room temperature overnight, the precipitated crystals were collected by filtration,
Washing with water gave white crystals. The obtained crystals were suspended in a mixed solution (200 mL) of water / methanol (1/8), heated under reflux in a suspended state for 30 minutes, cooled to room temperature, and the crystals were collected by filtration. At 3 ° C. for 3 hours.
[2-[[(1S, 2R) -2-hydroxy-2- (4
-Hydroxyphenyl) -1-methylethyl] amino]
Ethyl] phenoxy] acetic acid (anhydrous α-form crystal) (50.0 g)
I got

Melting point: 235.1 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.91 (3H, d, J = 6.6 Hz), 2.55-2.75 (2H, m), 2.90-3.05
(2H, m), 3.15-3.25 (1H, m), 4.25-4.40 (2H, m), 5.00-
5.10 (1H, m), 6.65-6.80 (4H, m), 6.91 (2H, d, J = 8.6H
z), 7.13 (2H, d, J = 8.6 Hz), 9.40 (1H, br) Specific rotation: [α] _D ²⁵ = -10.0 ° (c = 1.00,
1 mol / L hydrochloric acid)

Example 1 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate (Dihydrate α-form crystal) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] Acetic acid (anhydrous α-form crystals) (2.0 g) was added to methanol (100 mL) and water (33 m
The mixture was heated and dissolved in the mixture of L), and cooled to room temperature. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to about half the volume, and allowed to stand at room temperature for 20 minutes. After the precipitated crystals were collected by filtration, they were dried under reduced pressure at 40 ° C. for 3 hours to give 2- [4- [2-[[(1S, 2
R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate (dihydrate α-form crystal) (1.1 g) was obtained.

Melting point: 147.2 ° C.

2- [4- [2-[[(1S, 2R) -2
-Hydroxy-2- (4-hydroxyphenyl) -1-
The powder X-ray diffraction pattern of the crystalline polymorph (methyl α-form dihydrate) of methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate is as shown in FIG. 1 below.

[0024]

FIG.

Example 2 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate (Dihydrate α-form crystal) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] Acetic acid (anhydrous α-form crystals) (1.3 g) in methanol (80 mL) and water (20 mL)
Was dissolved in the mixture by heating and cooled to room temperature. After removing the insoluble matter by filtration, the filtrate was left at 5 ° C. for 40 hours. After the precipitated crystals were collected by filtration, they were dried under reduced pressure at 40 ° C. for 2 hours to give 2- [4-
[2-[[(1S, 2R) -2-hydroxy-2- (4
-Hydroxyphenyl) -1-methylethyl] amino]
Ethyl] phenoxy] acetic acid dihydrate (dihydrate α-form crystal) (0.6 g) was obtained. The melting point was 149.2 ° C., and the powder X-ray diffraction pattern was the same as in Example 1.

Test Example 1 β ₂ -Adrenergic Receptor Stimulating Action The uterus of an SD pregnant rat (21st day of gestation) was excised, avoiding the placenta attachment, and was about 5 mm wide and about 1 mm long in the longitudinal muscle direction.
A 5 mm specimen was prepared, and an experiment was performed according to the Magnus method. Specimens were suspended in Locke-Ringer solution aerated with a mixed gas containing 95% oxygen and 5% carbon dioxide at 37 ° C. and loaded with 1 g. Uterine motility was derived isometrically via a tension transducer and recorded by lectchograph. 2- [4- [2-[[(1S,
2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid was cumulatively added to the Magnus tube every 5 minutes. The drug evaluation of the present compound was performed by comparing the sum of the uterine contraction height for 5 minutes before the addition of the present compound with 100% and the sum of the uterine contraction height for 5 minutes after addition of the present compound at various concentrations. 3.1
× 10 ⁻⁸ (M) indicates the drug concentration (EC ₅₀ value) that inhibits the sum of uterine contractions by 50%.

Test Example 2 β ₃ -Adrenergic receptor stimulating action The ureter of a male ferret (weight: 1100 to 1400 g) was excised and the connective tissue was removed.
Was prepared, and an experiment was performed according to the Magnus method. Specimens were Krebs-Henseleit which was aerated with a mixed gas containing 95% oxygen and 5% carbon dioxide at 37 ° C.
It was suspended in the liquid and a load of 0.5 g was applied. Ureteral automatic movement isometrically derived via a tension transducer,
Recorded by rectigraph. 2- [4- [2-
[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid accumulates every three minutes in Magnus.
Added in tube. The drug evaluation of the present compound was made by comparing the sum of the ureteral contraction heights for 3 minutes before the addition of the present compound with 100% and comparing the sum of the ureteral contraction heights for 3 minutes after the addition of the present compound at various concentrations. The sum of ureteral contraction height is 50% at 4 × 10 ^-8 (M)
The inhibitory drug concentration (EC ₅₀ value) is shown.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view of a 2- [4- [2-[[(1S, 2R)
-2-hydroxy-2- (4-hydroxyphenyl)-
Powder X-ray diffraction data (using a monochromator) of a polymorph of 1-methylethyl] phenoxy] acetic acid dihydrate (α-form dihydrate crystal). The vertical axis represents the intensity of the X-ray (kc
ps), and the horizontal axis indicates the diffraction angle (2θ).

Continued on the front page (72) Inventor Junichi Sonehara 62-16-1 Omi Sakai-machi, Sakai-gun, Fukui Prefecture Dolly Mate House II 201 (72) Inventor ▲ Tsuru ▼ Eiji 1-2-34 Nozogi Woodworking, Matsumoto City, Nagano Prefecture Daini Seotoyu Dormitory F-term (reference) 4C206 GA07 MA01 MA04 NA05 ZA81 ZC02 4H006 AA01 AB20 AC90 AD15 BJ50 BN10 BN30 BP30 BS10 BU40

Claims (1)

[Claims] 1. A diffraction angle (2θ ± 2) in a powder X-ray diffraction pattern.
0.1 degrees), 3.4, 10.2, 13.7, 1
2- shows strong diffraction peaks at 7.1 and 20.7 degrees
[4- [2-[[(1S, 2R) -2-hydroxy-2
-(4-Hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid dihydrate polymorph.