Preparation method of olodaterol hydrochloride impurity

Abstract

The invention provides a preparation method of an olodaterol hydrochloride impurity. Specifically, the preparation method of the olodaterol hydrochloride impurity provided by the invention mainly comprises the step of cyclizing olodaterol hydrochloride and formaldehyde to obtain the impurity D provided by the invention. According to the preparation method of the olodaterol hydrochloride impurity D, the impurity D can be obtained only through one-step reaction, the treatment after the reaction is simple, the yield is high, the purity is high, and the reaction conditions are relatively mild.

Description

Technical Field

[0001] The present invention relates to the field of chemistry. Specifically, the present invention relates to a method for preparing an impurity of olodaterol hydrochloride, wherein the impurity is impurity D as described in the present invention. Background Art

[0002] Olodaterol spray was first approved for marketing in 2014. It is a long-acting β-2 adrenergic agonist (LABA), which can rapidly activate β-2 adrenergic receptors on airway smooth muscle, thereby maintaining bronchodilation, with fewer side effects and only requiring once-daily administration, showing good compliance. The structure of olodaterol hydrochloride is as follows:

[0003] Patent application CN 111380968 A discloses a detection method for impurity (ZZ-2) (i.e., impurity D as described in the present invention). Patent application CN115397417A discloses that impurity 0L0-14 (i.e., impurity D as described in the present invention) will increase significantly during the stability experiment and is easily affected by pH, indicating that the control and detection of this impurity are very important in the quality research of olodaterol.

[0004] The prior art has not reported the preparation method of this impurity. Therefore, it is difficult to obtain this impurity for the quality research of drugs (such as olodaterol hydrochloride). Therefore, there is an urgent need to develop a simple and efficient method for synthesizing this impurity. Summary of the Invention

[0005] The preparation method provided by the present invention uses olodaterol as the starting material to prepare impurity D of olodaterol hydrochloride. The synthesis method of this impurity mainly lies in that after cyclization of olodaterol hydrochloride with formaldehyde, impurity D as described in the present invention can be obtained. The preparation method of impurity D of olodaterol hydrochloride disclosed by the present invention can obtain impurity D through only one-step reaction, with simple post-treatment of the reaction, high yield, high purity, and relatively mild reaction conditions.

[0006] The present invention provides a method for preparing impurity D or its salt, which comprises a cyclization reaction of olodaterol or its salt with formaldehyde to obtain impurity D or its salt.

[0007]

[0008] In some embodiments of the present invention, the reaction temperature of the cyclization reaction is 45 - 80 °C; preferably 50 - 80 °C; more preferably 60 - 75 °C.

[0009] In some embodiments of the present invention, the cyclization reaction is carried out in the presence of solvent A.

[0010] In some embodiments of the present invention, the solvent A is methanol, N,N-dimethylformamide, water, or a combination thereof.

[0011] In some embodiments of the present invention, the molar ratio of indacaterol or its salt to formaldehyde is 1:1 to 1:20; preferably 1:5 to 1:18; more preferably 1:6 to 1:13.

[0012] In some embodiments of the present invention, the method further includes post-treatment: adding an aqueous hydrochloric acid solution and stirring.

[0013] In some embodiments of the present invention, the post-treatment further includes filtering the reaction mixture after adding the aqueous hydrochloric acid solution, and rinsing the obtained filter cake with solvent B.

[0014] In some embodiments of the present invention, the method further includes post-treatment: adding an aqueous hydrochloric acid solution, stirring, filtering, and rinsing the obtained filter cake with solvent B.

[0015] In some embodiments of the present invention, the concentration of the aqueous hydrochloric acid solution is 1 mol / L.

[0016] In some embodiments of the present invention, the amount of hydrochloric acid (i.e., HCl) added in the aqueous hydrochloric acid solution is 1.0 molar equivalent of indacaterol; preferably 1.0 to 1:18.0 molar equivalents.

[0017] In some embodiments of the present invention, the solvent B of the present invention is methanol, N,N-dimethylformamide, water, or a combination thereof (such as a mixed solvent of methanol and N,N-dimethylformamide).

[0018] The impurity D of the present invention can be used for drug quality research, especially for the quality research of indacaterol hydrochloride, such as for use as a standard in drug analysis, the study of the properties of impurities, etc.

[0019] General synthetic method of the compounds of the present invention

[0020] Generally, the compounds of the present invention can be prepared by the methods described in the present invention. The following reaction schemes and examples are used to further illustrate the content of the present invention.

[0021] For the embodiments described below, unless otherwise indicated, all temperatures are in degrees Celsius (°C). Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification, unless otherwise indicated. General reagents were obtained from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0022] Silica gel columns were used for chromatography. The silica gel (200 - 300 mesh) was purchased from Qingdao Ocean Chemical Factory. Nuclear magnetic resonance spectra were recorded in CDC13, DMSO-d6, CD3OD or acetone-d6 as solvents (reported in ppm), using TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks occurred, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), br.s (broadened singlet), q (quartet). The coupling constant J was expressed in Hertz (Hz).

[0023] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315B DAD detector for analysis, and an ESI source for the LC-MS spectrometer.

[0024] Low-resolution mass spectrometry (MS) data were determined using a spectrometer of Agilent 6120 series LC-MS equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 °C), with a G1329A autosampler and a G1315D DAD detector for analysis, and an ESI source for the LC-MS spectrometer.

[0025] Both of the above spectrometers are equipped with an Agilent Zorbax SB-C18 column, with a specification of 2.1×30 mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL / min; the HPLC peaks are recorded and read at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phase is a 0.1% formic acid acetonitrile solution (phase A) and a 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

[0026] Table 1: Gradient elution conditions

[0027] Time (min) <![CDATA[A(CH3CN, 0.1% HCOOH)]]> <![CDATA[B (H2O, 0.1% HCOOH) <!-- 2 -->]]> 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0028] The compound purity was evaluated by an Agilent 1260 series high performance liquid chromatography (HPLC), where UV detection was at 225 nm, a Synergi Hydro-RP column, with a specification of 4.6*150 mm, 4 μm, 38 minutes, the flow rate was 0.7 mL / min, the column temperature was maintained at 42 °C; mobile phase A: Take about 2.5 g of potassium dihydrogen phosphate, add 1 L of water to dissolve it, adjust the pH value to 3.2 with phosphoric acid, and filter through a 0.2 μm filter membrane to obtain; mobile phase B: methanol:acetonitrile = 9:1; gradient elution: 0 - 3 min 28% phase B, 3 - 16 min 28 - 39% phase B, 16 - 22 min 39 - 58% phase B, 22 - 27 min 58 - 75% phase B, 27 - 33 min 75% phase B, 33 - 33.1 min 75 - 28% phase B, 33.1 - 38 min 28% phase B.

[0029] The synthetic route of the present invention:

[0030]

[0031] Example 1

[0032] Weigh out indacaterol maleate (0.4993 g, 1.18 mmol) and 1.3 g of formalin (35 - 40% aqueous formaldehyde solution) into a reaction flask, then add 13 mL of methanol, and the reaction mixture is reacted at 60 °C for 12 h. After cooling, add hydrochloric acid aqueous solution (1.2 mL, 1 M), stir, filter, and the filter cake is washed with methanol (5 mL × 2), and then dried in vacuo at 60 °C for 10 h. 0.488 g of impurity D is obtained, which is a pale yellow solid powder, with a yield of 95.0% and a purity of 98.80%.

[0033] MS(ESI,pos,ion) m / z: 399.1914 [M+H] + ;

[0034] 1HNMR(600 MHz, DMSO-d6) δ 10.74 (1H, s), 10.06 (1H, s), 9.83 (1H, m), 7.24 (2H, d, J = 8.5 Hz), 6.91 (2H, d, J = 8.6 Hz), 6.64 (1H, s), 5.98 (1H, d, J = 6.4 Hz), 5.01 (1H, s), 4.52 (2H, m), 4.31 (1H, d, J = 14.6 Hz), 4.14 (1H, dd, J = 15.1, 9.7 Hz), 3.91 (1H, d, J = 12.3 Hz), 3.75 (3H, s), 3.38 (1H, m), 3.19 (1H, d, J = 12.7 Hz), 2.97 (1H, d, J = 12.6 Hz), 1.36 (3H, s), 1.31 (1H, s);

[0035] 13 C-NMR(151 MHz, DMSO-d6) δ 165.2, 158.2, 148.3, 133.6, 131.9, 127.0, 126.7, 122.8, 113.5, 110.3, 102.3, 66.9, 66.7, 58.8, 54.9, 51.6, 43.6, 39.0, 21.3, 20.8.

[0036] Example 2

[0037] Weigh out indacaterol maleate (0.4976 g, 1.18 mmol) and 0.6 g of formalin (35 - 40% aqueous formaldehyde solution) into a reaction flask, then add methanol (13 mL). The reaction mixture is reacted at 60 °C for 12 h. After cooling, add aqueous hydrochloric acid solution (1.2 mL, 1 M), stir, filter, and wash the filter cake with methanol (5 mL × 2). Then dry it under vacuum at 60 °C for 10 h. 0.470 g of impurity D is obtained as a pale yellow solid powder, with a yield of 91.8% and a purity of 99.73%.

[0038] Example 3

[0039] Weigh out indacaterol maleate (0.5023 g, 1.19 mmol) and 1.3 g of formalin (35 - 40% aqueous formaldehyde solution) into a reaction flask, then add N,N-dimethylformamide (13 mL). The reaction mixture is reacted at 75 °C for 12 h. After cooling, add aqueous hydrochloric acid solution (1.2 mL, 1 M), stir, filter, and wash the filter cake successively with N,N-dimethylformamide (5 mL) and methanol (5 mL); then dry it under vacuum at 60 °C for 12 h. 0.472 g of impurity D is obtained as a pale yellow solid powder, with a yield of 91.4% and a purity of 99.90%.

[0040] In the description of this specification, the descriptions referring to terms such as "one embodiment", "an embodiment", "example", "specific example", or "some examples", etc. mean that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic expressions of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0041] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing impurity D or a salt thereof, characterized in that, The method includes a cyclization reaction of indacaterol or a salt thereof with formaldehyde to obtain impurity D or a salt thereof.

2. The preparation method according to claim 1, characterized in that, The reaction temperature of the cyclization reaction is 45 - 80 °C, preferably 50 - 80 °C, and more preferably 60 - 75 °C.

3. The preparation method according to claim 1 or 2, characterized in that: The cyclization reaction is carried out in the presence of solvent A; optionally, solvent A is methanol, N,N-dimethylformamide, water, or a combination thereof.

4. The preparation method according to any one of claims 1-3, characterized in that, The molar ratio of indacaterol or a salt thereof to formaldehyde is 1:1 to 1:20, preferably 1:5 to 1:18, and more preferably 1:6 to 1:

13.

5. The preparation method according to any one of claims 1-4, characterized in that: The preparation method further includes post-treatment: adding an aqueous hydrochloric acid solution and stirring; optionally, the concentration of the aqueous hydrochloric acid solution is 1 mol / L; optionally, the addition amount of hydrochloric acid in the aqueous hydrochloric acid solution is 1.0 molar equivalent of indacaterol, preferably 1.0 to 1:18 molar equivalents.

6. The preparation method according to any one of claims 1-5, characterized in that: The preparation method further includes post-treatment: adding an aqueous hydrochloric acid solution, stirring, filtering, and rinsing the obtained filter cake with solvent B; optionally, solvent B is methanol, N,N-dimethylformamide, water, or a combination thereof.

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