CN108822054B - Oxydterol hydrochloride crystal form C and preparation method thereof - Google Patents

Abstract

The invention relates to a long-acting beta₂The crystal form C of the adrenergic agonist drug of the odaterol hydrochloride, a preparation method thereof and a pharmaceutical composition containing the crystal form C are characterized by an X-ray diffraction pattern characteristic absorption peak of the crystal form C. Compared with the prior art, the crystal form C of the olduterol hydrochloride provided by the invention is not easy to absorb moisture, has obviously improved stability and is convenient for the quality control of products; the preparation process is simple, is beneficial to cost control in industrial production and has higher economic value.

Description

Oxydterol hydrochloride crystal form C and preparation method thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a novel crystal form of olodaterol hydrochloride and a preparation method thereof.

Background

Oxdaterol hydrochloride, systematic name: 6-hydroxy-8- { (1R) -1-hydroxy-2- { [2- (4-methoxyphenyl) -1, 1-dimethylethyl]Amino } ethyl } -4H-benzo [1,4]]Oxazin-3-one hydrochloride (6-Hydroxy-8- { (1R) -1-Hydroxy-2- { [2- (4-methoxyphenyl) -1,1-dimethyl-ethyl]amino}ethyl}-4H-[1,4]-benzoxazin-3-one, hydrochloride), molecular formula C₂₁H₂₇ClN₂O₅Molecular weight of 386.44, CAS registry number of 868049-49-4, structural formula shown in 1

The olodaterol hydrochloride is long-acting beta₂A receptor agonist, suitable for use in patients with Chronic Obstructive Pulmonary Disease (COPD).

The specification of the chinese invention patent application publication No. CN101817800A (published 2010, 9/1) describes 6-hydroxy-8- { 1-hydroxy-2- { [2- (4-methoxyphenyl) -1, 1-dimethylethyl ] amino } ethyl } -4H-benzo [1,4] oxazin-3-one without enantiomer discrimination, and its preparation method and use. Chinese patent application publication No. CN102827097 a (publication No. 2012, 12, 19) discloses a pure enantiomer represented by structural formula 1, and discloses the following preparation methods:

"5.25 g (17.7 mmol) 6-benzyloxy-8- (R) -oxiranyl-4H-benzo [1,4] oxazin-3-one and 6.30 g (35.1 mmol) 2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamine are mixed with 21 ml isopropanol and stirred in a closed reaction vessel under microwave irradiation at 135 ℃ for 30 minutes. The solvent was evaporated off and the residue was chromatographed (alumina; ethyl acetate/methanol gradient). The product thus obtained was further purified "by recrystallization from a diethyl ether/diisopropyl ether mixture to give 6-benzyloxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1,4] oxazin-3-one.

Then "a suspension of 5.33 g (11.2 mmol) 6-benzyloxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1,4] oxazin-3-one in 120 ml methanol was mixed with 0.8 g palladium on charcoal (10%), heated to 50 ℃ and hydrogenated under 3 bar hydrogen pressure. The catalyst was then filtered off with suction and the filtrate was evaporated to dryness. The residue was dissolved in 20 ml of isopropanol and 2.5 ml of 5 mol hydrochloric acid in isopropanol were added. This product was precipitated with 200 ml of diethyl ether, filtered off with suction and dried to give 6-hydroxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1,4] oxazin-3-one-hydrochloride (olodaterol hydrochloride).

However, the inventor finds that the olodaterol hydrochloride is extremely easy to absorb moisture and is converted into oily matter during suction filtration according to the method, and cannot obtain a stable crystalline product, thereby causing great difficulty in subsequent quality control and preparation work.

As is well known, the physical and chemical properties of the same drug in various crystal forms such as solubility, stability, fluidity, compressibility, bioavailability and the like may be greatly different, thereby affecting the curative effect of the drug. Therefore, there is a need to develop a new crystal form of odaterol hydrochloride having superior physiochemical properties, thereby facilitating formulation processing and clinical use.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a novel crystal form of the oxdaterol hydrochloride, namely a crystal form C of the oxdaterol hydrochloride. The crystal form is not easy to absorb moisture, the stability is obviously improved, and the quality control of the product is convenient; and the preparation process is simple and is beneficial to cost control in industrial production.

In order to achieve the purpose of the invention, the invention adopts the following technical scheme:

a crystal form C of the olodaterol hydrochloride shown in the structural formula 1, wherein an X-ray diffraction pattern expressed by an angle of 2 theta by using Cu-Kalpha radiation has characteristic absorption peaks at 14.93 degrees +/-0.2 degrees, 19.32 degrees +/-0.2 degrees, 19.76 degrees +/-0.2 degrees, 19.97 degrees +/-0.2 degrees, 22.51 degrees +/-0.2 degrees, 25.98 degrees +/-0.2 degrees, 29.33 degrees +/-0.2 degrees, 29.61 degrees +/-0.2 degrees and 34.62 degrees +/-0.2 degrees.

Preferably, the oxdarterol hydrochloride crystal form C has characteristic absorption peaks at 12.79 ° ± 0.2 °, 14.93 ° ± 0.2 °, 18.66 ° ± 0.2 °, 19.32 ° ± 0.2 °, 19.76 ° ± 0.2 °, 19.97 ° ± 0.2 °, 20.88 ° ± 0.2 °, 22.51 ° ± 0.2 °, 24.69 ° ± 0.2 °, 25.98 ° ± 0.2 °, 27.78 ° ± 0.2 °, 28.24 ° ± 0.2 °, 29.33 ° ± 0.2 °, 29.61 ° ± 0.2 °, 31.53 ° ± 0.2 °, 34.36 ° ± 0.2 ° and 34.62 ° ± 0.2 ° in an X-ray diffraction pattern expressed by 2 θ using Cu-Ka radiation.

Preferably, the form C of the olodaterol hydrochloride has an X-ray diffraction pattern substantially in accordance with fig. 1, expressed in terms of 2 θ, using Cu-ka radiation.

The invention also aims to provide a preparation method of the crystal form C of the metaterol hydrochloride, which comprises the following steps:

I. putting the crude product of the olodaterol hydrochloride and the organic solvent into a reaction container, stirring, heating to ensure that the solution is clear, and keeping the temperature and continuing stirring;

and II, reducing the temperature, stirring, crystallizing, filtering and drying to obtain the product.

Preferably, the organic solvent is selected from two or more of isopropanol, methanol, ethyl acetate, dichloromethane, toluene and n-propanol.

More preferably, the mixed solvent is isopropanol-methanol.

More preferably, the volume ratio of isopropanol to methanol is:

isopropyl alcohol: the methanol is 7: 1-15: 1.

Most preferably, the volume ratio of isopropanol to methanol is:

isopropyl alcohol: methanol 10: 1.

Preferably, the weight-to-volume ratio of the crude olodaterol hydrochloride to the organic solvent is as follows:

crude product of olodaterol hydrochloride: 8 ml-1 g of organic solvent and 15ml of organic solvent;

more preferably, the weight-to-volume ratio of the crude olodaterol hydrochloride to the organic solvent is as follows:

crude product of olodaterol hydrochloride: organic solvent 1g:13 ml.

Preferably, in the step I, the temperature is 45-50 ℃, and the mixture is stirred for 20 min-1 h, preferably 0.5h, after being dissolved and cleaned.

Preferably, in the step II, the temperature is reduced to 20-25 ℃, and the mixture is stirred for 15-24 hours, preferably 18 hours.

The crude product of the olodaterol hydrochloride can be prepared by the method described in the following steps 1-3 of example 1.

The third objective of the present invention is to provide a pharmaceutical composition, which includes the crystal form C of the olodaterol hydrochloride or the crystal form C of the olodaterol hydrochloride prepared by the preparation method, and pharmaceutically acceptable excipients.

Preferably, the pharmaceutical composition is an inhalation aerosol, an inhalation powder or an inhalation solution.

In addition, the invention also aims to provide the crystal form C of the aortaterol hydrochloride, the crystal form C of the aortaterol hydrochloride prepared by the preparation method or the application of the pharmaceutical composition in preparing a medicament for treating COPD.

The crystal form C of the olodaterol hydrochloride provided by the invention is not easy to absorb moisture, the stability is obviously improved compared with the prior art, and the quality control of a product and the subsequent preparation processing are facilitated. Compared with the original crystal form, the solubility of the crystal form C of the odaterol in water is obviously improved, and the drug effect can be greatly improved. Meanwhile, the preparation process of the crystal form provided by the invention is simple, is beneficial to cost control in industrial production, and has high economic value.

Drawings

The invention will be further described with reference to the accompanying drawings.

Fig. 1 is an X-ray diffraction pattern of the crystal form of the olodaterol hydrochloride prepared in comparative example 2.

Detailed Description

The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teachings herein, and such equivalents may fall within the scope of the invention as defined in the appended claims.

The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagents used in the following examples are all commercially available products unless otherwise specified. Wherein, the purchase conditions of partial reagents, raw materials and instruments are as follows:

6-benzyloxy-8- ((R) -2-chloro-1-hydroxy-ethyl-4H-benzo [1,4] -oxazin-3-one, CAS 869478-11-5, 98% pure and 2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamine hydrochloride CAS 56490-93-8, 99% pure, all purchased from Gekko Ji pharmaceutical science, Inc. in Shanghai.

Nuclear magnetic resonance apparatus: bruker AVANCE III HD 500;

mass spectrometry: LTQ Orbitrap Elite;

liquid chromatograph: agilent 1260.

In the following examples and comparative examples, HPLC measurements were carried out as follows:

a chromatographic column: waters XBridge 5 μm (4.6 x 250 mm);

mobile phase: a0.1% aqueous solution of sodium heptanesulfonate (pH3.2) and B acetonitrile, the gradient elution procedure is shown in Table 1:

TABLE 1 HPLC gradient elution procedure

Time(min)	A％	B％
			0	73	27
3	69	27
			23	49	51
43	35	65
			55	32	68
55.1	73	27
			60	73	27

Flow rate: 1.0 ml/min;

column temperature: 30 ℃;

detection wavelength: 220 nm;

sample introduction volume: 10 mu L of the solution;

test sample diluent: and (3) acetonitrile.

In the following examples and comparative examples, the detection conditions for X-ray diffraction were:

the instrument model is as follows: bruker D8 Advance

And (3) testing conditions are as follows: x-ray source: Cu-K

Working current: 40mA

Working voltage: 40KV

A detector: PSD

Initial angle: 4 ° (2- θ)

End angle: 40 ° (2- θ)

Increment: 0.05 °/step

Scanning speed: 1sec/step

Example 1Preparation of crystal form C of Oldham hydrochloride

1)6-benzyloxy-8- (R) -oxiranyl-4H-benzo [1,4]]Preparation of oxazin-3-ones

Adding 100.6g (0.3mol) of 6-benzyloxy-8- ((R) -2-chloro-1-hydroxy-ethyl-4H-benzo [1,4] -oxazine-3-one and 2L of DMF into a reaction bottle, stirring, cooling in an ice bath, cooling to 0 ℃, adding 400ml of 2N sodium hydroxide aqueous solution, reacting for four hours at 0-5 ℃, pouring the reaction solution into ice water, stirring for 1 hour at 0-5 ℃, filtering, and drying a filter cake in vacuum at 50 ℃ to obtain 86g of white solid, the yield is 96%, and the purity HPLC is 96.5%.

2)6-benzyloxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino]-B Radical } -4H-benzo [1,4]]Preparation of oxazin-3-ones

Adding 52.5g (0.178mol) of 6-benzyloxy-8- (R) -oxiranyl-4H-benzo [1,4] oxazine-3-one prepared in the step 1), 63g (0.351mol) of 2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamine and 500ml of isopropanol into a reaction bottle, carrying out reflux reaction for 24 hours, cooling to 20-30 ℃, then adding 30g (0.3mol) of concentrated hydrochloric acid, stirring at 0-5 ℃ for 1 hour, filtering, and pulping a filter cake with 500ml of anhydrous methanol to obtain 60g of off-white solid, wherein the yield is as follows: 66.2 percent and the purity is 95.8 percent

3)Preparation of crude Oldhuterol hydrochloride

60g (0.117mol) of 6-benzyloxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1,4] oxazin-3-one prepared in step 2), 600ml of methanol and 8g of 10% palladium on charcoal were added to a reaction flask, heated to 50 ℃ and hydrogenated under 3 bar of hydrogen pressure. Then the catalyst was removed by suction filtration, and the filtrate was evaporated to dryness in vacuo at 50 ℃ to give 49.1g of a white foamy solid, yield: 99.27%, purity: 95.3 percent.

4)Preparation of crystal form C of Oldham hydrochloride

Adding 5g of the crude product of the olodaterol hydrochloride prepared in the step 3), 50ml of isopropanol and 5ml of methanol into a reaction bottle, stirring, heating to 45-50 ℃, dissolving, stirring for half an hour under heat preservation, cooling to 25 ℃, stirring for 18 hours under heat preservation at 20-25 ℃, filtering, and drying a filter cake under vacuum at 50 ℃ to obtain 4.75g of off-white solid, wherein the yield is as follows: 95%, purity: 99.9 percent.

¹HNMR(DMSO-d₆)：δppm 1.19(d，6H)，2.90(m，3H)，3.14(m，1H)，3.74(s，3H)，4.60(m，2H)，5.15(m，1H)，6.10(d，1H)，6.37(d，1H)，6.58(d，1H)，6.90(d，2H)，7.15(d，2H)，8.58(m，1H)，8.89(m，1H)，9.33(s，1H)，10.65(s，1H).

MS(ESI)387m/z(M-HCl+H)⁺。

The X-ray diffraction results of the crystal form C of the obtained olodaterol hydrochloride in this example are shown in table 2.

Table 2X-ray powder diffraction data for crystal form C of ondansterol hydrochloride

Serial number	Angle of rotation	Strength (%)
			1	12.79	11.3
2	14.93	43.3
			3	18.66	14.2
4	19.32	100
			5	19.76	59.1
6	19.97	51.4
			7	20.88	21.3
8	22.51	52.3
			9	24.69	16.7
10	25.98	35.4
			11	27.78	16.4
12	28.24	20.5
			13	29.33	44.7
14	29.61	36.3
			15	31.53	13.9
16	34.36	19.7
			17	34.62	28.5

The crystal form C of the ondansterol hydrochloride prepared in the example was tested according to the guidelines of the hygroscopicity test of the drug XIX J in the appendix of the second part of the chinese pharmacopoeia (2005 edition), and the hygroscopicity increased by 0.18%. The solubility of crystal C in water was 1050mg/10ml as measured at room temperature.

Example 2Preparation of crystal form C of Oldham hydrochloride

Adding 6g of the crude product of the olodaterol hydrochloride obtained in the example 1, 45ml of isopropanol and 3ml of methanol into a reaction bottle, stirring, heating to 45-50 ℃ to dissolve, stirring for half an hour under heat preservation, cooling to 20 ℃, stirring for 24 hours under heat preservation at 20-25 ℃, filtering, and drying a filter cake under vacuum at 50 ℃ to obtain 5.4g of off-white solid, wherein the yield is as follows: 90%, purity: 99.4 percent.

The crystal form C of the odaterol hydrochloride prepared in this example was tested according to the guidelines of the hygroscopicity test of the drug XIX J in the appendix of the second part of the chinese pharmacopoeia (2005 edition), and the hygroscopicity increased by 0.23%. The solubility of crystal C in water was 1050mg/10ml as measured at room temperature.

Example 3Preparation of crystal form C of Oldham hydrochloride

Adding 5.3g of the crude product of the olodaterol hydrochloride obtained in the example 1, 70ml of isopropanol and 10ml of methanol into a reaction bottle, stirring, heating to 45-50 ℃ to dissolve the crude product clearly, keeping the temperature and stirring for half an hour, cooling to 25 ℃, keeping the temperature and stirring for 15 hours at 20-25 ℃, filtering, and performing vacuum drying on a filter cake at 50 ℃ to obtain 4.8g of off-white solid with the yield: 91%, purity: 99.3 percent.

The crystal form C of the ondansterol hydrochloride prepared in the example was tested according to the guidance of the hygroscopicity test of the XIX J medicament in the appendix of the second part of the chinese pharmacopoeia (2005 edition), and the hygroscopicity increased by 0.21%. The solubility of crystal C in water was 1050mg/10ml as measured at room temperature.

Example 4Preparation of crystal form C of Oldham hydrochloride

Adding 5g of the crude product of the olodaterol hydrochloride obtained in the example 1, 60ml of isopropanol and 5ml of ethyl acetate into a reaction bottle, stirring, heating to 45-50 ℃ to dissolve, stirring for half an hour under heat preservation, cooling to 20 ℃, stirring for 18 hours under heat preservation at 20-25 ℃, filtering, and drying a filter cake in vacuum at 50 ℃ to obtain 4.4g of off-white solid with yield: 88%, purity: 99.2 percent.

The crystal form C of the odaterol hydrochloride prepared in this example was tested according to the guidelines of the hygroscopicity test of the drug XIX J in the appendix of the second part of the chinese pharmacopoeia (2005 edition), and the hygroscopicity increased by 0.29%. The solubility of crystal C in water was 1050mg/10ml as measured at room temperature.

Example 5Preparation of crystal form C of Oldham hydrochloride

Adding 5g of the crude product of the olodaterol hydrochloride obtained in the example 1, 60ml of isopropanol and 5ml of dichloromethane into a reaction bottle, stirring, heating to 45-50 ℃ to dissolve, stirring for half an hour under heat preservation, cooling to 20 ℃, stirring for 20 hours under heat preservation at 20-25 ℃, filtering, and drying a filter cake under vacuum at 50 ℃ to obtain 4.5g of off-white solid with yield: 90%, purity: 99.4 percent.

The crystal form C of the ondansterol hydrochloride prepared in the example was tested according to the guidelines of the hygroscopicity test of the drug XIX J in the appendix of the second part of the chinese pharmacopoeia (2005 edition), and the hygroscopicity increased by 0.28%. The solubility of crystal C in water was 1050mg/10ml as measured at room temperature.

Comparative example 1Preparation of odaterol hydrochloride

The preparation of odaterol hydrochloride was carried out according to the method described in the chinese invention patent application publication No. CN102827097 (example 1) and the procedure was as follows:

a suspension of 5.33 g (11.2 mmol) 6-benzyloxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1,4] oxazin-3-one in 120 ml methanol was mixed with 0.8 g palladium on charcoal (10%), heated to 50 ℃ and hydrogenated under 3 bar of hydrogen pressure. The catalyst was then filtered off with suction and the filtrate was evaporated to dryness. The residue is dissolved in 20 ml of isopropanol and 2.5 ml of 5 mol hydrochloric acid in isopropanol are added, the product is precipitated with 200 ml of diethyl ether, filtered off with suction and dried.

However, when the solution is filtered, the oldacterol hydrochloride is found to be extremely easy to absorb moisture and change into oily substance, and a stable crystal product cannot be obtained.

Comparative example 2Preparation of odaterol hydrochloride

The preparation of the odaterol hydrochloride was carried out according to the method described in example 1 of the chinese patent application publication No. CN 101208316A. The yield is 63-70%, and the purity is 98.5%. The crystal form of the olodaterol hydrochloride prepared by the patent uses Cu-Kalpha radiation, and an X-ray diffraction pattern expressed by a 2 theta angle has characteristic absorption peaks at 11.91 degrees +/-0.2 degrees, 15.19 degrees +/-0.2 degrees, 16.88 degrees +/-0.2 degrees, 17.34 degrees +/-0.2 degrees, 19.04 degrees +/-0.2 degrees, 19.71 degrees +/-0.2 degrees, 21.02 degrees +/-0.2 degrees, 21.35 degrees +/-0.2 degrees, 22.15 degrees +/-0.2 degrees, 23.21 degrees +/-0.2 degrees, 28.41 degrees +/-0.2 degrees, 29.79 degrees +/-0.2 degrees and 30.71 degrees +/-0.2 degrees, and the pattern is shown in figure 1. The crystal had a solubility in water of 900mg/10ml at room temperature.

In a word, the invention provides a new crystal form of the aodalterol hydrochloride, namely the crystal form C of the aodalterol hydrochloride, the crystal form is not easy to absorb moisture, the stability is obviously improved, and the quality control of a product and the subsequent preparation processing are convenient. Meanwhile, the preparation process of the crystal form provided by the invention is simple, is beneficial to cost control in industrial production, and has high economic value.

Claims (3)

1. The crystal form C of the olodaterol hydrochloride is characterized in that the crystal form C of the olodaterol hydrochloride has characteristic absorption peaks at 12.79 degrees, 14.93 degrees, 18.66 degrees, 19.32 degrees, 19.76 degrees, 19.97 degrees, 20.88 degrees, 22.51 degrees, 24.69 degrees, 25.98 degrees, 27.78 degrees, 28.24 degrees, 29.33 degrees, 29.61 degrees, 31.53 degrees, 34.36 degrees and 34.62 degrees by using Cu-Kalpha radiation and an X-ray diffraction pattern expressed by 2 theta angles; x-ray powder diffraction data are:

serial number Angle of rotation Strength (%) 1 12.79 11.3 2 14.93 43.3 3 18.66 14.2 4 19.32 100 5 19.76 59.1 6 19.97 51.4 7 20.88 21.3 8 22.51 52.3 9 24.69 16.7 10 25.98 35.4 11 27.78 16.4 12 28.24 20.5 13 29.33 44.7 14 29.61 36.3 15 31.53 13.9 16 34.36 19.7 17 34.62 28.5

The crystal form C of the olodaterol hydrochloride is prepared by the following method:

1)6-benzyloxy-8- (R) -oxiranyl-4H-benzo [1,4]]Preparation of oxazin-3-ones

Adding 100.6g (0.3mol) of 6-benzyloxy-8- ((R) -2-chloro-1-hydroxy-ethyl-4H-benzo [1,4] -oxazine-3-one and 2L of DMF into a reaction bottle, stirring, cooling in an ice bath, cooling to 0 ℃, adding 400ml of 2N sodium hydroxide aqueous solution, reacting at 0-5 ℃ for four hours, pouring the reaction solution into ice water, stirring at 0-5 ℃ for 1 hour, filtering, and drying a filter cake at 50 ℃ in vacuum to obtain 86g of white solid, wherein the yield is 96%, and the purity HPLC is 96.5%;

2) preparation of 6-benzyloxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1,4] oxazin-3-one

Adding 52.5g (0.178mol) of 6-benzyloxy-8- (R) -oxiranyl-4H-benzo [1,4] oxazine-3-one prepared in the step 1), 63g (0.351mol) of 2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamine and 500ml of isopropanol into a reaction bottle, carrying out reflux reaction for 24 hours, cooling to 20-30 ℃, then adding 30g (0.3mol) of concentrated hydrochloric acid, stirring at 0-5 ℃ for 1 hour, filtering, and pulping a filter cake with 500ml of anhydrous methanol to obtain 60g of off-white solid, wherein the yield is as follows: 66.2 percent and the purity is 95.8 percent;

3) preparation of crude Oldhuterol hydrochloride

60g (0.117mol) of 6-benzyloxy-8- { (R) -1-hydroxy-2- [2- (4-methoxy-phenyl) -1, 1-dimethyl-ethylamino ] -ethyl } -4H-benzo [1,4] oxazin-3-one prepared in step 2), 600ml of methanol and 8g of 10% palladium on charcoal were added to a reaction flask, heated to 50 ℃ and hydrogenated under 3 bar of hydrogen pressure; then the catalyst was removed by suction filtration, and the filtrate was evaporated to dryness in vacuo at 50 ℃ to give 49.1g of a white foamy solid, yield: 99.27%, purity: 95.3 percent;

4) preparation of crystal form C of Oldham hydrochloride

Adding 5g of the crude product of the olodaterol hydrochloride prepared in the step 3), 50ml of isopropanol and 5ml of methanol into a reaction bottle, stirring, heating to 45-50 ℃, dissolving, stirring for half an hour under heat preservation, cooling to 25 ℃, stirring for 18 hours under heat preservation at 20-25 ℃, filtering, and drying a filter cake under vacuum at 50 ℃ to obtain 4.75g of off-white solid, wherein the yield is as follows: 95%, purity: 99.9 percent.

2. A pharmaceutical composition comprising the form C of olodaterol hydrochloride of claim 1 and pharmaceutically acceptable excipients.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is an inhalation aerosol, an inhalation powder or an inhalation solution.

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