阅读说明：本技术 奥达特罗及其盐的制备方法 (Process for preparing odaterol and salts thereof ) 是由 黄才古 孙辉 于 2020-06-11 设计创作，主要内容包括：本发明涉及奥达特罗及其盐的制备方法,其包括如下步骤：在溶剂中,将式I化合物经氧化、亲核加成反应制得式II化合物；将式II化合物与式III化合物经手性还原反应制得式IV化合物；将所得式IV化合物经还原脱苄反应制得奥达特罗及其盐。本发明的奥达特罗及其盐制备方法具有选择性高,收率和纯度更高、操作简便,适合于工业化。(The invention relates to a preparation method of odaterol and salts thereof, which comprises the following steps: in a solvent, carrying out oxidation and nucleophilic addition reaction on a compound shown in a formula I to prepare a compound shown in a formula II; carrying out a manual reduction reaction on a compound of a formula II and a compound of a formula III to prepare a compound of a formula IV; and carrying out reduction debenzylation on the obtained compound shown in the formula IV to obtain the odaterol and salts thereof. The preparation method of the odaterol and the salt thereof has the advantages of high selectivity, higher yield and purity, simple and convenient operation and suitability for industrialization.)

1. The preparation method of the odaterol and the salt thereof comprises the following steps:

(a) carrying out oxidation and nucleophilic addition reaction on a compound of a formula I to prepare a compound of a formula II;

r1 in the compounds of formula I-II is a hydroxyl protecting group;

r2 in the compounds of formula I-II is aldehyde protecting group;

(b) carrying out chiral reduction reaction on the compound of the formula II and the compound of the formula III obtained in the previous step to obtain a compound of a formula IV;

HX in the compound of the formula III is an acid for forming a salt of the odaterol;

(c) and (3) carrying out reduction debenzylation on the compound of the formula IV obtained in the previous step to obtain the odaterol and salts thereof.

2. The method of claim 1, wherein the oxidizing agent in step (a) comprises selenium dioxide, hydrogen bromide/dimethylsulfoxide, carbamide peroxide, or the like.

3. The process according to claim 1, wherein the protecting group R1 comprises an aryl group, an alkyl group, an aralkyl group or a substituted silyl group.

4. The process according to claim 1, wherein the protecting group R2 comprises an aryl group, an alkyl group or an aralkyl group.

5. The method of claim 1, wherein the oxidation reaction temperature in step (a) is from 0 ℃ to 120 ℃.

6. The process of claim 1, wherein the chiral catalyst in step (b) comprises (R) -tetrahydro-1-methyl-3, 3-diphenyl- (1H, 3H) -pyrrolo [1, 2-c ] [1, 3, 2] -azaborole (R-Me-CBS), (-) -diisopinocampheylchloroborane ((-) -DIPCl), and the like.

7. The method according to claim 1, wherein the solvent in the step (b) is tetrahydrofuran, methyltetrahydrofuran, or methyl t-butyl ether.

8. The method of claim 1, wherein the reaction temperature in the step (b) is-30 ℃ to 100 ℃.

9. The process of claim 1, wherein the salt-forming solvent of step (b) comprises C_1-6One or more of alkyl alcohol, tetrahydrofuran, dichloromethane, ethyl acetate and N, N-dimethylformamide.

10. The method of claim 1, wherein step (c) comprises the steps of: removing the protecting group R1 of the compound shown in the formula IV to prepare a compound V; or neutralizing and dissociating by using alkali, converting the compound V into the free base of the odaterol, and then converting the compound V into the salt of the odaterol by salifying.

11. The method of claim 1, wherein the catalyst in step (c) comprises palladium on carbon, palladium hydroxide, or the like.

Technical Field

The invention particularly relates to a preparation method of the odaterol and salts thereof.

Background

Long acting beta₂The adrenergic agonist drug, Olodaterol Hydrochloride (Olodaterol Hydrochloride), is chemically 6-hydroxy-8- [ (1R) -1-hydroxy-2- [ [2- (4-methoxyphenyl) -1, 1-dimethylethyl]Amino group]Ethyl radical]-2H-1, 4-benzoxazin-3 (4H) -one hydrochloride of formula: c₂₁H₂₆N₂O₅HCl, molecular weight: 422.9, developed by the company bliringer-invagrehn, for the maintenance treatment of adult Chronic Obstructive Pulmonary Disease (COPD) patients, having the following structural formula:

the prior art discloses a synthesis process of odaterol hydrochloride, for example, patent CN200680023266 discloses that the odaterol hydrochloride is prepared by taking 8-acetyl-6- (phenylmethoxy) -4H-1, 4-benzoxazine-3-one and 1, 1-dimethyl-2- (4-methoxyphenyl) ethylamine hydrochloride as raw materials through five-step reactions of bromination, chiral reduction, cyclization, ring-opening substitution and reductive debenzylation, and the reaction route is as follows:

the chiral reduction step in this route, with low chiral selectivity, poses risks to subsequent steps and API isomer impurities. The ring-opening substitution reaction has poor selectivity, low yield and poor crude product purity, the reaction liquid contains more by-products (compounds of formula VI and formula VII), the crystallization and purification are difficult, and the impurity risk of the raw material medicines (formula VI-1 and formula VII-1) is increased.

In order to better meet the pharmaceutical requirements, the development of a preparation process of the bulk drug with low cost, high yield and high quality has higher commercial practical value and better meets the requirements of green chemistry. The preparation process can lead the yield of three reactions of oxidation, chiral reduction and reduction debenzylation to reach 64 percent, the purity of the raw material medicine to reach 99.8 percent, the contents of the formula VI-1 and the formula VII-1 in an impurity spectrum to be reduced to be below 0.1 percent, and the content of S isomer to be reduced to be below 0.1 percent, has the advantages of shortened synthesis route, simplicity, convenience, high efficiency and stable process, is suitable for industrial production, overcomes a plurality of defects in the prior art, and can effectively control the low cost and the high quality of the raw material medicine.

Disclosure of Invention

The invention provides a novel preparation method of the odaterol and the salt thereof, aiming at overcoming the defects of high cost, low yield and low purity of the preparation method of the odaterol and the salt thereof in the prior art. The preparation process of the odaterol and the salt thereof has the advantages of simple operation, low cost, high yield and high quality, is suitable for industrial production, and ensures the cost and the quality of the raw material medicaments.

The invention provides a preparation method of odaterol and salts thereof, which comprises the following steps:

(a) carrying out oxidation and nucleophilic addition reaction on a compound of a formula I to prepare a compound of a formula II;

r1 in the compounds of formula I-II is a hydroxyl protecting group;

r2 in the compounds of formula I-II is aldehyde protecting group;

in the preparation method of the odaterol and the salt thereof, the protecting group R1 comprises aryl, alkyl, aralkyl or substituted silyl. The protecting group R2 includes aryl, alkyl and aralkyl. The oxidant in the step (a) comprises selenium dioxide, hydrogen bromide/dimethyl sulfoxide, carbamide peroxide and the like; the oxidation reaction temperature is 0 ℃ to 120 ℃, preferably 80 ℃ to 110 ℃.

(b) Carrying out chiral reduction reaction on the compound of the formula II and the compound of the formula III obtained in the previous step to obtain a compound of a formula IV;

HX in the compound of the formula III is an acid for forming a salt of the odaterol, preferably hydrochloric acid;

in the preparation method of the odaterol and the salt thereof, the chiral catalyst in the step (b) comprises (R) -tetrahydro-1-methyl-3, 3-diphenyl- (1H, 3H) -pyrrolo [1, 2-c)][1，3，2]-azaborolinyl (R-Me-CBS), (-) -diisopinocampheylchloroborane ((-) -DIPCl), etc.; the solvent is tetrahydrofuran, methyltetrahydrofuran or methyl tert-butyl ether, preferably tetrahydrofuran; the reaction temperature is-30-100 ℃, and the preferable temperature is-20 ℃; the salt-forming solvent comprises C_1-6One or more of alkyl alcohol, tetrahydrofuran, dichloromethane, ethyl acetate and N, N-dimethylformamide.

(c) And (3) carrying out reduction debenzylation on the compound of the formula IV obtained in the previous step to obtain the odaterol and salts thereof.

In the preparation method of the odaterol and the salt thereof, the step (c) comprises the following steps: removing the protecting group R1 of the compound shown in the formula IV to prepare a compound V; or neutralizing and dissociating by using alkali, converting the compound V into the free base of the odaterol, and then converting the compound V into the salt of the odaterol by salifying; the catalyst in step (c) comprises palladium on carbon, palladium hydroxide, etc.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the odaterol and the salt thereof is simple, convenient and efficient, has high yield, low cost and high quality, is suitable for industrial production, and ensures the cost and the quality of the raw material medicaments.

Detailed Description

The technical solutions of the present invention are described below with reference to examples to better understand the technical features, objects and advantages of the present invention, but the present invention is not limited to the scope of the examples. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1: preparation of 8- (1-hydroxy-1-ethoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one

To a 100mL reaction flask were added 8-acetyl-6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one (5.0g), dioxane (50mL), and water (0.5mL), and SeO was added at room temperature₂(28.0g), the temperature was raised to 80 ℃ and the reaction was stirred for 8 hours, and the reaction was completed as checked by TLC. Cooling to room temperature, filtering, washing with dioxane (5mL) and water (25mL), separating the filtrates, extracting the aqueous phase with dioxane (30mL) for 1 time, and combining the organic phasesWashing with water for 1 time, and concentrating the organic phase under reduced pressure to obtain a light yellow oily crude product of glyoxal.

Adding ethanol (40mL) into the crude product at room temperature, stirring to dissolve the mixture, heating to reflux, stirring for 1 hour, stirring for 4 hours at room temperature, filtering, washing with ethanol, and drying at 60 ℃ for 8 hours to obtain a light yellow solid product 8- (1-hydroxy-1-ethoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazine-3-one (5.1g), wherein the yield is 85.2%.

Example 2: preparation of 8- (1-hydroxy-1-ethoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one

8-acetyl-6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one (5.0g), dimethylsulfoxide (50mL) and 48% hydrobromic acid (20mL) were added to a 100mL reaction flask at room temperature, the temperature was raised to 110 ℃ and the reaction was stirred for 12 hours and checked by TLC for completion. Cooled to room temperature, ethyl acetate (200mL) and water (20mL) were added, the layers were separated, the organic phase was washed 3 times with water (20mL), and the organic phase was concentrated under reduced pressure to give crude glyoxal as a pale yellow oil.

Adding ethanol (20mL) into the crude product at room temperature, stirring to dissolve the mixture, heating to reflux, stirring for 1 hour, stirring for 4 hours at room temperature, filtering, washing with ethanol, and drying at 60 ℃ for 8 hours to obtain a light yellow solid product, namely 8- (1-hydroxy-1-ethoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazine-3-one (5.2g), wherein the yield is 87.4%.

Example 3: preparation of 8- (1-hydroxy-1-methoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one

To a 100mL reaction flask were added 8-acetyl-6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one (5.0g), dioxane (50mL), and water (0.5mL), and SeO was added at room temperature₂(28.0g), the temperature was raised to 100 ℃ and the reaction was stirred for 8 hours, and the reaction was completed as checked by TLC. Cooling to room temperature, filtering, washing with dioxane (5mL) and water (25mL), separating the filtrate, extracting the water phase with dioxane (30mL) for 1 time, combining the organic phases, washing with water for 1 time, and concentrating the organic phase under reduced pressure to obtain a light yellow oily crude product of glyoxal.

Methanol (20mL) is added into the crude product at room temperature, the mixture is stirred to be clear, the mixture is heated to reflux and stirred for 1 hour, the mixture is stirred for 4 hours at room temperature, and the mixture is filtered, washed by methanol and dried for 8 hours at 60 ℃ to obtain a light yellow solid product, namely 8- (1-hydroxy-1-methoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazine-3-one (5.2g), with the yield of 90.2%.

¹HNMR(400MHz，DMSO-d6)δH(ppm)：10.81(s，1H)，7.34(m， 5H)，6.87(d，J＝1Hz，1H)，6.76(d，J＝0.5Hz，1H)，6.57(d，J＝2Hz，1H)，5.42(d，J＝2Hz，1H)，5.07(m，2H)，4.61(dd，J＝4Hz，2H)，3.35(s，3H)。

Example 4: preparation of 8- [ (1R) -1-hydroxy-2- [ [ 2-aryl-1, 1-dimethyl-ethyl ] -amino ] ethyl ] -6- (phenylmethoxy) -2H-1, 4-benzoxazin-3 (4H) -one hydrochloride

Intermediate III (0.66g) and ethyl acetate (10mL) were added to a reaction flask at room temperature, and 80mL of an aqueous NaOH (0.15g, 1M) solution was added thereto and stirred for 10 minutes. Standing for layering, extracting water phase with ethyl acetate for 1 time, mixing organic phases, washing with water for 1 time, and concentrating organic phase under reduced pressure to obtain light yellow liquid-free alkali.

The free base, 8- (1-hydroxy-1-ethoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one (1.0g) and tetrahydrofuran (10ml) were added to a reaction flask at room temperature, and the mixture was stirred for 2 hours while warming to 40 ℃.

At room temperature, add tetrahydrofuran (10ml) and R-Me-CBS toluene solution (0.6ml, 1M) to another flask, cool to-20 deg.C, add BH₃After stirring the resulting solution for 0.5 hour in THF (8.4ml, 1M), the above condensation reaction solution was dropped at-20 ℃ and stirred at-20 ℃ for 2 hours. The reaction was complete by TLC.

Methanol (1.5ml) was slowly added dropwise at 0 ℃ to quench, and the reaction solution was concentrated under reduced pressure to give a yellow oil. EA (25ml) and water (5ml) were added, the organic phase was washed 2 times with water (5ml), and the organic phase was concentrated under reduced pressure to give a crude yellow foam. THF (5ml) was added at room temperature, and stirred to dissolve, concentrated hydrochloric acid (0.36g) was added dropwise, stirred for 6 hours, filtered, washed with THF, and dried at 60 ℃ for 8 hours to obtain intermediate IV (1.26g) as a white solid product with a yield of 87.7%.

The HPLC purity was 99.0% (area normalization), the content of single impurities was less than 0.20%, and the content of S isomers was 0.16%. HPLC methods for impurity analysis: mobile phase: mobile phase A (KH of pH3.0)₂PO₄Buffer) and mobile phase B (methanol) gradient elution; a chromatographic column: SB-C8 column (5.0 μm, 4.6 x 150 mm); detection wavelength: 220 nm; column temperature: 40 ℃; flow rate: 1.0 ml/min; chiral HPLC analytical method: mobile phase: n-hexane, ethanol and diethanolamine is 40: 60: 0.1; a chromatographic column: lux Cellulose chiral column (5.0 μm, 4.6 x 250 mm); detection wavelength: 220nm, column temperature: 40 ℃; flow rate: 1.0 ml/min.

Example 5: preparation of 8- [ (1R) -1-hydroxy-2- [ [ 2-aryl-1, 1-dimethyl-ethyl ] -amino ] ethyl ] -6- (phenylmethoxy) -2H-1, 4-benzoxazin-3 (4H) -one hydrochloride

Intermediate III (0.66g) and ethyl acetate (10mL) were added to a reaction flask at room temperature, and 80mL of an aqueous NaOH (0.15g, 1M) solution was added thereto and stirred for 10 minutes. Standing for layering, extracting water phase with ethyl acetate for 1 time, mixing organic phases, washing with water for 1 time, and concentrating organic phase under reduced pressure to obtain light yellow liquid-free alkali.

The free base, 8- (1-hydroxy-1-ethoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one (1.0g) and methyltetrahydrofuran (10ml) were added to a reaction flask at room temperature, and the mixture was stirred for 2 hours while warming to 40 ℃.

A mixture of methyltetrahydrofuran (10ml) and (-) -DIPCl hexane solution (4.56g, 60%) was added dropwise to the condensation reaction mixture at 20 ℃ and stirred for 4 hours at 20 ℃. The reaction was complete by TLC.

Quenching was done at 0 ℃ slowly dropwise with dilute hydrochloric acid (10ml, 1.0M). EA (25ml) was added for extraction, the organic phase was washed with water (5ml) 2 times and concentrated under reduced pressure to give a yellow foamy crude product. At room temperature, isopropanol (10ml) was added, dissolved with stirring, concentrated hydrochloric acid (0.36g) was added dropwise, stirred for 6 hours, filtered, washed with isopropanol and dried at 60 ℃ for 8 hours to give intermediate IV (1.18g) as a white solid product in 82.3% yield.

The HPLC purity was 99.2% (area normalization), the content of single impurities was less than 0.20%, and the content of S isomers was 0.25%. The HPLC impurities and chiral analysis were the same as in example 4.

Example 6: preparation of 8- [ (1R) -1-hydroxy-2- [ [ 2-aryl-1, 1-dimethyl-ethyl ] -amino ] ethyl ] -6- (phenylmethoxy) -2H-1, 4-benzoxazin-3 (4H) -one hydrochloride

Intermediate III (0.66g) and ethyl acetate (10mL) were added to a reaction flask at room temperature, and 80mL of an aqueous NaOH (0.15g, 1M) solution was added thereto and stirred for 10 minutes. Standing for layering, extracting water phase with ethyl acetate for 1 time, mixing organic phases, washing with water for 1 time, and concentrating organic phase under reduced pressure to obtain light yellow liquid-free alkali.

The free base, 8- (1-hydroxy-1-methoxy-acetyl) -6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one (1.06g) and tetrahydrofuran (10ml) were added to a reaction flask at room temperature, and the mixture was stirred for 2 hours while warming to 40 ℃.

Dropping tetrahydrofuran (10ml) and R-Me-CBS toluene solution (0.6ml, 1M) into the condensation reaction solution at 0 deg.C, and dropping BH at 0 deg.C₃The THF solution of (8.4ml, 1M) was stirred at 0 ℃ for 4 hours. The reaction was complete by TLC.

Methanol (1.5ml) was slowly added dropwise at 0 ℃ to quench, and the reaction solution was concentrated under reduced pressure to give a yellow oil. EA (25ml) and water (5ml) were added, the organic phase was washed 2 times with water (5ml), and the organic phase was concentrated under reduced pressure to give a crude yellow foam. Adding ethanol (8ml) at room temperature, stirring for dissolving, dropwise adding concentrated hydrochloric acid (0.36g), stirring for 6 hours, filtering, washing with ethanol, and drying at 60 ℃ for 8 hours to obtain a white solid product, namely an intermediate IV (1.24g), wherein the yield is 86.3%.

The HPLC purity was 99.2% (area normalization), the content of single impurities was less than 0.20%, and the content of S isomers was 0.18%. The HPLC impurities and chiral analysis were the same as in example 4.

Example 7: preparation of 6-hydroxy-8- [ (1R) -1-hydroxy-2- [ [2- (4-methoxyphenyl) -1, 1-dimethylethyl ] amino ] ethyl ] -2H-1, 4-benzoxazin-3 (4H) -one hydrochloride

To the hydrogenation vessel, intermediate IV (12.5g) and MeOH (125ml) were added at room temperature, Pd/C (0.63g, 10%) was added, nitrogen was replaced, and then the mixture was hydrogenated to 0.3 MPa. The reaction was stirred at 40 ℃ for 4 hours. The reaction was complete by TLC.

The catalyst was removed by filtration at room temperature, washed with methanol, and the filtrate was concentrated under reduced pressure, followed by addition of isopropanol (30g), heating to reflux and clearing, and stirring at room temperature for 6 hours. Filtering, washing a filter cake with isopropanol to obtain a wet product of the oldacterol hydrochloride, and drying the wet product of the oldacterol hydrochloride for 8 hours in vacuum at 50 ℃ to obtain 8.76g of a white solid product of the oldacterol hydrochloride, wherein the yield is 85.5 percent.

The HPLC purity was 99.8% (area normalization), the content of single impurities was less than 0.10%, and the content of S isomers was 0.08%. HPLC methods for impurity analysis: mobile phase: mobile phase A (KH of pH3.0)₂PO₄Buffer) and mobile phase B (methanol) gradient elution; a chromatographic column: SB-C8 column (5.0 μm, 4.6 x 150 mm); detection wavelength: 220 nm; column temperature: 40 ℃; flow rate: 1.0 ml/mm; chiral HPLC analytical method: mobile phase: n-hexane, ethanol and diethanolamine is 40: 60: 0.2; a chromatographic column: lux Cellulose chiral column (5.0 μm, 4.6 x 250 mm); detection wavelength: 220nm, column temperature: 40 ℃; flow rate: 1.0 ml/min.

Example 8: preparation of 6-hydroxy-8- [ (1R) -1-hydroxy-2- [ [2- (4-methoxyphenyl) -1, 1-dimethylethyl ] amino ] ethyl ] -2H-1, 4-benzoxazin-3 (4H) -one hydrochloride

To the hydrogenation kettle, intermediate IV (12.5g) and MeOH (125ml) were added at room temperature followed by Pd (OH)₂C (0.63g, 20%), nitrogen was replaced, and then the mixture was hydrogenated to 0.3 MPa. The reaction was stirred at 40 ℃ for 2 hours. The reaction was complete by TLC.

The catalyst was removed by filtration at room temperature, washed with methanol, the filtrate was concentrated under reduced pressure, ethyl acetate (40ml) and water (60ml) were added, the aqueous phase was taken, ethyl acetate (100ml) and sodium hydroxide solution (15ml, 2M) were added, stirring was carried out for 10 minutes, and the organic phase was concentrated under reduced pressure to give a white solid, free base of olodaterol. Isopropanol (59g), concentrated hydrochloric acid (3.7g) and water (2.5ml) were added thereto, and the mixture was heated to reflux and dissolved, followed by stirring at room temperature for 6 hours. Filtering, washing a filter cake with isopropanol to obtain a wet product of the oldacterol hydrochloride, and drying the wet product of the oldacterol hydrochloride for 8 hours in vacuum at 50 ℃ to obtain 8.61g of a white solid product of the oldacterol hydrochloride, wherein the yield is 83.6 percent.

The HPLC purity was 99.7% (area normalization), the content of single impurities was less than 0.10%, and the content of S isomers was 0.06%. The HPLC impurities and chiral analysis were the same as in example 7.

Comparative example: preparation of Aodaterol hydrochloride (refer to patent CN200680023266)

Preparation of 8- (2R) -oxiranyl-6- (phenylmethoxy) -2H-1, 4-benzoxazin-3 (4H) -one

To the reaction flask were added 8-acetylbromo-6- (phenylmethoxy) -4H-1, 4-benzoxazin-3-one (127g) and tetrahydrofuran (1.1 kg). Cooled to-30 ℃ and (-) -DIPCl in hexane (520g, 60%) was slowly added dropwise. The temperature is raised to 0 ℃, and the reaction is stirred for 1 hour. The reaction was complete by TLC.

To the reaction mixture were added 50% NaOH solution (137.4g) and H at 0 deg.C₂O (400g), adjust pH to 13. The mixture was stirred at 20 ℃ for 3 hours. At room temperature, a mixture of concentrated hydrochloric acid (160g) and water (300g) was added dropwise to adjust the pH to 8-9, and the mixture was stirred at 35 ℃ for 20 minutes. After filtration, the filtrate was extracted 3 times with ethyl acetate (1.8kg), the organic phases were combined, washed 1 time with water, concentrated under reduced pressure, added with ethyl acetate (400ml) and stirred at room temperature for 6 hours. Filtering, washing with ethyl acetate, drying at 60 deg.C for 8 hr to obtain white solid product 8- (2R) -oxiranyl-6- (phenylmethoxy) -2H-1, 4-benzoxazine-3 (4H) -one (89.7g), yield 70.6%.

The HPLC purity was 97.5% (area normalization), the content of single impurities was less than 0.80%, and the content of S isomers was 2.2%. The HPLC impurities and chiral analysis were the same as in example 4.

Preparation of 8- [ (1R) -1-hydroxy-2- [ [ 2-aryl-1, 1-dimethyl-ethyl ] -amino ] ethyl ] -6- (phenylmethoxy) -2H-1, 4-benzoxazin-3 (4H) -one hydrochloride

Intermediate III (11.3g) and ethyl acetate (135g) were added to a reaction flask, and 80mL of aqueous NaOH (80mL, 1M) was added at room temperature and stirred. Standing for layering, extracting the water phase with ethyl acetate twice, mixing the organic phases, washing with water once, and distilling the organic phase under reduced pressure to obtain light yellow liquid-free alkali.

To a reaction flask, 8- (2R) -oxiranyl-6- (phenylmethoxy) -2H-1, 4-benzoxazin-3 (4H) -one (15.5g) and dioxane (150) were added, the temperature was raised to 100 ℃ and the reaction was stirred at that temperature for 48 hours and checked by TLC for completion.

The reaction mixture was distilled under reduced pressure to give a yellow oil, and ethanol (150ml) and concentrated hydrochloric acid (7.9g) were added thereto, and the mixture was stirred at room temperature for 6 hours, filtered, washed with ethanol, and dried at 60 ℃ for 8 hours to give intermediate IV (14.74g) as a white solid with a yield of 55.2%.

HPLC purity 94.5% (area normalization), impurity profile content: formula VI: 1.2%, formula VII: 3.7 percent, other single impurity less than 2.0 percent and S isomer content of 1.2 percent. The HPLC impurities and chiral analysis were the same as in example 4.

Preparation of 6-hydroxy-8- [ (1R) -1-hydroxy-2- [ [2- (4-methoxyphenyl) -1, 1-dimethylethyl ] amino ] ethyl ] -2H-1, 4-benzoxazin-3 (4H) -one hydrochloride

To the hydrogenation vessel, intermediate IV (12.5g) and MeOH (125ml) were added at room temperature, Pd/C (0.63g, 10%) was added, nitrogen was replaced, and then the mixture was hydrogenated to 0.3 MPa. The reaction was stirred at 40 ℃ for 4 hours. The reaction was complete by TLC.

The catalyst was removed by filtration at room temperature, washed with methanol, and the filtrate was concentrated under reduced pressure, followed by addition of isopropanol (30g), heating to reflux and clearing, and stirring at room temperature for 6 hours. Filtering, washing a filter cake with isopropanol to obtain a wet product of the oldacterol hydrochloride, and drying the wet product of the oldacterol hydrochloride for 8 hours in vacuum at 50 ℃ to obtain 8.72g of a white solid product of the oldacterol hydrochloride, wherein the yield is 84.8 percent.

The HPLC purity was 98.1% (area normalization), the content of single impurities was less than 0.70%, and the content of S isomers was 0.80%. The HPLC impurities and chiral analysis were the same as in example 7.

TABLE 1 comparison of inventive and reported routes for Mass Spectrometry