Preparation Method and Application of Salmeterol

Abstract

The present invention provides a preparation method and application of salmeterol, relating to the technical field of chemical synthesis. Using p-methoxyacetophenone as a raw material, salmeterol is obtained through ammoniation reaction, substitution reaction, formylation reaction, etherification reaction, reduction and hydrolysis reaction in sequence. The raw materials of the present invention are cheap and easily available, and the reagents used are conventional commercially available reagents, avoiding the cumbersome or difficult-to-control reaction steps such as deprotection and reduction using palladium carbon in the prior art, and avoiding the use of toxic and harmful reagents such as bromine. The reaction conditions of the present invention are mild, the reaction process is easy to control, the operation is safe, the safety factor is high, the production cost is saved, the obtained product has a high yield and high purity, and a process route for industrial production of a product with higher quality is provided.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a preparation method and application of salmeterol. Background Art

[0002] Salmeterol xinafoate, with the chemical name 4-hydroxy-α'-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-hydroxyformate), is an ideal drug for the treatment of asthma attacks and asthma maintenance treatment at present, and has become one of the main drugs for the treatment of bronchial asthma. It has the characteristics of small dosage, high β2 selectivity, long action duration, and few adverse reactions. In recent years, the clinical demand for salmeterol xinafoate at home and abroad has become increasingly prominent.

[0003] Currently, the reported synthetic methods of salmeterol mainly include the following several:

[0004] 1. US Patent US4992474 reported the following synthetic route:

[0005]

[0006] This route uses phenylbutanol as the starting material, reacts with 1,2-dibromohexane, and then successively undergoes benzylamine reaction, substitution reaction, and palladium-carbon reduction to obtain salmeterol. This reaction requires a reduction reaction under the conditions of palladium-carbon and hydrogen, the production operation is cumbersome, and an expensive palladium-carbon catalyst is used, with a low total yield and high production cost.

[0007] 2. European Patent EP0422889 reported the following synthetic route:

[0008]

[0009] This route uses an epoxide as the starting material and obtains salmeterol through substitution and reduction. The raw materials of this method are not easily available, are unconventional commercially available reagents, need to be prepared through multiple steps, and have a high production cost, which is not conducive to large-scale production.

[0010] 3. The Journal of East China Normal University reported the following synthetic route:

[0011]

[0012] This route uses p-hydroxyacetophenone as the starting material, prepares a benzyl chloride compound through hydrochloric acid / formaldehyde, and then successively undergoes acetylation reaction, bromination reaction, ammoniation reaction, reduction, and then reacts with a bromide to obtain salmeterol. This reaction has a long reaction step, is cumbersome to operate, involves the reactions of chloromethylation and bromine, and uses palladium-carbon hydrogen reduction, with a high risk coefficient and high cost, and is not suitable for industrial production.

[0013] 4. CN101712622A reported the following synthesis method:

[0014]

[0015] This route uses p - hydroxycinnamic acid as the raw material to prepare benzyl alcohol, and then uses lipase as a catalyst for nucleophilic addition, and then reacts with an amino compound to obtain the target product. Special reagents such as lipase are used in this reaction, and column chromatography is required for separation and purification.

[0016] Among the above four routes, some have long reaction routes, cumbersome operations, and low yields; some reactions require the use of dangerous reagents with a high risk factor; some reactions require the use of palladium - carbon reduction, which has poor economic applicability and is not easy to control; some use special reagents and have poor purification processes. The above routes are not conducive to industrial production.

[0017] In view of this, the present invention is specifically proposed. Summary of the Invention

[0018] The main object of the present invention is to provide a preparation method and application of salmeterol, in order to at least partially solve at least one of the above - mentioned technical problems.

[0019] As the first aspect of the present invention, the present invention provides a preparation method of salmeterol, comprising the following steps:

[0020] (a) Compound 1 reacts with N - haloamide and an ammoniating reagent to obtain compound 2;

[0021] (b) Compound 2 reacts with 1,6 - dibromohexane to obtain compound 3;

[0022] (c) Compound 3 reacts with a formamide reagent and a chlorinating reagent to obtain compound 4;

[0023] (d) Compound 4 reacts with phenylbutanol to obtain compound 5;

[0024] (e) After compound 5 reacts with a reducing agent, through a hydrolysis reaction, salmeterol is obtained; the reaction formula is as follows:

[0025]

[0026] The preparation method of salmeterol provided by the present invention uses p-methoxyacetophenone as a raw material, and obtains salmeterol through ammoniation reaction, substitution reaction, formylation reaction, etherification reaction, reduction and hydrolysis reaction in sequence. The raw materials of the present invention are cheap and easily available, and the reagents used are conventional commercially available reagents, avoiding the cumbersome or difficult-to-control reaction steps such as deprotecting groups and using palladium-carbon reduction in the prior art, and avoiding the use of toxic and harmful reagents such as bromine. The reaction conditions of the present invention are mild, the reaction process is easy to control, the operation is safe, the safety factor is high, the production cost is saved, the product obtained has a high yield and high purity, and a process route for industrially producing higher-quality products is provided.

[0027] Further, it includes the following steps:

[0028] (a) Compound 1 reacts with N-haloamide and ammoniating reagent to obtain compound 2;

[0029] (b) Compound 2 reacts with 1,6-dibromohexane under the action of a first acid-binding agent to obtain compound 3;

[0030] (c) Compound 3, formamide reagent and chlorinating reagent react to obtain compound 4;

[0031] (d) Compound 4 reacts with phenylbutanol under the action of a phase transfer catalyst and a second acid-binding agent to obtain compound 5;

[0032] (e) After compound 5 reacts with a reducing agent, it is hydrolyzed under acidic conditions to obtain salmeterol.

[0033] Further, in step (a), the ammoniating reagent is selected from one or a combination of several of ammonia water, ammonium bicarbonate, ammonium bisulfate or ammonium carbonate.

[0034] Further, in step (a), the N-haloamide is selected from one or a combination of several of N-chlorosuccinimide, N-bromosuccinimide or dibromohydantoin.

[0035] Further, in step (a), the temperature of the reaction is -10 - 10 °C.

[0036] In the present invention, in step (a), the typical but non-limiting temperature of the reaction can be, for example, -10 °C, -8 °C, -6 °C, -4 °C, -2 °C, 0 °C, 2 °C, 4 °C, 6 °C, 8 °C or 10 °C.

[0037] Further, in step (b), the first acid-binding agent is selected from one or a combination of several of triethylamine, diisopropylethylamine or tert-butylamine.

[0038] Further, in step (b), the temperature of the reaction is 30 - 50 °C.

[0039] In the present invention, in the step (b), the typical but non-limiting temperature of the reaction can be, for example, 30 °C, 32 °C, 34 °C, 36 °C, 38 °C, 40 °C, 42 °C, 44 °C, 46 °C, 48 °C or 50 °C.

[0040] Furthermore, in the step (c), the chlorinating reagent is selected from one or a combination of several of phosphorus oxychloride, thionyl chloride, pyrophosphoryl chloride or oxalyl chloride.

[0041] Furthermore, in the step (c), the formamide reagent is selected from one or a combination of several of N,N-dimethylformamide, N,N-diethylformamide or N-methylformamide.

[0042] Furthermore, in the step (c), the temperature of the reaction is 80 - 120 °C.

[0043] In the present invention, in the step (c), the typical but non-limiting temperature of the reaction can be, for example, 80 °C, 82 °C, 84 °C, 86 °C, 88 °C, 90 °C, 92 °C, 94 °C, 96 °C, 98 °C, 100 °C, 102 °C, 104 °C, 106 °C, 108 °C, 110 °C, 112 °C, 114 °C, 116 °C, 118 °C or 120 °C.

[0044] Furthermore, in the step (d), the acid-binding agent is selected from one or a combination of several of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium methoxide or sodium hydride.

[0045] Furthermore, in the step (d), the phase transfer catalyst is selected from one or a combination of several of tetrabutylammonium bromide, tetrabutylammonium fluoride or tetrabutylammonium chloride.

[0046] Furthermore, in the step (d), the temperature of the reaction is 15 - 30 °C.

[0047] In the present invention, in the step (d), the typical but non-limiting temperature of the reaction can be, for example, 15 °C, 17 °C, 18 °C, 20 °C, 22 °C, 24 °C, 26 °C, 28 °C or 30 °C.

[0048] Furthermore, in the step (e), the reducing agent is selected from one or a combination of several of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or lithium aluminum hydride.

[0049] Furthermore, in the step (e), the hydrolysis is carried out using an inorganic acid, and the inorganic acid is selected from one or a combination of several of hydrochloric acid, sulfuric acid or hydrobromic acid.

[0050] Furthermore, in the step (e), the temperature of the reaction is 60 - 80 °C.

[0051] In the present invention, in the step (e), the typical but non-limiting temperature of the reaction can be, for example, 60 °C, 62 °C, 64 °C, 66 °C, 68 °C, 70 °C, 72 °C, 74 °C, 76 °C, 78 °C or 80 °C.

[0052] Furthermore, in the step (a), the N-haloamide is selected from dibromohydantoin; the ammoniating agent is selected from ammonia water.

[0053] Furthermore, in the step (b), the acid-binding agent is selected from triethylamine.

[0054] Furthermore, in the step (c), the formamide reagent is selected from N,N-dimethylformamide; the chlorinating agent is selected from phosphorus oxychloride;

[0055] Furthermore, in the step (d), the phase transfer catalyst is selected from tetrabutylammonium bromide; the acid-binding agent is selected from potassium hydroxide.

[0056] Furthermore, in the step (e), the reducing agent is selected from sodium borohydride; the acidic reagent is selected from hydrochloric acid.

[0057] Furthermore, in the step (a), the solvent used is selected from one or a combination of several of tetrahydrofuran, dioxane or acetonitrile.

[0058] Furthermore, in the step (b), the solvent used is selected from one or a combination of several of acetonitrile, toluene, dioxane or tetrahydrofuran.

[0059] Furthermore, in the step (d), the solvent used is selected from one or a combination of several of toluene, tetrahydrofuran or acetonitrile;

[0060] Furthermore, in the step (e), the solvent used is selected from one or a combination of several of methanol, acetonitrile or tetrahydrofuran.

[0061] As the second aspect of the present invention, the present invention also provides the use of salmeterol prepared by the above preparation method in the preparation of salmeterol xinafoate.

[0062] Furthermore, it includes the following steps:

[0063] (f) Salmeterol reacts with xinafoic acid to obtain salmeterol xinafoate, and the reaction formula is as follows:

[0064]

[0065] Compared with the prior art, the present invention has the following beneficial effects:

[0066] The preparation method of salmeterol provided by the present invention uses p-methoxyacetophenone as a raw material, and successively obtains salmeterol through ammoniation reaction, substitution reaction, formylation reaction, etherification reaction, reduction and hydrolysis reaction. The raw materials of the present invention are cheap and easily available, and the reagents used are conventional commercially available reagents, avoiding the cumbersome or difficult-to-control reaction steps such as deprotecting groups and using palladium-carbon reduction in the prior art, and avoiding the use of toxic and harmful reagents such as bromine. The reaction conditions of the present invention are mild, the reaction process is easy to control, the operation is safe, the safety factor is high, the production cost is saved, the obtained product has a high yield and high purity, and a process route for industrially producing higher-quality products is provided. Detailed Embodiments

[0067] The following will describe the implementation embodiments of the present invention in detail. However, those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the embodiments, conventional conditions are used. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0068] To help a clearer understanding of the present invention, the technical solutions of the present invention will be further described below in conjunction with embodiments.

[0069] Example 1 Preparation of Compound 2

[0070]

[0071] Example 1-1

[0072] Add 15 g of p-methoxyacetophenone to 150 mL of tetrahydrofuran, cool down to 5 °C, add 14.3 g of dibromohydantoin in portions, stir and react at 5 °C for 2 h, then add 20 mL of ammonia water, stir and react at room temperature, and monitor the reaction by TLC until it is completed. Concentrate under reduced pressure to dryness, add 100 mL of ethyl acetate to dissolve, wash twice with 50 mL of water, dry with anhydrous sodium sulfate, and evaporate under reduced pressure to dryness to obtain 15.8 g of a yellow oil, with a yield of 95.7% and an HPLC purity of 98.3%.

[0073] Example 1-2

[0074] Add 15 g of p-methoxyacetophenone to 150 mL of acetone, cool down to -5 °C, add 20 g of N-chlorosuccinimide in portions, stir and react at -5 °C for 2 h, then add 20 mL of ammonia water, stir and react at room temperature, and monitor the reaction by TLC until it is completed. Concentrate under reduced pressure to dryness, add 100 mL of ethyl acetate to dissolve, wash twice with 50 mL of water, dry with anhydrous sodium sulfate, and evaporate under reduced pressure to dryness to obtain 15.1 g of a yellow oil, with a yield of 91.5% and an HPLC purity of 98.0%.

[0075] Example 1-3

[0076] 15 g of p-methoxyacetophenone was added to 150 mL of dioxane. The temperature was lowered to -10 °C, and 43 g of dibromohydantoin was added in portions. After stirring and reacting at -10 °C for 2 h, 15 mL of ammonia water was added, and the reaction was stirred at room temperature. The reaction was monitored by TLC until completion. It was concentrated to dryness under reduced pressure, dissolved in 100 mL of ethyl acetate, washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 15.2 g of a yellow oil, with a yield of 92.1% and an HPLC purity of 97.6%.

[0077] Example 1-4

[0078] 15 g of p-methoxyacetophenone was added to 151 mL of acetonitrile. The temperature was lowered to 10 °C, and 20 g of N-chlorosuccinimide was added in portions. After stirring and reacting at 10 °C for 2 h, 15 mL of saturated ammonium bicarbonate aqueous solution was added, and the reaction was stirred at room temperature. The reaction was monitored by TLC until completion. It was concentrated to dryness under reduced pressure, dissolved in 100 mL of ethyl acetate, washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 14.9 g of a yellow oil, with a yield of 90.3% and an HPLC purity of 96.5%.

[0079] Example 1-5

[0080] 15 g of p-methoxyacetophenone was added to 150 mL of tetrahydrofuran. The temperature was lowered to 0 °C, and 26.7 g of N-bromosuccinimide was added in portions. After stirring and reacting at 0 °C for 2 h, 15 mL of saturated ammonium bisulfate aqueous solution was added, and the reaction was stirred at room temperature. The reaction was monitored by TLC until completion. It was concentrated to dryness under reduced pressure, dissolved in 100 mL of ethyl acetate, washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 15.4 g of a yellow oil, with a yield of 93.3% and an HPLC purity of 95.3%.

[0081] Preparation of Compound 3 in Example 2

[0082]

[0083] Example 2-1

[0084] 15 g of Compound 2 was added to 75 mL of acetonitrile. 18.2 g of triethylamine was added at room temperature, and 26.8 g of 1,6-dibromohexane was slowly added. The temperature was raised to 50 °C and the reaction was kept at this temperature. The reaction was monitored by TLC until completion. It was concentrated to dryness under reduced pressure, dissolved in 150 mL of dichloromethane, washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 28.0 g of a yellow oil, with a yield of 94.8% and an HPLC purity of 95.1%.

[0085] Example 2-2

[0086] 215 g of the compound was added to 75 mL of toluene. 14.2 g of triethylamine was added at room temperature, and 24.4 g of 1,6-dibromohexane was slowly added. The temperature was raised to 45 °C and the reaction was carried out with heat preservation. The reaction was monitored by TLC until completion. The mixture was concentrated to dryness under reduced pressure, dissolved in 150 mL of dichloromethane, washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 27.7 g of a yellow oil, with a yield of 93.8% and an HPLC purity of 94.9%.

[0087] Example 2-3

[0088] 215 g of the compound was added to 75 mL of tetrahydrofuran. 16.8 g of diisopropylethylamine was added at room temperature, and 34.2 g of 1,6-dibromohexane was slowly added. The temperature was raised to 40 °C and the reaction was carried out with heat preservation. The reaction was monitored by TLC until completion. The mixture was concentrated to dryness under reduced pressure, dissolved in 150 mL of dichloromethane, washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 27.3 g of a yellow oil, with a yield of 92.4% and an HPLC purity of 94.5%.

[0089] Example 2-4

[0090] 215 g of the compound was added to 75 mL of dioxane. 19.7 g of tert-butylamine was added at room temperature, and 43.9 g of 1,6-dibromohexane was slowly added. The temperature was raised to 30 °C and the reaction was carried out with heat preservation. The reaction was monitored by TLC until completion. The mixture was concentrated to dryness under reduced pressure, dissolved in 150 mL of dichloromethane, washed twice with 50 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 27.8 g of a yellow oil, with a yield of 94.1% and an HPLC purity of 93.9%.

[0091] Preparation of Compound 4 in Example 3

[0092]

[0093] Example 3-1

[0094] 320 g of the compound was added to 40 mL of dimethylformamide. 10.7 g of phosphorus oxychloride was slowly added, and the temperature was raised to 100 °C. The reaction was monitored by TLC until completion. The temperature was lowered to room temperature, diluted in ice water, extracted with 100 mL of ethyl acetate, washed twice with 40 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 16.8 g of a yellow oil, with a yield of 78.6% and an HPLC purity of 90.3%.

[0095] Example 3-2

[0096] 320 g of the compound was added to 40 mL of N,N - diethylformamide, and 13.1 g of thionyl chloride was slowly added. The temperature was raised to 80 °C, and the reaction was monitored by TLC until completion. After cooling to room temperature, it was diluted in ice water, extracted with 100 mL of ethyl acetate, washed twice with 40 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 16.9 g of a yellow oil, with a yield of 79.1% and an HPLC purity of 92.3%.

[0097] Example 3 - 3

[0098] 320 g of the compound was added to 40 mL of N - methylformamide, and 22.7 g of phosphoryl chloride was slowly added. The temperature was raised to 120 °C, and the reaction was monitored by TLC until completion. After cooling to room temperature, it was diluted in ice water, extracted with 100 mL of ethyl acetate, washed twice with 40 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 16.2 g of a yellow oil, with a yield of 75.8% and an HPLC purity of 90.6%.

[0099] Example 3 - 4

[0100] 320 g of the compound was added to 40 mL of dimethylformamide, and 22.8 g of oxalyl chloride was slowly added. The temperature was raised to 90 °C, and the reaction was monitored by TLC until completion. After cooling to room temperature, it was diluted in ice water, extracted with 100 mL of ethyl acetate, washed twice with 40 mL of water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain 16.3 g of a yellow oil, with a yield of 76.3% and an HPLC purity of 91.8%.

[0101] Preparation of Compound 5 in Example 4

[0102]

[0103] Example 4 - 1

[0104] 7.5 g of phenylbutanol was added to 75 mL of toluene, 3.4 g of potassium hydroxide and 0.32 g of tetrabutylammonium bromide were added, and a toluene solution of compound 4 (15 g of compound 4 dissolved in 30 mL of toluene) was slowly added dropwise. After the addition was complete, the reaction was carried out at 30 °C with heat preservation, and the reaction was monitored by TLC until no raw materials remained. After filtration, the filtrate was washed twice with water and concentrated to dryness under reduced pressure to obtain 14.8 g of a yellow oil, with a yield of 87.1% and an HPLC purity of 92.3%.

[0105] Example 4 - 2

[0106] 9 g of phenylbutanol was added to 75 mL of tetrahydrofuran, 2.8 g of sodium hydroxide and 0.26 g of tetrabutylammonium fluoride were added, and a tetrahydrofuran solution of Compound 4 (15 g of Compound 4 dissolved in 30 mL of tetrahydrofuran) was slowly added dropwise. After the addition was complete, the reaction was carried out at 20 °C with heat preservation, and TLC was used to monitor until there was no raw material. It was filtered, the filtrate was washed with water twice, and concentrated under reduced pressure to dryness to obtain 14.6 g of a yellow oil, with a yield of 85.9% and an HPLC purity of 91.9%.

[0107] Example 4-3

[0108] 10.5 g of phenylbutanol was added to 75 mL of acetonitrile, 13.8 g of potassium carbonate and 0.2 g of tetrabutylammonium chloride were added, and an acetonitrile solution of Compound 4 (15 g of Compound 4 dissolved in 30 mL of acetonitrile) was slowly added dropwise. After the addition was complete, the reaction was carried out at 15 °C with heat preservation, and TLC was used to monitor until there was no raw material. It was filtered, the filtrate was washed with water twice, and concentrated under reduced pressure to dryness to obtain 14.4 g of a yellow oil, with a yield of 84.7% and an HPLC purity of 90.3%.

[0109] Example 4-4

[0110] 12 g of phenylbutanol was added to 75 mL of toluene, 4.9 g of sodium methoxide and 0.28 g of tetrabutylammonium bromide were added, and a toluene solution of Compound 4 (15 g of Compound 4 dissolved in 30 mL of toluene) was slowly added dropwise. After the addition was complete, the reaction was carried out at 25 °C with heat preservation, and TLC was used to monitor until there was no raw material. It was filtered, the filtrate was washed with water twice, and concentrated under reduced pressure to dryness to obtain 14.7 g of a yellow oil, with a yield of 86.5% and an HPLC purity of 90.4%.

[0111] Example 4-5

[0112] 9 g of phenylbutanol was added to 75 mL of tetrahydrofuran, 1.7 g of sodium hydride and 0.26 g of tetrabutylammonium fluoride were added, and a 30 mL tetrahydrofuran solution of Compound 4 (15 g of Compound 4 dissolved in 30 mL of tetrahydrofuran) was slowly added dropwise. After the addition was complete, the reaction was carried out at 20 °C with heat preservation, and TLC was used to monitor until there was no raw material. It was filtered, the filtrate was washed with water twice, and concentrated under reduced pressure to dryness to obtain 13.9 g of a yellow oil, with a yield of 81.8% and an HPLC purity of 89.9%.

[0113] Example 5 Preparation of Salmeterol

[0114]

[0115] Example 5-1

[0116] 512 g of the compound was added to 150 mL of methanol. After stirring to dissolve, the temperature was lowered to 0 °C, and 2.3 g of sodium borohydride was slowly added in portions. The reaction was stirred at room temperature and monitored by TLC until the reaction was complete. It was concentrated to dryness under reduced pressure, 10 mL of water and 30 mL of 30% hydrochloric acid were added, the temperature was raised to 80 °C and stirred for 2 h, the pH value was adjusted to 7 - 8 with sodium carbonate, extracted three times with 50 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, filtered, and dried to obtain 10.1 g of salmeterol, with a yield of 81.0% and an HPLC purity of 98.9%.

[0117] Example 5-2

[0118] 512 g of the compound was added to 150 mL of methanol. After stirring to dissolve, the temperature was lowered to 5 °C, and 3.1 g of sodium cyanoborohydride was slowly added in portions. The reaction was stirred at room temperature and monitored by TLC until the reaction was complete. It was concentrated to dryness under reduced pressure, 10 mL of water and 30 mL of 30% sulfuric acid were added, the temperature was raised to 80 °C and stirred for 2 h, the pH value was adjusted to 7 - 8 with sodium carbonate, extracted three times with 50 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, filtered, and dried to obtain 10.3 g of salmeterol, with a yield of 82.6% and an HPLC purity of 98.5%.

[0119] Example 5-3

[0120] 512 g of the compound was added to 150 mL of acetonitrile. After stirring to dissolve, the temperature was lowered to 2 °C, and 10.6 g of sodium triacetoxyborohydride was slowly added in portions. The reaction was stirred at room temperature and monitored by TLC until the reaction was complete. It was concentrated to dryness under reduced pressure, 10 mL of water and 30 mL of 30% hydrobromic acid were added, the temperature was raised to 80 °C and stirred for 2 h, the pH value was adjusted to 7 - 8 with sodium carbonate, extracted three times with 50 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, filtered, and dried to obtain 10.1 g of salmeterol, with a yield of 81.0% and an HPLC purity of 97.9%.

[0121] Example 5-4

[0122] 512 g of the compound was added to 150 mL of tetrahydrofuran. After stirring to dissolve, the temperature was lowered to 4 °C, and 1.5 g of lithium aluminum hydride was slowly added in portions. The reaction was stirred at room temperature and monitored by TLC until the reaction was complete. It was concentrated to dryness under reduced pressure, 10 mL of water and 30 mL of 30% hydrochloric acid were added, the temperature was raised to 80 °C and stirred for 2 h, the pH value was adjusted to 7 - 8 with sodium carbonate, extracted three times with 50 mL of ethyl acetate, the organic phases were combined, washed with saturated brine, filtered, and dried to obtain 10.0 g of salmeterol, with a yield of 80.2% and an HPLC purity of 97.8%.

[0123] Example 6

[0124]

[0125] Add 20.8 g of salmeterol and 15 g of xinafoate into 100 mL of dichloromethane, stir overnight at room temperature, filter, and wash with ethyl acetate to obtain 29.4 g of salmeterol xinafoate, with a yield of 97.4% and an HPLC purity of 98.2%.

[0126] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing salmeterol, characterized in that, It includes the following steps: (a) Compound 1 reacts with an N-haloamide and an amination reagent to obtain Compound 2; (b) Compound 2 reacts with 1,6-dibromohexane under the action of a first acid-binding agent to obtain Compound 3; (c) Compound 3 reacts with a formamide reagent and a chlorination reagent to obtain Compound 4; (d) Compound 4 reacts with phenylbutanol under the action of a phase transfer catalyst and a second acid-binding agent to obtain Compound 5; (e) After Compound 5 reacts with a reducing agent, it is hydrolyzed under acidic conditions to obtain salmeterol; The reaction formula is as follows: The N-haloamide is selected from one or a combination of several of N-chlorosuccinimide, N-bromosuccinimide or dibromohydantoin; The amination reagent is selected from one or a combination of several of ammonia water, ammonium bicarbonate, ammonium bisulfate or ammonium carbonate; The formamide reagent is selected from one or a combination of several of N,N-dimethylformamide, N,N-diethylformamide or N-methylformamide; The chlorination reagent is selected from one or a combination of several of phosphorus oxychloride, thionyl chloride, pyrophosphoryl chloride or oxalyl chloride; The reducing agent is selected from one or a combination of several of sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or lithium aluminum hydride.

2. The method for preparing salmeterol according to claim 1, characterized in that, In step (a), the temperature of the reaction is -10 - 10°C.

3. The method for preparing salmeterol according to claim 2, characterized in that, In step (b), the first acid-binding agent is selected from one or a combination of several of triethylamine, diisopropylethylamine or tert-butylamine; and / or, the temperature of the reaction is 30 - 50°C.

4. The method for preparing salmeterol according to claim 3, characterized in that, In step (c), the temperature of the reaction is 80 - 120°C.

5. The method for preparing salmeterol according to claim 4, characterized in that, In step (d), the second acid-binding agent is selected from one or a combination of several of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium methoxide or sodium hydride; and / or, the phase transfer catalyst is selected from one or a combination of several of tetrabutylammonium bromide, tetrabutylammonium fluoride or tetrabutylammonium chloride; and / or, the temperature of the reaction is 15 - 30°C.

6. The method for preparing salmeterol according to claim 5, characterized in that, In step (e), the hydrolysis uses an inorganic acid, and the inorganic acid is selected from one or a combination of several of hydrochloric acid, sulfuric acid or hydrobromic acid; and / or, the temperature of the reaction is 60 - 80°C.

7. The method for preparing salmeterol according to any one of claims 1-6, characterized in that, In step (a), the N-haloamide is selected from dibromohydantoin; the amination reagent is selected from ammonia water; In step (b), the first acid-binding agent is selected from triethylamine; In step (c), the formamide reagent is selected from N,N-dimethylformamide; The chlorination reagent is selected from phosphorus oxychloride; In step (d), the phase transfer catalyst is selected from tetrabutylammonium bromide; the second acid-binding agent is selected from potassium hydroxide; In step (e), the reducing agent is selected from sodium borohydride; the acidic reagent is selected from hydrochloric acid.

8. The method for preparing salmeterol according to claim 7, characterized in that, In step (a), the solvent used is selected from one or a combination of several of tetrahydrofuran, dioxane or acetonitrile; In step (b), the solvent used is selected from one or a combination of several of acetonitrile, toluene, dioxane or tetrahydrofuran; In step (d), the solvent used is selected from one or a combination of several of toluene, tetrahydrofuran or acetonitrile; In step (e), the solvent used is selected from one or a combination of several of methanol, acetonitrile or tetrahydrofuran.

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