Preparation method for efficiently preparing arformoterol tartrate intermediate and application

Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method for efficiently preparing an arformoterol tartrate intermediate and application. The invention provides the preparation method for efficiently preparing the arformoterol tartrate intermediate, the method synthesizes the efficiently prepared arformoterol tartrate intermediate from the raw materials different from the prior art through a new angle, and the whole preparation process is simple in purification means, cheap in reagent, low in cost and high in yield. The yield of the key intermediate (R)-N-(2-benzyloxy-5-epoxy ethyl) formamide is far higher than that of the prior art. The invention provides the application of the arformoterol tartrate intermediate, and the application process is simple to operate and few in repeated test interference factors.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and in particular to a method and application for efficiently preparing an arformoterol tartrate intermediate. Background Art

[0002] Arformoterol tartrate, also known as (R,R)-formoterol tartrate, has a chemical name of N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]carboxamide L-tartrate. It is a long-acting β2-adrenergic receptor agonist developed by Sepracor, USA. It is a commonly used drug for the treatment of severe chronic bronchial asthma. It has high pharmacological activity, rapid onset, long duration of action, and significant anti-inflammatory effect. It is used to treat chronic bronchial asthma and is used in combination with glucocorticoids for the treatment of severe asthma.

[0003] Arformoterol tartrate has two chiral centers. According to pharmacological studies, the pharmacological activity of the double R configuration of arformoterol is 1000 times that of the double S configuration, and the efficacy is twice that of the racemic arformoterol, and there is no side effect of the double S configuration that enhances the bronchoconstriction reaction caused by acetylcholine. There are many papers reporting its synthesis methods, which are mainly divided into two categories: racemate splitting method and asymmetric synthesis method. Although the racemate splitting method is simple to operate and has low cost, the overall loss is large. Although the latter improves the utilization rate of raw materials, the yield of some key intermediates, such as (R)-N-(2-benzyloxy-5-epoxyethyl)formamide, is still low, which increases the production cost, and the overall route synthesis process is relatively complicated. Summary of the invention

[0004] In order to overcome the deficiencies of the prior art, one of the objects of the present invention is to provide a method for efficiently preparing an arformoterol tartrate intermediate, which can improve the yield of key intermediates while simplifying the synthesis process.

[0005] The second purpose of the present invention is to use an arformoterol tartrate intermediate.

[0006] One of the purposes of the present invention is achieved by the following technical solution: A method for efficiently preparing an arformoterol tartrate intermediate comprises the following steps: (1) Synthesis of compound 2: adding halogenated hydroxyacetophenone, base, benzyl halide and catalyst to a solvent, reacting under heating conditions, and treating after the reaction to obtain compound 2; (2) Synthesis of compound 3: Compound 2 prepared in step (1) and a brominating agent are added to a solvent, stirred and mixed for reaction, and after the reaction is completed, the compound 3 is obtained by treatment; (3) Synthesis of compound 4: Add a reducing agent to a solvent, mix well, then add a solution containing the compound 3, react under temperature control conditions, and after the reaction is completed, treat to obtain compound 4; (4) Synthesis of compound 5: adding compound 4 and a base to a solvent, performing a cyclization reaction to obtain a reaction solution containing compound 5, and performing treatment after the reaction to obtain compound 5; (5) Synthesis of compound 6: using formamide as solvent, sequentially adding compound 5 and a formamide-promoting agent, reacting under heating conditions, and treating after the reaction to obtain compound 6; (6) Synthesis of compound 8: Compound 6 prepared in step (5) is reacted with compound 7 to obtain compound 8; .

[0007] Furthermore, in step (1), the solvent is one of acetonitrile and acetone, the base is potassium carbonate, the benzyl halide is benzyl bromide, the halogenated hydroxyacetophenone is 3-bromo-4-hydroxyacetophenone, the molar ratio of the halogenated hydroxyacetophenone, the benzyl halide and the base is 1:(1.1-1.5):(1.1-1.5), the amount ratio of the solvent to 3-bromo-4-hydroxyacetophenone is 5-8 mL:1 g, the reaction time is 2-3 h, and the reaction temperature is 60-70 ° C.

[0008] Furthermore, in step (2), the solvent is at least one of methanol, dichloromethane, and acetonitrile, the brominating agent is at least one of phenyltrimethylammonium tribromide, trimethylsilyl chloride, and N-bromosuccinimide, the molar ratio of the compound 2 to the brominating agent is 1:1-1:3, the amount ratio of the solvent to the compound 2 is 5-8mL:1g, the reaction time is 4-5h, and the reaction temperature is 25-30°C.

[0009] Furthermore, in step (3), the solvent is one of tetrahydrofuran and 1,4-dioxane, the reducing agent is borane dimethyl sulfide complex and (R)-2-methyl-CBS-oxazaborolidine, the molar ratio of the borane dimethyl sulfide complex, (R)-2-methyl-CBS-oxazaborolidine and compound 3 is 1:0.1:1, the amount ratio of the solvent to the compound 3 is 3-5.5mL:1g, the reaction time is 2-18h, and the reaction temperature is 25°C.

[0010] Furthermore, in step (4), the solvent is at least two of tetrahydrofuran, methanol and water, the base is one of potassium carbonate and sodium hydroxide, the molar ratio of the compound 4 to the base is 1:1.06-1:3, the amount ratio of the solvent to the compound 4 is 2.82-5.3mL:1g, the reaction time is 1-2h, and the reaction temperature is 25-45°C.

[0011] Furthermore, in step (5), the promoting formamidation reagent is potassium carbonate and copper sulfate pentahydrate, the molar ratio of the compound 5, potassium carbonate and copper sulfate pentahydrate is 1:(2-2.5):(1-1.2), the amount ratio of the solvent to the compound 5 is 8-16mL:1g, the reaction time is 3-7h, and the reaction temperature is 160-175°C.

[0012] Furthermore, the compound 7 in step (6) is prepared by post-treatment of the salt of compound 7A and compound 7B; .

[0013] Furthermore, in step (6), the molar ratio of compound 7 to compound 6 is 1:1, and the coupling reaction is carried out at 120° C. for 9 h.

[0014] The second object of the present invention is achieved by adopting the following technical solution: An application of an arformoterol tartrate intermediate, wherein the intermediate prepared by the method is used to prepare arformoterol tartrate.

[0015] Furthermore, the application of the arformoterol tartrate intermediate comprises the following steps: S1: Synthesis of arformoterol: adding the compound 8, a palladium catalyst, ammonium formate, formic acid and sodium dihydrogen phosphate into a solvent, and obtaining arformoterol after debenzylation; S2: Synthesis of arformoterol tartrate: the arformoterol in S1 is reacted with tartaric acid to obtain arformoterol tartrate; .

[0016] Furthermore, the solvent in step S1 is one of tetrahydrofuran and 1,4-dioxane, the palladium catalyst is one of palladium hydroxide and palladium chloride, the molar ratio of compound 8, palladium catalyst, ammonium formate, formic acid and sodium dihydrogen phosphate is 1: (0.2-0.5): (3.5-4.9): (1.8-3.0): (1.8-3.0), the amount ratio of the solvent to the compound 8 is 5-8mL: 1g, the reaction time is 12-18h, and the reaction temperature is 25-40°C.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The invention provides a method for efficiently preparing an arformoterol tartrate intermediate. The method synthesizes an efficient arformoterol tartrate intermediate from a new perspective by using raw materials different from those in the prior art, and the purification means of the entire preparation process is simple, the reagents are cheap, and the yield of the key intermediate (R)-N-(2-benzyloxy-5-epoxyethyl)formamide is much higher than that of the prior art.

[0018] The invention provides an application of an arformoterol tartrate intermediate. The application process is simple to operate and has few interference factors in repeated experiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The invention provides a synthetic route for efficiently preparing the intermediate of arformoterol tartrate; Figure 2 The synthetic route for preparing compound 7 of the present invention; Figure 3 The invention discloses a synthetic route for preparing arformoterol tartrate from an arformoterol tartrate intermediate. DETAILED DESCRIPTION

[0020] Below, in conjunction with the accompanying drawings and specific embodiments, the present invention is further described. It should be noted that, under the premise of no conflict, the embodiments described below or the technical features can be arbitrarily combined to form new embodiments. The specific conditions not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, unless otherwise specified, are conventional products obtained through commercial channels.

[0021] Example 1 A method for efficiently preparing an intermediate of arformoterol tartrate, the specific route is as follows Figure 1 , Figure 2 As shown, the following steps are included: (1) Preparation of compound 2 3-Bromo-4-hydroxyacetophenone (20 g), benzyl bromide (17.50 g), and potassium carbonate (14.14 g) were added to acetonitrile (100 mL) in a reaction flask in sequence. The reaction solution was stirred evenly and then heated to 70°C. The reaction was continued for 2 h. After the reaction of the raw material 3-bromo-4-hydroxyacetophenone was completed, the reaction solution was post-treated as follows: the reaction solution was cooled to room temperature and concentrated, diluted with water (80 mL) to obtain an aqueous phase, and the aqueous phase was extracted with ethyl acetate (50 mL × 3 times) to obtain an organic phase. The organic phase was washed with saturated sodium bicarbonate aqueous solution (70 mL) and saturated brine (100 mL) in sequence, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound 2 (28.15 g, Y: 99.18%). 1H NMR (400 MHz, CDCl3) δ: 8.19 (d, 1H), 7.87 (dd,1H), 7.48–7.34 (m,5H), 6.96 (d, 1H), 5.24 (s, 2H), 2.55 (s, 3H); C 15 H 13 BrO2, [M+H] + m / z: 306.17, ESI-MS (m / z): 306.03.

[0022] (2) Preparation of compound 3 Compound 2 (20 g) and phenyltrimethylammonium tribromide (24.64 g) were added to dichloromethane (80 mL) and methanol (80 mL) in the reaction flask in sequence. The reaction solution was stirred evenly and then heated to 30°C. The reaction was continued for 4 h. After the TLC plate monitored the complete reaction of compound 2, the reaction solution was post-treated: the reaction solution was poured into water (80 mL), the pH was adjusted to be close to neutral, and the liquid was separated to obtain a partial organic phase and an aqueous phase. After the aqueous phase was concentrated to remove methanol, the aqueous phase was extracted with dichloromethane (30 mL × 3 times) to obtain an organic phase. After the organic phase obtained by separation and extraction was dried and concentrated with anhydrous sodium sulfate, it was slurried with ethyl acetate (50 mL) at room temperature to obtain compound 3 (22.96 g, Y: 91.22%). 1 H NMR (400 MHz, CDCl3) δ: 8.19 (d 1H), 7.87 (dd,1H), 7.48–7.34 (m, 5H), 6.96 (d, 1H), 5.24 (s, 2H), 4.55 (s, 2H); 15 H 12 Br2O2, [M+H] + m / z: 385.07, ESI-MS (m / z): 385.13.

[0023] (3) Preparation of compound 4 1M (S)-2-methyl-CBS-oxazaborolidine (solvent: toluene, 5.21 mL) was added to a dried reaction bottle containing anhydrous tetrahydrofuran (10 mL), and then 2M borane dimethyl sulfide complex (solvent: tetrahydrofuran, 26 mL) was added dropwise to the reaction bottle at 0°C. After the addition was completed, the ice-water bath outside the reaction bottle was removed, and the mixture was stirred at 25°C for 30 minutes. The temperature in the reaction bottle was further lowered to 0°C with an ice-water bath, and then compound 3 (20 g) was dissolved in tetrahydrofuran (50 mL) and added dropwise to the reaction bottle. The temperature during the addition process was monitored not to exceed 10°C. After the addition was completed, the temperature was slowly raised to 25°C. The reaction was continued for 2 hours. After the TLC plate monitored the complete reaction of compound 3, the reaction solution was post-treated: the reaction was quenched with methanol, the concentrated reaction solution was passed through a column (eluent gradient V 正庚烷 :V 乙酸乙酯 =85:15) to obtain compound 4 (18.36 g, 91.32%); ee value 98.7%; 1 H NMR (400 MHz, CDCl3) δ: 7.48–7.32 (m, 6H), 7.23(dd,1H), 6.88 (d, 1H), 5.29(t, 1H), 5.24 (s, 2H), 3.80 (m,2H); C 15 H 14 Br2O2, [M+H] + m / z: 387.08, ESI-MS (m / z): 387.11.

[0024] (4) Preparation of compound 5 Compound 4 (15 g) and potassium carbonate (16.11 g) were added to tetrahydrofuran (40 mL) and methanol (40 mL) in a reaction flask in turn, and the mixture was reacted at 25°C. The reaction was continued for 2 h. After the reaction of compound 4 was completed, the reaction solution was post-treated by monitoring by TLC plate: the reaction solution was concentrated and diluted with acetone (35 mL), and the filtrate was obtained by filtration. The filtrate was concentrated and then passed through a column (eluent gradient V 正庚烷 :V 乙酸乙酯 =92:8) to obtain compound 5 (11.12 g, Y: 93.79%); 1 C 15 H 13 BrO2, [M+H] + m / z: 306.17, ESI-MS (m / z): 306.13.

[0025] (5) Preparation of compound 6 Compound 5 (10 g), potassium carbonate (11.32 g), and copper sulfate pentahydrate (9.85 g) were added to formamide (160 mL) in a reaction flask in sequence, stirred evenly, and the temperature was raised to 160°C; the reaction was continued for 3 h, and the reaction mixture was monitored by TLC plate after the reaction of compound 5 was complete; the reaction solution was concentrated and diluted with water (300 mL) to obtain an aqueous phase, and the aqueous phase was extracted with toluene (80 mL × 3 times) to obtain an organic phase, which was dried over anhydrous sodium sulfate and concentrated, and then dissolved in toluene (15 mL), and n-heptane (30 mL) was added dropwise at room temperature to precipitate more obvious solids, which were filtered to obtain a filter cake and dried, and then slurried with n-hexane (12 mL) to obtain compound 6 (8.23 g, Y: 93.26%); 1 H NMR (400MHz, CDCl3) δ: 8.48(d, 1H), 7.77(m, 1H), 7.33-7.40(m, 5H), 6.99-7.09(m, 2H), 5.24(s, 2H), 3.85(m, 1H), 3.15(m, 1H), 2.75 (m, 1H); C 16 H 15 NO3, [M+H] + m / z: 270.30, ESI-MS (m / z): 270.12.

[0026] (6) Preparation of compound 7 1-(4-methoxyphenyl)-2-benzylaminopropane (20 g) was added to ethyl acetate (250 mL) in a reaction flask. After starting the stirring instrument, (S)-2-hydroxy-2-phenylacetic acid (also known as mandelic acid, 15.2 g) was added. After stirring evenly, the temperature was raised to 70°C until the liquid became clear. After stirring for 1.5 h, the heating was stopped and the mixture was cooled to room temperature. A large amount of white solid was observed to precipitate in the system. After filtration and drying, the solid was recrystallized again with methanol to obtain compound 7C (12.5 g). Compound 7C was added to chloroform (80 mL) in a reaction flask. After dissolution, 10% potassium carbonate solution (70 mL) was added. After stirring for 1.5 h, the organic phase was separated and the aqueous phase was extracted with chloroform (20 mL × 3 times). The organic phase after separation and the organic phase after extraction were combined and dried over anhydrous sodium sulfate and concentrated to obtain compound 7 (9.6 g, Y: 48.00%); ee value 97.89%, 1H NMR (400MHz, CDCl3) δ: 7.33-7.15 (m, 5H), 7.10 (d, 2H), 6.8 (d, 2H), 3.88-3.72 (m, 2H), 3.80 (s, 3H), 2.97-2.88 (m, 1H), 2.76-2.57(m, 2H), 1.10 (d, 3H); C 17 H 21 NO, [M+H] + m / z: 256.36, ESI-MS (m / z): 256.20.

[0027] (7) Preparation of compound 8 Compound 6 (6 g) and compound 7 (5.69 g) were added to a reaction flask and heated to 120°C. The reaction was continued for 9 h. After the TLC plate detected that compound 6 had reacted completely, the reaction solution was cooled to room temperature to obtain compound 8 (11.6 g, Y: 99.23%). 1 H NMR (400MHz, DMSO-d6) δ: 9.52(s, 1H), 8.32(s, 1H), 8.15(s, 1H), 7.50-7.37(m, 5H), 7.32-7.20(m, 3H), 7.11-6.99(m, 3H), 6.95-6.88(m, 3H), 6.77-6.74(m, 2H), 5.17(s, 2H), 4.60-4.58(m, 1H), 3.68(s, 3H), 3.32-3.30(d, 2H), 2.81-2.72(m, 2H),2.60-2.52(m, 2H), 2.35-2.32(m, 1H), 1.08-1.05(d, 3H); C 33 H 36 N2O4, [M+H] + m / z: 525.66, ESI-MS(m / z): 525.32.

[0028] Example 2 A method for efficiently preparing an arformoterol tartrate intermediate comprises the following steps: (1) Preparation of compound 2 3-Bromo-4-hydroxyacetophenone (20 g), benzyl bromide (23.86 g) and potassium carbonate (19.28 g) were added to acetone (160 mL) in a reaction flask in sequence. The reaction solution was stirred evenly and then heated to 60° C. The reaction was continued for 3 h. After the reaction of the raw material 3-bromo-4-hydroxyacetophenone was completed as monitored by TLC plate, the reaction solution was post-treated: Compound 2 (27.12 g, Y: 95.55%) was obtained in the same manner as in Example 1. The structure of the compound 2 was consistent with that of Example 1 after NMR and LCMS detection and identification.

[0029] (2) Preparation of compound 3 Compound 2 (20 g) and trimethylsilyl chloride (7.26 g) were placed in acetonitrile (60 mL) in a reaction bottle in sequence, stirred evenly, and the temperature was controlled at 0°C. N-bromosuccinimide (11.90 g) was dissolved in acetonitrile (22 mL) to obtain an N-bromosuccinimide solution, and the N-bromosuccinimide solution was added dropwise to the reaction bottle to react at 25°C; the reaction was carried out for 5 hours, and the reaction solution was post-treated after the TLC plate monitored the complete reaction of compound 2: the reaction solution was poured into water (100 mL) to obtain an aqueous phase, the aqueous phase was extracted with dichloromethane (80 mL×3 times) to obtain an organic phase, the organic phase was washed with saturated brine (100 mL), and the organic phase was dried and concentrated over anhydrous sodium sulfate to obtain compound 2 (24.78 g, Y: 98.45%), which was detected and identified by NMR and LCMS, and its structure was consistent with that in Example 1.

[0030] (3) Preparation of compound 4 (S)-2-methyl-CBS-oxazaborolidine (1.44 g) was added to a dried reaction bottle containing anhydrous 1,4-dioxane (10 mL), and then 2M borane dimethyl sulfide complex (BH3·Me2S in THF, 26 mL) was added to the reaction solution. After stirring for 15 minutes, compound 3 (20 g) was dissolved in 1,4-dioxane (100 mL) and then added dropwise to the reaction bottle, and reacted at 25°C; the reaction was continued for 18 hours, and the reaction solution was post-treated after the TLC plate monitored the complete reaction of compound 3: Compound 4 (19.12 g, Y: 95.10%) was obtained in the same manner as in Example 2. The structure of the compound 4 was consistent with that of Example 1 after NMR, LCMS and ee value detection and identification.

[0031] (4) Preparation of compound 5 Compound 4 (15 g) was added to tetrahydrofuran (40 mL) in a reaction flask, sodium hydroxide (1.65 g) was dissolved in water (16.5 mL) to obtain a sodium hydroxide solution, the sodium hydroxide solution was added to the reaction flask, and the temperature was raised to 40°C; the reaction was carried out for 1 h, and the reaction solution was post-treated after the completion of the reaction of compound 4 monitored by TLC plate: the reaction solution was cooled to room temperature, and the rest was carried out in the same manner as in Example 1 to obtain compound 5 (11.13 g, Y: 93.87%), which was detected and identified by NMR and LCMS, and its structure was consistent with that in Example 1.

[0032] (5) Preparation of compound 6 Compound 5 (10 g), potassium carbonate (9.96 g) and copper sulfate pentahydrate (9 g) were added to formamide (80 mL) in the reaction bottle in sequence, stirred evenly and then the temperature was raised to 175°C; the reaction was continued for 5 h, and the reaction solution was post-treated after the completion of the reaction of compound 5 monitored by TLC plate: compound 6 (8.03 g, Y: 91.00%) was obtained in the same manner as in Example 1, and its structure was consistent with that in Example 1 after NMR and LCMS detection and identification.

[0033] (6) Preparation of compound 7 Ethyl acetate was replaced with isopropanol, and the other steps were carried out in the same manner as in Example 1 to obtain compound 7C; the same manner as in Example 1 was then carried out to obtain compound 7 (9 g, Y: 45%), which was identified by NMR, LCMS and ee value detection, and its structure was consistent with that in Example 1.

[0034] (7) Preparation of compound 8 The preparation process is the same as that of Example 1.

[0035] Example 3 A method for efficiently preparing an arformoterol tartrate intermediate comprises the following steps: (1) Preparation of compound 2 3-Bromo-4-hydroxyacetophenone (20 g), benzyl bromide (20.68 g) and potassium carbonate (16.71 g) were added to acetonitrile (130 mL) in a reaction bottle in sequence. The reaction solution was stirred evenly and then heated to 65° C. The reaction was continued for 2 h. After the reaction of the raw material 3-bromo-4-hydroxyacetophenone was completed, the reaction solution was post-treated by TLC plate: Compound 2 (27.83 g, Y: 98.06%) was obtained in the same manner as in Example 1. The structure of the compound 2 was consistent with that of Example 1 after NMR and LCMS detection and identification.

[0036] (2) Preparation of compound 3 Compound 2 (20 g) and trimethylsilyl chloride (10.68 g) were added to acetonitrile (90 mL) in a reaction flask in sequence, stirred evenly, and the temperature was controlled at 0°C. N-bromosuccinimide (17.5 g) was dissolved in acetonitrile (30 mL) to obtain an N-bromosuccinimide solution, and the N-bromosuccinimide solution was added dropwise to the reaction flask and reacted at 25°C; the reaction was carried out for 4 hours, and the reaction solution was post-treated after the TLC plate monitored the complete reaction of compound 2: the reaction solution was poured into water (100 mL) to obtain an aqueous phase, the aqueous phase was extracted with dichloromethane (80 mL×3 times) to obtain an organic phase, the organic phase was washed with saturated brine (100 mL), and the organic phase was dried and concentrated over anhydrous sodium sulfate to obtain compound 2 (24.52 g, Y: 97.42%), which was detected and identified by NMR and LCMS, and its structure was consistent with that in Example 1.

[0037] (3) Preparation of compound 4 (S)-2-methyl-CBS-oxazaborolidine (1.44 g) was added to a dried reaction bottle containing anhydrous 1,4-dioxane (10 mL), and then 2M borane dimethyl sulfide complex (BH3·Me2S in THF, 26 mL) was added to the reaction solution. After stirring for 15 minutes, compound 3 (20 g) was dissolved in 1,4-dioxane (80 mL) and then added dropwise to the reaction bottle, and reacted at 25°C; the reaction was carried out for 16 hours, and the reaction solution was post-treated after the TLC plate monitored the complete reaction of compound 3: Compound 4 (18.76 g, Y: 93.31%) was obtained in the same manner as in Example 2. The structure of the compound 4 was consistent with that of Example 1 after NMR, LCMS and ee value detection and identification.

[0038] (4) Preparation of compound 5 Compound 4 (15 g) was added to tetrahydrofuran (30 mL) in a reaction flask, sodium hydroxide (1.65 g) was dissolved in water (33 mL) to obtain a sodium hydroxide solution, the sodium hydroxide solution was added to the reaction flask, and the temperature was raised to 45° C. The reaction was carried out for 1 h, and the reaction solution was post-treated after the completion of the reaction of compound 4 monitored by TLC plate: the reaction solution was cooled to room temperature, and the rest was carried out in the same manner as in Example 1 to obtain compound 5 (11.16 g, Y: 94.13%), which was detected and identified by NMR and LCMS, and its structure was consistent with that in Example 1.

[0039] (5) Preparation of compound 6 Compound 5 (10 g), potassium carbonate (9.05 g) and copper sulfate pentahydrate (8.2 g) were added to formamide (100 mL) in a reaction bottle in sequence, stirred evenly and then the temperature was raised to 170°C; the reaction was carried out for 7 hours, and the reaction solution was post-treated after the completion of the reaction of compound 5 monitored by TLC plate: compound 6 (8.11 g, Y: 91.90%) was obtained in the same manner as in Example 1, and its structure was consistent with that in Example 1 after NMR and LCMS detection and identification.

[0040] (6) Preparation of compound 7 Ethyl acetate (250 mL) was replaced by ethyl acetate (200 mL), and the other procedures were carried out in the same manner as in Example 1 to obtain compound 7C; the same procedure as in Example 1 was then carried out to obtain compound 7 (9.4 g, Y: 47%), which was identified by NMR, LCMS, and ee value detection and identification, and its structure was consistent with that in Example 1.

[0041] (7) Preparation of compound 8 The preparation process is the same as that of Example 1.

[0042] Example 4 An application of an arformoterol tartrate intermediate, using compound 8 prepared in Example 1 to prepare arformoterol tartrate, the specific route is as follows Figure 3 As shown, the following steps are included: S1: Preparation of arformoterol Compound 8 (10 g), Pd(OH)2 (620 mg), ammonium formate (4.84 g), formic acid (2.19 g), and sodium dihydrogen phosphate (5.72 g) were placed in a reaction bottle containing tetrahydrofuran (80 mL) and reacted at 25°C. The reaction was continued for 18 h. After the TLC plate detected that the reaction of compound 8 was complete, the reaction solution was post-treated: the reaction solution was filtered, concentrated, and diluted with water (65 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3 times). The organic phase was dried and concentrated with anhydrous sodium sulfate to obtain arformoterol (5.8 g, Y: 88.35%); the ee value was 97.83%, 1 H NMR (400MHz, DMSO-d6) δ: 9.52(s, 1H), 8.26(s, 1H), 8.02-8.00 (d, 1H), 7.03-7.01(d, 2H), 6.86-6.79(d, 2H), 6.77-6.76 (d, 2H), 4.44-4.42(d, 1H), 3.70(s, 3H), 2.76-2.74(m, 2H), 2.62-2.60(m, 2H), 2.38(m, 1H), 1.08-1.05(d, 3H); C 19 H 24N2O4, [M+H] + m / z: 345.41, ESI-MS (m / z): 345.18.

[0043] S2: Preparation of arformoterol tartrate Arformoterol (5.8 g) and L-tartaric acid (2.53 g) were added to a reaction bottle containing isopropanol (75 ml), heated to 85°C and refluxed for 2 h, slowly cooled to room temperature, and filtered to obtain arformoterol tartrate (5.31 g, 73.97%) with an ee value of 97.63%; 1 H NMR (400MHz, DMSO-d6) δ: 9. 62 (s, 1H), 8. 32-8. 29 ( d, 1H), 8. 15-8.13 ( d, 1H), 7. 15-7. 13 (d, 2H), 6. 97- 6. 95 ( dd, 1H), 6. 89-6. 87 (d,2H),6. 85-6. 83 (d, 1H), 4. 89-4. 78 (d, 1H), 3. 99 (s, 2H), 3. 73 (s,3H), 3. 40-3. 28 (m, 1H), 3. 11- 3. 07 (dd, 1H),3. 03-3. 00 ( dd, 1H), 2.94-2. 81 (t, 1H), 2. 61- 2. 50 (dd, 1H), 1. 07-1. 05(d, 3H); C 23 H 30 N2O 10 , [M+H] + m / z: 495.50, ESI-MS(m / z): 345.41 .

[0044] Example 5 An application of an arformoterol tartrate intermediate, which uses the compound 8 prepared in Example 2 to prepare arformoterol tartrate, comprising the following steps: adding compound 8 (10 g), Pd(Cl)2 (675.94 mg), ammonium formate (3.97 g), formic acid (1.58 g), and sodium dihydrogen phosphate (4.12 g) into 1,4-dioxane (50 mL) in a reaction bottle, stirring evenly, and heating to 40°C; reacting for 12 hours, and after the TLC plate detects that the reaction of compound 8 is complete, the reaction solution is post-treated: the reaction solution is cooled to room temperature, and arformoterol (5.32 g, Y: 81.04%) is obtained in the same manner as in Example 4. The structure is consistent with that in Example 4 after NMR, LCMS, and ee value detection and identification; the rest is carried out in the same manner as in Example 4.

[0045] Example 6 An application of an arformoterol tartrate intermediate, which uses the compound 8 prepared in Example 3 to prepare arformoterol tartrate, comprising the following steps: adding compound 8 (10 g), Pd(OH)2 (1.34 g), ammonium formate (3.97 g), formic acid (2.63 g), and sodium dihydrogen phosphate (6.86 g) into tetrahydrofuran (65 mL) in a reaction bottle, stirring evenly, and heating to 35° C.; reacting for 16 hours, and after the TLC plate detects that the compound 8 is completely reacted, the reaction solution is post-treated: the reaction solution is cooled to room temperature, and arformoterol (5.42 g, Y: 82.57%) is obtained in the same manner as in Example 4. The structure is consistent with that in Example 4 after NMR, LCMS, and ee value detection and identification; the rest is carried out in the same manner as in Example 4.

[0046] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A method for efficiently preparing an arformoterol tartrate intermediate, characterized in that: The following steps are involved: (1) Synthesis of compound 2: adding halogenated hydroxyacetophenone, base, benzyl halide and catalyst to a solvent, reacting under heating conditions, and treating after the reaction to obtain compound 2; (2) Synthesis of compound 3: Compound 2 prepared in step (1) and a brominating agent are added to a solvent, stirred and mixed for reaction, and after the reaction is completed, the compound 3 is obtained by treatment; (3) Synthesis of compound 4: Add a reducing agent to a solvent, mix well, then add a solution containing the compound 3, react under temperature control conditions, and after the reaction is completed, treat to obtain compound 4; (4) Synthesis of compound 5: adding compound 4 and a base to a solvent, performing a cyclization reaction to obtain a reaction solution containing compound 5, and performing treatment after the reaction to obtain compound 5; (5) Synthesis of compound 6: using formamide as solvent, sequentially adding compound 5 and a formamide-promoting agent, reacting under heating conditions, and treating after the reaction to obtain compound 6; (6) Synthesis of compound 8: Compound 6 prepared in step (5) is reacted with compound 7 to obtain compound 8; 。 2. The method for efficiently preparing an arformoterol tartrate intermediate according to claim 1, characterized in that: In step (1), the solvent is one of acetonitrile and acetone, the base is potassium carbonate, the benzyl halide is benzyl bromide, the halogenated hydroxyacetophenone is 3-bromo-4-hydroxyacetophenone, the molar ratio of the halogenated hydroxyacetophenone, the benzyl halide and the base is 1:(1.1-1.5):(1.1-1.5), the amount ratio of the solvent to 3-bromo-4-hydroxyacetophenone is 5-8 mL:1 g, the reaction time is 2-3 h, and the reaction temperature is 60-70 ° C.

3. The method for efficiently preparing an arformoterol tartrate intermediate according to claim 1, characterized in that: In step (2), the solvent is at least one of methanol, dichloromethane, and acetonitrile, the brominating agent is at least one of phenyltrimethylammonium tribromide, trimethylsilyl chloride, and N-bromosuccinimide, the molar ratio of the compound 2 to the brominating agent is 1:1-1:3, the amount ratio of the solvent to the compound 2 is 4.1-8mL:1g, the reaction time is 4-5h, and the reaction temperature is 25-30°C.

4. The method for efficiently preparing an arformoterol tartrate intermediate according to claim 1, characterized in that: In step (3), the solvent is one of tetrahydrofuran and 1,4-dioxane, the reducing agent is borane dimethyl sulfide complex and (R)-2-methyl-CBS-oxazaborolidine, the molar ratio of the borane dimethyl sulfide complex, (R)-2-methyl-CBS-oxazaborolidine and compound 3 is 1:0.1:1, the amount ratio of the solvent to the compound 3 is 3-5.5mL:1g, the reaction time is 2-18h, and the reaction temperature is 25°C.

5. The method for efficiently preparing an arformoterol tartrate intermediate according to claim 1, characterized in that: In step (4), the solvent is at least two of tetrahydrofuran, methanol and water, the base is one of potassium carbonate and sodium hydroxide, the molar ratio of the compound 4 to the base is 1:1.06-1:3, the amount ratio of the solvent to the compound 4 is 2.82-5.3mL:1g, the reaction time is 1-2h, and the reaction temperature is 25-45°C.

6. The method for efficiently preparing an arformoterol tartrate intermediate according to claim 1, characterized in that: In step (5), the promoting formamidation reagent is potassium carbonate and copper sulfate pentahydrate, the molar ratio of the compound 5, potassium carbonate and copper sulfate pentahydrate is 1:(2-2.5):(1-1.2), the amount ratio of the solvent to the compound 5 is 8-16mL:1g, the reaction time is 3-7h, and the reaction temperature is 160-175°C.

7. The method for efficiently preparing an arformoterol tartrate intermediate according to claim 1, characterized in that: The compound 7 in step (6) is prepared by post-treatment of the salt of compound 7A and compound 7B; 。 8. An application of an arformoterol tartrate intermediate, characterized in that: Arformoterol tartrate is prepared by using the intermediate prepared by the method according to any one of claims 1 to 7.

9. The use of the arformoterol tartrate intermediate according to claim 8, characterized in that: The steps include: S1: Synthesis of arformoterol: adding the compound 8, a palladium catalyst, ammonium formate, formic acid and sodium dihydrogen phosphate into a solvent, and obtaining arformoterol after debenzylation; S2: Synthesis of arformoterol tartrate: the arformoterol in S1 is reacted with tartaric acid to obtain arformoterol tartrate; 。 10. The use of the arformoterol tartrate intermediate according to claim 9, characterized in that: The solvent in step S1 is one of tetrahydrofuran and 1,4-dioxane, the palladium catalyst is one of palladium hydroxide and palladium chloride, the molar ratio of the compound 8, palladium catalyst, ammonium formate, formic acid and sodium dihydrogen phosphate is 1: (0.2-0.5): (3.5-4.9): (1.8-3.0): (1.8-3.0), the amount ratio of the solvent to the compound 8 is 5-8mL: 1g, the reaction time is 12-18h, and the reaction temperature is 25-40°C.

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