Intermediate compound of tubuterol, tubuterol and preparation method of tubuterol
By using 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetic acid ester as an intermediate, the synthesis process of tobutero is simplified, solving the problems of multiple reaction steps, harsh conditions and environmental pollution in the existing technology, and realizing high-yield and environmentally friendly industrial production.
Patent Information
- Application Number
- CN202510478345.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-16
- Publication Date
- 2025-08-08
AI Technical Summary
Existing tobacteroide synthesis processes suffer from numerous reaction steps, stringent conditions, use of hazardous chemicals, and severe environmental pollution, making them unsuitable for industrial production.
Using 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetic acid ester as an intermediate, and through simplified chemical reaction steps, using widely available raw materials such as tert-butylamine, methyl formate, and phosphorus oxychloride, while avoiding expensive and harmful solvents and catalysts, tobbuterol is generated.
This method achieves high-yield synthesis of tobbuterol, simplifies the operation process, reduces costs, minimizes environmental pollution, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] The present application relates to the technical field of drug synthesis, and in particular to an intermediate compound of Tubuterol, Tubuterol and a preparation method thereof. Background Art
[0002] Tubuterol is an important pharmaceutical compound, its chemical name is 2-(butylamino)-1-(2-chlorophenyl)ethanol, and its molecular formula is C 12 H 18 ClNO, molecular weight is 227.73, chemical structure is:
[0003] The synthetic routes reported so far mainly include the following: (1) MAGlushkovaa et al. used o-chlorobenzaldehyde and potassium tert-butoxide as raw materials to synthesize tubutrol through intramolecular cyclization, alkaline ring opening and other steps. This route has many reaction steps, high process requirements, and is difficult to implement industrially, which has become one of the key problems restricting its large-scale production. (2) Synthetic route using 2-chloro-bromobenzene as raw material: This route involves multiple steps such as bromine substitution, oxidation, tert-butylamine substitution and reduction. The reaction process is complicated and requires the repeated use of dangerous reagents such as strong acids, resulting in increased costs, high operational difficulty, and easy production of by-products. The yield is low and it is difficult to meet the needs of industrial production. (3) Song Hui et al. used o-chloroacetophenone as the starting material to prepare the target product through liquid bromine substitution, reduction and tert-butylamine substitution reactions. However, this method has complex experimental operations and requires the use of dangerous chemicals such as strong acids, resulting in large amounts of waste emissions. It does not conform to the concept of green chemistry, and there are many impurities in the reaction process, which affects the purity and yield of the product. (4) Huang Lumin et al. also used o-chloroacetophenone as the starting material and obtained the target product through liquid bromine substitution, tert-butylamine substitution, and sodium borohydride reduction. Although this route is relatively short, it still has environmental pollution problems, such as high wastewater toxicity and the need to use controlled reagents such as chloroform and high-concentration hydrochloric acid, which further aggravates the environmental burden of the reaction and is not conducive to industrial promotion.
[0004] In summary, the existing synthesis process of tubuterol generally has the following technical problems: multiple reaction steps and harsh conditions lead to complex processes and difficult operations; the use of hazardous chemicals such as strong acids and controlled reagents increases safety risks and environmental pressures; many by-products and low yields affect product purity and economic efficiency; serious environmental pollution does not meet the requirements of green chemistry and sustainable development, and seriously limits the feasibility of its industrial production.
[0005] Therefore, there is an urgent need to develop a new synthesis process for tubuterol that is efficient, green, easy to operate and suitable for industrial production to meet market demand and promote the widespread application of this drug. Summary of the Invention
[0006] The present application aims to address one of the technical problems existing in the above-mentioned prior art. To this end, the present application provides an intermediate compound of tubuterol, tubuterol, and a method for preparing the same. The preparation method described herein is simple to operate, avoids the use of expensive and hazardous organic solvents and toxic catalysts, and provides a high overall yield of the target product, making it suitable for industrial production.
[0007] To achieve the above objectives, this application provides the following technical solutions:
[0008] In the first aspect, the present application provides an intermediate compound for preparing Tubuterol, whose chemical name is 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate, and whose structural formula is as shown in Formula I:
[0009] shown.
[0010] In a second aspect, the present application provides a method for preparing the intermediate compound shown in Formula I, comprising the following steps:
[0011] Step 1: Using tert-butylamine and methyl formate as raw materials, react to generate N-tert-butylformamide (structural formula: );
[0012] Step 2: N-tert-butylformamide reacts with phosphorus oxychloride (POCl3) and triethylamine to obtain tert-butyl isocyanide (structural formula: );
[0013] Step 3: o-chlorobenzaldehyde (structural formula ), tert-butyl isocyanide and acetic acid react to form an intermediate compound shown in formula I.
[0014] In a third aspect, the present application provides a method for preparing Tubuterol, the steps of which include:
[0015] The intermediate compound represented by the above formula I is used as a raw material, and lithium hydroxide solution is added to react to generate N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, whose structural formula is shown in formula II:
[0016] As shown;
[0017] It is composed of N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (structural formula is ) reacts to generate Tubuterol (structural formula: ).
[0018] In a fourth aspect, the present application provides a tubuterol prepared by the aforementioned preparation method of tubuterol.
[0019] Compared with the prior art, this application has at least the following beneficial effects:
[0020] The synthetic process of Tubuterol disclosed in the present application comprises raw materials such as ethyl formate, tert-butylamine, triethylamine, phosphorus oxychloride, o-chlorobenzaldehyde, lithium hydroxide, trifluoromethanesulfonic anhydride, and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate, which are widely available and easy to prepare, thus being conducive to industrial production. In addition, tert-butyl isonitrile is used to participate in a multi-component chemical reaction, resulting in a high yield and being environmentally friendly. Trifluoromethanesulfonic anhydride and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate are used in the reduction of amides, resulting in simple process steps, avoiding the use of expensive and harmful organic solvents and toxic catalysts, saving costs, and avoiding product loss during post-processing. The total yield of the target product is high, thus being suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0021] Figure 1 The synthetic route of 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate provided in the examples of the present application.
[0022] Figure 2 The synthetic route of Tubuterol provided in the examples of this application.
[0023] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate prepared in the examples of the present application.
[0024] Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide prepared in the examples of the present application.
[0025] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of tubuterol prepared in the examples of the present application. DETAILED DESCRIPTION
[0026] In order to make the purpose, technical solutions and advantages of this application more clear, the following further describes this application in detail with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain this application and are not intended to limit this application.
[0027] Those skilled in the art will understand that, unless otherwise stated, the terms "said," "the," "the aforementioned," and "above" used in this application may include plural forms. It should be further understood that the term "comprising" used in the specification of this application refers to the presence of the stated features, steps, or operations, but does not exclude the presence or addition of one or more other features, steps, or operations.
[0028] The "room temperature" in this application text may fluctuate in different seasons and is usually between 15 and 30°C.
[0029] Those skilled in the art will understand that if no specific experimental steps or conditions are specified in the examples, the experiments can be carried out according to the conventional experimental steps or conditions described in the literature in the field; if the raw materials or instruments and equipment used do not specify the manufacturer, they are all conventional products that can be purchased commercially.
[0030] Those skilled in the art will understand that, unless otherwise specified herein, when numerical ranges are given in the examples, both endpoints of each numerical range and any value between the two endpoints may be used. Unless otherwise defined, all technical and scientific terms used in this application are consistent with the prior art as understood by those skilled in the art and the description of this application. Any prior art methods, equipment, and materials similar or equivalent to those described in the examples of this application may also be used to implement this application.
[0031] In response to the problems of multiple reaction steps, harsh conditions, and serious pollution in the process of synthesizing Tubuterol in the prior art, this application proposes a method for reacting Tubuterol using N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester as raw materials. N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide is produced by reacting a new compound 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate with a lithium hydroxide solution. To this end, this application discloses a method for synthesizing 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate, thereby developing a new process for synthesizing Tubuterol using 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate as an intermediate compound.
[0032] Based on this, the present invention provides an intermediate compound for preparing Tubuterol, whose chemical name is 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate, and its structural formula is as shown in Formula I:
[0033] The intermediate compound shown in formula I is a brand-new compound, and the intermediate compound is a key compound in realizing the new synthesis route of Tubuterol in the present application.
[0034] Based on this, the present invention provides a method for preparing the intermediate compound shown in Formula I, which is carried out in the following steps: (1) using tert-butylamine and methyl formate as raw materials, heating under reflux, and reacting to generate N-tert-butylformamide (structural formula: ); (2) tert-butyl isocyanide (structural formula: ); (3) o-chlorobenzaldehyde (structural formula is ), tert-butyl isocyanide, and acetic acid react to form an intermediate compound as shown in Formula I. The specific synthetic route is as follows: Figure 1 shown.
[0035] In certain embodiments, in step (1), the molar ratio of tert-butylamine to ethyl formate is 1 to 1.5:1; and the heating and reflux conditions are: a temperature of 60 to 80° C., and a reflux time of 6 to 8 hours. In certain preferred embodiments, the molar ratio of tert-butylamine to ethyl formate is 1.5:1, and the heating and reflux conditions are: a temperature of 80° C., and a reflux time of 6 hours.
[0036] In certain embodiments, in step (2), the molar ratio of N-tert-butylformamide, phosphorus oxychloride, and triethylamine is 1:1-1.4:1.5-4.0, and the reaction time is 1-6 hours. In certain preferred embodiments, the molar ratio of N-tert-butylformamide, phosphorus oxychloride, and triethylamine is 1:1.4:3.5.
[0037] In certain embodiments, in step (3), the molar ratio of o-chlorobenzaldehyde, acetic acid, and tert-butyl isocyanide is 1:1-4:1-4, the reaction time is 2-8 hours, and the reaction temperature is 10-15° C. In certain preferred embodiments, the molar ratio of o-chlorobenzaldehyde, acetic acid, and tert-butyl isocyanide is 1:2:2.
[0038] Based on this, the present application provides a method for preparing tubuterol, which comprises the following steps: (1) using the intermediate compound represented by the aforementioned formula I as a raw material, adding a lithium hydroxide solution, and reacting to generate N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, the structural formula of which is shown in formula II: As shown; (2) N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (structural formula is ) reacts to generate Tubuterol (structural formula: ), its synthetic route is as follows Figure 2 shown.
[0039] In certain embodiments, in step (1), the mass concentration of the lithium hydroxide solution is 30%.
[0040] In certain embodiments, in step (1), the formula I: The molar ratio of the intermediate compound to the lithium hydroxide contained in the lithium hydroxide solution is 1:1-3, the reaction time is 6-12 hours, and the reaction temperature is 80-120° C. In certain preferred embodiments, the formula I: The molar ratio of the intermediate compound to the lithium hydroxide contained in the lithium hydroxide solution is 1:3, the reaction time is 9 hours, and the reaction temperature is 70°C.
[0041] In certain embodiments, in step (2), the molar ratio of N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 3:1-2:1-1.5, the reaction time is 1-6 hours, and the reaction temperature is 10-15° C. In certain preferred embodiments, the molar ratio of N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, and diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate is 3:2:1.5, and the reaction time is 1 hour.
[0042] In certain embodiments, the preparation method further comprises extraction, washing, drying, and purification steps.
[0043] In some preferred embodiments, the specific steps are as follows:
[0044] The mixture after the reaction in step (2) was transferred to a separatory funnel, diluted with ether, and extracted with a 5% by mass aqueous solution of sodium bisulfite, and the organic layer was further extracted with additional water;
[0045] The aqueous phases were combined and washed with ethyl acetate, and the organic layer was extracted with water;
[0046] To the combined aqueous phases was added an aqueous sodium hydroxide solution, the resulting solution was extracted with diethyl ether, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate;
[0047] The reaction solution was cooled to room temperature, filtered, and concentrated using a rotary evaporator to obtain a white crude product, which was then purified by column chromatography using petroleum ether (PE): ethyl acetate (EA): triethylamine = 10:1:0.1 (volume ratio) as eluent to obtain the Tubuterol compound.
[0048] Based on this, the embodiments of the present application provide a tubuterol, which is prepared from the intermediate compound of the aforementioned tubuterol or the intermediate compound prepared by the aforementioned method for preparing the intermediate compound or prepared by the aforementioned method for preparing tubuterol.
[0049] The technical solution of this application and the technical effects achieved are described in detail below through more specific embodiments.
[0050] Example 1
[0051] This embodiment provides an intermediate compound of Tubuterol (structural formula: ), the specific steps are:
[0052] (1) To a 250 mL two-necked flask equipped with a thermometer and a spherical condenser, 1.5 mol of tert-butylamine and 1 mol of ethyl formate were added; a magnetic stirrer was added, the magnetic stirrer was turned on, and the mixture was stirred and refluxed at 80° C. for 6 h. During the reaction, nitrogen was added to protect the reaction. Petroleum ether and ethyl acetate were used in a ratio of 5:1 as the developing solvent. A 15% potassium permanganate solution was used for color development to monitor whether the reaction was complete. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and evaporated on a rotary evaporator for 30 min. The mixture was then distilled under reduced pressure to obtain an oily compound, namely N-tert-butylformamide. The calculated yield was 63.7% and the vapor phase purity was 99%.
[0053] (2) 0.1 mol of N-tert-butylformamide was added to a 1000 mL flask. 200 mL of dichloromethane and 0.35 mol of triethylamine were added under ice-water bath conditions. The mixture was stirred with a magnetic stirrer, and then 0.14 mol of phosphorus oxychloride was slowly added dropwise. The reaction was allowed to proceed for 1 h. Petroleum ether (PE) and ethyl acetate (EA) = 10:1 (volume ratio) were used as the developing solvent. The degree of reaction was detected by color development with potassium permanganate solution. After the reaction was completed, a saturated aqueous sodium carbonate solution was added to terminate the reaction. After stirring at 0°C for 1 hour, the organic layer was separated, and the aqueous phase was extracted three times with 30 mL of DCM and dried over anhydrous sodium sulfate. The reaction solution was cooled to room temperature, filtered, and rotary evaporated on a rotary evaporator for 30 min. The product was then distilled under reduced pressure to obtain a colorless liquid with a foul odor, i.e., tert-butyl isocyanide. The yield was calculated to be 98.6% and the gas phase purity was 99%.
[0054] (3) Add 0.005 mol of o-chlorobenzaldehyde to a 100 mL three-necked flask, control the temperature below 30°C, first add 0.005 mol of acetic acid, and stir at 25°C for 30 min; then slowly add 0.01 mol of tert-butyl isocyanide dropwise, controlling the addition time between 20 and 30 min. After the addition is complete, slowly add 10 mL of water to precipitate a white precipitate. If no white precipitate is precipitated, continue to slowly add 20 mL of ethyl acetate, then transfer the entire mixed solution to a separatory funnel, wash the aqueous layer with ethyl acetate several times, collect the organic phase, and dry it over anhydrous sodium sulfate. Cool the reaction solution to 10-15°C, filter, and dry the solvent on a rotary evaporator. Dry it in a vacuum drying oven to obtain a white foamy solid with a calculated yield of 93.1% and an HPLC purity of 98.5%.
[0055] The white precipitate or white foamy solid obtained above was detected by nuclear magnetic resonance hydrogen spectrum (1H NMR). Figure 3As shown, the characterization results are 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.54-7.47 (m, 1H), 7.42-7.34 (m, 3H), 6.11 (s, 1H), 2.09 (s, 3H), 1.27 (s, 9H). The structural formula of the compound is shown in Formula I: As shown in (I), the compound is named 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate.
[0056] Example 2
[0057] In this example, N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide was prepared from 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate prepared in Example 1. The specific steps are as follows:
[0058] 0.5 mmol of 2-(tert-butylamino)-1-(2-chlorophenyl)-2-oxoacetate (prepared in Example 1) was added to a 100 mL round-bottom flask, and a 30% saturated aqueous lithium hydroxide solution (lithium hydroxide content was 1.5 mmol) was added. Then 10 mL of water was added, and the mixture was condensed and refluxed at 80° C. for 12 h. The mixture was filtered while hot, and the filtrate was dried over anhydrous sodium sulfate. The reaction solution was cooled to room temperature, filtered, and evaporated on a rotary evaporator for 45 min. Then, the mixture was dried in a vacuum drying oven at 40° C. to obtain 0.107 g of a white paste compound with an average HR of 89.1% and an HPLC purity of 99.7%.
[0059] The white paste compound product obtained above was detected by nuclear magnetic resonance hydrogen spectrum. Figure 4 As shown, the characterization results are 1HNMR (400MHz, DMSO-d6) δ7.92 (s, 1H), 7.54-7.47 (m, 1H), 7.42-7.34 (m, 3H), 6.11 (s, 1H), 2.09 (s, 3H), 1.27 (s, 9H). The structural formula of the compound is shown in Formula II: (II) is shown and named as N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide.
[0060] Example 3
[0061] In this example, N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide prepared in Example 2 was used as a raw material to prepare Tubuterol. In addition, the main synthetic raw materials included trifluoromethanesulfonic anhydride, 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester (structural formula: ), the specific preparation method is:
[0062] 0.6 mmol of N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide was added to a 50 mL round-bottom flask and placed under a nitrogen atmosphere; 10 mL of dichloromethane (solvent) was added to the round-bottom flask, followed by 0.4 mmol of trifluoromethanesulfonic anhydride, and the resulting colorless transparent solution was stirred at room temperature for 5 min; 0.3 mmol of diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylate was added to the above solution at once, and the mixed solution was stirred at 10-15°C for 1 h to react; during this period, the mixed solution changed from a bright yellow suspension to a clear orange-yellow solution; the reacted mixed solution was transferred to a separatory funnel, diluted with 50 mL of ether, and extracted with 100 mL of a 5% sodium bisulfite aqueous solution, and the organic layer was extracted with an additional 25 mL of water; the aqueous phases were combined and washed with 50 mL of ethyl acetate, and the organic layer was extracted with 25 mL of water; the combined aqueous phases were added to the flask. 20 mL of 2.5 mol / L sodium hydroxide solution was added, and the resulting solution was extracted with 100 mL of ether. The organic layer was washed with 100 mL of brine and dried over anhydrous magnesium sulfate. The reaction solution obtained above was cooled to room temperature, filtered, and evaporated on a rotary evaporator for 50 min. The liquid was concentrated to obtain a white crude product. The product was purified by column chromatography using petroleum ether (PE): ethyl acetate (EA): triethylamine = 10:1:0.1 (volume ratio) as eluent to obtain white crystals. The calculated average yield was 15.2%, and the HPLC purity was 99.3%.
[0063] The white crystalline product obtained above was detected by nuclear magnetic resonance hydrogen spectrum. Figure 5 As shown, the characterization results are 1H NMR (400MHz, DMSO-d6) δ7.58 (dd, J = 7.7, 1.8Hz, 1H), 7.40-7.30 (m, 2H), 7.26 (td, J = 7.6, 1.8Hz, 1H), 4.87 (dd, J = 8.7, 3.1Hz, 1H), 2..69 (dd, J = 11.5, 3.2Hz, 1H), 2.48-2.42 (m, 1H), 1.02 (s, 9H). The compound is tubuterol, and its chemical structure is
[0064] The present application provides a novel method for synthesizing Tubuterol by preparing a novel intermediate compound for synthesizing Tubuterol (the compound shown in Formula I). Based on the intermediate compound, the present application provides a novel method for synthesizing Tubuterol. The raw materials used in the method are widely available and low in cost. The method avoids the use of harmful organic solvents and toxic catalysts in the traditional process for synthesizing Tubuterol. The method has a high total yield of the target product and is suitable for industrial production.
[0065] The present application has been described in detail above. Specific examples have been used herein to illustrate the principles and implementation methods of the present application. The description of the above embodiments is intended only to facilitate understanding of the present application and its core concepts. It should be noted that, without departing from the principles of the present application, a number of improvements and modifications may be made to the present application by a person skilled in the art, and such improvements and modifications shall fall within the scope of protection of the claims of the present application.
Claims
1. An intermediate compound for preparing Tubuterol, characterized in that: Its structural formula is as follows: shown.
2. The method for preparing the intermediate compound according to claim 1, characterized in that: The following steps are involved: (1) Using tert-butylamine and methyl formate as raw materials, heating under reflux, the reaction generates N-tert-butylformamide, the structural formula of which is (2) Tert-butyl isocyanide is obtained by reacting N-tert-butylformamide with phosphorus oxychloride and triethylamine, and its structural formula is (3) o-chlorobenzaldehyde, tert-butyl isocyanide and acetic acid react to form the following formula: The intermediate compound shown.
3. The preparation method according to claim 2, characterized in that In step (1), the molar ratio of tert-butylamine to ethyl formate is 1 to 1.5:1; the heating and reflux conditions are: temperature 60 to 80° C., and reflux time 6 to 8 hours; preferably, the molar ratio of tert-butylamine to ethyl formate is 1.5:1, and the heating and reflux conditions are: temperature 80° C., and reflux time 6 hours.
4. The preparation method according to claim 2, characterized in that In step (2), the molar ratio of N-tert-butylformamide, phosphorus oxychloride, and triethylamine is 1:1-1.4:1.5-4.0, and the reaction time is 1-6 hours; preferably, the molar ratio of N-tert-butylformamide, phosphorus oxychloride, and triethylamine is 1:1.4:3.
5.
5. The preparation method according to claim 2, characterized in that In step (3), the molar ratio of o-chlorobenzaldehyde, acetic acid and tert-butyl isocyanide is 1:1-4:1-4, the reaction time is 2-8 hours, and the reaction temperature is 10-15°C; preferably, the molar ratio of o-chlorobenzaldehyde, acetic acid and tert-butyl isocyanide is 1:2:
2.
6. A method for preparing Tubuterol, characterized in that: The following steps are involved: (1) The intermediate compound of claim 1 is used as a raw material, lithium hydroxide solution is added, and the reaction generates N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, the structural formula of which is shown in Formula II: As shown; (2) Tubuterol is prepared by reacting N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester.
7. The preparation method according to claim 6, characterized in that In step (1), the mass concentration of the lithium hydroxide solution is 30%.
8. The preparation method according to claim 6, characterized in that In step (1), the molar ratio of the intermediate compound to the lithium hydroxide contained in the lithium hydroxide solution is 1:1-3, the reaction time is 6-12 hours, and the reaction temperature is 60-120°C; preferably, the molar ratio of the intermediate compound to the lithium hydroxide contained in the lithium hydroxide solution is 1:3, the reaction time is 9 hours, and the reaction temperature is 70°C.
9. The preparation method according to claim 6, characterized in that In step (2), the molar ratio of N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester is 3:1-2:1-1.5, the reaction time is 1-6 hours, and the reaction temperature is 10-15°C; preferably, the molar ratio of N-(tert-butyl)-2-(2-chlorophenyl)-2-hydroxyacetamide, trifluoromethanesulfonic anhydride, and 2,6-dimethyl-1,4-dihydro-3,5-pyridinedicarboxylic acid diethyl ester is 3:2:1.5, and the reaction time is 1 hour.
10. A tubuterol, characterized in that: It is prepared from the intermediate compound of Tulbuterol according to claim 1, or prepared from the intermediate compound prepared by the preparation method according to any one of claims 2 to 5, or prepared by the preparation method according to any one of claims 6 to 9.