阅读说明：本技术 福莫特罗及其药用盐的制备方法及应用 (Preparation method and application of formoterol and medicinal salt thereof ) 是由 孟庆礼 于占海 王亚江 杨娣 于 2019-09-30 设计创作，主要内容包括：本发明提供了一种福莫特罗及其药用盐的制备方法及应用,涉及化学合成技术领域。福莫特罗的制备方法包括如下步骤：式I化合物在含钯催化剂、氢供体和碱试剂的作用下反应,得到式II化合物；其中,所述氢供体为甲酸和甲酸铵的组合。本发明式I化合物含有O-苄基和N-苄基,且同时含有甲酰基和甲氧基,本发明采用氢供体和碱试剂的组合,在含钯催化剂的作用下,可以缓慢持续地产生氢气,替代了常规技术中直接通入氢气的方法,可将式I化合物上的O-苄基和N-苄基的苄基脱去,而甲酰基和甲氧基不受影响,保证了产物的收率和纯度,且反应条件温和,工艺操作安全易控、简便易行,适宜规模化生产。(The invention provides a preparation method and application of formoterol and medicinal salts thereof, and relates to the technical field of chemical synthesis. The preparation method of formoterol comprises the following steps: reacting the compound of the formula I under the action of a palladium-containing catalyst, a hydrogen donor and an alkali reagent to obtain a compound of a formula II; wherein the hydrogen donor is a combination of formic acid and ammonium formate. The compound of the formula I contains O-benzyl and N-benzyl, and contains formyl and methoxy simultaneously, the invention adopts the combination of a hydrogen donor and an alkali reagent, can slowly and continuously generate hydrogen under the action of a palladium-containing catalyst, replaces a method of directly introducing hydrogen in the conventional technology, can remove the O-benzyl and the N-benzyl on the compound of the formula I, does not influence the formyl and the methoxy, ensures the yield and the purity of the product, has mild reaction conditions, safe and easily-controlled process operation, is simple and easy to operate, and is suitable for large-scale production.)

1. A preparation method of formoterol is characterized by comprising the following steps: reacting a compound of formula I under the action of a palladium-containing catalyst, a hydrogen donor and an alkali reagent to obtain a compound of formula II, wherein the reaction formula is as follows:

wherein the hydrogen donor is a combination of formic acid and ammonium formate.

2. A process for the preparation of formoterol according to claim 1, characterized in that the basic agent is selected from the group consisting of one or more of carbonates, bicarbonates, phosphates, hydrogen phosphates or dihydrogen phosphates.

3. A process for the preparation of formoterol according to claim 1, wherein the palladium-containing catalyst is selected from Pd-C, Pd (OH)₂Or PdCl₂。

4. Process for the preparation of formoterol according to claim 1, characterized in that the molar ratio of the compound of formula I, ammonium formate, formic acid and the basic agent is 1: (2-8): (0.5-3): (0.5-3).

5. Process for the preparation of formoterol according to claim 4, characterized in that the molar ratio of the compound of formula I, ammonium formate, formic acid and the basic agent is 1: (4-6): (1-2.5): (1-2.5).

6. A process for preparing formoterol according to any one of claims 1 to 5, characterized by the following steps: adding the compound of the formula I, a palladium-containing catalyst, ammonium formate, formic acid and an alkali reagent into a solvent, and reacting at 20-50 ℃ to obtain the compound of the formula II.

7. A process for the preparation of formoterol according to claim 6, characterized in that the reaction temperature is 20-30 ℃.

8. The method of claim 6, wherein the solvent is selected from the group consisting of C1-C6 alcohols, tetrahydrofuran, and 2-methyltetrahydrofuran.

9. Formoterol when prepared according to the process of any one of claims 1 to 8.

10. Use of formoterol obtained by the process according to any one of claims 1 to 8 or formoterol according to claim 9 for the preparation of a pharmaceutically acceptable salt of formoterol.

Technical Field

The invention relates to the technical field of chemical synthesis, in particular to a preparation method and application of formoterol and medicinal salts thereof.

Background

The chemical name of the pharmaceutically acceptable salt of formoterol is: n- [ 2-hydroxy-5- [ (1RS) -1-hydroxy-2- [ [ (1RS) -2- (4-methoxyphenyl) -1-methylethyl ] amino ] ethyl ] phenyl ] formamide (E) -fumarate dihydrate is a beta 2 sympathomimetic drug and has the characteristics of long acting, high selectivity, stronger anti-inflammatory effect, quick response, slight side effect and the like; having all the basic structures typical of sympathomimetic agents, the substituents on the amino nitrogen make them highly selective for the β 2 receptor. Pharmacological studies show that formoterol fumarate dihydrate plays a role in anti-inflammatory action and edema inhibition by inhibiting multiple links and inflammatory mediator release in the pathological process of asthma. The clinical application shows that formoterol can effectively control asthma (especially asthma at night) by oral administration or inhalation, and the action can last for more than 12 hours.

Currently, some documents, such as: in the preparation process of WO9205147A1, WO2008/035380A2, CN103864627A and the like, flammable and explosive hydrogen is directly used for removing O-benzyl and N-benzyl on a formoterol intermediate, so that the danger coefficient of the production process is increased, the reaction condition is harsh, and industrialization is not easy to realize.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The main object of the present invention is to provide a method for preparing formoterol and pharmaceutically acceptable salts thereof and the use thereof, in order to at least partially solve at least one of the above-mentioned technical problems.

As a first aspect of the present invention, there is provided a process for the preparation of formoterol comprising the steps of: reacting a compound of formula I under the action of a palladium-containing catalyst, a hydrogen donor and an alkali reagent to obtain a compound of formula II, wherein the reaction formula is as follows:

wherein the hydrogen donor is a combination of formic acid and ammonium formate.

The invention adopts the combination of the hydrogen donor and the alkali reagent, can slowly and continuously generate hydrogen under the action of the palladium-containing catalyst, replaces the method of directly introducing hydrogen in the conventional technology, has safe and easily controlled process operation, is simple and convenient, and is suitable for large-scale production.

The alkali reagent is used for providing a weak alkaline environment, preventing formyl groups and methoxyl groups from being removed, and reducing the content of impurities in the product.

When formic acid is used alone in the reaction, formyl or methoxy on the compound of the formula I is easy to remove, so that the impurity content of the product is too high. And the consumption of formic acid is large, and the reaction time is long.

When ammonium formate is used alone in the reaction, the compound of the formula I hardly reacts at room temperature; under reflux conditions, the formyl or methoxy groups on the compound of formula I are easily removed, resulting in a product with too high content of impurities.

The combination of formic acid and ammonium formate is used in the reaction, and when no alkaline reagent is added, the formyl group or methoxy group on the compound of the formula I is easy to remove, so that the impurity content of the product is too high.

The compound of the formula I contains O-benzyl and N-benzyl, and contains formyl and methoxy simultaneously, the invention adopts the combination of a hydrogen donor and an alkali reagent, can slowly and continuously generate hydrogen under the action of a palladium-containing catalyst, replaces a method of directly introducing hydrogen in the conventional technology, can remove the O-benzyl and the N-benzyl on the compound of the formula I, does not influence the formyl and the methoxy, ensures the yield and the purity of the product, has mild reaction conditions, safe and easily-controlled process operation, is simple and easy to operate, and is suitable for large-scale production.

Further, the alkali reagent is selected from one or a combination of more of carbonate, bicarbonate, phosphate, hydrogen phosphate or dihydrogen phosphate.

Further, the carbonate is selected from one or a combination of more of sodium carbonate, potassium carbonate or ammonium carbonate.

Further, the bicarbonate is selected from one or a combination of more of sodium bicarbonate, potassium bicarbonate or ammonium bicarbonate.

Further, the hydrogen phosphate is selected from one or a combination of several of disodium hydrogen phosphate, dipotassium hydrogen phosphate and diammonium hydrogen phosphate.

Further, the dihydrogen phosphate is selected from one or more of sodium dihydrogen phosphate, potassium dihydrogen phosphate and ammonium dihydrogen phosphate.

The alkaline agent of the present invention includes, but is not limited to, the above-mentioned agents.

Further, the palladium-containing catalyst is selected from Pd-C, Pd (OH)₂Or PdCl₂。

Further, the Pd-C is selected from 10% Pd-C and/or 5% Pd-C.

The palladium-containing catalyst of the present invention includes, but is not limited to, the above-mentioned agents.

Further, the molar ratio of the compound of formula I, ammonium formate, formic acid and base reagent is 1: (2-8): (0.5-3): (0.5-3).

Typical but non-limiting molar ratios of the compound of formula I, ammonium formate, formic acid and the basic agent, among others, may be, for example, 1: 5: 1.5: 1.5, 1: 4: 2.5: 2.5, 1: 6: 1: 1. 1: 3: 2: 2. 1: 7: 1.2: 1.2, 1: 2: 3: 3. 1: 8: 0.5: 0.5, 1: 5: 1.8: 1.8, 1: 5.5: 2.2: 2.2, 1: 4.5: 1.6: 1.6, 1: 6.5: 2.6: 2.6 or 1: 7.5: 2.8: 2.8.

further, the molar ratio of the compound of formula I, ammonium formate, formic acid and base reagent is 1: (4-6): (1-2.5): (1-2.5).

The compound of formula I, ammonium formate, formic acid and a basic reagent of the present invention are present in a molar ratio of 1: (2-8): (0.5-3): (0.5-3), preferably 1: (4-6): (1-2.5): (1-2.5), the conversion of the compound of the formula I can be made higher.

Further, the mass ratio of the compound of formula I to the palladium-containing catalyst is 1: (0.03-0.1).

Typical but non-limiting mass ratios of the compound of formula I and the palladium-containing catalyst, among others, may be, for example, 1: 0.03, 1: 0.04, 1: 0.05, 1: 0.06, 1: 0.07, 1: 0.08, 1: 0.09 or 1: 0.1.

further, the method comprises the following steps: adding the compound of the formula I, a palladium-containing catalyst, ammonium formate, formic acid and an alkali reagent into a solvent, and reacting at 20-50 ℃ to obtain the compound of the formula II.

Typical but non-limiting temperatures for the reaction may be, for example, 20 ℃, 22 ℃, 24 ℃, 26 ℃, 28 ℃, 30 ℃, 32 ℃, 34 ℃, 36 ℃, 38 ℃, 40 ℃, 42 ℃, 44 ℃, 46 ℃, 48 ℃ or 50 ℃.

Further, the reaction temperature is 20-30 ℃.

The invention can complete the reaction at 20-50 ℃, preferably 20-30 ℃, has mild reaction conditions, strong operability and high safety factor, and improves the production applicability.

Further, the solvent is selected from one or a combination of several of C1-C6 alcohols, tetrahydrofuran or 2-methyltetrahydrofuran.

Further, the solvent is selected from alcohols of C1-C6.

Further, the solvent is selected from one or a combination of several of methanol, ethanol, isopropanol or n-butanol.

Solvents in the present invention include, but are not limited to, the above-mentioned agents.

As a second aspect of the present invention, there is provided formoterol prepared by the above-mentioned process.

As a second aspect of the present invention, there is provided a formoterol obtained by the above-mentioned process or the use of formoterol as defined above for the preparation of a pharmaceutically acceptable salt of formoterol.

Further, the formoterol pharmaceutically acceptable salt is selected from formoterol and salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, nitric acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalene carboxylic acid, 4-phenylcinnamic acid, 5- (2, 4-difluorophenyl) salicylic acid or maleic acid, and hydrates of salts thereof.

Further, the formoterol pharmaceutically acceptable salt is selected from formoterol fumarate dihydrate.

Further, the preparation method of the formoterol fumarate dihydrate comprises the following steps: formoterol and fumaric acid are added into a mixture of a solvent and water to react to obtain formoterol fumarate dihydrate, and the reaction formula is as follows:

compared with the prior art, the invention has the following beneficial effects:

the compound of the formula I contains O-benzyl and N-benzyl, and contains formyl and methoxy simultaneously, the invention adopts the combination of a hydrogen donor and an alkali reagent, can slowly and continuously generate hydrogen under the action of a palladium-containing catalyst, replaces a method of directly introducing hydrogen in the conventional technology, can remove the O-benzyl and the N-benzyl on the compound of the formula I, does not influence the formyl and the methoxy, ensures the yield and the purity of the product, has mild reaction conditions, safe and easily-controlled process operation, is simple and easy to operate, and is suitable for large-scale production.

The formoterol prepared by the method is used for preparing formoterol medicinal salt, and the obtained product has high quality and can meet the medicinal level.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples were carried out under the conventional conditions, unless otherwise specified. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

EXAMPLE 1 preparation of formoterol

Examples 1 to 1

To a reaction flask was added 260mL of tetrahydrofuran, 52.5g of the compound of formula I, Pd (OH)₂3.2g ammonium formate 25.2g formic acid 11.5g and sodium dihydrogen phosphate 30.0g, stirred at 24 deg.C and monitored by TLC to no compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.6g, yield 86.0%, and HPLC purity 99.3%.

Examples 1 to 2

340mL of 2-methyltetrahydrofuran, 52.5g of the compound of formula I, PdCl were added to the reaction flask₂3.7g, 38.0g ammonium formate, 4.6g formic acid and 11.5g ammonium dihydrogen phosphate, the reaction was stirred at 30 ℃ and monitored by TLC as free of compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.6g, yield 86.0%, and HPLC purity 99.1%.

Examples 1 to 3

300mL of absolute ethanol, 52.5g of the compound of formula I, 2.6g of 10% Pd/C, 31.6g of ammonium formate, 7.0g of formic acid and 12.6g of sodium bicarbonate were added to a reaction flask, and the reaction was stirred at 25 ℃ and monitored by TLC until the compound of formula I was absent. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.7g, with yield of 86.3% and HPLC purity of 99.5%.

Examples 1 to 4

240mL of n-butanol, 52.5g of the compound of formula I, 2.1g of 10% Pd/C, 19.0g of ammonium formate, 9.2g of formic acid and 27.2g of potassium dihydrogen phosphate were added to the reaction flask, and the reaction was stirred at 22 ℃ and monitored by TLC until the compound of formula I was absent. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.2g, with yield of 85.0% and HPLC purity of 99.0%.

Examples 1 to 5

360mL of isopropanol, 52.5g of the compound of formula I, 4.2g of 5% Pd/C, 44.2g of ammonium formate, 5.5g of formic acid and 16.0g of diammonium phosphate were added to the reaction flask, the reaction was stirred at 40 ℃ and monitored by TLC until no compound of formula I was present. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.4g, yield 85.4%, and HPLC purity 99.2%.

Examples 1 to 6

To a reaction flask was added 200mL of anhydrous methanol, 52.5g of the compound of formula I, Pd (OH)₂1.6g ammonium formate 12.6g formic acid 13.8g and potassium bicarbonate 30.0g, the reaction was stirred at 20 ℃ and monitored by TLC as free of compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.1g, yield 84.6%, and HPLC purity 99.0%.

Examples 1 to 7

Into a reaction flask were added anhydrous methanol and anhydrous ethanol (volume ratio 1:1)400mL, a compound of formula I52.5 g, PdCl₂5.3g, ammonium formate 50.5g, formic acid 2.3g and ammonium bicarbonate 4.0g, the reaction was stirred at 50 ℃ and monitored by TLC as free of compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.0g, yield 84.4%, and HPLC purity 98.9%.

Examples 1 to 8

To a reaction flask was added 220mL of methanol, 52.5g of the compound of formula I, Pd (OH)₂4.7g, ammonium formate 31.6g, formic acid 8.3g and disodium hydrogen phosphate 25.6g, the reaction was stirred at 25 ℃ and monitored by TLC as free of compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.5g, with yield of 85.9% and HPLC purity of 99.4%.

Examples 1 to 9

Into a reaction flask were added 280mL of ethanol, 52.5g of the compound of formula I, PdCl₂2.6g, 34.7g ammonium formate, 10.0g formic acid and 38.3g dipotassium hydrogen phosphate, the reaction was stirred at 20 ℃ and monitored by TLC as free of the compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.6g, yield 86.0%, and HPLC purity 99.4%.

Examples 1 to 10

To a reaction flask was added 320mL of isopropanol, 52.5g of the compound of formula I, 10% Pd-C3.2g, 28.4g of ammonium formate, 7.4g of formic acid and 17.0g of sodium carbonate, and the reaction was stirred at 30 ℃ and monitored by TLC as free of the compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.5g, with yield of 85.8% and HPLC purity of 99.2%.

Examples 1 to 11

350mL of n-butanol, 52.5g of the compound of formula I, 3.7g of 5% Pd-C, 41.0g of ammonium formate, 12.0g of formic acid and 36.0g of potassium carbonate were added to a reaction flask, and the reaction was stirred at 40 ℃ and monitored by TLC until the compound of formula I was absent. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 29.0g, yield 84.3%, and HPLC purity 98.7%.

Examples 1 to 12

380mL of tetrahydrofuran, 52.5g of the compound of formula I, 4.2g of 5% Pd-C, 47.3g of ammonium formate, 13.0g of formic acid and 27.0g of ammonium carbonate were added to the reaction flask, and the reaction was stirred at 50 ℃ and monitored by TLC as free of the compound of formula I. Filtering, concentrating under reduced pressure to dryness, adding ethyl acetate and water for extraction, washing the organic phase with water, drying, filtering, and concentrating under reduced pressure to dryness to obtain white solid compound of formula II 28.9g, yield 84.2%, and HPLC purity 98.5%.

Examples 1 to 13

This example differs from examples 1-3 in that 52.5g of compound of formula I, 63.1g of ammonium formate, 1.0g of formic acid and 1.7g of sodium bicarbonate, all under the same conditions, were worked up to give 26.4g of compound of formula II as a white solid in 76.6% yield and 95.1% HPLC purity.

Examples 1 to 14

This example differs from examples 1-3 in that 52.5g of compound of formula I, 6.3g of ammonium formate, 18.4g of formic acid and 33.6g of sodium bicarbonate, all under the same conditions, were worked up to give 27.0g of compound of formula II as a white solid in 78.5% yield and 94.3% HPLC purity.

Examples 1 to 15

This example differs from examples 1-3 in that 52.5g of compound of formula I, 25.2g of ammonium formate, 11.5g of formic acid and 21.0g of sodium bicarbonate, all under the same conditions, were worked up to give 29.6g of compound of formula II as a white solid in 86.2% yield and 99.4% HPLC purity.

Examples 1 to 16

This example differs from examples 1-3 in that 52.5g of compound of formula I, 38.0g of ammonium formate, 4.6g of formic acid and 8.4g of sodium bicarbonate were worked up to yield 29.7g of compound of formula II as a white solid in 86.3% yield and 99.5% HPLC purity, all under the same conditions.

Examples 1 to 17

This example differs from examples 1-3 in that 52.5g of compound of formula I, 12.6g of ammonium formate, 13.8g of formic acid and 25.2g of sodium bicarbonate were worked up to give 28.8g of compound of formula II as a white solid in 83.6% yield and 98.8% HPLC purity, all under the same conditions.

Examples 1 to 18

This example differs from examples 1-3 in that 52.5g of compound of formula I, 50.5g of ammonium formate, 2.3g of formic acid and 4.2g of sodium bicarbonate were worked up to yield 29.0g of compound of formula II as a white solid in 84.2% yield and 98.7% HPLC purity, all under the same conditions.

Examples 1 to 19

This example differs from examples 1-3 in that the reaction temperature was 10 ℃ and the conditions were otherwise the same, and that work-up gave 22.6g of the compound of formula II as a white solid in 65.6% yield and 92.2% HPLC purity.

Examples 1 to 20

This example differs from examples 1-3 in that the reaction temperature was 60 ℃ and the conditions were otherwise the same, and workup gave 25.1g of the compound of formula II as a white solid in 73.0% yield and 90.5% HPLC purity.

Examples 1 to 21

This example differs from examples 1-3 in that the reaction temperature was 40 ℃ and the conditions were otherwise the same, and that 28.6g of the compound of formula II was obtained as a white solid by work-up in 83.2% yield and 99.0% HPLC purity.

Examples 1 to 22

This example differs from examples 1-3 in that the reaction temperature was 50 ℃ and the conditions were otherwise the same, and that work-up gave 28.8g of the compound of formula II as a white solid in 83.8% yield and 99.1% HPLC purity.

Examples 1 to 23

This example differs from examples 1-3 in that the reaction temperature was 20 ℃ and the conditions were otherwise the same, and that the work-up gave 29.7g of the compound of formula II as a white solid in 86.2% yield and 99.5% HPLC purity.

Examples 1 to 24

This example differs from examples 1-3 in that the reaction temperature was 30 ℃ and the conditions were otherwise the same, and that the work-up gave 29.6g of the compound of formula II as a white solid in 86.0% yield and 99.4% HPLC purity.

Example 2 preparation of formoterol fumarate dihydrate

200mL of absolute ethanol, 50mL of water, 34.4g of formoterol and 13.9g of fumaric acid are added into a reaction flask, the mixture is stirred and reacted at 25 ℃, TLC monitors that no compound shown in the formula II is obtained, and 40.2g of formoterol fumarate dihydrate is obtained through post-treatment, the yield is 95.6%, and the HPLC purity is 99.6%.

Comparative example 1

This comparative example differs from examples 1-3 in that 17.9g of the compound of formula II was obtained as a white solid by workup, in 52.1% yield and 73.2% HPLC purity, without the addition of ammonium formate and sodium bicarbonate, under otherwise identical conditions.

Comparative example 2

This comparative example differs from examples 1 to 3 in that the compound of formula II is hardly obtained by working up, without addition of formic acid and sodium bicarbonate, but under otherwise identical conditions.

Comparative example 3

This comparative example differs from examples 1-3 in that formic acid and sodium bicarbonate were not added and the reaction was carried out under reflux conditions, all other conditions being the same, and 14.5g of the compound of formula II was obtained as a white solid by workup, with a yield of 42.1% and an HPLC purity of 50.2%.

Comparative example 4

This comparative example differs from examples 1-3 in that 16.1g of a white solid compound of formula II was obtained by workup without addition of sodium bicarbonate under otherwise identical conditions, with a yield of 46.8% and an HPLC purity of 66.7%.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.