CN114409552B - A kind of preparation method of salbutamol hydrochloride - Google Patents

A kind of preparation method of salbutamol hydrochloride Download PDF

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CN114409552B
CN114409552B CN202210096615.3A CN202210096615A CN114409552B CN 114409552 B CN114409552 B CN 114409552B CN 202210096615 A CN202210096615 A CN 202210096615A CN 114409552 B CN114409552 B CN 114409552B
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CN114409552A (en
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马仁强
王廷春
张海龙
苏建伟
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Guangzhou Huasheng Pharmaceutical Co.,Ltd.
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Guangzhou Boji Biomedical Science Park Co ltd
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    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
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Abstract

本发明属于化学合成技术领域，具体涉及一种盐酸左旋沙丁胺醇的制备方法。该方法以5‑(2‑溴乙酰基)‑2‑羟基苯甲醛为起始物料，依次经过醛基还原、丙叉保护、羰基不对称还原、环氧化、胺代、手性拆分和纯化、脱保护成盐制得盐酸左旋沙丁胺醇。整个方法均在较为温和的条件下进行反应，无需昂贵或易污染的试剂，不用结合柱层析纯化即可达到99％以上的纯度；并且合成路线操作简单、设备要求低，收率较好，非常适合工业化大规模生产。

The invention belongs to the technical field of chemical synthesis, and in particular to a method for preparing salbutamol hydrochloride. The method uses 5-(2-bromoacetyl)-2-hydroxybenzaldehyde as starting material, and sequentially undergoes aldehyde reduction, propylidene protection, carbonyl asymmetric reduction, epoxidation, amine generation, chiral separation and purification, and deprotection salt formation to prepare salbutamol hydrochloride. The whole method reacts under relatively mild conditions, without expensive or easily contaminated reagents, and can reach a purity of more than 99% without combining column chromatography purification; and the synthetic route is simple to operate, has low equipment requirements, and has a good yield, which is very suitable for industrial large-scale production.

Description

Levorotatory sand hydrochloride preparation method of butylamine alcohol
Technical Field
The invention belongs to the technical field of chemical synthesis. More particularly relates to a preparation method of levalbuterol hydrochloride.
Background
Salbutamol is a selective beta 2 receptor agonist, can effectively inhibit the release of allergic substances such as histamine and the like, prevents bronchospasm, is suitable for symptoms such as bronchial asthma, asthmatic bronchitis, bronchospasm, emphysema and the like, is a first-choice medicament for relieving acute asthma attack, and has become a popular single medicament in the world. The levosalbutamol hydrochloride is a single optical isomer of the salbutamol, the drug effect is 80 times of that of the dextrsalbutamol, the side effect is reduced, the curative effect is further improved, the same curative effect can be produced by only 1/4 dose of the raceme of the levosalbutamol hydrochloride, and the effect is better than that of the raceme at 1/2 dose. Therefore, the levalbuterol is hopeful to replace albuterol and becomes a first-choice drug for relieving the acute asthma attack.
At present, the synthetic route of levalbuterol hydrochloride is mainly divided into two types:
One is to use chiral reagent to separate and purify the albuterol of the racemate, such as Chen Yang et al (Chen Yang, liu Xiangkui, zhang Xiaomin, etc.. Preparation of albuterol hydrochloride [ J ]. J.Chinese medicine industry journal, volume 37, 6, pages 376-378, ISTIC PKU CSCD CA BP, 2006.) discloses a synthetic route for albuterol hydrochloride:
However, the method has low raw material utilization rate, and the total yield after purification is only 28.5%, so that the method is not suitable for large-scale industrialized production.
The other is to make the proportion of the levalbuterol hydrochloride far larger than that of the dextralbuterol hydrochloride by constructing a chiral center, and then to achieve the purpose of improving the product yield by purification, for example Cheng Qingfang and the like disclose an asymmetric synthesis method of (R) -albuterol hydrochloride (Cheng Qingfang, wang Qifa, xu Xingyou, she Yan, zhang Hui. Asymmetric synthesis of (R) -albuterol hydrochloride [ J ]. Organic chemistry, 2007 (12): 1558-1561.) which comprises the following specific synthesis route:
According to the method, chiral borneol-based beta-diketone iron compound is used as a catalyst to catalyze the asymmetric epoxidation reaction of the styrene compound, so that the high enantioselective epoxidation of the styrene compound is realized, and the purpose of synthesizing the levalbuterol is finally achieved, but the route needs to use an expensive iron complex, and post-treatment needs column chromatography, so that the industrial amplification is not facilitated.
Similarly, zhou Danyang et al disclose a chemical asymmetric synthesis method of (R) -salbutamol, which takes 1- (4-hydroxy-5-hydroxymethyl phenyl) -aminoethyl ketone as a raw material, carries out coupling reaction through CuI catalysis, and then uses (-) -Ipc 2 BCl as a reducing agent to enantioselectively reduce carbonyl, finally generates (R) -salbutamol (Zhou Danyang, chen Ling. (R) -salbutamol) and synthesizes [ J ]. Shenyang university (natural science edition), 2015,27 (06): 442-445.DOI: 10.16103/j.cnki.21-1583/n.2015.06.004.); however, the route needs a large amount of copper catalyst, and causes heavy metal pollution to the environment, which is not environment-friendly.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of low yield, expensive catalyst and heavy metal pollution existing in the existing method for synthesizing the levalbuterol hydrochloride, and the disadvantage that the purification by combining column chromatography is unfavorable for industrial amplification, and provides the preparation method of the levalbuterol hydrochloride, which has the advantages of low cost, high yield, mild condition, environment friendliness, simple operation and low equipment requirement, and is suitable for industrial mass production.
The above object of the present invention is achieved by the following technical scheme:
The preparation method of the levalbuterol hydrochloride is synthesized by the following steps:
The method specifically comprises the following steps:
S1, reacting a compound A (5- (2-bromoacetyl) -2-hydroxybenzaldehyde) in an organic solvent at 10-20 ℃ under the reduction condition of sodium triacetoxyborohydride to obtain a compound B (5- (2-bromoacetyl) -2-hydroxybenzaldehyde);
S2, cyclizing the compound B (5- (2-bromoacetyl) -2-hydroxybenzyl alcohol) obtained in the step S1 with 2, 2-dimethoxypropane under the action of a catalyst, and reacting in an organic solvent at 20-30 ℃ to obtain a compound C (6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin);
S3, reducing the compound C (6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin) obtained in the step S2 in an organic solvent at 0-10 ℃ in the presence of a borane complex and a chiral ligand to obtain a chiral intermediate compound D (6- (2-bromo-1- (S) -ethanol) -2, 2-dimethyl-4H-benzo [1,3] dioxin);
S4, reacting the compound D (6- (2-bromo-1- (S) -ethanol) -2, 2-dimethyl-4H-benzo [1,3] dioxin) obtained in the step S3 in an organic solvent at 20-30 ℃ in the presence of potassium carbonate to obtain an epoxide intermediate compound E (6- (2- (S) -ethylene oxide) -2, 2-dimethyl-4H-benzo [1,3] dioxin);
S5, performing ring-opening reaction on the compound E obtained in the step S4 in an organic solvent with the temperature of between 45 and 55 ℃ by using tert-butylamine, turning over the configuration, and performing chiral resolution on the compound E in an organic solvent with the temperature of between 45 and 55 ℃ by using a resolving agent D- (+) -dibenzoyl tartaric acid (D-DBTA) to obtain D- (+) -dibenzoyl tartrate of the compound F;
S6, deprotecting the D- (+) -dibenzoyl tartrate of the compound F obtained in the step S5 in an organic solvent at 15-25 ℃ under the action of hydrogen chloride, and refining to obtain the compound F.
Further, in step S1, the organic solvent is selected from one or more of dichloromethane, methanol, tetrahydrofuran, and acetonitrile. Preferably, the organic solvent is tetrahydrofuran.
Preferably, in the step S1, the mass volume ratio of the compound A to the organic solvent is 1 (5-10) g/ml.
Preferably, in step S1, the molar usage ratio of the compound a to sodium triacetoxyborohydride is 1: (1-2).
Further, in step S2, the catalyst is p-toluenesulfonic acid, glacial acetic acid or sulfuric acid. Preferably, the catalyst is p-toluene sulfonic acid.
Preferably, in step S2, the molar usage ratio of the compound B to the catalyst is 1: (0.01-0.05).
Preferably, in step S2, the organic solvent is dichloromethane, tetrahydrofuran, toluene or 1, 4-dioxane; more preferably, the organic solvent is dichloromethane.
Preferably, in the step S2, the mass-volume ratio of the compound B to the organic solvent is 1 (10-15).
Further, in step S3, the borane complex is N, N-diethylaniline.
Preferably, in step S3, the molar ratio of the compound C to the borane complex is (1-2): 1.
Preferably, in step S3, the chiral ligand is (1 r, 2S) - (+) -cis-1-amino-2-indanol.
Preferably, in step S3, the organic solvent is tetrahydrofuran.
Further, in the step S4, the molar ratio of the compound D to the potassium carbonate is 1 (1-3).
Preferably, in step S4, the organic solvent is methanol, ethanol or isopropanol. Preferably, the organic solvent is methanol.
Preferably, in the step S4, the mass volume ratio of the compound D to the organic solvent is 1 (5-10) g/ml.
Further, in step S5, the molar usage ratio of the compound E to t-butylamine is 1: (4-6).
Preferably, in step S5, the organic solvent of the ring-opening reaction is methanol, ethanol or isopropanol; preferably, the organic solvent of the ring-opening reaction is ethanol.
Preferably, in the step S5, the mass-volume ratio of the compound D of the ring-opening reaction to the organic solvent is 1 (5-10) ml/g.
Further, in step S5, the molar ratio of the compound E to the resolving agent is 1: (0.4-0.6).
Preferably, in step S5, the chiral-split organic solvent is a mixed solution of methanol and isopropanol at a volume ratio of 1:10.
Preferably, in step S5, the method further comprises a step of beating and purifying, wherein the beating and purifying solvent is a mixed solution of methanol and water, and the mass-volume ratio of the compound F to the methanol is 1:10, the mass volume ratio of the water to the water is 1: (0.5-2.0); the pulping temperature is 50 ℃, and the crystallization temperature is 20+/-5 ℃.
In step S6, the organic solvent is a mixed solvent obtained by mixing any one of ethyl acetate, methyl tert-butyl ether, isopropyl ether and methylene dichloride with methanol according to a volume ratio of 10:1.
Preferably, in the step S6, the mass-volume ratio of the D- (+) -dibenzoyl tartrate of the compound F to the mixed solvent is 1 (10-15) g/ml.
Preferably, in step S6, the refining is a recrystallized refining; the recrystallization solvent is a mixed solution of isopropanol and water, and the mass volume ratio of the crude product of the compound G to the isopropanol is 1:12g/ml, mass volume ratio with water is 1: (0.5-2.0), recrystallizing at 20-30 deg.C, and maintaining at-5 deg.C for 2h.
The invention has the following beneficial effects:
The invention takes 5- (2-bromoacetyl) -2-hydroxybenzaldehyde (compound A) as a starting material, and prepares the levalbuterol hydrochloride by aldehyde group reduction, propylidene protection, carbonyl asymmetric reduction, epoxidation, amine substitution, chiral resolution, purification and deprotection into salt. The whole method is carried out under milder conditions, expensive or easily polluted reagents are not needed, and the purity of the product can reach more than 99 percent without combining column chromatography purification; and the synthesis route is simple to operate, the equipment requirement is low, the yield is good, and the method is very suitable for industrial mass production.
Drawings
FIG. 1 is a liquid chromatogram of levalbuterol hydrochloride prepared by the present invention.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Specifically, the preparation method of the levalbuterol hydrochloride is synthesized according to the following route:
EXAMPLE 1 Synthesis of Compound B (5- (2-bromoacetyl) -2-hydroxybenzyl alcohol)
(1) 200.53G of compound A (5- (2-bromoacetyl) -2-hydroxybenzaldehyde) is weighed, 2.0L of tetrahydrofuran is added, stirred and dissolved, and the temperature is reduced to 15 ℃; 263.51g of sodium triacetoxyborohydride is weighed and added into the reaction system in batches, the temperature is controlled at 20+/-5 ℃, the feeding time is 120min, and the reaction is carried out for 60min at 20 ℃;
(2) Monitoring by HPLC and TLC until the reaction is complete, adding 2.0L of purified water, quenching at room temperature for 60min, concentrating at below 40 ℃ to remove most tetrahydrofuran, adding 1.6L of ethyl acetate, stirring for extraction, standing for layering, extracting the water phase with 0.4L of ethyl acetate for 1 time, mixing the organic phases, and washing with 1.0L of purified water for 1 time; adding a proper amount of anhydrous sodium sulfate for water removal;
(3) Filtering, washing filter residues with a small amount of ethyl acetate, collecting filtrate, concentrating at 40 ℃ under reduced pressure to remove most of solvent, adding 600mL of mixed solution of dichloromethane and 600mL of n-heptane when a large amount of solids are separated out, and pulping at room temperature for 1h; filtration, rinsing the filter cake with a small amount of n-heptane, and vacuum drying at 50℃for 8h gave 160.45g of a pale earthy yellow solid as compound B (5- (2-bromoacetyl) -2-hydroxybenzyl alcohol), molar yield: 79.36% and purity 92.80%;
(4) Compound B 1 HNMR (500 MHz, DMSO) 7.88-7.87 (d, 1H) 7.69-7.67 (m, 1H) 6.73-6.71 (d, 1H) 4.92 (s, 2H) 4.49 (s, 2H).
EXAMPLE 2 Synthesis of Compound C (6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin)
(1) 150.06G of compound B (5- (2-bromoacetyl) -2-hydroxybenzyl alcohol) was weighed, 1.5L of methylene chloride was added, stirred and dispersed at room temperature, and 1.16g of p-toluenesulfonic acid monohydrate was added; 128.87g of 2, 2-dimethoxy propane is weighed and added into a reaction system in a dropwise manner, and the reaction is carried out for 2 hours at room temperature;
(2) Monitoring by HPLC and TLC until the reaction is complete, adding 0.75L of purified water, regulating the pH to 7-8 by using saturated potassium bicarbonate solution, standing for layering, collecting a lower organic phase, and washing the organic phase for 1 time by using 0.75L of purified water; the organic phase is added with anhydrous sodium sulfate and water is removed;
(3) Filtering, washing filter residue with a small amount of dichloromethane, concentrating under reduced pressure to obtain 174.01g oily substance which is compound C (6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin) and directly used for the next reaction, wherein the yield is not calculated;
(4) Compound C 1 HNMR (500 MHz, DMSO) 7.83-7.81 (m, 1H) 7.79 (s, 1H) 6.93-6.91 (d, 1H) 5.06 (s, 2H) 4.89 (s, 2H) 1.50 (s, 6H).
EXAMPLE 3 Synthesis of Compound D (6- (2-bromo-1- (S) -ethanol) -2, 2-dimethyl-4H-benzo [1,3] dioxin)
(1) 9.21G of (1R, 2S) - (+) -cis-1-amino 2-indanol is weighed, 1.5L of anhydrous tetrahydrofuran is added, nitrogen is replaced, the temperature is reduced to 5+/-5 ℃, 150.31g of N, N-diethylaniline borane (DEANB) is slowly added dropwise under the protection of nitrogen, and the temperature is kept for 30min at 5+/-5 ℃ after the dropwise addition;
(2) Adding 1.5L of anhydrous tetrahydrofuran into a compound C (6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin), stirring and dissolving, dropwise adding the compound C into the reaction system of the step (1) under the protection of nitrogen, wherein the dropwise adding time is 180min, and the temperature is maintained at 5+/-5 ℃; after the dripping is finished, reacting for 30min;
(3) HPLC, TLC monitoring until compound C (6-bromoacetyl-2, 2-dimethyl-4H-benzo [1,3] dioxin) is consumed, intermediate compound D is formed;
(4) 200ml of acetone is added dropwise to quench borane at the temperature of 5+/-5 ℃, and after the dropwise addition is finished, the temperature is slowly raised to room temperature, and the reaction is carried out overnight;
(5) Concentrating to remove most tetrahydrofuran, adding 1.5L of ethyl acetate and 0.75L of purified water, stirring and extracting, collecting an upper organic phase, and washing the organic phase for 1 time with 0.5L of purified water; the aqueous phases were combined and back extracted 1 time with 0.35L ethyl acetate; the organic phases are combined and washed 1 time with 0.5L of saturated sodium chloride solution; anhydrous sodium sulfate is added, and the water is removed by drying;
(6) Filtering, washing filter residues with a small amount of ethyl acetate, collecting filtrate, concentrating under reduced pressure, removing most of ethyl acetate, adding 1.2L of n-heptane, pulping for 1h, filtering, and vacuum drying at 50 ℃ to obtain 134.12g of white solid; molar yield (calculated as compound B) 75.99%, HPLC purity 95.74%;
(7) Compounds of formula (I) D1HNMR(500MHz,DMSO)7.18-7.16(dd,1H)7.09(s,1H)6.76-6.73(d,1H)4.80(s,2H)4.71-4.68(m,1H)3.62-3.50(m,2H)1.45(s,1H).
EXAMPLE 4 Synthesis of Compound F (6- ((R) -hydroxy-2- (tert-butylamino) -ethyl) -2, 2-dimethyl-4H-benzo [1,3] dioxin)
(1) 130.88G of compound D is weighed, 1.3L of methanol is added, stirring is carried out to dissolve, 125.87g of potassium carbonate is added, and the mixture is reacted for 1h at room temperature;
(2) TLC was controlled to completion, the solids were removed by filtration, the solids were washed with ethyl acetate, and the filtrates were combined and collected; concentrating the filtrate below 40deg.C, removing most of solvent, adding 1.3L ethyl acetate and 0.7L purified water, stirring, extracting, standing, and layering; the organic phase was collected, the aqueous phase was extracted 1 more than 0.4L of ethyl acetate, the organic phases were combined and washed 1 more than 0.7L of saturated sodium chloride solution; anhydrous sodium sulfate is added, and the water is removed by drying;
(3) Filtering, washing with a small amount of ethyl acetate, and collecting filtrate; concentrating under reduced pressure below 40deg.C, and removing solvent to obtain yellow oily substance as crude product of compound E;
(4) Dissolving the obtained oily matter with 1.0L absolute ethyl alcohol, dropwise adding 132.65g of tert-butylamine, and reacting at 50+/-5 ℃ for 16 hours;
(5) TLC was controlled to completion; concentrating to remove most of solvent, adding 1.0L of ethyl acetate and 1.0L of purified water, stirring, extracting, standing and layering; the organic phase was collected and the aqueous phase was extracted 1 more times with 0.3L ethyl acetate; the organic phases were combined, washed 1 time with 0.5L of purified water and 0.5L of saturated sodium chloride solution, added with anhydrous sodium sulfate, and dried to remove water;
(6) Filtering, washing filter residues with a small amount of ethyl acetate, and collecting filtrate; concentrating the filtrate under reduced pressure to obtain yellow sticky substance as crude product of the compound F; the yield was not calculated and was used directly in the next reaction.
EXAMPLE 5 Synthesis and purification of D- (+) -dibenzoyltartrate of Compound F (6- ((R) -hydroxy-2- (tert-butylamino) -ethyl) -2, 2-dimethyl-4H-benzo [1,3] dioxin)
(1) Dissolving the crude compound F obtained in the example 4 by using a mixed solvent of 0.8L of methanol and 0.8L of isopropanol, and heating to 50+/-5 ℃ for later use;
(2) Weighing 68.13g D- (+) -dibenzoyl tartaric acid (D-DBTA), dissolving with 0.4L of mixed solvent of methanol and 0.4L of isopropanol, dropwise adding into a reaction system when the reaction temperature is raised to 50+/-5 ℃, and preserving heat for 2 hours after the dropwise addition is finished, so that a large amount of solids are separated out;
(3) Cooling to room temperature, and stirring at room temperature for 2h;
(4) Filtering, and vacuum drying at 50 ℃ to obtain 93.88g of white solid which is a crude product of the compound F;
(5) Adding the obtained crude product of the compound F into a reaction bottle, adding 940mL of methanol and 47mL of purified water, heating to 50+/-5 ℃, preserving heat and pulping for 2h;
(6) Cooling to room temperature, and preserving heat for 2h;
(7) Filtering, washing with a small amount of cold methanol, and vacuum drying at 50 ℃ for 5 hours to obtain 80.38g of white solid; molar yield: 40.12% (calculated as compound D); chiral purity: 99.74%;
(8) Compounds of formula (I) E1HNMR(500MHz,DMSO)7.13-7.11(dd,1H)7.04-7.03(d,1H)6.73-6.71(d,1H)4.80(s,2H)4.45-4.43(m,1H)2.61-2.54(m,2H)1.45(s,6H)1.02(s,9H);
(9) Compounds of formula (I) F1HNMR(500MHz,DMSO)7.99-7.97(d,4H)7.64-7.60(m,2H)7.51-7.48(m,4H)7.12-7.10(m,2H)7.01(s,2H)5.65(s,2H)4.77(s,4H)4.72-4.69(m,2H)2.90-2.87(m,4H)2.72-2.67(m,2H)1.45(s,12H)1.14(s,18H).
EXAMPLE 6 Synthesis and purification of levalbuterol hydrochloride
(1) 40.26G of D- (+) -dibenzoyl tartrate of chiral intermediate F (6- ((R) -hydroxy-2- (tert-butylamino) -ethyl) -2, 2-dimethyl-4H-benzo [1,3] dioxin) was weighed, 800mL of methyl tert-butyl ether and 80mL of methanol were added, nitrogen was replaced, and cooled to 20.+ -. 5 ℃;
(2) 45.7mL of 4M ethyl hydrogen chloride acetate is added under the protection of nitrogen, and the reaction is carried out for 5 hours at 20 ℃;
(3) Monitoring by HPLC and TLC until the reaction is complete, filtering, washing the filter cake with methyl tertiary butyl ether for 2-3 times, transferring to a blast drying oven and drying at 50 ℃ for 8h;
(4) 24.32g of off-white solid is obtained as a crude product of the levalbuterol hydrochloride;
(5) 292mL of isopropanol and 20mL of purified water are used for stirring and dissolving the crude product at a reflux temperature, filtering is carried out while the crude product is hot, cooling is carried out to room temperature for crystallization for 2h, and then the crude product is kept at 0 ℃ for 2h;
(6) Filtering, washing with a small amount of cold isopropanol; transferring to a vacuum drying oven at 60 ℃ for drying for 10 hours to obtain 13.19 white solid which is levalbuterol hydrochloride finished compound G with molar yield: 52.42%; HPLC purity 98.66%; chiral purity: 99.81%;
(7) Compounds of formula (I) G1HNMR(500MHz,DMSO)9.41-9.39(m,1H)9.25(s,1H)8.48-8.44(m,1H)7.34(s,1H)7.09-7.07(d,1H)6.80-6.77(m,1H)5.97-5.96(d,1H)5.00(s,1H)4.89-4.86(m,1H)4.48(s,2H)2.96-2.82(m,2H)1.31(s,9H).
(8) The liquid phase diagram of the relevant substances of the obtained product levosalbutamol hydrochloride is shown in figure 1.
As can be seen from the graph, the levalbuterol hydrochloride (retention time 16.222 min) prepared by the invention has higher purity.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (1)

1.一种盐酸左旋沙丁胺醇的制备方法，其特征在于，由以下路线合成得到：1. A method for preparing salbutamol hydrochloride, characterized in that it is synthesized by the following route: 具体包括以下步骤：The specific steps include: 一、化合物B 5-(2-溴乙酰基)-2-羟基苯甲醇的合成：1. Synthesis of Compound B 5-(2-bromoacetyl)-2-hydroxybenzyl alcohol: (1)称取200.53g化合物A 5-(2-溴乙酰基)-2-羟基苯甲醛，加入2.0L四氢呋喃搅拌溶解，降温到15℃；称取263.51g三乙酰氧基硼氢化钠，分批次加入到反应体系中，温度控制在20±5℃，投料耗时120min，20℃反应60min；(1) Weigh 200.53 g of compound A 5-(2-bromoacetyl)-2-hydroxybenzaldehyde, add 2.0 L of tetrahydrofuran, stir and dissolve, and cool to 15° C.; weigh 263.51 g of sodium triacetoxyborohydride, add it to the reaction system in batches, control the temperature at 20±5° C., add the materials for 120 min, and react at 20° C. for 60 min; (2)HPLC、TLC监控至反应完全，加入2.0L纯化水，室温淬灭60min，40℃以下浓缩除去大部分四氢呋喃，加入1.6L乙酸乙酯搅拌萃取，静置分层，水相再用0.4L乙酸乙酯萃取1次，合并有机相，用1.0L纯化水洗涤1次；加入适量无水硫酸钠除水；(2) HPLC and TLC monitoring until the reaction is complete, add 2.0 L of purified water, quench at room temperature for 60 min, concentrate below 40°C to remove most of the tetrahydrofuran, add 1.6 L of ethyl acetate, stir and extract, let stand to separate, extract the aqueous phase with 0.4 L of ethyl acetate once, combine the organic phases, wash once with 1.0 L of purified water; add an appropriate amount of anhydrous sodium sulfate to remove water; (3)过滤，用少量乙酸乙酯洗涤滤渣，收集滤液，40℃以下减压浓缩除去大部分溶剂，待有大量固体析出时，加入600mL二氯甲烷和600mL正庚烷混合溶液，室温打浆1h；过滤，滤饼用少量正庚烷淋洗，50℃真空干燥8h，得到160.45g浅土黄色固体，为化合物B 5-(2-溴乙酰基)-2-羟基苯甲醇，摩尔收率：79.36％，纯度92.80％；(3) Filter, wash the filter residue with a small amount of ethyl acetate, collect the filtrate, and concentrate under reduced pressure below 40° C. to remove most of the solvent. When a large amount of solid is precipitated, add 600 mL of a mixed solution of dichloromethane and 600 mL of n-heptane, and slurry at room temperature for 1 hour; filter, rinse the filter cake with a small amount of n-heptane, and vacuum dry at 50° C. for 8 hours to obtain 160.45 g of a light khaki solid, which is compound B 5-(2-bromoacetyl)-2-hydroxybenzyl alcohol, with a molar yield of 79.36% and a purity of 92.80%; 二、化合物C 6-溴乙酰基-2,2-二甲基-4H-苯并[1,3]二恶英的合成：2. Synthesis of Compound C 6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin: (1)称取150.06g化合物B 5-(2-溴乙酰基)-2-羟基苯甲醇，加入1.5L二氯甲烷，室温搅拌分散，加入1.16g一水合对甲苯磺酸；称取128.87g的2,2-二甲氧基丙烷，滴加入到反应体系中，室温反应2h；(1) Weigh 150.06 g of compound B 5-(2-bromoacetyl)-2-hydroxybenzyl alcohol, add 1.5 L of dichloromethane, stir and disperse at room temperature, add 1.16 g of p-toluenesulfonic acid monohydrate; weigh 128.87 g of 2,2-dimethoxypropane, add dropwise to the reaction system, and react at room temperature for 2 h; (2)HPLC、TLC监控至反应完全，加入0.75L纯化水，用饱和碳酸氢钾溶液调节pH为7～8，静置分层，收集下层有机相，有机相再用0.75L纯化水洗涤1次；有机相加入无水硫酸钠，除水；(2) HPLC and TLC monitoring until the reaction is complete, add 0.75 L of purified water, adjust the pH to 7-8 with saturated potassium bicarbonate solution, let stand for stratification, collect the lower organic phase, and wash the organic phase once with 0.75 L of purified water; add anhydrous sodium sulfate to the organic phase to remove water; (3)过滤，少量二氯甲烷洗涤滤渣，减压浓缩得174.01g油状物，为化合物C 6-溴乙酰基-2,2-二甲基-4H-苯并[1,3]二恶英；(3) Filter, wash the filter residue with a small amount of dichloromethane, and concentrate under reduced pressure to obtain 174.01 g of an oily substance, which is compound C 6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin; 三、化合物D 6-(2-溴-1-(S)-乙醇基)-2,2-二甲基-4H-苯并[1,3]二恶英的合成：3. Synthesis of Compound D 6-(2-bromo-1-(S)-ethanol)-2,2-dimethyl-4H-benzo[1,3]dioxin: (1)称取9.21g(1R，2S)-(+)-顺式-1-氨基2-茚满醇，加入1.5L无水四氢呋喃，置换氮气，降温到5±5℃，氮气保护下，缓慢滴加150.31g N,N-二乙基苯胺硼烷(DEANB)，滴加完毕，于5±5℃保温30min；(1) Weigh 9.21 g of (1R, 2S)-(+)-cis-1-amino-2-indanol, add 1.5 L of anhydrous tetrahydrofuran, replace nitrogen, cool to 5±5°C, slowly dropwise add 150.31 g of N,N-diethylaniline borane (DEANB) under nitrogen protection, and keep warm at 5±5°C for 30 min after the addition is complete; (2)将化合物C 6-溴乙酰基-2,2-二甲基-4H-苯并[1,3]二恶英，加入1.5L无水四氢呋喃搅拌溶解，氮气保护下，滴加到上述(1)的反应体系中，滴加时长为180min，温度维持在5±5℃；滴加完毕，反应30min；(2) Compound C 6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin was added to 1.5 L of anhydrous tetrahydrofuran and stirred to dissolve. The mixture was then added dropwise to the reaction system of (1) under nitrogen protection for 180 min. The temperature was maintained at 5±5° C. After the addition was complete, the reaction was continued for 30 min. (3)HPLC、TLC监控至化合物C 6-溴乙酰基-2,2-二甲基-4H-苯并[1,3]二恶英消耗完，中间体化合物D生成；(3) HPLC and TLC monitoring until compound C 6-bromoacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin is completely consumed and intermediate compound D is generated; (4)5±5℃滴加200ml丙酮淬灭硼烷，滴加完毕，缓慢升温到室温，反应过夜；(4) Add 200 ml of acetone at 5±5°C to quench the borane. After the addition is complete, slowly raise the temperature to room temperature and react overnight. (5)浓缩除去大部分四氢呋喃，加入1.5L乙酸乙酯和0.75L纯化水，搅拌萃取，收集上层有机相，再用0.5L纯化水洗涤有机相1次；合并水相，用0.35L乙酸乙酯回萃1次；合并有机相，用0.5L饱和氯化钠溶液洗涤1次；加入无水硫酸钠，干燥除水；(5) Concentrate to remove most of the tetrahydrofuran, add 1.5L of ethyl acetate and 0.75L of purified water, stir and extract, collect the upper organic phase, and wash the organic phase once with 0.5L of purified water; combine the aqueous phases, and back-extract once with 0.35L of ethyl acetate; combine the organic phases, and wash once with 0.5L of saturated sodium chloride solution; add anhydrous sodium sulfate, and dry to remove water; (6)过滤，滤渣用少量乙酸乙酯洗涤，收集滤液，减压浓缩，除去大部分乙酸乙酯后，加入1.2L正庚烷打浆1h，过滤，50℃真空干燥得134.12g白色固体；摩尔收率以化合物B计算为75.99％，HPLC纯度95.74％；(6) Filter, wash the filter residue with a small amount of ethyl acetate, collect the filtrate, concentrate under reduced pressure, remove most of the ethyl acetate, add 1.2 L of n-heptane to slurry for 1 h, filter, and dry under vacuum at 50 ° C to obtain 134.12 g of a white solid; the molar yield calculated based on compound B is 75.99%, and the HPLC purity is 95.74%; 四、化合物F 6-((R)-羟基-2-(叔丁氨基)-乙基)-2,2-二甲基-4H-苯并[1,3]二恶英的合成：4. Synthesis of Compound F 6-((R)-Hydroxy-2-(tert-butylamino)-ethyl)-2,2-dimethyl-4H-benzo[1,3]dioxin: (1)称取130.88g化合物D 6-(2-溴-1-(S)-乙醇基)-2,2-二甲基-4H-苯并[1,3]二恶英，加入1.3L甲醇搅拌溶解，加入125.87g碳酸钾，室温反应1h；(1) Weigh 130.88 g of compound D 6-(2-bromo-1-(S)-ethanol)-2,2-dimethyl-4H-benzo[1,3]dioxin, add 1.3 L of methanol and stir to dissolve, add 125.87 g of potassium carbonate, and react at room temperature for 1 h; (2)TLC中控至反应完全，过滤除去固体，用乙酸乙酯洗涤固体，滤液合并收集；滤液40℃以下浓缩，除去大部分溶剂，加入1.3L乙酸乙酯和0.7L纯化水，搅拌萃取，静置分层；收集有机相，水相再用0.4L乙酸乙酯萃取1次，合并有机相，用0.7L饱和氯化钠溶液洗涤1次；加入无水硫酸钠，干燥除水；(2) The reaction was controlled by TLC until it was complete, the solid was removed by filtration, the solid was washed with ethyl acetate, and the filtrates were combined and collected; the filtrate was concentrated below 40°C to remove most of the solvent, 1.3L ethyl acetate and 0.7L purified water were added, stirred for extraction, and allowed to stand for stratification; the organic phase was collected, the aqueous phase was extracted once with 0.4L ethyl acetate, the organic phases were combined, and washed once with 0.7L saturated sodium chloride solution; anhydrous sodium sulfate was added, and the water was dried to remove water; (3)过滤，少量乙酸乙酯洗涤，收集滤液；40℃以下减压浓缩，除去溶剂，得黄色油状物，为化合物E粗品；(3) Filter, wash with a small amount of ethyl acetate, collect the filtrate; concentrate under reduced pressure below 40° C. to remove the solvent to obtain a yellow oily substance, which is a crude product of compound E; (4)所得油状物E用1.0L无水乙醇溶解，滴加132.65g叔丁胺，50±5℃反应16h；(4) The obtained oily substance E was dissolved in 1.0 L of anhydrous ethanol, 132.65 g of tert-butylamine was added dropwise, and the reaction was carried out at 50±5°C for 16 h; (5)TLC中控至反应完全；浓缩除去大部分溶剂，加入1.0L乙酸乙酯和1.0L纯化水，搅拌萃取，静置分层；收集有机相，水相再用0.3L乙酸乙酯萃取1次；合并有机相，用0.5L纯化水和0.5L饱和氯化钠溶液各洗涤1次，加入无水硫酸钠，干燥除水；(5) The reaction was controlled by TLC until it was complete; most of the solvent was removed by concentration, 1.0 L of ethyl acetate and 1.0 L of purified water were added, the mixture was stirred for extraction, and the mixture was allowed to stand for stratification; the organic phase was collected, and the aqueous phase was extracted once with 0.3 L of ethyl acetate; the organic phases were combined, and the mixture was washed once with 0.5 L of purified water and once with 0.5 L of saturated sodium chloride solution, and anhydrous sodium sulfate was added, and the mixture was dried to remove water; (6)过滤，少量乙酸乙酯洗涤滤渣，收集滤液；滤液减压浓缩，得黄色粘稠状物，为化合物F粗品；不计算收率，直接用于下步反应；(6) Filter, wash the filter residue with a small amount of ethyl acetate, and collect the filtrate; the filtrate is concentrated under reduced pressure to obtain a yellow viscous substance, which is the crude product of compound F; the yield is not calculated and it is directly used in the next step reaction; 五、化合物F 6-((R)-羟基-2-(叔丁基氨基)-乙基)-2,2-二甲基-4H-苯并[1,3]二恶英的D-(+)-二苯酰酒石酸盐合成与精制：V. Synthesis and purification of compound F D-(+)-dibenzoyl tartrate salt of 6-((R)-hydroxy-2-(tert-butylamino)-ethyl)-2,2-dimethyl-4H-benzo[1,3]dioxin: (1)步骤四所得化合物F粗品用0.8L甲醇与0.8L异丙醇混合溶剂溶解，升温到50±5℃，备用；(1) The crude compound F obtained in step 4 was dissolved in a mixed solvent of 0.8 L methanol and 0.8 L isopropanol, and the temperature was raised to 50±5° C. for later use; (2)称取68.13g D-(+)-二苯酰酒石酸(D-DBTA)，用0.4L甲醇和0.4L异丙醇混合溶剂溶解，待上述反应温度升至50±5℃，滴加到反应体系中，滴加完毕，保温2h，有大量固体析出；(2) Weigh 68.13 g of D-(+)-dibenzoyltartaric acid (D-DBTA), dissolve it in a mixed solvent of 0.4 L methanol and 0.4 L isopropanol, and add it dropwise to the reaction system after the reaction temperature rises to 50±5°C. After the addition is complete, keep the temperature for 2 h, and a large amount of solid precipitates; (3)降温到室温，于室温保温搅拌2h；(3) Cool to room temperature and stir at room temperature for 2 h; (4)过滤，50℃真空干燥得93.88g白色固体，为化合物F粗品；(4) Filter and dry under vacuum at 50°C to obtain 93.88 g of a white solid, which is a crude compound F; (5)将所得化合物F粗品加入到反应瓶中，加入940mL甲醇与47ml纯化水，升温到50±5℃保温打浆2h；(5) Add the obtained crude compound F into a reaction bottle, add 940 mL of methanol and 47 mL of purified water, raise the temperature to 50±5°C and keep it for 2 h; (6)降温到室温，保温2h；(6) Cool down to room temperature and keep warm for 2 h; (7)过滤，少量冷甲醇洗涤，50℃真空干燥5h，得80.38g白色固体；摩尔收率以化合物D计算为40.12％；手性纯度：99.74％；(7) Filter, wash with a small amount of cold methanol, and dry in vacuo at 50°C for 5 h to obtain 80.38 g of a white solid; the molar yield calculated based on compound D is 40.12%; chiral purity: 99.74%; 六、化合物G盐酸左旋沙丁胺醇的合成与精制：VI. Synthesis and purification of compound G levosalbutamol hydrochloride: (1)称取40.26g手性中间体F 6-((R)-羟基-2-(叔丁基氨基)-乙基)-2,2-二甲基-4H-苯并[1,3]二恶英的D-(+)-二苯酰酒石酸盐，加入800mL甲基叔丁基醚和80mL甲醇，置换氮气，冷却至20±5℃；(1) Weigh 40.26 g of chiral intermediate F 6-((R)-hydroxy-2-(tert-butylamino)-ethyl)-2,2-dimethyl-4H-benzo[1,3]dioxin D-(+)-dibenzoyltartrate, add 800 mL of methyl tert-butyl ether and 80 mL of methanol, replace nitrogen, and cool to 20±5°C; (2)氮气保护下，加入45.7mL，4M氯化氢乙酸乙酯，20℃反应5h；(2) Under nitrogen protection, add 45.7 mL of 4 M ethyl acetate and react at 20 °C for 5 h; (3)HPLC、TLC监控至反应完全，过滤，滤饼用甲基叔丁基醚洗涤2～3次，转移到鼓风干燥箱50℃干燥8h；(3) HPLC and TLC monitoring until the reaction is complete, filtering, washing the filter cake with methyl tert-butyl ether 2 to 3 times, and transferring to a forced air drying oven at 50°C to dry for 8 h; (4)得类白色固体24.32g，为盐酸左旋沙丁胺醇粗品；(4) 24.32 g of off-white solid was obtained, which was crude salbutamol hydrochloride; (5)粗品用292mL的异丙醇与20mL的纯化水，于回流温度下搅拌溶清，趁热过滤，降温至室温析晶2h，后于0℃保温2h；(5) The crude product was dissolved in 292 mL of isopropanol and 20 mL of purified water under reflux temperature, filtered while hot, cooled to room temperature for crystallization for 2 h, and then kept at 0 °C for 2 h; (6)过滤，用少量冷异丙醇洗涤；转移到60℃真空干燥箱干燥10h，得13.19白色固体，为盐酸左旋沙丁胺醇成品化合物G，摩尔收率：52.42％；HPLC纯度98.66％；手性纯度：99.81％。(6) Filter and wash with a small amount of cold isopropanol; transfer to a 60° C. vacuum drying oven and dry for 10 h to obtain 13.19 g of a white solid, which is the finished product compound G of salbutamol hydrochloride, with a molar yield of 52.42%; HPLC purity of 98.66%; and chiral purity of 99.81%.
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