CN110950765B - Preparation method of terbutaline sulfate - Google Patents

Preparation method of terbutaline sulfate Download PDF

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CN110950765B
CN110950765B CN201911256929.XA CN201911256929A CN110950765B CN 110950765 B CN110950765 B CN 110950765B CN 201911256929 A CN201911256929 A CN 201911256929A CN 110950765 B CN110950765 B CN 110950765B
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terbutaline sulfate
acetophenone
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dibenzyloxy
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姚晓敏
贾姝
姚晓坤
吴静怡
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Zhejiang University ZJU
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Abstract

The invention discloses a preparation method of terbutaline sulfate, which adopts 3, 5-dihydroxy acetophenone as a starting material, obtains 3, 5-dibenzyloxy acetophenone after benzyl protection, obtains 3, 5-dibenzyloxy acetophenone aldehyde through bromination of copper bromide and oxidation of DMSO of the 3, 5-dibenzyloxy acetophenone, then obtains the 3, 5-dibenzyloxy acetophenone aldehyde through reductive amination with tert-butylamine to generate 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol, and finally obtains the terbutaline sulfate through hydrogenation debenzylation and salt formation by sulfuric acid. Compared with the prior art, the raw materials and auxiliary materials used in the invention are all cheap and easily available, high-risk and virulent reagents are avoided, high-temperature and high-pressure reaction is not carried out, the operation is simple and convenient, the reaction condition is mild, and the defects of long steps, low yield, potential safety hazard and the like in the prior art are overcome.

Description

Preparation method of terbutaline sulfate
Technical Field
The invention relates to a preparation method of terbutaline sulfate, and belongs to the technical field of terbutaline sulfate synthesis.
Background
Terbutaline Sulfate (Terbutaline Sulfate), also known as Mexican, Terbutaline, is an adrenergic agonist, selectively stimulates beta 2 receptor to relax bronchial smooth muscle, inhibits the release of endogenous spasmodic substances and edema caused by endogenous mediators, and improves the clearance capability of bronchial mucociliary epithelium. It was first developed by the pharmaceutical company of astrazeneca, inc, and was produced and marketed abroad in 1988. Clinically, the traditional Chinese medicine composition is mainly used for treating the bronchospasm during bronchial asthma, asthmatic bronchitis and chronic obstructive pulmonary diseases.
At present, a plurality of processes for synthesizing terbutaline sulfate have been reported at home and abroad, but all have certain technical problems, such as long process route, expensive raw material price, use of highly toxic or flammable and explosive raw material reagents in the synthesis process, complex operation, unsuitability for industrial production and the like. The preparation process is as follows:
1. the route reported by patent US3937838 of astrazene pharmaceutical company is: the preparation method comprises the steps of using 3, 5-dihydroxybenzoic acid as a starting material, forming ester from carboxyl, sequentially carrying out benzyl protection, ester group hydrolysis and carboxyl acyl chlorination after esterification, acylating with diazomethane, reacting with hydrogen bromide to obtain alpha-bromo-3, 5-dibenzyloxyacetophenone, condensing the alpha-bromo-3, 5-dibenzyloxyacetophenone with N-benzyl tert-butylamine, carrying out hydrogenation debenzylation, and salifying with sulfuric acid to obtain terbutaline sulfate. The process uses the highly toxic and highly explosive diazomethane, brings great potential safety hazards to actual production, has longer reaction steps and low yield in the whole process, and is not suitable for industrial production.
2. The method reported by Yindonxiang et al, Shanghai pharmaceutical research institute of Chinese academy of sciences, also takes 3, 5-dihydroxybenzoic acid as a starting raw material, sequentially performs carboxyl esterification, benzyl protection and ester group hydrolysis, then performs condensation on carboxyl and methyl lithium to obtain 3, 5-dibenzyloxyacetophenone, then performs oxidation to obtain 3, 5-dibenzyloxyacetophenone aldehyde, performs reductive amination on the 3, 5-dibenzyloxyacetophenone aldehyde and tert-butylamine, then performs hydrogenation debenzylation, and finally forms salt with sulfuric acid to obtain terbutaline sulfate. The route uses methyllithium, a metal reagent with flammable danger, and selenium dioxide, a highly toxic oxidant, and therefore is difficult to industrialize.
3. Chinese patent CN2018108503554 takes 3, 5-dihydroxy acetophenone as a starting material, after benzyl protection, DMSO is taken as an oxidant, hydrobromic acid is taken as a catalyst, 3, 5-dibenzyloxy acetophenone is oxidized to obtain 3, 5-dibenzyloxy acetophenone aldehyde, and then the 3, 5-dibenzyloxy acetophenone aldehyde is subjected to hemiacetalization, reductive amination and hydrogenation debenzylation in sequence, and finally salifying with sulfuric acid to obtain terbutaline sulfate. The route is actually an improvement on the reported route of invan xiang and the like, 3, 5-dihydroxy acetophenone is directly adopted as the starting raw material, the steps are obviously shortened, a metal reagent is avoided, and DMSO is adopted for the oxidation reaction to replace virulent selenium dioxide as an oxidant, so that the whole route is safer, but side reactions are more when 3, 5-dibenzyloxy acetophenone is directly oxidized by DMSO, the conditions are not easy to control, the product purity is poorer, the purification is difficult, and if the problem is not solved, the industrial production is not suitable.
4. Chinese patent CN2017106831452 uses 3, 5-dihydroxy acetophenone as starting material, and obtains alpha-bromo-3, 5-dihydroxy acetophenone by bromination reaction of copper bromide, and then the alpha-bromo-3, 5-dihydroxy acetophenone is reduced by carbonyl group, condensed with tert-butylamine, and finally salified with sulfuric acid to obtain terbutaline sulfate. The method has few reaction steps and high yield, but the hydroxyl is easy to oxidize and deteriorate when undergoing bromination reaction under the unprotected condition, and the treatment after sodium borohydride reduction is more complicated, so the method is difficult to be applied to industrial production.
5. In the Chinese patent CN201310560213.5, the commercial bambuterol hydrochloride is used as a raw material, and the terbutaline sulfate is obtained by two steps of alkaline hydrolysis and final salt formation with sulfuric acid.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the technical problems of expensive and not easy-to-obtain raw materials, use of high-risk highly toxic reagents, long reaction steps, low yield, complex operation and the like in the existing terbutaline sulfate synthesis process, a preparation method of terbutaline sulfate is provided.
The technical scheme is as follows: in order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of terbutaline sulfate comprises the following steps:
(1) and (3) benzyl protection reaction: carrying out substitution reaction on the 3, 5-dihydroxy acetophenone and a benzylation reagent in an organic solvent in the presence of an acid-binding agent to obtain 3, 5-dibenzyloxy acetophenone;
(2) bromination and oxidation reaction: brominating 3, 5-dibenzyloxy acetophenone and copper bromide in a mixed organic solvent to obtain alpha-bromo-3, 5-dibenzyloxy acetophenone, and then performing oxidation reaction with dimethyl sulfoxide (DMSO) under the catalysis of alkali to obtain 3, 5-dibenzyloxy acetophenone aldehyde;
(3) reductive amination reaction: 3, 5-dibenzyloxy phenylacetaldehyde and tert-butylamine are subjected to condensation reaction in an organic solvent to generate aldimine, and then the aldimine reacts with a reducing agent to obtain 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol;
(4) preparation of terbutaline sulfate: 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol reacts with a reducing agent and a catalyst in an organic solvent, and then salified with sulfuric acid to obtain terbutaline sulfate.
The reaction formula of each step of the preparation method is as follows (including the preferable reaction conditions):
Figure BDA0002310519710000031
in the step (1), the organic solvent is any one of N, N-Dimethylformamide (DMF), N-methylpyrrolidone (NMP), acetonitrile, acetone and butanone, and acetone is preferred; the dosage of the organic solvent is 5-10 times of the mass of the 3, 5-dihydroxy acetophenone.
In the step (1), the benzylation reagent is any one of benzyl bromide and benzyl chloride, preferably benzyl chloride; the acid-binding agent is any one of sodium carbonate, potassium carbonate, triethylamine and N, N-Diisopropylethylamine (DIPEA), and preferably potassium carbonate; the raw material molar ratio of the 3, 5-dihydroxyacetophenone to the benzylation reagent and the acid-binding agent is 1 (2-2.3) to 2-2.5; the temperature of the substitution reaction is 50-80 ℃.
In the step (2), the mixed organic solvent is a combination of ethyl acetate and any one of Dichloromethane (DCM) and chloroform, and the volume ratio of the combination is V (DCM or chloroform): V (ethyl acetate) ═ 1 (1-3); the dosage of the mixed organic solvent is 5-10 times of the mass of the 3, 5-dibenzyloxyacetophenone; the raw material molar ratio of the 3, 5-dibenzyloxyacetophenone to the copper bromide is 1 (2-2.5); the temperature of the bromination reaction is 30-80 ℃; the organic solvent of the oxidation reaction is dimethyl sulfoxide (DMSO); the amount of the DMSO is 2-5 times of the mass of the 3, 5-dibenzyloxy acetophenone; the temperature of the oxidation reaction is 30-80 ℃.
In the step (2), the alkali is any one of pyridine, triethylamine, sodium bicarbonate, sodium carbonate and potassium carbonate, preferably sodium bicarbonate, and the dosage of the alkali is 1-3 times of the molar weight of the 3, 5-dibenzyloxyacetophenone.
In the step (3), the organic solvent is any one of methanol, ethanol, n-propanol, isopropanol and butanol, preferably ethanol; the dosage of the organic solvent is 5-10 times of the mass of the 3, 5-dibenzyloxy acetophenone aldehyde.
In the step (3), the molar ratio of the 3, 5-dibenzyloxy phenylacetaldehyde to the tert-butylamine is 1: 1-4; the temperature of the condensation reaction is 40-80 ℃; the reducing agent is any one of lithium borohydride, sodium borohydride and potassium borohydride, and potassium borohydride is preferred; the dosage of the reducing agent is 2-5 times of the molar weight of the 3, 5-dibenzyloxy acetophenone aldehyde; the temperature for reaction with the reducing agent is 20-60 ℃.
In the step (4), the organic solvent is any one of methanol and ethanol, preferably ethanol; the dosage of the organic solvent is 5-10 times of the mass of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol.
In the step (4), the reducing agent is hydrogen; the catalyst is Pd (OH)2Any one of/C or Pd/C, preferably Pd/C; the dosage of the catalyst is 1- [3, 5-bis (benzyloxy) phenyl]5-10% of the mass of the-2- (tert-butylamino) ethanol; the reaction pressure is 0.1-0.5 MPa; the reaction temperature is 20-50 ℃.
In the step (4), the temperature for forming the salt with the sulfuric acid is 0-5 ℃, and the pH value of the sulfuric acid is adjusted to 5-6.
The technical effects are as follows: compared with the prior art, the raw materials and auxiliary materials used in the invention are all cheap and easily available, high-risk and virulent reagents are avoided, high-temperature and high-pressure reaction is not carried out, the operation is simple and convenient, the reaction condition is mild, and the defects of long steps, low yield, potential safety hazard and the like in the prior art are overcome.
Drawings
FIG. 1 is a schematic representation of 3, 5-dibenzyloxyacetophenone1H-NMR spectrum.
FIG. 2 shows a 1- [3, 5-bis (benzyloxy) phenyl group]Method for producing (E) -2- (tert-butylamino) ethanol1H-NMR spectrum.
FIG. 3 is a schematic representation of terbutaline sulfate1H-NMR spectrum.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples.
Example 1
A preparation method of terbutaline sulfate specifically comprises the following steps:
(1) preparation of 3, 5-dibenzyloxyacetophenone
100.0g (657.25mmol) of 3, 5-dihydroxyacetophenone, 227.1g (1.64 mol) of anhydrous potassium carbonate, 1L of acetone and 174.7g (1.38mol) of benzyl chloride were added in this order to a reaction vessel at room temperature, and after the addition, the reaction was carried out at 50 ℃ for 6 hours. The reaction solution is cooled to room temperature, filtered, the filter cake is washed by acetone (2X 100mL), the combined filtrate is decompressed and evaporated to remove the acetone, and the residue is recrystallized by methanol to obtain off-white solid, namely 175.0g of 3, 5-dibenzyloxyacetophenone, with the yield of 80%.
1H NMR(300MHz,DMSO-d6)：δ＝7.32-7.47(m,10H),7.18(d,J＝1.8Hz,2H),6.96 (t,J＝1.8Hz,1H),5.16(s,4H),2.55(s,3H).
(2) Preparation of 3, 5-dibenzyloxyacetophenonal
100.0g (300.84mmol) of 3, 5-dibenzyloxyacetophenone, 500mL of chloroform and 500mL of ethyl acetate were added to a reaction vessel at room temperature, and after stirring and dissolution, 141.1g (631.77mmol) of copper bromide was added thereto, and the mixture was stirred at 50 ℃ for 5 hours. And (3) carrying out suction filtration on the reaction solution, washing the filtrate by using concentrated hydrochloric acid, drying the organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and carrying out reduced pressure evaporation to remove chloroform, wherein the residue is the alpha-bromo-3, 5-dibenzyloxyacetophenone. After α -bromo-3, 5-dibenzyloxyacetophenone was dissolved in 500mL of DMSO, 75.8g (902.53mmol) of sodium hydrogencarbonate was added and the mixture was reacted at 50 ℃ for 2 hours. Adding 1L of water into the reaction solution, extracting with 500mL of ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, and evaporating under reduced pressure to remove the ethyl acetate to obtain 110.5g of brown yellow oily liquid, namely 3, 5-dibenzyloxy acetophenone aldehyde, which can be directly used for the next reaction without purification.
(3) Preparation of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol
Dissolving the 3, 5-dibenzyloxy acetophenone aldehyde prepared in the last step in 1L of ethanol, adding 46.7g (638.02mmol) of tert-butylamine, and heating to 80 ℃ for reaction for 3 hours; after cooling to 60 ℃ 68.8g (1.28mmol) of potassium borohydride are added and the reaction is continued at this temperature for 1 h. The ethanol was distilled off under reduced pressure, 200mL of a saturated sodium bicarbonate solution was added to the residue, followed by extraction with 500mL of dichloromethane, drying over anhydrous sodium sulfate of the organic phase, suction filtration, distillation under reduced pressure to remove dichloromethane, and recrystallization with acetone to give 76.9g of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol as a white crystal with a yield of 63% (based on 3, 5-dibenzyloxyacetophenone).
1H NMR(300MHz,DMSO-d6)：δ＝7.31-7.44(m,10H),6.60(d,J＝1.8Hz,2H),6.53 (t,J＝1.8Hz,1H),5.20(s,1H),5.07(s,4H),4.44(t,J＝3.0Hz,1H),2.54-2.58(m,2H),1.00 (s,9H).
HRMS(ESI)found 406.2341[M+H]+.
(4) Preparation of terbutaline sulfate
50.0g (123.29mmol) of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol and 5.0g of 10% Pd/C were added to 500mL of ethanol, and the reaction was stirred under a hydrogen atmosphere of 0.3MPa for 3 hours. And (3) carrying out suction filtration to remove palladium carbon, adjusting the pH value of the filtrate to 5.0-6.0 by using sulfuric acid, carrying out reduced pressure evaporation to dryness of the solvent to obtain white-like solid powder, and recrystallizing by using methanol to obtain a white crystal, namely 27.0g of terbutaline sulfate, wherein the yield is 80%.
1H NMR(300MHz,DMSO-d6)：δ＝9.18(s,2H),7.80(br,2H),6.27(d,J＝1.5Hz, 2H),6.10(t,J＝1.8Hz,1H),4.71(d,J＝6.6Hz),2.86-2.89(m,1H),2.68-2.74(m,1H),1.23 (s,9H).
HRMS(ESI)found 226.1432[M+H]+.
Example 2
A preparation method of terbutaline sulfate specifically comprises the following steps:
(1) preparation of 3, 5-dibenzyloxyacetophenone
150.0g (985.88mmol) of 3, 5-dihydroxyacetophenone, 313.4g (2.27 mol) of anhydrous potassium carbonate, 1L of acetone and 262.1g (2.07mol) of benzyl chloride were added in this order to a reaction vessel at room temperature, and after the addition, the reaction was carried out at 60 ℃ for 4 hours. The reaction solution is cooled to room temperature, filtered, the filter cake is washed by acetone (2X 100mL), the combined filtrate is decompressed and evaporated to remove the acetone, and the residue is recrystallized by methanol to obtain off-white solid, namely 268.7g of 3, 5-dibenzyloxyacetophenone with the yield of 82%.
1H NMR(300MHz,DMSO-d6)：δ＝7.32-7.47(m,10H),7.18(d,J＝1.8Hz,2H),6.96 (t,J＝1.8Hz,1H),5.16(s,4H),2.55(s,3H).
(2) Preparation of 3, 5-dibenzyloxyacetophenonal
150.0g (451.26mmol) of 3, 5-dibenzyloxyacetophenone, 500mL of chloroform and 1L of ethyl acetate were added to a reaction vessel at room temperature, and after stirring and dissolving, 221.7g (992.78mmol) of copper bromide was added and the mixture was stirred at 80 ℃ for 2 hours. And (3) carrying out suction filtration on the reaction solution, washing the filtrate by using concentrated hydrochloric acid, drying the organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and carrying out reduced pressure evaporation to remove chloroform, wherein the residue is the alpha-bromo-3, 5-dibenzyloxyacetophenone. After α -bromo-3, 5-dibenzyloxyacetophenone was dissolved in 300mL of DMSO, 45.5g (541.52mmol) of sodium hydrogencarbonate was added and the mixture was reacted at 50 ℃ for 2 hours. Adding 1L of water into the reaction solution, extracting with 750mL of ethyl acetate, drying the organic phase with anhydrous sodium sulfate, filtering, and evaporating under reduced pressure to remove the ethyl acetate to obtain 155.1g of brown yellow oily liquid, namely 3, 5-dibenzyloxy acetophenone aldehyde, which can be directly used for the next reaction without purification.
(3) Preparation of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol
Dissolving the 3, 5-dibenzyloxy acetophenone aldehyde prepared in the last step in 1L of ethanol, adding 98.3g (1.34mol) of tert-butylamine, and heating to 80 ℃ for reaction for 4 hours; after cooling to 40 ℃ 120.8g (2.24mmol) of potassium borohydride are added and the reaction is continued at this temperature for 1 h. The ethanol was distilled off under reduced pressure, 200mL of a saturated sodium bicarbonate solution was added to the residue, followed by extraction with 500mL of dichloromethane, drying over anhydrous sodium sulfate of the organic phase, suction filtration, distillation under reduced pressure to remove dichloromethane, and recrystallization with acetone to give white crystals, i.e., 118.9g of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol, in a yield of 65% (based on 3, 5-dibenzyloxyacetophenone).
1H NMR(300MHz,DMSO-d6)：δ＝7.31-7.44(m,10H),6.60(d,J＝1.8Hz,2H),6.53 (t,J＝1.8Hz,1H),5.20(s,1H),5.07(s,4H),4.44(t,J＝3.0Hz,1H),2.54-2.58(m,2H),1.00 (s,9H).
HRMS(ESI)found 406.2341[M+H]+.
(4) Preparation of terbutaline sulfate
100.0g (246.59mmol) of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol and 10.0g of 10% Pd/C were added to 700mL of ethanol, and the reaction was stirred under a hydrogen atmosphere of 0.1MPa for 5 hours. And (3) removing palladium carbon by suction filtration, adjusting the pH value of the filtrate to 5.0-6.0 by using sulfuric acid, evaporating the solvent by reduced pressure to obtain white-like solid powder, and recrystallizing by using methanol to obtain white crystals, namely 56.1g of terbutaline sulfate, wherein the yield is 83%.
1H NMR(300MHz,DMSO-d6)：δ＝9.18(s,2H),7.80(br,2H),6.27(d,J＝1.5Hz, 2H),6.10(t,J＝1.8Hz,1H),4.71(d,J＝6.6Hz),2.86-2.89(m,1H),2.68-2.74(m,1H),1.23 (s,9H).
HRMS(ESI)found 226.1432[M+H]+。

Claims (10)

1. A preparation method of terbutaline sulfate is characterized by comprising the following steps:
(1) and (3) benzyl protection reaction: carrying out substitution reaction on the 3, 5-dihydroxy acetophenone and a benzylation reagent in an organic solvent in the presence of an acid-binding agent to obtain 3, 5-dibenzyloxy acetophenone;
(2) bromination and oxidation reaction: brominating 3, 5-dibenzyloxyacetophenone and copper bromide in a mixed organic solvent to obtain alpha-bromo-3, 5-dibenzyloxyacetophenone, and then carrying out oxidation reaction with dimethyl sulfoxide under the catalysis of alkali to obtain 3, 5-dibenzyloxyacetophenone aldehyde; the alkali is any one of pyridine, triethylamine, sodium bicarbonate, sodium carbonate and potassium carbonate;
(3) reductive amination reaction: 3, 5-dibenzyloxy phenylacetaldehyde and tert-butylamine are subjected to condensation reaction in an organic solvent to generate aldimine, and then the aldimine reacts with a reducing agent to obtain 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol;
(4) preparation of terbutaline sulfate: 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol reacts with a reducing agent and a catalyst in an organic solvent, and then salified with sulfuric acid to obtain terbutaline sulfate.
2. The method for preparing terbutaline sulfate according to claim 1, wherein in step (1), said organic solvent is any one of N, N-dimethylformamide DMF, N-methylpyrrolidone NMP, acetonitrile, acetone, butanone; the dosage of the organic solvent is 5-10 times of the mass of the 3, 5-dihydroxy acetophenone.
3. The method for preparing terbutaline sulfate according to claim 1, wherein in step (1), the benzylation reagent is any one of benzyl bromide and benzyl chloride; the acid-binding agent is any one of sodium carbonate, potassium carbonate, triethylamine and N, N-diisopropylethylamine DIPEA; the raw material molar ratio of the 3, 5-dihydroxyacetophenone to the benzylation reagent and the acid-binding agent is 1 (2-2.3) to 2-2.5; the temperature of the substitution reaction is 50-80 ℃.
4. The preparation method of terbutaline sulfate according to claim 1, wherein in step (2), the mixed organic solvent is a combination of ethyl acetate and any one of dichloromethane and DCM, and chloroform, and the volume ratio of the combination is V (DCM or chloroform): V (ethyl acetate) ═ 1 (1-3); the dosage of the mixed organic solvent is 5-10 times of the mass of the 3, 5-dibenzyloxy acetophenone; the raw material molar ratio of the 3, 5-dibenzyloxyacetophenone to the copper bromide is 1 (2-2.5); the temperature of the bromination reaction is 30-80 ℃; the dimethyl sulfoxide DMSO is simultaneously used as a reaction raw material and a reaction solvent; the amount of the DMSO is 2-5 times of the mass of the 3, 5-dibenzyloxy acetophenone; the temperature of the oxidation reaction is 30-80 ℃.
5. The method for preparing terbutaline sulfate according to claim 1, wherein in step (2), the base is sodium bicarbonate, and the amount of the base is 1 to 3 times of the molar amount of 3, 5-dibenzyloxyacetophenone.
6. The method for preparing terbutaline sulfate according to claim 1, wherein in step (3), the organic solvent is any one of methanol, ethanol, n-propanol, isopropanol, and butanol; the dosage of the organic solvent is 5-10 times of the mass of the 3, 5-dibenzyloxy acetophenone aldehyde.
7. The method for preparing terbutaline sulfate according to claim 1, wherein in step (3), the molar ratio of 3, 5-dibenzyloxy phenylacetaldehyde to tert-butylamine is 1: 1-4; the temperature of the condensation reaction is 40-80 ℃; the reducing agent is any one of lithium borohydride, sodium borohydride and potassium borohydride; the dosage of the reducing agent is 2-5 times of the molar weight of the 3, 5-dibenzyloxy acetophenone aldehyde; the temperature for reaction with the reducing agent is 20-60 ℃.
8. The method for preparing terbutaline sulfate according to claim 1, wherein in step (4), the organic solvent is any one of methanol and ethanol; the dosage of the organic solvent is 5-10 times of the mass of 1- [3, 5-bis (benzyloxy) phenyl ] -2- (tert-butylamino) ethanol.
9. The process for the preparation of terbutaline sulfate according to claim 1, wherein in step (4), said reducing agent is hydrogen; the catalyst is Pd (OH)2Any one of/C or Pd/C; the dosage of the catalyst is 1- [3, 5-bis (benzyloxy) phenyl]5-10% of the mass of the-2- (tert-butylamino) ethanol; the reaction pressure is 0.1-0.5 MPa; the reaction temperature is 20-50 ℃.
10. The method for preparing terbutaline sulfate according to claim 1, wherein in step (4), the temperature for forming salt with sulfuric acid is 0-5 ℃, and the pH value of sulfuric acid is adjusted to 5-6.
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