CN111499528A - Terbutaline sulfate intermediate, preparation method thereof and method for preparing terbutaline sulfate by using terbutaline sulfate intermediate - Google Patents

Abstract

The invention discloses a terbutaline sulfate intermediate, a preparation method thereof and a method for preparing terbutaline sulfate by using the terbutaline sulfate intermediate, and belongs to the technical field of medical chemistry. The invention aims to provide a method for preparing a compound of a compoundA new method for preparing terbutaline sulfate with high efficiency and environmental protection is provided, firstly, a terbutaline sulfate intermediate shown in formula I is provided; then, the terbutaline sulfate in the formula II is obtained by hydrogenation reduction with 10% Pd/C as a catalyst and an alcohol-water solution as a solvent. The free base hydrochloride or hydrobromide of the formula I is converted into the formula I before hydrogenation reduction, and then directly obtains the terbutaline sulfate after hydrogenation reduction, so that the independent occurrence of extremely unstable terbutaline free alkali is avoided, and the method has the advantages of mild reaction conditions, high product yield, high purity, low production cost and the like, and is beneficial to realizing industrial production.

Description

Terbutaline sulfate intermediate and preparation method thereof and method for preparing terbutaline sulfate by using the same

technical field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a terbutaline sulfate intermediate and a preparation method thereof, and a method for preparing terbutaline sulfate by using the same.

Background technique

Terbutaline, chemically named 1-(3,5-dihydroxyphenyl)-2-tert-butylaminoethanol, is an adrenergic β2 receptor (β2 receptor) agonist. one of the main drugs. The drug is highly selective for β2 receptors and has few cardiac side effects, and is suitable for asthma patients with cardiovascular diseases such as hypertension and coronary heart disease. It has the advantages of high curative effect, fast onset, long action time and small side effects. Inhalation therapy is the first choice for clinical application of β2-receptor agonists, which are quite effective for mild and moderate asthma patients with less side effects.

According to domestic and foreign literature research, the synthesis method of terbutaline is mainly: from 3,5-diacetoxyacetophenone or 3,5-dibenzyloxyacetophenone as raw material, bromination to obtain 2-bromo Substituted-3,5-diacetoxyacetophenone or 2-bromo-3,5-dibenzyloxyacetophenone, and then aminated and condensed with N-benzyl-tert-butylamine to obtain 2-N-benzyl-tert-butylamine -3,5-Diacetoxyacetophenone or 2-N-benzyl-tert-butylamino-3,5-dibenzyloxyacetophenone, finally debenzyl and carbonyl reduction by 10% Pd-C pressurized hydrogenolysis Or use sodium borohydride to reduce carbonyl to obtain 2-tert-butylamino-1-(3,5-diacetoxyphenyl)ethanol or 2-tert-butylamino-1-(3,5-dihydroxyphenyl)ethanol, 2- Tert-butylamino-1-(3,5-diacetoxyphenyl)ethanol is hydrolyzed with hydrobromic acid to obtain 2-tert-butylamino-1-(3,5-dihydroxyphenyl)ethanol. The main reaction formula involved in the above method is:

The above-mentioned synthetic method mainly has the following shortcomings: first, it is necessary to carry out high-pressure reaction in the reactor, and the safety requirements are high; second, although the reduction of carbonyl with sodium borohydride can avoid the pressure reaction, after the reduced reaction solution Difficult to handle; because the borate and terbutaline free base or the salt formed by the free base and acid produced by sodium borohydride reduction of carbonyl group are particularly water-soluble, so it is difficult to separate them from the aqueous solution ; Third, the method of "reduction first - sulfate later" is adopted, the reduction conditions are more severe, the extraction of terbutaline free base is difficult, and the properties of the free base are extremely unstable, resulting in a decline in product quality and yield; fourth , the reaction needs to use a class of organic solvents such as chloroform and benzene.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a new method for preparing terbutaline sulfate with mild reaction conditions, high yield and environmental protection.

Based on the above object, the present invention first provides a kind of terbutaline sulfate intermediate, and its structural formula is as shown in formula I:

wherein R is H or benzyl.

The application further provides the preparation method of above-mentioned terbutaline sulfate intermediate, and its synthetic route is as follows:

Wherein, R' is acetyl or benzyl; When R' is acetyl, R is H, when R' is benzyl, R is benzyl;

Include the following steps:

A, compound 1 reacts with bromine to obtain compound 2;

B, compound 2 reacts with compound 3, and the reaction is completed, and after recovering the solvent, a residue is obtained;

When R' is acetyl, the residue is extracted with hydrochloric acid or hydrobromic acid, the acid water extract is hydrolyzed by heating, cooled and filtered to obtain compound 4 hydrochloride or hydrobromide (ie 2-benzyl tert-butylamino-1 -(3,5 dihydroxy)acetophenone hydrochloride or hydrobromide);

When R' is benzyl, organic solvent is added to the residue, extracted with hydrochloric acid or hydrobromic acid, and the aqueous acid layers are combined to obtain compound 4 as an aqueous solution of hydrochloride or hydrobromide (ie, 2-benzyl-tert-butylamino-1 -(3,5dibenzyloxy)acetophenone hydrochloride or hydrobromide aqueous solution);

C. Compound 4 is made into a mixed solution of water and an organic solvent, and after alkalization is freed, an organic layer is obtained, and sulfuric acid is added to the organic layer to form a salt to obtain the compound of formula I.

Wherein, in the above-mentioned preparation method of terbutaline sulfate intermediate, in step A, the molar ratio of compound 1 and bromine is 1:1-1.3.

Wherein, in the preparation method of the above-mentioned terbutaline sulfate intermediate, the specific operation of step A is as follows: compound 1 is dissolved in dichloromethane, a small amount of bromine-dichloromethane solution is added dropwise to it to initiate the reaction, and then cooled to 10° C. The bromine-dichloromethane solution is continued to be added dropwise below, and after the dropwise addition, the reaction solution is washed with water, concentrated, and crystallized from anhydrous ethanol to obtain compound 2.

Wherein, in the above-mentioned preparation method of terbutaline sulfate intermediate, in step B, the molar ratio of compound 2 and compound 3 is 1:2-3.

Wherein, in the above-mentioned preparation method of the terbutaline sulfate intermediate, in step B, the reaction conditions of compound 2 and compound 3 are as follows: using ketone as a solvent, and performing a reflux reaction for 2-4 hours.

Preferably, in the preparation method of the above-mentioned terbutaline sulfate intermediate, in step B, the ketone is at least one of butanone, 2-pentanone, methyl isopropyl ketone or methyl tert-butyl ketone .

More preferably, in the above-mentioned preparation method of terbutaline sulfate intermediate, in step B, the ketone is butanone.

Wherein, in the above-mentioned preparation method of terbutaline sulfate intermediate, in step B, the concentration of hydrochloric acid or hydrobromic acid is 0.5mol-1.5mol/L, and the thin-layer method is used to monitor whether the extraction is complete.

Wherein, in the preparation method of the above-mentioned terbutaline sulfate intermediate, in step B, when R' is an acetyl group, the conditions for the heating and hydrolysis are: 30～60 ℃ thermal insulation reaction, and the end point of the hydrolysis is monitored by a thin layer method.

Wherein, in the preparation method of the above-mentioned terbutaline sulfate intermediate, in step C, the conditions for alkalization and disassociation are: alkalization until the pH of the reaction solution is 8-9, and the alkali is sodium carbonate, potassium carbonate, and sodium hydroxide or at least one of potassium hydroxide.

Preferably, in the preparation method of the above-mentioned terbutaline sulfate intermediate, in step C, the alkali is sodium carbonate or potassium carbonate.

Wherein, in the above-mentioned preparation method of terbutaline sulfate intermediate, in step C, the conditions for sulfuric acid salification are: sulfuric acid adjusts the pH of the organic layer to 5±0.2.

The present invention further utilizes the method for preparing the obtained terbutaline sulfate intermediate to prepare the terbutaline sulfate by the above-mentioned method, and its synthetic route is as follows:

Wherein, R is H or benzyl;

The method comprises the following steps: using 10% Pd/C as a catalyst, an aqueous alcohol solution as a solvent, and introducing H ₂ to reduce the intermediate of formula I terbutaline sulfate to obtain terbutaline sulfate of formula II.

Wherein, in the above-mentioned method for preparing terbutaline sulfate, the mass ratio of the compound of formula I to 10% Pd/C is 1:0.02-0.1.

Preferably, in the above-mentioned method for preparing terbutaline sulfate, the mass ratio of the compound of formula I to 10% Pd/C is 1:0.03-0.05.

Wherein, in the above-mentioned method for preparing terbutaline sulfate, the aqueous alcohol solution is an aqueous methanol solution or an aqueous ethanol solution with a content of 50% to 95%.

Preferably, in the above-mentioned method for preparing terbutaline sulfate, the aqueous alcohol solution is a 60% to 90% aqueous methanol solution or an aqueous ethanol solution.

Wherein, in the above-mentioned method for preparing terbutaline sulfate, the dosage ratio of the compound of formula I to the aqueous alcohol solution is 1 g: 10-20 mL.

Preferably, in the above-mentioned method for preparing terbutaline sulfate, the dosage ratio of the compound of formula I to the aqueous alcohol solution is 1 g: 15 mL.

Wherein, in the above-mentioned method for preparing terbutaline sulfate, the hydrogenation reduction temperature is 15-50°C.

Preferably, in the above-mentioned method for preparing terbutaline sulfate, the hydrogenation reduction temperature is 15-35°C.

Wherein, in the above-mentioned method for preparing terbutaline sulfate, the hydrogenation reduction pressure is normal pressure～0.5Mpa.

Preferably, in the above-mentioned method for preparing terbutaline sulfate, the hydrogenation reduction pressure is normal pressure～0.2Mpa.

Beneficial effects of the present invention:

In the present invention, compound 4 is converted into formula I before hydrogenation reduction, and its advantages are: 1. The salt properties are stable, and terbutaline sulfate is directly obtained after hydrogenation reduction. The extremely unstable terbutaline free base alone causes the product quality and yield to decline; 2. The reaction conditions are mild: hydrogenation reduction can be performed at normal temperature and pressure, and the reaction time is short; 3. The yield is high, and the hydrogenation reduction yields The rate is 90-98%, and the terbutaline sulfate is less than 0.1%; 4. The amount of palladium carbon added is reduced by 3-5% of the main drug (10% in the literature), reducing product cost; 5. Avoid The use of a class of organic solvents.

The method of the invention has the advantages of mild reaction conditions, high product yield, high purity, low production cost and the like, fully meets the requirements of industrial production, and has popularization value.

Description of drawings

Fig. 1 is the carbon nuclear magnetic resonance spectrum of the compound of formula I (R is H).

Figure 2 is a hydrogen nuclear magnetic resonance spectrum of the compound of formula I (R is H).

Figure 3 is an infrared spectrum of terbutaline sulfate.

Figure 4 is a carbon spectrum of terbutaline sulfate.

Figure 5 is a hydrogen spectrum of terbutaline sulfate.

6 is the HPLC detection chart of the purified terbutaline sulfate in Example 17.

Fig. 7 is the HPLC detection chart of purified terbutaline sulfate in Example 18.

Fig. 8 is the HPLC detection chart of purified terbutaline sulfate in Example 19.

Detailed ways

The inventor's experiments found that: Compound 4 hydrochloride or hydrobromide is relatively stable. According to the literature method, compound 4 hydrochloride or hydrobromide is used for hydrogenation reduction at 35 ° C and 0.5Mpa, and the benzyl group is easy to hydrogenolysis, but The carbonyl group is difficult to reduce, the temperature is raised to 50°C, the pressure is raised to 1.2-1.5Mpa, and it takes more than 15 hours to complete the hydrogenation, and the yield is generally about 70%; at the same time, the free base of terbutaline is water-soluble. It is extremely large and cannot be extracted from water at all, and the free base is extremely unstable, and it is easily oxidized and discolored during storage at room temperature, resulting in a decrease in product quality and yield. Therefore, after a lot of attempts in the present invention, before hydrogenation reduction, compound 4 hydrochloride or hydrobromide is converted into formula I, so as to avoid the above situation, and obtain terbutaline sulfate in a more excellent situation.

Concrete, terbutaline sulfate intermediate, its structural formula is as shown in formula I:

wherein R is H or benzyl.

The application further provides the preparation method of above-mentioned terbutaline sulfate intermediate, and its synthetic route is as follows:

Wherein, R' is acetyl or benzyl; When R' is acetyl, R is H, when R' is benzyl, R is benzyl;

Include the following steps:

A, compound 1 reacts with bromine to obtain compound 2;

B, compound 2 reacts with compound 3, and the reaction is completed, and after recovering the solvent, a residue is obtained;

When R' is an acetyl group, the residue is extracted with hydrochloric acid or hydrobromic acid, the acid water extract is hydrolyzed by heating, cooled, filtered and dried to obtain compound 4 hydrochloride or hydrobromide;

When R' is benzyl, the residue is added with an organic solvent, then extracted with hydrochloric acid or hydrobromic acid, and the acid water layers are combined to obtain an aqueous solution of compound 4 hydrochloride or hydrobromide;

C. Compound 4 is made into a mixed solution of water and an organic solvent, and after alkalization is freed, an organic layer is obtained, and sulfuric acid is added to the organic layer to form a salt to obtain the compound of formula I.

In step A, the molar ratio of compound 1 to bromine is 1:1 to 1.3; the specific operation is as follows: compound 1 is dissolved in dichloromethane, a small amount of bromine-dichloromethane solution is added dropwise to it to initiate the reaction, and then cooled to The bromine-dichloromethane solution was continued to be added dropwise below 10°C. After the dropwise addition, the reaction solution was washed with water, concentrated, and crystallized from anhydrous ethanol to obtain compound 2 with a bromination yield of 78-86%.

In step B, the molar ratio of compound 2 to compound 3 is 1:2 to 3; the reaction conditions of compound 2 and compound 3 are as follows: using ketone as a solvent, the reaction is refluxed for 2 to 4 hours. The ketone may be butanone, 2-pentanone, methyl isopropyl ketone, methyl tert-butyl ketone, preferably butanone.

In step B, the inventors have tried to directly extract the residue with sulfuric acid to prepare formula I, but the obtained compound of formula I has low yield and poor quality, so the sulfuric acid extraction and hydrolysis method is not used. In step B, the concentration of hydrochloric acid or hydrobromic acid is 0.5mol～1.5mol/L, adopt the thin layer method to monitor whether the extraction is complete (the thin layer condition is: silica gel GF254 thin layer plate, and the developing agent is dichloromethane: ethyl acetate) : triethylamine volume ratio 10:1:0.4, UV lamp 254nm color development).

In step B, after acid extraction, according to different substituents, the acid water treatment method is different: when R' is an acetyl group, the acid water extract needs to be heated and hydrolyzed to remove the acetyl group. The reaction was incubated at 60°C, and the end point of the hydrolysis was monitored by the thin-layer method (the thin-layer conditions were: silica gel GF254 thin-layer plate, the developing solvent was dichloromethane:ethyl acetate:triethylamine volume ratio of 10:1:0.4, and the UV lamp was displayed at 254 nm. color), after the reaction is completed, cool and filter, collect the solid compound 4 (this compound 4 needs to add water and an organic solvent in step C, so as to basify free and sulfuric acid into a salt); when R' is benzyl, combine the acid The aqueous layer is obtained to obtain an aqueous solution of compound 4 hydrochloride or hydrobromide (this aqueous solution needs to add an organic solvent in step C, so as to basify the free and sulfuric acid to form a salt). In step B, the yield of the two steps of condensation and hydrolysis is 60-70%.

In step C, the conditions for alkalization and dissociation are: adding alkali to neutralize the pH of the reaction solution to 8 to 9; then separating the organic layer, dehydrating anhydrous sodium sulfate, and forming salts with sulfuric acid; The pH of the layer is to 5±0.2; when sulfuric acid is formed into a salt, the pH requirement needs to be more precise, so it is preferable to adjust the pH of the organic layer to 5 with sulfuric acid. In step C, the yield of compound 4 hydrochloride or hydrobromide converted to sulfate is 95-98%.

In steps B and C, the purpose of adding organic solvent and water is for alkalization, the free base of formula I is immediately introduced into the organic layer, and the inorganic salt produced after neutralization is dissolved in the water layer, so it can be reacted according to actual conditions. And the separation situation, control the amount of water and organic solvent added. The organic solvent can be ethyl acetate, dichloromethane, diethyl ether, isopropyl ether, preferably ethyl acetate.

The present invention further utilizes the method for preparing the obtained terbutaline sulfate intermediate to prepare the terbutaline sulfate by the above-mentioned method, and its synthetic route is as follows:

Wherein, R is H or benzyl;

The method comprises the following steps: using 10% Pd/C as a catalyst, an aqueous alcohol solution as a solvent, and introducing H ₂ to reduce the intermediate of formula I terbutaline sulfate to obtain terbutaline sulfate of formula II.

In the above method for preparing terbutaline sulfate, the mass ratio of the compound of formula I to 10% Pd/C is 1:0.02-0.1, preferably 1:0.03-0.05; the aqueous alcohol solution is an aqueous methanol solution with a content of 50%-95% or ethanol aqueous solution, preferably 60%～90% methanol aqueous solution or ethanol aqueous solution; the dosage ratio of the compound of formula I to the alcoholic aqueous solution is 1g: 10～20mL, preferably 1g: 15mL; the reduction temperature is 15～50 ℃, preferably 15～35℃; the reduction pressure is normal pressure～0.5Mpa, preferably normal pressure～0.2Mpa. In this step, TLC is monitored until the hydrogenation reaction of the raw materials is complete, silica gel GF ₂₅₄ , the developing solvent is dichloromethane:methanol:triethylamine volume ratio 10:2:1, UV lamp 254nm color development; hydrogenation reduction yield 90～98 %.

As can be seen from the above, the present invention adopts formula I reduction to prepare terbutaline sulfate, the reaction can be hydrogenated and reduced at normal temperature and pressure, the amount of palladium carbon is small, the reaction time is short, and the yield of terbutaline sulfate is as high as 90-98%, The single-impurity average of the refined product is less than 0.1%, which is more conducive to realizing the industrial production of terbutaline sulfate.

The refining steps of the crude terbutaline sulfate are as follows: decolorization with activated carbon, crystallization from alcohol (methanol or ethanol); the refining yield is 90-95%.

The present invention will be further described in detail below through the examples, but the protection scope of the present invention is not limited to the scope of the described examples.

Example 1: Preparation of compound 2 (R' is acetyl)

76mL of dichloromethane and 38g of 3,5-diacetoxyacetophenone were added to the reaction flask with the tail gas absorption device, after stirring and dissolving completely, several drops of bromine-dichloromethane mixed solution (bromine) were added dropwise at room temperature. 27g of dichloromethane 27ml), keep stirring until there is acid gas (check with moist pH test paper) and cool to below 10°C when escaping, and keep adding bromine-dichloromethane solution dropwise, TLC monitoring raw material spots basically disappear ( TLC monitoring method: silica gel GF ₂₅₄ , developing solvent: dichloromethane-ethyl acetate (10:1), UV lamp 254nm color development), stop the reaction. The reaction solution was washed with water until the pH of the aqueous layer was 6-7, the dichloromethane layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to dryness under reduced pressure. The residue was crystallized by adding anhydrous ethanol to obtain 41.6 g of compound 2 with a yield of 82%. .

Example 2: Preparation of compound 2 (R' is acetyl)

Add 236g of 3,5-diacetoxyacetophenone and 500mL of dichloromethane to the reaction flask with the tail gas absorption device, after stirring and dissolving completely, add a few drops of a solution of 160g of bromine and 160ml of dichloromethane at room temperature, Keep stirring until hydrogen bromide gas (check with wet pH test paper) escapes, cool down to below 10°C, continue to add bromine dichloromethane solution dropwise, TLC monitoring raw material spots basically disappear (thin layer monitoring method: silica gel GF ₂₅₄ , developing solvent: dichloromethane-ethyl acetate (10:1), UV lamp 254nm color development), washed with water to pH 6-7, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure, the residue was Add anhydrous ethanol for crystallization to obtain compound 2, the yield is 246 g, and the yield is 78%.

Example 3: Preparation of compound 2 (R' is acetyl)

Add 236g of 3,5-diacetoxyacetophenone and 472mL of dichloromethane to the reaction flask with the tail gas absorption device, after stirring and dissolving completely, add 176g of bromine and 176mL of dichloromethane solution dropwise with stirring at room temperature. After hydrogen bromide gas (check with wet pH test paper) escapes, cool down to below 10°C, continue to add bromine dichloromethane solution dropwise, TLC monitoring raw material spots basically disappear (thin layer monitoring method: silica gel GF ₂₅₄ , Developing solvent: dichloromethane-ethyl acetate (10:1), UV lamp 254nm color development), pass nitrogen or air to remove hydrogen bromide, wash with water to pH 6-7, dry the organic layer over anhydrous magnesium sulfate, filter, reduce The solvent was removed by pressure, and the residue was crystallized by adding anhydrous ethanol to obtain compound 2, the yield was 271 g, and the yield was 86%.

Example 4: Preparation of compound 2 (R' is benzyl)

Add 332g of 3,5-dibenzyloxyacetophenone and 665mL of dichloromethane to the reaction flask with the tail gas absorption device, after stirring and dissolving completely, add 165g of bromine and 165ml of dichloromethane solution dropwise with stirring at room temperature. After hydrogen bromide gas (check with wet pH test paper) escapes, cool down to below 10°C, continue to add bromine dichloromethane solution dropwise, TLC monitoring raw material spots basically disappear (thin layer monitoring method: silica gel GF ₂₅₄ , Developing solvent: dichloromethane-ethyl acetate (10:1), UV lamp 254nm color development), pass nitrogen or air to remove hydrogen bromide, wash with water to pH 6-7, dry the organic layer over anhydrous magnesium sulfate, filter, reduce The solvent was removed by pressure, and the residue was crystallized by adding anhydrous ethanol to obtain compound 2, the yield was 329 g, and the yield was 80%.

Example 5: Preparation of compound 4 (R' is acetyl)

315g of compound 2 (R' is acetyl), 400g of N-benzyl tert-butylamine and 3.5L of butanone were added to the reaction flask, heated to reflux for about 2 hours, and the thin-layer method monitored and monitored whether the reaction was complete (the thin-layer conditions were: silica gel GF254 thin layer) Layer plate, developing solvent: dichloromethane-ethyl acetate (10:1), cooled, filtered to remove insoluble matter, recovered under reduced pressure, butanone, and the residue was extracted with 1 mol/L hydrochloric acid for 2 to 3 times, about 800 mL each time, Monitor whether the extraction is complete by thin-layer method (the thin-layer conditions are: silica gel GF254 thin-layer plate, developing solvent: dichloromethane-ethyl acetate-triethylamine (10:1:0.4), UV lamp 254nm color development). Combine acid The water layer was kept at 30°C for about 15 hours, the end point of the hydrolysis was monitored by the thin-layer method (the thin-layer conditions were the same as above), cooled, filtered, and dried to obtain 245 g of compound 4 (hydrochloride, R is H), with a yield of 70%.

Example 6: Preparation of compound 4 (R' is acetyl)

315g of compound 2 (R' is acetyl), 326g of N-benzyl tert-butylamine and 3.5L of butanone were added to the reaction flask, heated to reflux for about 3 hours (whether the extraction was complete by thin-layer method, the method was the same as above), cooled, filtered to remove insoluble The residue was extracted with 1 mol/L hydrochloric acid for 2 to 3 times, with about 800 mL each time (the thin-layer method was used to monitor whether the extraction was complete, the method was the same as above), the acid water layers were combined, and the temperature was kept at 50 °C for about 6 hours. The end point of hydrolysis was monitored by thin-layer method (the thin-layer conditions were the same as above), filtered by cooling, and dried to obtain 210 g of compound 4 (hydrochloride, R is H), with a yield of 60%.

Example 7: Preparation of compound 4 (R' is acetyl)

315g of compound 2 (R' is acetyl), 450g of N-benzyl tert-butylamine and 3.5L of butanone were added to the reaction flask, heated to reflux for about 3 hours (whether the reaction was completed by thin-layer method, the method was the same as above), cooled, filtered to remove insoluble The residue was extracted with 1 mol/L hydrobromic acid for 2 to 3 times (the thin-layer method was used to monitor whether the extraction was complete, the method was the same as above), 800 mL each time, and the acid water layer was combined, and the temperature was kept at 55 °C for about 3.5 hours. , the end point of hydrolysis was monitored by thin-layer method (the thin-layer conditions were the same as above), cooled, filtered, and dried to obtain 267 g of compound 4 (hydrobromide salt, R is H), with a yield of 68%.

Example 8: Preparation of compounds of formula I (R is H)

Add 55 g of compound 4 (hydrochloride) obtained in Example 5 and 250 mL of water into the reaction flask, add 250 mL of ethyl acetate, add sodium carbonate to pH 8-9 under stirring, separate the organic layer and dry with anhydrous sodium sulfate, and add dropwise sulfuric acid. The pH was adjusted to 5, filtered and dried to obtain 55.8 g of the compound of formula I (R is H) with a yield of 98%.

Example 9: Preparation of compound of formula I (R is H)

50 g of compound 4 (hydrobromide) obtained in Example 7 and 220 mL of water were added to the reaction flask, 220 mL of ethyl acetate was added, and sodium carbonate was added to pH 8 to 9 under stirring. Under stirring at room temperature, sulfuric acid was added dropwise to pH 5 to precipitate a solid, which was filtered and dried to obtain 44.1 g of the compound of formula I (R is H) with a yield of 96%.

Example 10: Preparation of compounds of formula I (R is benzyl)

41g of compound 2 (R' is benzyl), 40g of N-benzyl tert-butylamine and 350mL of butanone were added to the reaction flask, heated under reflux for about 3 hours (whether the reaction was complete by thin-layer method, the method is the same as above), cooled and filtered to remove insolubles , recover butanone under reduced pressure, add 200 mL of ethyl acetate to the residue, extract with 1 mol/L hydrobromic acid for 2 to 3 times (the thin-layer method monitors whether the extraction is complete, the method is the same as above), 80 mL each time, and combine the acid water layers to obtain Aqueous hydrobromic acid solution of compound 4 (R is benzyl); 300 mL of ethyl acetate was added thereto, and the pH was adjusted to 8-9 with sodium carbonate under stirring, the organic layer was separated, dehydrated with anhydrous sodium sulfate, and the ethyl acetate layer was adjusted with sulfuric acid pH5, filtration and drying to obtain 33 g of formula I (R is benzyl) with a yield of 61%.

Example 11: Preparation of Terbutaline Sulfate

36.2g of formula I compound (R=H), 540mL of 90% ethanol, 1.8g of 10% Pd-C were added to the reaction flask, the air was exhausted, and the hydrogen was hydrogenated at atmospheric pressure for about 20 hours (TLC monitoring until the hydrogenation reaction of the raw materials was complete, Silica gel GF ₂₅₄ , developing solvent: dichloromethane-methanol-triethylamine (10:2:1), UV lamp 254nm color development), filter, remove the solvent under reduced pressure, add absolute ethanol to cool and crystallize, filter and dry to obtain sulfuric acid The crude product of terbutaline was 26.8 g, and the yield was 98%.

Example 12: Preparation of Terbutaline Sulfate

36.2g of the compound of formula I (R=H), 450mL of 80% ethanol, 1.6g of 10% Pd-C were added to the reaction flask, the air was exhausted, and the hydrogen was hydrogenated at atmospheric pressure for 20 hours (TLC was monitored until the hydrogenation reaction of the raw materials was complete, silica gel GF ₂₅₄ , developing solvent: dichloromethane-methanol-triethylamine (10:2:1), UV lamp 254nm color development), filter, remove the solvent under reduced pressure, add absolute ethanol to cool and crystallize, filter and dry to obtain special sulfate. 24.7g crude butaline, the yield is 90%.

Example 13: Preparation of Terbutaline Sulfate

36.2g of formula I compound (R=H) and 540mL of 90% ethanol, 1.1g of 10% Pd-C were added to the reactor, the air was exhausted, and the hydrogen pressure 0.15mpa was hydrogenated for about 10 hours (TLC monitoring until the raw material hydrogenation reaction was complete, Silica gel GF ₂₅₄ , developing solvent: dichloromethane-methanol-triethylamine (10:2:1), UV lamp 254nm color development), filter, remove the solvent under reduced pressure, add absolute ethanol to cool and crystallize, filter and dry to obtain sulfuric acid The crude product of terbutaline was 25.2 g, and the yield was 92%.

Example 14: Preparation of Terbutaline Sulfate

36.2g of formula I compound (R=H) and 540mL of 90% ethanol, 1.8g of 10% Pd-C were added to the reaction flask, the air was exhausted, and the hydrogen pressure 0.2mpa was hydrogenated for 7 hours (TLC was monitored until the hydrogenation reaction of the raw material was complete, Silica gel GF ₂₅₄ , developing solvent: dichloromethane-methanol-triethylamine (10:2:1), UV lamp 254nm color development), filter, remove the solvent under reduced pressure, add absolute ethanol to cool and crystallize, filter and dry to obtain sulfuric acid The crude product of terbutaline was 26.6 g, and the yield was 98%.

Example 15: Preparation of Terbutaline Sulfate

36.2g of the compound of formula I (R=H), 600mL of 95% methanol, 1.7g of 10% Pd-C were added to the reaction flask, the air was exhausted, and the hydrogen was hydrogenated at atmospheric pressure for about 25 hours (TLC monitoring until the hydrogenation reaction of the raw materials was complete, Silica gel GF ₂₅₄ , developing solvent: dichloromethane-methanol-triethylamine (10:2:1), UV lamp 254nm color development), filter, remove the solvent under reduced pressure, add absolute ethanol to cool and crystallize, filter and dry to obtain sulfuric acid The crude product of terbutaline was 25.2 g, and the yield was 92%.

Example 16: Preparation of Terbutaline Sulfate

33g of the compound of formula I (R=benzyl) obtained in Example 10, 480mL of 90% ethanol, 1.6g of 10% Pd-C were added to the reaction flask, the air was exhausted, and the hydrogen pressure 0.2mpa was hydrogenated for about 7 hours (TLC monitoring to The hydrogenation reaction of the raw materials is complete, silica gel GF ₂₅₄ , developing solvent: dichloromethane-methanol-triethylamine (10:2:1), UV lamp 254nm color development), filter, remove the solvent under reduced pressure, add anhydrous ethanol to cool and crystallize , filtered and dried to obtain 15 g of crude terbutaline sulfate, with a yield of 90%.

Example 17: Purification of Terbutaline Sulfate

50g and 1500mL of 95% ethanol obtained in Examples 11-16 were added to the reaction flask, heated and refluxed to dissolve, 3g of activated carbon was added for decolorization for 20mins, filtered, and the filtrate was crystallized by cooling to obtain 47.5g of terbutaline sulfate, the yield was 95%, and the related substances were less than 0.1%, see Figure 6 for HPLC results.

Example 18: Purification of Terbutaline Sulfate

50g of the crude product and 1000mL of 95% methanol obtained in Examples 11-16 were added to the reaction flask, heated and refluxed to dissolve, 3g of activated carbon was added for decolorization for 20mins, filtered, and the filtrate was crystallized by cooling to obtain 46.5g of terbutaline sulfate, the yield was 93%, and the related substances were less than 0.1%, the HPLC results are shown in Figure 7.

Example 19: Purification of Terbutaline Sulfate

Add 50 g of the crude product obtained in Examples 11 to 16 and 1100 mL of 95% methanol into a reaction flask, heat under reflux to dissolve, add 3 g of activated carbon for decolorization for 20 mins, filter, and crystallize the filtrate by cooling to obtain 45 g of terbutaline sulfate, yield 90%, and related substances less than 0.1 %, and the HPLC results are shown in Figure 8.

Claims (10)

1. Terbutaline sulfate intermediate, is characterized in that: its structural formula is as shown in formula I:

wherein R is H or benzyl. 2. the preparation method of the described terbutaline sulfate intermediate of claim 1, is characterized in that: synthetic route is as follows:

Wherein, R' is acetyl or benzyl; When R' is acetyl, R is H, when R' is benzyl, R is benzyl; Include the following steps: A, compound 1 reacts with bromine to obtain compound 2; B, compound 2 reacts with compound 3, and the reaction is completed, and after recovering the solvent, a residue is obtained; When R' is an acetyl group, the residue is extracted with hydrochloric acid or hydrobromic acid, the acid water extract is hydrolyzed by heating, cooled, filtered and dried to obtain compound 4; When R' is benzyl, the residue is added with an organic solvent, then extracted with hydrochloric acid or hydrobromic acid, and the aqueous acid layers are combined to obtain an aqueous solution of compound 4; C. Compound 4 is made into a mixed solution of water and an organic solvent, and after alkali is added to make it free, an organic layer is obtained, and sulfuric acid is added to the organic layer to form a salt to obtain the compound of formula I. 3. The preparation method of the terbutaline sulfate intermediate according to claim 2, characterized in that: in step A, the molar ratio of compound 1 to bromine is 1:1 to 1.3. 4. the preparation method of terbutaline sulfate intermediate according to claim 2, is characterized in that: the concrete operation of step A is: compound 1 is dissolved in dichloromethane, to wherein drip a small amount of bromine-dichloromethane The solution initiates the reaction, and then cooled to below 10° C. to continue adding the bromine-dichloromethane solution dropwise. After the dropwise addition, the reaction solution is washed with water, concentrated, and crystallized from anhydrous ethanol to obtain compound 2. 5. The preparation method of the terbutaline sulfate intermediate according to claim 2, characterized in that: in step B, the molar ratio of compound 2 to compound 3 is 1:2 to 3; the reaction conditions of compound 2 and compound 3 are: : use ketone as solvent, and conduct reflux reaction for 2 to 4 hours; the ketone is at least one of butanone, 2-pentanone, methyl isopropyl ketone or methyl tert-butyl ketone; preferably butanone. 6. the preparation method of terbutaline sulfate intermediate according to claim 2, is characterized in that: in step B, the concentration of hydrochloric acid or hydrobromic acid is 0.5mol～1.5mol/L, adopts thin layer method to monitor and extract whether Complete; when R' is an acetyl group, the conditions for the heating and hydrolysis are: 30-60° C. for the reaction, and the end point of the hydrolysis is monitored by a thin-layer method. 7. according to the preparation method of the described terbutaline sulfate intermediate of any one of claim 2～6, it is characterized in that: in step C, the condition that alkalization is free is: adding alkali and neutralizing to reaction solution pH is 8～ 9. The alkali is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; preferably sodium carbonate or potassium carbonate; the conditions for sulfuric acid salification are: sulfuric acid adjusts the pH of the organic layer to 5±0.2. 8. Utilize any one method of claim 2～7 to prepare the method for gained terbutaline sulfate intermediate to prepare terbutaline sulfate, it is characterized in that: synthetic route is as follows:

Wherein, R is H or benzyl; The method comprises the following steps: using 10% Pd/C as a catalyst, an aqueous alcohol solution as a solvent, and introducing H ₂ to reduce the intermediate of formula I terbutaline sulfate to obtain terbutaline sulfate of formula II. 9. the method for preparing terbutaline sulfate according to claim 8 is characterized in that: at least the following one is satisfied: The mass ratio of the compound of formula I to 10% Pd/C is 1:0.02-0.1; preferably 1:0.03-0.05; The alcohol aqueous solution is an aqueous methanol solution or an aqueous ethanol solution with a content of 50% to 95%; preferably an aqueous methanol solution or an aqueous ethanol solution of 60% to 90%; The dosage ratio of the compound of formula I to the aqueous alcohol solution is 1 g: 10-20 mL; preferably, it is 1 g: 15 mL. 10. The method for preparing terbutaline sulfate according to claim 8 or 9, characterized in that: at least one of the following is satisfied: The reduction temperature is 15～50℃; preferably 15～35℃; The reduction pressure is from normal pressure to 0.5Mpa; preferably from normal pressure to 0.2Mpa.

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