CN111499528A - Terbutaline sulfate intermediate, preparation method thereof and method for preparing terbutaline sulfate by using terbutaline sulfate intermediate - Google Patents
Terbutaline sulfate intermediate, preparation method thereof and method for preparing terbutaline sulfate by using terbutaline sulfate intermediate Download PDFInfo
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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
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a terbutaline sulfate intermediate, a preparation method thereof and a method for preparing terbutaline sulfate by using the terbutaline sulfate intermediate.
Background
The terbutaline (terbutaline) is chemically named as 1- (3, 5-dihydroxyphenyl) -2-tert-butylaminoethanol, is an adrenergic β 2 receptor (β 2 receptor) agonist, is one of the main current antiasthmatic drugs, has high selectivity on a β 2 receptor and small cardiac side effect, is suitable for asthma patients with cardiovascular diseases such as hypertension and coronary heart disease, has the advantages of high curative effect, quick response, long acting time, small side effect and the like, and the clinical application of the β 2 receptor agonist is preferred for inhalation treatment, is an effective method for light and moderate asthma patients and has small side effect.
According to the research of domestic and foreign documents, the synthesis method of terbutaline mainly comprises the following steps: bromizing 3, 5-diacetoxyacetophenone or 3, 5-dibenzyloxyacetophenone as a raw material to obtain 2-bromo-3, 5-diacetoxyacetophenone or 2-bromo-3, 5-dibenzyloxyacetophenone, aminating and condensing the product with N-benzyl tert-butylamine to obtain 2-N-benzyl tert-butylamine-3, 5-diacetoxyacetophenone or 2-N-benzyl tert-butylamine-3, 5-dibenzyloxyacetophenone, carrying out Pd-C pressure hydrogenolysis on debenzyl by 10% and reducing carbonyl by using 10% of Pd-C or reducing carbonyl by using sodium borohydride to obtain 2-tert-butylamine-1- (3, 5-diacetoxyphenyl) ethanol or 2-tert-butylamine-1- (3, 5-dihydroxyphenyl) ethanol, hydrolyzing the 2-tert-butylamine-1- (3, 5-diacetyloxyphenyl) ethanol by hydrobromic acid to obtain the 2-tert-butylamine-1- (3, 5-dihydroxyphenyl) ethanol. The main reaction formula involved in the method is as follows:
the above synthesis method mainly has the following disadvantages: firstly, high-pressure reaction is required to be carried out in a reaction kettle, and the requirement on safety is high; secondly, reducing carbonyl by sodium borohydride can avoid a pressurization reaction, but post-treatment of the reduced reaction liquid is difficult; because the borate and terbutaline free base generated after the carbonyl is reduced by sodium borohydride or the salt formed by the free base and the acid have particularly good water solubility, the borate and the terbutaline free base are difficult to separate from the aqueous solution; thirdly, the mode of reducing firstly and then forming sulfate is adopted, the reduction condition is harsh, the extraction difficulty of terbutaline free alkali is high, and the property of the free alkali is extremely unstable, so that the product quality and the yield are reduced; fourthly, organic solvents such as chloroform, benzene and the like are needed for the reaction.
Disclosure of Invention
The invention aims to provide a novel method for preparing terbutaline sulfate, which has mild reaction conditions, high yield and environmental protection.
Based on the purpose, the invention firstly provides a terbutaline sulfate intermediate, the structural formula of which is shown as the formula I:
wherein R is H or benzyl.
The application further provides a preparation method of the terbutaline sulfate intermediate, and the synthetic route is as follows:
wherein R' is acetyl or benzyl; when R 'is acetyl, R is H, and when R' is benzyl, R is benzyl;
the method comprises the following steps:
A. reacting the compound 1 with bromine to obtain a compound 2;
B. reacting the compound 2 with the compound 3, and after the reaction is finished, recovering the solvent to obtain a residue;
when R' is acetyl, extracting the residue with hydrochloric acid or hydrobromic acid, heating and hydrolyzing the acid water extract, cooling and filtering to obtain compound 4 hydrochloride or hydrobromide (namely 2-benzyl tert-butylamine-1- (3,5 dihydroxy) acetophenone hydrochloride or hydrobromide);
when R' is benzyl, adding organic solvent into the residue, extracting with hydrochloric acid or hydrobromic acid, and mixing the acid water layers to obtain compound 4 hydrochloride or hydrobromide aqueous solution (i.e. 2-benzyl tert-butylamine-1- (3,5 dibenzyloxy) acetophenone hydrochloride or hydrobromide aqueous solution);
C. preparing the compound 4 into a mixed solution of water and an organic solvent, carrying out alkalization and dissociation, separating to obtain an organic layer, and adding sulfuric acid into the organic layer to form a salt, thereby obtaining the compound shown in the formula I.
In the preparation method of the terbutaline sulfate intermediate, in the step A, the molar ratio of the compound 1 to bromine is 1: 1 to 1.3.
The preparation method of the terbutaline sulfate intermediate comprises the following specific operations in the step A: dissolving the compound 1 in dichloromethane, dropwise adding a small amount of bromine-dichloromethane solution to the solution to initiate reaction, then cooling the solution to below 10 ℃, continuously dropwise adding the bromine-dichloromethane solution, washing the reaction solution with water after the dropwise adding is finished, concentrating the reaction solution, and crystallizing the reaction solution with absolute ethyl alcohol to obtain a compound 2.
In the preparation method of the terbutaline sulfate intermediate, in the step B, the molar ratio of the compound 2 to the compound 3 is 1: 2 to 3.
In the preparation method of the terbutaline sulfate intermediate, in the step B, the reaction conditions of the compound 2 and the compound 3 are as follows: and (3) taking ketone as a solvent, and carrying out reflux reaction for 2-4 h.
Preferably, in the preparation method of 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 preparation method of the terbutaline sulfate intermediate, in the step B, the ketone is butanone.
In the preparation method of the terbutaline sulfate intermediate, in the step B, the concentration of hydrochloric acid or hydrobromic acid is 0.5-1.5 mol/L, and whether the extraction is complete is monitored by adopting a thin layer method.
In the preparation method of the terbutaline sulfate intermediate, in the step B, when R' is acetyl, the heating hydrolysis conditions are as follows: and (3) carrying out heat preservation reaction at 30-60 ℃, and monitoring the hydrolysis end point by adopting a thin layer method.
In the preparation method of the terbutaline sulfate intermediate, in the step C, the alkalization dissociating condition is as follows: alkalizing until the pH of the reaction liquid is 8-9, wherein the alkali is at least one of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Preferably, in the preparation method of the terbutaline sulfate intermediate, in the step C, the base is sodium carbonate or potassium carbonate.
In the preparation method of the terbutaline sulfate intermediate, in the step C, the condition of salt formation of sulfuric acid is as follows: sulfuric acid adjusted the organic layer pH to 5 ± 0.2.
The invention further discloses a method for preparing terbutaline sulfate by utilizing the terbutaline sulfate intermediate prepared by the method, and the synthetic route is as follows:
wherein R is H or benzyl;
the method comprises the following steps: using 10% Pd/C as catalyst and alcohol-water solution as solvent, introducing H2And reducing the terbutaline sulfate intermediate in the formula I to obtain terbutaline sulfate in the formula II.
Wherein, in the method for preparing terbutaline sulfate, the mass ratio of the compound in the formula I to 10% Pd/C is 1: 0.02 to 0.1.
Preferably, in the above method for preparing terbutaline sulfate, the mass ratio of the compound of formula I to 10% Pd/C is 1: 0.03 to 0.05.
Wherein, in the method for preparing terbutaline sulfate, the alcohol-water solution is methanol water solution or ethanol water solution with the content of 50-95 percent.
Preferably, in the above method for preparing terbutaline sulfate, the alcohol aqueous solution is 60% to 90% methanol aqueous solution or ethanol aqueous solution.
In the method for preparing terbutaline sulfate, the dosage ratio of the compound in the formula I to the alcohol-water solution is 1 g: 10-20 m L.
Preferably, in the above-mentioned process for preparing terbutaline sulfate, the ratio of the compound of formula I to the aqueous alcohol solution is 1 g: 15m L.
Wherein, in the method for preparing terbutaline sulfate, the hydrogenation reduction temperature is 15-50 ℃.
Preferably, in the method for preparing terbutaline sulfate, the hydrogenation reduction temperature is 15-35 ℃.
Wherein, in the method for preparing the terbutaline sulfate, the hydrogenation reduction pressure is between normal pressure and 0.5 Mpa.
Preferably, in the above method for preparing terbutaline sulfate, the hydrogenation reduction pressure is from atmospheric pressure to 0.2 MPa.
The invention has the beneficial effects that:
the present invention converts compound 4 to formula I prior to the hydrogenation reduction, with the advantages: 1. the salt property is stable, the terbutaline sulfate is directly obtained after hydrogenation reduction, the post-treatment is simpler, the salt is not required to be formed after hydrogenation, and the product quality and yield are prevented from being reduced due to the independent occurrence of extremely unstable terbutaline free alkali; 2. the reaction conditions are mild: hydrogenation reduction can be carried out at normal temperature and normal pressure, and the reaction time is short; 3. the yield is high, the hydrogenation reduction yield is 90-98%, and the terbutaline sulfate single impurity is below 0.1%; 4. the addition amount of the palladium-carbon is reduced to 3-5 percent of the main dosage (the document is 10 percent), and the product cost is reduced; 5. the use of a class of organic solvents is avoided.
The method has the advantages of mild reaction conditions, high product yield, high purity, low production cost and the like, completely meets the requirements of industrial production, and has popularization value.
Drawings
FIG. 1 shows the NMR carbon spectrum of a compound of formula I (R is H).
FIG. 2 shows the NMR spectrum of the compound of formula I (R is H).
FIG. 3 is an infrared spectrum of terbutaline sulfate.
FIG. 4 is a carbon spectrum of terbutaline sulfate.
FIG. 5 is a terbutaline sulfate hydrogen spectrum.
FIG. 6 is a graph of HP L C of purified terbutaline sulfate of example 17.
FIG. 7 is a graph showing the HP L C assay of purified terbutaline sulfate from example 18.
FIG. 8 is a graph of HP L C of purified terbutaline sulfate of example 19.
Detailed Description
The inventor finds out through experiments that: the compound 4 hydrochloride or hydrobromide is relatively stable, the compound 4 hydrochloride or hydrobromide is subjected to hydrogenation reduction at 35 ℃ and 0.5Mpa according to a literature method, benzyl is easy to hydrogenolyze, but carbonyl is difficult to reduce, the temperature is increased to 50 ℃, the pressure is increased to 1.2-1.5 Mpa, the hydrogenation is completed for more than 15 hours, and the yield is generally about 70%; after reduction, terbutaline free alkali (base) has extremely high water solubility, cannot be extracted from water at all, has extremely unstable properties, and is easy to oxidize and discolor in the process of being placed at room temperature, so that the product quality and the yield are reduced. The present inventors have therefore made extensive attempts to convert the hydrochloride or hydrobromide salt of compound 4 to formula I prior to hydrogenation reduction, avoiding the above and obtaining terbutaline sulfate in a more excellent case.
Specifically, the structural formula of the terbutaline sulfate intermediate is shown as a formula I:
wherein R is H or benzyl.
The application further provides a preparation method of the terbutaline sulfate intermediate, and the synthetic route is as follows:
wherein R' is acetyl or benzyl; when R 'is acetyl, R is H, and when R' is benzyl, R is benzyl;
the method comprises the following steps:
A. reacting the compound 1 with bromine to obtain a compound 2;
B. reacting the compound 2 with the compound 3, and after the reaction is finished, recovering the solvent to obtain a residue;
when R' is acetyl, extracting the residue with hydrochloric acid or hydrobromic acid, heating and hydrolyzing the acid water extract, cooling, filtering and drying to obtain compound 4 hydrochloride or hydrobromide;
when R' is benzyl, adding organic solvent into the residue, extracting with hydrochloric acid or hydrobromic acid, and combining acid water layers to obtain aqueous solution of hydrochloride or hydrobromide of compound 4;
C. preparing the compound 4 into a mixed solution of water and an organic solvent, carrying out alkalization and dissociation, separating to obtain an organic layer, and adding sulfuric acid into the organic layer to form a salt, thereby obtaining the compound shown in the 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: dissolving the compound 1 in dichloromethane, dropwise adding a small amount of bromine-dichloromethane solution to the dichloromethane solution to initiate reaction, then cooling to below 10 ℃, continuously dropwise adding the bromine-dichloromethane solution, washing the reaction solution with water after dropwise adding, concentrating, and crystallizing with absolute ethyl alcohol to obtain a compound 2, wherein the bromination yield is 78-86%.
In step B, the molar ratio of compound 2 to compound 3 is 1: 2-3; the reaction conditions of compound 2 and compound 3 are: and (3) taking ketone as a solvent, and carrying out reflux reaction for 2-4 h. The ketone can be butanone, 2-pentanone, methyl isopropyl ketone, methyl tert-butyl ketone, preferably butanone.
In step B, the concentration of hydrochloric acid or hydrobromic acid is 0.5-1.5 mol/L, and a thin layer method is adopted to monitor whether the extraction is complete (thin layer conditions are: silica gel GF254 thin layer plate, developing agent is dichloromethane: ethyl acetate: triethylamine volume ratio 10: 1: 0.4, ultraviolet lamp 254nm color development).
In the step B, after acid extraction, the acid water treatment modes are different according to different substituents: when R' is acetyl, heating and hydrolyzing the acid water extracting solution to remove acetyl, keeping the temperature of 30-60 ℃ for reaction under the condition of heating and hydrolyzing, monitoring the hydrolysis end point by adopting a thin-layer method (the thin-layer condition is a silica gel GF254 thin-layer plate, a developing agent is dichloromethane, ethyl acetate and triethylamine in a volume ratio of 10: 1: 0.4, and an ultraviolet lamp 254nm develops color), cooling and filtering after the reaction is finished, and collecting solid, namely a compound 4 (the compound 4 needs to be added with water and an organic solvent in the step C so as to be free by alkalization and form salt by sulfuric acid); when R' is benzyl, the acid aqueous layers are combined to give an aqueous solution of the hydrochloride or hydrobromide salt of compound 4 (which in step C requires the addition of an organic solvent to alkalify the free and sulphuric acid salts). In the step B, the yield of the condensation and hydrolysis steps is 60-70%.
In the step C, the alkalization dissociating conditions are as follows: adding alkali to neutralize until the pH of the reaction solution is 8-9; then separating an organic layer, dehydrating with anhydrous sodium sulfate, and salifying with sulfuric acid; the conditions for the salt formation of sulfuric acid are as follows: adjusting the pH value of the organic layer to 5 +/-0.2 by using sulfuric acid; sulfuric acid is preferred to adjust the pH of the organic layer to 5, since the pH requirement for the sulfuric acid salt formation needs to be relatively precise. In the step C, the yield of the compound 4 hydrochloride or hydrobromide converted into sulfate is 95-98%.
In steps B and C, the organic solvent and water are added in order that when alkalizing, the free base of formula I is immediately extracted into the organic layer, and the inorganic salt generated after neutralization is dissolved in the aqueous layer, so that the amount of water and organic solvent added can be controlled according to the actual reaction and separation conditions. The organic solvent may be ethyl acetate, dichloromethane, diethyl ether, isopropyl ether, preferably ethyl acetate.
The invention further discloses a method for preparing terbutaline sulfate by utilizing the terbutaline sulfate intermediate prepared by the method, and the synthetic route is as follows:
wherein R is H or benzyl;
the method comprises the following steps: using 10% Pd/C as catalyst and alcohol-water solution as solvent, introducing H2And reducing the terbutaline sulfate intermediate in the formula I to obtain terbutaline sulfate in the formula II.
In the method for preparing terbutaline sulfate, the mass ratio of the compound of the formula I to 10% Pd/C is 1: 0.02-0.1, preferably 1: 0.03-0.05, the alcohol-water solution is a methanol water solution or an ethanol water solution with the content of 50-95%, preferably a 60-90% methanol water solution or an ethanol water solution, the dosage ratio of the compound of the formula I to the alcohol-water solution is 1 g: 10-20 m L, preferably 1 g: 15m L, the reduction temperature is 15-50 ℃, preferably 15-35 ℃, the reduction pressure is normal pressure-0.5 MPa, preferably normal pressure-0.2 MPa, in the step, T L C is monitored until the hydrogenation reaction of the raw materials is complete, and the silica gel GF254The developing solvent is dichloromethane: methanol: triethylamine volume ratio 10: 2: 1, developing color under an ultraviolet lamp at 254 nm; the yield of hydrogenation reduction is 90-98%.
According to the invention, the terbutaline sulfate is prepared by reduction of the formula I, the reaction can be subjected to hydrogenation reduction at normal temperature and normal pressure, the consumption of palladium-carbon is low, the reaction time is short, the yield of the terbutaline sulfate is up to 90-98%, the single impurity of the refined product is below 0.1%, and the industrial production of the terbutaline sulfate is more favorably realized.
The refining steps of the terbutaline sulfate crude product are as follows: decolorizing with activated carbon, and crystallizing with alcohol (methanol or ethanol); the purification yield is 90-95%.
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1: preparation of Compound 2 (R' is acetyl)
Adding 76m L dichloromethane and 38g 3, 5-diacetoxyacetophenone into a reaction bottle with a tail gas absorption device, stirring and dissolving completely, dropwise adding a plurality of drops of a bromine-dichloromethane mixed solution (27 g of bromine and 27ml of dichloromethane) at room temperature, keeping the temperature and stirring until the mixture is completely dissolvedCooling to below 10 deg.C when acid gas (detected by wet pH paper) escapes, maintaining temperature, continuously dripping bromine-dichloromethane solution, and monitoring that raw material spot basically disappears by T L C (thin layer monitoring method: silica gel GF)254And a developing agent: dichloromethane-ethyl acetate (10: 1), ultraviolet lamp 254nm color development), stop the reaction. Washing the reaction solution with water until the pH value of a water layer is 6-7, drying a dichloromethane layer by using anhydrous magnesium sulfate, filtering, evaporating the solvent by reduced pressure, and adding anhydrous ethanol into residues for crystallization to obtain 41.6 g of compound 2 with the yield of 82%.
Example 2: preparation of Compound 2 (R' is acetyl)
Adding 236g of 3, 5-diacetoxy acetophenone and 500m of L dichloromethane into a reaction bottle with a tail gas absorption device, stirring and dissolving completely, dropwise adding 160g of bromine and 160ml of dichloromethane solution at room temperature, keeping the temperature and stirring until hydrogen bromide gas escapes (checked by a wet pH test paper), cooling to below 10 ℃, continuously dropwise adding the bromine dichloromethane solution, and monitoring that raw material spots basically disappear by T L C (thin layer monitoring method: silica gel GF254And a developing agent: dichloromethane-ethyl acetate (10: 1), ultraviolet lamp 254nm color development), water washing to pH 6-7, drying the organic layer with anhydrous magnesium sulfate, filtering, removing the solvent under reduced pressure, adding anhydrous ethanol into the residue for crystallization to obtain the compound 2, wherein the yield is 246g and 78%.
Example 3: preparation of Compound 2 (R' is acetyl)
Adding 236g of 3, 5-diacetoxy acetophenone and 472m of L dichloromethane into a reaction bottle with a tail gas absorption device, stirring and dissolving completely, then dropwise adding 176g of bromine and 176m of L dichloromethane solution at room temperature under stirring for several drops, cooling to below 10 ℃ after hydrogen bromide gas escapes (checked by a wet pH test paper), continuously dropwise adding the bromine dichloromethane solution, and monitoring that raw material spots basically disappear by T L C (thin layer monitoring method: silica gel GF254And a developing agent: dichloromethane-ethyl acetate (10: 1), ultraviolet lamp 254nm color development), introducing nitrogen or air to remove hydrogen bromide, washing with water to pH 6-7, drying the organic layer with anhydrous magnesium sulfate, filtering, removing the solvent under reduced pressure, and adding anhydrous ethanol into the residue to crystallize to obtain the compound 2 with yield of 271g and yield of 86%.
Example 4: preparation of Compound 2 (R' is benzyl)
Adding 332g of 3, 5-dibenzyloxy acetophenone and 665m of L dichloromethane into a reaction bottle with a tail gas absorption device, stirring and dissolving completely, then dropwise adding 165g of bromine and 165ml of dichloromethane solution at room temperature under stirring, cooling to below 10 ℃ after hydrogen bromide gas escapes (checked by wet pH test paper), continuously dropwise adding bromine dichloromethane solution, and monitoring that raw material spots basically disappear by T L C (thin layer monitoring method: silica gel GF254And a developing agent: dichloromethane-ethyl acetate (10: 1), ultraviolet lamp 254nm color development), introducing nitrogen or air to remove hydrogen bromide, washing with water to pH 6-7, drying organic layer with anhydrous magnesium sulfate, filtering, removing solvent under reduced pressure, adding anhydrous ethanol into residue, and crystallizing to obtain compound 2 with yield of 329g and yield of 80%.
Example 5: preparation of Compound 4 (R' is acetyl)
315g of compound 2 (R' is acetyl), 400g of N-benzyl tert-butylamine and 3.5 g of 3.5L butanone are added into a reaction bottle, heating and refluxing are carried out for about 2 hours, the thin layer method is used for monitoring whether the reaction is complete (the thin layer condition is a silica gel GF254 thin layer plate, a developing agent is dichloromethane-ethyl acetate (10: 1), cooling and filtering are carried out to remove insoluble substances, the butanone is recovered under reduced pressure, the residue is extracted for 2-3 times with 1 mol/L hydrochloric acid, each time is about 800m L, the thin layer method is used for monitoring whether the extraction is complete (the thin layer condition is a silica gel 254 thin layer plate, the developing agent is dichloromethane-ethyl acetate-triethylamine (10: 1: 0.4), an ultraviolet lamp 254nm is used for color development), acid water layers are combined, the temperature is kept for about 15 hours at 30 ℃, the hydrolysis end point is monitored by the thin layer method (the thin layer condition is the same as the above), cooling and filtering.
Example 6: preparation of Compound 4 (R' is acetyl)
315g of compound 2 (R' is acetyl), 326g of N-benzyl tert-butylamine and 3.5 g of 3.5L g of butanone are added into a reaction bottle, the mixture is heated and refluxed for about 3 hours (whether the extraction is complete or not is monitored by a thin layer method, the method is the same as the above), the mixture is cooled, insoluble substances are removed by filtration, the butanone is recovered under reduced pressure, the residue is extracted for 2 to 3 times with 1 mol/L hydrochloric acid, the concentration of the residue is about 800m L each time (whether the extraction is complete or not is monitored by the thin layer method, the method is the same as the above), acid water layers are combined, the temperature is kept at 50 ℃ for about 6 hours, the hydrolysis endpoint is monitored by the thin layer method (the thin layer condition is the.
Example 7: preparation of Compound 4 (R' is acetyl)
315g of the compound 2 (R' is acetyl), 450g of N-benzyl tert-butylamine and 3.5L g of butanone are added into a reaction bottle, the mixture is heated and refluxed for about 3 hours (whether the reaction is complete or not is monitored by a thin layer method, the method is the same as the above), the mixture is cooled, insoluble matters are removed by filtration, the butanone is recovered under reduced pressure, the residue is extracted for 2-3 times by 1 mol/L of hydrobromic acid (whether the extraction is complete or not is monitored by the thin layer method, the method is the same as the above), 800m L is carried out each time, acid water layers are combined, the temperature is kept at 55 ℃ for about 3.5 hours, the hydrolysis endpoint is monitored by the thin layer method (the thin layer condition is the same as the above), the.
Example 8: preparation of a Compound of formula I (R is H)
55g of the compound 4 (hydrochloride) obtained in example 5 and 250m of water L are added into a reaction bottle, 250m of L of ethyl acetate is added, sodium carbonate is added to the mixture to reach the pH of 8-9 under the stirring, an organic layer is separated, anhydrous sodium sulfate is dried, sulfuric acid is added dropwise to adjust the pH of 5, and the mixture is filtered and dried to obtain 55.8g of the compound (R is H) of the formula I, wherein the yield is 98%.
Example 9: preparation of a Compound of formula I (R is H)
50g of the compound 4 (hydrobromide) obtained in example 7 and 220m of water L were put in a reaction flask, 220m of ethyl acetate L was added, sodium carbonate was added under stirring to a pH of 8 to 9, the ethyl acetate layer was dried over anhydrous sodium sulfate, sulfuric acid was added dropwise at room temperature under stirring to a pH of 5 to precipitate a solid, and the solid was filtered and dried to obtain 44.1g of the compound of formula I (R is H) with a yield of 96%.
Example 10: preparation of a Compound of formula I (R is benzyl)
Adding 41g of compound 2 (R' is benzyl), 40g of N-benzyl tert-butylamine and 350m of L g of butanone into a reaction bottle, heating and refluxing for about 3 hours (monitoring whether the reaction is complete or not by a thin layer method, the same method as above), cooling, filtering to remove insoluble substances, recovering butanone under reduced pressure, adding 200m of L ethyl acetate into the residue, extracting 2-3 times with 1 mol/L of hydrobromic acid (monitoring whether the extraction is complete or not by the thin layer method, the same method as above) and 80m of L each time, combining acid water layers to obtain an aqueous hydrobromic acid solution (R is benzyl) of a compound 4, adding 300m of ethyl acetate L into the residue, adjusting the pH to 8-9 by sodium carbonate under stirring, separating an organic layer, dehydrating by anhydrous sodium sulfate, adjusting the pH of the ethyl acetate layer to 5 by sulfuric acid, filtering and drying to obtain 33g of formula I (R is benzyl).
Example 11: preparation of terbutaline sulfate
36.2g of the compound of the formula I (R ═ H), 90% ethanol 540m L and 1.8g of 10% Pd — C were placed in a reaction flask, evacuated of air and hydrogenated under normal pressure with hydrogen (T L C monitored until the hydrogenation of the starting material was complete, silica gel GF was added254And a developing agent: dichloromethane-methanol-triethylamine (10: 2: 1), ultraviolet lamp 254nm color development), filtering, decompressing to remove solvent, adding absolute ethyl alcohol to cool and crystallize, filtering and drying to obtain the crude product of terbutaline sulfate 26.8g, the yield is 98%.
Example 12: preparation of terbutaline sulfate
36.2g of the compound of the formula I (R ═ H), 80% ethanol 450m L and 1.6g of 10% Pd — C were placed in a reaction flask, evacuated of air and hydrogenated under normal pressure with hydrogen (T L C monitored until the hydrogenation of the starting material was complete, and the silica gel GF was added254And a developing agent: dichloromethane-methanol-triethylamine (10: 2: 1), ultraviolet lamp 254nm color development), filtering, decompressing to remove solvent, adding absolute ethyl alcohol to cool and crystallize, filtering and drying to obtain crude terbutaline sulfate 24.7g, yield 90%.
Example 13: preparation of terbutaline sulfate
36.2g of the compound of the formula I (R ═ H), 540m L of 90% ethanol and 1.1g of 10% Pd — C were placed in a reactor, the air was vented off and the hydrogenation was carried out under 0.15mpa (T L C monitored until the hydrogenation of the starting material was complete and the silica gel GF was added for 10 hours254And a developing agent: dichloromethane-methanol-triethylamine (10: 2: 1), ultraviolet lamp 254nm color development, filtering, decompressing to remove solvent, adding absolute ethyl alcohol to cool and crystallize, filtering and drying to obtain 25.2g of crude terbutaline sulfate with 92% yield.
Example 14: preparation of terbutaline sulfate
36.2g of the compound of the formula I (R ═ H), 90% ethanol 540m L and 1.8g of 10% Pd-C were placed in a reaction flask, the air was evacuated and the mixture was hydrogenated under a hydrogen pressure of 0.2mpa for 7 hours(T L C monitor until hydrogenation of the starting material is complete, silica GF254And a developing agent: dichloromethane-methanol-triethylamine (10: 2: 1), ultraviolet lamp 254nm color development), filtering, decompressing to remove solvent, adding absolute ethyl alcohol to cool and crystallize, filtering and drying to obtain the crude product of terbutaline sulfate 26.6g, the yield is 98%.
Example 15: preparation of terbutaline sulfate
36.2g of the compound of formula I (R ═ H), 95% methanol 600m L, 1.7g of 10% Pd-C were placed in a reaction flask, evacuated of air, and hydrogenated under normal pressure with hydrogen for about 25 hours (T L C monitored until the hydrogenation of the starting material was complete, silica gel GF was added254And a developing agent: dichloromethane-methanol-triethylamine (10: 2: 1), ultraviolet lamp 254nm color development, filtering, decompressing to remove solvent, adding absolute ethyl alcohol to cool and crystallize, filtering and drying to obtain 25.2g of crude terbutaline sulfate with 92% yield.
Example 16: preparation of terbutaline sulfate
33g of the compound of the formula I from example 10 (R ═ benzyl), 480m L% ethanol and 1.6g of 10% Pd-C were placed in a reaction flask, the air was vented off and the hydrogenation was carried out under a hydrogen pressure of 0.2mpa for about 7 hours (T L C monitored until the hydrogenation of the starting material was complete and the silica gel GF254And a developing agent: dichloromethane-methanol-triethylamine (10: 2: 1), ultraviolet lamp 254nm color development), filtering, decompressing to remove solvent, adding absolute ethyl alcohol to cool and crystallize, filtering and drying to obtain 15g of crude terbutaline sulfate with yield of 90%.
Example 17: terbutaline sulfate refining
50g of the crude product obtained in the example 11-16 and 1500m L95% ethanol are added into a reaction bottle, heating reflux is carried out for dissolution, 3g of activated carbon is added for decoloration for 20mins, filtration is carried out, the filtrate is cooled and crystallized, 47.5g of terbutaline sulfate is obtained, the yield is 95%, related substances are less than 0.1%, and the HP L C result is shown in the attached figure 6.
Example 18: terbutaline sulfate refining
50g of the crude product obtained in the example 11-16 and 1000m of L95% methanol are added into a reaction bottle, heating reflux is carried out for dissolution, 3g of activated carbon is added for decoloration for 20mins, filtration is carried out, the filtrate is cooled and crystallized, 46.5g of terbutaline sulfate is obtained, the yield is 93%, related substances are less than 0.1%, and the HP L C result is shown in the attached figure 7.
Example 19: terbutaline sulfate refining
50g of the crude product obtained in the example 11-16 and 1100m L95% methanol are added into a reaction bottle, heating reflux is carried out for dissolution, 3g of activated carbon is added for decoloration for 20mins, filtration is carried out, the filtrate is cooled and crystallized, 45g of terbutaline sulfate is obtained, the yield is 90%, related substances are less than 0.1%, and the HP L C result is shown in the attached figure 8.
Claims (10)
1. A terbutaline sulfate intermediate characterized by: the structural formula is shown as formula I:
wherein R is H or benzyl.
2. A process for the preparation of the terbutaline sulfate intermediate of claim 1, wherein: the synthetic route is as follows:
wherein R' is acetyl or benzyl; when R 'is acetyl, R is H, and when R' is benzyl, R is benzyl;
the method comprises the following steps:
A. reacting the compound 1 with bromine to obtain a compound 2;
B. reacting the compound 2 with the compound 3, and after the reaction is finished, recovering the solvent to obtain a residue;
when R' is acetyl, extracting the residue with hydrochloric acid or hydrobromic acid, heating and hydrolyzing the acid water extract, cooling, filtering and drying to obtain a compound 4;
when R' is benzyl, adding organic solvent into the residue, extracting with hydrochloric acid or hydrobromic acid, and mixing acid water layers to obtain water solution of compound 4;
C. preparing the compound 4 into a mixed solution of water and an organic solvent, adding alkali for alkalization and dissociation, separating to obtain an organic layer, and adding sulfuric acid into the organic layer for salification to obtain the compound shown in the formula I.
3. The process for the preparation of terbutaline sulfate intermediate as claimed in claim 2, wherein: in step a, the molar ratio of compound 1 to bromine is 1: 1 to 1.3.
4. The process for the preparation of terbutaline sulfate intermediate as claimed in claim 2, wherein: the specific operation of the step A is as follows: dissolving the compound 1 in dichloromethane, dropwise adding a small amount of bromine-dichloromethane solution to the solution to initiate reaction, then cooling the solution to below 10 ℃, continuously dropwise adding the bromine-dichloromethane solution, washing the reaction solution with water after the dropwise adding is finished, concentrating the reaction solution, and crystallizing the reaction solution with absolute ethyl alcohol to obtain a compound 2.
5. The process for the preparation of terbutaline sulfate intermediate as claimed in claim 2, wherein: in step B, the molar ratio of compound 2 to compound 3 is 1: 2-3; the reaction conditions of compound 2 and compound 3 are: taking ketone as a solvent, and carrying out reflux reaction for 2-4 h; the ketone is at least one of butanone, 2-pentanone, methyl isopropyl ketone or methyl tert-butyl ketone; butanone is preferred.
6. The preparation method of terbutaline sulfate intermediate according to claim 2, wherein in step B, the concentration of hydrochloric acid or hydrobromic acid is 0.5-1.5 mol/L, and the completion of extraction is monitored by thin layer method, and when R' is acetyl, the heating hydrolysis condition is 30-60 deg.C incubation reaction, and the end point of hydrolysis is monitored by thin layer method.
7. The process for the preparation of a terbutaline sulfate intermediate as claimed in any of claims 2 to 6, wherein: in the step C, the alkalization dissociating conditions are as follows: adding alkali to neutralize until the pH of the reaction liquid is 8-9, wherein the alkali is sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; preferably sodium carbonate or potassium carbonate; the conditions for the salt formation of sulfuric acid are as follows: sulfuric acid adjusted the organic layer pH to 5 ± 0.2.
8. A method for preparing terbutaline sulfate by using the terbutaline sulfate intermediate prepared by any one of the methods of claims 2 to 7, which is characterized in that: the synthetic route is as follows:
wherein R is H or benzyl;
the method comprises the following steps: using 10% Pd/C as catalyst and alcohol-water solution as solvent, introducing H2And reducing the terbutaline sulfate intermediate in the formula I to obtain terbutaline sulfate in the formula II.
9. The process for the preparation of terbutaline sulfate according to claim 8, wherein: at least one of the following is satisfied:
the mass ratio of the compound of formula I to 10% Pd/C was 1: 0.02 to 0.1; preferably 1: 0.03 to 0.05;
the alcohol-water solution is a methanol water solution or an ethanol water solution with the content of 50-95 percent; preferably 60 to 90 percent of methanol water solution or ethanol water solution;
the dosage ratio of the compound of the formula I to the alcohol aqueous solution is 1 g: 10-20 m L, preferably 1 g: 15m L.
10. The process for the preparation of terbutaline sulfate according to claim 8 or 9, wherein: at least one of the following is satisfied:
the reduction temperature is 15-50 ℃; preferably 15-35 ℃;
the reduction pressure is between normal pressure and 0.5 Mpa; preferably from atmospheric pressure to 0.2 MPa.
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