Patent Application
20240190807
The present invention belongs to the field of pharmaceutical technology, and specifically relates to a chiral method for preparing R-terbutaline.
Tebutaline is a rapid-acting and short-acting (3-adrenal receptor agonist, which selectively agonizes β2 receptors, relaxes bronchial smooth muscle, inhibits the release of endogenous spasmolytics, and suppresses edema caused by increased clearance of endogenous transmitters and mucosal cilia (Kyeong H. K., Hyun J. K., Seon-Pyo H., Sang D. S., Arch. Pharm. Res. 2000,23:441-445). It is mainly clinically used to treat bronchial asthma, asthmatic bronchitis, emphysema, and bronchospasm in chronic obstructive pulmonary disease. Terbutaline has a chiral center of benzylic secondary alcohols, but currently, racemates are used in clinical practice. Research has shown that the levoisomer of terbutaline is the effective ingredient for its efficacy (J. Med. Chem., 1972, 15, 1182-1183). The dextroisomer is not only ineffective, but also has toxic side effects. Therefore, studying the preparation method for R-terbutaline and re-marketing this levoisomer has important clinical application value. For example, CN110156614A has disclosed that R(−)terbutaline can significantly increase its anti-asthma efficacy compared to commercially available racemates, providing a new preferred treatment option for asthma related diseases.
The preparation methods for R-terbutaline that have been disclosed mainly include the following:
The existing technology has various disadvantages, so it is of great significance to develop a new method that is simple, efficient, and low-cost to prepare R-terbutaline.
The purpose of the present invention is to provide a method for preparing R-terbutaline; and this method is simple and reliable, with low preparation cost, and the ee of chiral products is as high as 99.9%.
The technical solution of the present invention is: a method for preparing R-terbutaline using chiral auxiliary, wherein compound 7 is hydrogenated in an alcohol solvent in the presence of palladium catalyst and hydrochloric acid to obtain R-terbutaline; The chemical structural formula of compound 7 is as follows:
The chemical structural formula of R-terbutaline is as follows:
In the above technical solution, the palladium catalyst is a palladium carbon catalyst; The alcohol solvent is a small molecule alcohol, preferably methanol. Specifically, compound 7 is dissolved in methanol, a palladium carbon catalyst is added, hydrochloric acid is dropped dropwise, and hydrogenolysis is carried out in atmospheric hydrogen gas for 1-3 hours. The palladium carbon is removed by filtration, and the filtrate is distilled under reduced pressure, and the remaining solid is crystallized to obtain the product R-terbutaline hydrochloride.
In the present invention, S-(−)-tert-butylsulfinamide is used as the starting material to react with tert-butyl bromide and 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one sequentially to obtain compound 5; compound 5 underwent a reduction reaction to obtain compound 6; compound 6 is de-protected from tert-butylsulfonyl group to obtain Intermediate 7. The specific steps and compound structural formula are as follows:
Due to the use of the above technical solutions, the present invention has the following advantages over the prior art: The present invention uses for the first time a commercial and inexpensive chiral source of tert-butyl sulfinamide as a cofactor to control the asymmetric reduction of the ketone, and a small amount of the diastereoisomer is easily removed by crystallization, with an ee of the product as high as 99.9%; and the whole route is very simple to operate, and the reagents used are cheap, easy to obtain, non-toxic, so it's very suitable for industrialized production.
The specific preparation and testing methods of the present invention are conventional methods, such as testing the purity and ee values by conventional liquid chromatography (HPLC+chiral column). With reference to the Example, the present invention will be described in detail.
The preparation method of the present invention may be represented as follows:
S-(−)-tert-butylsulfinamide (14.8 g, 110 mmol) was dissolved in acetonitrile (300 mL), potassium carbonate (18.0 g, 130 mmol) was added followed by a dropwise addition of tert-butyl bromide (17.8 g, 130 mmol), and then it was heated to 50° C. for reaction for 4 h and then 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one (41.1 g, 100 mmol) was added and then reacted at 60° C. for 6 hours. At the end of the reaction, the solids were removed by filtration and then the solvent was removed by distillation under reduced pressure to obtain the compound 5, which was used directly in the next step of the reaction.
The compound 5 obtained above was dissolved in a mixed solvent of THF (200 mL) and isopropanol (200 mL), tetrabutylammonium bromide (3.22 g, 10 mmol) was added, the reaction system was cooled down to 0° C., and then sodium borohydride (3.02 g, 80 mmol) was added uniformly in three batches within 1.5 hours. After addition, stirring was continued at 0° C. for 1 h. The mixture was quenched by adding aqueous ammonium chloride (50 mL), extracted with ethyl acetate, the extracts were combined, dried over sodium sulfate, distilled under reduced pressure, and the residual solids were crystallized with ethanol (90 mL) to obtain the compound 6 as a white solid of 37.1 g with a yield of 71% after two steps.
The compound 6 (26.1 g, 50 mmol) was dissolved in methanol (150 mL), and concentrated hydrochloric acid (12.5 mL, 37.5 wt %) was added, and the reaction was carried out for 3 hours at 50° C. And after the reaction, the solvent was removed by distillation under reduced pressure, and the residue was added with saturated solution of sodium bicarbonate (80 mL), extracted with ethyl acetate to combine organic layer, dried and distilled under reduced pressure to remove the solvent to obtain the compound 7, which was directly used in the next step of the reaction.
The above obtained compound 7 was dissolved in methanol (200 mL), 10 wt % of palladium-carbon catalyst (2.0 g) was added, and 2 mol/L of hydrogen chloride methanol solution (25 mL) was added dropwise, and then hydrogenated under atmospheric pressure hydrogen for 2 h. Then it was then filtered to remove the palladium-carbon, and the filtrate was distilled under conventional reduced-pressure to remove the solvent, and the residual solids were crystallized with tetrahydrofuran (100 mL) to obtain a total of 11.7 g of R-terbutaline hydrochloride with the two-step yield of 85%, purity of 99.7% and optical rotation of [α]D20=−39.2 (c=1.0 in MeOH).
On the basis of the Example 1, potassium carbonate (18.0 g, 130 mmol) was replaced with sodium carbonate (130 mmol), and the rest remained unchanged to obtain the R-terbutaline hydrochloride with a purity of 99.6% and an ee of 99.7%.
On the basis of the Example 1, tetrabutylammonium bromide (3.22 g, 10 mmol) was replaced with tetrabutylammonium chloride (10 mmol) and the rest remained unchanged to obtain the R-terbutaline hydrochloride with a purity of 99.5% and an ee of 99.1%.
On the basis of the Example 1, isopropanol (200 mL) was replaced with ethanol (200 mL) and the rest remained unchanged to obtain the R-terbutaline hydrochloride with a purity of 99.1% and an ee of 99.2%.
On the basis of Example 1, tetrabutylammonium bromide was removed and the rest remain unchanged to obtain the compound 6 with the two-step yield of 55%, which was further prepared to obtain the R-terbutaline hydrochloride with an ee of 95.2%.
On the basis of Example 1, the mixture of THF (200 mL) and isopropanol (200 mL) were replaced with isopropanol (400 mL), and the rest remained unchanged to obtain the compound 6 with the two-step yield of 60%, which was further prepared to obtain the R-terbutaline hydrochloride with an ee of 98.8%.
On the basis of Example 1, the sodium borohydride (3.02 g, 80 mmol) was replaced with potassium borohydride (80 mmol), and the rest remained unchanged to obtain the compound 6 with the two-step yield of 59%, which was further prepared to obtain the R-terbutaline hydrochloride with an ee of 98.3%.
S-(−)-tert-butylsulfinamide (14.8 g, 110 mmol) was dissolved in acetonitrile (300 mL), potassium carbonate (18.0 g, 130 mmol) was added followed by a dropwise addition of tert-butyl bromide (17.8 g, 130 mmol), and then it was heated to 40° C. for reaction for 3 h and then 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one (41.1 g, 100 mmol) was added and then reacted at 60° C. for 6 hours. At the end of the reaction, the solids were removed by filtration and then the solvent was removed by distillation under reduced pressure to obtain the compound 5, which was used directly in the next step of the reaction.
The compound 5 obtained above was dissolved in a mixed solvent of THF (200 mL) and isopropanol (200 mL), tetrabutylammonium bromide (3.22 g, 10 mmol) was added, the reaction system was cooled down to 0° C., and then sodium borohydride (3.02 g, 80 mmol) was added uniformly in three batches within 1.5 hours. After addition, stirring was continued at 0° C. for 1 h. The mixture was quenched by adding aqueous ammonium chloride (50 mL), extracted with ethyl acetate, the extracts were combined, dried over sodium sulfate, distilled under reduced pressure, and the residual solids were crystallized with ethanol (90 mL) to obtain the compound 6.
The compound 6 (26.1 g, 50 mmol) was dissolved in methanol (150 mL), and concentrated hydrochloric acid (12.5 mL, 37.5wt %) was added, and the reaction was carried out for 3 hours at 50° C. And after the reaction, the solvent was removed by distillation under reduced pressure, and the residue was added with saturated solution of sodium bicarbonate (80 mL), extracted with ethyl acetate to combine organic layer, dried and distilled under reduced pressure to remove the solvent to obtain the compound 7, which was directly used in the next step of the reaction.
The above obtained compound 7 was dissolved in methanol (200 mL), 10 wt % of palladium-carbon catalyst (2.0 g) was added, and 2 mol/L of hydrogen chloride methanol solution (25 mL) was added dropwise, and then hydrogenated under atmospheric pressure hydrogen for 2 h. Then it was then filtered to remove the palladium-carbon, and the filtrate was distilled under conventional reduced-pressure to remove the solvent, and the residual solids were crystallized with tetrahydrofuran (100 mL) to obtain R-terbutaline hydrochloride.
S-(−)-tert-butylsulfinamide (14.8 g, 110 mmol) was dissolved in acetonitrile (300 mL), potassium carbonate (18.0 g, 130 mmol) was added followed by a dropwise addition of tert-butyl bromide (17.8 g, 130 mmol), and then it was heated to 50° C. for reaction for 4 h and then 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one (41.1 g, 100 mmol) was added and then reacted at 60° C. for 6 hours. At the end of the reaction, the solids were removed by filtration and then the solvent was removed by distillation under reduced pressure to obtain the compound 5, which was used directly in the next step of the reaction.
The compound 5 obtained above was dissolved in a mixed solvent of THF (200 mL) and isopropanol (200 mL), tetrabutylammonium bromide (3.22 g, 10 mmol) was added, the reaction system was cooled down to 5° C., and then sodium borohydride (3.02 g, 80 mmol) was added uniformly in two batches within 1 h. After addition, stirring was continued at 0° C. for 1 h. The mixture was quenched by adding aqueous ammonium chloride (50 mL), extracted with ethyl acetate, the extracts were combined, dried over sodium sulfate, distilled under reduced pressure, and the residual solids were crystallized with ethanol (90 mL) to obtain the compound 6.
The compound 6 (26.1 g, 50 mmol) was dissolved in methanol (150 mL), and concentrated hydrochloric acid (12.5 mL, 37.5wt %) was added, and the reaction was carried out for 3 hours at 50° C. And after the reaction, the solvent was removed by distillation under reduced pressure, and the residue was added with saturated solution of sodium bicarbonate (80 mL), extracted with ethyl acetate to combine organic layer, dried and distilled under reduced pressure to remove the solvent to obtain the compound 7, which was directly used in the next step of the reaction.
The above obtained compound 7 was dissolved in methanol (200 mL), 10 wt % of palladium-carbon catalyst (2.0 g) was added, and 2 mol/L of hydrogen chloride methanol solution (25 mL) was added dropwise, and then hydrogenated under atmospheric pressure hydrogen for 2 h. Then it was then filtered to remove the palladium-carbon, and the filtrate was distilled under conventional reduced-pressure to remove the solvent, and the residual solids were crystallized with tetrahydrofuran (100 mL) to obtain R-terbutaline hydrochloride.
S-(−)-tert-butylsulfinamide (14.8 g, 110 mmol) was dissolved in acetonitrile (300 mL), potassium carbonate (18.0 g, 130 mmol) was added followed by a dropwise addition of tert-butyl bromide (17.8 g, 130 mmol), and then it was heated to 50° C. for reaction for 4 h and then 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one (41.1 g, 100 mmol) was added and then reacted at 60° C. for 6 hours. At the end of the reaction, the solids were removed by filtration and then the solvent was removed by distillation under reduced pressure to obtain the compound 5, which was used directly in the next step of the reaction.
The compound 5 obtained above was dissolved in a mixed solvent of THF (200 mL) and isopropanol (200 mL), tetrabutylammonium bromide (3.22 g, 10 mmol) was added, the reaction system was cooled down to 0° C., and then sodium borohydride (3.02 g, 80 mmol) was added uniformly in three batches within 1.5 hours. After addition, stirring was continued at 0° C. for 1 h. The mixture was quenched by adding aqueous ammonium chloride (50 mL), extracted with ethyl acetate, the extracts were combined, dried over sodium sulfate, distilled under reduced pressure, and the residual solids were crystallized with ethanol (90 mL) to obtain the compound 6.
The compound 6 (26.1 g, 50 mmol) was dissolved in methanol (150 mL), and concentrated hydrochloric acid (12.5 mL, 37.5wt %) was added, and the reaction was carried out for 4 hours at 50° C. And after the reaction, the solvent was removed by distillation under reduced pressure, and the residue was added with saturated solution of sodium bicarbonate (80 mL), extracted with ethyl acetate to combine organic layer, dried and distilled under reduced pressure to remove the solvent to obtain the compound 7, which was directly used in the next step of the reaction.
The above obtained compound 7 was dissolved in methanol (200 mL), 10 wt % of palladium-carbon catalyst (2.0 g) was added, and 2mol/L of hydrogen chloride methanol solution (25 mL) was added dropwise, and then hydrogenated under atmospheric pressure hydrogen for 2 h. Then it was then filtered to remove the palladium-carbon, and the filtrate was distilled under conventional reduced-pressure to remove the solvent, and the residual solids were crystallized with tetrahydrofuran (100 mL) to obtain R-terbutaline hydrochloride.
S-(−)-tert-butylsulfinamide (14.8 g, 110 mmol) was dissolved in acetonitrile (300 mL), potassium carbonate (18.0 g, 130 mmol) was added followed by a dropwise addition of tert-butyl bromide (17.8 g, 130 mmol), and then it was heated to 50° C. for reaction for 4 h and then 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one (41.1 g, 100 mmol) was added and then reacted at 60° C. for 6 hours. At the end of the reaction, the solids were removed by filtration and then the solvent was removed by distillation under reduced pressure to obtain the compound 5, which was used directly in the next step of the reaction.
The compound 5 obtained above was dissolved in a mixed solvent of THF (200 mL) and isopropanol (200 mL), tetrabutylammonium bromide (3.22 g, 10 mmol) was added, the reaction system was cooled down to 0° C., and then sodium borohydride (3.02 g, 80 mmol) was added uniformly in three batches within 1.5 hours. After addition, stirring was continued at 0° C. for 1 h. The mixture was quenched by adding aqueous ammonium chloride (50 mL), extracted with ethyl acetate, the extracts were combined, dried over sodium sulfate, distilled under reduced pressure, and the residual solids were crystallized with ethanol (90 mL) to obtain the compound.
The compound 6 (26.1 g, 50 mmol) was dissolved in methanol (150 mL), and concentrated hydrochloric acid (12.5 mL, 37.5wt %) was added, and the reaction was carried out for 3 hours at 50° C. And after the reaction, the solvent was removed by distillation under reduced pressure, and the residue was added with saturated solution of sodium bicarbonate (80mL), extracted with ethyl acetate to combine organic layer, dried and distilled under reduced pressure to remove the solvent to obtain the compound 7, which was directly used in the next step of the reaction.
The above obtained compound 7 was dissolved in methanol (200 mL), 10 wt % of palladium-carbon catalyst (2.0 g) was added, and 2 mol/L of hydrogen chloride methanol solution (25 mL) was added dropwise, and then hydrogenated under atmospheric pressure hydrogen for 2.5 h. Then it was then filtered to remove the palladium-carbon, and the filtrate was distilled under conventional reduced-pressure to remove the solvent, and the residual solids were crystallized with tetrahydrofuran (100 mL) to obtain R-terbutaline hydrochloride.
The method provided by the present invention is to use cheap and readily available chiral tert butyl sulfonamide as a chiral auxiliary, and reduce it to the desired chiral secondary alcohol by controlling the asymmetric reduction of ketone, and the chiral auxiliary can be removed under simple acidic conditions.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/090369 | 4/27/2021 | WO |
