A METHOD FOR PREPARING R-TERBUTALINE USING CHIRAL AUXILIARY GROUPS

Abstract

A method for preparing R-terbutaline by using a chiral auxiliary uses S-(?)-tert-butylsulfinamide as a starting material to sequentially react with tert-butylbromide and 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one to obtain a compound 5; the compound 5 is subjected to a reduction reaction under the catalysis of a quaternary ammonium salt to obtain a compound 6; the tert-butylsulfinyl group of compound 6 is deprotected to obtain a compound 7, and in the presence of a palladium catalyst and hydrochloric acid, the compound 7 is hydrogenolyzed in an alcohol solvent to obtain the R-terbutaline. The method is simple and reliable, the preparation costs are low, and the ee of the chiral product is as high as 99.9%.

Claims

1. A method for preparing R-terbutaline using chiral auxiliary, comprising hydrogenating a compound 7 in an alcohol solvent in the presence of a palladium catalyst and hydrochloric acid to obtain R-terbutaline; the chemical structural formula of the compound 7 is as follows: ##STR00008## the chemical structural formula of R-terbutaline is as follows: ##STR00009##

2. The method for preparing R-terbutaline using chiral auxiliary according to claim 1, wherein S-(?)-tert-butylsulfinamide is used as starting material to react with tert-butyl bromide and 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one sequentially to obtain a compound 5; compound 5 undergoes a reduction reaction to obtain a compound 6; the compound 6 is de-protected from tert-butylsulfonyl group to obtain the compound 7; the chemical structural formula of compound 5 is as follows: ##STR00010## the chemical structural formula of compound 6 is as follows: ##STR00011##

3. The method for preparing R-terbutaline using chiral auxiliary according to claim 2, wherein S-(?)-tert-butylsulfinamide is dissolved in an organic solvent, a base is added, then tert-butyl bromide is added dropwise, and the reaction is carried out at 0-60? C. for 2-5 hours, followed by the addition of 1-(3,5-bis(benzyloxy)phenyl)-2-bromoethan-1-one 4, and the reaction is continued at 30-80? C. for 2-8 hours to obtain the compound 5.

4. The method for preparing R-terbutaline using chiral auxiliary according to claim 2, wherein the compound 5 is dissolved in a solvent, a quaternary ammonium salt is added, then sodium borohydride is added at 0-10? C., after reduction reaction to obtain the compound 6.

5. The method for preparing R-terbutaline using chiral auxiliary according to claim 2, wherein compound 6 is dissolved in methanol, and concentrated hydrochloric acid is added, and the reaction is carried out for 2-5 hours at 0-60? C. to obtain the compound 7.

6. The method for preparing R-terbutaline using chiral auxiliary according to claim 1, wherein the palladium catalyst is an inorganic palladium catalyst; and the alcohol solvent is a small molecular alcohol.

7. The method for preparing R-terbutaline using chiral auxiliary according to claim 6, wherein the palladium catalyst is a palladium-carbon catalyst; and the alcohol solvent is methanol.

8. The method for preparing R-terbutaline using chiral auxiliary according to claim 1, wherein the compound 7 is dissolved in the alcohol solvent, the palladium catalyst is added, hydrochloric acid is dropped dropwise, and hydrogenolysis is carried out in atmospheric hydrogen gas for 1-3 hours to obtain R-terbutaline.

9. An application of S-(?)-tert-butylsulfinamide in the preparation of R-terbutaline.

10. A compound used for the preparation of R-terbutaline, having the following chemical structural formula: ##STR00012##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 shows the NMR hydrogen spectrum of the R-terbutaline hydrochloride prepared in the Example 1.

[0020] FIG. 2 shows the NMR carbon spectrum of the R-terbutaline hydrochloride prepared in the Example 1.

[0021] FIG. 3 shows the mass spectrum of the R-terbutaline hydrochloride prepared in the Example 1.

[0022] FIG. 4 shows the liquid chromatogram of the R-terbutaline hydrochloride prepared in the Example 1.

[0023] FIG. 5 shows the liquid chromatography of the existing racemic Terbutaline (Homesun Pharmaceutical).

EXAMPLES OF THE PRESENT INVENTION

[0024] 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.

[0025] The preparation method of the present invention may be represented as follows:

##STR00007##

EXAMPLE 1

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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 [?].sub.D.sup.20=?39.2 (c=1.0 in MeOH).

EXAMPLE 2

[0030] 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%.

[0031] 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%.

[0032] 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%.

Control 1

[0033] 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%.

[0034] 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%.

[0035] 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%.

EXAMPLE 3

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

EXAMPLE 4

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

EXAMPLE 5

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

EXAMPLE 6

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.