Preparation method of terbutaline

Abstract

The present invention provides a method for preparing terbutaline, which relates to the technical field of chemical synthesis. The method for preparing terbutaline comprises the following steps: (a) Compound 1 reacts with haloepoxyethane through Suzuki reaction to obtain Compound 2; (b) Compound 2 reacts with tert-butylamine to obtain terbutaline. The present invention creatively applies the Suzuki reaction to the preparation of terbutaline, greatly shortening the reaction steps, avoiding the use of bromination reaction, the processes of protecting and deprotecting the protecting group on the hydroxyl group, and also eliminating the need for catalytic hydrogenation. The reaction conditions are mild, the reaction process is easy to control, and the safety factor is high. The raw materials are simple and easily available, saving the industrialization cost. The product has a high yield and high purity, providing a process route for industrial production of products with higher quality.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a preparation method of terbutaline. Background Art

[0002] Terbutaline sulfate, chemically named α-[(tert-butylamino)methyl]-3,5-dihydroxybenzyl alcohol sulfate, is used to treat bronchial asthma, asthmatic bronchitis, emphysema, etc. β2-receptor stimulants have bronchodilator effects. They have a high selectivity for bronchial smooth muscle, a very small excitatory effect on the heart, and no central effect. They are used for bronchial asthma, asthmatic bronchitis, obstructive emphysema and other pulmonary diseases accompanied by bronchospasm. They are especially suitable for asthmatic patients accompanied by cardiovascular diseases such as hypertension and coronary heart disease.

[0003] Currently, the reported synthetic methods of terbutaline mainly include the following several:

[0004] 1. Using 3,5-dihydroxybenzoic acid as a raw material, through esterification, benzyl protection, hydrolysis, acylation, oxidation, condensation, reduction, and debenzylation to prepare terbutaline sulfate, with an overall yield of 21%. This route has more steps, and the steps of benzyl protection and deprotection are added. Nickel and hydrogen are required during the debenzylation process, with low safety, cumbersome operation, and low yield. (Chinese Journal of Pharmaceutical Industry 1999, 30(1))

[0005]

[0006] 2. Using 3,5-dihydroxybenzoic acid as a raw material, through esterification, benzyl protection, hydrolysis, acylation, bromination, amination, reduction, and debenzylation to prepare terbutaline sulfate. This route has many steps and the operation is relatively cumbersome. (Journal of Shenzhen University Science and Engineering 2005, 22(2), 105 - 108)

[0007]

[0008] 3. Chinese Patent CN103664654A uses bambuterol hydrochloride as a raw material and hydrolyzes it under alkaline conditions to obtain the crude product of terbutaline sulfate. The raw materials of this route are not easily available, and bambuterol hydrochloride needs to be synthesized first.

[0009]

[0010] 4. Chinese Patent CN109305920A uses 3,5-dibenzyloxyacetophenone as a raw material, through bromination, substitution, carbonyl reduction, hydrogenation reduction, and salification with sulfuric acid to obtain terbutaline sulfate. This route has many steps, and nickel and hydrogen are also required during the debenzylation process, with poor safety.

[0011]

[0012] 5. The Chinese patent CN105254512A uses 3,5-dihydroxyacetophenone as a raw material, and obtains terbutaline sulfate through hydroxyl protection, bromination reaction, carbonyl reduction, condensation, and salification with sulfuric acid. This route has many steps, the operation is relatively cumbersome, and the bromination reaction is not easy to control.

[0013]

[0014] 6. The Chinese patent CN108503554A uses 3,5-dihydroxyacetophenone as a raw material, and obtains terbutaline sulfate through benzyl protection, oxidation and acetalization, reductive amination, debenzylation, and salification with sulfuric acid. This route has many steps and the operation is relatively cumbersome.

[0015]

[0016] 7. Using 3,5-dibenzyloxyacetophenone as a raw material, terbutaline sulfate is obtained through bromination, alkylation, carbonyl reduction, and catalytic hydrogenation debenzylation. (Journal of Hebei University of Science and Technology 2019, 40(5), 379-384)

[0017]

[0018] Among the above seven routes, some synthetic routes are long and require hydroxyl protection and deprotection reactions, with cumbersome steps; some require catalytic hydrogenation reactions, which are not safe; some require bromination reactions, which are not easy to control; some raw materials are expensive and difficult to obtain, lacking economy.

[0019] In view of this, the present invention is specifically proposed. Summary of the Invention

[0020] The main object of the present invention is to provide a method for preparing terbutaline, in order to at least partially solve at least one of the above technical problems.

[0021] The present invention provides a method for preparing terbutaline, which includes the following steps:

[0022] (a) Compound 1 reacts with haloepoxyethane through Suzuki reaction to obtain compound 2;

[0023] (b) Compound 2 reacts with tert-butylamine to obtain terbutaline; the reaction formula is as follows:

[0024]

[0025] R is selected from borate group or boric acid group;

[0026] X1 is selected from any one of Cl, Br, and I.

[0027] The preparation method of terbutaline provided by the present invention is as follows: intermediate compound 2 is obtained by the Suzuki reaction of compound 1 and haloepoxyethane, and then terbutaline is obtained by the reaction of compound 2 and tert-butylamine. The present invention creatively applies the Suzuki reaction to the preparation of terbutaline, greatly shortening the reaction steps, avoiding the use of bromination reaction, the process of protecting and deprotecting the hydroxyl group, and also eliminating the need for catalytic hydrogenation. The reaction conditions are mild, the reaction process is easy to control, and the safety factor is high. The raw materials are simple and easy to obtain, saving the industrial cost. The product has a high yield and high purity, providing a process route for industrial production of higher-quality products.

[0028] Further, R is selected from the pinacol borate group, that is, compound 1 is 3,5-dihydroxybenzeneboronic acid pinacol ester; X1 is selected from Br; the method includes the following steps:

[0029] (a) 3,5-Dihydroxybenzeneboronic acid pinacol ester reacts with bromoepoxyethane through the Suzuki reaction to obtain compound 2;

[0030] (b) Compound 2 reacts with tert-butylamine to obtain terbutaline; the reaction formula is as follows:

[0031]

[0032] Further, R is selected from the boronic acid group, that is, compound 1 is 3,5-dihydroxybenzeneboronic acid; X1 is selected from Br; the method includes the following steps:

[0033] (a) 3,5-Dihydroxybenzeneboronic acid reacts with bromoepoxyethane through the Suzuki reaction to obtain compound 2;

[0034] (b) Compound 2 reacts with tert-butylamine to obtain terbutaline; the reaction formula is as follows:

[0035]

[0036] Further, in the step (a), compound 1 reacts with haloepoxyethane under the action of a palladium catalyst and a base reagent to obtain compound 2.

[0037] Further, in the step (a), the palladium catalyst is selected from one or a combination of several of Pd(PPh3)4, PdCl2, PdCl2(dppf), Pd(OAc)2 or Pd(PPh3)2Cl2.

[0038] Further, in the step (a), the base reagent is selected from one or a combination of several of cesium carbonate, potassium carbonate, potassium phosphate, sodium carbonate, sodium phosphate or lithium carbonate.

[0039] Further, in the step (a), the solvent used is selected from one or more combinations of toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide (DMF), or dimethyl ether (DME), or a mixture with water.

[0040] Further, in the step (a), the reaction temperature is 80°C - 120°C.

[0041] Among them, the typical but non-limiting temperatures of the reaction can be, for example, 80°C, 82°C, 84°C, 86°C, 88°C, 90°C, 92°C, 94°C, 96°C, 98°C, 100°C, 102°C, 104°C, 106°C, 108°C, 110°C, 112°C, 114°C, 116°C, 118°C, or 120°C.

[0042] Further, in the step (b), the compound 2 reacts with tert-butylamine under the action of a base reagent to obtain terbutaline.

[0043] Further, in the step (b), the base reagent is selected from one or more combinations of sodium methoxide, sodium ethoxide, potassium tert-butoxide, or sodium tert-butoxide.

[0044] Further, in the step (b), the solvent used is selected from one or more combinations of toluene, 1,4-dioxane, or N,N-dimethylformamide (DMF).

[0045] Further, in the step (b), the reaction temperature is 100°C - 120°C.

[0046] Among them, the typical but non-limiting temperatures of the reaction can be, for example, 100°C, 102°C, 104°C, 106°C, 108°C, 110°C, 112°C, 114°C, 116°C, 118°C, or 120°C.

[0047] Further, the preparation method of the 3,5-dihydroxybenzeneboronic acid pinacol ester includes the following steps: 5-halogenated resorcinol reacts with bis(pinacolato)diboron to obtain 3,5-dihydroxybenzeneboronic acid ester; the reaction formula is as follows:

[0048]

[0049] X2 is selected from any one of Cl, Br, and I.

[0050] Further, the preparation method of the 3,5-dihydroxybenzeneboronic acid pinacol ester includes the following steps: 5-halogenated resorcinol reacts with bis(pinacolato)diboron under the action of a palladium catalyst and a base reagent to obtain 3,5-dihydroxybenzeneboronic acid pinacol ester.

[0051] Further, the palladium catalyst is selected from one or a combination of several of Pd(PPh3)4, PdCl2, PdCl2(dppf), Pd(OAc)2 or Pd(PPh3)2Cl2.

[0052] Further, the base reagent is selected from one or a combination of several of potassium acetate, sodium acetate or ammonium acetate.

[0053] Further, the solvent used is selected from one or a combination of several of acetonitrile, 1,4-dioxane, N,N-dimethylformamide (DMF) or dimethyl sulfoxide (DMSO).

[0054] Further, the temperature of the reaction is 80°C - 120°C.

[0055] It should be noted that in the present invention, Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium, PdCl2 represents palladium chloride, PdCl2(dppf) represents dichloride [1,1-bis(diphenylphosphino)ferrocene]palladium, Pd(OAc)2 represents palladium acetate, and Pd(PPh3)2Cl2 represents dichloride bis(triphenylphosphine)palladium.

[0056] The present invention also provides a preparation method of terbutaline sulfate, comprising the following steps:

[0057] Terbutaline forms a salt with sulfuric acid to obtain terbutaline sulfate: The reaction formula is as follows:

[0058]

[0059] Compared with the prior art, the present invention has the following beneficial effects:

[0060] In the preparation method of terbutaline provided by the present invention, compound 1 reacts with haloepoxyethane through Suzuki reaction to obtain intermediate compound 2, and compound 2 reacts with tert-butylamine to obtain terbutaline. The present invention creatively applies Suzuki reaction to the preparation of terbutaline, greatly shortening the reaction steps, avoiding the use of bromination reaction, the process of protecting and deprotecting the protecting group on the hydroxyl group, and also eliminating the need for catalytic hydrogenation. The reaction conditions are mild, the reaction process is easy to control, and the safety factor is high. The raw materials are simple and easily available, saving industrial costs. The product has a high yield and high purity, providing a process route for industrial production of higher-quality products. Specific Embodiments

[0061] The following will describe the embodiments of the present invention in detail. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. Those not specified in the examples are carried out under conventional conditions. Those reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0062] To facilitate a clearer understanding of the present invention, the technical solutions of the present invention will be further described below in conjunction with embodiments.

[0063] Preparation of Compound 1b (3,5-Dihydroxybenzeneboronic Acid Pinacol Ester) in Example 1

[0064] Example 1-1

[0065]

[0066] Under nitrogen protection, 19.0 g of 5-bromoresorcinol, 28.0 g of bis(pinacolato)diboron, 30.0 g of potassium acetate, and 2.2 g of Pd(dppf)Cl2 were dissolved in 150 mL of 1,4-dioxane, heated to 100 °C, and monitored by TLC until no 5-bromoresorcinol remained. After cooling to room temperature, it was diluted with toluene, the insoluble matter was filtered off, the filtrate was washed with an equal volume of water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 21.1 g of Compound 1b, with a yield of 89.0% and an HPLC purity of 95.8%.

[0067] Example 1-2

[0068]

[0069] Under nitrogen protection, 14.0 g of 5-chlororesorcinol, 28.0 g of bis(pinacolato)diboron, 25.0 g of sodium acetate, and 2.2 g of Pd(dppf)Cl2 were dissolved in 150 mL of DMSO, heated to 120 °C, and monitored by TLC until no 5-chlororesorcinol remained. After cooling to room temperature, it was diluted with toluene, the insoluble matter was filtered off, the filtrate was washed with an equal volume of water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 19.5 g of Compound 1b, with a yield of 82.3% and an HPLC purity of 95.6%.

[0070] Example 1-3

[0071]

[0072] Under nitrogen protection, 24.0 g of 5-iodoresorcinol, 28.0 g of bis(pinacolato)diboron, 23.0 g of ammonium acetate, and 3.4 g of Pd(PPh3)4 were dissolved in 150 mL of acetonitrile, heated to 80 °C, and monitored by TLC until no 5-iodoresorcinol remained. After cooling to room temperature, it was diluted with toluene, the insoluble matter was filtered off, the filtrate was washed with an equal volume of water, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 18.6 g of Compound 1b, with a yield of 78.5% and an HPLC purity of 94.4%.

[0073] Preparation of Compound 2 in Example 2

[0074] Example 2-1

[0075]

[0076] Example 2-1-1

[0077] Under nitrogen atmosphere, 15.4 g of compound 1a, 13.4 g of bromoethylene oxide and 1.2 g of Pd(PPh3)4 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2M aqueous Na2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until there was no compound 1a. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was filtered off, and the filtrate was concentrated to dryness to obtain 13.5 g of compound 2 with a yield of 88.8% and an HPLC purity of 99.8%.

[0078] Example 2-1-2

[0079] Under nitrogen atmosphere, 15.4 g of compound 1a, 14.6 g of bromoethylene oxide and 1.4 g of Pd(PPh3)4 were dissolved in 160 mL of 1,4-dioxane. After adding 20 mL of 2M aqueous K2CO3 solution, the reaction was carried out at 120 °C and monitored by TLC until there was no compound 1a. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was filtered off, and the filtrate was concentrated to dryness to obtain 13.5 g of compound 2 with a yield of 88.8% and an HPLC purity of 99.6%.

[0080] Example 2-1-3

[0081] Under nitrogen atmosphere, 15.4 g of compound 1a, 14.0 g of bromoethylene oxide and 2.3 g of Pd(PPh3)4 were dissolved in 160 mL of DMF. After adding 20 mL of 2M aqueous K3PO4 solution, the reaction was carried out at 110 °C and monitored by TLC until there was no compound 1a. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was filtered off, and the filtrate was concentrated to dryness to obtain 13.8 g of compound 2 with a yield of 90.7% and an HPLC purity of 99.5%.

[0082] Example 2-1-4

[0083] Under nitrogen atmosphere, 15.4 g of compound 1a, 13.8 g of bromoethylene oxide and 1.8 g of Pd(PPh3)4 were dissolved in a mixed solvent of 160 mL of DME and 40 mL of water. After adding 20 mL of 2M aqueous Na2CO3 solution, the reaction was carried out at 90 °C and monitored by TLC until there was no compound 1a. The reaction mixture was cooled to room temperature, filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was filtered off, and the filtrate was concentrated to dryness to obtain 13.6 g of compound 2 with a yield of 89.4% and an HPLC purity of 99.4%.

[0084] Example 2-1-5

[0085] Under nitrogen atmosphere, 15.4 g of compound 1a, 14.2 g of bromoethylene oxide and 1.6 g of Pd(PPh3)4 were dissolved in a mixed solvent of 160 mL of toluene and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 100 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.7 g of compound 2, with a yield of 90.1% and an HPLC purity of 99.9%.

[0086] Example 2-1-6

[0087] Under nitrogen atmosphere, 15.4 g of compound 1a, 14.4 g of bromoethylene oxide and 1.3 g of Pd(dppf)Cl2 were dissolved in a mixed solvent of 160 mL of DMF and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 120 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.4 g of compound 2, with a yield of 88.1% and an HPLC purity of 99.7%.

[0088] Example 2-1-7

[0089] Under nitrogen atmosphere, 15.4 g of compound 1a, 13.4 g of bromoethylene oxide and 0.3 g of PdCl2 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2 M aqueous Cs2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.4 g of compound 2, with a yield of 88.1% and an HPLC purity of 99.7%.

[0090] Example 2-1-8

[0091] Under nitrogen atmosphere, 15.4 g of compound 1a, 13.4 g of bromoethylene oxide and 0.4 g of Pd(OAc)2 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2 M aqueous Na3PO4 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.3 g of compound 2, with a yield of 87.4% and an HPLC purity of 99.1%.

[0092] Example 2-1-9

[0093] Under nitrogen atmosphere, 15.4 g of compound 1a, 13.4 g of bromoethylene oxide and 1.1 g of Pd(PPh3)2Cl2 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2 M aqueous Li2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.0 g of compound 2, with a yield of 85.5% and an HPLC purity of 99.5%.

[0094] Example 2-2

[0095]

[0096] Example 2-2-1

[0097] Under nitrogen atmosphere, 15.4 g of compound 1a, 8.6 g of chloroethylene oxide and 1.2 g of Pd(PPh3)4 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.4 g of compound 2, with a yield of 88.1% and an HPLC purity of 99.5%.

[0098] Example 2-2-2

[0099] Under nitrogen atmosphere, 15.4 g of compound 1a, 9.4 g of chloroethylene oxide and 1.4 g of Pd(PPh3)4 were dissolved in 160 mL of 1,4-dioxane. After adding 20 mL of 2 M aqueous K2CO3 solution, the reaction was carried out at 100 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.6 g of compound 2, with a yield of 89.4% and an HPLC purity of 99.4%.

[0100] Example 2-2-3

[0101] Under nitrogen atmosphere, 15.4 g of compound 1a, 9.0 g of chloroethylene oxide and 1.3 g of Pd(dppf)Cl2 were dissolved in a mixed solvent of 160 mL of DMF and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 120 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated to dryness to obtain 13.1 g of compound 2, with a yield of 86.1% and an HPLC purity of 99.7%.

[0102] Example 2-2-4

[0103] Under nitrogen atmosphere, 15.4 g of compound 1a, 9.2 g of epichlorohydrin and 0.3 g of PdCl2 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2 M aqueous Cs2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 13.4 g of compound 2 with a yield of 88.1% and an HPLC purity of 99.0%.

[0104] Example 2-3

[0105]

[0106] Example 2-3-1

[0107] Under nitrogen atmosphere, 15.4 g of compound 1a, 18.7 g of epiiodohydrin and 1.2 g of Pd(PPh3)4 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 13.2 g of compound 2 with a yield of 86.8% and an HPLC purity of 99.8%.

[0108] Example 2-3-2

[0109] Under nitrogen atmosphere, 15.4 g of compound 1a, 20.4 g of epiiodohydrin and 1.4 g of Pd(PPh3)4 were dissolved in 160 mL of 1,4-dioxane. After adding 20 mL of 2 M aqueous K2CO3 solution, the reaction was carried out at 100 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 13.5 g of compound 2 with a yield of 88.8% and an HPLC purity of 99.5%.

[0110] Example 2-3-3

[0111] Under nitrogen atmosphere, 15.4 g of compound 1a, 19.0 g of epiiodohydrin and 2.3 g of Pd(PPh3)4 were dissolved in 160 mL of DMF. After adding 20 mL of 2 M aqueous K3PO4 solution, the reaction was carried out at 120 °C and monitored by TLC until no compound 1a remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 13.3 g of compound 2 with a yield of 87.4% and an HPLC purity of 99.9%.

[0112] Example 2-3-4

[0113] Under nitrogen atmosphere, 15.4 g of compound 1a, 20.0 g of epoxyethane iodide and 1.8 g of Pd(PPh3)4 were dissolved in a mixed solvent of 160 mL of DME and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1a remained. After cooling to room temperature, the mixture was filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was removed by filtration, and the filtrate was concentrated to dryness to obtain 13.2 g of compound 2 with a yield of 86.8% and an HPLC purity of 99.2%.

[0114] Example 2-4

[0115]

[0116] Example 2-4-1

[0117] Under nitrogen atmosphere, 23.6 g of compound 1b, 13.4 g of epoxyethane bromide and 1.2 g of Pd(PPh3)4 were dissolved in a mixed solvent of 160 mL of acetonitrile and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1b remained. After cooling to room temperature, the mixture was filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was removed by filtration, and the filtrate was concentrated to dryness to obtain 13.5 g of compound 2 with a yield of 88.8% and an HPLC purity of 99.9%.

[0118] Example 2-4-2

[0119] Under nitrogen atmosphere, 23.6 g of compound 1b, 14.6 g of epoxyethane bromide and 1.4 g of Pd(PPh3)4 were dissolved in 160 mL of 1,4-dioxane. After adding 20 mL of 2 M aqueous K2CO3 solution, the reaction was carried out at 100 °C and monitored by TLC until no compound 1b remained. After cooling to room temperature, the mixture was filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was removed by filtration, and the filtrate was concentrated to dryness to obtain 13.7 g of compound 2 with a yield of 90.0% and an HPLC purity of 99.7%.

[0120] Example 2-4-3

[0121] Under nitrogen atmosphere, 23.6 g of compound 1b, 14.0 g of epoxyethane bromide and 1.3 g of Pd(dppf)Cl2 were dissolved in 160 mL of DMF. After adding 20 mL of 2 M aqueous K3PO4 solution, the reaction was carried out at 110 °C and monitored by TLC until no compound 1b remained. After cooling to room temperature, the mixture was filtered, and the obtained solid was dissolved in ethyl acetate. The insoluble matter was removed by filtration, and the filtrate was concentrated to dryness to obtain 13.6 g of compound 2 with a yield of 89.4% and an HPLC purity of 99.6%.

[0122] Example 2-4-4

[0123] Under nitrogen atmosphere, 23.6 g of compound 1b, 14.4 g of bromoethylene oxide and 0.3 g of PdCl2 were dissolved in a mixed solvent of 160 mL of DME and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 80 °C and monitored by TLC until no compound 1b remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 13.5 g of compound 2 with a yield of 88.8% and an HPLC purity of 99.3%.

[0124] Example 2-4-5

[0125] Under nitrogen atmosphere, 23.6 g of compound 1b, 13.7 g of bromoethylene oxide and 0.4 g of Pd(OAc)2 were dissolved in a mixed solvent of 160 mL of toluene and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 100 °C and monitored by TLC until no compound 1b remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 13.7 g of compound 2 with a yield of 90.0% and an HPLC purity of 99.0%.

[0126] Example 2-4-6

[0127] Under nitrogen atmosphere, 23.6 g of compound 1b, 13.9 g of bromoethylene oxide and 1.3 g of Pd(dppf)Cl2 were dissolved in a mixed solvent of 160 mL of DMF and 40 mL of water. After adding 20 mL of 2 M aqueous Na2CO3 solution, the reaction was carried out at 120 °C and monitored by TLC until no compound 1b remained. The reaction mixture was cooled to room temperature and filtered. The obtained solid was dissolved in ethyl acetate, and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 13.5 g of compound 2 with a yield of 88.8% and an HPLC purity of 99.5%.

[0128] Preparation of Terbutaline in Example 3

[0129]

[0130] Example 3-1

[0131] 15.2 g of compound 2 and 7.3 g of tert-butylamine were dissolved in 100 mL of toluene. Then 11.2 g of potassium tert-butoxide was added, and the reaction was carried out at 110 °C and monitored by TLC until no compound 2 remained. The reaction mixture was cooled to room temperature and the insoluble substances were removed by filtration. The filtrate was concentrated to dryness to obtain 21.0 g of terbutaline with a yield of 93.2% and an HPLC purity of 99.8%.

[0132] Example 3-2

[0133] Dissolve 15.2 g of Compound 2 and 7.3 g of tert-butylamine in 100 mL of 1,4-dioxane, then add 9.6 g of sodium tert-butoxide, and react at 100 °C. Monitor by TLC until there is no Compound 2. Cool to room temperature, filter off the insoluble matter, and concentrate the filtrate to dryness to obtain 20.0 g of terbutaline, with a yield of 88.8% and an HPLC purity of 99.1%.

[0134] Example 3-3

[0135] Dissolve 15.2 g of Compound 2 and 7.3 g of tert-butylamine in 100 mL of DMF, then add 5.4 g of sodium methoxide, and react at 120 °C. Monitor by TLC until there is no Compound 2. Cool to room temperature, filter off the insoluble matter, and concentrate the filtrate to dryness to obtain 19.8 g of terbutaline, with a yield of 87.9% and an HPLC purity of 90.5%.

[0136] Example 3-4

[0137] Dissolve 15.2 g of Compound 2 and 7.3 g of tert-butylamine in 100 mL of toluene, then add 6.8 g of sodium ethoxide, and react at 110 °C. Monitor by TLC until there is no Compound 2. Cool to room temperature, filter off the insoluble matter, and concentrate the filtrate to dryness to obtain 19.5 g of terbutaline, with a yield of 86.6% and an HPLC purity of 96.5%.

[0138] Preparation of Terbutaline Sulfate in Example 4

[0139]

[0140] Dissolve 20.0 g of terbutaline in 100 mL of dichloromethane. Slowly add 10% sulfuric acid methanol solution dropwise with stirring until the pH value is 4 - 5. Stop adding, cool to about -10 °C, continue stirring for crystallization, and filter to obtain 20.5 g of terbutaline sulfate, with a yield of 84.2% and an HPLC purity of 99.5%.

[0141] Finally, it should be noted that: the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: they can still modify the technical solutions recorded in the foregoing embodiments, or perform equivalent replacements on some or all of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing terbutaline, characterized in that, It includes the following steps: (a) Compound 1 undergoes a Suzuki reaction with haloethylene oxide under the action of a palladium catalyst and a base reagent to obtain Compound 2; (b) Compound 2 reacts with tert-butylamine under the action of a base reagent to obtain terbutaline; The reaction formula is as follows: R is selected from a borate group or a boric acid group; X1 is selected from any one of Cl, Br, and I; In step (a), the palladium catalyst is selected from one or a combination of several of Pd(PPh3)4, PdCl2, PdCl2(dppf), Pd(OAc)2, or Pd(PPh3)2Cl2; In step (a), the base reagent is selected from one or a combination of several of cesium carbonate, potassium carbonate, potassium phosphate, sodium carbonate, sodium phosphate, or lithium carbonate; The reaction temperature is 80°C - 120°C.

2. The method for preparing terbutaline according to claim 1, characterized in that, R is selected from a pinacol borate group, that is, Compound 1 is 3,5-dihydroxybenzeneboronic acid pinacol ester; X1 is selected from Br; It includes the following steps: (a) 3,5-Dihydroxybenzeneboronic acid pinacol ester undergoes a Suzuki reaction with bromoethylene oxide to obtain Compound 2; (b) Compound 2 reacts with tert-butylamine to obtain terbutaline; The reaction formula is as follows: 。 3. The method for preparing terbutaline according to claim 1, characterized in that, R is selected from a boric acid group, that is, Compound 1 is 3,5-dihydroxybenzeneboronic acid; X1 is selected from Br; It includes the following steps: (a) 3,5-Dihydroxybenzeneboronic acid undergoes a Suzuki reaction with bromoethylene oxide to obtain Compound 2; (b) Compound 2 reacts with tert-butylamine to obtain terbutaline; The reaction formula is as follows:

4. The method for preparing terbutaline according to claim 1, characterized in that, In step (b), the base reagent is selected from one or a combination of several of sodium methoxide, sodium ethoxide, potassium tert-butoxide, or sodium tert-butoxide.

5. The method for preparing terbutaline according to claim 1, characterized in that, In step (b), the reaction temperature is 100°C - 120°C.

6. The method for preparing terbutaline according to claim 2, characterized in that, The preparation method of the 3,5-dihydroxybenzeneboronic acid pinacol ester includes the following steps: 5-haloresorcinol reacts with bis(pinacolato)diboron to obtain 3,5-dihydroxybenzeneboronic acid ester; The reaction formula is as follows: X2 is selected from any one of Cl, Br, and I.

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