A preparation method of bisoprolol fumarate intermediate

Abstract

The invention relates to the technical field of drug synthesis, in particular to a method for preparing a bisoprolol fumarate intermediate. The method comprises the following steps: in the presence of a base, a base, a copper catalyst and a ligand, heating a compound II and a compound III to 80-120 DEG C in an organic solvent to prepare a key compound IV; in the invention, the Ullman reaction can better solve the problems of stability and impurities, and at the same time, the inventor unexpectedly finds that the yield can be increased from about 60% to more than 80% by adding a ligand dibenzoyltartaric acid (DMTA) during the experiment, and at the same time, the reaction temperature can be further reduced from 140 DEG C to about 80 DEG C, which is more conducive to industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing a bisoprolol fumarate intermediate. Background Art

[0002] Bisoprolol fumarate is suitable for treating hypertension, coronary heart disease, and moderate to severe chronic stable heart failure. It has a long duration of action, can be administered once a day, and has little adverse effect on lung function. Bisoprolol fumarate was patented in Belgium in 1978, in the United States in 1979 and 1981, and was officially launched in April 1986. It has now been launched in more than 20 countries and regions including the United Kingdom, France, and Japan. The specific results are as follows.

[0003]

[0004] At present, the main process routes of bisoprolol fumarate are as follows:

[0005]

[0006] The relevant patent uses 4-hydroxybenzaldehyde as the starting material, reduces 4-hydroxybenzyl alcohol with borohydride, or directly uses 4-hydroxybenzyl alcohol as a raw material to undergo an etherification reaction with isopropoxyethanol to obtain 4-isopropoxyethoxymethylphenol, which is then replaced by epichlorohydrin to obtain an epoxide, which is then opened with isopropylamine to obtain the free base of bisoprolol, and finally salified with fumaric acid to obtain bisoprolol fumarate.

[0007] The main problem of the above routes is that there is no oil in multiple steps, which increases the difficulty of purification and creates certain risks for the quality of subsequent API. Further, based on patent reports, we found that after constructing compound III, the corresponding intermediates are all solids, which can be recrystallized and purified, thereby greatly improving the industrial production capacity and facilitating the quality control of API. The corresponding route is as follows.

[0008]

[0009] In further research, we found that the process control of step 1 is difficult, and its process impurity compound 07 will be introduced into the bisoprolol fumarate API, causing API quality risks and thus API quality problems. The structure of the process impurity is as follows:

[0010]

[0011] Since compound 07 cannot be removed below the required limit by conventional purification methods, and its presence itself has a huge impact on the quality risk of API, it is necessary to further develop a new synthesis method of compound IV to solve the problems in the bisoprolol fumarate process. Summary of the invention

[0012] The purpose of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing a bisoprolol fumarate intermediate with high reaction temperature and high yield.

[0013] To achieve the above purpose, the technical solution adopted in the present invention is as follows:

[0014] A method for preparing a bisoprolol fumarate intermediate, wherein the intermediate is 5-((4-((2-isopropoxyethoxy)methyl)phenoxy)methyl)-3-isopropyloxazolidin-2-one, and the preparation method comprises the following steps:

[0015]

[0016] In the presence of a base, a copper catalyst and a ligand, compound II and compound III are heated to 80-120° C. in an organic solvent to prepare key compound IV.

[0017] Furthermore, the catalyst may be cuprous bromide, cupric acetate, cuprous iodide and cupric oxide.

[0018] Furthermore, the catalyst is cuprous iodide.

[0019] Furthermore, the molar ratio of the catalyst to compound II is 1:20-1:10.

[0020] Furthermore, the preferred ratio is 1:10.

[0021] Furthermore, the base is selected from cesium carbonate, potassium carbonate, potassium tert-butoxide and lithium tert-butoxide.

[0022] Furthermore, the base is potassium tert-butoxide.

[0023] Furthermore, the ligand is dibenzoyltartaric acid (DMTA).

[0024] Furthermore, the molar ratio of the ligand to the catalyst is 1:1.

[0025] Furthermore, the solvent is one of N,N-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide.

[0026] The technical solution of the present invention has the following beneficial effects:

[0027] In the present invention, the Ullman reaction can better solve the problems of stability and impurities. At the same time, the inventor unexpectedly found during the experiment that the yield can be increased from about 60% to more than 80% by adding a ligand dibenzoyltartaric acid (DMTA). At the same time, the reaction temperature can be further reduced from 140° C. to about 80° C., which is more conducive to industrial production. DETAILED DESCRIPTION

[0028] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0029] The preparation method of the bisoprolol fumarate intermediate of the present invention, the intermediate is 5-((4-((2-isopropoxyethoxy)methyl)phenoxy)methyl)-3-isopropyloxazolidin-2-one, and the preparation method comprises the following steps:

[0030]

[0031] In the presence of a base, a copper catalyst and a ligand, compound II and compound III are heated to 80-120° C. in an organic solvent to prepare key compound IV.

[0032] The Ullman reaction can better solve the problems of stability and impurities. At the same time, we unexpectedly found that by adding the ligand dibenzoyltartaric acid (DMTA), the yield can be increased from about 60% to more than 80%. At the same time, the reaction temperature can be further reduced from 140°C to about 80°C, which is more conducive to industrial production. From the reaction mechanism, it should be because its ligand coordinates with copper ions to reduce its reaction activation energy and stabilize the reaction intermediate state, thus achieving better results.

[0033] Embodiment 1:

[0034]

[0035] In a 2L three-necked reaction flask, 1-bromo-4-((2-isopropoxyethoxy)methyl)benzene (compound II, 50 g, 1.0 equivalent), 5-(hydroxymethyl)-3-isopropyloxazolidin-2-one (compound III, 32.03 g, 1.1 equivalent) and DMF (350 mL) were added in sequence, the system was stirred at room temperature, and nitrogen was replaced three times, and then cuprous iodide (3.5 g, 0.1 equivalent), dibenzoyltartaric acid (DMTA) (6.6 g, 0.1 equivalent) and potassium tert-butoxide (24.6 g, 1.2 equivalent) were added. The system was heated to 80 ° C for 16 hours. After TLC showed that the raw material was completely converted, the system was cooled to room temperature, and then water (400 mL) was added to quench the reaction, the precipitated solid was filtered, and the filter cake was collected and dried in vacuo to obtain compound IV (52.7 g yield: 82% off-white solid).

[0036] 1H-NMR(300MHz,d6-DMSO)δ7.27(d,2H),6.94(d,2H),4.81-4.83(m.1H), 4.43(s,2H),4.18-4.11(m,2H),3.95-3.91(m,1H),3.56-3.39(m,4H),3.37-3.35(m,2H),2.56(s,1H),1.16-1.08(m,12H).

[0037] LCMS (ESI) m / z, 352.44 (M+H)+

[0038] Embodiment 2:

[0039]

[0040] In a 2L three-necked reaction flask, 1-bromo-4-((2-isopropoxyethoxy)methyl)benzene (compound II, 50 g, 1.0 equivalent), 5-(hydroxymethyl)-3-isopropyloxazolidin-2-one (compound III, 32.03 g, 1.1 equivalent) and DMSO (500 mL) were added in sequence. The system was stirred at room temperature and replaced with nitrogen three times. Subsequently, cuprous iodide (7.0 g, 0.2 equivalent) and potassium tert-butoxide (24.6 g, 1.2 equivalent) were added. The system was heated to 140°C for 18 hours. After TLC showed that the raw material was completely converted, the system was cooled to room temperature, and then water (800 mL) was added to quench the reaction. The precipitated solid was filtered out, and the filter cake was collected and subjected to silica gel (100-200 mesh) column chromatography to obtain compound IV (37.2 g, yield: 58% off-white solid).

[0041] Embodiment 3:

[0042]

[0043] In a 100 mL three-necked reaction bottle, 1-bromo-4-((2-isopropoxyethoxy)methyl)benzene (compound II, 5 g, 1.0 equivalent), 5-(hydroxymethyl)-3-isopropyloxazolidin-2-one (compound III, 3.0 g, 1.1 equivalent) and N-methylpyrrolidone (50 mL) were added in sequence. The system was stirred at room temperature and replaced with nitrogen three times. Subsequently, cuprous bromide (0.26 g, 0.1 equivalent) and potassium tert-butoxide (2.5 g, 1.2 equivalent) were added. The system was heated to 100 ° C for 18 hours. After TLC showed that the raw material was completely converted, the system was cooled to room temperature, and then water (50 mL) was added to quench the reaction. The precipitated solid was filtered out, and the filter cake was collected and subjected to silica gel (100-200 mesh) column chromatography to obtain compound IV (4.5 g yield: 70% off-white solid).

[0044] Embodiment 4:

[0045]

[0046] In a 100 mL three-necked reaction bottle, 1-bromo-4-((2-isopropoxyethoxy)methyl)benzene (compound II, 5 g, 1.0 equivalent), 5-(hydroxymethyl)-3-isopropyloxazolidin-2-one (compound III, 3.2 g, 1.1 equivalent) and DMF (40 mL) were added in sequence. The system was stirred at room temperature and replaced with nitrogen three times. Subsequently, cuprous iodide (0.18 g, 0.05 equivalent), dibenzoyltartaric acid (DMTA) (0.33 g, 0.05 equivalent) and potassium tert-butoxide (2.5 g, 1.2 equivalent) were added. The system was heated to 80 ° C for 16 hours. After TLC showed that the raw material was not further converted, the system was cooled to room temperature, and then water (400 mL) was added to quench the reaction. The precipitated solid was filtered out, and the filter cake was collected and purified by column chromatography (100-200 mesh) to obtain compound IV (3.6 g, yield: 56% off-white solid).

[0047] Embodiment 5:

[0048]

[0049] In a 100 mL three-necked reaction bottle, 1-bromo-4-((2-isopropoxyethoxy)methyl)benzene (compound II, 5 g, 1.0 equivalent), 5-(hydroxymethyl)-3-isopropyloxazolidin-2-one (compound III, 3.2 g, 1.1 equivalent) and DMF (50 mL) were added in sequence. The system was stirred at room temperature and replaced with nitrogen three times. Subsequently, copper acetate (0.33 g, 0.1 equivalent), dibenzoyltartaric acid (DMTA) (0.66 g, 0.1 equivalent) and potassium tert-butoxide (2.5 g, 1.2 equivalent) were added. The system was heated to 80 ° C for 16 hours. After TLC showed that the raw material was completely converted, the system was cooled to room temperature, and then water (40 mL) was added to quench the reaction. The precipitated solid was filtered out, and the filter cake was collected and purified by column chromatography (100-200 mesh) to obtain compound IV (4.5 g yield: 70% off-white solid).

[0050] Embodiment 6:

[0051]

[0052] In a 100 mL three-necked reaction bottle, 1-bromo-4-((2-isopropoxyethoxy)methyl)benzene (compound II, 5 g, 1.0 equivalent), 5-(hydroxymethyl)-3-isopropyloxazolidin-2-one (compound III, 3.2 g, 1.1 equivalent) and DMF (50 mL) were added in sequence. The system was stirred at room temperature and replaced with nitrogen three times. Subsequently, cuprous iodide (0.35 g, 0.1 equivalent), dibenzoyltartaric acid (DMTA) (0.66 g, 0.1 equivalent) and cesium carbonate (7.14 g, 1.2 equivalent) were added. The system was heated to 80 ° C for 36 hours. After TLC showed that the raw material was completely converted, the system was cooled to room temperature, and then water (100 mL) was added to quench the reaction. The precipitated solid was filtered out, and the filter cake was collected and purified by column chromatography (100-200 mesh) to obtain compound IV (4.3 g, yield: 66.9% off-white solid).

[0053] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the invention patent. It should be pointed out that for ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing a bisoprolol fumarate intermediate, wherein the intermediate is 5-((4-((2-isopropoxyethoxy)methyl)phenoxy)methyl)-3-isopropyloxazolidin-2-one, characterized in that: The preparation method comprises the following steps: Wherein, X in compound II is Br; In the presence of a base, a copper catalyst and a ligand, compound II and compound III are heated to 80-120° C. in an organic solvent to prepare a key compound IV; The catalyst is cuprous iodide; The base is potassium tert-butoxide; The ligand is dibenzoyltartaric acid; The molar ratio of the catalyst to compound II is 1:20-1:10; The molar ratio of the ligand to the catalyst is 1:1; The solvent is one of N,N-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide.

2. The method for preparing a bisoprolol fumarate intermediate according to claim 1, wherein: The molar ratio of the catalyst to compound II is 1:10.

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