CN115974802A - Preparation method of bisoprolol fumarate intermediate - Google Patents

Preparation method of bisoprolol fumarate intermediate Download PDF

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CN115974802A
CN115974802A CN202211272521.3A CN202211272521A CN115974802A CN 115974802 A CN115974802 A CN 115974802A CN 202211272521 A CN202211272521 A CN 202211272521A CN 115974802 A CN115974802 A CN 115974802A
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bisoprolol fumarate
fumarate intermediate
preparing
compound
ligand
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方同华
李天翥
孙元广
徐丹
张哲鸣
刘敏
周艳谋
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Jixi Branch Heilongjiang Zbd Pharmaceutical Co ltd
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Jixi Branch Heilongjiang Zbd Pharmaceutical Co ltd
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a bisoprolol fumarate intermediate, which comprises the following steps:

Description

Preparation method of bisoprolol fumarate intermediate
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of a bisoprolol fumarate intermediate.
Background
Bisoprolol fumarate is suitable for treating hypertension, coronary heart disease, moderate to severe chronic stable heart failure and other symptoms, has long action time, can realize once-a-day administration, and basically has no adverse effect on lung function. Bisoprolol fumarate was patented in Belgium in 1978, in the United states in 1979 and 1981, respectively, and formally marketed in 4 months 1986, and is currently marketed in more than twenty countries and regions, english, fair, japan, etc. Specific results are as follows.
Figure SMS_1
The main process route of bisoprolol fumarate at present is as follows:
Figure SMS_2
in related patents, 4-hydroxybenzaldehyde is used as a starting material, 4-hydroxybenzyl alcohol is reduced by borohydride, or 4-hydroxybenzyl alcohol is directly used as a raw material to be subjected to etherification reaction with isopropoxy ethanol to obtain 4-isopropoxy ethoxy methyl phenol, epoxy chloropropane is used for substitution to obtain epoxide, isopropylamine is used for epoxy opening to obtain free alkali of bisoprolol, and finally, the fumaric acid is used for salifying to obtain the bisoprolol fumarate.
The above route has the main problem that multiple steps are not provided with oil, which increases the difficulty of purification and causes certain risks for the subsequent API quality. Further, based on patent reports, it is found that after the compound III is constructed, corresponding intermediates are all solids, and can be recrystallized and purified, so that the industrial productivity is greatly improved, and the quality control of API is facilitated, and a corresponding route is as follows.
Figure SMS_3
In further research, we found that the process control difficulty of step 1 is high, and the process impurity compound 07 can be brought into bisoprolol fumarate API to cause API quality risk, thereby causing API quality problem. The process impurity structure is as follows:
Figure SMS_4
since compound 07 cannot be removed below the required limit by conventional purification means and its presence itself has a great risk impact on API quality. Therefore, there is a need to further develop a new synthesis method of compound IV to solve the problems in the bisoprolol fumarate process.
Disclosure of Invention
The purpose of the invention is: overcomes the defects in the prior art, and provides a preparation method of bisoprolol fumarate intermediate with high reaction condition temperature and yield. .
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a method for preparing a bisoprolol fumarate intermediate, said intermediate being 5- ((4- ((2-isopropoxyethoxy) methyl) phenoxy) methyl) -3-isopropyloxazolidin-2-one, comprising the steps of:
Figure SMS_5
heating the compound II and the compound III in an organic solvent to 80-120 ℃ in the presence of alkali, a copper catalyst and a ligand to prepare the key compound IV.
Furthermore, the catalyst can be selected from cuprous bromide, cupric acetate, cuprous iodide and cupric oxide.
Further, cuprous iodide is selected as the catalyst.
Further, the molar ratio of the catalyst to the compound II is 1.
Further, the preferred ratio is 1.
Further, the alkali is cesium carbonate, potassium tert-butoxide or lithium tert-butoxide.
Further, the alkali is potassium tert-butoxide.
Further, the ligand is dibenzoyl tartaric acid (DMTA).
Further, the molar ratio of the ligand to the catalyst is 1:1.
Further, the solvent is one of N, N-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide.
The technical scheme adopted by the invention has the following beneficial effects:
the problems of stability and impurities can be better solved through Ullman reaction, and meanwhile, the inventor unexpectedly finds that the yield can be improved from about 60 percent to more than 80 percent by adding the ligand dibenzoyltartaric acid (DMTA) in the experimental process, and simultaneously, the reaction temperature is further reduced from 140 ℃ to about 80 ℃, so that the method is more favorable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The preparation method of the bisoprolol fumarate intermediate is 5- ((4- ((2-isopropoxyethoxy) methyl) phenoxy) methyl) -3-isopropyloxazolidin-2-one, and comprises the following steps:
Figure SMS_6
heating the compound II and the compound III in an organic solvent to 80-120 ℃ in the presence of alkali, a copper catalyst and a ligand to prepare the key compound IV.
The problems of stability and impurities can be better solved through Ullman reaction, and meanwhile, the fact that the yield can be improved to more than 80% from about 60% by adding the ligand dibenzoyltartaric acid (DMTA) is unexpectedly found, the reaction temperature is further reduced to about 80 ℃ from 140 ℃, and the method is more favorable for industrial production. From the view of reaction mechanism, it should be because the ligand thereof coordinates with copper ion to lower the activation energy of the reaction and stabilize the intermediate state of the reaction, thereby achieving better results.
Example 1:
Figure SMS_7
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in a 2L three-necked reaction flask, a system of 1-bromo-4- ((2-isopropoxyethoxy) methyl) benzene (compound II,50g,1.0 eq), 5- (hydroxymethyl) -3-isopropyloxazolidin-2-one (compound III,32.03 g,1.1 eq) and DMF (350 mL) was added in this order, stirred at room temperature and replaced with nitrogen three times, followed by addition of cuprous iodide (3.5 g,0.1 eq), dibenzoyltartaric acid (DMTA) (6.6 g,0.1 eq) and potassium tert-butoxide (24.6 g,1.2 eq), heating of the system to 80 ℃ for 16 hours, TLC showed complete conversion of the starting material, cooling of the system to room temperature, followed by addition of water (400 mL) to quench the reaction, filtration of the precipitated solid, collection of the filter cake, and vacuum drying to give compound IV (52.7 g yield: 82% off-white solid).
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)。
LCMS(ESI)m/z,352.44(M+H)+
Example 2:
Figure SMS_8
1-bromo-4- ((2-isopropoxyethoxy) methyl) benzene (compound II,50g,1.0 equivalent), 5- (hydroxymethyl) -3-isopropyloxazolidin-2-one (compound III,32.03 g,1.1 equivalent) and DMSO (500 mL) system were added sequentially in a 2L three-port reaction flask, stirred at room temperature and replaced with nitrogen three times, followed by addition of cuprous iodide (7.0 g,0.2 equivalent) and potassium tert-butoxide (24.6 g,1.2 equivalent), the system was heated to 140 ℃ for 18 hours, after TLC showed complete conversion of the starting material, the system was cooled to room temperature, followed by addition of water (800 mL) for quenching reaction, filtration to precipitate a solid, and after collection of the filter cake, silica gel (100-200 mesh) column chromatography to obtain compound IV (37.2 g yield: 58% white-like solid).
Example 3:
Figure SMS_9
1-bromo-4- ((2-isopropoxyethoxy) methyl) benzene (compound II,5g,1.0 equivalent), 5- (hydroxymethyl) -3-isopropyloxazolidin-2-one (compound III, 3.0g,1.1 equivalent) and N-methylpyrrolidone (50 mL) are added in a 100mL three-port reaction flask in sequence, the mixture is stirred at room temperature and replaced by nitrogen for three times, cuprous bromide (0.26g, 0.1 equivalent) and potassium tert-butoxide (2.5g, 1.2 equivalents) are added, the system is heated to 100 ℃ and reacted for 18 hours, TLC shows that the raw materials are completely converted, the system is cooled to room temperature, then water (50 mL) is added to quench the reaction, the solid is separated out by filtration, and after collecting the filter cake, silica gel (100-200 mesh) column chromatography is carried out to obtain compound IV (4.5 g yield: 70% white-like solid).
Example 4:
Figure SMS_10
1-bromo-4- ((2-isopropoxyethoxy) methyl) benzene (compound II,5g,1.0 eq), 5- (hydroxymethyl) -3-isopropyloxazolidin-2-one (compound III, 3.2g,1.1 eq) and DMF (40 mL) were added sequentially to a 100mL three-neck reaction flask, stirred at room temperature and replaced with nitrogen three times, followed by addition of cuprous iodide (0.18g, 0.05 eq), dibenzoyltartaric acid (DMTA) (0.33g, 0.05 eq) and potassium tert-butoxide (2.5g, 1.2 eq), heating the system to 80 ℃ for 16 hours, TLC showed no further conversion of the starting material, cooling the system to room temperature, quenching the reaction in water (400 mL), filtering to precipitate a solid, collecting the filter cake, and purifying by column chromatography (100-200 mesh) to obtain compound IV (3.6 g: 56% white-like solid).
Example 5:
Figure SMS_11
1-bromo-4- ((2-isopropoxyethoxy) methyl) benzene (compound II,5g,1.0 eq), 5- (hydroxymethyl) -3-isopropyloxazolidin-2-one (compound III, 3.2g,1.1 eq) and DMF (50 mL) were added sequentially to a 100mL three-necked reaction flask, the system was stirred at room temperature and replaced with nitrogen three times, then copper acetate (0.33g, 0.1 eq), dibenzoyltartaric acid (DMTA) (0.66g, 0.1 eq) and potassium tert-butoxide (2.5g, 1.2 eq) were added, the system was heated to 80 ℃ for 16 hours, TLC showed complete conversion of the starting material, the system was cooled to room temperature, then water (40 mL) was added to quench the reaction, the solid was precipitated by filtration, the filter cake was collected and purified using (100-200 mesh) to give compound IV (4.5 g yield: 70% white-like solid).
Example 6:
Figure SMS_12
in a 100mL three-necked reaction flask, a system of 1-bromo-4- ((2-isopropoxyethoxy) methyl) benzene (compound II,5g,1.0 equivalent), 5- (hydroxymethyl) -3-isopropyloxazolidin-2-one (compound III, 3.2g,1.1 equivalent) and DMF (50 mL) was added in this order, stirred at room temperature and replaced with nitrogen three times, followed by addition of cuprous iodide (0.35g, 0.1 equivalent), dibenzoyltartaric acid (DMTA) (0.66g, 0.1 equivalent) and cesium carbonate (7.14g, 1.2 equivalent), heating of the system to 80 ℃ for 36 hours, TLC showed complete conversion of the raw material, cooling of the system to room temperature, followed by addition of water (100 mL) to quench the reaction, filtration of the precipitated solid, collection of the filter cake, and purification using (100-200 mesh) to obtain compound IV (4.3 g yield: 66.9% white-like solid).
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.

Claims (10)

1. A method for preparing a bisoprolol fumarate intermediate, said intermediate being 5- ((4- ((2-isopropoxyethoxy) methyl) phenoxy) methyl) -3-isopropyloxazolidin-2-one, characterized by: the preparation method comprises the following steps:
Figure FDA0003895277980000011
heating the compound II and the compound III in an organic solvent to 80-120 ℃ in the presence of alkali, a copper catalyst and a ligand to prepare the key compound IV.
2. The method for preparing the bisoprolol fumarate intermediate according to claim 1, characterized in that: the catalyst can be selected from cuprous bromide, cupric acetate, cuprous iodide and cupric oxide.
3. The method for preparing the bisoprolol fumarate intermediate according to claim 2, wherein the bisoprolol fumarate intermediate comprises the following steps: the catalyst is cuprous iodide.
4. The method for preparing the bisoprolol fumarate intermediate according to claim 2, characterized in that: the molar ratio of the catalyst to the compound II is 1.
5. The method for preparing the bisoprolol fumarate intermediate according to claim 4, wherein the bisoprolol fumarate intermediate is prepared from the following raw materials: the preferred ratio is 1.
6. The method for preparing the bisoprolol fumarate intermediate according to claim 1, wherein the bisoprolol fumarate intermediate comprises the following steps: the alkali is cesium carbonate, potassium tert-butoxide or lithium tert-butoxide.
7. The method for preparing the bisoprolol fumarate intermediate according to claim 1, wherein the bisoprolol fumarate intermediate comprises the following steps: the alkali is potassium tert-butoxide.
8. The method for preparing the bisoprolol fumarate intermediate according to claim 1, wherein the bisoprolol fumarate intermediate comprises the following steps: the ligand is dibenzoyltartaric acid (DMTA).
9. The method for preparing the bisoprolol fumarate intermediate according to claim 8, wherein the bisoprolol fumarate intermediate is prepared from the following raw materials: the molar ratio of the ligand to the catalyst was 1:1.
10. The method for preparing the bisoprolol fumarate intermediate according to claim 1, characterized in that: the solvent is one of N, N-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide.
CN202211272521.3A 2022-10-18 2022-10-18 Preparation method of bisoprolol fumarate intermediate Pending CN115974802A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664657A (en) * 2013-11-25 2014-03-26 四川大学 New preparation method for bisoprolol fumarate
CN112194587A (en) * 2020-11-18 2021-01-08 江苏悦兴医药技术有限公司 Preparation method of chiral bisoprolol fumarate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103664657A (en) * 2013-11-25 2014-03-26 四川大学 New preparation method for bisoprolol fumarate
CN112194587A (en) * 2020-11-18 2021-01-08 江苏悦兴医药技术有限公司 Preparation method of chiral bisoprolol fumarate

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HYE SUN LIM ET AL: "Synthesis of Dibenzoxepine Lactams via a Cu-Catalyzed One-Pot Etherification/Aldol Condensation Cascade Reaction: Application toward the Total Synthesis of Aristoyagonine", ORGANIC LETTERS, vol. 15, no. 18, pages 4718 - 4721, XP055814556, DOI: 10.1021/ol402036t *
HYUNG YOON ET AL: "Atroposelective Desymmetrization of Resorcinol-Bearing Quinazolinones via Cu-Catalyzed C−O Bond Formation", ORGANIC LETTERS, vol. 24, pages 762 - 766 *

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