Preparation method of methyl (4-hydroxyphenyl) glycine methyl ester

Abstract

The invention discloses a preparation method of methyl (4-hydroxyphenyl) glycine methyl ester, which comprises the following steps: the preparation method of methyl (4-hydroxyphenyl) glycine methyl ester provided by the invention is mild in condition, simple in process, green and environment-friendly, cheap and easily available in raw materials, simple and convenient to operate and very suitable for industrial large-scale production, and the comprehensive yield is up to 85%; the industrial application prospect and the market value are very wide.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate preparation technology, specifically, it relates to a method for preparing methyl (4-hydroxyphenyl)glycine methyl ester. Background Technology

[0002] Cefprozil belongs to the second-generation cephalosporin class of antibiotics and was the first oral cephalosporin antibiotic approved by the US FDA for the treatment of otitis media and sinusitis in children. Its antibacterial efficacy is superior to cefaclor, and it is suitable for infants over 6 months of age and adult patients. The drug's bactericidal mechanism involves binding to penicillin-binding proteins (PBPs) on the bacterial cell membrane, inhibiting bacterial cell wall synthesis, thereby leading to bacterial lysis and death. P-hydroxyphenylglycine methyl ester is an important precursor molecule of the amide fragment of the cefprozil drug molecule (the dashed box portion of the cefprozil chemical structure). Therefore, a green and efficient preparation process for p-hydroxyphenylglycine methyl ester has become an urgent need in the industrial production of cefprozil.

[0003]

[0004] Chemical structural formula of cefprozil

[0005] Patent applications US6057336A and US2003120073A1 disclose the synthesis of p-hydroxyphenylglycine methyl ester via methylation using p-hydroxyphenylglycine as a substrate. However, this method requires large amounts of hydrogen chloride gas and thionyl chloride liquid, which are highly corrosive to equipment and unsuitable for industrial production. Patent application WO2005085232A1 discloses the synthesis of p-hydroxyphenylglycine methyl ester from a methanol solution of p-hydroxyphenylglycine under the action of concentrated sulfuric acid. However, the concentrated sulfuric acid used in this method has strong oxidizing and corrosive properties, resulting in numerous side reactions, severe equipment corrosion, and significant amounts of waste, making it unsuitable for scale-up production. Patent application CN101687787A discloses the synthesis of p-hydroxyphenylglycine methyl ester from p-hydroxyphenylglycine and 2,2-dimethoxypropane. The raw materials used in this process are irritating and costly, making it unsuitable for scale-up production. Patent application CN102718672A discloses a method for obtaining p-hydroxyphenylglycine methyl ester by methylation of p-hydroxyphenylglycine as a substrate under solid acid catalysis. However, the raw materials for this method are not readily available and are relatively expensive. It requires the additional preparation of solid acid catalysts, resulting in a complex manufacturing process and unstable catalytic activity.

[0006] The preparation process of p-hydroxyphenylglycine methyl ester, which uses inexpensive and readily available raw materials, is environmentally friendly, has mild reaction conditions, high reaction yield, and simple post-processing, is suitable for large-scale production and has become an urgent need in pharmaceutical production. Summary of the Invention

[0007] The purpose of this invention is to provide a method for preparing methyl (4-hydroxyphenyl)glycine methyl ester.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] This invention provides a method for preparing methyl (4-hydroxyphenyl)glycine methyl ester suitable for industrial-scale production, comprising the following steps:

[0010]

[0011] The first step involves adding p-aminophenol (compound A), tert-butyldimethylchlorosilane, and imidazole in a molar ratio of 1:1~2:0.4~2 to a first organic solvent. The reaction is carried out at a temperature of 15~30℃ (preferably 15, 20, 25, or 30℃) for 0.5~3 hours (preferably 0.5, 1, 1.5, 2, or 2.5 hours). The reaction is then detected by high-performance liquid chromatography (HPLC) to indicate its completion. After post-processing, compound B is obtained.

[0012] In the second step, compound B, methyl bromoacetate (compound C), and anhydrous sodium acetate in a molar ratio of 1:0.9~2:0.4~3 are added to ethanol and reacted at a temperature of 70~90℃ (preferably 70, 75, 80, 85, 90℃) for 1~48 hours (preferably 6, 12, 18, 24, 30, 36, 42, 48 hours). The reaction is detected by high performance liquid chromatography and after post-processing, compound D is obtained.

[0013] The third step involves dissolving tetrabutylammonium fluoride in tetrahydrofuran, adding compound D, and reacting the mixture at a temperature of 15-30°C (preferably 15, 20, 25, or 30°C) for 1-3 hours (preferably 1, 1.5, 2, 2.5, or 3 hours). The reaction is then detected by high-performance liquid chromatography (HPLC) to indicate the end of the reaction. After post-processing, compound E, namely methyl (4-hydroxyphenyl)glycine methyl ester, is obtained.

[0014] The molar ratios of p-aminophenol, tert-butyldimethylchlorosilane, and imidazole are 1:1.01:1.1, 1:1.01:2, and 1:1.01:0.5.

[0015] The first organic solvent is selected from dichloromethane, 1,2-dichloroethane, ethyl acetate, and tetrahydrofuran.

[0016] In the first step, the conditions for high performance liquid chromatography (HPLC) detection of the reaction are as follows: chromatographic column: YMC-PACK, ODS-A, 150mm*4.6nn*5um, detection wavelength 254nm, water:methanol=1:9, flow rate=1ml / min, column temperature 40℃.

[0017] In the first step, the post-processing steps are as follows: add saturated brine to the reaction solution, extract with dichloromethane, wash with saturated brine again, and dry and concentrate the organic phase.

[0018] The molar ratios of compound B, methyl bromoacetate (i.e., compound C), and anhydrous sodium acetate are 1:1:1.1, 1:1:2.1, and 1:0.96:0.48.

[0019] In the second step, the conditions for high performance liquid chromatography (HPLC) detection of the reaction are as follows: chromatographic column: YMC-PACK, ODS-A, 150mm*4.6nn*5um, detection wavelength 254nm, water:methanol=1:9, flow rate=1ml / min, column temperature 40℃.

[0020] In the second step, the post-processing steps are: concentration under reduced pressure, extraction with ethyl acetate and saturated brine, washing with saturated brine, drying and concentrating the organic phase.

[0021] The molar ratio of the tetrabutylammonium fluoride and compound D is 1:1, 2:1, or 1.2:1.

[0022] In the third step, the conditions for high performance liquid chromatography (HPLC) detection of the reaction are as follows: chromatographic column: YMC-PACK, ODS-A, 150mm*4.6nn*5um, detection wavelength 254nm, water:methanol=1:9, flow rate=1ml / min, column temperature 40℃.

[0023] In the third step, the post-processing steps are as follows: extract with saturated brine and ethyl acetate, wash with saturated brine, dry and concentrate the organic phase.

[0024] By adopting the above technical solution, the present invention has the following advantages and beneficial effects:

[0025] The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester provided by this invention has mild conditions, a comprehensive yield of up to 85%, a simple process, is environmentally friendly, uses inexpensive and readily available raw materials, and is easy to operate. It is extremely suitable for industrial-scale production and has a very broad industrial application prospect and market value. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of the proton NMR spectrum of compound B in Example 1.

[0027] Figure 2 This is a schematic diagram of the proton NMR spectrum of compound D in Example 1.

[0028] Figure 3 This is a schematic diagram of the proton NMR spectrum of compound E in Example 1. Detailed Implementation

[0029] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments, further clarifies the invention. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.

[0030] Example 1

[0031] A method for preparing methyl (4-hydroxyphenyl)glycine methyl ester suitable for industrial-scale production includes the following steps:

[0032]

[0033] The CAS number of the methyl (4-hydroxyphenyl)glycine methyl ester prepared in this invention is 56405-21-1.

[0034] In the first step, p-aminophenol (91.6 mmol, 10 g), compound A, tert-butyldimethylchlorosilane (92.6 mmol, 14.0 g, TBSCl), and imidazole (100.8 mmol, 6.9 g) were added to 150 ml of dichloromethane and reacted at 25 °C for 2 hours. The reaction was detected by high performance liquid chromatography (HPLC) (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, 200 ml of saturated saline solution was added to the reaction solution, and 300 ml of dichloromethane was used for extraction. Then, 200 ml of saturated saline solution was added to wash twice. The organic phase was dried and concentrated to obtain 20.1 g of compound B, with a yield of 98%.

[0035] The spectrum of compound B is as follows Figure 1 As shown, Figure 1 This is a schematic diagram of the proton NMR spectrum of compound B in Example 1.

[0036]

[0037] In the second step, compound B (67.2 mmol, 15 g), methyl bromoacetate (compound C, 67.8 mmol, 10.4 g), and anhydrous sodium acetate (73.86 mmol, 6.1 g) were added to 100 ml of ethanol and reacted at 80 °C for 24 hours. The reaction was detected by high performance liquid chromatography (HPLC) (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, the solution was concentrated under reduced pressure to 10 ml. 100 ml of ethyl acetate and 100 ml of saturated brine were added to the reaction solution for extraction. The solution was then washed twice with 200 ml of saturated brine. The organic phase was dried and concentrated to obtain 25.6 g of compound D, with a yield of 97%.

[0038] The spectrum of compound D is as follows Figure 2 As shown, Figure 2 This is a schematic diagram of the proton NMR spectrum of compound D in Example 1.

[0039]

[0040] In the third step, tetrabutylammonium fluoride (33.9 mmol, 8.9 g) was dissolved in 150 ml of tetrahydrofuran, and compound D (33.9 mmol, 10 g) was added. The reaction was carried out at 25 °C for 2 hours, and detected by high performance liquid chromatography (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, 100 ml of saturated saline and 100 ml of ethyl acetate were added to the reaction solution for extraction, and then 100 ml of saturated saline was added to wash twice. The organic phase was dried and concentrated to obtain 6.1 g of compound E, namely methyl (4-hydroxyphenyl)glycine methyl ester, with a yield of 99%.

[0041] The spectrum of compound E is as follows Figure 3 As shown, Figure 3 This is a schematic diagram of the proton NMR spectrum of compound E in Example 1.

[0042]

[0043] Example 2

[0044] A method for preparing methyl (4-hydroxyphenyl)glycine methyl ester suitable for industrial-scale production includes the following steps:

[0045] In the first step, p-aminophenol (91.6 mmol, 10 g), compound A, tert-butyldimethylchlorosilane (92.6 mmol, 14.0 g, TBSCl), and imidazole (183.3 mmol, 12.5 g) were added to 150 ml of dichloromethane and reacted at 25 °C for 2 hours. The reaction was detected by high performance liquid chromatography (HPLC) (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, 200 ml of saturated saline solution was added to the reaction solution, and 300 ml of dichloromethane was used for extraction. Then, 200 ml of saturated saline solution was added to wash twice. The organic phase was dried and concentrated to obtain 19.9 g of compound B, with a yield of 97%.

[0046] In the second step, compound B (89.5 mmol, 20 g), methyl bromoacetate (compound C, 90.4 mmol, 13.8 g), and anhydrous sodium acetate (188 mmol, 15.4 g) were added to 200 ml of ethanol and reacted at 80 °C for 24 hours. The reaction was detected by high performance liquid chromatography (HPLC) (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, the solution was concentrated under reduced pressure to 10 ml. 100 ml of ethyl acetate and 100 ml of saturated brine were added to the reaction solution for extraction. The solution was then washed twice with 200 ml of saturated brine. The organic phase was dried and concentrated to obtain 25.4 g of compound D, with a yield of 96%.

[0047] In the third step, tetrabutylammonium fluoride (135.4 mmol, 35.4 g) was dissolved in 200 ml of tetrahydrofuran, and compound D (67.7 mmol, 20 g) was added. The reaction was carried out at 25 °C for 2 hours, and detected by high performance liquid chromatography (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, 100 ml of saturated saline and 100 ml of ethyl acetate were added to the reaction solution for extraction, and then 100 ml of saturated saline was added to wash twice. The organic phase was dried and concentrated to obtain 12.0 g of compound E, namely methyl (4-hydroxyphenyl)glycine methyl ester, with a yield of 99%.

[0048] Example 3

[0049] A method for preparing methyl (4-hydroxyphenyl)glycine methyl ester suitable for industrial-scale production includes the following steps:

[0050] In the first step, p-aminophenol (91.6 mmol, 10 g), compound A, tert-butyldimethylchlorosilane (92.6 mmol, 14.0 g, TBSCl), and imidazole (45.8 mmol, 3.1 g) were added to 150 ml of dichloromethane and reacted at 25 °C for 2 hours. The reaction was detected by high performance liquid chromatography (HPLC) (column: YMC-PACK, ODS-A, 150 mm * 4.6 nm * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, 200 ml of saturated saline solution was added to the reaction solution, and 300 ml of dichloromethane was used for extraction. The solution was then washed twice with 200 ml of saturated saline solution. The organic phase was dried and concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 9.8 g of compound B, with a yield of 48%.

[0051] In the second step, compound B (42.3 mmol, 9 g), methyl bromoacetate (compound C, 40.7 mmol, 6.2 g), and anhydrous sodium acetate (20.1 mmol, 1.7 g) were added to 50 ml of ethanol and reacted at 80 °C for 24 hours. The reaction was detected by high performance liquid chromatography (HPLC) (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, the mixture was concentrated to 10 ml under reduced pressure. 50 ml of ethyl acetate and 50 ml of saturated brine were added to the reaction solution for extraction, and then 100 ml of saturated brine was added to each solution twice for washing. The organic phase was dried and concentrated. The concentrated mixture was purified by column chromatography (petroleum ether:ethyl acetate = 8:1) to obtain 6 g of compound D, with a yield of 50%.

[0052] In the third step, tetrabutylammonium fluoride (8.5 mmol, 2.2 g) was dissolved in 50 ml of tetrahydrofuran, and compound D (17.0 mmol, 5 g) was added. The reaction was carried out at 25 °C for 2 hours, and detected by high performance liquid chromatography (HPLC) (column: YMC-PACK, ODS-A, 150 mm * 4.6 nn * 5 μm, detection wavelength 254 nm, water:methanol = 1:9, flow rate = 1 ml / min, column temperature 40 °C). After the reaction was completed, 50 ml of saturated saline and 50 ml of ethyl acetate were added to the reaction solution for extraction, and then 50 ml of saturated saline was added to wash twice. The organic phase was dried and concentrated, and the concentrated mixture was purified by column chromatography (petroleum ether:ethyl acetate = 6:1) to obtain 1.5 g of compound E, namely methyl (4-hydroxyphenyl)glycine methyl ester, with a yield of 49%.

[0053] Example 4

[0054] The screening results for the first step reaction time and temperature are shown in Table 1:

[0055] Table 1

[0056]

[0057] Example 5

[0058] The results of the screening of reaction time and temperature in the second step are shown in Table 2:

[0059] Table 2

[0060]

[0061] Example 6

[0062] The results of the screening of reaction time and temperature in the third step are shown in Table 3:

[0063] Table 3

[0064]

[0065] Patent application CN102718672A discloses a method for obtaining p-hydroxyphenylglycine methyl ester by methylation of p-hydroxyphenylglycine as a substrate under solid acid catalysis. However, the raw materials for this method are not readily available and are relatively expensive. It requires the additional preparation of solid acid catalysts, resulting in a complex manufacturing process and unstable catalytic activity.

[0066] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-described technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A method for preparing methyl (4-hydroxyphenyl)glycine methyl ester, characterized in that, Includes the following steps: ； The first step involves adding p-aminophenol (compound A), tert-butyldimethylchlorosilane, and imidazole in a molar ratio of 1:1~2:0.4~2 to the first organic solvent and reacting at 15~30℃ for 0.5~3 hours. The reaction is then detected by high performance liquid chromatography and, after post-processing, compound B is obtained. In the second step, compound B, methyl bromoacetate (i.e., compound C), and anhydrous sodium acetate in a molar ratio of 1:0.9~2:0.4~3 were added to ethanol and reacted at a temperature of 70~90℃ for 1~48 hours. The reaction was detected by high performance liquid chromatography and after post-processing, compound D was obtained. The third step involves dissolving tetrabutylammonium fluoride in tetrahydrofuran, adding compound D, and reacting the tetrabutylammonium fluoride and compound D at a molar ratio of 1 to 2:1 at a temperature of 15 to 30°C for 1 to 3 hours. The reaction is then detected by high performance liquid chromatography to indicate the end of the reaction. After post-processing, compound E, namely methyl (4-hydroxyphenyl)glycine methyl ester, is obtained.

2. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, The molar ratios of p-aminophenol, tert-butyldimethylchlorosilane, and imidazole are 1:1.01:1.1, 1:1.01:2, and 1:1.01:0.

5.

3. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, The first organic solvent is selected from dichloromethane, 1,2-dichloroethane, ethyl acetate, and tetrahydrofuran.

4. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, In the first step, the conditions for high performance liquid chromatography (HPLC) detection of the reaction are as follows: chromatographic column: YMC-PACK, ODS-A, 150mm*4.6nn*5um, detection wavelength 254nm, water:methanol=1:9, flow rate=1ml / min, column temperature 40℃.

5. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, In the first step, the post-processing steps are as follows: add saturated brine to the reaction solution, extract with dichloromethane, wash with saturated brine again, and dry and concentrate the organic phase.

6. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, The molar ratios of compound B, methyl bromoacetate, and anhydrous sodium acetate are 1:1:1.1, 1:1:2.1, and 1:0.96:0.

48.

7. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, In the second step, the conditions for high performance liquid chromatography (HPLC) detection of the reaction are as follows: chromatographic column: YMC-PACK, ODS-A, 150mm*4.6nn*5um, detection wavelength 254nm, water:methanol=1:9, flow rate=1ml / min, column temperature 40℃.

8. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, In the second step, the post-processing steps are: concentration under reduced pressure, extraction with ethyl acetate and saturated brine, washing with saturated brine, drying and concentrating the organic phase.

9. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, The molar ratio of the tetrabutylammonium fluoride and compound D is 1:1, 2:1, or 1.2:

1.

10. The method for preparing methyl (4-hydroxyphenyl)glycine methyl ester according to claim 1, characterized in that, In the third step, the conditions for high performance liquid chromatography detection of the reaction are as follows: chromatographic column: YMC-PACK, ODS-A, 150mm*4.6nn*5um, detection wavelength 254nm, water:methanol=1:9, flow rate=1ml / min, column temperature 40℃. In the third step, the post-processing steps are as follows: extract with saturated brine and ethyl acetate, wash with saturated brine, dry and concentrate the organic phase.

Images