Method for catalytically synthesizing HO-EPCP by DMAP

Abstract

The invention belongs to the technical field of HO-EPCP synthesis, and particularly relates to a method for catalytically synthesizing HO-EPCP through DMAP. The method for catalytic synthesis of HO-EPCP by DMAP comprises the following steps: taking 4-ethyl-2, 3-dioxypiperazine and triphosgene as raw materials, and obtaining 4-ethyl-2, 3-dioxypiperazine acyl chloride in the presence of triethylamine and trimethylsilane; the preparation method comprises the following steps: by taking p-hydroxyphenylglycine and trimethylchlorosilane as raw materials and triethylamine as an acid-binding agent, obtaining silanized p-hydroxyphenylglycine; and carrying out a reaction on the silanized p-hydroxyphenylglycine and 4-ethyl-2, 3-dioxypiperazine acyl chloride under the catalysis of DMAP, and refining to obtain the finished product HO-EPCP. The method for catalytically synthesizing HO-EPCP by DMAP has the advantages of mild reaction conditions, higher reaction yield and product purity under the condition of lower catalyst dosage, higher reaction rate and greatly saved cost.

Description

Technical Field

[0001] The invention belongs to the technical field of HO-EPCP synthesis, and particularly relates to a method for synthesizing HO-EPCP with DMAP catalysis. Background Art

[0002] D(-)-α-(4-ethyl-2,3-dioxypiperazine-1-carboxamide)-4-hydroxyphenylacetic acid, referred to as HO-EPCP, has a molecular formula of C 14 H 17 O6N3, the appearance is white or off-white crystalline powder, and its structural formula is as follows: .

[0003] Cefoperazone, as a third-class broad-spectrum cephalosporin antibiotic, has the function of coordinated inhibition of lactonamide enzymes, which expands the antibacterial spectrum and enhances the antibacterial effect. It has been increasingly valued in anti-infection treatment and has become a cephalosporin antibiotic with the largest market share. HO-EPCP is an important intermediate in the production of cefoperazone.

[0004] The synthesis of HO-EPCP usually consists of two steps: first, dioxypiperazine is used to synthesize dioxypiperazine chloride, and then further condenses and hydrolyzes with silylated p-hydroxyphenylglycine to obtain HO-EPCP. In the process of synthesizing 4-ethyl-2,3-dioxypiperazine chloride, PCl5, POCl3, diphosgene and phosgene are often used as chlorination reagents. These chlorination reagents have the disadvantages of high toxicity, dangerous operation and strong irritation. At the same time, the reaction solution contains a large amount of by-products that affect the quality of the next product. Triphosgene is a white crystalline solid with the characteristics of stability at room temperature, low toxicity, and accurate metering. It also has the advantages of mild reaction conditions, good selectivity and high yield. Therefore, it is of great significance to use triphosgene instead of gaseous and liquid phosgene to prepare dioxypiperazine chloride.

[0005] 4-Dimethylaminopyridine (DMAP) has the resonance of the electron-donating dimethylamino group and the pyridine ring in its structure, which can strongly activate the nitrogen atom on the pyridine ring for nucleophilic substitution. DMAP has the advantages of excellent catalytic performance, small dosage, short reaction time, and few side reactions. The product yield and purity obtained by using DMAP as a catalyst are high, and even the yield of highly hindered substrates can reach more than 90%.

[0006] CN102432554A discloses a method for synthesizing HO-EPCP. HO-EPCP is synthesized by using pyridine as an acid-binding agent and a catalyst. However, pyridine has a pungent odor and toxicity, and is relatively expensive. In addition, when pyridine is used as a catalyst, the reaction yield is high in the reaction synthesis stage, but the purity of the product and the yield of the product in the refining stage are low.

[0007] CN1508132A discloses a method for synthesizing D(-)-α-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-p-hydroxyphenylacetic acid, which uses triethylamine alone to initiate triphosgene, thereby increasing the production process. Meanwhile, only triethylamine is used as an acid-binding agent during the reaction, resulting in a long reaction time and a relatively low yield.

[0008] Therefore, it is necessary to develop a synthetic method with low toxicity, low cost, high yield and fast reaction rate to improve the yield and reaction efficiency of the reaction. Summary of the invention

[0009] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a method for synthesizing HO-EPCP by using DMAP as catalyst. The reaction conditions are mild, and the reaction yield and product purity are higher under a lower catalyst dosage, and the reaction rate is improved. Compared with the pyridine catalyst, the cost is greatly saved, and the product yield and product purity are improved.

[0010] The method for synthesizing HO-EPCP catalyzed by DMAP of the present invention comprises the following steps: (1) Trimethylsilyl chloride is added dropwise to a dichloromethane solution of 4-ethyl-2,3-dioxypiperazine, and the reaction is continued for 30-40 minutes. The temperature is lowered, and triethylamine is added dropwise to continue the reaction for 30-40 minutes. Triphosgene is added in batches, and the temperature is then raised to react to obtain a 4-ethyl-2,3-dioxypiperazine acyl chloride reaction solution; (2) Add p-hydroxyphenylglycine to dichloromethane, add trimethylchlorosilane dropwise, then cool to -15~-10°C, add triethylamine dropwise and continue the reaction for 50-70 minutes, and finally add DMAP to obtain a p-hydroxyphenylglycine reaction solution; (3) adding the reaction solution of 4-ethyl-2,3-dioxypiperazine chloride to the reaction solution of p-hydroxyphenylglycine to react, adding distilled water under vigorous stirring to crystallize, filtering and drying to obtain a crude HO-EPCP product; (4) Acetone and distilled water were added to the crude HO-EPCP and mixed evenly, followed by adding 10 wt.% sodium carbonate solution until the solution was clear, adding activated carbon, stirring, filtering, adjusting the pH to 1.8-2.0 with 10 wt.% hydrochloric acid, crystallizing, filtering, and drying to obtain the finished HO-EPCP.

[0011] The molar ratio of 4-ethyl-2,3-dioxypiperazine to triphosgene is 1.0:(0.4-0.6).

[0012] The molar ratio of 4-ethyl-2,3-dioxypiperazine, p-hydroxyphenylglycine and DMAP is 1.0:(1.0-1.3):(0.05-0.15).

[0013] In the step (1), the molar ratio of 4-ethyl-2,3-dioxypiperazine, trimethylsilyl chloride and triethylamine is 1.0:(1.0-1.5):(1.0-1.4).

[0014] In the step (1), when triphosgene is added in batches, the temperature of the reaction system is ≤5°C, the heating reaction time is 1-2h, and the temperature is 15-25°C.

[0015] In the step (2), the molar ratio of p-hydroxyphenylglycine, trimethylsilyl chloride and triethylamine is 1.0:(3.0-4.0):(3.0-4.0).

[0016] In the step (3), the reaction solution of 4-ethyl-2,3-dioxypiperazineyl chloride is added to the reaction solution of p-hydroxyphenylglycine for reaction, the reaction time is 1-2 hours, and the reaction temperature is 15-25°C.

[0017] The crystallization temperature in step (3) and step (4) is 0-5°C.

[0018] The mass ratio of the crude HO-EPCP, acetone and distilled water is 1.0:(1.0-1.2):(5.0-6.0).

[0019] The present invention firstly uses 4-ethyl-2,3-dioxypiperazine and triphosgene as raw materials, reacts in the presence of triethylamine and trimethylsilane to obtain 4-ethyl-2,3-dioxypiperazine acid chloride; secondly, uses p-hydroxyphenylglycine and trimethylchlorosilane as raw materials and triethylamine as an acid-binding agent to obtain silylated p-hydroxyphenylglycine; finally, the silylated p-hydroxyphenylglycine and 4-ethyl-2,3-dioxypiperazine acid chloride are reacted under the catalysis of DMAP and refined to obtain the finished product HO-EPCP. The synthetic route is as follows: .

[0020] Compared with the prior art, the present invention has the following beneficial effects: (1) In the method for synthesizing HO-EPCP using DMAP as a catalyst, DMAP is added as a catalyst in the condensation reaction with silylated p-hydroxyphenylglycine, thereby effectively improving the reaction rate and product purity; and the catalyst DMAP still has a high catalytic efficiency even when used in a low dosage, thereby effectively improving the reaction rate.

[0021] (2) The DMAP-catalyzed synthesis of HO-EPCP of the present invention uses only dichloromethane as a solvent, and the reaction system is safer than a mixed solvent. Secondly, triphosgene is used as a raw material and DMAP is used in combination, and the reaction conditions are mild, which has the advantages of high reaction yield and high product purity.

[0022] (3) The DMAP-catalyzed synthesis of HO-EPCP of the present invention has simple raw materials, and the raw materials used are all of low toxicity, thereby improving the safety of the reaction process. DETAILED DESCRIPTION

[0023] The present invention is further described below in conjunction with examples and comparative examples. The raw materials used in the examples and comparative examples are conventional commercially available raw materials unless otherwise specified, and the process methods used are conventional methods in the art unless otherwise specified.

[0024] The method for synthesizing HO-EPCP by DMAP catalysis comprises the following steps: (1) Dissolve 4-ethyl-2,3-dioxypiperazine in dichloromethane, add trimethylsilyl chloride dropwise at 0°C, react for 30-40 min at this temperature, cool to -15~-10°C, add triethylamine dropwise, continue to react for 30-40 min, keep the reaction system temperature ≤5°C, add triphosgene in batches, then naturally raise the temperature to 15-25°C, react for 1-2 h, and obtain 4-ethyl-2,3-dioxypiperazine acyl chloride reaction solution (I); (2) Add p-hydroxyphenylglycine to dichloromethane, add trimethylsilyl chloride dropwise at 0°C, then cool to -15~-10°C, add triethylamine dropwise and continue the reaction for 50-70 minutes, and finally add DMAP to obtain p-hydroxyphenylglycine reaction solution (II); (3) Add (I) dropwise into (II) at 0-5°C for reaction at a temperature of 15-25°C for 1-2h, add distilled water under vigorous stirring, crystallize at 0-5°C, filter, wash and dry after 2h to obtain a crude HO-EPCP; (4) Add acetone and distilled water to the crude HO-EPCP and mix well. Then add 10 wt.% sodium carbonate solution until the solution is clear. Add activated carbon, stir for 1 hour and filter. Adjust the pH to 1.9±0.1 with 10 wt.% hydrochloric acid. Crystallize at 0-5°C for 2 hours, filter and dry to obtain the finished HO-EPCP.

[0025] Example 1 The method for synthesizing HO-EPCP by DMAP catalysis comprises the following steps: (1) Dissolve 14.2 g of 4-ethyl-2,3-dioxypiperazine in 129 g of dichloromethane, add 10.8 g of trimethylsilyl chloride at 0°C, react at this temperature for 30 min, cool to -10°C, add 10.1 g of triethylamine dropwise, continue to react for 30 min, keep the reaction system temperature ≤ 5°C, add 11.9 g of triphosgene in batches, then naturally raise the temperature to 15°C, react for 2 h, and obtain 4-ethyl-2,3-dioxypiperazine acyl chloride reaction solution (I); (2) Add 16.7 g of p-hydroxyphenylglycine to 129 g of dichloromethane, add 32.6 g of trimethylsilyl chloride dropwise at 0°C, then cool to -10°C, add 30.4 g of triethylamine dropwise, react for 50 min, and finally add 0.6 g of DMAP to obtain p-hydroxyphenylglycine reaction solution (II); (3) At 0°C, (I) was added dropwise to (II) for reaction at 15°C for 1 h. 131.25 mL of distilled water was added under vigorous stirring and crystallization was carried out at 0°C. After crystallization for 2 h, a large amount of white solid was precipitated. The solid was filtered, washed and dried to obtain 32.6 g of crude HO-EPCP with a yield of 97.9%; (4) Add 32.6 g of acetone and 163 g of distilled water to 32.6 g of the crude HO-EPCP and mix well. Then add 10 wt.% sodium carbonate solution until the solution is clear. Add activated carbon, stir for 1 h and filter. Adjust the pH to 1.9±0.1 with 10 wt.% hydrochloric acid. Crystallize at 0°C for 2 h. White needle-like crystals precipitate. Filter and dry to obtain 30.5 g of white crystalline powder with a yield of 91.0%, a content of 99.81%, a specific rotation of α=-88.5°, and a pH of 2.93.

[0026] Example 2 The method for synthesizing HO-EPCP by DMAP catalysis comprises the following steps: (1) Dissolve 14.2 g of 4-ethyl-2,3-dioxypiperazine in 129 g of dichloromethane, add 13.6 g of trimethylsilyl chloride at 0°C, react at this temperature for 35 min, cool to -15°C, add 12.1 g of triethylamine dropwise, continue to react for 35 min, keep the reaction system temperature ≤ 5°C, add 14.8 g of triphosgene in batches, then naturally raise the temperature to 20°C, react for 1 h, and obtain 4-ethyl-2,3-dioxypiperazine acyl chloride reaction solution (I); (2) Add 20.1 g of p-hydroxyphenylglycine to 129 g of dichloromethane, add 45.7 g of trimethylsilyl chloride dropwise at 0°C, then cool to -10°C, add 42.6 g of triethylamine dropwise, react for 60 min, and finally add 1.2 g of DMAP to obtain p-hydroxyphenylglycine reaction solution (II); (3) Add (I) dropwise into (II) at 5°C for reaction at 20°C for 1.5 h. Add 131.25 mL of distilled water under vigorous stirring and crystallize at 5°C. After crystallization for 2 h, a large amount of white solid precipitated. The solid was filtered, washed and dried to obtain 33.1 g of crude HO-EPCP with a yield of 98.8%. (4) Add 36.4 g of acetone and 182.1 g of distilled water to 33.1 g of crude HO-EPCP and mix well. Then add 10 wt.% sodium carbonate solution until the solution is clear. Add activated carbon, stir for 1 h and filter. Adjust the pH to 1.9±0.1 with 10 wt.% hydrochloric acid. Crystallize at 5 °C for 2 h. White needle-like crystals precipitate. Filter and dry to obtain 31.3 g of white crystalline powder. The yield of HO-EPCP is 93.4%, the content is 99.96%, the specific rotation α is -88.7°, and the pH is 2.84.

[0027] Example 3 The method for synthesizing HO-EPCP by DMAP catalysis comprises the following steps: (1) Dissolve 14.2 g of 4-ethyl-2,3-dioxypiperazine in 129 g of dichloromethane, add 16.3 g of trimethylsilyl chloride at 0°C, react at this temperature for 40 min, cool to -15°C, add 14.2 g of triethylamine dropwise, react for 40 min, keep the reaction system temperature ≤ 5°C, add 17.8 g of triphosgene in batches, then naturally raise the temperature to 25°C, react for 2 h, and obtain 4-ethyl-2,3-dioxypiperazine acyl chloride reaction solution (I); (2) Add 21.7 g of p-hydroxyphenylglycine to 129 g of dichloromethane, add 56.4 g of trimethylsilyl chloride dropwise at 0°C, then cool to -10°C, add 52.5 g of triethylamine dropwise, react for 70 min, and finally add 1.8 g of DMAP to obtain p-hydroxyphenylglycine reaction solution (II); (3) Add (I) dropwise into (II) at 5°C for reaction at 25°C for 2 h. Add 131.25 mL of distilled water under vigorous stirring and crystallize at 5°C. After crystallization for 2 h, a large amount of white solid precipitates. The solid is filtered, washed and dried to obtain 32.9 g of crude HO-EPCP with a yield of 98.2%. (4) Add 39.5 g of acetone and 197.4 g of distilled water to 32.9 g of crude HO-EPCP and mix well. Then add 10 wt.% sodium carbonate solution until the solution is clear. Add activated carbon, stir for 1 h and filter. Adjust the pH to 1.9±0.1 with 10 wt.% hydrochloric acid. Crystallize at 5 °C for 2 h. White needle-like crystals precipitate. Filter and dry to obtain 30.5 g of white crystalline powder. The yield is 91.0%, the content is 99.89%, the specific rotation α is -88.5°, and the pH is 2.93.

[0028] Comparative Example 1 The method for synthesizing HO-EPCP by DMAP catalysis comprises the following steps: (1) Dissolve 14.2 g of 4-ethyl-2,3-dioxypiperazine in 129 g of dichloromethane and chloroform, add 13.6 g of trimethylsilyl chloride at 0°C, react at this temperature for 30 min, cool to -10°C, add 12.1 g of triethylamine dropwise, react for 30 min, keep the reaction system temperature ≤ 5°C, add 14.8 g of triphosgene in batches, naturally raise the temperature to 20°C, react for 2 h, and obtain 4-ethyl-2,3-dioxypiperazine acyl chloride reaction solution (I); (2) Add 20.1 g of p-hydroxyphenylglycine to 129 g of dichloromethane and chloroform, add 45.7 g of trimethylsilyl chloride dropwise at 0°C, then cool to -10°C, add 42.6 g of triethylamine dropwise, and react for 60 min to obtain p-hydroxyphenylglycine reaction solution (II); (3) At 0°C, (I) was added dropwise to (II) at a reaction temperature of 20°C for 2 h. 131.25 mL of distilled water was added under vigorous stirring and crystallization was carried out at 5°C. After crystallization for 2 h, a large amount of white solid was precipitated. After filtration, washing and drying, 28.3 g of crude HO-EPCP was obtained with a yield of 84.5%; (4) Add crude HO-EPCP, acetone and water (mass ratio 1:1:5) and mix well. Add 10 wt.% sodium bicarbonate until the solution is clear. Add activated carbon, stir for 1 h and filter. Adjust the pH to 1.5 with 10 wt.% hydrochloric acid. Crystallize at 5 °C for 1 h. White needle-shaped crystals precipitate. Filter to obtain the finished product. Dry to obtain 24.5 g of white crystalline powder. The HO-EPCP yield is 73.1%, the content is 99.35%, the specific rotation α is -88.2°, and the pH is 2.71.

[0029] Comparative Example 2 The method for synthesizing HO-EPCP by DMAP catalysis comprises the following steps: (1) Dissolve 14.2 g of 4-ethyl-2,3-dioxypiperazine in 129 g of dichloromethane, add 13.6 g of trimethylsilyl chloride at 0°C, react at this temperature for 30 min, cool to -10°C, add 12.1 g of triethylamine dropwise, react for 30 min, keep the reaction system temperature ≤ 5°C, add 14.8 g of triphosgene in batches, naturally raise the temperature to 25°C, react for 2 h, and obtain dioxypiperazine acyl chloride reaction solution (I); (2) Add 20.1 g of p-hydroxyphenylglycine to 129 g of dichloromethane, add 45.7 g of trimethylsilyl chloride dropwise at 0°C, then cool to -10°C, add 42.6 g of triethylamine dropwise, and react for 30 min to obtain p-hydroxyphenylglycine reaction solution (II); (3) Add (I) dropwise into (II) at 0°C, the reaction temperature is 25°C, the reaction is carried out for 3 h, 131.25 mL of distilled water is added under vigorous stirring, and crystallization is carried out at 5°C. After crystallization for 2 h, a large amount of white solid is precipitated, which is filtered, washed and dried to obtain 29.2 g of crude HO-EPCP with a yield of 87.2%; (4) Add crude HO-EPCP, acetone and water (mass ratio 1:1:5) and mix well. Add 10 wt.% sodium carbonate solution until the solution is clear. Add activated carbon, stir for 1 h and filter. Adjust the pH to 1.9±0.1 with 10 wt.% hydrochloric acid. Crystallize at 5°C for 3 h. White needle-shaped crystals precipitate. Filter to obtain the finished product. Dry to obtain 26.5 g of white crystalline powder. The HO-EPCP yield is 79.1%, the content is 99.77%, the specific rotation α is -89.0°, and the pH is 2.91.

Claims

1. A method for synthesizing HO-EPCP using DMAP catalyst, characterized in that: The following steps are involved: (1) Trimethylsilyl chloride is added dropwise to a dichloromethane solution of 4-ethyl-2,3-dioxypiperazine, and the reaction is continued for 30-40 minutes. The temperature is lowered, and triethylamine is added dropwise to continue the reaction for 30-40 minutes. Triphosgene is added in batches, and the temperature is then raised to react to obtain a 4-ethyl-2,3-dioxypiperazine acyl chloride reaction solution; (2) Add p-hydroxyphenylglycine to dichloromethane, add trimethylchlorosilane dropwise, then cool to -15~-10°C, add triethylamine dropwise and continue the reaction for 50-70 minutes, and finally add DMAP to obtain a p-hydroxyphenylglycine reaction solution; (3) adding the reaction solution of 4-ethyl-2,3-dioxypiperazine chloride to the reaction solution of p-hydroxyphenylglycine to react, adding distilled water under vigorous stirring to crystallize, filtering and drying to obtain a crude HO-EPCP product; (4) Acetone and distilled water were added to the crude HO-EPCP and mixed evenly, followed by adding 10 wt.% sodium carbonate solution until the solution was clear, adding activated carbon, stirring, filtering, adjusting the pH to 1.8-2.0 with 10 wt.% hydrochloric acid, crystallizing, filtering, and drying to obtain the finished HO-EPCP.

2. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: The molar ratio of 4-ethyl-2,3-dioxypiperazine to triphosgene is 1.0:(0.4-0.6).

3. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: The molar ratio of 4-ethyl-2,3-dioxypiperazine, p-hydroxyphenylglycine and DMAP is 1.0:(1.0-1.3):(0.05-0.15).

4. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: In the step (1), the molar ratio of 4-ethyl-2,3-dioxypiperazine, trimethylsilyl chloride and triethylamine is 1.0:(1.0-1.5):(1.0-1.4).

5. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: In the step (1), when triphosgene is added in batches, the temperature of the reaction system is ≤5°C, the heating reaction time is 1-2h, and the temperature is 15-25°C.

6. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: In the step (2), the molar ratio of p-hydroxyphenylglycine, trimethylsilyl chloride and triethylamine is 1.0:(3.0-4.0):(3.0-4.0).

7. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: In the step (3), the reaction solution of 4-ethyl-2,3-dioxypiperazineyl chloride is added to the reaction solution of p-hydroxyphenylglycine for reaction, the reaction time is 1-2 hours, and the reaction temperature is 15-25°C.

8. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: The crystallization temperature in step (3) and step (4) is 0-5°C.

9. The method for synthesizing HO-EPCP by DMAP catalysis according to claim 1, characterized in that: The mass ratio of the crude HO-EPCP, acetone and distilled water is 1.0:(1.0-1.2):(5.0-6.0).