CN102432554A - Method for synthesizing D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-methanamide) hydroxyphenylacetic acid (HO-EPCP) - Google Patents
Method for synthesizing D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-methanamide) hydroxyphenylacetic acid (HO-EPCP) Download PDFInfo
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- CN102432554A CN102432554A CN2011104446624A CN201110444662A CN102432554A CN 102432554 A CN102432554 A CN 102432554A CN 2011104446624 A CN2011104446624 A CN 2011104446624A CN 201110444662 A CN201110444662 A CN 201110444662A CN 102432554 A CN102432554 A CN 102432554A
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Abstract
The invention relates to a method for synthesizing D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-methanamide) hydroxyphenylacetic acid (HO-EPCP), and belongs to the field of medicinal intermediates. The method comprises the following steps of: (1) dripping pyridine into a mixed system of 4-ethyl-2,3-dioxypiperazine, trimethyl chlorosilane, dichloromethane and chloroform and reacting to obtain 4-ethyl-2,3-dioxypiperazine which is subjected to silicon esterification; dripping the 4-ethyl-2,3-dioxypiperazine which is subjected to the silicon esterification into a system of dichloromethane and the chloroform which contain triphosgene and pyridine, and reacting to obtain 4-ethyl-2,3-dioxypiperazine acyl chloride; adding the pyridine into a system of the dichloromethane and the chloroform which contain D-p-hydroxyphenylglycine, and dripping the trimethyl chlorosilane to obtain D-p-hydroxyphenylglycine subjected to the silicon esterification; and dripping the 4-ethyl-2,3-dioxypiperazine acyl chloride into the D-p-hydroxyphenylglycine subjected to the silicon esterification to perform reaction, hydrolyzing at the temperature of 12 DEG C, stirring for 20 minutes, and regulating the pH value to 1.5 to prepare the D(-)-alpha-(4-ethyl-2,3-dioxypiperazine-1-methanamide) hydroxyphenylacetic acid. Compared with the prior art, the method has the advantages that due to the adoption of a mixed solvent, reaction efficiency is high, the yield of products is high, the reaction condition is mild and safe.
Description
Technical field
The present invention relates to the compound method of a kind of HO-EPCP, belong to the medicine intermediate field.
Background technology
HO-EPCP, chemical name: D (-)-α-(4-ethyl-2,3-dioxypiperazine piperazine-1-methane amide) p-hydroxyphenylaceticacid, molecular formula: C
14H
17O
6N
3, structure is following:
The HO-EPCP outward appearance: white or off-white color crystalloid powder are the important intermediate of synthetic third generation cephalosporin-cefoperazone.
Reaction equation is as follows:
Summary of the invention
The object of the present invention is to provide the compound method of a kind of efficient, product yield is high, reaction conditions is gentle, safe HO-EPCP.
The compound method of described HO-EPCP may further comprise the steps:
(1) at 4-ethyl-2, in 3-dioxygen ethylene imine, trimethylchlorosilane, methylene dichloride and the chloroform mixed system, drip pyridine, reaction obtains the 4-ethyl-2 of estersilization, 3-dioxygen ethylene imine;
The 4-ethyl-2 of the estersilization that (2) step (1) is obtained, 3-dioxygen ethylene imine are added drop-wise in the methylene dichloride that contains TRIPHOSGENE 99.5 and pyridine and the chloroform system and react, and obtain 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides;
(3) in methylene dichloride that contains the D-D-pHPG and chloroform system, drip trimethylchlorosilane behind the adding pyridine, obtain the D-D-pHPG of estersilization;
(4) step (2) is obtained 4-ethyl-2; 3-dioxygen ethylene imine acyl chlorides is added drop-wise in the D-D-pHPG that step (3) obtains estersilization and reacts; 20min is stirred in 12 ℃ of hydrolysis, and transferring pH value is 1.5; Make D (-)-α-(4-ethyl-2,3-dioxypiperazine piperazine-1-methane amide) p-hydroxyphenylaceticacid.
Described 4-ethyl-2, the mol ratio of 3-dioxygen ethylene imine, TRIPHOSGENE 99.5, D-D-pHPG, pyridine and trimethylchlorosilane is 1.0: 0.35～0.45: 1.0～1.2: 1.0～1.2: 1.0～1.4; Described 4-ethyl-2, the ratio of 3-dioxygen ethylene imine, methylene dichloride and chloroform are 14.2: 125: 125, and 4-ethyl-2,3-dioxygen ethylene imine are in g, and methylene dichloride and chloroform are in ml.
The consumption of the described methylene dichloride of step (1) is 1/5 of a methylene dichloride TV, and the consumption of chloroform is 1/5 of a chloroform TV, and the consumption of pyridine is 1/4 of a pyridine total mass, and the trimethylchlorosilane consumption is 1/3 of a trimethylchlorosilane total mass.
0～5 ℃ of the described dropping temperature of step (1), reaction times 1～1.5h.
The consumption of the described methylene dichloride of step (2) is 1/5 of a methylene dichloride TV, and the consumption of chloroform is 1/5 of a chloroform TV, and the consumption of pyridine is 1/40 of a pyridine total mass.
0～5 ℃ of the described dropping temperature of step (2), reaction times 1～1.5h.
The consumption of the described methylene dichloride of step (3) is 3/5 of a methylene dichloride TV, and the consumption of chloroform is 3/5 of a chloroform TV, and the consumption of pyridine is 29/40 of a pyridine total mass, and the trimethylchlorosilane consumption is 2/3 of a trimethylchlorosilane total mass.
10～15 ℃ of the described dropping temperatures of step (3), reaction times 1～3.5h.
10～15 ℃ of the described dropping temperatures of step (4), reaction times 1.5～2h.
Beneficial effect of the present invention is following:
The present invention compared with prior art adopt mixed solvent to make that reaction efficiency is high, product yield is high, and reaction conditions is gentle, safety.
Embodiment
Below through embodiment the present invention is further described.
Embodiment 1:
(1) with 14.2g 4-ethyl-2, the 3-dioxygen ethylene imine is dissolved in 25ml methylene dichloride and the 25ml chloroform, adds the 3.7g trimethylchlorosilane, drips the 2g pyridine at 0 ℃, finishes reaction 1h, obtains the 4-ethyl-2 of estersilization, the 3-dioxygen ethylene imine;
(2) the 10g TRIPHOSGENE 99.5 is dissolved in 25ml methylene dichloride and the 25ml chloroform, adds the 0.2g pyridine, in the 1h, at 2 ℃ of 4-ethyls-2 with estersilization, the 3-dioxygen ethylene imine is added drop-wise in this system, obtains 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides;
(3) the 17gD-D-pHPG is joined in 75ml methylene dichloride and the 75ml chloroform, add the 5.8g pyridine, drip the 7.3g trimethylchlorosilane, stir 2.5h, obtain the D-D-pHPG of estersilization at 10 ℃;
(4) 10 ℃, with 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides splashes in the D-D-pHPG of estersilization, reaction 2h, and 20min is stirred in 12 ℃ of hydrolysis, with hydrochloric acid adjust pH to 1.5, obtains the HO-EPCP bullion.Productive rate 97.1%.
Embodiment 2:
(1) with 14.2g4-ethyl-2, the 3-dioxygen ethylene imine is dissolved in 25ml methylene dichloride and the 25ml chloroform, adds the 4g trimethylchlorosilane, drips the 2g pyridine at 2 ℃, finishes reaction 1h, obtains the 4-ethyl-2 of estersilization, the 3-dioxygen ethylene imine;
(2) the 12g TRIPHOSGENE 99.5 is dissolved in 25ml methylene dichloride and the 25ml chloroform, adds the 0.2g pyridine, in the 1h, at 2 ℃ of 4-ethyls-2 with estersilization, the 3-dioxygen ethylene imine is added drop-wise in this system, obtains 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides;
(3) the 19gD-D-pHPG is joined in 75ml methylene dichloride and the 75ml chloroform, add the 5.8g pyridine, drip the 8g trimethylchlorosilane, stir 2.5h, obtain the D-D-pHPG of estersilization at 13 ℃;
(4) 13 ℃, with 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides splashes in the D-D-pHPG of estersilization, reaction 2h, and 20min is stirred in 12 ℃ of hydrolysis, with hydrochloric acid adjust pH to 1.5, obtains the HO-EPCP bullion.Productive rate 97.2%.
Embodiment 3:
(1) with 14.2g4-ethyl-2, the 3-dioxygen ethylene imine is dissolved in 25ml methylene dichloride and the 25ml chloroform, adds the 5g trimethylchlorosilane, drips the 2.4g pyridine at 2 ℃, finishes reaction 1h, obtains the 4-ethyl-2 of estersilization, the 3-dioxygen ethylene imine;
(2) the 12g TRIPHOSGENE 99.5 is dissolved in 25ml methylene dichloride and the 25ml chloroform, adds the 0.24g pyridine, in the 1h, at 2 ℃ of 4-ethyls-2 with estersilization, the 3-dioxygen ethylene imine is added drop-wise in this system, obtains 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides;
(3) the 19gD-D-pHPG is joined in 75ml methylene dichloride and the 75ml chloroform, add the 6.84g pyridine, drip the 10g trimethylchlorosilane, stir 3h, obtain the D-D-pHPG of estersilization at 13 ℃;
(4) 13 ℃, with 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides splashes in the D-D-pHPG of estersilization, reaction 2h, and 20min is stirred in 12 ℃ of hydrolysis, with hydrochloric acid adjust pH to 1.5, obtains the HO-EPCP bullion.Productive rate 97.4%.
Claims (9)
1. the compound method of a HO-EPCP is characterized in that may further comprise the steps:
(1) at 4-ethyl-2, in 3-dioxygen ethylene imine, trimethylchlorosilane, methylene dichloride and the chloroform mixed system, drip pyridine, reaction obtains the 4-ethyl-2 of estersilization, 3-dioxygen ethylene imine;
The 4-ethyl-2 of the estersilization that (2) step (1) is obtained, 3-dioxygen ethylene imine are added drop-wise in the methylene dichloride that contains TRIPHOSGENE 99.5 and pyridine and the chloroform system and react, and obtain 4-ethyl-2,3-dioxygen ethylene imine acyl chlorides;
(3) in methylene dichloride that contains the D-D-pHPG and chloroform system, drip trimethylchlorosilane behind the adding pyridine, obtain the D-D-pHPG of estersilization;
(4) step (2) is obtained 4-ethyl-2; 3-dioxygen ethylene imine acyl chlorides is added drop-wise in the D-D-pHPG that step (3) obtains estersilization and reacts; 20min is stirred in 12 ℃ of hydrolysis, and transferring pH value is 1.5; Make D (-)-α-(4-ethyl-2,3-dioxypiperazine piperazine-1-methane amide) p-hydroxyphenylaceticacid.
2. the compound method of HO-EPCP according to claim 1; It is characterized in that described 4-ethyl-2, the mol ratio of 3-dioxygen ethylene imine, TRIPHOSGENE 99.5, D-D-pHPG, pyridine and trimethylchlorosilane is 1.0: 0.35～0.45: 1.0～1.2: 1.0～1.2: 1.0～1.4; Described 4-ethyl-2, the ratio of 3-dioxygen ethylene imine, methylene dichloride and chloroform are 14.2: 125: 125, and 4-ethyl-2,3-dioxygen ethylene imine are in g, and methylene dichloride and chloroform are in ml.
3. the compound method of HO-EPCP according to claim 1; The consumption that it is characterized in that the described methylene dichloride of step (1) is 1/5 of a methylene dichloride TV; The consumption of chloroform is 1/5 of a chloroform TV; The consumption of pyridine is 1/4 of a pyridine total mass, and the trimethylchlorosilane consumption is 1/3 of a trimethylchlorosilane total mass.
4. the compound method of HO-EPCP according to claim 1 is characterized in that 0～5 ℃ of the described dropping temperature of step (1), reaction times 1～1.5h.
5. the compound method of HO-EPCP according to claim 1 is characterized in that the consumption of the described methylene dichloride of step (2) is 1/5 of a methylene dichloride TV, and the consumption of chloroform is 1/5 of a chloroform TV, and the consumption of pyridine is 1/40 of a pyridine total mass.
6. the compound method of HO-EPCP according to claim 1 is characterized in that 0～5 ℃ of the described dropping temperature of step (2), reaction times 1～1.5h.
7. the compound method of HO-EPCP according to claim 1; The consumption that it is characterized in that the described methylene dichloride of step (3) is 3/5 of a methylene dichloride TV; The consumption of chloroform is 3/5 of a chloroform TV; The consumption of pyridine is 29/40 of a pyridine total mass, and the trimethylchlorosilane consumption is 2/3 of a trimethylchlorosilane total mass.
8. the compound method of HO-EPCP according to claim 1 is characterized in that 10～15 ℃ of the described dropping temperatures of step (3), reaction times 1～3.5h.
9. the compound method of HO-EPCP according to claim 1 is characterized in that 10～15 ℃ of the described dropping temperatures of step (4), reaction times 1.5～2h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566350A (en) * | 2015-12-30 | 2016-05-11 | 河南康达制药有限公司 | Synthetic method of cefoperazone acid |
| CN109438476A (en) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | The preparation method of Piperacillin acid |
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| CN1446807A (en) * | 2002-03-22 | 2003-10-08 | 浙江工业大学 | Chemosynthesis method of 1-chloroformyl-4-ethyl-2, 3-dioxopiperazine |
| CN1508132A (en) * | 2002-12-19 | 2004-06-30 | 上海应用技术学院 | HO-EPCP synthesizing method |
| CN101508679A (en) * | 2009-03-31 | 2009-08-19 | 山西新天源医药化工有限公司 | Synthesis of D(-)-alpha-(4-ethyl-2,3-dioxygen ethylene imine-1-formamido) p-hydroxybenzene acetic acid |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1446807A (en) * | 2002-03-22 | 2003-10-08 | 浙江工业大学 | Chemosynthesis method of 1-chloroformyl-4-ethyl-2, 3-dioxopiperazine |
| CN1508132A (en) * | 2002-12-19 | 2004-06-30 | 上海应用技术学院 | HO-EPCP synthesizing method |
| CN101508679A (en) * | 2009-03-31 | 2009-08-19 | 山西新天源医药化工有限公司 | Synthesis of D(-)-alpha-(4-ethyl-2,3-dioxygen ethylene imine-1-formamido) p-hydroxybenzene acetic acid |
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| 《精细化工》 20030930 陆庆宁 等 D(-)-alpha-(4-乙基-2,3-双氧代哌嗪-1-甲酰胺基)对羟基苯乙酸的合成 第570-574页 1-9 第20卷, 第9期 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105566350A (en) * | 2015-12-30 | 2016-05-11 | 河南康达制药有限公司 | Synthetic method of cefoperazone acid |
| CN109438476A (en) * | 2018-12-24 | 2019-03-08 | 常州红太阳药业有限公司 | The preparation method of Piperacillin acid |
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