CN102190626A - Synthesis method of sodium glycididazole - Google Patents
Synthesis method of sodium glycididazole Download PDFInfo
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- CN102190626A CN102190626A CN2010101237463A CN201010123746A CN102190626A CN 102190626 A CN102190626 A CN 102190626A CN 2010101237463 A CN2010101237463 A CN 2010101237463A CN 201010123746 A CN201010123746 A CN 201010123746A CN 102190626 A CN102190626 A CN 102190626A
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Abstract
Relating to the field of medicinal chemistry, the invention discloses a synthesis method of sodium glycididazole. According to the method, iminodiacetic acid as a starting material reacts with acethlchloride/anhydrous sodium acetate in DMF (dimethyl formamide), and then reacts with metronidazole to generate imido bisazolyl ester which is further condensed with chloroacetic acid into acid glycididazole. And finally, an ethanol solution with 40 wt% of sodium hydroxide is added to generate sodium glycididazole salt trihydrate. According to the invention, the synthesis method of sodium glycididazole, without using pyridine and acetic anhydride, is environmentally friendly. With an overall yield of 34.5%, the method is suitable for industrial production.
Description
Technical field
The invention belongs to the medical chemistry field, be specifically related to a kind of tumour radiotherapy chemotherapeutic sensitizer--the synthetic method of-sodium glycididazole.
Background technology
Sodium glycididazole is tumour radiotherapy and chemotherapeutic sensitizer, the compound that belongs to nitro glyoxaline, in the time of can be with ray and chemotherapy to tumor hypoxia cell DNA damaging fixed, suppress the reparation of its dna damage, thereby improve the susceptibility of tumor hypoxia cell, and sodium glycididazole is less to the general loss of normal cell group of aerobic to radiation and chemotherapy.
Chinese invention patent ZL89102182.5 discloses a kind of chemicotherapy sensitizer--the preparation method of-Glycididazole and calcium salt thereof, this method is starting raw material with the nitrilotriacetic acid(NTA), in the presence of pyridine, react with aceticanhydride, become ester with metronidazole again, then with oxide compound salify, especially calcium, sodium, the sylvite of alkaline-earth metal.Shortcoming is to use the so poisonous scent of of the pyridine acid binding agent of contaminate environment again.
Then, it is raw material that Chinese invention patent ZL99116128.9 discloses with the nitrilotriacetic acid(NTA), uses N, and N-dimethylformamide (DMF) replaces pyridine, still reacts with it with aceticanhydride, becomes ester with metronidazole again; Use NaHCO
3Become the Glycididazole sodium salt.Yet total recovery is lower, only is 21.2-28.9%.It should be noted that above two kinds of methods can not be got rid of a part nitrilotriacetic acid(NTA) and three molecule metronidazoles react the possibility that generates the aminotriazole ester.
Above-mentioned two kinds of method reaction formula are as follows:
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, should get rid of pyridine, improves the reaction total efficiency again.
It is starting raw material that the present invention replaces nitrilotriacetic acid(NTA) with imino-acetic acid, replaces aceticanhydride with Acetyl Chloride 98Min./sodium acetate, again with the Mono Chloro Acetic Acid condensation, generates the Glycididazole sodium salt; Improve yield, avoided to generate by product aminotriazole ester; Glycididazole sodium salt content (HPLC is by anhydride): 99.6%, infrared consistent with the medicinal standard sample with mass spectrum.
The invention provides a kind of synthesis technique of sodium glycididazole, this reaction scheme is as follows:
The synthesis technique distinguishing feature of sodium glycididazole of the present invention is:
1,, helps staff's operation and environmental protection without pyridine;
2, without aceticanhydride with Acetyl Chloride 98Min./sodium acetate, help the buying, the transportation and the operation;
3, total recovery reaches 34.5%, helps large-scale production;
4, be starting raw material with the iminodiethanoic acid, avoid possible by product aminotriazole ester.
The synthesis technique concrete operations step of sodium glycididazole of the present invention is as follows:
One, the preparation-esterification of iminodiacetic acid acid anhydride
(1) in the three-necked bottle of 3000ml, add 266.2g (2mol) iminodiethanoic acid successively, 220ml (2.9mol) Acetyl Chloride 98Min., 238g (2.9mol) anhydrous sodium acetate and 1600mlDMF stirred 0.5-2 hour, and be roughly even until stirring;
(2) continue to stir, the oil bath heating makes system be elevated to 50-80 ℃ gradually from 30 ℃ of interior temperature;
(3) under 50-80 ℃ of condition, react 5-9h;
(4) stop to stir and heating, add the 456g metronidazole;
(5) stir, the oil bath heating makes in the system temperature rise to 40 ℃-60 ℃, reaction 2-5h;
(6) stop stirring heating, reaction solution is poured in the 2000ml water, adjust pH 3-4 ,-10 ℃ are freezing, and standing over night is separated out the two azoles esters of first imido;
(7) filtrate is again with the dilution of 2000ml water, again 0-10 ℃ freezing, suction filtration, second batch of two azoles ester of imido, secondary amounts to 618.6g, yield 70.6%;
Two, the preparation-condensation of sodium glycididazole, salify
(1) in the three-necked bottle of 2000ml, add the two azoles esters of 438.2g (1.0mol) imido successively, 100ml (1.1mol) Mono Chloro Acetic Acid adds 1000mlTHF, 67g (1.1mol) sodium-acetate;
(2) continue to stir, the oil bath heating makes system be elevated to 70-80 ℃ from 30 ℃;
(3) under 70-80 ℃ of condition stirring reaction 4-8 hour, be cooled to room temperature;
(4) under the condition of ice bath, slowly drip the ethanolic soln (200ml dissolve with ethanol 11.6gNaOH) of 49ml5.8%NaOH in the system;
(5) dropwise, remove ice bath, stirred 24 hours under the room temperature, existing a small amount of white solid is separated out;
(6) stop to stir, solution is at room temperature left standstill 24h, separate out a large amount of solids, suction filtration gets 451.6g Glycididazole sodium salt, yield 80.5%.
Three, sodium glycididazole is refining
580g sodium glycididazole crude product is dropped in the 2000ml reaction flask, add the 800ml pure water, medicinal 95% ethanol of 200ml, be heated to 40-50 ℃ under stirring, stir and make dissolving fully, stir adding gac and an amount of ETDA sodium, be incubated 30 minutes, filtered while hot, filtrate are cooled to 5-10 ℃, stir to add dehydrated alcohol down, be chilled to 0-5 ℃, separate out crystallization, dry white crystalline powder sodium glycididazole (containing 3 crystal water 464g), yield 80-86%.
The invention will be further described by the following examples.It should be understood that the described preparation method of the embodiment of the invention is only used for illustrating the present invention, rather than limitation of the present invention.
Preparation-the esterification of embodiment one, iminodiacetic acid acid anhydride
(1) in the three-necked bottle of 3000ml, add 266.2g (2mol) iminodiethanoic acid successively, 220ml (2.9mol) Acetyl Chloride 98Min., 238g (2.9mol) anhydrous sodium acetate and 1600mlDMF stir half an hour, and be roughly even until stirring;
(2) continue to stir, the oil bath heating makes system be elevated to 50 ℃ gradually from 30 ℃ of interior temperature;
(3) under 50 ℃ of conditions, react 5-6h;
(4) stop to stir and heating, add the 456g metronidazole;
(5) stir, the oil bath heating makes in the system temperature rise to 40 ℃--and 45 ℃, reaction 2h;
(6) stop stirring heating, reaction solution is poured in the 2000ml water, adjust pH 3-4 ,-10 ℃ are freezing, and standing over night is separated out the two azoles esters of first imido;
(7) filtrate is again with the dilution of 2000ml water, again-10 ℃ freezing, suction filtration, second batch of two azoles ester of imido, amount to 618.6g, yield 70.6%;
Preparation-the condensation of embodiment two, sodium glycididazole, salify
(1) in the three-necked bottle of 2000ml, add the two azoles esters of 438.2g (1.0mol) imido successively, 100ml (1.1mol) Mono Chloro Acetic Acid adds 1000mlTHF, 67g (1.1mol) sodium-acetate;
(2) continue to stir, the oil bath heating makes system be elevated to 70-80 ℃ from 30 ℃;
(3) stirring reaction 4 hours under 70-80 ℃ of condition is cooled to room temperature;
(4) under the condition of ice bath, slowly drip the ethanolic soln (200ml dissolve with ethanol 11.6gNaOH) of 49ml5.8%NaOH in the system;
(5) dropwise, remove ice bath, stirred 24 hours under the room temperature, existing a small amount of white solid is separated out;
(6) stop to stir, solution is at room temperature left standstill 24h, separate out a large amount of solids, suction filtration gets 451.6g Glycididazole sodium salt, yield 80.5%.
Making with extra care of embodiment three, sodium glycididazole
580g sodium glycididazole crude product is dropped in the 2000ml reaction flask, add the 800ml pure water, 200g95% ethanol, be heated to 40-50 ℃ under stirring, stir and make dissolving fully, stir adding gac and an amount of ETDA sodium, be incubated 30 minutes, filtered while hot, filtrate are cooled to 5-10 ℃, stir to add dehydrated alcohol down, be chilled to 0-5 ℃, separate out crystallization, dry white crystalline powder sodium glycididazole (containing 3 crystal water) 464g, yield 80-86%.Glycididazole sodium salt content (HPLC is by anhydride): 99.6%, infrared consistent with the medicinal standard sample with mass spectrum.
Claims (2)
1. a tumour radiotherapy chemotherapeutic sensitizer--the synthetic method of-sodium glycididazole.Its reaction scheme is as follows:
2. the synthesis technique of a sodium glycididazole, the concrete operations step is as follows:
One, the preparation-esterification of iminodiacetic acid acid anhydride
(1) in the three-necked bottle of 3000ml, add 266.2g (2mol) iminodiethanoic acid successively, 220ml (2.9mol) Acetyl Chloride 98Min., 238g (2.9mol) anhydrous sodium acetate and 1600mlDMF stirred 0.5-2 hour, and be roughly even until stirring;
(2) continue to stir, the oil bath heating makes system be elevated to 50-80 ℃ gradually from 30 ℃ of interior temperature;
(3) under 50-80 ℃ of condition, react 5-9h;
(4) stop to stir and heating, add the 456g metronidazole;
(5) stir, the oil bath heating makes in the system temperature rise to 40 ℃-60 ℃, reaction 2-5h;
(6) stop stirring heating, reaction solution is poured in the 2000ml water, adjust pH 3-4 ,-10 ℃ are freezing, and standing over night is separated out the two azoles esters of first imido;
(7) filtrate is again with the dilution of 2000ml water, again 0-10 ℃ freezing, suction filtration, second batch of two azoles ester of imido, secondary amounts to 618.6g, yield 70.6%;
Two, the preparation-condensation of sodium glycididazole, salify
(1) in the three-necked bottle of 2000ml, add the two azoles esters of 438.2g (1.0mol) imido successively, 100ml (1.1mol) Mono Chloro Acetic Acid adds 1000mlTHF, 67g (1.1mol) sodium-acetate;
(2) continue to stir, the oil bath heating makes system be elevated to 70-80 ℃ from 30 ℃;
(3) under 70-80 ℃ of condition stirring reaction 4-8 hour, be cooled to room temperature;
(4) under the condition of ice bath, slowly drip the ethanolic soln (200ml dissolve with ethanol 11.6gNaOH) of 49ml5.8%NaOH in the system;
(5) dropwise, remove ice bath, stirred 24 hours under the room temperature, existing a small amount of white solid is separated out;
(6) stop to stir, solution is at room temperature left standstill 24h, separate out a large amount of solids, suction filtration gets 451.6g Glycididazole sodium salt, yield 80.5%.
Three, sodium glycididazole is refining
580g sodium glycididazole crude product is dropped in the 2000ml reaction flask, add the 800ml pure water, be heated to 40-50 ℃ under medicinal 95% ethanol of 200ml stirs, stirring makes dissolving fully, stir adding gac and an amount of ETDA sodium, be incubated 30 minutes, filtered while hot, filtrate is cooled to 5-10 ℃, stir adding dehydrated alcohol down, be chilled to 0-5 ℃, separate out crystallization, dry white crystalline powder Glycididazole (containing 3 crystal water 464g), yield 80-86%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356070A (en) * | 2014-12-05 | 2015-02-18 | 江苏艾凡生物医药有限公司 | Synthesis method of sodium glycididazole |
| CN105541727A (en) * | 2016-01-15 | 2016-05-04 | 徐州医学院 | Lipid molecule with radiotherapy sensitization, preparation method of lipid molecule and application of lipid molecule in tumor radiotherapy drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1046157A (en) * | 1989-04-08 | 1990-10-17 | 中国人民解放军第二军医大学 | A kind of synthetic method of cancer-eliminating medicine-metronizolamic acid |
| CN1270062A (en) * | 1999-04-08 | 2000-10-18 | 广州山河药业股份有限公司 | Glycobiazole metal salt as synergist for radiotherapy or chemicotherapy and its preparing process and application |
| CN1603312A (en) * | 2003-09-29 | 2005-04-06 | 广州莱泰制药有限公司 | Process for synthesis of sodium glycididazole |
-
2010
- 2010-03-15 CN CN2010101237463A patent/CN102190626A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1046157A (en) * | 1989-04-08 | 1990-10-17 | 中国人民解放军第二军医大学 | A kind of synthetic method of cancer-eliminating medicine-metronizolamic acid |
| CN1270062A (en) * | 1999-04-08 | 2000-10-18 | 广州山河药业股份有限公司 | Glycobiazole metal salt as synergist for radiotherapy or chemicotherapy and its preparing process and application |
| CN1603312A (en) * | 2003-09-29 | 2005-04-06 | 广州莱泰制药有限公司 | Process for synthesis of sodium glycididazole |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104356070A (en) * | 2014-12-05 | 2015-02-18 | 江苏艾凡生物医药有限公司 | Synthesis method of sodium glycididazole |
| CN105541727A (en) * | 2016-01-15 | 2016-05-04 | 徐州医学院 | Lipid molecule with radiotherapy sensitization, preparation method of lipid molecule and application of lipid molecule in tumor radiotherapy drugs |
| CN105541727B (en) * | 2016-01-15 | 2018-01-30 | 徐州医学院 | A kind of lipid molecular, its preparation method and its application in tumour radiotherapy medicine for having radio therapy sensitization function |
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Application publication date: 20110921 |