CN104356070A - Synthesis method of sodium glycididazole - Google Patents
Synthesis method of sodium glycididazole Download PDFInfo
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- CN104356070A CN104356070A CN201410737685.8A CN201410737685A CN104356070A CN 104356070 A CN104356070 A CN 104356070A CN 201410737685 A CN201410737685 A CN 201410737685A CN 104356070 A CN104356070 A CN 104356070A
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- glycididazole
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
Abstract
The invention discloses a synthesis method of sodium glycididazole, belonging to the field of medical chemistry. The method comprises the following steps: carrying out esterification reaction on metronidazole and nitrilotriacetic acid by using concentrated sulfuric acid as a solvent and catalyst, and salifying with sodium bicarbonate. The preparation method disclosed by the invention has the adavantages of short steps, high yield and low cost, and is simple to operate, beneficial to environmental protection and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of synthetic method of sodium glycididazole, belong to medicinal chemistry arts.
Background technology
Cancer is a class disease higher with mortality ratio of falling ill in the world, the life of the serious threat mankind.Radiotherapy is one of Main Means for the treatment of malignant tumour at present, and Tumor cell hypoxia is the major reason causing radiotherapy failure, because noumenal tumour is central and connect the situation that ectocentral tumour cell all exists blood supply insufficiency, Cell hypoxia, and anoxic cell has resistance effect to low LET ray.Sodium glycididazole (CMNa) is that the anoxic cell of a unique high-efficiency low-toxicity formally applied clinically both at home and abroad at present has obvious radiosensitizing effect, and normal tissue has no significant effect.
The chemical combination synthetic method of sodium glycididazole mainly contains following several: (1) is under strict anhydrous condition, with nitrilotriacetic acid(NTA), acetic anhydride, metronidazole Reactive Synthesis Glycididazole in pyridine, the technique of Reactive Synthesis sodium glycididazole after mixing with sodium bicarbonate again, but the smell is awful for the pyridine used by reaction, harmful, and environmental pollution.(2) take nitrilotriacetic acid(NTA) as raw material, with acetic anhydride in N, N-dimethylformamide, obtain with sodium bicarbonate salify again after product purification, but the reagent used is difficult has pollution to environment, and overall yield of reaction is lower, only 21.2-28.9%.(3) take iminodiethanoic acid as starting raw material, react with Acetyl Chloride 98Min./anhydrous sodium acetate in DMF, the two azoles ester of imido is become again with metronidazole, then glycididazole acid is condensed into Mono Chloro Acetic Acid, finally become Glycididazole sodium salt trihydrate with 40% sodium hydroxide ethanolic soln, Acetyl Chloride 98Min. is used in this invention, and the smell is awful, and corrodibility is strong, and the Mono Chloro Acetic Acid used is for have infringement to health.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned mentioned series of problems, should environmentally safe, and harmless to operator, source chemicals low price, improves reaction yield again.
The invention provides a kind of synthetic method of sodium glycididazole, its reaction scheme is as follows:
Described synthetic method be with metronidazole and nitrilotriacetic acid(NTA) for substrate, using the vitriol oil as catalysts and solvents, carry out esterification and obtain glycididazole acid, then obtain sodium glycididazole through salt-forming reaction.
In one embodiment of the invention, the preparation of glycididazole acid mainly comprises the following steps:
(1) three-necked flask in add the vitriol oil, and add nitrilotriacetic acid(NTA), under strong stirring, add metronidazole and holding temperature 0-15 DEG C in batches;
(2) finish, oil bath is heated, and to make in system temperature rise to 55-85 DEG C;
(3) stirring reaction 20-30h at 55-85 DEG C;
(4) stop stirring, while hot by reaction solution down in frozen water, stirring lower is 6-7 with mineral alkali adjust pH, controls interior temperature and is less than 10 DEG C;
(5) reaction solution is left standstill 12h at 0 DEG C, solid is separated out;
(6) filter, filter cake is washed; Vacuum drying obtains white crude solid.
In one embodiment of the invention, the consumption mol ratio of nitrilotriacetic acid(NTA) and metronidazole is 1:2.2.
In another embodiment of the invention, described mineral alkali is strong aqua, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide.
In another embodiment of the invention, described mineral alkali is strong aqua.
In another embodiment of the invention, the preparation of glycididazole acid also comprises further purification step: added to by crude product in organic solvent, and add hot breakdown backflow, filter, solid dries to obtain white solid.
Described making beating organic solvent is ethanol, methylene dichloride, methyl alcohol or tetrahydrofuran (THF), particular methanol.
In one embodiment of the invention, described salt-forming reaction is that glycididazole acid and sodium carbonate are obtained by reacting sodium glycididazole.
In one embodiment of the invention, described salt-forming reaction mainly comprises the following steps:
(1) water is added in reaction flask, be warming up to 40 ~ 60 DEG C, glycididazole acid is scattered in water, adds sodium bicarbonate solid in batches;
(2) in 40 ~ 60 DEG C of stirring and dissolving.Add gac insulation 0.5h, filter, filtrate is washed by ethyl acetate, and concentrated aqueous phase obtains off-white color to micro-yellow crystalline powder shape sodium glycididazole (containing 3 crystal water).Yield 82-87%.
The consumption mol ratio of described glycididazole acid and sodium bicarbonate is 1:0.85.
The inventive method environmentally safe, harmless to operator, source chemicals low price, and improve reaction yield.
Embodiment
The present invention is further illustrated by the following examples.Preparation method described in the embodiment of the present invention is only for illustration of the present invention, is not limitation of the present invention.
Embodiment 1
1, the preparation of glycididazole acid
(1) in the three-necked flask of 5000mL, add the 1200g vitriol oil, and add 401g (2.1mol) nitrilotriacetic acid(NTA), add 790g (4.62mol) metronidazole under strong stirring, holding temperature 0-15 DEG C in process in batches.
(2) finish, oil bath is heated, and makes temperature rise to 55 DEG C in system.
(3) stirring reaction 24h at 55 DEG C.
(4) stop stirring, while hot by reaction solution down in 5000mL frozen water, stirring lower is 6-7 with strong aqua adjust pH, controls interior temperature and is less than 10 DEG C.
(5) reaction solution is left standstill 12h at 0 DEG C, solid is separated out.
(6) filter, filter cake is washed.Vacuum drying obtains 300g white crude solid.
(7) added in 2000mL methyl alcohol by 300g crude product, add hot breakdown and reflux 1 hour, filter, solid dries to obtain 260g white solid, is glycididazole acid.The ratio of actual output and theoretical yield, i.e. yield are 26%.
2, the preparation-salt-forming reaction of sodium glycididazole
(1) 500mL water is added in reaction flask, be warming up to 40 DEG C, 100g (0.2mol) glycididazole acid is scattered in water, add and add 14.3g (0.17mol) sodium bicarbonate solid in batches.
(2) in 40 ~ 60 DEG C of stirring and dissolving.Add gac insulation 0.5h, filter, filtrate is washed by ethyl acetate, and concentrated aqueous phase obtains 90g off-white color to micro-yellow crystalline powder shape sodium glycididazole (containing 3 crystal water), yield 78%.
Embodiment 2
1, the preparation of glycididazole acid
(1) in the three-necked flask of 5000mL, add the 1200g vitriol oil, and add 401g (2.1mol) nitrilotriacetic acid(NTA), add 790g (4.62mol) metronidazole under strong stirring, holding temperature 0-15 DEG C in process in batches.
(2) finish, oil bath is heated, and makes temperature rise to 65 DEG C in system.
(3) stirring reaction 24h at 65 DEG C.
(4) stop stirring, while hot by reaction solution down in 5000mL frozen water, stirring lower is 6-7 with strong aqua adjust pH, controls interior temperature and is less than 10 DEG C.
(5) reaction solution is left standstill 12h at 0 DEG C, solid is separated out.
(6) filter, filter cake is washed.Vacuum drying obtains 450g white crude solid.
(7) added in 2000mL methyl alcohol by 450g crude product, add hot breakdown and reflux 1 hour, filter, solid dries to obtain 400g white solid, is the glycididazole acid of purity 95%, yield 38.5%.
2, the preparation-salt-forming reaction of sodium glycididazole
(1) 500mL water is added in reaction flask, be warming up to 40 DEG C, 100g (0.2mol) glycididazole acid is scattered in water, add and add 14.3g (0.17mol) sodium bicarbonate solid in batches.
(2) in 40 ~ 60 DEG C of stirring and dissolving.Add gac insulation 0.5h, filter, filtrate is washed by ethyl acetate, and concentrated aqueous phase obtains the sodium glycididazole 100g (containing 3 crystal water) of off-white color to micro-yellow crystalline powder shape purity 98.5%, yield 87%.Embodiment 3
1, the preparation of glycididazole acid
(1) in the three-necked flask of 5000mL, add the 1200g vitriol oil, and add 401g (2.1mol) nitrilotriacetic acid(NTA), add 790g (4.62mol) metronidazole under strong stirring, holding temperature 0-15 DEG C in process in batches.
(2) finish, oil bath is heated, and makes temperature rise to 85 DEG C in system.
(3) stirring reaction 24h at 85 DEG C.
(4) stop stirring, while hot by reaction solution down in 5000mL frozen water, stirring lower is 6-7 with strong aqua adjust pH, controls interior temperature and is less than 10 DEG C.
(5) reaction solution is left standstill 12h at 0 DEG C, solid is separated out.
(6) filter, filter cake is washed.Vacuum drying obtains 350g white crude solid.
(7) added in 2000mL methyl alcohol by 350g crude product, add hot breakdown and reflux 1 hour, filter, solid dries to obtain 300g white solid, is glycididazole acid.Yield: 29%.
2, the preparation-salt-forming reaction of sodium glycididazole
(1) 500mL water is added in reaction flask, be warming up to 40 DEG C, 100g (0.2mol) glycididazole acid is scattered in water, add and add 14.3g (0.17mol) sodium bicarbonate solid in batches.
(2) in 40 ~ 60 DEG C of stirring and dissolving.Add gac insulation 0.5h, filter, filtrate is washed by ethyl acetate, and concentrated aqueous phase obtains 93g off-white color to micro-yellow crystalline powder shape sodium glycididazole (containing 3 crystal water), yield: 81%.
Although the present invention with preferred embodiment openly as above; but it is also not used to limit the present invention, any person skilled in the art, without departing from the spirit and scope of the present invention; all can do various changes and modification, what therefore protection scope of the present invention should define with claims is as the criterion.
Claims (10)
1. a synthetic method for sodium glycididazole, is characterized in that, with metronidazole and nitrilotriacetic acid(NTA) for substrate, using the vitriol oil as catalysts and solvents, carries out esterification and obtains glycididazole acid, then obtain sodium glycididazole through salt-forming reaction.
2. method according to claim 1, it is characterized in that, the preparation of described glycididazole acid mainly comprises the following steps: (1) adds the vitriol oil in three-necked flask, and adds nitrilotriacetic acid(NTA), adds metronidazole and holding temperature 0-15 DEG C under strong stirring in batches; (2) finish, oil bath is heated, and to make in system temperature rise to 55-85 DEG C; (3) stirring reaction 20-30h at 55-85 DEG C; (4) stop stirring, while hot by reaction solution down in frozen water, stirring lower is 6-7 with mineral alkali adjust pH, controls interior temperature and is less than 10 DEG C; (5) reaction solution is left standstill 12h at 0 DEG C, solid is separated out; (6) filter, filter cake is washed, and dries to obtain Glycididazole acid crude.
3. method according to claim 2, is characterized in that, the mol ratio of nitrilotriacetic acid(NTA) and metronidazole is 1:2.2.
4. method according to claim 2, is characterized in that, described mineral alkali is strong aqua, salt of wormwood, sodium carbonate, sodium bicarbonate, saleratus, sodium hydroxide or potassium hydroxide.
5. the method according to claim 2 or 4, is characterized in that, described mineral alkali is strong aqua.
6. method according to claim 2, is characterized in that, also comprises and adds in organic solvent by crude product, and add hot breakdown backflow, filter, solid dries to obtain white solid.
7. method according to claim 6, is characterized in that, selected making beating organic solvent is ethanol, methylene dichloride, methyl alcohol or tetrahydrofuran (THF).
8. the method according to claim 6 or 7, is characterized in that, selected making beating organic solvent is methyl alcohol.
9. method according to claim 1, is characterized in that, described salt-forming reaction mainly comprises the following steps: water adds in reaction flask by (1), is warming up to 40 ~ 60 DEG C, is scattered in by glycididazole acid in water, adds and add sodium bicarbonate solid in batches; (2) in 40 ~ 60 DEG C of stirring and dissolving, add gac insulation 0.5h, filter, filtrate is washed by ethyl acetate, and concentrated aqueous phase obtains off-white color to micro-yellow crystalline powder shape sodium glycididazole.
10. a synthetic method for glycididazole acid, is characterized in that, with metronidazole and nitrilotriacetic acid(NTA) for substrate, using the vitriol oil as catalysts and solvents, carries out esterification and obtains glycididazole acid.
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Citations (4)
| 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 |
| CN102190626A (en) * | 2010-03-15 | 2011-09-21 | 南京莱因医药科技有限公司 | Synthesis method of sodium glycididazole |
-
2014
- 2014-12-05 CN CN201410737685.8A patent/CN104356070A/en active Pending
Patent Citations (4)
| 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 |
| CN102190626A (en) * | 2010-03-15 | 2011-09-21 | 南京莱因医药科技有限公司 | Synthesis method of sodium glycididazole |
Non-Patent Citations (4)
| Title |
|---|
| 吕亮: "《精细有机合成单元反应》", 30 June 2012, article "酯化反应", pages: 135-136 * |
| 房鼎业等: "《化学工艺学 精编版》", 31 December 2012, article "酯化", pages: 354 * |
| 胡昱等: "《有机化学实验》", 31 August 2012, article "酯化反应", pages: 101-102 * |
| 赵宪瑞等: "含氮羧酸的羟乙基甲硝唑酯的合成", 《北京大学学报》, vol. 38, no. 2, 31 March 2002 (2002-03-31), pages 175 - 180 * |
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Application publication date: 20150218 |