CN100465169C - Method for preparing nitazoxanide - Google Patents
Method for preparing nitazoxanide Download PDFInfo
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- CN100465169C CN100465169C CNB2006100528041A CN200610052804A CN100465169C CN 100465169 C CN100465169 C CN 100465169C CN B2006100528041 A CNB2006100528041 A CN B2006100528041A CN 200610052804 A CN200610052804 A CN 200610052804A CN 100465169 C CN100465169 C CN 100465169C
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Abstract
The invention relates to a nidazolenit preparing method, mainly solving the technical problems of large utilization of tetrahydrofuran and higher cost; and also resolving the technical problem of bad quality of product by selecting organic alkali triethylamine as acid binder. And it comprises the steps of: dissolving 2-amino-5-nitrothiazole in enough nitrogen-containing compound solvent, adding in enough acid binder and blending, and lowering the temperature; adding in ortho-acetyl salicyl chloride and making full condensation reaction; dissolving idazolenit crude in nitrogen-containing compound solvent, and adding in activated carbon to decolor; filtering and adding alcohol in mother solution for alcohol precipitation, filtering and drying.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate, especially relate to a kind of preparation method who is used for the treatment of the nitazoxanide of protozoal diarrhea disease.
Background technology
Developed country's dysentery philtrum according to statistics, the Cryptosporidium spp rate is 0.6%～7.3%; Developing country is 3%～13%; China's infection rate is 1.4%～13.3%.Nitazoxanide is through external clinical repetition test, and the children's diarrhae that Cryptosporidium, Giardia lamblia etc. is caused has special efficacy,
The chemical name of nitazoxanide is 2-acetoxyl group-N-(5-nitro-2-thiazolyl) benzamide, and its reaction formula is
The preparation nitazoxanide adopts following method mostly at present: behind tetrahydrofuran (THF) dissolving 2-amino-5-nitrothiazole, add adjacent acetyl bigcatkin willow acyl chlorides and react at low temperatures, reaction finishes the back and uses in the triethylamine and the HCl that generates, and is diluted in the water, filter, dry the crude product nitazoxanide.Crude product with tetrahydrofuran (THF) dissolving, adds activated carbon decolorizing again, and product is separated out in the mother liquor cooling, filters, dry the elaboration nitazoxanide.But making in this way, there is following shortcoming in preparation: because 2-amino-5-nitrothiazole, adjacent acetyl bigcatkin willow acyl chlorides and nitazoxanide solubleness in tetrahydrofuran (THF) are not high, cause the tetrahydrofuran (THF) consumption very big, cost is higher; And acid binding agent is selected organic alkali triethylamine for use, and triethylamine has smelly fishiness, and is bad to operating environment, and triethylamine is water insoluble again, and after system was diluted in the water, a small amount of excessive triethylamine became oily matter, forms piece with material, and quality product is relatively poor.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of nitazoxanide, it mainly is that solution existing in prior technology 2-amino-5-nitrothiazole, adjacent acetyl bigcatkin willow acyl chlorides and nitazoxanide solubleness in tetrahydrofuran (THF) are not high, cause the tetrahydrofuran (THF) consumption very big, the cost technical problems of high; The present invention has also solved acid binding agent and has selected organic alkali triethylamine for use, and triethylamine has smelly fishiness, and is bad to operating environment, triethylamine is water insoluble again, and after system was diluted in the water, a small amount of excessive triethylamine became oily matter, form piece with material, the technical problem of the relatively poor grade of quality product.
Above-mentioned technical problem of the present invention is mainly solved by following technical proposals:
The preparation method of nitazoxanide of the present invention is characterized in that:
A, 2-amino-5-nitrothiazole is dissolved in the capacity nitrogenous compound kind solvent, adds the capacity acid binding agent and stir, cooling;
B, add adjacent acetyl bigcatkin willow acyl chlorides, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1;
C, the abundant condensation reaction of the adjacent laggard row of acetyl bigcatkin willow acyl chlorides of adding;
D, with the nitazoxanide crude product with the dissolving of nitrogenous compound kind solvent, add activated carbon decolorizing;
E, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains product of the present invention.
The pure analysis method of refining employing is separated out product, makes the advantages of good crystallization of product, and quality is also higher.As preferably, it is methyl alcohol or ethanol that alcohol is analysed with alcohol.The decon effect of methyl alcohol is better.Mother liquor goes to reclaim DMF and methyl alcohol after the rectifying, is used after can reclaiming.
As preferably, the preparation method of nitazoxanide is characterized in that:
A, 2-amino-5-nitrothiazole is dissolved in the nitrogenous compound kind solvent, adds acid binding agent and stir, be cooled to-5～10 ℃;
B, add adjacent acetyl bigcatkin willow acyl chlorides, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1, and the dropping time is 1.5～3.0 hours, and temperature is-5～10 ℃;
C, the laggard capable condensation reaction of the adjacent acetyl bigcatkin willow acyl chlorides of adding, the condensation time is 1.5～3.0 hours, and setting-up point is 10～30 ℃, and reaction is diluted in the water after finishing, and separates out after the filtration, gets the nitazoxanide crude product;
D, the nitazoxanide crude product is put into methanol wash, oven dry;
E, with the nitazoxanide crude product with the dissolving of nitrogenous compound kind solvent, add activated carbon decolorizing, bleaching temperature is 40～60 ℃;
F, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains product of the present invention.
After obtaining the nitazoxanide crude product, crude product can be removed impurity with methanol wash, significantly reduce the bath water amount, reduce the generation of waste water.
The preparation method of nitazoxanide of the present invention is characterized in that:
A, in the nitrogenous compound kind solvent, add adjacent acetyl bigcatkin willow acyl chlorides, be stirred to dissolving fully, make adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution;
B, 2-amino-5-nitrothiazole is dissolved in the nitrogenous compound kind solvent, adds acid binding agent and stir, cooling;
C, drip adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1;
Carry out abundant condensation reaction behind d, the adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution of adding;
E, with the nitazoxanide crude product with the dissolving of nitrogenous compound kind solvent, add activated carbon decolorizing;
F, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains product of the present invention.
In the nitrogenous compound kind solvent, add adjacent acetyl bigcatkin willow acyl chlorides, be stirred to dissolving fully after, can place dropping funnel standby earlier.
As preferably, the preparation method of nitazoxanide of the present invention is characterized in that:
A, in the nitrogenous compound kind solvent, add adjacent acetyl bigcatkin willow acyl chlorides, be stirred to dissolving fully, make adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution;
B, 2-amino-5-nitrothiazole is dissolved in the nitrogenous compound kind solvent, adds acid binding agent and stir, be cooled to-5～10 ℃;
C, drip adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1, and the dropping time is 1.5～3.0 hours, and temperature is-5～10 ℃;
Carry out condensation reaction behind d, the adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution of adding, the condensation time is 1.5～3.0 hours, and setting-up point is 10～30 ℃, and reaction is diluted in the water after finishing, and separates out after the filtration, gets the nitazoxanide crude product;
E, the nitazoxanide crude product is put into methanol wash, oven dry;
F, with the nitazoxanide crude product with the dissolving of nitrogenous compound kind solvent, add activated carbon decolorizing, bleaching temperature is 40～60 ℃;
G, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains product of the present invention.
As preferably, the mass ratio of described adjacent acetyl bigcatkin willow acyl chlorides or adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution and 2-amino-5-nitrothiazole is 1.5～2,0:1.
As preferably, the mass ratio of described adjacent acetyl bigcatkin willow acyl chlorides or adjacent acetyl bigcatkin willow acyl chlorides nitrogenous compound class solution and 2-amino-5-nitrothiazole is 1.7:1.
As preferably, described reaction and purified nitrogenous compound kind solvent all are N, dinethylformamide.Reaction and refining all select for use dimethyl formamide be DMF as solvent, significantly reduce solvent load, minimum dosage can reduce to 2 times of product, has improved yield simultaneously.
As preferably, acid binding agent is mineral-type alkali or basic salt.Select for use mineral-type alkali or basic salt as acid binding agent, improved operating environment; Caking phenomenon can not occur after system is diluted in the water yet, improve product quality.
As preferably, described acid binding agent is a salt of wormwood.Acid binding agent also can be a yellow soda ash.
As preferably, activated carbon dosage is 3～10% of a nitazoxanide crude product.
Therefore, the present invention has reaction and makes with extra care and select N for use, and dinethylformamide is as solvent, and solvent load is less, save cost, yield is higher, selects for use mineral-type alkali or basic salt as acid binding agent, improved operating environment, caking phenomenon can not occur, the characteristics that product quality is higher; The present invention also has crude product and removes impurity with methanol wash, and the bath water amount is less, and the waste water of generation is less, and the pure analysis method of refining employing is separated out product, product advantages of good crystallization, characteristics such as quality height.
Embodiment
Below by embodiment, and in conjunction with the accompanying drawings, technical scheme of the present invention is described in further detail.
Embodiment 1: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Add N in a, the 250ml flask, dinethylformamide is DMF:50ml, adds adjacent acetyl bigcatkin willow acyl chlorides: 60g again, is stirred to dissolving fully, places dropping funnel standby;
Add DMF:70ml in b, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 42g stirs, and is cooled to 0 ℃;
C, slowly drip above-mentioned adjacent acetyl bigcatkin willow acyl chlorides DMF solution, control temperature well at 0～5 ℃, about 2 hours of dropping time;
D, drip after, carry out condensation reaction, be warming up to 25 ℃, insulation is 2 hours about 25 ℃, is diluted in the water, separates out product, filters;
E, once with methanol wash, dry the crude product nitazoxanide.Methanol mother liquor goes distillation to recycle.
Add DMF:80ml in f, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 55～60 ℃;
G, 55～60 ℃ of insulations 1 hour, filter, add methyl alcohol: 100ml in the mother liquor, be cooled to 0～5 ℃, separate out product, filter, oven dry, the elaboration nitazoxanide, mother liquor goes rectifying to reclaim DMF and methyl alcohol, reclaims the back and utilizes.
Embodiment 2: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Add DMF:80ml in a, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 36g stirs, and is cooled to 0 ℃;
B, the adjacent acetyl bigcatkin willow of adding in batches slowly acyl chlorides solid 52g control temperature well at 0～5 ℃, about 2 hours of joining day;
C, add after, carry out condensation reaction, be warming up to 25 ℃, insulation is 2 hours about 25 ℃, is diluted in the water, separates out product, filters;
D, once with methanol wash, dry the crude product nitazoxanide, methanol mother liquor goes distillation to recycle;
Add DMF:80ml in e, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 55～60 ℃;
F, 55～60 ℃ of insulations 1.0 hours, heat filtering adds methyl alcohol: 100mi in the mother liquor, be cooled to 0～5 ℃, separates out product, filter, oven dry, the elaboration nitazoxanide.Mother liquor goes rectifying to reclaim DMF and methyl alcohol, reclaims the back and utilizes.
Embodiment 3: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Add DMF:40ml in a, the 250ml flask, add adjacent acetyl bigcatkin willow acyl chlorides: 48g again, be stirred to dissolving fully, place dropping funnel standby then;
Add DMF:70ml in b, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 34g stirs, and is cooled to 0 ℃;
C, slowly drip above-mentioned adjacent acetyl bigcatkin willow acyl chlorides DMF solution, control temperature well at 0～5 ℃, about 2 hours of dropping time;
D, drip after, carry out condensation reaction, be warming up to 25 ℃, insulation is 2 hours about 25 ℃, is diluted in the water, separates out product, filters;
E, once with methanol wash, dry the crude product nitazoxanide, methanol mother liquor goes distillation to recycle;
Add DMF:80ml in f, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 55～60 ℃;
G, 55～60 ℃ of insulations 1.0 hours, heat filtering adds ethanol: 100ml in the mother liquor, be cooled to 0～5 ℃, separates out product, filter, oven dry, the elaboration nitazoxanide.Mother liquor goes rectifying to reclaim DMF and ethanol, reclaims the back and utilizes.
Embodiment 4: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Add DMF:50ml in a, the 250ml flask, add adjacent acetyl bigcatkin willow acyl chlorides: 60g again, be stirred to dissolving fully, place dropping funnel standby;
Add DMF:70ml in b, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 42g stirs, and is cooled to 5 ℃;
C, slowly drip above-mentioned adjacent acetyl bigcatkin willow acyl chlorides DMF solution, control temperature well at 5～10 ℃, about 2 hours of dropping time;
D, drip after, carry out condensation reaction, be warming up to 20 ℃, insulation is 2 hours about 20～25 ℃, is diluted in the water, separates out product, filters;
E, once with methanol wash, dry the crude product nitazoxanide, methanol mother liquor goes distillation to recycle;
Add DMF:80ml in f, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 46～50 ℃;
G, 46～50 ℃ of insulations 1.0 hours, heat filtering adds methyl alcohol: 100ml in the mother liquor, be cooled to 0～5 ℃, separates out product, filter, oven dry, the elaboration nitazoxanide.Mother liquor goes rectifying to reclaim DMF and methyl alcohol, reclaims the back and utilizes.
Embodiment 5: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Adding dimethyl formamide in a, the 250ml flask is DMF:40ml, adds adjacent acetyl bigcatkin willow acyl chlorides: 47.6g again, is stirred to dissolving fully, places dropping funnel standby;
Add DMF:70ml in b, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 33.1g stirs, and is cooled to 5 ℃;
C, slowly drip above-mentioned adjacent acetyl bigcatkin willow acyl chlorides DMF solution, control temperature well at 5～10 ℃, about 2 hours of dropping time;
D, drip after, carry out condensation reaction, be warming up to 25 ℃, insulation is 2 hours about 25 ℃, is diluted in the water, separates out product, filters;
E, once with methanol wash, dry the crude product nitazoxanide.Methanol mother liquor goes distillation to recycle.
Add DMF:80ml in f, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 55～60 ℃;
G, 55～60 ℃ of insulations 1 hour, filter, add methyl alcohol: 100ml in the mother liquor, be cooled to 0～5 ℃, separate out product, filter, oven dry, the elaboration nitazoxanide, mother liquor goes rectifying to reclaim DMF and methyl alcohol, reclaims the back and utilizes.
Embodiment 6: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Adding dimethyl formamide in a, the 250ml flask is DMF:75ml, adds adjacent acetyl bigcatkin willow acyl chlorides: 79.2g again, is stirred to dissolving fully, places dropping funnel standby;
Add DMF:70ml in b, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 55.2g stirs, and is cooled to 5 ℃;
C, slowly drip above-mentioned adjacent acetyl bigcatkin willow acyl chlorides DMF solution, control temperature well at 5～10 ℃, about 2 hours of dropping time;
D, drip after, carry out condensation reaction, be warming up to 25 ℃, insulation is 2 hours about 25 ℃, is diluted in the water, separates out product, filters;
E, once with methanol wash, dry the crude product nitazoxanide.Methanol mother liquor goes distillation to recycle.
Add DMF:80ml in f, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 55～60 ℃;
G, 55～60 ℃ of insulations 1 hour, filter, add methyl alcohol: 100ml in the mother liquor, be cooled to 0～5 ℃, separate out product, filter, oven dry, the elaboration nitazoxanide, mother liquor goes rectifying to reclaim DMF and methyl alcohol, reclaims the back and utilizes.
Embodiment 7: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Adding dimethyl formamide in a, the 250ml flask is DMF:55ml, adds adjacent acetyl bigcatkin willow acyl chlorides: 59.6g again, is stirred to dissolving fully, places dropping funnel standby;
Add DMF:70ml in b, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 41.4g stirs, and is cooled to 5 ℃;
C, slowly drip above-mentioned adjacent acetyl bigcatkin willow acyl chlorides DMF solution, control temperature well at 5～10 ℃, about 2 hours of dropping time;
D, drip after, carry out condensation reaction, be warming up to 25 ℃, insulation is 2 hours about 25 ℃, is diluted in the water, separates out product, filters;
E, once with methanol wash, dry the crude product nitazoxanide.Methanol mother liquor goes distillation to recycle.
Add DMF:80ml in f, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 55～60 ℃;
G, 55～60 ℃ of insulations 1 hour, filter, add methyl alcohol: 150ml in the mother liquor, be cooled to 0～5 ℃, separate out product, filter, oven dry, the elaboration nitazoxanide, mother liquor goes rectifying to reclaim DMF and methyl alcohol, reclaims the back and utilizes.
Embodiment 8: the preparation method of the nitazoxanide that this is routine, be used for the intermediate of the nitazoxanide of production for treating protozoal diarrhea disease, and the steps include:
Adding dimethyl formamide in a, the 250ml flask is DMF:64ml, adds adjacent acetyl bigcatkin willow acyl chlorides: 67.5g again, is stirred to dissolving fully, places dropping funnel standby;
Add DMF:70ml in b, the 250m flask, add 2-amino-5-nitrothiazole: 29g again, salt of wormwood: 46.9g stirs, and is cooled to 5 ℃;
C, slowly drip above-mentioned adjacent acetyl bigcatkin willow acyl chlorides DMF solution, control temperature well at 5～10 ℃, about 2 hours of dropping time;
D, drip after, carry out condensation reaction, be warming up to 25 ℃, insulation is 2 hours about 25 ℃, is diluted in the water, separates out product, filters;
E, once with methanol wash, dry the crude product nitazoxanide.Methanol mother liquor goes distillation to recycle.
Add DMF:80ml in f, the 250ml flask, add the crude product nitazoxanide of oven dry: 50g, gac: 2.5g is warming up to 55～60 ℃;
G, 55～60 ℃ of insulations 1 hour, filter, add methyl alcohol: 150ml in the mother liquor, be cooled to 0～5 ℃, separate out product, filter, oven dry, the elaboration nitazoxanide, mother liquor goes rectifying to reclaim DMF and methyl alcohol, reclaims the back and utilizes.
Claims (7)
1. the preparation method of a nitazoxanide is characterized in that:
A, 2-amino-5-nitrothiazole is dissolved among the capacity DMF, adds capacity salt of wormwood or yellow soda ash and stir, cooling;
B, add adjacent acetyl bigcatkin willow acyl chlorides, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1;
C, the abundant condensation reaction of the adjacent laggard row of acetyl bigcatkin willow acyl chlorides of adding obtain the nitazoxanide crude product;
D, the nitazoxanide crude product is dissolved with DMF, add activated carbon decolorizing;
E, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains the elaboration nitazoxanide.
2. the preparation method of nitazoxanide according to claim 1 is characterized in that:
A, 2-amino-5-nitrothiazole is dissolved among the DMF, adds salt of wormwood or yellow soda ash and stir, be cooled to-5～10 ℃;
B, add adjacent acetyl bigcatkin willow acyl chlorides, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1, and the dropping time is 1.5～3.0 hours, and temperature is-5～10 ℃;
C, the laggard capable condensation reaction of the adjacent acetyl bigcatkin willow acyl chlorides of adding, the condensation time is 1.5～3.0 hours, and setting-up point is 10～30 ℃, and reaction is diluted in the water after finishing, and separates out after the filtration, gets the nitazoxanide crude product;
D, the nitazoxanide crude product is put into methanol wash, oven dry;
E, the nitazoxanide crude product is dissolved with DMF, add activated carbon decolorizing, bleaching temperature is 40～60 ℃;
F, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains the elaboration nitazoxanide.
3. the preparation method of a nitazoxanide is characterized in that:
A, in DMF, add adjacent acetyl bigcatkin willow acyl chlorides, be stirred to dissolving fully, make adjacent acetyl bigcatkin willow acyl chlorides DMF solution;
B, 2-amino-5-nitrothiazole is dissolved among the DMF, adds salt of wormwood or yellow soda ash and stir, cooling;
C, drip adjacent acetyl bigcatkin willow acyl chlorides DMF solution, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1;
Carry out abundant condensation reaction behind d, the adjacent acetyl bigcatkin willow acyl chlorides DMF of adding, obtain the nitazoxanide crude product;
E, the nitazoxanide crude product is dissolved with DMF, add activated carbon decolorizing;
F, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains the elaboration nitazoxanide.
4. the preparation method of nitazoxanide according to claim 3 is characterized in that:
A, in DMF, add adjacent acetyl bigcatkin willow acyl chlorides, be stirred to dissolving fully, make adjacent acetyl bigcatkin willow acyl chlorides DMF solution;
B, 2-amino-5-nitrothiazole is dissolved among the DMF, adds salt of wormwood or yellow soda ash and stir, be cooled to-5～10 ℃;
C, drip adjacent acetyl bigcatkin willow acyl chlorides DMF solution, the mass ratio of itself and 2-amino-5-nitrothiazole is 1.2～2.0:1, and the dropping time is 1.5～3.0 hours, and temperature is-5～10 ℃;
Carry out condensation reaction behind d, the adjacent acetyl bigcatkin willow acyl chlorides DMF solution of adding, the condensation time is 1.5～3.0 hours, and setting-up point is 10～30 ℃, and reaction is diluted in the water after finishing, and separates out after the filtration, gets the nitazoxanide crude product;
E, the nitazoxanide crude product is put into methanol wash, oven dry;
F, the nitazoxanide crude product is dissolved with DMF, add activated carbon decolorizing, bleaching temperature is 40～60 ℃;
G, filter after, add alcohol in the mother liquor and carry out alcohol and analyse, mass ratio is 1:0.8～2.0, filters, oven dry obtains the elaboration nitazoxanide.
5. according to the preparation method of claim 1 or 2 or 3 or 4 described nitazoxanides, it is characterized in that the mass ratio of described adjacent acetyl bigcatkin willow acyl chlorides or adjacent acetyl bigcatkin willow acyl chlorides DMF solution and 2-amino-5-nitrothiazole is 1.5～2.0:1.
6. the preparation method of nitazoxanide according to claim 5 is characterized in that the mass ratio of described adjacent acetyl bigcatkin willow acyl chlorides or adjacent acetyl bigcatkin willow acyl chlorides DMF solution and 2-amino-5-nitrothiazole is 1.7:1.
7. the preparation method of nitazoxanide according to claim 6 is characterized in that activated carbon dosage is 3～10% of a nitazoxanide crude product.
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| CN106831640A (en) * | 2015-12-03 | 2017-06-13 | 江苏正大丰海制药有限公司 | A kind of preparation method of Nitazoxanide crystal |
| CA3233848A1 (en) * | 2021-10-05 | 2023-04-13 | Sasidhar Balappa SOMAPPA | An improved process for the preparation of nitazoxanide and intermediates thereof |
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| US5578621A (en) * | 1994-09-08 | 1996-11-26 | Romark Lab Lc | Benzamide derivatives |
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| 2-乙酰基-N-(5-硝基噻唑)苯甲酰胺的高效液相色谱法测定. 徐林祥等.浙江化工，第33卷第2期. 2002 * |
| 治疗肠道寄生虫和细菌感染的新药-nitazoxanide. 尚炜等.国外医学寄生虫病分册，第31卷第6期. 2004 |
| 治疗肠道寄生虫和细菌感染的新药-nitazoxanide. 尚炜等.国外医学寄生虫病分册，第31卷第6期. 2004 * |
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|---|---|
| CN1935796A (en) | 2007-03-28 |
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