CN103788077B - A kind of synthetic method of hydrochloric acid Itraconazole - Google Patents
A kind of synthetic method of hydrochloric acid Itraconazole Download PDFInfo
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- CN103788077B CN103788077B CN201410074644.5A CN201410074644A CN103788077B CN 103788077 B CN103788077 B CN 103788077B CN 201410074644 A CN201410074644 A CN 201410074644A CN 103788077 B CN103788077 B CN 103788077B
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- itraconazole
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The present invention relates to the synthetic method of hydrochloric acid Itraconazole, can effectively solve yield low, product stability is bad, of poor quality, and cost is high, the problem of contaminate environment, method is, is added by itraconazole in organic solvent, mixes thoroughly, the mass ratio of machine solvent and itraconazole is 1-5 ︰ 1, dripping mass concentration is the hydrochloric acid of 36% ~ 38%, and the mass ratio of itraconazole and hydrochloric acid is 2 ~ 8 ︰ 1, stirs 3-6 hour, be cooled to 10-30 DEG C, filter, obtain xln, xln organic solvent washing 2-3 time, drying, obtains hydrochloric acid Itraconazole; The no longer logical hydrogen chloride gas of the present invention, removes the potential safety hazard preparing hydrogen chloride gas; Alleviate the corrosion to equipment; Improve quality product, product yield can reach 98.5% ~ 100%, without the need to refining; Decrease unit consumption of energy; Reduce production cost; Improve dissolution rate and the stability of preparation; Be conducive to the healthy and large-scale industrial production of environment protection, workman.
Description
Technical field
The present invention relates to pharmaceutical chemistry technical field, particularly a kind of synthetic method of hydrochloric acid Itraconazole.
Background technology
Hydrochloric acid Itraconazole is to improve itraconazole dissolution rate, and a kind of wide spectrum of exploitation, the antifungal triazole kind new medicine that efficient, curative ratio is high.Experiment proves, hydrochloric acid Itraconazole is the same with contrast medicine itraconazole, and external all have wide spectrum and efficient antifungic action, and be widely used in the multiple fungal infectious disease for the treatment of.The synthesis technique more complicated of hydrochloric acid Itraconazole, have 13 steps, the final step of its reaction is salt-forming reaction, by itraconazole and 4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolane-4-base] methoxyl group] phenyl] piperazine-1-base] phenyl]-2-[(1RS)-1-methyl-propyl]-1,2,4-triazole-3-ketone and hydrochloric acid are combined into the hydrochloride of 2 molecules.Its structural formula is as follows:
Patent CN1285590C mentions and itraconazole is dissolved in organic solvent, pass into hydrogen chloride gas and carry out salt-forming reaction, then cold filtration obtains the method for hydrochloric acid Itraconazole.
And the main method preparing hydrogen chloride gas has: 1. sodium bisulfite and solid potassium chloride heating obtain 250 DEG C of reactions, and stir and want evenly, gas production rate is far below theoretical amount; 2.. sulfuric acid is added drop-wise in hydrochloric acid or hydrochloric acid drips in sulfuric acid, requires uninterrupted evenly to stir, concentration of hydrochloric acid is greater than 31%, sulfuric acid concentration is greater than 98% and has suck-back device; 3.. the vitriol oil is added drop-wise on sodium-chlor/chloride solid, slowly heats, then uses vitriol oil scrubbing bottle gas washing, and shortcoming is that reaction is slow, and gas production rate is lower than theoretical amount.4.. add Thickish hot hydrochloric acid and also can obtain hydrogen chloride gas, but a lot of water vapor and hydrogen chloride gas are emerged, and make gaseous mass poor simultaneously.Hydrochloric acid Itraconazole has the character of easy moisture absorption, requires that again sodium-chlor gas water content controls within the specific limits, and this compares aborning and is difficult to control.
There is following deficiency in this salifying method:
1, the method for making of hydrogen chloride gas is complicated, and multiplex exists larger potential safety hazard to the vitriol oil, logical hydrogen chloride gas to breather line and equipment corrosion too large, environmental pollution is serious, and gas water content and the difficult control of air flow.
2, because itraconazole can not all dissolve in a solvent, in ventilatory response process, reaction solution retrogradation, has a strong impact on mixing effect.
3, the hydrochloric acid Itraconazole obtained is pulverulent solids, affects product dissolution rate and stability after making preparation.Yield is low, and product stability is bad, of poor quality, and cost is high, contaminate environment, and therefore, its improvement and bring new ideas is imperative.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the object of the present invention is just to provide a kind of synthetic method of hydrochloric acid Itraconazole, and can effectively solve yield low, product stability is bad, of poor quality, and cost is high, the problem of contaminate environment.
The technical scheme that the present invention solves is that this synthetic method is, is added by itraconazole in organic solvent, mix thoroughly, the mass ratio of machine solvent and itraconazole is 1-5 ︰ 1, and dripping mass concentration is the hydrochloric acid of 36% ~ 38%, the mass ratio of itraconazole and hydrochloric acid is 2 ~ 8 ︰ 1, stir 3-6 hour, be cooled to 10-30 DEG C, filter, obtain xln, xln organic solvent washing 2-3 time, dry, obtain hydrochloric acid Itraconazole;
Described organic solvent is methyl alcohol, dehydrated alcohol or the mixture of the two;
Described organic solvent and the mass ratio of itraconazole are 2 ~ 4 ︰ 1; The mass ratio of itraconazole and hydrochloric acid is 4 ~ 6 ︰ 1.
From the above, the no longer logical hydrogen chloride gas of the present invention, removes the potential safety hazard preparing hydrogen chloride gas; Alleviate the corrosion to equipment; Improve quality product, product yield can reach 98.5% ~ 100%, without the need to refining; Decrease unit consumption of energy; Reduce production cost; Improve dissolution rate and the stability of preparation; Be conducive to the healthy and large-scale industrial production of environment protection, workman.
Embodiment
Below in conjunction with embodiment, the specific embodiment of the present invention is elaborated.
Embodiment 1
The present invention in the specific implementation, is realized by following methods: in reaction flask, add 120g dehydrated alcohol, 50g itraconazole, stir, then drip the hydrochloric acid 12g that mass concentration is 37%, stirring reaction 3 hours, be cooled to 20 DEG C, filter, obtain xln, xln absolute ethanol washing 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 98.1%, mass content 98.8%.
Embodiment 2
The present invention in the specific implementation, may also be and realized by following methods: in reaction flask, add 200g dehydrated alcohol, 50g itraconazole, stir, then drip the hydrochloric acid 10g that mass concentration is 38%, stirring reaction 5 hours, be cooled to 10 DEG C, filter, obtain xln, xln absolute ethanol washing 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 96.8%, mass content 99.2%.
Embodiment 3
The present invention in the specific implementation, is realized by following methods: in reaction flask, add 140g methyl alcohol, 50g itraconazole, stir, then drip the hydrochloric acid 9g that mass concentration is 36%, stirring reaction 6 hours, be cooled to 30 DEG C, filter, obtain xln, xln methanol wash 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 90.8%, mass content 98.5%.
Embodiment 4
The present invention in the specific implementation, is realized by following methods: in reaction flask, add 80g methyl alcohol, 50g itraconazole, stir, then drip the hydrochloric acid 13g that mass concentration is 37%, stirring reaction 4 hours, be cooled to 10 DEG C, filter, obtain xln, xln methanol wash 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 97.9%, mass content 99.0%.
The inventive method is reliable and stable, product yield is high, quality is good, energy-conserving and environment-protective, through repetition test and test, achieve satisfied Advantageous Effects, hydrochloric acid Itraconazole dissolution rate and stability are improved largely, improve the security of salify simultaneously, reduce energy consumption, decrease production cost, be conducive to environment protection, healthy and the large-scale industrial production of workman, after tested, compared to the prior art, method is simple, first product content can reach 98.5% ~ 100%, dissolution rate improves greatly, reduce unit consumption of energy 20-40%, production cost reduces about 30%, extended shelf-life more than 1 year, and significantly reduce environmental pollution, its method is benefited the nation and the people, that one in hydrochloric acid Yi Qu health preparation method innovates greatly, there is huge economic and social benefit.
Claims (6)
1. a synthetic method for hydrochloric acid Itraconazole, is characterized in that, is realized by following steps: added by itraconazole in organic solvent, mix thoroughly, the mass ratio of organic solvent and itraconazole is 1-5 ︰ 1, and dripping mass concentration is the hydrochloric acid of 36% ~ 38%, the mass ratio of itraconazole and hydrochloric acid is 2 ~ 8 ︰ 1, stir 3-6 hour, be cooled to 10-30 DEG C, filter, obtain xln, xln organic solvent washing 2-3 time, dry, obtain hydrochloric acid Itraconazole;
Described organic solvent is methyl alcohol, dehydrated alcohol or the mixture of the two.
2. the synthetic method of hydrochloric acid Itraconazole according to claim 1, is characterized in that, described organic solvent and the mass ratio of itraconazole are 2 ~ 4 ︰ 1; The mass ratio of itraconazole and hydrochloric acid is 4 ~ 6 ︰ 1.
3. the synthetic method of hydrochloric acid Itraconazole according to claim 1, is characterized in that, is realized by following methods: in reaction flask, add 120g dehydrated alcohol, 50g itraconazole, stirs, then drips the hydrochloric acid 12g that mass concentration is 37%, stirring reaction 3 hours, is cooled to 20 DEG C, filters, obtain xln, xln absolute ethanol washing 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 98.1%, mass content 98.8%.
4. the synthetic method of hydrochloric acid Itraconazole according to claim 1, is characterized in that, is realized by following methods: in reaction flask, add 200g dehydrated alcohol, 50g itraconazole, stirs, then drips the hydrochloric acid 10g that mass concentration is 38%, stirring reaction 5 hours, is cooled to 10 DEG C, filters, obtain xln, xln absolute ethanol washing 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 96.8%, mass content 99.2%.
5. the synthetic method of hydrochloric acid Itraconazole according to claim 1, is characterized in that, is realized by following methods: in reaction flask, add 140g methyl alcohol, 50g itraconazole, stirs, then drips the hydrochloric acid 9g that mass concentration is 36%, stirring reaction 6 hours, is cooled to 30 DEG C, filters, obtain xln, xln methanol wash 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 90.8%, mass content 98.5%.
6. the synthetic method of hydrochloric acid Itraconazole according to claim 1, is characterized in that, is realized by following methods: in reaction flask, add 80g methyl alcohol, 50g itraconazole, stirs, then drips the hydrochloric acid 13g that mass concentration is 37%, stirring reaction 4 hours, is cooled to 10 DEG C, filters, obtain xln, xln methanol wash 2-3 time, dry, obtain hydrochloric acid Itraconazole crystallization, yield 97.9%, mass content 99.0%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660841A (en) * | 2004-02-23 | 2005-08-31 | 上海医药工业研究院 | Itraconazole hydrochloride, oral solid combination and preparation method |
| CN1663566A (en) * | 2004-03-01 | 2005-09-07 | 上海医药工业研究院 | Itraconazole hydrochloride composition and freeze-dried powder injection thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US7446107B2 (en) * | 2002-02-15 | 2008-11-04 | Transform Pharmaceuticals, Inc. | Crystalline forms of conazoles and methods of making and using the same |
| EP1511490A4 (en) * | 2002-05-31 | 2009-03-11 | Transform Pharmaceuticals Inc | Novel conazole crystalline forms and related processes, pharmaceutical compositions and methods |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1660841A (en) * | 2004-02-23 | 2005-08-31 | 上海医药工业研究院 | Itraconazole hydrochloride, oral solid combination and preparation method |
| CN1663566A (en) * | 2004-03-01 | 2005-09-07 | 上海医药工业研究院 | Itraconazole hydrochloride composition and freeze-dried powder injection thereof |
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Inventor after: Diao Wenrui Inventor after: Jiang Zhengxiang Inventor after: Chen Hong Inventor after: Song Zhenfeng Inventor after: Zhang Feng Inventor after: Zhu Yongxin Inventor after: Guo Haibo Inventor before: Diao Wenrui Inventor before: Jiang Zhengxiang Inventor before: Chen Hong Inventor before: Song Zhenfeng |
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