CN108101859A - A kind of process for purification of Sulfamethoxazole - Google Patents
A kind of process for purification of Sulfamethoxazole Download PDFInfo
- Publication number
- CN108101859A CN108101859A CN201611045554.9A CN201611045554A CN108101859A CN 108101859 A CN108101859 A CN 108101859A CN 201611045554 A CN201611045554 A CN 201611045554A CN 108101859 A CN108101859 A CN 108101859A
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- China
- Prior art keywords
- sulfamethoxazole
- filtrate
- molecular sieve
- iron
- limewash
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
- C07D261/14—Nitrogen atoms
- C07D261/16—Benzene-sulfonamido isoxazoles
Abstract
The present invention discloses a kind of process for purification of Sulfamethoxazole, comprises the following steps：Sulfamethoxazole is dissolved in limewash, by the molecular sieve of load iron and the mixture of activated carbon, keeps the temperature press filtration, then into filtrate, addition iron powder is anti-oxidant, adds in hydrochloric acid and neutralizes, then crystallisation by cooling, it is dry.The invention avoids the uses of high toxic and high risk raw material, improve the utilization rate of raw material, reduce the danger and production cost of production process, and improve the yield and purity of product.
Description
Technical field
The present invention relates to a kind of process for purification of Sulfamethoxazole, belong to field of medicine and chemical technology.
Background technology
Sulfamethoxazole（Radonil, Sulfamethoxazol, Sinomin）, molecular formula C10H11N3O3S, chemical name
For：N-（5- methyl -3- isoxazolyls）- 4- aminobenzene sulfonamides（N-（5-methyl-isoxazol-3-ly）-4-
sulfanilamide）, abbreviation SMZ, No. CAS：723-46-6, for white crystalline powder, odorless, mildly bitter flavor.Chemical structural formula
For：。
Sulfamethoxazole belongs to median acting sulfonamide class drug, has broad-spectrum antibacterial action, to non-producing enzyme S. aureus L-forms, suppurative chain
The part bacterial strain of the enterobacteriaceaes such as coccus, streptococcus pneumonia, escherichia coli, Klebsiella, Salmonella, Shigella,
Gonococcus, meningococcus, haemophilus influenzae have antibacterial action, in addition in vitro to chlamydia trachomatis, star-shaped nocardia,
Plasmodium falciparum and category Infection of Toxoplasma Gondii also have antimicrobial acivity.Urinary tract infections, respiratory system sense caused by being mainly used for sensitive bacteria
Dye, enteric infection, infection of biliary tract and local soft tissue and trauma surface infestation etc..
For the commercial synthesis of Sulfamethoxazole, there are sulfanilamide (SN) sodium salt method and benzene sulfonyl chloride method, wherein benzene sulfonyl chloride method synthesizes
The method of-isoxazole of intermediate 3- amino -5- methyl has：1st, using butene nitrile as raw material 2, using butine nitrile as raw material 3, with acetyl second
Nitrile is raw material 4, using pendant acetoacetonate moieties as raw material.At present, industrially refined method is carried out after synthesis Sulfamethoxazole crude product
It is as follows：Crude product Sulfamethoxazole is dissolved in limewash, and hydrazine hydrate is anti-oxidant, adds in activated carbon decolorizing, and warm press filtration is filtered
Liquid, filtrate are neutralized using 30% hydrochloric acid, and sodium hydrosulfite is anti-oxidant, dry then through crystallisation by cooling, obtain crystallinity Huang An Jia Evil
Azoles powder, it is 88-90% to refine yield.Sulfamethoxazole heated in strong acid or highly basic it is oxidable, in traditional handicraft, by sulfanilamide (SN)
Jia oxazoles can add in the reducing agents such as hydrazine hydrate after being dissolved in limewash, and hydrazine hydrate is a kind of extremely toxic substance.In N-process
The antioxidant sodium hydrosulfite of addition has pyrophorisity, explosivity, toxic, chance water or sour inflammable property, once accident occurs,
Its fire risk is huge.
In the technological process of production of Sulfamethoxazole, subtractive process has the status of the sufficient weight of tool.It is not only determined
The quality of final Sulfamethoxazole product, and product yield and public work is controlled to consume, it can be rated as Sulfamethoxazole production
The key technology of process.Therefore, using contemporary process for refining development result, the technological process of Sulfamethoxazole product, drop are simplified
Low production cost improves product quality, could meet requirement of the people to drug safety.
In order to obtain the standard for meeting the medicinal Sulfamethoxazole of country, existing Sulfamethoxazole purification techniques is overcome not
Foot, it is an object of the invention to provide a kind of process for purification of Sulfamethoxazole, and the technical process is simple and direct, low energy consumption for material consumption, sets
Standby small investment, production cost are low.
The content of the invention
There are both sexes using Sulfamethoxazole when refined, in isoelectric point（pH5.5）The smaller feature of solubility, carry out alkali
Molten, acid out realizes recrystallization.The present invention overcomes the deficiencies of the prior art and provide a kind of process for purification of Sulfamethoxazole.
1st, a kind of process for purification of Sulfamethoxazole, it is characterised in that comprise the following steps：
A, Sulfamethoxazole crude product is dissolved in limewash, is warming up to about 65-75 DEG C, add in the molecular sieve and activity of load iron
The mixture of charcoal keeps the temperature 50 minutes at 70-80 DEG C；It is filtered by being pumped into filter press, obtains filtrate；
B, filtrate is warming up to 80-85 DEG C, adds in iron powder, pH=5.5, slow cooling to 25-30 are neutralized to the hydrochloric acid of 25-30%
DEG C, crystallization washes away Fe2+、Cl-Plasma, dry Sulfamethoxazole white crystalline powder.
Further, the mass ratio of Sulfamethoxazole and limewash is 1 in the step A:11-13.
Further, a kind of molecular sieve of load iron and the mixture of activated carbon, the two matter are used in the step A
Amount is than being 0.8-1.5:0.5-1.0.
Further, a kind of molecular sieve of carried metal iron and the mixture of activated carbon are used in the step A,
Dosage is the 2-5% of solution quality.
Further, filter press uses plate and frame filter press in the step A, and filter pressure maintains 0.2-0.35MPa.
Further, the addition of iron powder is the heavy 0.1-0.5% of filtrate in the step B.
Further, rate of temperature fall is not more than 5 DEG C/h in affiliated step B.
Sulfamethoxazole heated in strong acid or highly basic it is oxidable, the present invention Sulfamethoxazole is dissolved in limewash after,
Using a kind of molecular sieve of carried metal iron and activated carbon combined use, Sulfamethoxazole crude product is refined.The gold of load
Belong to iron and anti-oxidation protection is carried out to Sulfamethoxazole, molecular sieve has good absorption for polarity, easily polarization, undersaturated substance
Effect, activated carbon can be up to more than 80% in processing coloring, the effect of flavored organic matter, so molecular sieve and activated carbon
Being used in combination can greatly improve to the impurity removal of Sulfamethoxazole and decolorizing effect.When being neutralized with hydrochloric acid, using few
The iron powder of amount carries out anti-oxidation protection, the Fe of generation2+With reproducibility, and Fe2+It exists in solution, it is not easy to be precipitated, reach
To the effect of purifying.
Advantageous effect
The method according to the invention refines Sulfamethoxazole, can avoid using the hydrazine hydrate of high toxic and high risk, protect
Dangerous powder improves production security, realizes green production.The molecular sieve of load iron and activated carbon combined use, improve refined receipts
Rate and product purity, activated carbon can recycle by post-processing with molecular sieve, reduce production cost, be more suitable for industrializing
Production.
Description of the drawings：
Fig. 1 is the process for refining figure of Sulfamethoxazole.
Specific embodiment
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
100 g of Sulfamethoxazole crude product is dissolved in limewash, in mass, the ratio between Sulfamethoxazole and limewash are 1：
11,65 DEG C are warming up to, and make its pH stable in 10-11, load iron molecular sieve and activated carbon ratio are 1:1 mixing, mixture
Addition is the 2% of solution weight, keeps the temperature 90 minutes at 70 DEG C, is filtered by being pumped into filter press, and filter pressure maintains
In 0.2MPa, filtrate is obtained；
（2）Filtrate is warming up to 80 DEG C, adds in iron powder, addition is the 0.05% of filtrate weight, with 30% hydrochloric acid be neutralized to pH=
5.5, slow cooling is to 25 DEG C, and rate of temperature fall is 5 DEG C/h, is crystallized, washing, dry Sulfamethoxazole white crystalline powder
97.5 g, it is 99.5% to refine purity, yield 97.5%.
Embodiment 2
（1）100 g of Sulfamethoxazole crude product is dissolved in limewash, in mass, the ratio between Sulfamethoxazole and limewash are
1：12,70 DEG C are warming up to, and make its pH stable in 10-11, load iron molecular sieve and activated carbon ratio are 0.8:1.0 mixing,
Mixture addition is the 3% of solution weight, keeps the temperature 50 minutes at 75 DEG C, is filtered by being pumped into filter press, filtration pressure
Power maintains 0.30MPa, obtains filtrate；
（2）Filtrate is warming up to 84 DEG C, adds in iron powder, addition is the 0.1% of filtrate weight, with 30% hydrochloric acid be neutralized to pH=
5.5, slow cooling is to 25 DEG C, and rate of temperature fall is 4 DEG C/h, is crystallized, washing, dry Sulfamethoxazole white crystalline powder
98.0 g, it is 99.7% to refine purity, yield 98.0%..
Embodiment 3
（1）100 g of Sulfamethoxazole crude product is dissolved in limewash, in mass, the ratio between Sulfamethoxazole and limewash are
1：13,75 DEG C are warming up to, and make its pH stable in 10-11, load iron molecular sieve and activated carbon ratio are 1.5:0.5 mixing,
Mixture addition is the 5% of solution weight, keeps the temperature 30 minutes at 80 DEG C, is filtered by being pumped into filter press, filtration pressure
Power maintains 0.35MPa, obtains filtrate；
（2）Filtrate is warming up to 85 DEG C, adds in iron powder, addition is the 0.15% of filtrate weight, with 30% hydrochloric acid be neutralized to pH=
5.5, slow cooling is to 25 DEG C, and rate of temperature fall is 3 DEG C/h, is crystallized, washing, dry Sulfamethoxazole white crystalline powder
96.3 g, it is 99.8% to refine purity, yield 96.3%..
Embodiment 4
（1）100 g of Sulfamethoxazole crude product is dissolved in limewash, in mass, the ratio between Sulfamethoxazole and limewash are
1：11.5,70 DEG C are warming up to, and make its pH stable in 10-11, load iron molecular sieve and activated carbon ratio are 0.8:It is 1.0 mixed
It closes, mixture addition is the 2% of solution weight, keeps the temperature 45 minutes at 80 DEG C, is filtered by being pumped into filter press,
Filter pressure maintains 0.30MPa, obtains filtrate；
（2）Filtrate is warming up to 80 DEG C, adds in iron powder, addition is the 0.3% of filtrate weight, with 30% acetic acid be neutralized to pH=
5.5, slow cooling is to 25 DEG C, and rate of temperature fall is 2 DEG C/h, is crystallized, washing, dry Sulfamethoxazole white crystalline powder
97.1 g, it is 99.2% to refine purity, yield 97.1%..
Comparative example 1
（1）100 g of Sulfamethoxazole crude product is dissolved in limewash, in mass, the ratio between Sulfamethoxazole and limewash water
For 1：12, hydrazine hydrate is added in, addition is the 0.5% of solution weight, is warming up to about 70 DEG C, and its pH stable is made to add in 10-11
Activated carbon keeps the temperature 50 minutes at 75 DEG C, and weight is the 6% of solution weight, is filtered by being pumped into filter press, filters
Pressure maintains 0.25MPa, obtains filtrate；
（2）Filtrate is warming up to 80 DEG C, take a policy powder, addition be filtrate weight 0.2%, with 30% hydrochloric acid be neutralized to pH=
5.5, slow cooling is crystallized to 25 DEG C, and washing is dry that 88.5 g of Sulfamethoxazole white crystalline powder, refined purity are
98.5%, yield 88.5%..
Comparative example 2
1）100 g of Sulfamethoxazole crude product is dissolved in limewash, in mass, the ratio between Sulfamethoxazole and limewash are 1：
11,70 DEG C are warming up to, and make its pH stable in 10-11, the molecular sieve of loading iron, weight is the 5% of solution weight, in 75
DEG C heat preservation 50 minutes, be filtered by being pumped into filter press, filter pressure maintains 0.35MPa, obtains filtrate；
（2）Filtrate is warming up to 80 DEG C, adds in iron powder, addition is the 0.1% of filtrate weight, with 30% hydrochloric acid be neutralized to pH=
5.5, slow cooling is crystallized to 25 DEG C, and washing is dry that 85.5 g of Sulfamethoxazole light yellow crystal powder, refined purity are
96.5%, yield 85.5%.
Comparative example 3
1）100 g of Sulfamethoxazole crude product is dissolved in limewash, in mass, the ratio between Sulfamethoxazole and limewash are 1：
13,70 DEG C are warming up to, and its pH stable is made activated carbon to be added to keep the temperature 50 minutes at 80 DEG C, weight is solution weight in 10-11
6%, be filtered by being pumped into filter press, filter pressure maintains 0.35MPa, obtains filtrate；
（2）Filtrate is warming up to 80 DEG C, adds in iron powder, addition is the 0.15% of filtrate weight, with 30% hydrochloric acid be neutralized to pH=
5.5, slow cooling is crystallized to 25 DEG C, and washing is dry that 68.1 g of Sulfamethoxazole white crystalline powder, refined purity are
97.5%, yield 68.1%.
Performance test
According to the detection method of Chinese Pharmacopoeia 2015 editions to the product obtained by embodiment 1 to 4 and comparative example 1 to 3 into
Row test：
| Detection | Standard items | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Comparative example 1 | Comparative example 2 | Comparative example 3 |
| Acidity | 4.0-6.0 | 4.9 | 5.3 | 5.5 | 4.7 | 5.0 | 4.5 | 4.8 |
| The clarity of alkaline solution | Clarification | Clarification | Clarification | Clarification | Clarification | Clarification | Clarification | Clarification |
| Chloride/% | <0.01% | 0.001 | 0.001 | 0.001 | 0.002 | 0.07 | 0.08 | 0.09 |
| Sulfate | <0.02% | 0.008 | 0.011 | 0.012 | 0.009 | 0.011 | 0.005 | 0.017 |
| Loss on drying | <0.5% | 0.1 | 0.12 | 0.15 | 0.17 | 0.25 | 0.3 | 0.35 |
| Heavy metal | Less than 15/1000000ths | Meet regulation | Meet regulation | Meet regulation | Meet regulation | Meet regulation | Meet regulation | Meet regulation |
As a result：Crude product is consistent with comparative example used by embodiment 1 to 4, but according to different process for purification at
Reason.Testing result meets Chinese Pharmacopoeia standard.
From embodiment 1-4 and comparative example 1, the present invention is compared with conventional method, process for purification of the invention institute
The Sulfamethoxazole purity obtained is all higher than conventional method with yield.
From embodiment 1-4 and comparative example 2, it is refining to obtain with the molecular sieve of load iron and the mixture of activated carbon
To pure white Sulfamethoxazole crystalline powder, and it is the Huang An Jia Evil of pale that the molecular sieve for only using load iron, which is refining to obtain,
Azoles crystal powder.It is more preferable using the molecular sieve of load iron and the mixture refining effect of activated carbon.
From embodiment 1-4 and comparative example 3, embodiment 1-4 is with the molecular sieve of load iron and mixing for activated carbon
It closes object and is refining to obtain pure white Sulfamethoxazole crystalline powder, purity is higher than 99.2%, and yield is higher than 96.3%, and comparative example
Activated carbon is only added in 3 to decolourize, and does not carry out anti-oxidation protection using the molecular sieve of load iron, Sulfamethoxazole is in strong acid
Or heating is aoxidized in highly basic.
Claims (7)
1. a kind of process for purification of Sulfamethoxazole, it is characterised in that comprise the following steps：
A, Sulfamethoxazole crude product is dissolved in limewash, is warming up to about 65-75 DEG C, add in the molecular sieve and activity of load iron
The mixture of charcoal keeps the temperature 50 minutes at 70-80 DEG C；It is filtered by being pumped into filter press, obtains filtrate；
B, filtrate is warming up to 80-85 DEG C, adds in iron powder, pH=5.5, slow cooling to 25-30 are neutralized to the hydrochloric acid of 25-30%
DEG C, crystallization washes away Fe2+、Cl-Plasma, dry Sulfamethoxazole white crystalline powder.
2. a kind of Sulfamethoxazole process for purification according to claim 1, it is characterised in that：Sulfalene in the step A
The mass ratio of oxazole and limewash is 1:11-13.
3. a kind of Sulfamethoxazole process for purification according to claim 1, it is characterised in that：It is used in the step A
It is a kind of molecular sieve of load iron and the mixture of activated carbon, the two mass ratio is 0.8-1.5:0.5-1.0.
4. a kind of Sulfamethoxazole process for purification according to claim 1, it is characterised in that：It is used in the step A
It is a kind of molecular sieve of carried metal iron and the mixture of activated carbon, dosage is the 2-5% of solution quality.
5. a kind of Sulfamethoxazole process for purification according to claim 1, it is characterised in that：Filter press in the step A
Using plate and frame filter press, filter pressure maintains 0.2-0.35MPa.
6. a kind of Sulfamethoxazole process for purification according to claim 1, it is characterised in that：Iron powder in the step B
Addition is the 0.1-0.5% of filtrate weight.
7. a kind of Sulfamethoxazole process for purification according to claim 1, it is characterised in that：Cool down speed in affiliated step B
Rate is not more than 5 DEG C/h.
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| CN201611045554.9A CN108101859A (en) | 2016-11-24 | 2016-11-24 | A kind of process for purification of Sulfamethoxazole |
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| CN201611045554.9A CN108101859A (en) | 2016-11-24 | 2016-11-24 | A kind of process for purification of Sulfamethoxazole |
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| CN108101859A true CN108101859A (en) | 2018-06-01 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160904A (en) * | 2018-09-09 | 2019-01-08 | 寿光富康制药有限公司 | The preparation method of sulfamethoxazole sodium |
-
2016
- 2016-11-24 CN CN201611045554.9A patent/CN108101859A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109160904A (en) * | 2018-09-09 | 2019-01-08 | 寿光富康制药有限公司 | The preparation method of sulfamethoxazole sodium |
| CN109160904B (en) * | 2018-09-09 | 2022-09-16 | 寿光富康制药有限公司 | Preparation method of sulfamethoxazole sodium |
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