CN106748912A - A kind of synthesis technique of sodium azulenesulfonate monohydrate - Google Patents
A kind of synthesis technique of sodium azulenesulfonate monohydrate Download PDFInfo
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- CN106748912A CN106748912A CN201611254408.7A CN201611254408A CN106748912A CN 106748912 A CN106748912 A CN 106748912A CN 201611254408 A CN201611254408 A CN 201611254408A CN 106748912 A CN106748912 A CN 106748912A
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- sodium azulenesulfonate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
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Abstract
The invention belongs to the field of chemical synthesis, a kind of synthetic method of sodium azulenesulfonate monohydrate is disclosed.During sodium azulenesulfonate monohydrate can be by sodium azulenesulfonate semihydrate addition mixed solution of the water with small polar organic solvent, it is sufficiently stirred for, crystallization is obtained.The method is simple to operate, and being amplified to production can be with cost-effective, and operating personnel's left-hand seat is easy.Meanwhile, the method can obtain single sodium azulenesulfonate monohydrate, and purity is higher.Waste liquid in the method is mainly the aqueous solution of sodium azulenesulfonate, and petroleum ether is also possible to subsequent recovery and uses, and the pollution of environment is small.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to the sodium azulenesulfonate preparation method containing the crystallization water.
Background technology
Sodium azulenesulfonate, is the active ingredient of anthemidis flos, with very strong antipepsin, anti-inflammatory, antibacterial, antiallergy,
Promote the effect of mucous membrane metabolism, the mechanism of action：Inflammatory cell is suppressed by local direct effect and discharges histamine；Increase mucous membrane
The synthesis of interior PGE2, promotes granulation to be formed and epithelial cell new life；And the activity of pepsin can be reduced.Due to its peace
Quan Xinggao, can be widely applied to various pharmaceutical preparations, and prevention from suffering from the diseases, treatment especially to skin and oral cavity, effect are obvious.Also may be used
In for configuring cosmetics, showering agent, soap.
Sodium azulenesulfonate, chemical name：1,4- dimethyl -7- isopropyl Azulene -3- sodium sulfonates.It is unstable in chemical property, light
According to, can be decomposed under air oxidation and hot environment, easily slough sulfonic group.According to existing report, sodium azulenesulfonate contains the crystallization water
Number is common situations half or one.In Chinese Journal of Pharmaceuticals in 2002, the 4th phase of volume 33, " croak is write by Zhang Zhanhui etc.
Sodium azulenesulfonate preparation method is disclosed in the synthesis of logical sequence acid sodium ".By introducing sulfonic group after guaiazulene sulfonating reaction, passing through
Neutralize into salt and sodium azulenesulfonate is obtained.The document reports sodium azulenesulfonate crude product and can obtain Azulene sulfonic acid by water recrystallization simultaneously
Sodium crystalline hydrate thing.But the document does not report specific re-crystallization step, while not reporting the determination side of semihydrate yet
Method, without any determination data.The crystalline hydrate of document report sodium azulenesulfonate has semihydrate and monohydrate, cannot now determine
The crystallization water number that sodium azulenesulfonate after being recrystallized with water contains, it is more likely that form mixed crystal form.
The stability of medicine is to evaluate one of important indicator of pharmaceutical preparation quality, medicine in production, storage, use process
It is middle can because the influence of various factors decompose it is rotten, so as to cause curative effect of medication reduction or side effect increase, some even produce
Raw noxious material.Thus, the crystal formation or crystalline hydrate of bulk drug prioritizing selection stabilization in drug development.Long-term experiment number
According to display, sodium azulenesulfonate monohydrate is more more stable than sodium azulenesulfonate semihydrate.Sodium azulenesulfonate semihydrate illumination 10 days,
60%30 days conditions of relative humidity place an order miscellaneous exceeded, and sodium azulenesulfonate monohydrate is attained by the limit of impurities under these conditions
It is required that.
The sodium azulenesulfonate semihydrate of table 1, sodium azulenesulfonate monohydrate stability experiment result
RH：Relative humidity
The method for preparing sodium azulenesulfonate monohydrate is not retrieved temporarily, and sodium azulenesulfonate crystalline hydrate preparation research still belongs to empty
In vain.
The content of the invention
In order to solve the above problems, this patent provides a kind of preparation method of sodium azulenesulfonate monohydrate.
The technical solution adopted in the present invention is as follows：
A kind of preparation method of sodium azulenesulfonate monohydrate, sodium azulenesulfonate semihydrate adds water and small polar organic solvent
Mixed solution in, be sufficiently stirred for, crystallization obtains sodium azulenesulfonate monohydrate.The water of sodium azulenesulfonate one can be obtained using the method
Compound, moisture determination water content is 7% or so, and simultaneous reactions yield is also higher, yield 90-95%.
Organic solvent of the present invention uses small polar solvent, if using the larger solvent of polarity, such as methyl alcohol or ethyl acetate, producing
Raw similar dissolution reagent, dissolves sodium azulenesulfonate, and sodium azulenesulfonate monohydrate yield decrement is more.
Small polar organic solvent is preferably petroleum ether or dichloromethane.Further preferably, it is petroleum ether.Petroleum ether pollutes
It is smaller, and can reclaim, for amplifying, producing significant.
Preferred scheme, water is 1 with small polar organic solvent volume ratio:0.8-1.8.Further preferably, institute's volume ratio is 1:
0.8-1.5。
Preferred scheme, the mixed solvent is water and petroleum ether, and the volume ratio is 1:1.
Preferred scheme, the crystallization obtains sodium azulenesulfonate monohydrate, is separated by suction filtration, and by crystal ion.
Gained crystal is vacuum dried, at 35 DEG C, by product vacuum drying after washing to constant weight.
Preferred scheme, by sodium azulenesulfonate, the heating recrystallization that adds water is obtained the sodium azulenesulfonate semihydrate.The Azulene sulfonic acid
Sodium recrystallization specific steps include：Sodium azulenesulfonate is dissolved in the water, 80-90 DEG C is heated to；Reactant aqueous solution system, is cooled to
0~25 DEG C, separate out crystal；Crystal suction filtration, washing will be separated out, dried.The sodium azulenesulfonate can be by guaiazulene through the concentrated sulfuric acid
With in alkali and being obtained after sulfonating reaction.
It is preferred that sodium azulenesulfonate semihydrate prepares scheme：With sodium azulenesulfonate crude product obtained in water dissolves, 85 DEG C of weights are heated to
Crystallization, crystallization of lowering the temperature, after precipitation crystal is washed with water, 35 DEG C are dried under vacuum to constant weight, obtain sodium azulenesulfonate semihydrate, Moisture Meter
Moisture content is determined 3% or so.
Preferably, the quality of water is 9-12 times of sodium azulenesulfonate crude product quality.
Preferably, the processing step of sodium azulenesulfonate monohydrate is：
A) semihydrate transfer process：Sodium gualenate aqueous solution reacts more than 2 hours for (85 DEG C) at the heating temperature, conversion
For
More high level obtains the sodium azulenesulfonate semihydrate aqueous solution；
B) the cooling down stage：By the sodium azulenesulfonate semihydrate aqueous solution, 2 hours crystallizations of cooling down in ice-water bath；
C) separation phase：By sodium azulenesulfonate semihydrate Buchner funnel suction filtration, crystal will be separated out and separated；
D) water rinses：The crystal at separated place is washed；
E) drying stage：At 35 DEG C, by product vacuum drying after washing to constant weight, sodium azulenesulfonate semihydrate is obtained,
Card
Er Feixiu Moisture Meters measurement result is 3% or so；
F) monohydrate transfer process：By sodium azulenesulfonate semihydrate, the water and petroleum ether of equal proportion are added, fully stirred
Mix；
G) separation process：By sodium azulenesulfonate monohydrate Buchner funnel suction filtration, crystal will be separated out and separated；
H) water rinses：The crystal at separated place is washed；
I) drying stage：At 35 DEG C, by product vacuum drying after washing to constant weight, plate water sodium azulenesulfonate, karr are obtained
Expense is stopped
Moisture Meter measurement result is 7% or so.
Beneficial effect
The advantage of the invention is that：
(1) the present invention program can obtain single sodium azulenesulfonate monohydrate；
(2) during synthesis, reagent used is water and petroleum ether to preferred scheme of the present invention, and waste liquid is mainly Azulene
The aqueous solution of sodium sulfonate, petroleum ether is also possible to subsequent recovery and uses, and reduces the pollution to environment；
(3) this technology can be with facilitating succinct one-step method that sodium azulenesulfonate monohydrate is quickly obtained；
Brief description of the drawings
Fig. 1 is the sodium azulenesulfonate semihydrate karl Fischer moisture teller testing result of embodiment 1；
Fig. 2 is the sodium azulenesulfonate semihydrate thermogravimetric analysis TG testing results of embodiment 1；
Fig. 3 is the sodium azulenesulfonate monohydrate karl Fischer moisture teller testing result of embodiment 1；
Fig. 4 is the sodium azulenesulfonate monohydrate thermogravimetric analysis TG testing results of embodiment 1.
Specific embodiment
Below by specific embodiment, further illustrate how the present invention realizes.
Embodiment 1
Shown in the synthetic method following equation of sodium azulenesulfonate monohydrate：
20g sodium azulenesulfonates are added in the there-necked flask of 500ml, adds 200ml water to be sufficiently stirred for 30 minutes, by interior temperature rise
Flowed back 2 hours to 85 DEG C, be placed in system in ice bath after 2 hours continue to stir 2 hours by backflow, stirring and crystallizing.
Crystal Buchner funnel suction filtration will be separated out to go out, with 150ml water washings 2 times, continue suction filtration, filter cake is positive empty at 35 DEG C
Dry to constant weight, obtain sodium azulenesulfonate semihydrate 14g.To dry to constant weight, moisture content will be detected with karl Fischer moisture teller
It is 3.06%, as a result as shown in figure 1, its TG testing result is as shown in Figure 2.
14g sodium azulenesulfonate semihydrates are added in the there-necked flask of 500mL, the mixed of 70mL water and 70mL petroleum ethers is added
Solution is closed, is sufficiently stirred for 1 hour, by not molten crystal suction filtration, with 100mL water washings 2 times, continue suction filtration, filter cake is at 35 DEG C
It is positive empty dry to constant weight, obtain sodium azulenesulfonate monohydrate 13g, yield 95%.
Above-mentioned steps products obtained therefrom is dried under being vacuum dried at 35 DEG C, while the change of its moisture is monitored, as shown in table 2：
2 sodium azulenesulfonate monohydrate product of table, 35 DEG C of vacuum drying moisture delta datas
Above table data display, after the sodium azulenesulfonate monohydrate for preparing is vacuum dried 4 hours at 35 DEG C, in water
Part 6.8% or so is invariable, as a result as shown in figure 3, TG testing results water content is 7.41% or so, as shown in Figure 4.Very
Empty drying can only remove free water, and the crystallization water is retained.Above-mentioned prepared product contains 7.2% or so the crystallization water.Azulene
The theoretical water content of sodium sulfonate semihydrate is 2.91%, and the theoretical water content of sodium azulenesulfonate monohydrate is 5.66%, if producing
Sodium azulenesulfonate monohydrate and sodium azulenesulfonate semihydrate are mixed with product, water content can be less than 5.66%.Due to sodium azulenesulfonate
Stability is not very high, and long-time drying can degrade, thus the allowed band of the water of Japanese description one be 6%~8% between.Through
Cross and compare, above method products obtained therefrom is the sodium azulenesulfonate monohydrate for meeting the drug standards.
Embodiment 2
Sodium azulenesulfonate semihydrate preparation method is with embodiment 1.
The sodium azulenesulfonate semihydrate 10g obtained after recrystallization, it is 1 to be added to volume ratio：1 water/dichloromethane mixing
Solvent, is sufficiently stirred for, and the volume of water used is about 5 times of sodium azulenesulfonate semihydrate quality, after treat crystal color by black-and-blue
After conversion au bleu, suction filtration, washing is dried, and obtains sodium azulenesulfonate monohydrate 11.3g, yield 91%.
To dry to constant weight, moisture content result, water content 7.21% will be detected with karl Fischer moisture teller.
Embodiment 3
Sodium azulenesulfonate semihydrate preparation method is with embodiment 1.
The sodium azulenesulfonate semihydrate 10g obtained after recrystallization, it is 1 to be added to volume ratio：1 water/ethyl acetate mixing
Solvent, is sufficiently stirred for, and the volume of water used is about 5 times of sodium azulenesulfonate semihydrate quality, after treat crystal color by black-and-blue
After conversion au bleu, suction filtration, washing is dried, and obtains sodium azulenesulfonate monohydrate 5.2g, yield 51%.
To dry to constant weight, moisture content result, water content 7.33% will be detected with karl Fischer moisture teller.
Embodiment 4
Sodium azulenesulfonate semihydrate preparation method is with embodiment 1.
The sodium azulenesulfonate semihydrate 10g obtained after recrystallization, it is 1 to be added to volume ratio：1 water/methanol mixed solvent,
Be sufficiently stirred for, the volume of water used is about 5 times of sodium azulenesulfonate semihydrate quality, after treat that crystal color is converted into by black-and-blue
After blueness, suction filtration, washing is dried, and obtains sodium azulenesulfonate monohydrate 0.9g, yield 9%.
Comparative example 1,2,3,4, and petroleum ether, dichloromethane are the pole of the less solvent of polarity, methyl alcohol and ethyl acetate
Property is slightly larger, and polarity is big, and sodium azulenesulfonate can be dissolved in mixed solvent.After being stirred with methyl alcohol and ethyl acetate, similar rush is produced
Molten reagent, dissolves sodium azulenesulfonate, and sodium azulenesulfonate monohydrate yield decrement is more；Due to dichloromethane environmental pollution
It is bigger than petroleum ether, therefore preferably petroleum ether is used as moisture transferring reagent.
Embodiment 5
Re-crystallization step：Sodium azulenesulfonate semihydrate preparation method is with embodiment 1.The sodium azulenesulfonate obtained after recrystallization half
Hydrate, is added to the different water of volume ratio/petroleum ether mixed solvent, is sufficiently stirred for, and the quality of water used is about sodium azulenesulfonate
5 times of semihydrate quality, after after crystal color by it is black-and-blue conversion au bleu after, suction filtration, washing, dry, obtain Azulene sulfonic acid
Sodium-hydrate.
Determination of moisture step：To dry to constant weight, moisture content result will be detected with karl Fischer moisture teller.Different volumes ratio
Water-petroleum ether mixed solvent, obtained product moisture content, yield situation see the table below 3：
Table 3：Water-petroleum ether different volumes are than product situation obtained in mixed solvent
| Numbering | Solvent group | Volume ratio | Karl Fischer moisture teller testing result | Yield |
| 1 (embodiment 1) | Water-petroleum ether | 1:1 | 6.78% | 95% |
| 2 | Water-petroleum ether | 1:1.5 | 7.14% | 91% |
| 3 | Water-petroleum ether | 1:2 | 5.33% | 94% |
| 4 | Water-petroleum ether | 1:3 | 4.95% | 94% |
| 5 | Water-petroleum ether | 1:0.8 | 7.08% | 94% |
| 6 | Water-petroleum ether | 2:1 | 3.21% | 89% |
| 7 | Water-petroleum ether | 3:1 | 3.32% | 85% |
From contrast test, in the case where water is different with petroleum ether ratio, sodium azulenesulfonate semihydrate can be caused to turn
Change to that sodium azulenesulfonate monohydrate is insufficient, so as to produce the situation of half water and sodium azulenesulfonate monohydrate mixture.Water and stone
The volume range of oily ether is 1:0.8-1.8 or so is more suitable.
Claims (10)
1. a kind of preparation method of sodium azulenesulfonate monohydrate, it is characterised in that sodium azulenesulfonate semihydrate adds water and small pole
In the mixed solution of property organic solvent, it is sufficiently stirred for, crystallization obtains sodium azulenesulfonate monohydrate.
2. preparation method according to claim 1, it is characterised in that the small polar organic solvent is petroleum ether or two
Chloromethanes.
3. preparation method according to claim 2, it is characterised in that the small polar organic solvent is petroleum ether.
4. preparation method according to claim 1, it is characterised in that the water is 1 with small polar organic solvent volume ratio:
0.8-1.8。
5. preparation method according to claim 4, it is characterised in that the water is 1 with small polar organic solvent volume ratio:
0.8-1.5。
6. preparation method according to claim 5, it is characterised in that the water is 1 with small polar organic solvent volume ratio:
1。
7. preparation method according to claim 1, it is characterised in that the crystallization obtains sodium azulenesulfonate monohydrate, warp
Suction filtration separation is crossed, and by crystal ion.
8. preparation method according to claim 7, it is characterised in that methods described also includes drying steps, at 35 DEG C,
By product vacuum drying after washing to constant weight.
9. the preparation method according to claim any one of 1-6, it is characterised in that the sodium azulenesulfonate semihydrate is by Azulene
Sodium sulfonate, the heating recrystallization that adds water is obtained.
10. preparation method according to claim 9, it is characterised in that the sodium azulenesulfonate recrystallization specific steps include：
Sodium azulenesulfonate is dissolved in the water, 80-90 DEG C is heated to；Reactant aqueous solution system, is cooled to 0~25 DEG C, separates out crystal；
Crystal suction filtration, washing will be separated out, dried.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113582884A (en) * | 2021-07-13 | 2021-11-02 | 成都大学 | Preparation method of sodium azulene sulfonate monohydrate with high stability |
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| CN1803768A (en) * | 2005-01-10 | 2006-07-19 | 天津市顶硕科贸有限公司 | Process for synthesizing stable sodium azulene sulfonate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1803768A (en) * | 2005-01-10 | 2006-07-19 | 天津市顶硕科贸有限公司 | Process for synthesizing stable sodium azulene sulfonate |
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| CN113582884A (en) * | 2021-07-13 | 2021-11-02 | 成都大学 | Preparation method of sodium azulene sulfonate monohydrate with high stability |
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