CN105061360B - A kind of 3,4- diaminostilbenes, the method for purification of 2,5- thiadiazoles - Google Patents
A kind of 3,4- diaminostilbenes, the method for purification of 2,5- thiadiazoles Download PDFInfo
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- CN105061360B CN105061360B CN201510452525.3A CN201510452525A CN105061360B CN 105061360 B CN105061360 B CN 105061360B CN 201510452525 A CN201510452525 A CN 201510452525A CN 105061360 B CN105061360 B CN 105061360B
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- thiadiazoles
- diaminostilbenes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
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Abstract
A kind of method of purification of 1,2,5 thiadiazoles of 3,4 diamino belongs to the purification technique field of 3,4 diamino, 1,2,5 thiadiazoles.Hydrochloric acid is added in 1,2,5 thiadiazoles crude product of light yellow 3,4 diamino, is filtered, sodium hydrate solid is added in into filtrate makes solution alkaline, stands a period of time, filtering, water washing, 3 purified, 4 diamino, 1,2,5 thiadiazoles product.It is easy to operate, product purity is high, basically reach 100%, only need to adjust pH value change solubility can obtain high-purity product.
Description
Technical field
The present invention relates to one kind 3,4- diaminostilbenes, the method for purification of 2,5- thiadiazoles belongs to 3,4- diaminostilbenes, and 2,5-
The purification technique field of thiadiazoles.
Background technology
Protein phosphorylation plays a decisive role for cell function, and the most important effect of protein phosphorylation is that signal passes
It leads, extracellular signal is amplified and is propagated by protein phosphorylation and dephosphorylation.Signal transduction is for tumour cell egg
The proliferation of white matter and transfer also play a leading role, and the multiple proteins kinases of decision is played during protein phosphorylation, according to
The structure of these enzymes, using enzyme as drug target, can be adjusted the amount of these enzymes in human body with design medicine.
It has been found that the drug with following miscellaneous multiring structure can play regulatory role protein kinase.
3,4- diaminostilbenes, 2,5- thiadiazoles are used for preparing the substance of above-mentioned miscellaneous multiring structure, can prepare containing pyrazine simultaneously
The drug of thiadiazoles structure.In addition to this, 3,4- diaminostilbenes, 2,5- thiadiazoles are also used to prepare containing adjacent diaminopyrazine
The intermediate of structure, this intermediate can prepare the drug for the treatment of AIDS virus, and such drug can be by swashing Src families
The targeting of enzyme prevents it from being acted on Nef protein, so as to prevent the proliferation of HIV-1 types virus.
3,4- diaminostilbenes, 2,5- thiadiazoles are especially when preparing drug or otherwise in application, its purity right and wrong
Chang Guanjian's and important.
At present, 3,4- diaminostilbenes, the purification of 2,5- thiadiazoles is a problem, and existing method of purification has repeated recrystallize
Method, the method extracted with ethanol water mixture, general purity is difficult more than 90%, hardly results in the very high product of purity, and
It operates more complicated.
Invention content
The purpose of the present invention is to provide a kind of purification 3,4- diaminostilbenes, the short-cut methods of 2,5- thiadiazoles.
The present invention realizes that purpose method includes the following steps：
Hydrochloric acid is added in light yellow 3,4- diaminostilbenes, 2,5- thiadiazoles crude products, filters, hydrogen-oxygen is added in into filtrate
Changing sodium solid makes solution alkaline, stands a period of time, filtering, water washing, 3, the 4- diaminostilbenes purified, 2,5- thiophenes two
Azoles product.
It is preferred that concentration of hydrochloric acid used, between 0.5mol/L~2.0mol/L, use hydrochloric acid volume as few as possible dissolves 3,4-
Diaminostilbene, 2,5- thiadiazoles crude products.
Further preferred 3,4- diaminostilbenes, 2,5- thiadiazoles crude product and the dosage relation of above-mentioned hydrochloric acid are 3,4- diaminos
Base -1,2,5- thiadiazoles crude product quality g：Volume ml >=0.1 of hydrochloric acid.
Adding in sodium hydrate solid makes pH value of solution be maintained between 8-14.
Wherein 3,4- diaminostilbenes, the preparation method of 2,5- thiadiazoles crude products are as follows：By potassium phthalimide
With 3,4- bis- chloro- 1,2,5- thiadiazoles are added in super dry DMF, are stirred 5 hours at 65 DEG C, cooling, add in water, rapid to filter,
It is dry, obtain faint yellow solid 3,4- bis- (N- phthaloyl iminos) -1,2,5- thiadiazoles；By (the N- O-phthalics of 3,4- bis-
Acylimino) -1,2,5- thiadiazoles acetone recrystallizations, obtain white solid；White solid is added in DMF, in ice bath
Under be passed through ammonia, then stir 1 hour at normal temperatures, DMF is evaporated by rotating pressure-decreasing, obtains light yellow 3,4- diaminostilbenes, 2,
5- thiadiazoles crude products.
The advantages of the present invention are：
1st, crude product, which successively adds in acid, makes product more dissolve, and filters, adding alkali is precipitated high-purity product, finally
Filtration drying.The method of purification for adjusting pH change solubility of the present invention is compared with existing method of purification, easy to operate, product
Purity is high, basically reaches 100%, while ensure yield.
2nd, the purification time is short, need to only adjust pH value change solubility and can obtain high-purity product.
Description of the drawings
Fig. 1 is the 3,4- diaminostilbenes of 1 gained refined product of embodiment, the carbon-13 nmr spectra figure of 2,5- thiadiazoles.
Fig. 2 is the 3,4- diaminostilbenes of 2 gained refined product of embodiment, the carbon-13 nmr spectra figure of 2,5- thiadiazoles.
Fig. 3 is the 3,4- diaminostilbenes of 3 gained refined product of embodiment, the carbon-13 nmr spectra figure of 2,5- thiadiazoles.
Fig. 4 is the 3,4- diaminostilbenes of 4 gained refined product of embodiment, the carbon-13 nmr spectra figure of 2,5- thiadiazoles.
Specific embodiment
With reference to embodiment, the present invention will be further described, but the present invention is not limited to following embodiments.
Its purity is levied below by way of carbon stave, especially in the crude product preparation method, in-between product or impurity
It is raw material or intermediate carbon containing by-product or inorganic potassium salt, due to being that in aqueous solution, inorganic potassium salt is easy to be dissolved in water, very
It easily washes off, so the impurity in final products is carbon containing substance.
Embodiment 1
First according to literature method, crude product 3 is made, 4- diaminostilbenes, 2,5- thiadiazoles, step is as follows, by 1.0g3,
4- bis- chloro- 1,2,5- thiadiazoles, 3.3g potassium phthalimides are added in the super dry DMF of 45ml, and 5 are stirred under 65 DEG C of room temperature
Hour, cooling adds in 65ml water, filters, be washed with water at once, dries, obtain faint yellow solid, then with acetone recrystallization,
Filtering obtains -1,2, the 5- thiadiazoles 1.6452g of 3,4- bis- (N- phthaloyl iminos) of white.By (the N- neighbour's benzene of 3,4- bis-
Phthalimido group) -1,2,5- thiadiazoles are added in the super dry DMF of 16ml, ammonia are passed through under ice bath 10 minutes, then normal
Solution, with Rotary Evaporators is evaporated, obtains crude product 3,4- diaminostilbenes, 2,5- thiadiazoles 1.7736g by temperature stirring 1 hour.
To 1.7736g crude products 3,4- diaminostilbenes add in the hydrochloric acid solution of 15ml1.0mol/L in 2,5- thiadiazoles, fill
Point stirring, filtering adds in NaOH solids in filtrate, until detecting that pH value of solution is 8-14 with pH test paper, stands a period of time,
Filtering, obtains yellow crystals 0.1224g, yield 24.11%, mp=181.5~182.5 DEG C；13CNMR[(CD3)2SO]:δ=
149.463。
Fig. 1 is 3,4- diaminostilbenes in this embodiment, the carbon-13 nmr spectra figure of 2,5- thiadiazoles.According to reaction used
Object has sylvite and carbonaceous organic material in the by-product that entire reaction process is likely to be obtained, because of sylvite good water solubility, in the first step
Reaction prepares 3,4- bis- (N- phthaloyl iminos) -1, and when 2,5- thiadiazoles has been washed with water repeatedly, and sylvite will necessarily be by
Wash off, and if have carbonaceous organic material, must have embodiment in nuclear-magnetism figure, it is general by observing nuclear-magnetism figure, except 39.518~40.352
DMSO solvent peaks outside, only 149.463 1 peaks, this is 3,4- diaminostilbenes, the characteristic peak of 2,5- thiadiazoles, in addition to this
Completely without the characteristic peak of other organic matters, it can thus be appreciated that product purity is high, basic 100%.
Embodiment 2
First according to literature method, crude product 3 is made, 4- diaminostilbenes, 2,5- thiadiazoles, step is as follows, by 1.5g3,
4- bis- chloro- 1,2,5- thiadiazoles, 4.6g potassium phthalimides are added in the super dry DMF of 70ml, and 5 are stirred under 65 DEG C of room temperature
Hour, cooling adds in 100ml water, filters, be washed with water at once, dries, obtain faint yellow solid, then with acetone recrystallization,
Filtering obtains -1,2, the 5- thiadiazoles 2.5871g of 3,4- bis- (N- phthaloyl iminos) of white.By (the N- neighbour's benzene of 3,4- bis-
Phthalimido group) -1,2,5- thiadiazoles are added in the super dry DMF of 25ml, ammonia are passed through under ice bath 10 minutes, then normal
Solution, with Rotary Evaporators is evaporated, obtains crude product 3,4- diaminostilbenes, 2,5- thiadiazoles 2.8072g by temperature stirring 1 hour.
To 2.8072g crude products 3,4- diaminostilbenes add in the hydrochloric acid solution of 20ml1.5mol/L in 2,5- thiadiazoles, fill
Point stirring, filtering adds in NaOH solids in filtrate, until detecting that pH value of solution is 8-14 with pH test paper, stands a period of time,
Filtering, obtains yellow crystals 0.1845g, yield 23.12%, mp=181.5~182.5 DEG C；13CNMR[(CD3)2SO]:δ=
149.460。
Fig. 2 is 3,4- diaminostilbenes in this embodiment, and the carbon-13 nmr spectra figure of 2,5- thiadiazoles, product is pure as seen from the figure
Spend it is high, essentially 100%, make a concrete analysis of same embodiment 1.
Embodiment 3
First according to literature method, crude product 3 is made, 4- diaminostilbenes, 2,5- thiadiazoles, step is as follows, by 1.0g3,
4- bis- chloro- 1,2,5- thiadiazoles, 4.6g potassium phthalimides are added in the super dry DMF of 70ml, and 5 are stirred under 65 DEG C of room temperature
Hour, cooling adds in 100ml water, filters, be washed with water at once, dries, obtain faint yellow solid, then with acetone recrystallization,
Filtering obtains -1,2, the 5- thiadiazoles 1.6750g of 3,4- bis- (N- phthaloyl iminos) of white.By (the N- neighbour's benzene of 3,4- bis-
Phthalimido group) -1,2,5- thiadiazoles are added in the super dry DMF of 25ml, ammonia are passed through under ice bath 10 minutes, then normal
Solution, with Rotary Evaporators is evaporated, obtains crude product 3,4- diaminostilbenes, 2,5- thiadiazoles 1.7801g by temperature stirring 1 hour.
To 1.7801g crude products 3,4- diaminostilbenes add in the hydrochloric acid solution of 13ml0.5mol/L in 2,5- thiadiazoles, fill
Point stirring, filtering adds in NaOH solids in filtrate, until detecting that pH value of solution is 8-14 with pH test paper, stands a period of time,
Filtering, obtains yellow crystals 0.1088g, yield 21.41%, mp=181.5~182.5 DEG C；13CNMR[(CD3)2SO]:δ=
149.470。
Fig. 3 is 3,4- diaminostilbenes in this embodiment, and the carbon-13 nmr spectra figure of 2,5- thiadiazoles, product is pure as seen from the figure
Spend it is high, essentially 100%, make a concrete analysis of same embodiment 1.
Embodiment 4
First according to literature method, crude product 3 is made, 4- diaminostilbenes, 2,5- thiadiazoles, step is as follows, by 1.0g3,
4- bis- chloro- 1,2,5- thiadiazoles, 4.6g potassium phthalimides are added in the super dry DMF of 70ml, and 5 are stirred under 65 DEG C of room temperature
Hour, cooling adds in 100ml water, filters, be washed with water at once, dries, obtain faint yellow solid, then with acetone recrystallization,
Filtering obtains -1,2, the 5- thiadiazoles 1.6222g of 3,4- bis- (N- phthaloyl iminos) of white.By (the N- neighbour's benzene of 3,4- bis-
Phthalimido group) -1,2,5- thiadiazoles are added in the super dry DMF of 25ml, ammonia are passed through under ice bath 10 minutes, then normal
Solution, with Rotary Evaporators is evaporated, obtains crude product 3,4- diaminostilbenes, 2,5- thiadiazoles 1.7274g by temperature stirring 1 hour.
To 1.7274g crude products 3,4- diaminostilbenes add in the hydrochloric acid solution of 10ml2.0mol/L in 2,5- thiadiazoles, fill
Point stirring, filtering adds in NaOH solids in filtrate, until detecting that pH value of solution is 8-14 with pH test paper, stands a period of time,
Filtering, obtains yellow crystals 0.0896g, yield 17.75%, mp=181.5~182.5 DEG C；13CNMR[(CD3)2SO]:δ=
149.475。
Fig. 4 is 3,4- diaminostilbenes in this embodiment, and the carbon-13 nmr spectra figure of 2,5- thiadiazoles, product is pure as seen from the figure
Spend it is high, essentially 100%, make a concrete analysis of same embodiment 1.
Claims (4)
1. one kind 3,4- diaminostilbenes, the method for purification of 2,5- thiadiazoles, which is characterized in that include the following steps：Light yellow
3,4- diaminostilbenes add in hydrochloric acid in 2,5- thiadiazoles crude products, filter, and sodium hydrate solid is added in into filtrate makes the solution be in
Alkalinity stands a period of time, filtering, water washing, 3, the 4- diaminostilbenes purified, 2,5- thiadiazoles products.
2. according to one kind 3,4- diaminostilbenes of claim 1, the method for purification of 2,5- thiadiazoles, which is characterized in that salt used
Acid concentration is between 0.5mol/L~2.0mol/L, use hydrochloric acid volume dissolving 3,4- diaminostilbenes as few as possible, 2,5- thiophenes two
Azoles crude product.
3. according to one kind 3,4- diaminostilbenes of claim 2, the method for purification of 2,5- thiadiazoles, which is characterized in that 3,4- bis-
The dosage relation of amino -1,2,5- thiadiazoles crude product and above-mentioned hydrochloric acid is 3,4- diaminostilbenes, 2,5- thiadiazoles crude product matter
Measure g：Volume ml >=0.1 of hydrochloric acid.
4. according to one kind 3,4- diaminostilbenes of claim 1, the method for purification of 2,5- thiadiazoles, which is characterized in that add in hydrogen
Sodium oxide molybdena solid makes pH value of solution be maintained between 8-14.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4374248A (en) * | 1979-09-04 | 1983-02-15 | Bristol-Myers Company | 3,4-Disubstituted-1,2,5-thiadiazole-1-oxide compounds |
| US20020035251A1 (en) * | 2000-07-06 | 2002-03-21 | Zaihui Zhang | Heteropolycyclic inhibitors of protein kinases |
| CN101229235A (en) * | 2008-01-11 | 2008-07-30 | 南京弘景医药科技有限公司 | Process for preparing corydalis saxicola bunting total alkali |
| CN102285982A (en) * | 2011-08-30 | 2011-12-21 | 聊城大学 | Method for separating and purifying monomer compounds from Chinese medicinal herb golden thread |
-
2015
- 2015-07-28 CN CN201510452525.3A patent/CN105061360B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4374248A (en) * | 1979-09-04 | 1983-02-15 | Bristol-Myers Company | 3,4-Disubstituted-1,2,5-thiadiazole-1-oxide compounds |
| US20020035251A1 (en) * | 2000-07-06 | 2002-03-21 | Zaihui Zhang | Heteropolycyclic inhibitors of protein kinases |
| CN101229235A (en) * | 2008-01-11 | 2008-07-30 | 南京弘景医药科技有限公司 | Process for preparing corydalis saxicola bunting total alkali |
| CN102285982A (en) * | 2011-08-30 | 2011-12-21 | 聊城大学 | Method for separating and purifying monomer compounds from Chinese medicinal herb golden thread |
Non-Patent Citations (1)
| Title |
|---|
| 育亨宾生物总碱的分离与纯化;王锦雨等;《北京农业》;20110930;第7-10页 * |
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