CN107721938A - A kind of method that dry stir-fry method prepares the dihydroxy-pyrimidine of 4 amino 2,6 - Google Patents
A kind of method that dry stir-fry method prepares the dihydroxy-pyrimidine of 4 amino 2,6 Download PDFInfo
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- CN107721938A CN107721938A CN201711110372.XA CN201711110372A CN107721938A CN 107721938 A CN107721938 A CN 107721938A CN 201711110372 A CN201711110372 A CN 201711110372A CN 107721938 A CN107721938 A CN 107721938A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to a kind of method that dry stir-fry method prepares the dihydroxy-pyrimidine of 4 amino 2,6.The invention provides a kind of method that dry stir-fry method prepares the dihydroxy-pyrimidine of 4 amino 2,6, concretely comprise the following steps：Reacted under certain condition as raw material using sodium methoxide dry powder, urea, methyl cyanoacetate, the methanol for steaming generation is heated under certain temperature, ultimately generates the dihydroxy-pyrimidine of 4 amino 2,6.The yield of 4 aminopyrimidines made from ring-closure reaction of the present invention is up to 80 ~ 85%, the purity more than 99% of product.Compared with liquid phase cyclization method, the reaction yield of the present invention can improve more than 15%, reaction time more than hour is down to 2 ~ 3 hours from former 8 and completed, and water methanol is not produced, greatly reduce the pollution of organic wastewater, and the preparation cost and energy consumption of the dihydroxy-pyrimidine of 4 amino 2,6 are substantially reduced, it is expected to be applied in industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry to synthesize field, and in particular to it is phonetic that a kind of dry stir-fry method prepares 4- amino -2,6- dihydroxy
The method of pyridine.
Background technology
4- amino -2,6- dihydroxy-pyrimidines, also referred to as 4- semicarbazides pyrimidine.It is the intermediate of synthetic caffeine, Ye Shihe
Into the precursor of 4- amino -2,6- dimethoxypyridins.4- amino -2,6- dimethoxypyridins are to be used to synthesize 2,6- dimethoxies
Base -4- (P-aminobenzene-sulfonamide pyrimidine) (SDM), the drug toxicity is very low, special to the infection in terms of the upper respiratory tract and urethra
Effectively.
According to US2804459,《Medical industry》The synthesis report of (1960,15 (2)), intermediate 4- semicarbazides pyrimidines
General synthetic method is：
1st, cyanogen acetylurea method：
2nd, methyl cyanoacetate method：
Cyanogen acetylurea raw material is more expensive in cyanogen acetylurea method, and in alkaline cyclization with cyan-hydrolysis, relative cost is higher,
Purity is poor.And methyl cyanoacetate method is widely used because methyl cyanoacetate abundance is cheap.
In above-mentioned document, the method for 4- semicarbazides pyrimidines is：First methanol solution of sodium methylate is added in reactor, added
Urea, methyl cyanoacetate is added dropwise under agitation, is then heated to reflux.Or so half an hour is heated to reflux at 70~80 DEG C, with 4-
The generation of semicarbazides pyrimidine sodium, material is gradually thickening, and stirring can kill, and reaction can only be under static state in 70~80 DEG C of backflows
5h, recycling absolute methanol and has water methanol.The technique in production, due to killing too early for stirring, causes ring-closure reaction not
Thoroughly, reaction yield is relatively low, and actual yield only has 65~70%.In preparation, due to killing too early for stirring, make substantial amounts of
Absolute methanol can not reclaim out, can only add water, and recovery has water methanol, virtually adds consumption and the energy consumption of material.
Therefore, it is necessary to the preparation method of 4- semicarbazides pyrimidines is further studied, to improve answering for 4- semicarbazides pyrimidines
With value.
The content of the invention
It is an object of the invention to overcome defect present in prior art, there is provided a kind of dry stir-fry method prepares 4- aminopyrimidines
Method.
Specifically, in embodiments of the invention, comprise the following steps：
A certain amount of sodium methoxide dry powder, urea are added in reaction bulb, stirring, are well mixed above-mentioned material；Cooling down
Under water cooling, control in temperature be certain value under a certain amount of methyl cyanoacetate is added dropwise, be added dropwise, under certain temperature stir one section
Time, heating steam the methanol of generation, reaction product is in powdered, rise to and a period of time is incubated under certain temperature；Upper
State and water is added in reaction product, heated under certain temperature, dissolve reaction product, obtain mixed liquor, with certain density hydrochloric acid
The pH of mixed liquor is adjusted to after certain value, is filtered while hot, obtained solid is washed with water, and drying, obtains off-white powder, is
4- aminopyrimidines.
In above-mentioned steps, sodium methoxide dry powder, the mass ratio of methyl cyanoacetate are 50~68：50, optimum quality ratio 55：
50；Urea, the mass ratio of methyl cyanoacetate are 37：50；Temperature is 30~75 DEG C in controlling, and optimum temperature is 50 DEG C；The temperature of stirring
Spend for 50 DEG C, mixing time is 5~10min；100~105 DEG C are warming up to, soaking time is 1~1.5h；The temperature of heating is 80
~85 DEG C；The mass fraction of hydrochloric acid is 30%, and the pH of mixed liquor is 7 after regulation.
Compared with prior art, advantage of the invention is that：
The present invention is to replace methanol solution of sodium methylate with dry powder sodium methoxide, first by dry powder sodium methoxide and urea under solid phase
It is sufficiently mixed, under agitation, methyl cyanoacetate is added dropwise, and rapid steaming sends the methanol of reaction generation, reaction mass is located all the time
In powder solid state shape, 1~1.5 hour is incubated then at 100~105 DEG C of dry fry, reaction is completed.Preparation method letter of the present invention
Single, ring-closure reaction is thorough, substantially reduces the reaction time, and makes the yields of ring-closure reaction 4- aminopyrimidines up to 80~85%,
The purity more than 99% of product.Compared with liquid phase cyclization method, reaction yield can improve more than 15%, and reaction time is 8 small from original
When more than be down to 2~3 hours and complete, and do not produced water methanol, greatly reduced the pollution of organic wastewater, and substantially reduce 4-
The preparation cost and energy consumption of semicarbazides pyrimidine.
Brief description of the drawings
Fig. 1 is the chromatogram of 4- aminopyrimidines prepared by the embodiment of the present invention 1；
Fig. 2 is the chromatogram of 4- aminopyrimidines prepared by the embodiment of the present invention 2；
Fig. 3 is the chromatogram of 4- aminopyrimidines prepared by the embodiment of the present invention 3.
Embodiment
With reference to specific embodiment, the present invention will be further described.
Embodiment 1：
55g dry powder sodium methoxide, 37g urea are put into 500ml reaction bulb, stirring is sufficiently mixed above-mentioned material,
Cool down under water cooling, 50 DEG C or so dropwise addition 50g methyl cyanoacetates of temperature in control, after adding, 50 DEG C of stirring insulation 5min, heating is steamed
Go out the methanol of reaction generation, material is in powdered, be then incubated 1h in 100 DEG C, insulation terminates.Adding 400ml water makes admittedly
Body all dissolves, and is heated to 80 DEG C, is that 30% hydrochloric acid is neutralized to pH value 7 or so with mass fraction, filters while hot, filter out solid simultaneously
It is washed with water, drains, dries, obtain off-white powder 55g, as 4- semicarbazides pyrimidine, yield 85.7%, HPLC purity is
99.38% (see Fig. 1).
Embodiment 2：
50g dry powder sodium methoxide, 37g urea are put into 500ml reaction bulb, stirring is sufficiently mixed above-mentioned material,
Cool down under water cooling, 30 DEG C or so dropwise addition 50g methyl cyanoacetates of temperature in control, after adding, 50 DEG C of stirring insulation 8min, heating is steamed
Go out the methanol of reaction generation, material is in powdered, be then incubated 1.2h in 102 DEG C, insulation terminates.Adding 420ml water makes
Solid all dissolves, and is heated to 82 DEG C, is that 30% hydrochloric acid is neutralized to pH value 7 or so with mass concentration, filters while hot, filter out solid
And be washed with water, drain, dry, obtain off-white powder 50g, as 4- semicarbazides pyrimidine, yield 78%, HPLC purity is
99.23% (see Fig. 2).
Embodiment 3：
68g dry powder sodium methoxide, 37g urea are put into 500ml reaction bulb, stirring is sufficiently mixed above-mentioned material,
Cool down under water cooling, 50 DEG C or so dropwise addition 50g methyl cyanoacetates of temperature in control, 50 DEG C are stirred insulation 10min after adding, and heating is steamed
Go out the methanol of reaction generation, material is in powdered, be then incubated 1.5h in 105 DEG C, insulation terminates.Adding 450ml water makes
Solid all dissolves, and is heated to 85 DEG C, is that 30% hydrochloric acid is neutralized to pH value 7 or so with mass concentration, filters while hot, filter out solid
And be washed with water, drain, dry, obtain off-white powder 52g, as 4- semicarbazides pyrimidine, yield 81%, HPLC purity is
99.16% (see Fig. 3).
Claims (8)
1. a kind of method that dry stir-fry method prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that comprise the following steps：
A certain amount of sodium methoxide dry powder, urea are added in reaction bulb, stirring, are well mixed above-mentioned material；In cooling water cooling
But under, control in temperature be certain value under a certain amount of methyl cyanoacetate is added dropwise, be added dropwise, under certain temperature stir one section when
Between, heating steams the methanol of generation, reaction product is in powdered, rises to and a period of time is incubated under certain temperature；
Water is added in obtained reaction product, is heated under certain temperature, dissolves reaction product, obtain mixed liquor, with certain
The pH of the hydrochloric acid regulation mixed liquor of concentration is filtered, obtained solid is washed with water, and drying, it is white to obtain class while hot to after certain value
Color powder, as 4- aminopyrimidines.
2. the method that dry stir-fry method according to claim 1 prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that institute
State sodium methoxide dry powder, the mass ratio of methyl cyanoacetate is 50 ~ 68：50；The urea, the mass ratio of methyl cyanoacetate are 37：50.
3. the method that dry stir-fry method according to claim 2 prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that institute
State sodium methoxide dry powder, the mass ratio of methyl cyanoacetate is 55：50.
4. the method that dry stir-fry method according to claim 1 prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that institute
It is 30 ~ 75 DEG C to state temperature in controlling.
5. the method that dry stir-fry method according to claim 1 prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that institute
The temperature for stating stirring is 50 DEG C, and mixing time is 5 ~ 10min.
6. the method that dry stir-fry method according to claim 5 prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that institute
It is 50 DEG C to state temperature in controlling.
7. the method that dry stir-fry method according to claim 1 prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that institute
State and be warming up to 100 ~ 105 DEG C, soaking time is 1 ~ 1.5h；The temperature of the heating is 80 ~ 85 DEG C.
8. the method that dry stir-fry method according to claim 1 prepares 4- amino -2,6- dihydroxy-pyrimidines, it is characterised in that institute
The mass fraction for stating hydrochloric acid is 30%, and the pH of mixed liquor is 7 after regulation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232441A (en) * | 2018-08-30 | 2019-01-18 | 南京工业大学 | A kind of preparation method of 4- amino -2,6- dimethoxypyridin |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646373A (en) * | 2016-02-18 | 2016-06-08 | 滨海新东方医化有限公司 | Preparation method of 4-amino-2,6-dimethoxypyrimidine |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105646373A (en) * | 2016-02-18 | 2016-06-08 | 滨海新东方医化有限公司 | Preparation method of 4-amino-2,6-dimethoxypyrimidine |
Non-Patent Citations (2)
| Title |
|---|
| R. SARIRI等: "Synthesis of Purine Antiviral Agents,Hypoxanthine and 6-Mercaptopurine.", 《RUSSIAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| 杨珍珍等: "2，6-二甲氧基-4-氨基嘧啶及其金属(Cu，Co) 配合物的合成与表征", 《合成化学》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109232441A (en) * | 2018-08-30 | 2019-01-18 | 南京工业大学 | A kind of preparation method of 4- amino -2,6- dimethoxypyridin |
| CN109232441B (en) * | 2018-08-30 | 2021-08-24 | 南京工业大学 | Preparation method of 4-amino-2, 6-dimethoxypyrimidine |
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Application publication date: 20180223 |