CN105294697B - The synthetic method of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine - Google Patents
The synthetic method of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine Download PDFInfo
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- CN105294697B CN105294697B CN201510813319.0A CN201510813319A CN105294697B CN 105294697 B CN105294697 B CN 105294697B CN 201510813319 A CN201510813319 A CN 201510813319A CN 105294697 B CN105294697 B CN 105294697B
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
The invention discloses a kind of 2- amino -5,8- dimethoxy [1,2,4] synthetic method of triazol [1,5-c] pyrimidine (AMTP), it is with 4- amino -2,5- dimethoxypyridin and carbobenzoxy isothiocyanates are base stock, under special catalyst effect, synthesize to obtain through reactions such as nucleophilic addition, azanol substitution, aromatization cyclizations, it has innovatively selected the compound of phenyloxycarbonyl structure for substrate, has been obviously improved reaction rate.The reaction route is short, easy to operate, and reaction condition is mild, and operation is smooth, and the three wastes are easily handled, and whole process time-consuming is less, has great industrial value.
Description
Technical field
The present invention relates to compound synthesis technical fields, in particular to a kind of pesticide and medical important intermediate 2-
The synthetic method of amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine (AMTP).
Background technique
Sulfonamides herbicide be occur after the imidazolinone herbicide found after sulfonylurea and later it is another
The kind of serial high activity, it is by a new class of of U.S. road agricultural sciences (Dow Agroscience) company development
Inhibitor of acetolactate synthetase, primary structure form are triazolopyrimidine sulfonamides, and penoxsuam therein is rice
Main force's kind of field herbicidal.Wherein, 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine (AMTP) is to close
At the important scaffold intermediates of penoxsuam, therefore, the synthetic route for studying AMTP has important significance of scientific research and practical
Value.
Wherein, the structural formula of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine (AMTP) is as follows:
About the preparation method of AMTP, there are mainly two types of at present: (1) with ethoxy acetate, methyl formate, thiocarbamide
Or methyl isothiourea and bromine cyanogen are raw material method (CN103232453)；(2) with 4- amino -2,5- dimethoxypyridin and different sulphur cyanogen
Acid esters is raw material method (US814339B2, CN103025735A, CN103739606A).
Wherein, (1) used raw material is compared with based on for route, but processing step is longer, and product yield is relatively low, and (total recovery is lower than
40%), and the use of severe toxicity dangerous material bromine cyanogen involved in process, higher cost, buying are not easy, and are also easy to produce a large amount of high dirty
Contaminate waste water.Route is (2) few due to the three wastes, and it is the process route paid close attention at present that reaction yield is higher (total recovery about 70%),
But partially long there is also the reaction time, the polar impurity being mingled in product is not easy the defects of removing, and influences product quality, it is therefore desirable to
It advanced optimizes.
Summary of the invention
The purpose of the present invention is intended to provide a kind of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine
Synthetic method uses conventional raw material 4- amino -2,5- dimethoxypyridin and phenyloxycarbonyl isothiocyanates, urges specific
It under agent effect, synthesizes to obtain through reactions such as nucleophilic addition, azanol substitution, aromatization cyclizations, has reaction route short, operation letter
The advantages that single, reaction condition is mild, time-consuming shorter, and the purity of product and yield increase substantially, and product purity is up to
98% or more, total recovery is greater than 75%.
To achieve the goals above, according to an aspect of the invention, there is provided a kind of 2- amino -5,8- dimethoxy
The synthetic method of [1,2,4] triazol [1,5-c] pyrimidine, comprising the following steps: firstly, alkali thiocyanates and haloformic acid benzene
Ester reaction generates phenyloxycarbonyl isothiocyanates；After through phenyloxycarbonyl isothiocyanates and 4- amino -2,5- dimethoxy
Yl pyrimidines reaction generates 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester, and by 4- [4- (2,5- diformazans
Oxygroup pyrimidine radicals)] -3- thiourea acid phenenyl ester and azanol reaction generate 2- amino -5,8- dimethoxy [1,2,4] triazol [1,
5-c] pyrimidine.
According to the present invention, alkali thiocyanates employed in above-mentioned synthesis step for example can be potassium rhodanide or sulphur
Zassol.Used haloformic acid phenyl ester for example can be phenyl chloroformate or bromine phenyl formate.
Specifically, the present invention provides the synthesis of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine
Route reacts as follows:
Comprising:
Step S1, a certain amount of catalyst is added in the mixed solution formed to sodium sulfocyanate, water and the first organic solvent
Then phenyl chloroformate is added dropwise in Cat-1, stirring and dissolving, can stir later 2~3 hours, and stratification is successive by organic phase
It is washed with water and saturated sodium bicarbonate solution, is directly used in reacts in next step later.
According to the present invention, used first organic solvent for example can be methyl acetate, ethyl acetate, toluene, diformazan
One of benzene and tetrahydrofuran are a variety of, preferably can be toluene.Used catalyst Cat-1 can for example be selected from N, N-
One of dimethylformamide (DMF), n,N-Dimethylaniline, triethylamine and pyridine are a variety of, preferably can be N, N- bis-
Methylaniline.
According to the present invention, in step sl, reaction is carried out within the temperature range of 15~40 DEG C, preferably 25~30
℃。
Step S2: to a dropping step S1 in the mixed system of 4- amino -2,5- dimethoxypyridin and the second organic solvent
The organic phase of middle acquisition is added dropwise subsequent continuation of insurance temperature, such as can keep the temperature 2~5 hours, and HPLC tracking is until reaction terminates.
It is down to room temperature, is filtered, filter cake ethanol washing obtains the wet of 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester
Product, be placed on 60 DEG C of drying, investment is reacted in next step.
According to the preferred embodiment of the present invention, in step s 2, reaction carries out within the temperature range of 50~80 DEG C, excellent
Select 70~75 DEG C.Wherein, the second organic solvent for example can be selected from methyl acetate, ethyl acetate, toluene, dimethylbenzene and tetrahydro
One of furans is a variety of, and preferably the second solvent is toluene.
Step S3: under conditions of 35~40 DEG C, 4- [4- (2,5- dimethoxypyridin base)]-is sequentially added into system
The aqueous solution of alkali, after being added dropwise, example is added dropwise in 3- thiourea acid phenenyl ester, third organic solvent, water and hydroxylamine hydrochloride while stirring
2 hours can be such as kept the temperature, is warming up to 45~85 DEG C again later, continues heat preservation such as 2~3 hours, HPLC tracking is until reaction knot
Beam.It is cooled to 0 DEG C, is slowly stirred half an hour, is filtered, washs filter cake, such as concentration can be used for the second of 30%~70wt%
Alcohol cleaning, it is preferred to use the ethyl alcohol of 50wt%.
White 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine crude product is obtained, can be further processed
Purifying.
In step s3, reaction is carried out within the temperature range of 45~85 DEG C, preferably 50~55 DEG C.Its used
Three organic solvents for example can be methanol, ethyl alcohol, tetrahydrofuran, dioxane, toluene or dimethylbenzene, preferably third organic solvent
For ethyl alcohol.According to the present invention, in step s3, used alkali for example can be sodium methoxide, sodium hydroxide, sodium carbonate or carbonic acid
Potassium, it is preferred to use sodium hydroxide.
The present invention uses conventional raw material 4- amino -2,5- dimethoxypyridin and phenyloxycarbonyl isothiocyanates, in spy
Determine under catalyst action, synthesizes to have obtained 2- amino -5,8- diformazan through reactions such as nucleophilic addition, azanol substitution, aromatization cyclizations
Oxygroup [1,2,4] triazol [1,5-c] pyrimidine (AMTP), has the advantages that
(1) present invention innovatively introduces phenyloxycarbonyl isothiocyanates as reaction substrate, so that in step S2
Reaction time significantly shorten and (be down to from 7~10 hours 2~3 hours)；
(2) reaction route is short, and time-consuming short, easy to operate, reaction condition is mild, and the present invention is easy entrainment for target product
The problem of polar impurity, filters out the mixed solvent washing method of optimal proportion, it is ensured that the quality of product, so that final products
Purity and yield increase substantially, and if final product purity is up to 98% or more, total recovery is up to 76.4%, and effectively letter simultaneously
Operation difficulty is changed.
(3) preparation process simplifies smooth, reacts without harsh conditions, the three wastes are easily handled, and production cycle is fast, are very suitable for
Industrialized production.
According to hereafter to the detailed description of the specific embodiment of the invention, will become more apparent to one of ordinary skill in the art the present invention
Above-mentioned and other purposes, advantages and features.
Specific embodiment
Embodiment 1
1, the preparation of phenyloxycarbonyl isothiocyanates
Sodium sulfocyanate (126.4g, 1.56mol), water (202g), toluene (186g) are sequentially added in 1000ml four-hole bottle
And n,N-Dimethylaniline (8.9g), stirring and dissolving are heated to 25 DEG C, start be added dropwise phenyl chloroformate (187.8g,
1.2mol), it drips off within about 0.5 hour, continues heat preservation 2.5 hours, stratification, organic phase successively uses 50ml water and 50ml saturated carbon
Sour hydrogen sodium water solution washing, investment are reacted in next step.
2, the preparation of 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester
4- amino -2,5- dimethoxypyridin (116.7g, 0.75mol) and toluene are sequentially added in 2000ml four-hole bottle
(188g) is heated to 70~75 DEG C, starts the toluene solution that phenyloxycarbonyl isothiocyanates is added dropwise, drips off within about 1 hour, continues
Heat preservation 2 hours, HPLC, which is monitored to reaction, to be terminated.Be down to room temperature, filter, filter cake with 50ml ethanol washing twice, 60 DEG C drying after
Title intermediate 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester 234.9g is obtained, content 98.1% is received
Rate is up to 92.0%, and product passes through1H NMR and MS confirmation:1HNMR(400Hz,DMSO-d6)3,88(brs,6H),7,28-7.49
(m, 5H), 8.35 (s, 1H), 11.56 (s, 1H), 12.33 (s, 1H)；MS(HPLC,ESI)335(M+H).
3, the synthesis of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine
4- [4- (2,5- dimethoxypyridin base)] -3- obtained in above-mentioned steps is sequentially added in 2000ml four-hole bottle
Thiourea acid phenenyl ester (234.9g, 0.69mol), ethyl alcohol (294g), water (202g), hydroxylamine hydrochloride (61.3g, 0.88mol), heating
To 40 DEG C, starts that sodium hydrate aqueous solution (33.5g/78.2g) is added dropwise, drip off within about 0.5 hour, keep the temperature 2 hours, be warming up to 50 DEG C
Continue heat preservation 2 hours, HPLC, which is monitored to reaction, to be terminated.It is cooled to 0 DEG C, is slowly stirred 0.5 hour, is filtered, filter cake is dense with 150g
Degree is stirred for the ethyl alcohol of 50wt% and is washed twice, dry, obtains white solid 113.4g, content 98.5%, structure warp1H NMR and
MS confirmation: 1HNMR (400Hz, DMSO-d6) 3,90 (s, 3H), 4.06 (s, 3H), 6.29 (brs, 2H), 7.49 (s, 1H)；MS
(HPLC,ESI)196(M+H).It is computed, route total recovery is up to 76.4%.
Embodiment 2
1, the preparation of phenyloxycarbonyl isothiocyanates
Sodium sulfocyanate (126.4g, 1.56mol), water (202g), toluene (186g) are sequentially added in 1000ml four-hole bottle
And triethylamine (7g), stirring and dissolving are heated to 35 DEG C, start that phenyl chloroformate (187.8g, 1.2mol) is added dropwise, about 0.5 is small
When drip off, continue heat preservation 2.5 hours, stratification, organic phase is successively washed with 50ml water and 50ml saturated sodium bicarbonate aqueous solution
It washs, investment is reacted in next step.
2, the preparation of 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester
4- amino -2,5- dimethoxypyridin (116.7g, 0.75mol) and tetrahydro are sequentially added in 2000ml four-hole bottle
Furans (188g), is heated to 60 DEG C, starts the toluene solution that phenyloxycarbonyl isothiocyanates is added dropwise, drips off within about 1 hour, continues
Heat preservation 3.5 hours, HPLC, which is monitored to reaction, to be terminated.It is down to room temperature, is filtered, the ethanol washing that filter cake is 70wt% with 50ml concentration
Twice, title intermediate 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester 230.9g is obtained after 60 DEG C of drying,
Its content is up to 98.5%, and yield is up to 90.8%.
3, the synthesis of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine
4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester is sequentially added in 2000ml four-hole bottle
(230.9g, 0.68mol), tetrahydrofuran (254g), water (190g), hydroxylamine hydrochloride (61.3g, 0.88mol), are heated to 35~40
DEG C, start that NaOH aqueous solution (33.5g/78.2g) is added dropwise, drip off within about 0.5 hour, keeps the temperature 2 hours, be warming up to 65 DEG C and continue to keep the temperature
2 hours, HPLC, which is monitored to reaction, to be terminated.It is cooled to 0 DEG C, is slowly stirred 0.5 hour, is filtered, the 70wt% second of filter cake 150g
Alcohol, which stirs, to be washed twice, dry, obtains white solid 108.7g, content is up to 98.2%.It is computed, which is up to
73.0%.
So far, although those skilled in the art will appreciate that present invention has been shown and described in detail herein multiple shows
Example property embodiment still without departing from the spirit and scope of the present invention, still can according to the present disclosure directly
Determine or deduce out many other variations or modifications consistent with the principles of the invention.Therefore, the scope of the present invention is understood that and recognizes
It is set to and covers all such other variations or modifications.
Claims (9)
1. a kind of synthetic method of 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine, comprising the following steps:
Firstly, alkali thiocyanates are reacted with haloformic acid phenyl ester generates phenyloxycarbonyl isothiocyanates；
The phenyloxycarbonyl isothiocyanates is reacted with 4- amino -2,5- dimethoxypyridin later and generates 4- [4- (2,5-
Dimethoxypyridin base)] -3- thiourea acid phenenyl ester；And
The 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester and azanol reaction are generated into the 2- amino -
5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine；
Wherein, the alkali thiocyanates are sodium sulfocyanate, and the haloformic acid phenyl ester is phenyl chloroformate, and the azanol is salt
Sour azanol；
It reacts as follows:
The synthetic method further comprise the following three steps:
Step S1: a certain amount of catalyst Cat- is added in the mixed solution formed to sodium sulfocyanate, water and the first organic solvent
1, then phenyl chloroformate is added dropwise in stirring and dissolving, and organic phase is successively used water and saturated sodium bicarbonate molten by stirring, stratification
Liquid washing, is directly used in reacts in next step later；
Step S2: to the step S1 is added dropwise in the mixed system of 4- amino -2,5- dimethoxypyridin and the second organic solvent
The organic phase of middle acquisition continues heat preservation 2~5 hours, and HPLC tracking terminates up to reaction, is down to room temperature, filters, filter cake ethyl alcohol
Washing, obtains the wet product of 4- [4- (2,5- dimethoxypyridin base)] -3- thiourea acid phenenyl ester, dries in 60 DEG C, and investment is in next step
Reaction；And
Step S3: under conditions of 35~40 DEG C, the 4- [4- (2,5- dimethoxypyridin base)]-is sequentially added into system
The aqueous solution of alkali is added dropwise in 3- thiourea acid phenenyl ester, third organic solvent, water and hydroxylamine hydrochloride while stirring, after being added dropwise, protects
Temperature is warming up to 45~85 DEG C, continues to keep the temperature, and HPLC tracking terminates up to reaction, is cooled to 0 DEG C, is slowly stirred, and filters, washing
Filter cake obtains white 2- amino -5,8- dimethoxy [1,2,4] triazol [1,5-c] pyrimidine crude product, can be further processed pure
Change.
2. synthetic method according to claim 1, which is characterized in that first organic solvent is selected from methyl acetate, second
One of acetoacetic ester, toluene, dimethylbenzene and tetrahydrofuran are a variety of.
3. synthetic method according to claim 1 or 2, which is characterized in that the catalyst Cat-1 in the step S1 is selected from
N,N-dimethylformamide, N, one of accelerine, triethylamine and pyridine or a variety of.
4. synthetic method according to claim 1 or 2, which is characterized in that in the step S1, react at 15~40 DEG C
At a temperature of carry out.
5. synthetic method according to claim 1 or 2, which is characterized in that second organic solvent be selected from methyl acetate,
One of ethyl acetate, toluene, dimethylbenzene and tetrahydrofuran are a variety of.
6. synthetic method according to claim 1 or 2, which is characterized in that in the step S2, react at 50~80 DEG C
At a temperature of carry out.
7. synthetic method according to claim 1 or 2, which is characterized in that the third organic solvent is selected from methanol, second
One of alcohol, tetrahydrofuran, dioxane, toluene and dimethylbenzene are a variety of.
8. synthetic method according to claim 1 or 2, which is characterized in that the alkali in the step S3 is selected from sodium methoxide, hydrogen
One of sodium oxide molybdena, sodium carbonate and potassium carbonate are a variety of.
9. synthetic method according to claim 1 or 2, which is characterized in that in the step S3, react at 45~85 DEG C
At a temperature of carry out.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103025735A (en) * | 2010-05-25 | 2013-04-03 | 陶氏益农公司 | Process for the preparation of 5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines |
| CN103232453A (en) * | 2013-04-18 | 2013-08-07 | 黑龙江大学 | Synthesizing method of 2-amino-5,8-dimethoxy[1,2,4]-triazolo[1,5-c]-pyrimidine |
| CN103739606A (en) * | 2013-12-12 | 2014-04-23 | 江苏富鼎化学有限公司 | Environment-friendly synthetic method for 2-amino-5,8-disubstituted-[1,2,4]triazole[1,5-c]pyrimidine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103025735A (en) * | 2010-05-25 | 2013-04-03 | 陶氏益农公司 | Process for the preparation of 5-substituted-8-alkoxy[1,2,4]triazolo[1,5-c]pyrimidin-2-amines |
| CN103232453A (en) * | 2013-04-18 | 2013-08-07 | 黑龙江大学 | Synthesizing method of 2-amino-5,8-dimethoxy[1,2,4]-triazolo[1,5-c]-pyrimidine |
| CN103739606A (en) * | 2013-12-12 | 2014-04-23 | 江苏富鼎化学有限公司 | Environment-friendly synthetic method for 2-amino-5,8-disubstituted-[1,2,4]triazole[1,5-c]pyrimidine |
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