CN105294697A - Synthesis method of 2-amino-5, 8-dimethoxy[1, 2, 4]triazolo[1, 5-c]pyrimidine - Google Patents
Synthesis method of 2-amino-5, 8-dimethoxy[1, 2, 4]triazolo[1, 5-c]pyrimidine Download PDFInfo
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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 synthesis method of 2-amino-5, 8-dimethoxy[1, 2, 4]triazolo[1, 5-c]pyrimidine (AMTP). 4-amino-2, 5-dimethoxy pyrimidine and phenoxy carbonyl isothiocyanate are adopted as the basic raw materials, under the action of a specific catalyst, nucleophilic addition, hydroxylamine substituttion, aromatic cyclization and other reactions are carried out to synthesize the product. The method innovatively selects phenoxy carbonyl structure compound as the substrate and significantly enhances the reaction rate. The method has the advantages of short reaction route, simple operation, mild reaction conditions, smooth operation, easy treatment of three wastes, and short full flow, thus having great industrial value.
Description
Technical field
The present invention relates to compou nd synthesis technical field, in particular to the synthetic method of amino-5, the 8-dimethoxys [1,2,4] triazolo [1,5-c] pyrimidine (AMTP) of a kind of agricultural chemicals and medical important intermediate 2-.
Background technology
Sulfonamides herbicide is the highly active kind of another series occurred after sulfonylurea and the imidazolinone herbicide that found afterwards, it is by the new inhibitor of acetolactate synthetase of a class of U.S. road agricultural sciences (DowAgroscience) company development, its primary structure form is triazolopyrimidine sulfonamide, and penoxsuam is wherein main force's kind of herbicide for paddy field.Wherein, amino-5, the 8-dimethoxys [1,2,4] triazolo [1,5-c] pyrimidine (AMTP) of 2-are the important scaffold intermediates of synthesis penoxsuam, and therefore, the synthetic route of research AMTP has important significance of scientific research and practical value.
Wherein, the structural formula of amino-5, the 8-dimethoxys [1,2,4] triazolo [1,5-c] pyrimidine (AMTP) of 2-is as follows:
Preparation method at present about AMTP mainly contains following two kinds: (1) with ethoxy acetate, methyl-formiate, thiocarbamide or methyl-isothiourea and bromine cyanogen for raw material method (CN103232453); (2) be raw material method (US814339B2, CN103025735A, CN103739606A) with amino-2, the 5-dimethoxypyridins of 4-and lsothiocyanates.
Wherein, route raw material (1) used comparatively based on, but processing step is longer, product yield is on the low side (total recovery is lower than 40%), and relates to the use of hypertoxic hazardous substance bromine cyanogen in process, and cost is higher, buying not easily, and easily produces a large amount of high pollution waste water.Route is (2) few due to the three wastes, and reaction yield higher (total recovery about 70%) is the operational path paid close attention at present, but it is partially long also to there is the reaction times, the defects such as the polar impurity be mingled with in product not easily removes, affect quality product, therefore need to be optimized.
Summary of the invention
Object of the present invention aims to provide a kind of 2-amino-5,8-dimethoxy [1,2,4] triazolo [1,5-c] synthetic method of pyrimidine, it adopts amino-2, the 5-dimethoxypyridins of convenient source 4-and phenyloxycarbonyl lsothiocyanates, under special catalyst effect, obtain through Reactive Synthesis such as nucleophilic addition(Adn), azanol replacement, aromatize cyclizations, have reaction scheme short, simple to operate, reaction conditions is gentle, the advantage such as shorter consuming time, and the purity of product and yield increase substantially, product purity is up to more than 98%, and total recovery is greater than 75%.
To achieve these goals, according to an aspect of the present invention, provide a kind of 2-amino-5,8-dimethoxy [1,2,4] synthetic method of triazolo [1,5-c] pyrimidine, comprise the following steps: first, alkali thiocyanates and haloformic acid phenyl ester react and generate phenyloxycarbonyl lsothiocyanates; After through phenyloxycarbonyl lsothiocyanates and 4-amino-2, the reaction of 5-dimethoxypyridin generates 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester, and by 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester and azanol reaction generate amino-5, the 8-dimethoxys [1,2 of 2-, 4] triazolo [1,5-c] pyrimidine.
According to the present invention, the alkali thiocyanates adopted in above-mentioned synthesis step can be such as potassium sulfocyanate or Sodium Thiocyanate 99.The haloformic acid phenyl ester adopted can be such as phenyl chloroformate or bromine phenyl formate.
Particularly, the invention provides the synthetic route of 2-amino-5,8-dimethoxy [1,2,4] triazolo [1,5-c] pyrimidine, react as follows:
It comprises:
Step S1, to Sodium Thiocyanate 99, water and the first organic solvent formed mixing solutions in add a certain amount of catalyzer Cat-1, stirring and dissolving, then phenyl chloroformate is dripped, 2 ~ 3 hours can be stirred afterwards, stratification, by organic phase priority water and saturated sodium bicarbonate solution washing, be directly used in next step reaction afterwards.
According to the present invention, the first organic solvent adopted can be such as one or more in methyl acetate, ethyl acetate, toluene, dimethylbenzene and tetrahydrofuran (THF), can be preferably toluene.The catalyzer Cat-1 adopted such as can be selected from DMF (DMF), DMA, triethylamine and pyridine one or more, can be preferably DMA.
According to the present invention, in step sl, reaction carries out in the temperature range of 15 ~ 40 DEG C, is preferably 25 ~ 30 DEG C.
Step S2: drip the organic phase obtained in step S1 in the mixed system of amino-2, the 5-dimethoxypyridins of 4-and the second organic solvent, dropwise follow-up continuation of insurance temperature, such as, can be incubated 2 ~ 5 hours, HPLC follows the tracks of until reaction end.Be down to room temperature, filter, filter cake washing with alcohol, obtains the wet product of 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester, be placed on 60 DEG C of oven dry, drop into next step react.
According to the preferred embodiment of the present invention, in step s 2, react and carry out in the temperature range of 50 ~ 80 DEG C, preferably 70 ~ 75 DEG C.Wherein, the second organic solvent can be such as be selected from methyl acetate, ethyl acetate, toluene, dimethylbenzene and tetrahydrofuran (THF) one or more, preferably the second solvent is toluene.
Step S3: under the condition of 35 ~ 40 DEG C, 4-[4-(2 is added successively in system, 5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester, the 3rd organic solvent, water and oxammonium hydrochloride, drip the aqueous solution of alkali while stirring, after dropwising, such as, can be incubated 2 hours, be warming up to 45 ~ 85 DEG C more afterwards, continue insulation such as 2 ~ 3 hours, HPLC follows the tracks of until reaction terminates.Be cooled to 0 DEG C, slowly stir half an hour, filter, washing leaching cake, such as, concentration can be adopted to be the ethanol purge of 30% ~ 70wt%, preferably adopt the ethanol of 50wt%.
Obtain amino-5,8-dimethoxys [1,2,4] triazolo [1,5-c] the pyrimidine crude product of white 2-, purifying can be processed further.
In step s3, reaction carries out in the temperature range of 45 ~ 85 DEG C, preferably 50 ~ 55 DEG C.Its 3rd organic solvent adopted can be such as methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, toluene or dimethylbenzene, and preferably the 3rd organic solvent is ethanol.According to the present invention, in step s3, the alkali adopted can be such as sodium methylate, sodium hydroxide, sodium carbonate or salt of wormwood, preferably adopts sodium hydroxide.
The present invention adopts convenient source 4-amino-2,5-dimethoxypyridin and phenyloxycarbonyl lsothiocyanates, under special catalyst effect, 2-amino-5 is obtained through Reactive Synthesis such as nucleophilic addition(Adn), azanol replacement, aromatize cyclizations, 8-dimethoxy [1,2,4] triazolo [1,5-c] pyrimidine (AMTP), there is following beneficial effect:
(1) the present invention introduces phenyloxycarbonyl lsothiocyanates innovatively as reaction substrate, and the reaction times in step S2 is shortened (being down to 2 ~ 3 hours from 7 ~ 10 hours) significantly;
(2) reaction scheme is short, consuming time short, simple to operate, reaction conditions is gentle, the present invention is directed to the problem that target product easily carries polar impurity secretly, filter out the mixed solvent washing method of optimal proportion, ensure that the quality of product, the purity of the finished product and yield are increased substantially, as final product high purity more than 98%, total recovery up to 76.4%, and effectively simplifies operation easier simultaneously.
(3) preparation technology simplifies smoothness, and reaction is without severe condition, and the three wastes are easy to process, and production cycle is fast, is very suitable for suitability for industrialized production.
According to hereafter to the detailed description of the specific embodiment of the invention, those skilled in the art will understand above-mentioned and other objects, advantage and feature of the present invention more.
Embodiment
Embodiment 1
1, the preparation of phenyloxycarbonyl lsothiocyanates
Sodium Thiocyanate 99 (126.4g is added successively in 1000ml four-hole bottle, 1.56mol), water (202g), toluene (186g) and DMA (8.9g), stirring and dissolving, be heated to 25 DEG C, start to drip phenyl chloroformate (187.8g, 1.2mol), within about 0.5 hour, drip off, continue insulation 2.5 hours, stratification, organic phase with 50ml water and the washing of 50ml saturated sodium bicarbonate aqueous solution, drops into next step reaction successively.
2, the preparation of 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester
4-amino-2 is added successively in 2000ml four-hole bottle, 5-dimethoxypyridin (116.7g, 0.75mol) with toluene (188g), be heated to 70 ~ 75 DEG C, start the toluene solution dripping phenyloxycarbonyl lsothiocyanates, within about 1 hour, drip off, continue insulation 2 hours, HPLC monitoring is to reacting end.Be down to room temperature, filter, filter cake 50ml washing with alcohol twice, 60 DEG C dry after obtain title intermediate 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester 234.9g, content is 98.1%, and yield is up to 92.0%, and product passes through
1hNMR and MS confirms:
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 amino-5,8-dimethoxys [1,2,4] triazolo [1, the 5-c] pyrimidine of 2-
4-[the 4-(2 obtained in above-mentioned steps is added successively in 2000ml four-hole bottle, 5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester (234.9g, 0.69mol), ethanol (294g), water (202g), oxammonium hydrochloride (61.3g, 0.88mol), be heated to 40 DEG C, start to drip aqueous sodium hydroxide solution (33.5g/78.2g), within about 0.5 hour, drip off, be incubated 2 hours, be warming up to 50 DEG C and continue insulation 2 hours, HPLC monitoring is to reacting end.Be cooled to 0 DEG C, slowly stir 0.5 hour, filter, filter cake 150g concentration is that the ethanol of 50wt% stirs and washes twice, and dry, obtain white solid 113.4g, its content is 98.5%, structure warp
1hNMR and MS confirms: 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).As calculated, route total recovery reaches 76.4%.
Embodiment 2
1, the preparation of phenyloxycarbonyl lsothiocyanates
Sodium Thiocyanate 99 (126.4g is added successively in 1000ml four-hole bottle, 1.56mol), water (202g), toluene (186g) and triethylamine (7g), stirring and dissolving, is heated to 35 DEG C, starts to drip phenyl chloroformate (187.8g, 1.2mol), within about 0.5 hour, drip off, continue insulation 2.5 hours, stratification, organic phase with 50ml water and the washing of 50ml saturated sodium bicarbonate aqueous solution, drops into next step reaction successively.
2, the preparation of 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester
4-amino-2 is added successively in 2000ml four-hole bottle, 5-dimethoxypyridin (116.7g, 0.75mol) with tetrahydrofuran (THF) (188g), be heated to 60 DEG C, start the toluene solution dripping phenyloxycarbonyl lsothiocyanates, within about 1 hour, drip off, continue insulation 3.5 hours, HPLC monitoring is to reacting end.Be down to room temperature, filter, filter cake 50ml concentration is the washing with alcohol twice of 70wt%, title intermediate 4-[4-(2 is obtained after 60 DEG C of oven dry, 5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester 230.9g, its content is up to 98.5%, and yield is up to 90.8%.
3, the synthesis of amino-5,8-dimethoxys [1,2,4] triazolo [1, the 5-c] pyrimidine of 2-
4-[4-(2 is added successively in 2000ml four-hole bottle, 5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester (230.9g, 0.68mol), tetrahydrofuran (THF) (254g), water (190g), oxammonium hydrochloride (61.3g, 0.88mol), be heated to 35 ~ 40 DEG C, start to drip the NaOH aqueous solution (33.5g/78.2g), within about 0.5 hour, drip off, be incubated 2 hours, be warming up to 65 DEG C and continue insulation 2 hours, HPLC monitoring is to reacting end.Be cooled to 0 DEG C, slowly stir 0.5 hour, filter, the 70wt% ethanol of filter cake 150g stirs washes twice, and dry, obtain white solid 108.7g, its content is up to 98.2%.As calculated, this route total recovery is up to 73.0%.
So far, those skilled in the art will recognize that, although multiple exemplary embodiment of the present invention is illustrate and described herein detailed, but, without departing from the spirit and scope of the present invention, still can directly determine or derive other modification many or amendment of meeting the principle of the invention according to content disclosed by the invention.Therefore, scope of the present invention should be understood and regard as and cover all these other modification or amendments.
Claims (10)
1. the synthetic method of 2-amino-5,8-dimethoxy [1,2,4] triazolo [1, a 5-c] pyrimidine, comprises the following steps:
First, alkali thiocyanates and haloformic acid phenyl ester react and generate phenyloxycarbonyl lsothiocyanates;
Afterwards described phenyloxycarbonyl lsothiocyanates and amino-2, the 5-dimethoxypyridins of 4-are reacted and generate 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester; And
Described 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester and azanol reaction are generated amino-5,8-dimethoxys [1,2,4] triazolo [1, the 5-c] pyrimidine of described 2-.
2. the synthetic method of 2-amino-5,8-dimethoxy [1,2,4] triazolo [1, a 5-c] pyrimidine, react as follows:
Described synthetic method comprises following three steps:
Step S1: add a certain amount of catalyzer Cat-1 in the mixing solutions that Sodium Thiocyanate 99, water and the first organic solvent are formed, stirring and dissolving, then phenyl chloroformate is dripped, stir, stratification, by organic phase priority water and saturated sodium bicarbonate solution washing, be directly used in next step reaction afterwards;
Step S2: to 4-amino-2, the organic phase obtained in described step S1 is dripped in the mixed system of 5-dimethoxypyridin and the second organic solvent, continue insulation 2 ~ 5 hours, HPLC follows the tracks of until reaction terminates, and is down to room temperature, filter, filter cake washing with alcohol, obtains the wet product of 4-[4-(2,5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester, in 60 DEG C of oven dry, drop into next step reaction; And
Step S3: under the condition of 35 ~ 40 DEG C, described 4-[4-(2 is added successively in system, 5-dimethoxypyridin base)]-3-thiourea acid phenenyl ester, the 3rd organic solvent, water and oxammonium hydrochloride, drip the aqueous solution of alkali while stirring, after dropwising, insulation, be warming up to 45 ~ 85 DEG C, continue insulation, HPLC follows the tracks of until reaction terminates, be cooled to 0 DEG C, slow stirring, filters, washing leaching cake, obtain white 2-amino-5,8-dimethoxy [1,2,4] triazolo [1,5-c] pyrimidine crude product, purifying can be processed further.
3. synthetic method according to claim 2, is characterized in that, described first organic solvent be selected from methyl acetate, ethyl acetate, toluene, dimethylbenzene and tetrahydrofuran (THF) one or more.
4. the synthetic method according to Claims 2 or 3, is characterized in that, the catalyzer Cat-1 in described step S1 be selected from DMF, DMA, triethylamine and pyridine one or more.
5. the synthetic method according to any one of claim 2-4, is characterized in that, in described step S1, reacts and carries out at the temperature of 15 ~ 40 DEG C.
6. the synthetic method according to any one of claim 2-5, is characterized in that, described second organic solvent be selected from methyl acetate, ethyl acetate, toluene, dimethylbenzene and tetrahydrofuran (THF) one or more.
7. the synthetic method according to any one of claim 2-6, is characterized in that, in described step S2, reacts and carries out at the temperature of 50 ~ 80 DEG C.
8. the synthetic method according to any one of claim 2-7, is characterized in that, described 3rd organic solvent be selected from methyl alcohol, ethanol, tetrahydrofuran (THF), dioxane, toluene and dimethylbenzene one or more.
9. the synthetic method according to any one of claim 2-8, is characterized in that, the alkali in described step S3 be selected from sodium methylate, sodium hydroxide, sodium carbonate and salt of wormwood one or more.
10. the synthetic method according to any one of claim 2-9, is characterized in that, in described step S3, reacts and carries out at the temperature of 45 ~ 85 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111217817A (en) * | 2020-02-26 | 2020-06-02 | 山东潍坊润丰化工股份有限公司 | Preparation method of triazolopyrimidine herbicide |
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| 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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| 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 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217817A (en) * | 2020-02-26 | 2020-06-02 | 山东潍坊润丰化工股份有限公司 | Preparation method of triazolopyrimidine herbicide |
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