CN103951669A - Synthesis method of Anagliptin key intermediate - Google Patents
Synthesis method of Anagliptin key intermediate Download PDFInfo
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- CN103951669A CN103951669A CN201410156984.2A CN201410156984A CN103951669A CN 103951669 A CN103951669 A CN 103951669A CN 201410156984 A CN201410156984 A CN 201410156984A CN 103951669 A CN103951669 A CN 103951669A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- 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 Anagliptin key intermediate. The synthesis method comprises the following steps: jointing cyanoacetaldehyde with N,N-dimethylformamide dimethyl acetal to obtain (2E)-3-(dimethylamino)-2-formylacrylonitrile, further performing ring closing with 3-amino-5-methylpyrazole to obtain 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carbonitrile, and then hydrolyzing to obtain the Anagliptin key intermediate. The invention relates to a brand-new method for synthesizing 2-methyl-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid, and the method has the advantages of use of raw materials, less side products, high product purity, and low whole cost.
Description
Technical field
The present invention relates to the synthetic field of medicine, particularly a kind of synthetic method of my Ge Lieting key intermediate 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid.
Background technology
My Ge Lieting, is a kind of DPP IV Inhibitors, by hindering the activity of DPP IV, thereby reaches prevention and treat such as diabetes (particularly type-II diabetes), diabetes the effect of combining the diseases such as complication.
Conventionally key intermediate formula (I) 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid preparation that, I Ge Lieting of formula V can obtain according to the present invention.
Up to the present, the synthetic route of formula (I) 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid report is less.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of method of brand-new synthetic my Ge Lieting key intermediate 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid is provided.
For realizing above object of the present invention, the present invention adopts following technical scheme:
A synthetic method for my Ge Lieting key intermediate, comprises the following steps:
1) step of replacing, by formula (IV) cyanoacetaldehyde dock with DMF dimethylacetal the formula of obtaining (III) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen;
2) close ring step, described formula (III) is closed ring with 3-amino-5-methylpyrazole and is obtained formula (II) 2-methyl-pyrazolo (1,5-a) pyrimidine-6-formonitrile HCN;
3) hydrolysing step, described formula (II) compound makes my Ge Lieting key intermediate 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid of formula (I) through acidic hydrolysis.
In a specific embodiment, described step 1) step of replacing should add (IV) in suitable solvent, control suitable temperature, react with DMF dimethylacetal certain hour make formula (III) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen;
Further, above-mentioned suitable solvent is methyl alcohol, ethanol, Virahol, methylene dichloride or chloroform, and suitable temperature is-5-25 DEG C that the reaction times is 20-25h;
In a specific embodiments, described step 2) close ring step raw material formula (III) and 3-amino-5-methylpyrazole are added in the middle of alcoholic solvent, add suitable alkali, obtain formula (II) 2-methyl-pyrazolo (1,5-a) pyrimidine-6-formonitrile HCN at comparatively high temps reaction certain hour;
Wherein, above-mentioned alcoholic solvent is one or more of C1-C4 saturated alcohol; Described alkali is organic bases;
Preferably, described alcoholic solvent is that one or more of C1-C4 saturated alcohol are selected from ethanol, but is not limited to this; Described organic bases is selected from piperidines, but is not limited to this;
Wherein, above-mentioned 3-amino-5-methylpyrazole and (2E)-3-(dimethylamino) mol ratio of-2-formyl radical propylene cyanogen is 1:1-2;
Above-mentioned temperature is 70-90 DEG C; The described reaction times is 6-12h;
In a specific embodiments, described step 1) hydrolysing step should be by formula (II) 2-methyl-pyrazolo (1,5-a) pyrimidine-6-formonitrile HCN is dissolved in alcoholic solvent, add mineral alkali, back flow reaction acid adjustment obtain key intermediate 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid;
Above-mentioned alcoholic solvent is preferably ethanol, and mineral alkali is preferably sodium hydroxide.
The present invention is by some simple intermediate reactions, by replacing, close ring and hydrolysing step, with synthetic 2-methyl-pyrazolo [1, the 5-A] pyrimidine-6-carboxylic acid of brand-new method.Compared with prior art, the method is simple to operate, and product purity is high, and side reaction is few, and mild condition is easily controlled, convenient post-treatment, and environmental friendliness, total recovery is higher.
Embodiment
Below in conjunction with embodiment more specifically, the present invention is done to further expansion explanation, but it is pointed out that the synthetic method of my Ge Lieting key intermediate of the present invention is not limited to this specific technique or reagent.Obviously be understandable that for those skilled in the art, even if the following description content does not make any adjustments or revises, also can be directly applied at these unspecified other processing parameters.
A synthetic method for my Ge Lieting key intermediate, as described in following equation.
Specifically comprise the following steps:
(1) formula III 2E)-3-(dimethylamino) preparation of-2-formyl radical propylene cyanogen:
Under optimal temperature, cyanoacetaldehyde is added in suitable solvent, control suitable temperature, react with DMF dimethylacetal certain hour make formula (III) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen;
Preferably, in case study on implementation, suitable solvent is methyl alcohol, ethanol, Virahol, methylene dichloride, chloroform, and suitable temperature is-5-25 DEG C that the reaction times is 20-25h;
(2) preparation of formula (II) 2-methyl-pyrazolo (1,5-a) pyrimidine-6-formonitrile HCN:
Raw material formula (III) and 3-amino-5-methylpyrazole are added in the middle of alcoholic solvent, add suitable alkali, obtain formula (II) 2-methyl-pyrazolo (1,5-a) pyrimidine-6-formonitrile HCN at comparatively high temps reaction certain hour;
In preferred embodiment, alcoholic solvent is ethanol; Organic bases is piperidines; 3-amino-5-methylpyrazole and (2E)-3-(dimethylamino) mol ratio of-2-formyl radical propylene cyanogen is 1:1.1; Temperature of reaction 70-90 DEG C; Reaction times 10-12h.
(3) preparation of formula (I) 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid:
At a certain temperature, formula (II) 2-methyl-pyrazolo (1,5-a) pyrimidine-6-formonitrile HCN is dissolved in alcoholic solvent, adds mineral alkali, back flow reaction acid adjustment obtain key intermediate 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid;
Preferably, in case study on implementation, reaction solvent is selected from ethanol; Mineral alkali is selected from sodium hydroxide.
In context, all temperature are all DEG C to represent.In an embodiment, the centre that medicine is synthetic or final product need conventional aftertreatment conventionally, and this is well-known to those skilled in the art, for example, select suitable solvent wash according to product, select suitable solvent extraction and separation, adopt washed with de-ionized water etc.In the present invention " conventional aftertreatment " represent but be not limited to: if needs, add water, regulate as required pH value to depend on the formation of product to 1-13(), ethyl acetate, chloroform or dichloromethane extraction for mixture, separation of phases, anhydrous sodium sulphate or anhydrous magnesium sulfate drying for organic phase, underpressure distillation, product is purified by silica gel chromatography and/or recrystallization, and Rf value obtains on silica gel.
Below by embodiment more specifically, the present invention is conducted further description, but invention of the present invention is not limited to the following examples, the scope that these embodiment do not limit the present invention in any way.
embodiment 1
Cyanoacetaldehyde 69.06g(1.0mol), be dissolved in methyl alcohol 300ml, add DMF dimethylacetal 132g(1.1mol), 20-25 DEG C of reaction 20-25h, after finishing, concentrating under reduced pressure obtains orange/yellow solid, ethyl alcohol recrystallization, obtains light yellow crystal, 50 DEG C of forced air drying 10h, obtain solid 87g, yield 70%.
embodiment 2
Cyanoacetaldehyde 69.06g(1.0mol), be dissolved in ethanol 400ml, add DMF dimethylacetal 132g(1.1mol), 20-25 DEG C of reaction 20-25h, after finishing, concentrating under reduced pressure obtains orange/yellow solid, ethyl alcohol recrystallization, obtains light yellow crystal, 50 DEG C of forced air drying 10h, obtain solid 75g, yield 61.3%.
embodiment 3
Cyanoacetaldehyde 69.06g(1.0mol), be dissolved in Virahol 550ml, add DMF dimethylacetal 132g(1.1mol), 20-25 DEG C of reaction 20-25h, after finishing, concentrating under reduced pressure obtains orange/yellow solid, ethyl alcohol recrystallization, obtains light yellow crystal, 50 DEG C of forced air drying 10h, obtain solid 76g, yield 70%.
embodiment 4
Under normal temperature; successively by 13.7g(0.22mol) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen, 19.4g(0.2mol) and 3-amino-5-methylpyrazole; and 18.7g(0.22mol) piperidines join in the flask that fills 100ml ethanol; temperature rising reflux 10-12h; reaction finishes, cooling, and concentrating under reduced pressure is removed solvent; re-crystallizing in ethyl acetate obtains the crystal 27g of formula II, yield 85.4% afterwards.
embodiment 5
Under normal temperature; successively by 14.9g(0.24mol) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen, 19.4g(0.2mol) and 3-amino-5-methylpyrazole; and 20.4g(0.24mol) piperidines join in the flask that fills 120ml ethanol; temperature rising reflux 10-12h; reaction finishes, cooling, and concentrating under reduced pressure is removed solvent; re-crystallizing in ethyl acetate obtains the crystal 27g of formula II, yield 85.4% afterwards.
embodiment 6
Under normal temperature; successively by 13.7g(0.22mol) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen, 19.4g(0.2mol) and 3-amino-5-methylpyrazole; and 18.7g(0.22mol) piperidines join in the flask that fills 100ml methyl alcohol; temperature rising reflux 15h; reaction finishes, cooling, and concentrating under reduced pressure is removed solvent; re-crystallizing in ethyl acetate obtains the crystal 25g of formula II, yield 79.1% afterwards.
embodiment 7
Under normal temperature; successively by 13.7g(0.22mol) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen, 19.4g(0.2mol) and 3-amino-5-methylpyrazole; and 18.7g(0.22mol) piperidines join in the flask that fills 150ml Virahol alcohol; temperature rising reflux 15h; reaction finishes, cooling, and concentrating under reduced pressure is removed solvent; re-crystallizing in ethyl acetate obtains the crystal 20g of formula II, yield 63.2% afterwards.
embodiment 8
Under normal temperature; successively by 13.7g(0.22mol) (2E)-3-(dimethylamino)-2-formyl radical propylene cyanogen, 19.4g(0.2mol) and 3-amino-5-methylpyrazole; and 18.7g(0.22mol) piperidines join in the flask that fills 100ml ethanol; temperature rising reflux 20h; reaction finishes, cooling, and concentrating under reduced pressure is removed solvent; re-crystallizing in ethyl acetate obtains the crystal 27.2g of formula II, yield 86% afterwards.
embodiment 9
Under normal temperature, by 15.8g(0.1mol) 2-methyl-pyrazolo (1,5-a) pyrimidine-6-formonitrile HCN is dissolved in 150ml ethanol, drip afterwards 5N aqueous sodium hydroxide solution (100ml), temperature rising reflux 1h, reaction finishes, cooling, the concentrated ethanol of removing of step-down, under ice-water bath, adjust Ph≤1 with the dilute hydrochloric acid of 2N, separate out solid, filter, filter cake successively water and sherwood oil is washed, obtain formula 1) 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid near-white powder 12.4g, yield 70%.
Although above the specific embodiment of the present invention has been given to describe in detail and explanation; but what should indicate is; we can carry out various equivalences to above-mentioned embodiment according to conception of the present invention and change and amendment; when its function producing does not exceed spiritual that specification sheets contains yet, all should be within protection scope of the present invention.
Claims (8)
1. a synthetic method for my Ge Lieting key intermediate, described my Ge Lieting key intermediate structural formula is as formula I:
It is characterized in that comprising the following steps:
1) step of replacing, by the cyanoacetaldehyde shown in formula (IV)
Dock (the 2E)-3-(dimethylamino shown in the formula of obtaining (III) with DMF dimethylacetal)-2-formyl radical propylene cyanogen;
2) close ring step, by (the 2E)-3-(dimethylamino shown in described formula (III))-2-formyl radical propylene cyanogen and 3-amino-5-methylpyrazole close ring and obtain 2-methyl-pyrazolo (1, the 5-a) pyrimidine-6-formonitrile HCN shown in formula (II);
3) hydrolysing step, makes my Ge Lieting key intermediate 2-methyl-pyrazolo [1,5-A] pyrimidine-6-carboxylic acid by 2-methyl-pyrazolo (1, the 5-a) pyrimidine-6-formonitrile HCN shown in described formula (II) through acidic hydrolysis.
2. the synthetic method of a kind of my Ge Lieting key intermediate according to claim 1, is characterized in that: the solvent of described step 1) is methyl alcohol, ethanol, Virahol, methylene dichloride or chloroform, and temperature of reaction is-5～25 DEG C, and the reaction times is 20-25h.
3. the synthetic method of a kind of my Ge Lieting key intermediate according to claim 1; it is characterized in that: described step 2) by (the 2E)-3-(dimethylamino shown in formula (III))-2-formyl radical propylene cyanogen and 3-amino-5-methylpyrazole add in alcoholic solvent; add organic bases, at 70-90 DEG C of reaction 6-12h.
4. the synthetic method of a kind of my Ge Lieting key intermediate according to claim 3, is characterized in that: described alcoholic solvent is one or more of C1-C4 saturated alcohol.
5. the synthetic method of a kind of my Ge Lieting key intermediate according to claim 3, is characterized in that: described alcohol is selected from ethanol, and described organic bases is selected from piperidines.
6. the synthetic method of a kind of my Ge Lieting key intermediate according to claim 3, is characterized in that: (the 2E)-3-(dimethylamino shown in described 3-amino-5-methylpyrazole and formula (III)) mol ratio of-2-formyl radical propylene cyanogen is 1:1-2.
7. the synthetic method of a kind of my Ge Lieting key intermediate according to claim 1, it is characterized in that: described step 3) is by the 2-methyl-pyrazolo (1 shown in formula (II), 5-a) pyrimidine-6-formonitrile HCN is dissolved in alcoholic solvent, add mineral alkali, back flow reaction acid adjustment obtain key intermediate.
8. the synthetic method of a kind of my Ge Lieting key intermediate according to claim 7, is characterized in that: described alcoholic solvent is selected from ethanol, and described mineral alkali is selected from sodium hydroxide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110003218A (en) * | 2019-03-26 | 2019-07-12 | 杭州瀚康生物医药科技有限公司 | The preparation method of my Ge Lieting intermediate |
| CN110734375A (en) * | 2018-07-19 | 2020-01-31 | 上海天慈中商药业有限公司 | Preparation method of bilastine intermediates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626775A (en) * | 2013-12-02 | 2014-03-12 | 南京华威医药科技开发有限公司 | DPP-4 inhibitor with diazine structure |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103626775A (en) * | 2013-12-02 | 2014-03-12 | 南京华威医药科技开发有限公司 | DPP-4 inhibitor with diazine structure |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110734375A (en) * | 2018-07-19 | 2020-01-31 | 上海天慈中商药业有限公司 | Preparation method of bilastine intermediates |
| CN110734375B (en) * | 2018-07-19 | 2022-09-13 | 上海天慈中商药业有限公司 | Preparation method of bilastine intermediate |
| CN110003218A (en) * | 2019-03-26 | 2019-07-12 | 杭州瀚康生物医药科技有限公司 | The preparation method of my Ge Lieting intermediate |
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