CN104926717A - Preparation method for ethyl 3-(pyridin-2-ylamino) propanoate - Google Patents
Preparation method for ethyl 3-(pyridin-2-ylamino) propanoate Download PDFInfo
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- CN104926717A CN104926717A CN201510319624.4A CN201510319624A CN104926717A CN 104926717 A CN104926717 A CN 104926717A CN 201510319624 A CN201510319624 A CN 201510319624A CN 104926717 A CN104926717 A CN 104926717A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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Abstract
The invention provides a preparation method for ethyl 3-(pyridin-2-ylamino) propanoate. The preparation method comprises the following steps: under the protection of nitrogen, using 2-aminopyridine and ethyl acrylate as raw materials, anhydrous ethanol as a solvent and trifluoromethanesulfonic acid as a catalyst, performing oil bath heating to control the temperature to be 120-160 DEG C, and carrying out catalytic reaction for 16-20 hours to obtain a reacting liquid; washing the reacting liquid with a first organic solvent under the temperature of 35-40 DEG C and the pressure of 0.09-0.1 MPa, concentrating under reduced pressure, washing the treated reacting liquid with a second organic solvent, and recrystallizing to obtain white lamellar crystal, namely ethyl 3-(pyridin-2-ylamino) propanoate. According to the preparation method, the raw materials are cheap and easy to obtain, the production cost is low, the synthesis process is simple and convenient, the product is easy to separate, and the productivity and the purity are relatively high; the preparation method is environmentally friendly, and high in production safety.
Description
Technical field
The present invention relates to pharmaceutical chemistry, particularly the preparation method of a kind of 3-(pyridine-2-base is amino) ethyl propionate.
Background technology
3-(pyridine-2-base is amino) ethyl propionate (compound 1) is direct thrombin inhibitor dabigatran etcxilate (dabigatrau etexilate, one of commodity are called Pradaxa, compound 2) intermediate important in pharmaceutical synthesis.Dabigatran etcxilate is the new classification oral anticoagulant thing of first listing over 50 years after warfarin.Compared with warfarin, dabigatran etcxilate have can oral, rapid-action, without the need to features such as special Medication monitor, drug interaction are few, in body, in vitro tests and clinical every research all shows that it has good curative effect and pharmaco-kinetic properties, has good potential applicability in clinical practice.
In prior art, such as CN1088702C, the synthetic route of dabigatran as shown in Equation 1:
In prior art, such as the synthetic route of 3-(pyridine-2-base is amino) ethyl propionate is as shown in Equation 2:
The method first synthesizes 2-chloropyridine N-oxide compound (yield 87%) and β-alanine carbethoxy hydrochloride (yield: 93%); 3-(pyridine-2-base is amino) ethyl propionate N-oxide compound (yield: 70%) is generated again by 2-chloropyridine N-oxide compound and β-alanine ethyl ester reactant salt; 3-(pyridine-2-base is amino) ethyl propionate (yield: 92%), total recovery 52%, altogether about 100h consuming time is generated finally by Pd/C catalytic hydrogenation.
In prior art, such as the synthetic route of 3-(pyridine-2-base is amino) ethyl propionate is as shown in Equation 3:
The method directly generates 3-(pyridine-2-base is amino) ethyl propionate by PA and ethyl propenoate in 100 DEG C of backflow 24h mono-steps, but its productive rate only has about 30%.Because above method production cost is higher, productive rate is lower, is generally 30 ~ 52%, and the reaction times is longer, generally reaches 24 ~ 100h.
From above-mentioned prior art, the principal synthetic routes of dabigatran etcxilate is found out, compound (1) is the important intermediate of dabigatran etcxilate, and method reaction process disclosed in prior art is complicated, long reaction time, and yield is not high again.
Summary of the invention
Object of the present invention, exactly in order to solve the problem, provides the preparation method of a kind of new 3-(pyridine-2-base is amino) ethyl propionate.
In order to achieve the above object, present invention employs following technical scheme: the preparation method of a kind of 3-(pyridine-2-base is amino) ethyl propionate, with PA and ethyl propenoate for raw material, take dehydrated alcohol as solvent, be that catalyzer carries out catalyzed reaction with trifluoromethanesulfonic acid, gained reaction solution first carries out concentrating under reduced pressure with after the first organic solvent washing, again through the second organic solvent washing, recrystallization, namely obtain white plates crystal 3-(pyridine-2-base is amino) ethyl propionate.
The reaction conditions of described catalyzed reaction is, under nitrogen protection, and stirring and refluxing reaction 16 ~ 20h in the oil bath of 120 ~ 160 DEG C.
The condition of carrying out concentrating under reduced pressure after described use first organic solvent washing is that control temperature is 35 ~ 40 DEG C, and pressure is 0.09 ~ 0.1MPa.
Described first organic solvent is selected from the mixed solution of one or more in sherwood oil, ethyl acetate, methylene dichloride.
Described second organic solvent is selected from the mixed solution of one or more in sherwood oil, ethyl acetate, methylene dichloride.
The consumption mol ratio of described raw material PA and ethyl propenoate is 1:1 ~ 2.
The consumption volume of described solvent dehydrated alcohol is 1/4 ~ 1 of ethyl propenoate consumption volume.
The consumption mole number of described catalyzer trifluoromethanesulfonic acid is 5 ~ 10% of ethyl propenoate consumption mole number.
The reaction formula of above-mentioned preparation method is as follows:
The present invention is owing to have employed PA, ethyl propenoate as raw material, and employing trifluoromethanesulfonic acid is catalyzer, direct one-step synthesis 3-(pyridine-2-base is amino) ethyl propionate.Because the reaction that building-up process is used is popular response, and the economic environmental protection of aftertreatment, therefore there is the features such as building-up process is simple, easy and simple to handle, product is easily separated.The cost of material of this reaction is cheap, and the reaction times foreshortens to 16 ~ 20h, and therefore final production cost is lower, and the total recovery of final obtained 3-(pyridine-2-base is amino) ethyl propionate is also higher, is 80 ~ 85%.
The present invention compares with prior art, and the raw materials cost of its preparation method is cheaper, synthesis step is short, simple to operate, the operating time is short, product is easily separated and productive rate is high, purity is higher, production cost is low, environmentally friendly, and production security is high.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Implement process of the present invention, condition, reagent, implementation method etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The present invention's raw material used, reagent are commercially available AR, CP level.
Gained intermediate product of the present invention and final product adopt nucleus magnetic resonance to detect.
The calculation formula of the productive rate of gained 3-of the present invention (pyridine-2-base is amino) ethyl propionate is as follows:
3-(pyridine-2-base is amino) ethyl propionate is relative to the productive rate of PA:
W=actual output/theoretical yield × 100%
The present invention's nuclear magnetic resonance spectrometer used is Avance III 500M, and Bruker company of Switzerland produces.
Embodiment 1:
(1) in 500mL round-bottomed flask, put into induction stirring of suitable size, take 50g o-aminopyridine and be placed in bottle, add 50mL dehydrated alcohol;
(2) stir, after dissolution of solid or major part dissolve, in step (1), add 56.5mL ethyl propenoate;
(3) stir a moment, slowly drip 9mL trifluoromethanesulfonic acid;
(4) nitrogen protection is added, stirring and refluxing reaction 18h in the oil bath of 120 ~ 160 DEG C;
(5) after question response completes, reaction solution is 35 ~ 40 DEG C in temperature, and pressure is carry out concentrating under reduced pressure with after petroleum ether under 0.09 ~ 0.1MPa;
(7) concentrated solution obtains white plates crystal through petrol ether/ethyl acetate (volume ratio 5:1) washing, recrystallization, suction filtration.
White plates crystal is 3-(pyridine-2-base is amino) ethyl propionate, yield 80%, purity 99% (HPLC).
Embodiment 2:
(1) in 500mL round-bottomed flask, put into induction stirring of suitable size, take 100g o-aminopyridine and be placed in bottle, add 100mL dehydrated alcohol;
(2) stir, treat that dissolution of solid or major part are dissolved, in step (1), add 113mL acryllic acid ethyl ester;
(3) a moment is stirred, slowly dropwise 15mL trifluoromethanesulfonic acid;
(4) nitrogen protection is added, stirring and refluxing reaction 20h in the oil bath of 120 ~ 160 DEG C;
(5) after question response completes, reaction solution is 35 ~ 40 DEG C in temperature, and pressure is carry out concentrating under reduced pressure with after petroleum ether under 0.09 ~ 0.1MPa;
(7) concentrated solution obtains white plates crystal through petrol ether/ethyl acetate (volume ratio 8:1) washing, recrystallization, suction filtration.
White plates crystal is 3-(pyridine-2-base is amino) ethyl propionate, yield 83%, purity 99% (HPLC).
Embodiment 3:
(1) in 1000mL round-bottomed flask, put into induction stirring of suitable size, take 150g o-aminopyridine and be placed in bottle, add 80mL dehydrated alcohol;
(2) stir, treat that dissolution of solid or major part are dissolved, in step (1), add 169.5mL acryllic acid ethyl ester;
(3) stir a moment, slowly drip 25mL trifluoromethanesulfonic acid;
(4) nitrogen protection is added, stirring and refluxing reaction 16h in the oil bath of 120 ~ 160 DEG C;
(5) after question response completes, reaction solution is 35 ~ 40 DEG C in temperature, and pressure is carry out concentrating under reduced pressure with after petroleum ether under 0.09 ~ 0.1MPa;
(7) concentrated solution obtains white plates crystal through petrol ether/ethyl acetate (volume ratio 10:1) washing, recrystallization, suction filtration.
White plates crystal is 3-(pyridine-2-base is amino) ethyl propionate, yield 85%, purity 99% (HPLC).
The preparation method of 3-of the present invention (pyridine-2-base-amino) ethyl propionate, because reaction raw materials is cheap, synthesis step is short, simple to operate, the operating time is shorter and productive rate is higher, therefore cost is lower, meets industrialization basic demand.
Claims (8)
1. the preparation method of 3-(pyridine-2-base is an amino) ethyl propionate, it is characterized in that: with PA and ethyl propenoate for raw material, take dehydrated alcohol as solvent, be that catalyzer carries out catalyzed reaction with trifluoromethanesulfonic acid, gained reaction solution first carries out concentrating under reduced pressure with after the first organic solvent washing, again through the second organic solvent washing, recrystallization, namely obtain white plates crystal 3-(pyridine-2-base is amino) ethyl propionate.
2. the preparation method of 3-according to claim 1 (pyridine-2-base is amino) ethyl propionate, is characterized in that: the reaction conditions of described catalyzed reaction is, under nitrogen protection, and stirring and refluxing reaction 16 ~ 20h in the oil bath of 120 ~ 160 DEG C.
3. the preparation method of 3-according to claim 1 (pyridine-2-base is amino) ethyl propionate, it is characterized in that: the condition of carrying out concentrating under reduced pressure after described use first organic solvent washing is, control temperature is 35 ~ 40 DEG C, and pressure is 0.09 ~ 0.1MPa.
4. the preparation method of 3-according to claim 1 (pyridine-2-base is amino) ethyl propionate, is characterized in that: described first organic solvent is selected from the mixed solution of one or more in sherwood oil, ethyl acetate, methylene dichloride.
5. the preparation method of 3-according to claim 1 (pyridine-2-base is amino) ethyl propionate, is characterized in that: described second organic solvent is selected from the mixed solution of one or more in sherwood oil, ethyl acetate, methylene dichloride.
6. the preparation method of a kind of 3-according to claim 1 (pyridine-2-base is amino) ethyl propionate, is characterized in that: the consumption mol ratio of described raw material PA and ethyl propenoate is 1:1 ~ 2.
7. the preparation method of 3-according to claim 1 (pyridine-2-base is amino) ethyl propionate, is characterized in that: the consumption volume of described solvent dehydrated alcohol is 1/4 ~ 1 of ethyl propenoate consumption volume.
8. the preparation method of 3-according to claim 1 (pyridine-2-base is amino) ethyl propionate, is characterized in that: the consumption mole number of described catalyzer trifluoromethanesulfonic acid is 5 ~ 10% of ethyl propenoate consumption mole number.
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| CN201510319624.4A CN104926717A (en) | 2015-06-11 | 2015-06-11 | Preparation method for ethyl 3-(pyridin-2-ylamino) propanoate |
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| CN201510319624.4A CN104926717A (en) | 2015-06-11 | 2015-06-11 | Preparation method for ethyl 3-(pyridin-2-ylamino) propanoate |
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- 2015-06-11 CN CN201510319624.4A patent/CN104926717A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| YU JIE REN ET AL.: "Triflic Acid as Efficient Catalyst for the Hydroamination of Ethyl Acrylate with 2-Aminopyridines", 《LETTERS IN ORGANIC CHEMISTRY》 * |
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