CN110981795B - Method for preparing 2-aminoacyl isonicotinic acid by using methyl 2-cyanoisonicotinate - Google Patents
Method for preparing 2-aminoacyl isonicotinic acid by using methyl 2-cyanoisonicotinate Download PDFInfo
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- CN110981795B CN110981795B CN201911313721.7A CN201911313721A CN110981795B CN 110981795 B CN110981795 B CN 110981795B CN 201911313721 A CN201911313721 A CN 201911313721A CN 110981795 B CN110981795 B CN 110981795B
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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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Abstract
The invention discloses a method for preparing 2-aminoacyl isonicotinic acid by utilizing methyl 2-cyanoisonicotinate, wherein dioxane is added to react in an aqueous solution of sodium hydroxide, so that the yield of 2-aminoacyl isonicotinic acid is obviously improved; the whole preparation method is simple and easy to operate, and is very suitable for industrial scale production.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a method for preparing 2-aminoacyl isonicotinic acid by using methyl 2-cyanoisonicotinate.
Background
AMG333 is a potent, highly selective TRPM8 receptor antagonist, IC5013nM, which can be prepared by a variety of methods, and has the chemical formula:
2-aminoacyl isonicotinic acid is an important raw material of one method for preparing AMG333, and the chemical structural formula is as follows:
the chemical reaction equation for preparing AMG333 using 2-aminoacyl isonicotinic acid is:
in the prior art, a plurality of technical methods for obtaining different target products by utilizing the hydrolysis of methyl 2-cyanoisonicotinate under different conditions exist, but no corresponding intensive research report is found for how to specifically utilize methyl 2-cyanoisonicotinate to prepare 2-aminoacyl-isonicotinate.
The existing technologies for obtaining different products by hydrolyzing methyl 2-cyanoisonicotinate are various, and different products can be obtained by hydrolyzing under the conditions of different temperatures and mixed solvents of alkali and other components. The prior patent CN107573330A provides a preparation method of topiroxostat, which uses 2-cyano methyl isonicotinate as a raw material to obtain an intermediate through hydrazinolysis, and then the intermediate reacts with 4-cyanopyridine under the action of sodium ethoxide to obtain the topiroxostat. Patent CN104910068B discloses a synthesis method of 2-cyanoisonicotinic acid hydrazide 1.5 p-toluenesulfonate, which comprises using methyl 2-cyanoisonicotinic acid as a starting material, obtaining 2-cyanoisonicotinic acid through alkaline hydrolysis, condensing with tert-butoxycarbonylhydrazine under the action of a condensing agent, and hydrolyzing the condensation product with p-toluenesulfonic acid-hydrate to obtain the target compound.
Because 2-cyanoisonicotinic acid methyl ester contains both cyano and ester groups, amino and carboxyl are easily generated after substitution and hydrolysis, so that the yield of the target product has great difference due to different reaction conditions, which also causes difficulty in how to prepare 2-aminoacyl isonicotinic acid. The prior art does not find a technology for preparing 2-aminoacyl isonicotinic acid by using 2-cyanoisonicotinic acid methyl ester, and the 2-aminoacyl isonicotinic acid is used as an important raw material required by a method for preparing AMG333 and has very important practical significance for the chemical synthesis of the AMG 333.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a method for preparing 2-aminoacyl isonicotinic acid by using 2-cyanoisonicotinic acid methyl ester, which can prepare 2-aminoacyl isonicotinic acid by using 2-cyanoisonicotinic acid methyl ester through selecting special solvents and other special conditions, and has very high yield. Specifically, the following technique is used.
A process for preparing 2-aminoacyl isonicotinic acid using methyl 2-cyanoisonicotinate comprising the steps of:
s1, mixing the 2-cyano methyl isonicotinate and dioxane uniformly;
s2, adding 4M sodium hydroxide aqueous solution, reacting for 3-8h at 20-50 ℃, and tracking the reaction by TLC until the raw materials are completely reacted;
s3, adjusting pH to 6-7 with 4M hydrochloric acid, extracting twice with DCM extractant, combining DCM layers, drying with magnesium sulfate, and concentrating to remove solvent to obtain 2-aminoacyl isonicotinic acid.
In the preparation method, the chemical reaction equation of the methyl 2-cyanoisonicotinate under the conditions of Dioxane (Dioxane), sodium hydroxide and water is as follows:
by adopting the method, the ester group can be effectively hydrolyzed to form carboxyl, the cyano group can also react to form amide group, the yield of the finally prepared 2-aminoacyl isonicotinic acid reaches more than 80 percent, and the highest yield is close to 90 percent. If other solvent combinations are adopted, such as dioxane and sodium carbonate aqueous solution, the yield of the 2-aminoacyl isonicotinic acid is less than 20 percent, the rest is mostly unreacted raw materials, and the small part is impurities of non-target products; only other impurities can be obtained by adopting tetrahydrofuran and a potassium carbonate/sodium carbonate aqueous solution, or isopropanol and a sodium carbonate/sodium bicarbonate aqueous solution, and the target product 2-aminoacyl isonicotinic acid cannot be obtained.
Preferably, the volume-mass ratio of the dioxane to the 2-cyanoisonicotinic acid is 5-10 mL/g.
More preferably, the volume-to-mass ratio of the dioxane to the 2-cyanoisonicotinic acid is 8 mL/g.
Preferably, the volume-to-mass ratio of the 4M aqueous sodium hydroxide solution to the 2-cyanoisonicotinic acid is 6-8 mL/g.
More preferably, the volume-to-mass ratio of the 4M aqueous sodium hydroxide solution to the 2-cyanoisonicotinic acid is 6.5 mL/g.
Preferably, in step S2, the reaction temperature is 35 ℃ and the reaction time is 5 h.
Preferably, in step S3, the pH adjusted with 4M hydrochloric acid is 6.2.
Compared with the prior art, the invention has the advantages that: by adopting the preparation method, 2-cyano methyl isonicotinate can be fully utilized to prepare 2-aminoacyl isonicotinate, and very high yield can be obtained; the reaction condition is mild, the operation is simple, and the method is very suitable for industrial large-scale production.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
A process for preparing 2-aminoacyl isonicotinic acid using methyl 2-cyanoisonicotinate comprising the steps of:
s1, adding 1g (6.17mmol) of methyl 2-cyanoisonicotinate and 8mL of dioxane into a reaction bottle, and uniformly stirring;
s2, adding 6.5mL of 4M sodium hydroxide aqueous solution, reacting for 5h at 35 ℃, and tracking the reaction by TLC until the raw materials react completely;
s3, pH 6.2 with 4M hydrochloric acid, two extractions with DCM extractant, combined DCM layers at 40 deg.C and dried over magnesium sulfate, concentrated to dryness to remove solvent to obtain 2-aminoacyl isonicotinic acid.
By calculation, 0.92g of white solid was finally prepared with a yield of 89.5%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 2
The preparation method of this example is substantially the same as that of example 1 except that: step S1 is: methyl 2-cyanoisonicotinate (1 g, 6.17mmol) and dioxane (10 mL) were added to the reaction flask and stirred uniformly.
By calculation, 0.87g of white solid was finally prepared with a yield of 84.7%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 3
The preparation method of this example is substantially the same as that of example 1 except that: step S1 is: methyl 2-cyanoisonicotinate (1 g, 6.17mmol) and dioxane (5 mL) were added to the reaction flask and stirred uniformly.
By calculation, 0.89g of white solid was finally prepared with a yield of 86.8%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 4
The preparation method of this example is substantially the same as that of example 1 except that: step S2 is: then 8mL of 4M aqueous sodium hydroxide solution was added, the reaction was carried out at 35 ℃ for 5 hours, and the reaction was followed by TLC until the starting material reaction was complete.
By calculation, 0.88g of white solid was finally prepared with a yield of 86.4%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 5
The preparation method of this example is substantially the same as that of example 1 except that: step S2 is: then 6mL of 4M aqueous sodium hydroxide solution was added, the reaction was carried out at 35 ℃ for 5 hours, and the reaction was followed by TLC until the starting material was reacted completely.
By calculation, 0.84g of white solid was finally prepared with a yield of 82.1%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 6
The preparation method of this example is substantially the same as that of example 1 except that: step S2 is: then 6.5mL of 4M aqueous sodium hydroxide solution was added and the reaction was followed by TLC for 3h at 50 ℃ until the starting material was reacted completely.
By calculation, 0.86g of a white solid was finally prepared in a yield of 83.9%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 7
The preparation method of this example is substantially the same as that of example 1 except that: step S2 is: then 6.5mL of 4M aqueous sodium hydroxide solution was added, the reaction was carried out at 20 ℃ for 8 hours, and the reaction was followed by TLC until the starting material reaction was complete.
By calculation, 0.82g of white solid was finally prepared with a yield of 80.6%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 8
The preparation method of this example is substantially the same as that of example 1 except that: in step S3, the pH was adjusted to 7 with 4M hydrochloric acid.
By calculation, 0.83g of white solid was finally prepared with a yield of 81.2%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
example 9
The preparation method of this example is substantially the same as that of example 1 except that: in step S3, the pH is adjusted to 6 with 4M hydrochloric acid.
By calculation, 0.84g of white solid was finally prepared with a yield of 82.2%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 1
The comparative example was prepared substantially the same as example 1 except that step S1 was: methyl 2-cyanoisonicotinate (1 g, 6.17mmol) and dioxane (12 mL) were added to the reaction flask and stirred uniformly.
By calculation, 0.50g of white solid was finally prepared with a yield of 48.5%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 2
The comparative example was prepared substantially the same as example 1 except that step S1 was: methyl 2-cyanoisonicotinate (1 g, 6.17mmol) and dioxane (3 mL) were added to the reaction flask and stirred uniformly.
By calculation, 0.44g of white solid was finally prepared with a yield of 42.6%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 3
The comparative example was prepared essentially the same as example 1, except that: step S2 is: then 10mL of 4M aqueous sodium hydroxide solution was added, the reaction was carried out at 35 ℃ for 5 hours, and the reaction was followed by TLC until the starting material reaction was complete.
By calculation, 0.42g of white solid was finally prepared with a yield of 40.9%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 4
The comparative example was prepared essentially the same as example 1, except that: step S2 is: then 4mL of 4M aqueous sodium hydroxide solution was added, the reaction was carried out at 35 ℃ for 5 hours, and the reaction was followed by TLC until the starting material reaction was complete.
By calculation, 0.53g of white solid was finally prepared in 41.4% yield. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 5
The comparative example was prepared essentially the same as example 1, except that: step S2 is: then 6.5mL of 4M aqueous sodium hydroxide was added and the reaction was followed by TLC for 2h at 55 ℃ until the starting material was completely reacted.
By calculation, 0.51g of a white solid was finally prepared in a yield of 52.1%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 6
The comparative example was prepared essentially the same as example 1, except that: step S2 is: then 6.5mL of 4M aqueous sodium hydroxide was added, the reaction was carried out at 15 ℃ for 9 hours, and the reaction was followed by TLC until the starting material reaction was complete.
By calculation, 0.50g of white solid was finally prepared with a yield of 49.2%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 7
The comparative example was prepared essentially the same as example 1, except that: in step S3, the pH was adjusted to 7.5 with 4M hydrochloric acid.
By calculation, 0.53g of white solid was finally prepared in 51.8% yield. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 8
The comparative example was prepared essentially the same as example 1, except that: in step S3, the pH was adjusted to 5.5 with 4M hydrochloric acid.
By calculation, 0.52g of white solid was finally prepared with a yield of 50.6%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 9
The preparation method of the comparative example comprises the following steps:
s1, adding 1g (6.17mmol) of methyl 2-cyanoisonicotinate and 8mL of dioxane into a reaction bottle, and uniformly stirring;
s2, adding 6.5mL of 4M sodium carbonate aqueous solution, and reacting at 35 ℃ for 5 h;
s3, pH 6.2 with 4M hydrochloric acid, two extractions with DCM extractant, combined DCM layers at 40 deg.C and dried over magnesium sulfate, concentrated to dryness to remove solvent to obtain 2-aminoacyl isonicotinic acid.
By calculation, 0.14g of a white solid was finally prepared in a yield of 13.5%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 10
The preparation method of the comparative example comprises the following steps:
s1, adding 1g (6.17mmol) of methyl 2-cyanoisonicotinate and 8mL of tetrahydrofuran into a reaction bottle, and uniformly stirring;
s2, adding 6.5mL of 4M potassium carbonate aqueous solution, reacting for 5h at 35 ℃, and tracking the reaction by TLC until the raw materials are completely reacted;
s3, adjusting the pH value to 6.2 by using 4M hydrochloric acid, and extracting twice by using a DCM extractant.
By calculation, 0.05g of a white solid was finally prepared in a yield of 4.7%. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
comparative example 11
The preparation method of the comparative example comprises the following steps:
s1, adding 1g (6.17mmol) of methyl 2-cyanoisonicotinate and 8mL of isopropanol into a reaction bottle, and uniformly stirring;
s2, adding 6.5mL of 4M sodium bicarbonate aqueous solution, and reacting at 35 ℃ for 5 h;
s3, pH 6.2 with 4M hydrochloric acid, two extractions with DCM extractant, combined DCM layers at 40 deg.C and dried over magnesium sulfate, concentrated to dryness to remove solvent to obtain 2-aminoacyl isonicotinic acid.
The final liquid phase yield was calculated to be 0.3%, mostly other impurities. And (3) product verification:1H-NMR(400MHz,DMSO-d6):δ7.52(br s,1H),7.81(dd,J＝4.8,1.5Hz,1H),8.03(br s,1H),8.34(dd,J＝1.5,0.8Hz,1H),8.52ppm(dd,J＝4.8,0.8Hz,1H)。
by the preparation methods of the above examples 1 to 9 and comparative examples 1 to 11, the parameters such as the yield and the like obtained by the calculation and detection can be known as follows: by adopting the preparation method of the invention, the yield of the prepared 2-aminoacyl isonicotinic acid is higher and is not less than 80 percent. This shows that the ratio of the amount of methyl 2-cyanoisonicotinate to the amount of dioxane and sodium hydroxide has a significant effect on the yield of the final target product. In addition, the temperature, time and final pH of the reaction can affect the yield of the final desired product. If the dioxane is replaced by other materials such as tetrahydrofuran, isopropanol and the like or the sodium hydroxide solution is replaced by sodium carbonate, potassium carbonate and sodium bicarbonate aqueous solution instead of the combination of dioxane and sodium hydroxide of the invention, a large amount of 2-aminoacyl isonicotinic acid cannot be obtained, and even 2-aminoacyl isonicotinic acid is not basically produced. In step S3 of the above comparative examples 9-11, it was found by TLC tracing that the reaction was not completed after 5h, and the analysis may result in that the reaction itself could not proceed due to the change of the preparation method or condition parameters, or the reaction rate was very slow, which all indicate that the technical effects of the solutions of the comparative examples 9-11 are not as good as the solutions of the present application.
Claims (5)
1. A process for preparing 2-aminoacyl isonicotinic acid using methyl 2-cyanoisonicotinate comprising the steps of:
s1, uniformly mixing 2-cyanoisonicotinic acid methyl ester and dioxane, wherein the volume-to-mass ratio of dioxane to 2-cyanoisonicotinic acid is 5-10 mL/g;
s2, adding a 4M sodium hydroxide aqueous solution, reacting at 20-50 ℃ for 3-8h, and tracking the reaction by TLC until the raw materials are completely reacted, wherein the volume-to-mass ratio of the 4M sodium hydroxide aqueous solution to the 2-cyano methyl isonicotinate is 6-8 mL/g;
s3, adjusting pH to 6-7 with 4M hydrochloric acid, extracting twice with DCM extractant, combining DCM layers, drying with magnesium sulfate, and concentrating to remove solvent to obtain 2-aminoacyl isonicotinic acid.
2. The method for preparing 2-aminoacyl isonicotinic acid using methyl 2-cyanoisonicotinate according to claim 1, wherein the volume to mass ratio of dioxane to methyl 2-cyanoisonicotinate is 8 mL/g.
3. The process for preparing 2-aminoacyl isonicotinic acid using methyl 2-cyanoisonicotinate according to claim 1, wherein the volume to mass ratio of the 4M aqueous sodium hydroxide solution to methyl 2-cyanoisonicotinate is 6.5 mL/g.
4. The process for preparing 2-aminoacyl-isonicotinic acid using methyl 2-cyanoisonicotinate according to claim 1, wherein the reaction temperature is 35 ℃ and the reaction time is 5 hours in step S2.
5. The process for preparing 2-aminoacyl-isonicotinic acid using methyl-2-cyanoisonicotinate according to claim 1, wherein the pH of the solution is adjusted to 6.2 with 4M hydrochloric acid in step S3.
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| CA2539969C (en) * | 1993-06-01 | 2009-07-07 | Lonza Ltd. | Process for the preparation of carboxylic acids of nitrogen-containing aromatic heterocyclic compounds |
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| CN104910068B (en) * | 2015-04-24 | 2017-07-14 | 南京医科大学 | A kind of synthetic method of the tosilate of 2 cyano group isonicotinic acid hydrazide 1.5 |
| CN105130958B (en) * | 2015-08-31 | 2017-10-31 | 济南康和医药科技有限公司 | The preparation technology of 5 (pyridine radicals of 2 cyano group 4) 3 (4 pyridine radicals) 1,2,4 triazoles |
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