CN111285839A - Preparation method of medical intermediate 6-amino piperonal - Google Patents
Preparation method of medical intermediate 6-amino piperonal Download PDFInfo
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- CN111285839A CN111285839A CN202010118533.5A CN202010118533A CN111285839A CN 111285839 A CN111285839 A CN 111285839A CN 202010118533 A CN202010118533 A CN 202010118533A CN 111285839 A CN111285839 A CN 111285839A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/66—Nitrogen atoms not forming part of a nitro radical
Abstract
The invention discloses a preparation method of a medical intermediate 6-amino piperonal, which comprises the following steps: s1, adding piperonal into concentrated nitric acid for reaction, and then pouring into water; s2, extracting by using an organic solvent, and collecting an organic phase; s3, adding potassium permanganate into the organic phase, reacting at 90-120 ℃, filtering to remove solids, and collecting filtrate; s4, adding a palladium-carbon catalyst into the filtrate, reducing at 80-100 ℃ under the mixed gas of hydrogen and inert gas to obtain a crude product, and recrystallizing the crude product. Compared with the prior art, the preparation method omits the purification step of the intermediate product; the yield of the final product 6-amino piperonal is about 40-50%, so that the utilization rate of raw materials is obviously improved, the operation efficiency of enterprises is improved, the time cost and the material cost are saved for the enterprises, and the method has wide industrialization prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a medical intermediate 6-amino piperonal.
Background
Quinoline and derivatives thereof have important application in the aspect of resisting malaria of human bodies as core components of medicaments. In recent years, quinoline and various derivatives thereof synthesized by people are combined with carriers taking various proteins/amino acids as carriers, and have the characteristics of precise targeted delivery, low toxicity, high load capacity and the like. As reported, amino acid-8-aminoquinoline is important for eradicating recurrent Plasmodium vivax and Plasmodium ovale, and can effectively kill gametophyte and sporophyte, and the Plasmodium is hard to have drug resistance to the drug. With the expanding use of quinoline drugs in malaria, the demand for quinoline compounds is rising.
An important pharmaceutical intermediate for the artificial synthesis of quinoline is 6-amino piperonal, which has an amino group and an aldehyde group, both of which are very reactive, and thus can undergo a series of reactions such as cyclization, azidation, sulfonation, alkylation and the like. The chemical formula of 6-amino piperonal is shown as follows:
the traditional synthesis method is to nitrify piperonal to generate 6-nitro piperonal and then reduce nitro to generate 6-amino piperonal, and the preparation route is as follows:
however, this synthesis method has major disadvantages, which are mainly reflected as: in the step of nitrating piperonal into 6-nitro piperonal, the used oxidant is concentrated nitric acid with strong oxidability; the aldehyde group is an active group with reducibility, and is very easy to be oxidized by concentrated nitric acid, so that byproducts except 6-nitro piperonal are generated, and the proportion of the byproducts in the final product is large and about 40-50% of the final product, so that the yield of the product is inevitably reduced; the polarity of the by-product is equivalent to that of 6-nitro piperonal, so that the by-product is difficult to separate, and the yield of the 6-nitro piperonal obtained in the step is only about 50 percent; then the 6-nitro piperonal is reduced into 6-amino piperonal, the adopted reducing agent is iron, and the yield is only about 60 percent. Therefore, the total yield of the two-step reaction is only 30%, so that a large amount of raw material cost and time cost are greatly consumed, the large-scale application of the 6-amino piperonal is prevented, and the production cost of enterprises is also increased.
Therefore, a new method for preparing 6-amino piperonal is needed to solve the problems of low production yield and high production cost of the final product.
Disclosure of Invention
The invention aims to provide a preparation method of 6-amino piperonal, which takes piperonal as a raw material, does not need further purification in the intermediate reaction process, and finally obtains the 6-amino piperonal with the total yield of about 60-70%. Compared with the prior art, the method greatly reduces the time cost and the material cost of enterprise production, and has an industrial prospect.
The present invention is realized by the following technical means.
A preparation method of a medical intermediate 6-amino piperonal comprises the following steps:
s1, adding piperonal into concentrated nitric acid for reaction, and then pouring into water;
s2, extracting by using an organic solvent, and collecting an organic phase;
s3, adding potassium permanganate into the organic phase, reacting at 90-120 ℃, filtering to remove solids, and collecting filtrate;
s4, adding a palladium-carbon catalyst into the filtrate, reducing at 80-100 ℃ under the mixed gas of hydrogen and inert gas to obtain a crude product, and recrystallizing the crude product.
Further, the reaction in S1 is performed in an ice bath for 0.5 to 2 hours.
Further, the organic solvent in S2 is selected from dichloromethane or ethyl acetate.
Further, the adding amount of the potassium permanganate in the S3 is 2-4 times of the molar amount of the piperonal.
Further, the S3 adopts mechanical stirring, and the rotating speed is 200-500 rpm.
Further, the palladium-carbon catalyst in S4 is prepared by the following steps:
(1) putting activated carbon into deionized water, and stirring at 60-80 ℃ to form slurry;
(2) gradually dripping hydrochloric acid solution of palladium chloride into the slurry, and stirring to form a mixture;
(3) dripping aldehyde into the mixture, reacting for 3-5h at 80-100 ℃, and then filtering and drying to obtain a solid;
(4) and soaking the solid in concentrated sulfuric acid for 24-48h, and then washing and drying to obtain the palladium-carbon catalyst.
Further, in the S4, the molar ratio of the hydrogen to the inert gas is 1:1-4: 1.
Further, in the S4, the reaction time is 2-4 h.
Further, in S4, the solvent used for recrystallization is a mixed solvent of a polar solvent and a non-polar solvent,
wherein the polar solvent is selected from methanol, ethanol, n-propanol, n-butanol or tert-butanol,
the nonpolar solvent is selected from petroleum ether, cyclohexane or carbon tetrachloride;
the volume ratio of the polar solvent to the non-polar solvent is 1:1-3: 1;
the recrystallization temperature is-15-0 ℃.
The invention has the following beneficial effects:
the method comprises the steps of nitrifying raw material piperonal with concentrated nitric acid, deeply oxidizing the obtained nitrified crude product solution with potassium permanganate to obtain a completely oxidized intermediate product 6-nitro-piperic acid, wherein the intermediate product is directly reduced by using mixed gas of hydrogen and inert gas under the catalysis system of a palladium-carbon catalyst without further purification. Wherein, the ratio of hydrogen and inert gas in the mixed gas needs to be controlled: experiments are carried out in the later examples of the invention, if the content of hydrogen in the mixed gas is too high (such as 5:1, n/n), the reducibility of the reduction system is too strong, so that the reduction degree of carboxyl on the 6-nitro-piperic acid is difficult to control at the stage of aldehyde group in the reduction process of the hydrogen on the 6-nitro-piperic acid, and the hydrogen is further reduced into alcohol group, thereby reducing the yield and purity of the final product; if the hydrogen content in the mixed gas is too low (e.g., 0.6:1, n/n), the reducibility is insufficient, and the nitro group and the carboxyl group in the 6-nitro piperic acid cannot be sufficiently reduced to the amino group and the aldehyde group, respectively. The final purity of the crude product of the 6-amino piperonal is more than 99 percent after recrystallization treatment.
The prior art prepares 6-amino piperonal by two steps of nitrating piperonal into 6-nitro piperonal and reducing 6-nitro piperonal into 6-amino piperonal. Wherein, the yield of the first step is only about 50 percent, and the yield of the second step is only about 60 percent, so the total yield of the two steps is low and is only about 30 percent, thereby greatly consuming a large amount of raw material cost and time cost, also preventing the large-scale application of the 6-amino piperonal and improving the production cost of enterprises. The method adopted by the invention is that the raw material piperonal is firstly nitrified by concentrated nitric acid and then deeply oxidized by potassium permanganate to respectively oxidize all groups with reducibility in related compounds into carboxyl and nitro, and the obtained intermediate product does not need to be further purified, thereby reducing the loss of the compounds and saving the time and labor cost consumed by purification; and then reducing the intermediate product under the reducing system of the mixed gas to obtain the 6-amino piperonal. The yield of the 6-amino piperonal prepared by the synthetic route disclosed by the invention is about 40-50%, which is far higher than 30% reported by the prior art. Therefore, the utilization rate of the raw materials is remarkably improved, the operation efficiency of enterprises is improved, the time cost and the material cost are saved for the enterprises, the method is expected to replace the prior art, becomes a new technology for preparing the 6-amino piperonal, is popularized, and has wide industrialization prospect.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. The starting materials and methods described in the examples herein are, unless otherwise indicated, conventional in the art.
Example 1
A preparation method of a medical intermediate 6-amino piperonal comprises the following steps:
s1, under an ice bath, adding 100g of piperonal into 500ml of concentrated nitric acid for reaction for 0.5h, and then pouring into 10L of water;
s2, extracting the product by using 200ml of dichloromethane, and collecting an organic phase;
s3 adding 2 times molar weight of potassium permanganate into the organic phase, and reacting for 3h at 90 ℃ under the condition of mechanical stirring, wherein the rotation speed of the mechanical stirring is 200 rpm. Then filtering to remove a solid mixture of potassium permanganate and manganese dioxide, and collecting filtrate;
s4, adding a palladium carbon catalyst with the amount of 0.2 wt% of piperonal into the filtrate, reacting at 80 ℃ under the mixed gas of hydrogen and argon gas (1:1, n/n) to obtain a crude product of 6-amino piperonal, and recrystallizing the crude product to obtain the 6-amino piperonal with the yield of 45%.
Wherein, the solvents adopted by the recrystallization are methanol and petroleum ether (1:1, v/v), and the recrystallization temperature is-15 ℃.
The palladium-carbon catalyst is prepared by the following steps:
(1) 2g of activated carbon is placed in 10g of deionized water and stirred for 0.5h at the temperature of 60 ℃ to form slurry;
(2) preparing 20 wt% hydrochloric acid solution of palladium chloride from palladium chloride in an equimolar amount with the activated carbon, gradually dropping the hydrochloric acid solution into the slurry, and stirring for 2 hours to form a mixture;
(3) dripping 2ml of formaldehyde into the mixture, reacting for 3 hours at 80 ℃, and then filtering and drying to obtain a solid;
(4) and soaking the solid in concentrated sulfuric acid for 24 hours, taking out, washing and drying to obtain the palladium-carbon catalyst.
Example 2
A preparation method of a medical intermediate 6-amino piperonal comprises the following steps:
s1, under an ice bath, adding 100g of piperonal into 500ml of concentrated nitric acid for reaction for 2 hours, and then pouring into 10L of water;
s2, extracting the product by using 200ml of ethyl acetate, and collecting an organic phase;
s3 adding 4 times molar weight of potassium permanganate into the organic phase, and reacting for 3h at 120 ℃ under the condition of mechanical stirring, wherein the rotation speed of the mechanical stirring is 500 rpm. Then filtering to remove a solid mixture of potassium permanganate and manganese dioxide, and collecting filtrate;
s4, adding a palladium carbon catalyst with the amount of 0.5 wt% of piperonal into the filtrate, reacting at 100 ℃ under a mixed gas of hydrogen and argon gas (4:1, n/n) to obtain a crude product of 6-amino piperonal, and recrystallizing the crude product to obtain the 6-amino piperonal with the yield of 50%.
Wherein, the solvents adopted by recrystallization are ethanol and carbon tetrachloride (3:1, v/v), and the recrystallization temperature is 0 ℃.
The palladium-carbon catalyst is prepared by the following steps:
(1) 2g of activated carbon is placed in 10g of deionized water and stirred for 0.5h at 80 ℃ to form slurry;
(2) preparing a hydrochloric acid solution of palladium chloride with the molar quantity equal to that of the activated carbon into 30 wt% palladium chloride, gradually dropping the hydrochloric acid solution into the slurry, and stirring for 3 hours to form a mixture;
(3) dripping 3ml of formaldehyde into the mixture, reacting for 5 hours at 100 ℃, and then filtering and drying to obtain a solid;
(4) and soaking the solid in concentrated sulfuric acid for 48 hours, taking out, washing and drying to obtain the palladium-carbon catalyst.
Example 3
A preparation method of a medical intermediate 6-amino piperonal comprises the following steps:
s1, under an ice bath, adding 100g of piperonal into 500ml of concentrated nitric acid for reaction for 2 hours, and then pouring into 10L of water;
s2, extracting the product by using 200ml of ethyl acetate, and collecting an organic phase;
s3 Potassium permanganate with 3 times of molar weight of piperonal is added into the organic phase and reacts for 3 hours at 100 ℃ under the condition of mechanical stirring, and the rotating speed of the mechanical stirring is 300 rpm. Then filtering to remove a solid mixture of potassium permanganate and manganese dioxide, and collecting filtrate;
s4, adding a palladium carbon catalyst with the amount of 0.4 wt% of piperonal into the filtrate, reacting at 90 ℃ under a mixed gas of hydrogen and argon gas (2:1, n/n) to obtain a crude product of 6-amino piperonal, and recrystallizing the crude product to obtain the 6-amino piperonal with the yield of 46%.
Wherein, the solvents adopted by the recrystallization are n-propanol and cyclohexane (2:1, v/v), and the recrystallization temperature is-5 ℃.
The palladium-carbon catalyst is prepared by the following steps:
(1) 2g of activated carbon is placed in 10g of deionized water and stirred for 1 hour at 70 ℃ to form slurry;
(2) preparing 25 wt% hydrochloric acid solution of palladium chloride from palladium chloride in an amount equal to the molar amount of the activated carbon, gradually dropping the hydrochloric acid solution into the slurry, and stirring for 3 hours to form a mixture;
(3) dripping 3ml of formaldehyde into the mixture, reacting for 4 hours at 90 ℃, and then filtering and drying to obtain a solid;
(4) and soaking the solid in concentrated sulfuric acid for 30 hours, taking out, washing and drying to obtain the palladium-carbon catalyst.
Example 4
A preparation method of a medical intermediate 6-amino piperonal comprises the following steps:
s1, under an ice bath, adding 100g of piperonal into 500ml of concentrated nitric acid for reaction for 2 hours, and then pouring into 10L of water;
s2, extracting the product by using 200ml of dichloromethane, and collecting an organic phase;
s3 Potassium permanganate with the molar weight being 2.5 times of that of piperonal is added into the organic phase to react for 3 hours at the temperature of 105 ℃ under the condition of mechanical stirring, and the rotating speed of the mechanical stirring is 300 rpm. Then filtering to remove a solid mixture of potassium permanganate and manganese dioxide, and collecting filtrate;
s4, adding a palladium carbon catalyst with the amount of 0.4 wt% of piperonal into the filtrate, reacting at 95 ℃ under a mixed gas of hydrogen and argon gas (3:1, n/n) to obtain a crude product of 6-amino piperonal, and recrystallizing the crude product to obtain the 6-amino piperonal with the yield of 46%.
Wherein, the solvents adopted by the recrystallization are n-butanol and cyclohexane (2.5:1, v/v), and the recrystallization temperature is-6 ℃.
The palladium-carbon catalyst is prepared by the following steps:
(1) 2g of activated carbon is placed in 10g of deionized water and stirred for 1 hour at the temperature of 75 ℃ to form slurry;
(2) preparing 25 wt% hydrochloric acid solution of palladium chloride from palladium chloride in an amount equal to the molar amount of the activated carbon, gradually dropping the hydrochloric acid solution into the slurry, and stirring for 3 hours to form a mixture;
(3) dripping 4ml of formaldehyde into the mixture, reacting for 3.5 hours at 95 ℃, and then filtering and drying to obtain a solid;
(4) and soaking the solid in concentrated sulfuric acid for 36 hours, taking out, washing and drying to obtain the palladium-carbon catalyst.
Comparative example 1
Comparative example 1 is the same as the preparation method of example 1, except that the preparation method of comparative example 1 does not include S3, but the organic phase in S2 is directly subjected to the treatment of S4.
Comparative example 2
Comparative example 2 is the same as the preparation method of example 1, except that in S3 of the preparation method of comparative example 2, mechanical stirring is not employed, but magnetic stirring is employed.
Comparative example 3
Comparative example 3 is the same as the preparation method of example 1 except that pure hydrogen gas is introduced in S4 of the preparation method of comparative example 3.
Comparative example 4
Comparative example 4 is the same as the production method of example 1 except that in S4 of the production method of comparative example 4, a mixed gas of hydrogen gas and argon gas (5:1, n/n) was introduced.
Comparative example 5
Comparative example 5 is the same as the production method of example 1 except that in S4 of the production method of comparative example 5, a mixed gas of hydrogen gas and argon gas (0.6:1, n/n) was introduced.
Comparative example 6
Comparative example 6 is the same as the preparation method of example 1, except that the palladium on carbon catalyst is not soaked in concentrated sulfuric acid in S4 of the preparation method of comparative example 6.
Example 5
The purity and yield of 6-aminopiperonal of examples 1 to 4 and comparative examples 1 to 6 were examined and the results are shown in Table 1.
Wherein, the purity of the 6-amino piperonal is measured by a GC-MS instrument produced by Agilent company;
the yield of 6-aminopiperonal was determined according to the following formula:
[ (n) 6-Aminopiperidal ]/[ (n) piperonal ]. times.100%
Table 1 purity and yield results for example 1 and comparative examples 1-4
| Purity of 6-amino piperonal (%) | Yield (%) of 6-aminopiperonal | |
| Example 1 | 99.1 | 45 |
| Example 2 | 99.3 | 50 |
| Example 3 | 99.1 | 46 |
| Example 4 | 99.5 | 46 |
| Comparative example 1 | 94.3 | 32 |
| Comparative example 2 | 95.5 | 32 |
| Comparative example 3 | 96.7 | 35 |
| Comparative example 4 | 98.7 | 31 |
| Comparative example 5 | 98.5 | 28 |
| Comparative example 6 | 97.5 | 28 |
As can be seen from the above table, the purity of the 6-amino piperonal obtained in examples 1 to 4 is above 99%, and the yield is above 60%, and can reach 50% at most, which is obviously improved compared with the yield in the prior art. In comparative examples 1 to 6, the preparation methods were different from those of example 1, and thus 6-aminopiperonal was obtained in a lower degree of purity and yield than those of example 1. The specific reason is as follows: in comparative example 1, the intermediate product was not deeply oxidized with potassium permanganate, so that the intermediate product obtained contained a small amount of a mixture of other components such as an intermediate oxide formed from 6-nitro piperonal which was not sufficiently oxidized, but not efficiently reduced to 6-amino piperonal in a reduction system of palladium on carbon catalyst and hydrogen, resulting in excessive impurities in the final product, and high purity of 6-amino piperonal could not be obtained even by recrystallization; in comparative example 2, potassium permanganate, a solid, was not allowed to react sufficiently with the intermediate product in the organic phase without using a strong mechanical stirring method, resulting in a similar result to comparative example 1; the reduction systems used in comparative examples 3 to 4 were pure hydrogen and a mixed gas of hydrogen and argon gas (5:1, n/n), respectively, and the reducibility of the two reduction systems was so strong that it was difficult for hydrogen to control the degree of reduction of carboxyl groups on 6-nitropiperic acid at the stage of aldehyde groups in the reduction process for 6-nitropiperic acid, but further reduced to alcohol groups, thereby causing a decrease in yield and purity of the final product; the reduction system used in comparative example 5 was a mixed gas of hydrogen and argon gas (0.6:1, n/n), in which the hydrogen content was too small and thus the reduction was insufficient, resulting in too much insufficiently reduced substances in the resulting product. Therefore, it is difficult to obtain the final product with high purity and high yield after recrystallization in comparison 3-5. In comparative example 6, sulfur element can be introduced on the surface of the palladium-carbon catalyst by sufficiently soaking the palladium-carbon catalyst with concentrated sulfuric acid, which is helpful for forming a catalytic activity center, thereby improving the reaction activity of the palladium-carbon catalyst. In contrast, in comparative example 4, the palladium-carbon catalyst is not soaked in concentrated sulfuric acid, so that the high-activity center formed in the palladium-carbon catalyst is insufficient, thereby affecting the reaction activity of the palladium-carbon catalyst and slightly reducing the yield and purity of the final product.
The above comparison of examples 1-4 with comparative examples 1-6 fully demonstrates the advancement of the presently disclosed solution.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and are intended to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (9)
1. A preparation method of a medical intermediate 6-amino piperonal is characterized by comprising the following steps:
s1, adding piperonal into concentrated nitric acid for reaction, and then pouring into water;
s2, extracting by using an organic solvent, and collecting an organic phase;
s3, adding potassium permanganate into the organic phase, reacting at 90-120 ℃, filtering to remove solids, and collecting filtrate;
s4, adding a palladium-carbon catalyst into the filtrate, reducing at 80-100 ℃ under the mixed gas of hydrogen and inert gas to obtain a crude product, and recrystallizing the crude product.
2. The preparation method of the pharmaceutical intermediate 6-aminopiperonal as claimed in claim 1, wherein the reaction in S1 is performed in ice bath for 0.5-2 h.
3. The method for preparing 6-amino piperonal as a pharmaceutical intermediate of claim 1, wherein the organic solvent in S2 is selected from dichloromethane or ethyl acetate.
4. The preparation method of the medical intermediate 6-amino piperonal as claimed in claim 1, wherein the amount of potassium permanganate added in S3 is 2-4 times the molar amount of piperonal.
5. The preparation method of the pharmaceutical intermediate 6-aminopiperonal as claimed in claim 1, wherein the S3 is mechanically stirred at 200-500 rpm.
6. The preparation method of 6-aminopiperonal as a pharmaceutical intermediate of claim 1, wherein the palladium-carbon catalyst in S4 is prepared by the following steps:
(1) putting activated carbon into deionized water, and stirring at 60-80 ℃ to form slurry;
(2) gradually dripping hydrochloric acid solution of palladium chloride into the slurry, and stirring to form a mixture;
(3) dripping aldehyde into the mixture, reacting for 3-5h at 80-100 ℃, and then filtering and drying to obtain a solid;
(4) and soaking the solid in concentrated sulfuric acid for 24-48h, and then washing and drying to obtain the palladium-carbon catalyst.
7. The method for preparing 6-amino piperonal as a medical intermediate of claim 1, wherein the molar ratio of hydrogen to inert gas in S4 is 1:1-4: 1.
8. The method for preparing 6-aminopiperonal as a pharmaceutical intermediate of claim 1, wherein the reaction time in S4 is 2-4 h.
9. The method for preparing 6-amino piperonal as a pharmaceutical intermediate of claim 1, wherein the solvent used for recrystallization in S4 is a mixed solvent of a polar solvent and a nonpolar solvent,
wherein the polar solvent is selected from methanol, ethanol, n-propanol, n-butanol or tert-butanol,
the nonpolar solvent is selected from petroleum ether, cyclohexane or carbon tetrachloride;
the volume ratio of the polar solvent to the non-polar solvent is 1:1-3: 1;
the recrystallization temperature is-15-0 ℃.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030774A1 (en) * | 2003-09-26 | 2005-04-07 | Rigel Pharmaceuticals, Inc. | Hcv inhibitors and methods of using them |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030774A1 (en) * | 2003-09-26 | 2005-04-07 | Rigel Pharmaceuticals, Inc. | Hcv inhibitors and methods of using them |
Non-Patent Citations (4)
| Title |
|---|
| BHUPESH S.SAMANT: "Synthesis and Comparison of Antimalarial Activity of Febrifugine Derivatives Including Halofuginone", 《MEDICINAL CHEMISTRY》 * |
| JORGE LUIZ R. DE MELOS等: "Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 邢其毅: "《基础有机化学 上 第3版》", 30 June 2005 * |
| 韩英峰等: "6-硝基胡椒酸的合成", 《合成化学》 * |
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