CN115108975A - Preparation method of nicotinic acid - Google Patents
Preparation method of nicotinic acid Download PDFInfo
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- CN115108975A CN115108975A CN202210801432.7A CN202210801432A CN115108975A CN 115108975 A CN115108975 A CN 115108975A CN 202210801432 A CN202210801432 A CN 202210801432A CN 115108975 A CN115108975 A CN 115108975A
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- nicotinic acid
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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
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
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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
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a preparation method of nicotinic acid, belonging to the technical field of chemical synthesis. According to the preparation method of the nicotinic acid, quinoline and an oxidant are subjected to oxidation reaction, and then the nicotinic acid is obtained through oxidation hydrolysis, reduced pressure distillation, cooling crystallization and separation in sequence; the method has the advantages of simple process, mild reaction conditions, no pollution and easy product separation, the yield of the prepared nicotinic acid product reaches up to 90 percent, the product content reaches 99.8 percent, the maximum impurity content is 0.02 percent, the quality requirement is met, and the requirement of high-standard medicine production is met. The method for preparing nicotinic acid represents the scientific development trend of energy conservation, consumption reduction and resource environmental protection, and has high technical content and obvious environmental protection significance.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of nicotinic acid.
Background
Nicotinic acid belongs to vitamin B3, also called nicotinic acid, scabby disease resisting factor, molecular formula: c 6 H 5 NO 2 3-picolinic acid, which has good thermal stability and can be sublimed, and the nicotinic acid is purified by a sublimation method in industry. Nicotinic acid is white or white-like crystal in appearance, is soluble in water, and mainly exists in internal organs and muscles of animalsMeat tissue, fruits and egg yolks are also present in a trace amount, are one of 13 vitamins essential to human bodies and belong to a vitamin B group. Nicotinic acid is an important medical raw material and chemical intermediate. Nicotinic acid can be used for synthesizing a plurality of medicines for treating various skin diseases, hypertension, coronary heart disease and the like, and can also be used as a medicine intermediate for producing isoniazid, nicotemamil and inositol nicotinate. Nicotinic acid is also widely used in luminescent materials, dyes, animal feeds, and the like.
At present, 3-methylpyridine and 2-methyl-5-ethylpyridine are used as raw materials, potassium permanganate, nitric acid, mixed acid or air are used as oxidants, and nicotinic acid is obtained through oxidation or catalytic oxidation. These methods require high temperature and high pressure, the reaction conditions are severe, the pollution of three costs is serious, and the separation of products is difficult.
Disclosure of Invention
The invention aims to provide a preparation method of nicotinic acid, which has the advantages of simple process, mild reaction condition, no pollution and easy product separation.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of nicotinic acid, which comprises the following steps:
mixing quinoline, an oxidant and water, and carrying out an oxidation reaction under the condition of introducing oxygen to obtain an oxidation product;
and mixing the oxidation product with hydrogen peroxide, carrying out oxidation hydrolysis reaction, and sequentially carrying out reduced pressure distillation, crystallization and separation on the obtained product to obtain the nicotinic acid.
Preferably, the oxidizing agent is sulfuric acid; the mass concentration of the sulfuric acid is 98%.
Preferably, the mass ratio of the quinoline to the oxidant to the water is (150-160): 15: 1500.
Preferably, the gas flow rate of the oxygen is 2.0-2.5L/min.
Preferably, the temperature of the oxidation reaction is 40-50 ℃ and the time is 4-5 h.
Preferably, the mass ratio of the quinoline to the hydrogen peroxide is (150-160) to (270-280); the mass concentration of the hydrogen peroxide is 27%.
Preferably, the temperature of the oxidation hydrolysis reaction is 70-80 ℃, and the time is 2-3 h.
Preferably, the temperature of the reduced pressure distillation is 60-70 ℃, and the vacuum degree is-0.06-0.08 MPa.
Preferably, the crystallization temperature is 0-5 ℃, and the heat preservation time is 1-2 h.
Preferably, the separation mode is centrifugal separation.
The invention provides a preparation method of nicotinic acid, which comprises the following steps: mixing quinoline, an oxidant and water, and carrying out an oxidation reaction under the condition of introducing oxygen to obtain an oxidation product; and mixing the oxidation product with hydrogen peroxide, carrying out oxidation hydrolysis reaction, and sequentially carrying out reduced pressure distillation, crystallization and separation on the obtained product to obtain the nicotinic acid. After quinoline and an oxidant are subjected to oxidation reaction, sequentially carrying out oxidation hydrolysis, reduced pressure distillation, cooling crystallization and separation to obtain nicotinic acid; the method has the advantages of simple process, mild reaction conditions, no pollution and easy product separation, the yield of the prepared nicotinic acid product reaches up to 90 percent, the product content reaches 99.8 percent, the maximum impurity content is 0.02 percent, the quality requirement is met, and the requirement of high-standard medicine production is met. The method for preparing nicotinic acid represents the scientific development trend of energy conservation, consumption reduction and resource environmental protection, and has high technical content and obvious environmental protection significance.
Drawings
FIG. 1 is a process flow diagram for the preparation of nicotinic acid according to the present invention;
FIG. 2 is a liquid chromatogram for measuring the nicotinic acid content in example 1.
Detailed Description
As shown in fig. 1, the invention provides a method for preparing nicotinic acid, which comprises the following steps:
mixing quinoline, an oxidant and water, and carrying out an oxidation reaction under the condition of introducing oxygen to obtain an oxidation product;
and mixing the oxidation product with hydrogen peroxide, carrying out oxidation hydrolysis reaction, and sequentially carrying out reduced pressure distillation, crystallization and separation on the obtained product to obtain the nicotinic acid.
In the present invention, unless otherwise specified, all the starting materials required for the preparation are commercially available products well known to those skilled in the art.
Quinoline, an oxidant and water are mixed, and oxidation reaction is carried out under the condition of introducing oxygen to obtain an oxidation product.
In the present invention, the oxidizing agent is preferably sulfuric acid; the mass concentration of the sulfuric acid is preferably 98%.
In the present invention, the process of mixing quinoline, oxidant and water is preferably: adding water and sulfuric acid into a four-neck flask, adding quinoline under the condition of stirring, uniformly stirring, and pouring into a bubbling reactor. The stirring rate is not particularly limited in the present invention and may be carried out according to a procedure well known in the art.
In the invention, the mass ratio of quinoline to oxidant to water is preferably (150-160): 15:1500, and more preferably 150:15: 1500.
The process of introducing oxygen is not particularly limited in the present invention, and oxygen may be introduced into the bubble reactor according to a process well known in the art. The invention selects a bubbling reactor as a main reactor, liquid is filled in a tower, gas is introduced from the bottom of the reactor and dispersed into bubbles to rise along the liquid, and the bubbles are contacted with the liquid phase for reaction and simultaneously stir the liquid to increase the mass transfer rate.
In the invention, the gas flow of the oxygen is preferably 2.0-2.5L/min.
In the invention, the temperature of the oxidation reaction is preferably 40-50 ℃, more preferably 45 ℃, and the time is preferably 4-5 h.
In the oxidation reaction process, oxygen reacts with benzene rings in quinoline to generate oxides, and quinoline can be generated into quinoline sulfate by adding concentrated sulfuric acid, so that pyridine is protected from being oxidized, and side reactions are reduced.
After the oxidation reaction is finished, preferably, the obtained product is sampled and detected, when the detection is qualified (the quinoline content is less than or equal to 0.5 wt%), the oxidation reaction is ended to obtain an oxidation product, and if the detection is unqualified, the heat preservation reaction is continued. In the present invention, the method of detection is preferably liquid chromatography detection; the liquid chromatography detection process is not particularly limited in the present invention, and the detection may be performed according to a method well known in the art.
After an oxidation product is obtained, the oxidation product is directly mixed with hydrogen peroxide to carry out oxidation hydrolysis reaction, and the obtained product is subjected to reduced pressure distillation, crystallization and separation in sequence to obtain the nicotinic acid.
In the invention, the mass ratio of quinoline to hydrogen peroxide is preferably (150-160) to (270-280); the mass concentration of the hydrogen peroxide is preferably 27%.
The method preferably transfers the oxidation product into a reaction bottle, the temperature is raised to 55-60 ℃, and hydrogen peroxide is dripped, and the method preferably finishes dripping hydrogen peroxide within 1.5-2 h and raises the temperature to the temperature of the oxidation hydrolysis reaction. The rate of the addition and the temperature rise is not particularly limited in the present invention, and may be carried out according to a procedure well known in the art.
In the invention, the temperature of the oxidation hydrolysis reaction is preferably 70-80 ℃, and the time is preferably 2-3 h; in the oxidation hydrolysis reaction process, the oxidation reaction product and hydrogen peroxide are subjected to hydrolysis reaction to obtain nicotinic acid, and the reaction formula is as follows:
during the oxidation hydrolysis reaction, the invention preferably samples and detects until the content of the oxidation product is less than or equal to 1.0 wt%, and the reaction is finished.
In the invention, the temperature of the reduced pressure distillation is preferably 60-70 ℃, and more preferably 65 ℃; the vacuum degree is preferably-0.06 to-0.08 MPa; the present invention preferably removes 1/2 volumes of water by distillation under reduced pressure.
After the reduced pressure distillation is finished, the obtained product is cooled and crystallized; the crystallization temperature is preferably 0-5 ℃, and the heat preservation time is preferably 1-2 h. The process of cooling is not particularly limited in the present invention, and cooling may be performed according to a process well known in the art.
After the crystallization is finished, separating the precipitated product to obtain nicotinic acid; the separation is preferably by centrifugation. The separation process is not particularly limited in the present invention, and may be carried out according to a process well known in the art.
The nicotinic acid product prepared by the invention has a nicotinic acid content of more than or equal to 99 wt%.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. 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.
Examples 1 to 2
1500g of process water and 15g of sulfuric acid are added into a 2L four-neck flask, 150g of quinoline is added under stirring, the mixture is poured into a bubbling reactor after being evenly stirred, and O is started to be introduced 2 Reacting, wherein the gas flow is 2.5L/min, the reaction temperature is controlled (the specific temperature is shown in table 1), sampling and detecting are carried out after 4 hours of reaction until the quinoline content is less than or equal to 0.5 wt%, and the reaction is finished to obtain an oxidation product;
transferring the oxidation product into a 2L reaction bottle, heating to 55 ℃, starting to dropwise add 270g of 27% hydrogen peroxide, slowly dropwise adding, controlling the dropwise adding within 1.5h, heating to 80 ℃ after the dropwise adding, preserving heat for reaction for 3h until the content of the oxidation product is less than or equal to 1.0 wt%, and finishing the reaction; distilling the obtained product under reduced pressure to remove 1/2 volumes of water, wherein the distillation temperature is 65 ℃, and the vacuum is-0.06 MPa; and cooling the obtained product after distillation to 0 ℃ for crystallization, preserving heat for 1h, and centrifuging the separated product to obtain the nicotinic acid product.
Performing liquid chromatography detection on nicotinic acid products prepared in different cases, wherein the detection conditions are as follows: a chromatographic column: ZORBBAX extended-C18 high performance liquid chromatography column or performance equivalent chromatography column, the column temperature is 35 ℃; mobile phase: mixing 20mL of isopropanol and 1.0g of sodium heptanesulfonate, dissolving the mixture to 1L by using deionized water, adjusting the pH value to 3.0 by using glacial acetic acid, adjusting the pH value to 2 by using 0.1mol/L hydrochloric acid, and obtaining a chromatogram shown in figure 2; as can be seen from FIG. 2, the nicotinic acid content in the prepared nicotinic acid product is 99.8 wt%.
Comparative examples 1 to 2
Comparative examples 1-2 differ from example 1 only in that: the oxidation reaction temperatures are shown in Table 1.
TABLE 1 raw material amounts, reaction conditions and product indexes of examples 1 to 2 and comparative examples 1 to 2
| Case(s) | Quinoline g | Sulfuric acid g | Temperature of | G hydrogen peroxide | Yield% | The content wt% |
| Example 1 | 150 | 15 | 40 | 270 | 90.3 | 99.8 |
| Example 2 | 150 | 15 | 50 | 270 | 90.5 | 99.6 |
| Comparative example 1 | 150 | 15 | 30 | 270 | 84.5 | 85.5 |
| Comparative example 2 | 150 | 15 | 60 | 270 | 86.3 | 83.4 |
As can be seen from Table 1, the temperature of the oxidation reaction needs to be controlled to be 40-50 ℃, and excessive high or low temperature can affect the oxidation reaction, thereby affecting the yield and the content of the hydrochloric acid product.
Comparative examples 3 to 5
The only difference from example 1 is: the amount of sulfuric acid used was varied and is shown in Table 2.
TABLE 2 raw material amounts, reaction conditions and product indices of comparative examples 3 to 5 and example 1
| Case(s) | Quinoline g | Sulfuric acid g | Temperature of | Color of solution | Yield% | The content wt% |
| Comparative example 3 | 150 | 0 | 40 | Yellow brown | 64.5 | 75.5 |
| Comparative example 4 | 150 | 10 | 40 | Light yellow | 78.3 | 85.8 |
| Comparative example 5 | 150 | 20 | 40 | Yellow colour | 85.5 | 95.6 |
| Example 1 | 150 | 15 | 40 | Light yellow | 90.3 | 99.8 |
As can be seen from table 2, m (quinoline): the mass ratio of m (concentrated sulfuric acid) is preferably 10:1, and the presence of excessive concentrated sulfuric acid results in deepening of the reaction color and lowering of the yield of the product.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The preparation method of the nicotinic acid is characterized by comprising the following steps:
mixing quinoline, an oxidant and water, and carrying out an oxidation reaction under the condition of introducing oxygen to obtain an oxidation product;
and mixing the oxidation product with hydrogen peroxide, carrying out oxidation hydrolysis reaction, and sequentially carrying out reduced pressure distillation, crystallization and separation on the obtained product to obtain the nicotinic acid.
2. The production method according to claim 1, wherein the oxidizing agent is sulfuric acid; the mass concentration of the sulfuric acid is 98%.
3. The preparation method according to claim 1, wherein the mass ratio of the quinoline to the oxidizing agent to the water is (150-160) to 15: 1500.
4. The method according to claim 1, wherein the flow rate of the oxygen gas is 2.0 to 2.5L/min.
5. The preparation method according to claim 1, wherein the temperature of the oxidation reaction is 40-50 ℃ and the time is 4-5 h.
6. The preparation method according to claim 1, wherein the mass ratio of quinoline to hydrogen peroxide is (150-160): (270-280); the mass concentration of the hydrogen peroxide is 27%.
7. The preparation method according to claim 1, wherein the temperature of the oxidative hydrolysis reaction is 70-80 ℃ and the time is 2-3 h.
8. The method according to claim 1, wherein the temperature of the reduced pressure distillation is 60 to 70 ℃ and the degree of vacuum is-0.06 to-0.08 MPa.
9. The preparation method according to claim 1, wherein the temperature for crystallization is 0-5 ℃ and the holding time is 1-2 h.
10. The method of claim 1, wherein the separation is by centrifugation.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4537971A (en) * | 1981-05-06 | 1985-08-27 | The Hilton-Davis Chemical Co. | Process for preparing quinolinic acid |
| CN1141288A (en) * | 1996-04-26 | 1997-01-29 | 清华紫光(集团)总公司 | Process for preparing nicotinic acid |
| CN1962637A (en) * | 2006-11-27 | 2007-05-16 | 中国科学院新疆理化技术研究所 | Ozonization method for preparing nicotinic acid |
| CN109651244A (en) * | 2019-01-31 | 2019-04-19 | 安徽泰格生物技术股份有限公司 | A kind of preparation method of niacin |
| CN111701423A (en) * | 2020-07-30 | 2020-09-25 | 山东泓瑞医药科技股份公司 | Method for recycling ozonization reaction tail gas |
| CN113185456A (en) * | 2021-05-11 | 2021-07-30 | 沧州临港亚诺化工有限公司 | Method for refining nicotinic acid |
-
2022
- 2022-07-07 CN CN202210801432.7A patent/CN115108975A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4537971A (en) * | 1981-05-06 | 1985-08-27 | The Hilton-Davis Chemical Co. | Process for preparing quinolinic acid |
| CN1141288A (en) * | 1996-04-26 | 1997-01-29 | 清华紫光(集团)总公司 | Process for preparing nicotinic acid |
| CN1962637A (en) * | 2006-11-27 | 2007-05-16 | 中国科学院新疆理化技术研究所 | Ozonization method for preparing nicotinic acid |
| CN109651244A (en) * | 2019-01-31 | 2019-04-19 | 安徽泰格生物技术股份有限公司 | A kind of preparation method of niacin |
| CN111701423A (en) * | 2020-07-30 | 2020-09-25 | 山东泓瑞医药科技股份公司 | Method for recycling ozonization reaction tail gas |
| CN113185456A (en) * | 2021-05-11 | 2021-07-30 | 沧州临港亚诺化工有限公司 | Method for refining nicotinic acid |
Non-Patent Citations (1)
| Title |
|---|
| WOODWARD, C. F. 等: "Chemical-catalytic liquid-phase oxidation of nicotine, β-picoline and quinoline to nicotinic acid", INDUSTRIAL AND ENGINEERING CHEMISTRY, vol. 36, pages 544 - 546 * |
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