CN112521332A - Preparation method of 6- (tert-butylamino) -2-chloronicotinic acid - Google Patents
Preparation method of 6- (tert-butylamino) -2-chloronicotinic acid Download PDFInfo
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- CN112521332A CN112521332A CN202011015944.8A CN202011015944A CN112521332A CN 112521332 A CN112521332 A CN 112521332A CN 202011015944 A CN202011015944 A CN 202011015944A CN 112521332 A CN112521332 A CN 112521332A
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- butylamino
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention provides a preparation method of 6- (tert-butylamino) -2-chloronicotinic acid, which relates to the technical field of chemical intermediate synthesis, and specifically comprises the following steps: in an aprotic polar solvent, 2, 6-dichloronicotinic acid is taken as a raw material to react with tert-butylamine in one step under the alkaline condition to obtain 6- (tert-butylamino) -2-chloronicotinic acid; the six-position substitution product 6- (tert-butylamino) -2-chloronicotinic acid is prepared by one step through a simple process; in addition, the invention improves the selectivity of the six-position on the 6- (tert-butylamino) -2-chloronicotinic acid by using the aprotic polar solvent and selecting the amine with large steric hindrance as a substrate, thereby obtaining higher yield.
Description
Technical Field
The invention relates to the technical field of chemical intermediate synthesis, and particularly relates to a preparation method of 6- (tert-butylamino) -2-chloronicotinic acid.
Background
2-chloronicotinic acid is a pyridine substituted heterocyclic compound and is widely used for producing pesticides and pharmaceutical intermediates due to the special physiological activity of the compound. The 6- (tert-butylamino) -2-chloronicotinic acid is a derivative amino substituent of 2-chloronicotinic acid, is an important intermediate of novel pesticides and anti-inflammatory drugs, and can be used for preparing selective herbicides with low toxicity, high efficiency and broad spectrum, and for producing agricultural herbicides, insecticides, medicinal antibacterial agents and the like. Meanwhile, the method can also be used for preparing selective biological agents for targeted therapy of inflammatory diseases, such as Rheumatoid Arthritis (RA), psoriasis and inflammatory bowel disease, and has potential application value in the fields of biological medicines and the like.
For nucleophilic substitution of 2, 6-dichloronicotinic acid, the 2-position substitution product is generally adopted; with respect to the 6-position substitution products, the literature reports that they are obtained by coupling using palladium catalysis, which is expensive and not suitable for process scale-up.
For example, the following reaction process takes 2, 6-dichloronicotinic acid and aryl boric acid as raw materials, and the 6-aryl-2-chloronicotinic acid is obtained by regioselective coupling under the conditions of palladium tetratriphenylphosphine and sodium carbonate.
For another example, 2, 6-dichloronicotinic acid and hydrazine hydrate are used as raw materials, absolute ethyl alcohol is used as a solvent, and the raw materials are heated, cooled, kept stand and separated out to obtain the 6-hydrazino-2-chloronicotinic acid. The method uses highly toxic hydrazine hydrate, has strong basicity and reducibility, is easy to spontaneously combust and explode and has strong corrosivity; has irritation to eyes, and can irritate nose and respiratory tract when inhaled, and dizziness and nausea can occur.
The two methods for preparing the 6-substituted chloronicotinic acid derivative are not suitable for synthesizing 6- (tert-butylamino) -2-chloronicotinic acid, firstly, the substrates and reaction conditions adopted by the reaction are different, and secondly, the corresponding substitution position cannot be ensured.
Disclosure of Invention
The invention aims to provide a preparation method of 6- (tert-butylamino) -2-chloronicotinic acid, which can prepare a six-position substitution product 6- (tert-butylamino) -2-chloronicotinic acid in one step with high yield and purity by a simple process.
In order to achieve the above purpose, the invention provides the following technical scheme: a process for preparing 6- (tert-butylamino) -2-chloronicotinic acid includes such steps as reaction of 2, 6-dichloronicotinic acid with tert-butylamine in non-proton polar solvent under the action of temp and alkali to obtain 6- (tert-butylamino) -2-chloronicotinic acid.
Furthermore, the molar ratio of the reactant 2, 6-dichloronicotinic acid to the tert-butylamine to the alkali is 1: 1-4: 1-6.
Further, the alkali is one or more of sodium hydrogen, potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide, N-diisopropylethylamine and pyridine.
Further, the aprotic polar solvent is N-methylimidazole, NMP, DMSO, DMF, DMA, or TMU.
Furthermore, the dosage ratio of the reactant 2, 6-dichloronicotinic acid to the aprotic polar solvent is 1g:10 mL-20 mL.
Further, the reaction temperature of the 2, 6-dichloronicotinic acid, the alkali and the tert-butylamine in the aprotic polar solvent is 20-130 ℃.
Further, the reaction time of the 2, 6-dichloronicotinic acid, the alkali and the tert-butylamine in the aprotic polar solvent is 12-24 h.
Further, the 2, 6-dichloronicotinic acid is firstly dissolved in an aprotic polar solvent, alkali is added, oxygen is removed through nitrogen replacement, and then tert-butylamine is added into the mixed solution.
Furthermore, the molar ratio of the reactant 2, 6-dichloronicotinic acid to the tert-butylamine to the alkali is 1: 1-3.
Further, the reaction time of the 2, 6-dichloronicotinic acid, the alkali and the tert-butylamine in the aprotic polar solvent is 20 h.
According to the technical scheme, the preparation method of the 6- (tert-butylamino) -2-chloronicotinic acid provided by the technical scheme of the invention has the following beneficial effects:
the invention discloses a preparation method of 6- (tert-butylamino) -2-chloronicotinic acid, and provides a new method for preparing 6- (tert-butylamino) -2-chloronicotinic acid, which comprises the steps of taking 2, 6-dichloronicotinic acid as a raw material to react with tert-butylamine in an aprotic polar solvent in one step under an alkaline condition to obtain 6- (tert-butylamino) -2-chloronicotinic acid; the six-position substitution product 6- (tert-butylamino) -2-chloronicotinic acid is prepared by one step through a simple process; and the invention improves the selectivity of six sites on 6- (tert-butylamino) -2-chloronicotinic acid by selecting the solvent, namely using the aprotic polar solvent such as NMP, DMSO, DMF, DMA or TMU and selecting the large steric hindrance amine as the substrate, thus obtaining higher yield.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below are contemplated as being part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects and features of the present teachings will be more fully understood from the following description taken in conjunction with the accompanying examples. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments 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 embodiments described are only a few embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the described embodiments of the invention without any inventive step, are within the scope of protection of the invention. Unless defined otherwise, technical or scientific terms used herein shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
The use of "first," "second," and similar terms in the description and claims of the present application do not denote any order, quantity, or importance, but rather the terms are used to distinguish one element from another. Similarly, the singular forms "a," "an," or "the" do not denote a limitation of quantity, but rather denote the presence of at least one, unless the context clearly dictates otherwise. The terms "comprises," "comprising," or the like, mean that the element or item appearing before "comprises" or "comprising" covers the features, integers, steps, operations, elements, and/or components listed after "comprising" or "comprises," and does not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. "upper", "lower", "left", "right", and the like are used only to indicate relative positional relationships, and when the absolute position of the object to be described is changed, the relative positional relationships may also be changed accordingly.
Based on the lack of a method for synthesizing 6- (tert-butylamino) -2-chloronicotinic acid in the prior art, the method for preparing the 6-substituted chloronicotinic acid derivative in the prior art focuses on obtaining a two-position substituent and not obtaining a target product, or uses a toxic reagent for reaction, which is not beneficial to amplification production; the invention aims to provide a method for preparing 6- (tert-butylamino) -2-chloronicotinic acid by a one-step method, which has higher yield and is suitable for large-scale production.
The invention discloses a method for preparing 6- (tert-butylamino) -2-chloronicotinic acid, which comprises the following steps of reacting 2, 6-dichloronicotinic acid with tert-butylamine in an aprotic polar solvent under the action of temperature control and alkali to obtain 6- (tert-butylamino) -2-chloronicotinic acid in one step, wherein the reaction route is as follows:
wherein the aprotic polar solvent is N-methylimidazole, NMP, DMSO, DMF, DMA or TMU, and the base is one or more of sodium hydrogen, potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide, N-diisopropylethylamine and pyridine; in an aprotic polar solvent, the molar ratio of the reactant 2, 6-dichloronicotinic acid to the tert-butylamine to the alkali is 1: 1-4: 1-6, the dosage ratio of the 2, 6-dichloronicotinic acid to the aprotic polar solvent is 1g:10 mL-20 mL, and the temperature of the 2, 6-dichloronicotinic acid, the alkali and the tert-butylamine in the aprotic polar solvent is controlled at 20-130 ℃ for reaction for 12-24 h.
The preparation of 6- (tert-butylamino) -2-chloronicotinic acid according to the present invention will be described in more detail with reference to the following examples; all chemical reagents adopted by the embodiment of the invention are commercially available chemical reagents, and the room temperature is 10-30 ℃; wherein NMP represents N-methylpyrrolidone, DMSO represents dimethyl sulfoxide, DMF represents N, N-dimethylformamide, DMA represents N, N-dimethylacetamide, and TMU represents tetramethylurea.
Example 1
Dissolving a raw material 2, 6-dichloronicotinic acid (100g, 0.52mol, 1.0eq) in 1L DMSO, adding N, N-diisopropylethylamine (201.9g, 1.56mol, 3.0eq), replacing for 2 times by nitrogen, and removing dissolved oxygen; then adding tert-butylamine (38.1g, 0.52mol, 1.0eq) to react for 20 hours at room temperature, pouring the reaction liquid into a saturated sodium hydrogen sulfate aqueous solution to quench, and stirring for 30 minutes at room temperature; the solution was filtered, the filter cake was washed with water and then with ethyl acetate, the filter cake was collected and dried in vacuo to give the product 6- (tert-butylamino) -2-chloronicotinic acid (109g, 0.48mol, yield 91.52%).
Examples 2-6 are different from example 1 in that the molar ratio of the reactants in the aprotic polar solvent is different, and specific reaction conditions and yields of 6- (tert-butylamino) -2-chloronicotinic acid prepared are shown in table 1 below.
TABLE 1 influence of the molar ratio of the reactants on the product yield
Example 2 and example 3 differ from example 1 in that the equivalent ratio of the base N, N-diisopropylethylamine is different, and when the reaction equivalent of the base is increased from 1eq to 3eq, the yield increases from 80.45% to 91.52%; the reaction amount was increased to 6eq, and the yield was not greatly affected, i.e., a proper amount of base participated in the reaction to help the reaction proceed forward.
Examples 4 to 6 are different from example 1 in the equivalent ratio of tert-butylamine. The equivalent ratio of the tert-butylamine is increased, and the product yield is reduced, because excessive amine causes the loss of selectivity of the reaction, the increase of byproducts and the reduction of yield.
Examples 7-11 differ from example 1 in the choice of aprotic polar solvent in the reaction, and the specific reaction conditions and yields of 6- (tert-butylamino) -2-chloronicotinic acid prepared are shown in Table 2 below.
TABLE 2 Effect of solvent on product yield
Examples 7 to 11 differ from example 1 in that different solvents are used, the yields differ, and the yields, in order from low to high, are: DMF < DMA < N-methylimidazole < NMP < TMU < DMSO, where DMSO is the highest solvent yield, different solvents have different selectivity effects on the reaction, resulting in different product yields, and DMSO is preferred as the solvent for the example reactions. In the prior art, documents explain the influence of a solvent on the selectivity of a reaction region, for example, a DCM solvent is used as a weak hydrogen bond acceptor, and a pyridine 3-site carboxylic acid and an amino group guide a nucleophilic reagent to react at a 2-site by forming a hydrogen bond. While solvents like DMSO dimethyl sulfoxide, a strong hydrogen bond acceptor, do not have such hydrogen bond guiding effect. Wherein the amino group and the hydrogen bond of the 3-position carboxylic acid of DMSO and pyridine compete with each other. The selectivity can be further improved by selecting a bulky hindered amine.
Examples 12-16 differ from example 1 in the choice of amine in the reaction, and the specific reaction conditions and yields of the 6-position substituted product produced are shown in table 3 below. Examples 12 to 16 differ from example 1 in that different amines were used as reaction substrates and the yields of the 6-position substitution products were, in order from low to high: ammonia water < methylamine < diisopropylamine < aniline < N-methylpiperazine < tert-butylamine), wherein tert-butylamine is the solvent with the highest yield, and is reversely arranged in the yield sequence of 2-position substitution products, and the smaller the steric hindrance, the higher the yield of 2-position. This further demonstrates that the bulky hindered amine can improve selectivity.
TABLE 3 influence of the Amines on the product yield
The invention provides a process for preparing 6- (tert-butylamino) -2-chloronicotinic acid by taking 2, 6-dichloronicotinic acid as a raw material to react with tert-butylamine in one step in an aprotic polar solvent under an alkaline condition, which improves the selectivity and yield of the six-position on the 6- (tert-butylamino) -2-chloronicotinic acid by selecting the aprotic polar solvent and taking large steric hindrance amine as a substrate, and provides a novel preparation method for the commercial production of the 6- (tert-butylamino) -2-chloronicotinic acid, wherein the yield is high, and the process is simple.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (10)
1. A preparation method of 6- (tert-butylamino) -2-chloronicotinic acid is characterized in that 2, 6-dichloronicotinic acid reacts with tert-butylamine in an aprotic polar solvent in one step under the action of temperature control and alkali to obtain the 6- (tert-butylamino) -2-chloronicotinic acid.
2. The method for preparing 6- (tert-butylamino) -2-chloronicotinic acid according to claim 1, wherein the molar ratio of the reactant 2, 6-dichloronicotinic acid, tert-butylamine and base is 1: 1-4: 1-6.
3. The method for preparing 6- (tert-butylamino) -2-chloronicotinic acid as claimed in claim 1, wherein the base is one or more of sodium hydrogen, potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide, N-diisopropylethylamine, and pyridine.
4. The method of claim 1, wherein the aprotic polar solvent is N-methylimidazole, NMP, DMSO, DMF, DMA or TMU.
5. The method for preparing 6- (tert-butylamino) -2-chloronicotinic acid as claimed in claim 1, wherein the dosage ratio of the reactant 2, 6-dichloronicotinic acid to the aprotic polar solvent is 1g:10 mL-20 mL.
6. The process for the preparation of 6- (tert-butylamino) -2-chloronicotinic acid as claimed in claim 1, wherein the reaction temperature of 2, 6-dichloronicotinic acid, base and tert-butylamine in aprotic polar solvent is 20 ℃ to 130 ℃.
7. The method for preparing 6- (tert-butylamino) -2-chloronicotinic acid as claimed in claim 1, wherein the reaction time of 2, 6-dichloronicotinic acid, alkali and tert-butylamine in aprotic polar solvent is 12-24 h.
8. The method for preparing 6- (tert-butylamino) -2-chloronicotinic acid as claimed in claim 1, wherein the 2, 6-dichloronicotinic acid is dissolved in an aprotic polar solvent, alkali is added, oxygen is removed by nitrogen displacement, and tert-butylamine is added to the mixed solution.
9. The method for preparing 6- (tert-butylamino) -2-chloronicotinic acid according to claim 2, wherein the molar ratio of the reactant 2, 6-dichloronicotinic acid, tert-butylamine and base is 1: 1-3.
10. The process for the preparation of 6- (tert-butylamino) -2-chloronicotinic acid as claimed in claim 7, wherein the reaction time of 2, 6-dichloronicotinic acid, base and tert-butylamine in aprotic polar solvent is 20 h.
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| CN202011015944.8A CN112521332A (en) | 2020-09-24 | 2020-09-24 | Preparation method of 6- (tert-butylamino) -2-chloronicotinic acid |
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| CN202011015944.8A CN112521332A (en) | 2020-09-24 | 2020-09-24 | Preparation method of 6- (tert-butylamino) -2-chloronicotinic acid |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992022203A1 (en) * | 1991-06-12 | 1992-12-23 | E.I. Du Pont De Nemours And Company | Substituted pyridine herbicides |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992022203A1 (en) * | 1991-06-12 | 1992-12-23 | E.I. Du Pont De Nemours And Company | Substituted pyridine herbicides |
Non-Patent Citations (2)
| Title |
|---|
| CA: "CAS RN 2631011-95-3", 《STN》 * |
| PETER BACH ET AL.: "Effects of the Pyridine 3-Substituent on Regioselectivity in the Nucleophilic Aromatic Substitution Reaction of 3-Substituted 2,6-Dichloropyridines with 1-Methylpiperazine Studied by a Chemical Design Strategy", 《EUR. J. ORG. CHEM.》 * |
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