CN109678793B - Preparation method of 5-fluoro-3-aminopyridine - Google Patents
Preparation method of 5-fluoro-3-aminopyridine Download PDFInfo
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- 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
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Abstract
The invention discloses a preparation method of 5-fluoro-3-aminopyridine, which belongs to the technical field of pyridine compounds and is characterized by comprising the following operation steps of dripping 5-fluoronicotinamide into hypohalite solution, stirring at 0-100 ℃ until T L C reaction is completed, cooling to room temperature, adding sodium hydroxide solution, continuing stirring for 20-40min, and filtering and drying to obtain 5-fluoro-3-aminopyridine solid.
Description
Technical Field
The invention belongs to the technical field of pyridine compounds, and particularly relates to a preparation method of 5-fluoro-3-aminopyridine.
Background
Pyridine is a six-membered heterocyclic compound containing one nitrogen heteroatom. Can be regarded as a compound in which one (CH) in benzene molecules is substituted by N, and is also called nitrobenzene, colorless or yellowish liquid with malodor. The structural formula is as follows:
pyridine and its homologues exist in bone tar, coal gas, shale oil and petroleum, and pyridine can be used as denaturant and dyeing assistant in industry and as raw material for synthesizing a series of products (including medicines, disinfectants, dyes and the like), and has wide application value.
3-amino-5-fluoropyridine is an important intermediate mainly used in medicine and organic synthesis, for example, 3-amino-5-fluoropyridine is an important intermediate of Ivosidenib (AG-120) medicine.
The current method for synthesizing 3-amino-5-fluoropyridine is reported by Journal of Medicinal Chemistry,1999, vol.42, # 18p.3701-3710 and WO2007076034, and 3-fluoronicotinic acid (structural formula is shown in the specification)
) Rearrangement into N-Cbz-3-amino-5-fluoropyridine under the action of diphenyl phosphorylazide and elimination of protecting group Cbz with palladium-carbon to obtain 3-amino-5-fluoropyridine, and features expensive 3-fluoronicotinic acid as initial material, use of diphenyl phosphorylazide-containing azide during reaction and generation of acyl azide intermediate (structure formula: diphenyl phosphorylazide)
) There is a risk of explosion, and it is not suitable for mass production.
In addition, the Journal of the Chemical Society-Perkin Transactions 1,1998, #10 p.1705-1713 also reports that 3-amino-5-fluoropyridine is obtained by a three-step reaction using pentafluoropyridine, which requires high pressure for the amination and which is expensive in the market and unsuitable for mass production.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the preparation method of the 5-fluoro-3-aminopyridine, which has the advantages of safe, simple and convenient operation process and low requirement on production equipment, and is suitable for large-scale production on the basis of ensuring the product quality and good yield.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of 5-fluoro-3-aminopyridine comprises the following operation steps:
dripping 5-fluoronicotinamide into hypohalite solution, and stirring at 0-100 ℃ until the T L C reaction is completed;
cooling to room temperature, adding sodium hydroxide solution, stirring for 20-40min, filtering, and drying to obtain 5-fluoro-3-aminopyridine solid;
the reaction equation is as follows:
by adopting the technical scheme, sodium hydroxide and Br are added2The sodium hypobromite generated by the reaction and the 5-fluoronicotinamide are subjected to Hofmann degradation reaction, so that the 5-fluoro-3-aminopyridine obtained by the method has the advantages of simple and convenient operation process and low requirement on production equipment, and can effectively improve the yield of the product on the basis of ensuring the product quality.
Further: the preparation method of the 5-fluoronicotinamide comprises the following operation steps:
adding 2, 6-dichloro-3-fluoronicotinamide into methanol, then adding alkali and a catalyst, introducing hydrogen, reacting at room temperature for 10-20h, and filtering out the catalyst to obtain 5-fluoronicotinamide;
the reaction equation is as follows:
by adopting the technical scheme, the 2, 6-dichloro-3-fluoronicotinamide is adopted to carry out dehalogenation hydrogenolysis reaction under the action of palladium carbon and hydrogen, at the moment, hydrogen chloride can be removed to obtain 5-fluoronicotinamide, and simultaneously, the removed hydrogen chloride can be captured by triethylamine, at the moment, the reaction is continuously carried out rightwards, so that the reaction speed of the 5-fluoronicotinamide is effectively improved, and the preparation in the previous stage is prepared for synthesizing the 5-fluoro-3-aminopyridine by adopting the 5-fluoronicotinamide in the next step.
Further: the preparation method of the 2, 6-dichloro-3-fluoronicotinamide comprises the following operation steps:
adding 2, 6-dichloro-5-fluoronicotinic acid into toluene, adding thionyl chloride, heating and refluxing for 2-4h, and evaporating the toluene and the thionyl chloride under reduced pressure to obtain yellow liquid;
slowly dripping the yellow liquid into ammonia water, stirring for 1-2h, filtering, and washing a filter cake twice with water to obtain 2, 6-dichloro-3-fluoronicotinamide;
the reaction equation is as follows:
by adopting the technical scheme, in the process of taking 2, 6-dichloro-5-fluoronicotinic acid as a raw material, acyl chlorination reaction is carried out under the action of thionyl chloride to obtain an intermediate product 2, 6-dichloro-3-fluoronicotinoyl chloride (yellow liquid), at the moment, the intermediate product is slowly dripped into ammonia water to be stirred, and the acyl chloride can quickly react with ammonia to obtain stable white solid 2, 6-dichloro-3-fluoronicotinamide.
Further, dripping 5-fluoronicotinamide into the hypohalite solution, controlling the temperature at 0-30 ℃ after finishing dripping 5-fluoronicotinamide, stirring for 2-3h, heating to 60-100 ℃, and reacting for 2-3h, wherein T L C is completely reacted.
Further: after the completion of the dropwise addition of 5-fluoronicotinamide, the temperature was controlled at 20-30 ℃.
Further: after stirring for 2-3h, the temperature was raised to 80 ℃.
By adopting the technical scheme, firstly, 5-fluoronicotinamide is stirred at a low temperature of 0-30 ℃ (optimally 20-30 ℃) for 2-3h, so that Hofmann degradation reaction is facilitated, and an intermediate product R-CONHBr; then raising the temperature to 60-100 ℃ (optimally 85 ℃),under the action of alkali, HBr can be removed easily, and R-NH can be obtained by synthesis2。
Further: after adding sodium hydroxide solution, filtering to obtain a crude product of the 5-fluoro-3-aminopyridine, and then controlling the temperature to be 40-70 ℃ and drying in vacuum for 2-3 h.
Further: after adding sodium hydroxide solution, filtering to obtain a crude product of the 5-fluoro-3-aminopyridine, and then controlling the temperature at 50 ℃ and drying in vacuum for 2-3 h.
By adopting the technical scheme, the drying is carried out under the vacuum condition, and the oxidation reaction of active hydrogen on the ortho-position and para-position of pyridine can be reduced, so that the quality change probability of the product is effectively reduced, and the quality and the yield of the product are further improved.
Further: the weight ratio of the sodium hydroxide solid, the bromine and the 5-fluoronicotinamide is (1.5-1.8): (1-1.1):1, and the volume ratio of the water to the sodium hydroxide solution is 1: (1-1.2).
By adopting the technical scheme and preferably selecting the proportion for testing, the waste can be reduced, and the yield of the 5-fluoro-3-aminopyridine can be improved.
Further: the alkali is selected from one of triethylamine, inorganic alkali sodium bicarbonate, sodium carbonate or potassium carbonate, and the catalyst is selected from one of palladium carbon, palladium hydroxide, palladium acetate, tetrakis (triphenylphosphine) palladium, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride or [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex.
By adopting the technical scheme, the chemical structural formula of the triethylamine is shown as
The solution is alkaline; inorganic base sodium bicarbonate NaHCO3Commonly known as "baking soda", the solution is alkaline, white powder or monoclinic crystalline powder. And sodium carbonate Na2CO3The solution is alkaline, and is an important organic chemical raw material. Furthermore, potassium carbonate K2CO3Dissolved in water, the aqueous solution of potassium carbonate is alkaline.
Pd/C is a chemical substance of black powdery particles, Pd/C is a catalyst, and the Pd/C is prepared by loading metal palladium powder on active carbon and mainly used for catalytic hydrogenation of unsaturated hydrocarbon or CO. And palladium hydroxide Pd (OH)2Black powder, which is a hydrogenation catalyst, can hydrogenate a benzene ring and synthesize an a-amino acid or the like from an amine and a b-keto acid. In addition, palladium acetate Pd (C)2H3O2)2The catalyst can catalyze olefin aromatization, cross-coupling reaction catalysis and Suzuki coupling reaction to be effectively carried out. The molecular formula of the tetrakis (triphenylphosphine) palladium is Pd [ P (C)6H5)3]4The catalyst has wide application range, and can be used for reactions such as hydrosilation, isomerization, carbonylation, oxidation, C-C bond formation and the like; but also can be used for coupling reaction, Heck reaction, Sonogashira reaction, Stille reaction and Suzuki reaction. And [1, 1' -bis (diphenylphosphino) ferrocene]The chemical structural formula of the palladium dichloride dichloromethane complex is
It is a catalyst with molecular weight of 816.64 and can be used for carbonylation reaction, cross-coupling reaction and Suzuki reaction.
Further: the molar ratio of the 2, 6-dichloro-3-fluoronicotinamide to the catalyst is 1 (0.03-0.2).
Further: the volume ratio of the toluene to the thionyl chloride to the ammonia water is (2-4) to (1-2) to (8-12).
By adopting the technical scheme and preferably selecting the proportion for testing, the waste can be reduced, and the yield of the 2, 6-dichloro-3-fluoronicotinamide can be improved.
In conclusion, the invention has the following beneficial effects:
1. the invention has safe, simple and convenient operation process and low requirement on production equipment, and is suitable for large-scale production on the basis of ensuring the product quality and good yield;
2. optimally, the reaction temperature is controlled in two sections after the dropwise addition of the 5-fluoronicotinamide is completed, the gradual progress of the Hofmann degradation reaction can be effectively promoted, and the preparation in the early stage is made for improving the yield of the 5-fluoro-3-aminopyridine in the later stage;
3. the input proportion of each component or raw material is optimized, so that the waste can be reduced, and the yield of the finally obtained 5-fluoro-3-aminopyridine can be improved.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 5-fluoronicotinamide according to the invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of 5-fluoro-3-aminopyridine according to the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1: a preparation method of 5-fluoro-3-aminopyridine comprises the following specific operation steps:
step one, preparing 2, 6-dichloro-3-fluoronicotinamide:
s1, adding 43g of 2, 6-dichloro-5-fluoronicotinic acid into 150ml of toluene, then adding 86ml of thionyl chloride, heating and refluxing for 3 hours, and then evaporating the toluene and the thionyl chloride under reduced pressure to obtain yellow liquid 2, 6-dichloro-3-fluoronicotinoyl chloride;
s2, slowly dropping the yellow liquid in the step S1 into 500ml of ammonia water at the speed of 5-10 drops/min, stirring for 1h, performing suction filtration under pressure, and washing the filter cake twice with water to obtain 40g of white solid 2, 6-dichloro-3-fluoronicotinamide.
The reaction equation is as follows:
step two, preparation of 5-fluoronicotinamide:
adding 30g of 2, 6-dichloro-3-fluoronicotinamide into 300ml of methanol, then adding 28.8g of triethylamine and 3g of palladium-carbon, continuously introducing hydrogen, reacting at room temperature for 15h, filtering out the palladium-carbon to obtain 19g of solid, then taking a small sample to perform nuclear magnetic hydrogen spectrum detection, wherein the test detection result is shown in figure 1, and jointly analyzing according to the data of the nuclear magnetic hydrogen spectrum and the principle of a reaction equation to obtain the solid, namely the 5-fluoronicotinamide.
The reaction equation is as follows:
step three, preparing 5-fluoro-3-aminopyridine:
mixing and dissolving 32g of sodium hydroxide solid in 140ml of water, then dropwise adding 19.2g of bromine at 8 ℃, and continuously mixing and stirring for 1h after completion to obtain a mixed solution I;
then, dripping 19g of 5-fluoronicotinamide into the mixed solution I, controlling the temperature at 25 ℃, stirring for 2 hours, then heating to 85 ℃, and reacting for 2 hours until the thin-layer chromatography T L C completely reacts;
cooling to room temperature, adding 160ml of sodium hydroxide solution, continuing stirring for 30min, filtering to obtain a solid substance, controlling the temperature at 50 ℃, performing vacuum drying for 2h to obtain 15g of yellow solid 5-fluoro-3-aminopyridine, then taking a small sample to perform nuclear magnetic hydrogen spectrum detection, wherein the test detection result is shown in figure 2, and the solid 5-fluoro-3-aminopyridine is obtained by analyzing the data of the nuclear magnetic hydrogen spectrum and the principle of a reaction equation together, and the yield of the 5-fluoro-3-aminopyridine is 87.2%.
The reaction equation is as follows:
in summary, the general reaction equation is:
example 2: a method for producing 5-fluoro-3-aminopyridine, which is different from example 1 in that: in the first step, S1, adding 45g of 2, 6-dichloro-5-fluoronicotinic acid into 160ml of toluene, then adding 88ml of thionyl chloride, heating and refluxing for 4 hours, and then evaporating the toluene and the thionyl chloride under reduced pressure to obtain yellow liquid;
s2, slowly dropping the yellow liquid in the step S1 into 500ml of ammonia water at the speed of 5-10 drops/min, stirring for 1h, performing suction filtration under pressure, and washing the filter cake twice with water to obtain 38g of white solid 2, 6-dichloro-3-fluoronicotinamide.
In addition, the remaining steps were carried out in the same manner as in example 1, and 15g of 5-fluoro-3-aminopyridine was obtained as a yellow solid in a yield of 79.2% of 5-fluoro-3-aminopyridine.
Example 3: a method for producing 5-fluoro-3-aminopyridine, which is different from example 1 in that: step two, adding 33g of 2, 6-dichloro-3-fluoronicotinamide into 320ml of methanol, then adding 28g of inorganic base sodium bicarbonate and 2.5g of tetrakis (triphenylphosphine) palladium, continuously introducing hydrogen, reacting at room temperature for 15 hours, and filtering out tetrakis (triphenylphosphine) palladium to obtain 17g of 5-fluoronicotinamide. In addition, the remaining steps were carried out in the same manner as in example 1, and 12g of 5-fluoro-3-aminopyridine was obtained as a yellow solid in a yield of 63.4% of 5-fluoro-3-aminopyridine.
Example 4: a method for producing 5-fluoro-3-aminopyridine, which is different from example 3 in that: and step two, adding 33g of 2, 6-dichloro-3-fluoronicotinamide into 320ml of methanol, then adding 28g of sodium carbonate and 2.6g of palladium acetate, continuously introducing hydrogen, reacting at room temperature for 15 hours, and filtering out the palladium acetate to obtain 17g of 5-fluoronicotinamide. In addition, the remaining steps were carried out in the same manner as in example 1, and 5-fluoro-3-aminopyridine was obtained as a yellow solid in a yield of 63.2%.
Example 5: a method for producing 5-fluoro-3-aminopyridine, which is different from example 3 in that: and step two, adding 33g of 2, 6-dichloro-3-fluoronicotinamide into 320ml of methanol, then adding 28g of potassium carbonate and 2.5g of catalyst [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, continuously introducing hydrogen, reacting for 15 hours at room temperature, and filtering out the catalyst [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride to obtain 17g of 5-fluoronicotinamide. In addition, the remaining steps were carried out according to the procedure in example 1, and a yield of 5-fluoro-3-aminopyridine was obtained as a yellow solid of 65.1%.
Example 6A 5-fluoro-3-aminopyridine is prepared by mixing 35g of solid potassium hydroxide in 150ml of water, dissolving, adding 18.6g of bromine dropwise at 10 ℃, stirring for 1h to obtain a first mixed solution (i.e. potassium hypobromite), adding 19g of 5-fluoronicotinamide dropwise into the first mixed solution, controlling the temperature at 22 ℃, stirring for 2h, heating to 90 ℃, and reacting for 2.5h until T L C is completely reacted;
after cooling to room temperature, 150ml of potassium hydroxide solution was added, and stirring was continued for 30min, and the temperature was controlled at 40 ℃ and vacuum-dried for 2h to obtain 12g of yellow solid (5-fluoro-3-aminopyridine) with a yield of 5-fluoro-3-aminopyridine of 69.8%.
Example 7: a method for producing 5-fluoro-3-aminopyridine, which is different from example 1 in that: and step three, mixing and dissolving 35g of potassium hydroxide solid in 150ml of water, then dissolving chlorine in the sodium hydroxide solution at 5 ℃, and continuously mixing and stirring for 1h after completion to obtain a mixed solution I (namely potassium hypochlorite).
Example 8: a method for producing 5-fluoro-3-aminopyridine, which is different from example 1 in that: and step three, mixing and dissolving 32g of sodium hydroxide solid in 150ml of water, then dissolving chlorine in the sodium hydroxide solution at 0 ℃, and continuously mixing and stirring for 1.5 hours after the chlorine is dissolved to obtain a mixed solution I (namely sodium hypochlorite).
The above specific embodiments are merely illustrative of the present invention, and not restrictive, and those skilled in the art can modify the embodiments without inventive contribution as required after reading the present specification, but only protected by the patent laws within the scope of the claims.
Claims (8)
1. A preparation method of 5-fluoro-3-aminopyridine is characterized by comprising the following operation steps:
adding 2, 6-dichloro-3-fluoronicotinamide into methanol, then adding alkali and a catalyst, introducing hydrogen, reacting at room temperature for 10-20h, and filtering out the catalyst to obtain 5-fluoronicotinamide;
the reaction equation is as follows:
dripping 5-fluoronicotinamide into hypohalite solution, stirring at 0-100 deg.C until T L C reaction is completed, cooling to room temperature, adding sodium hydroxide solution, stirring for 20-40min, filtering, and drying to obtain 5-fluoro-3-aminopyridine solid;
the reaction equation is as follows:
triethylamine is selected as the alkali, and palladium carbon is selected as the catalyst.
2. The process for preparing 5-fluoro-3-aminopyridine according to claim 1, wherein the process for preparing 2, 6-dichloro-3-fluoronicotinamide comprises the following steps:
adding 2, 6-dichloro-5-fluoronicotinic acid into toluene, adding thionyl chloride, heating and refluxing for 2-4h, and evaporating the toluene and the thionyl chloride under reduced pressure to obtain yellow liquid;
slowly dripping the yellow liquid into ammonia water, stirring for 1-2h, filtering, and washing a filter cake twice with water to obtain 2, 6-dichloro-3-fluoronicotinamide;
the reaction equation is as follows:
3. the method for preparing 5-fluoro-3-aminopyridine according to claim 1, wherein 5-fluoronicotinamide is added dropwise to the hypohalite solution, after the 5-fluoronicotinamide is added dropwise, the temperature is controlled to be 0-30 ℃, stirring is carried out for 2-3h, then heating is carried out to 60-100 ℃, and after 2-3h of reaction, T L C is reacted completely.
4. The method of claim 1 or 3, wherein the hypohalite is one selected from sodium hypobromite, potassium hypobromite, sodium hypochlorite and potassium hypochlorite.
5. The process according to claim 1, wherein the crude 5-fluoro-3-aminopyridine is obtained by filtration after adding sodium hydroxide solution, and then dried under vacuum at 40-70 ℃ for 2-3 h.
6. The method for preparing 5-fluoro-3-aminopyridine according to claim 1, wherein the weight ratio of the sodium hydroxide solid, bromine and 5-fluoronicotinamide is (1.5-1.8): 1-1.1):1, and the volume ratio of the water and the sodium hydroxide solution is 1: (1-1.2).
7. The process according to claim 1, wherein the molar ratio of 2, 6-dichloro-3-fluoronicotinamide to catalyst is 1 (0.03-0.2).
8. The method of claim 2, wherein the volume ratio of toluene, thionyl chloride and ammonia is (2-4): 1-2): 8-12.
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