CN112358442B - Preparation method of 2-fluoro-5-formyl chloropyridine - Google Patents
Preparation method of 2-fluoro-5-formyl chloropyridine Download PDFInfo
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- CN112358442B CN112358442B CN202011312262.3A CN202011312262A CN112358442B CN 112358442 B CN112358442 B CN 112358442B CN 202011312262 A CN202011312262 A CN 202011312262A CN 112358442 B CN112358442 B CN 112358442B
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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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- 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
Abstract
The invention relates to a preparation method of 2-fluoro-5-formyl chloropyridine, belonging to the technical field of organic chemistry. The method comprises the following steps: 1) taking 2-fluoro-5-methylpyridine as a raw material, and reacting in the presence of potassium permanganate or sodium permanganate to obtain 2-fluoro-5-pyridine formate; 2) refluxing 2-fluoro-5-pyridine formate and thionyl chloride or oxalyl chloride in a chlorinated solvent for reaction, distilling the solvent under reduced pressure, adding an alkane solvent, freezing, filtering to obtain a 2-fluoro-5-formyl chloropyridine solution, and rectifying under reduced pressure to obtain the 2-fluoro-5-formyl chloropyridine. The invention has high conversion rate, the purity of the obtained product is up to more than 99.0 percent, the single impurity is less than 0.5 percent, the production cost is low, and the invention is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-fluoro-5-formyl chloropyridine.
Background
2-fluoro-5-formylchloropyridine (6-fluoro-3-formylchloropyridine), formula C6H3ClFNO, CAS: 65352-94-5. The product is an important chemical intermediate raw material, can further generate hydrazide, acylhydrazone and amide, plays an important role in pesticides and medicines, has considerable application value and market prospect, and can be used for preparing 2- (6-fluoropyridine-3-yl) -4, 5-dihydropyridazole.
At present, only reagent companies provide small amount of samples in domestic markets, the purity is usually only 98%, and no mature process technology report exists for obtaining high-purity products.
Disclosure of Invention
The invention aims to provide a preparation method of 2-fluoro-5-formyl chloropyridine, which has the advantages of high conversion rate, good reaction selectivity, high product purity and low production cost and is suitable for industrial production.
The invention comprises two steps of reaction: the oxidation reaction and the acyl chlorination reaction adopt the following routes:
the specific embodiment comprises the following steps:
1) oxidation of 2-fluoro-5-methylpyridine
2-fluoro-5-methylpyridine is taken as a raw material and is heated to react in the presence of an oxidant to obtain the 2-fluoro-5-pyridine formate.
2) Acyl chlorination of 2-fluoro-5-pyridinecarboxylic acid
Reacting 2-fluoro-5-pyridine formate with oxalyl chloride or thionyl chloride in a chlorinated solvent, distilling to remove the reaction solvent, adding an alkane solvent, cooling, filtering to obtain a 2-fluoro-5-formyl chloropyridine mixed solution, and performing reduced pressure rectification to obtain the 2-fluoro-5-formyl chloropyridine.
Further, in the above technical solution, the oxidant in the first step is KMnO4Or NaMnO4。
In the oxidation experiment, the raw materials are always obviously present, and the effect of increasing the equivalent of the oxidant is not obvious. Attempts have been made to increase the reaction conversion significantly when a certain amount of base is mixed into the oxidizing agent. Preferably 1 to 1.3 equivalents of sodium hydroxide or potassium hydroxide.
Further, in the above technical solution, the molar ratio of the oxidant to 2-fluoro-5-methylpyridine in the first step is 2-4: 1. the molar ratio of the alkali to the 2-fluoro-5-methylpyridine is 1-1.3: 1.
furthermore, in the above technical solution, the chlorinated solvent in the second step is dichloromethane, chloroform, 1, 2-dichloroethane, or the like.
Further, in the above technical solution, the alkane solvent in the second step is n-pentane, n-hexane, cyclohexane, n-heptane, or the like.
Further, in the above technical scheme, the equivalent of oxalyl chloride or thionyl chloride and 2-fluoro-5-carboxylic acid pyridine in the second step is 1-2.5: 1, preferably equivalent weight of 1.3 to 1.8.
In the acid chloride reaction, the yield gradually decreases as the scale of the reaction increases. It was found by extensive studies that a certain amount of solid was visible during the reaction and analyzed as 2-fluoro-5-formylchloropyridine hydrochloride after filtration. The solution is achieved by three methods: 1. increasing the stirring speed to 200-400 rpm; 2. introducing nitrogen or argon to the liquid level in the reaction kettle; 3. after the reaction is finished, cooling, sealing, filtering and rectifying.
Further, in the technical scheme, the colorless liquid product 2-fluoro-5-formyl chloropyridine is obtained by collecting the fraction of 90-94 ℃/15mm Hg during reduced pressure rectification, and the product is a white to off-white solid after being frozen and is frozen to be stored as the solid when being stored for a long time.
Advantageous effects of the invention
The invention takes 2-fluoro-5-methylpyridine as a raw material, and synthesizes the high-purity 2-fluoro-5-formyl chloropyridine through two-step reactions of oxidation and acyl chlorination. The invention has high conversion rate and low production cost, and is suitable for industrial production.
Detailed Description
The present invention will be further specifically described below by way of specific examples, but it should not be construed as limiting the scope of the present invention.
The invention relates to a preparation method of 2-fluoro-5-formyl chloropyridine, which takes 2-fluoro-5-methylpyridine as a raw material, synthesizes a crude product of the 2-fluoro-5-formyl chloropyridine through two steps of reactions of oxidation and acyl chlorination, and obtains the high-purity 2-fluoro-5-formyl chloropyridine by rectifying an organic phase under reduced pressure. The specific process is as follows:
example 1:
in a 500mL three-necked flask, 11.1g (0.1mol) of 2-fluoro-5-methylpyridine and 250mL of water were added, and mechanical stirring was started, and 31.6g (0.2mol) of KMnO was added in this order4And 5.6g (0.1mol) of KOH, heated to 95 ℃ in an oil bath, reacted for 5 hours, filtered while hot, and the filtrate was collected. After the filtrate is cooled to the normal temperature, adjusting the pH value to 2-4 by using concentrated hydrochloric acid, separating out solids, and filtering; the filtrate was extracted twice with dichloroethane. And mixing the filtered solid with the extracted oil phase, and performing rotary evaporation to obtain 11.8g of white-like solid, namely 2-fluoro-5-pyridine formate (the melting point is 275-278 ℃).
Putting the 2-fluoro-5-pyridine formate obtained in the first step into a 500mL three-necked flask, adding 200mL dichloromethane, starting stirring, dropwise adding thionyl chloride 16.0g, carrying out reflux reaction for 6 hours, and then evaporating the solvent and excessive thionyl chloride. Adding 80mL of n-heptane, cooling, sealing and filtering, performing reduced pressure rectification on the filtrate, collecting a fraction of 90-94 ℃/15mm Hg to obtain 12.76g of colorless liquid product 2-fluoro-5-formyl chloropyridine, and freezing to obtain a white solid with the purity of 99.0% and the total yield of 80.1%.
Example 2:
in a 500mL three-necked flask, 11.1g (0.1mol) of 2-fluoro-5-methylpyridine was charged, 250mL of water was added, mechanical stirring was started, and 28.4g (0.2mol) of NaMnO was sequentially added4And 4.0g (0.1mol) of NaOH, heated to 95 ℃ in an oil bath, reacted for 5 hours, filtered while hot, and the filtrate was collected. After the filtrate is cooled to the normal temperature, adjusting the pH value to 2-4 by using concentrated hydrochloric acid, separating out solids, and filtering; the filtrate was extracted twice with dichloroethane. And mixing the filtered solid with the extracted oil phase, and performing rotary evaporation to obtain 11.5g of white-like solid, namely 2-fluoro-5-pyridine formate (the melting point is 275-278 ℃).
The other steps are the same as example 1, and colorless liquid product 2-fluoro-5-formyl chloropyridine 12.55g is obtained, and is a white solid after being frozen, the purity of the product reaches 99.0 percent, and the total yield reaches 78.7 percent.
Example 3:
in a 500mL three-necked flask, 11.1g (0.1mol) of 2-fluoro-5-methylpyridine was added, 250mL of water was added, mechanical stirring was started, and 47.4g (0.3mol) of KMnO was added in this order4And 5.6g (0.1mol) of KOH, heated to 95 ℃ in an oil bath, reacted for 5 hours, filtered while hot, and the filtrate was collected. After the filtrate is cooled to the normal temperature, adjusting the pH value to 2-4 by using concentrated hydrochloric acid, separating out solids, and filtering; the filtrate was extracted twice with dichloroethane. Mixing the filtered solid with the extracted oil phase, and performing rotary evaporation to obtain 12.1g of white-like solid, namely 2-fluoro-5-pyridine formate (the melting point is 275-278 ℃).
Putting the 2-fluoro-5-pyridine formate obtained in the first step into a 500mL three-necked flask, adding 200mL dichloromethane, starting stirring, dropwise adding thionyl chloride 16.0g, carrying out reflux reaction for 6 hours, and then evaporating the solvent and excessive thionyl chloride. Adding 85mL of n-heptane, cooling, sealing, filtering, performing reduced pressure rectification on the filtrate, collecting a fraction of 90-94 ℃/15mm Hg to obtain 12.85g of colorless liquid product 2-fluoro-5-formyl chloropyridine, and freezing to obtain a white solid with the purity of 99.1% and the total yield of 80.56%.
Example 4:
in a 500mL three-necked flask, 11.1g (0.1mol) of 2-fluoro-5-methylpyridine was added, 250mL of water was added, mechanical stirring was started, and 47.4g (0.3mol) of KMnO was added in this order4And 5.6g (0.1mol) of KOH, heated to 95 ℃ in an oil bath, reacted for 5 hours, filtered while hot, and the filtrate was collected. After the filtrate is cooled to the normal temperature, adjusting the pH value to 2-4 by using concentrated hydrochloric acid, separating out solids, and filtering; the filtrate was extracted twice with dichloroethane. Mixing the filtered solid with the extractedMixing the oil phases, and performing rotary evaporation to obtain 12.1g of a white-like solid, namely 2-fluoro-5-pyridine formate (the melting point is 275-278 ℃).
The pyridine 2-fluoro-5-carboxylate obtained in the first step was put into a 500mL three-necked flask, 200mL of methylene chloride was added, stirring was started, 18.0g of oxalyl chloride was added dropwise, and after 6 hours of reflux reaction, the solvent and excess oxalyl chloride were distilled off. Adding 90mL of cyclohexane, cooling, sealing and filtering, carrying out reduced pressure rectification on the filtrate, collecting the fraction of 90-94 ℃/15mm Hg to obtain 12.2g of colorless liquid product 2-fluoro-5-formyl chloropyridine, and freezing the product to obtain white to off-white solid, wherein the purity of the product reaches 98.5%, and the total yield reaches 76.73%.
Example 5:
1.11Kg (10mol) of 2-fluoro-5-methylpyridine is added into a 10L reaction kettle, 4.5L of water is added, mechanical stirring is started, and 4.74Kg (30mol) of KMnO is sequentially added4And 5.6Kg (10mol) of KOH, heated to 95 ℃ in an oil bath, reacted for 5 hours, filtered while hot, and the filtrate was collected. After the filtrate is cooled to the normal temperature, adjusting the pH value to 2-4 by using concentrated hydrochloric acid, separating out solids, and filtering; the filtrate was extracted twice with dichloroethane. Mixing the filtered solid with the extracted oil phase, and performing rotary evaporation to obtain 1.25Kg of white-like solid, namely the 2-fluoro-5-pyridine formate.
Putting the 2-fluoro-5-pyridine formate obtained in the first step into a 10L three-necked bottle, adding 3.5L dichloromethane, starting stirring (the rotating speed is 300 r/min), dropwise adding 2.20Kg of thionyl chloride, inserting nitrogen into the reaction system under the liquid level, keeping the uniform speed, bubbling, performing reflux reaction for 6 hours, evaporating the solvent and the excessive thionyl chloride, and adding 8.5L cyclohexane. And (3) cooling, sealing and filtering, carrying out reduced pressure rectification on the filtrate, and collecting 90-94 ℃/15mm Hg fractions to obtain 1.26kg of colorless liquid product 2-fluoro-5-formyl chloropyridine, wherein the purity of the obtained product is 98.5% and the total yield is 79.2% after the product is frozen into a white solid.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (6)
1. A preparation method of 2-fluoro-5-formyl chloropyridine is characterized by comprising the following steps:
1) oxidation reaction
Taking 2-fluoro-5-methylpyridine as a raw material, and heating to react in the presence of an oxidant to obtain 2-fluoro-5-pyridine formate; the oxidant is KMnO4Or NaMnO4(ii) a Mixing a certain amount of alkali selected from sodium hydroxide or potassium hydroxide into an oxidant; the molar ratio of the alkali to the 2-fluoro-5-methylpyridine is 1-1.3: 1;
2) acyl chlorination reaction
Reacting 2-fluoro-5-pyridine formate with oxalyl chloride or thionyl chloride in a chlorinated solvent, distilling to remove the reaction solvent, adding an alkane solvent, cooling, filtering to obtain a 2-fluoro-5-formyl chloropyridine mixed solution, and performing reduced pressure rectification to obtain 2-fluoro-5-formyl chloropyridine; in the reaction of the step, the stirring speed of 200 plus 400 turns/min is adopted, and nitrogen or argon is introduced into the reaction kettle for carrying out the reaction.
2. The process for preparing 2-fluoro-5-formylchloropyridine of claim 1, wherein: in the first step, the molar ratio of the oxidant to the 2-fluoro-5-methylpyridine is 2-4: 1.
3. the process for preparing 2-fluoro-5-formylchloropyridine of claim 1, wherein: and in the second step, the chlorinated solvent is dichloromethane, chloroform or 1, 2-dichloroethane.
4. The process for preparing 2-fluoro-5-formylchloropyridine of claim 1, wherein: and in the second step, the alkane solvent is n-pentane, n-hexane, cyclohexane or n-heptane.
5. The process for preparing 2-fluoro-5-formylchloropyridine of claim 1, wherein: in the second step, the equivalent of oxalyl chloride or thionyl chloride and 2-fluorine-5-pyridine formate is 1-2.5: 1.
6. the process for preparing 2-fluoro-5-formylchloropyridine of claim 1, wherein: and (3) collecting 90-94 ℃/15mm Hg fractions during reduced pressure rectification to obtain a colorless liquid product, namely 2-fluoro-5-formyl chloropyridine.
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| DE3707429A1 (en) * | 1987-03-07 | 1988-09-15 | Hoechst Ag | SUBSTITUTED PYRIDINE-2,4-DICARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, USE OF THE SAME AND MEDICINAL PRODUCTS BASED ON THESE COMPOUNDS |
| JPH05501103A (en) * | 1989-06-26 | 1993-03-04 | ザ・リサーチ・ファウンデーション・オヴ・ステイト・ユニヴァーシティ・オヴ・ニューヨーク | Bis-acyloxymethyl derivative |
| EP1257536A1 (en) * | 2000-01-27 | 2002-11-20 | Cytovia, Inc. | Substituted nicotinamides and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| WO2002059077A1 (en) * | 2001-01-26 | 2002-08-01 | Takeda Chemical Industries, Ltd. | Aminoethanol derivatives |
| EP1612204A4 (en) * | 2003-03-31 | 2007-04-11 | Daiichi Seiyaku Co | Hydrazone derivative |
| JP2018090531A (en) * | 2016-12-02 | 2018-06-14 | 日立化成テクノサービス株式会社 | Method for producing heteroaromatic carboxylic acid |
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