34 results about "Grignard reaction" patented technology

The invention relates to the technical field of organic synthesis, in particular to a method for constructing Orforglipron tetrahydropyran ring chirality through enzyme catalysis, which comprises the following steps: step S1, taking SM1 as a raw material, and carrying out hydrolysis resolution in a solvent, a buffer salt system and enzyme catalysis to obtain a chiral pure intermediate INT-1; step S2; performing ring closing on the INT-1 through Grignard reaction to synthesize a lactone intermediate; s3, carrying out Diball-H reduction, quenching, dichloromethane extraction and anhydrous sodium sulfate drying on the INT-4, and then reducing the INT-4 by using triethyl silane to obtain an intermediate INT3; step S4, coupling the INT-3 in the presence of a catalyst and a ligand to obtain an intermediate INT-4; step S5, carrying out deprotection and salification on the INT-4 to obtain an intermediate INT5; s6, closing an indole ring from INT5 to obtain a compound of which the general formula is A; chirality is constructed through enzyme catalysis, isomer impurities do not need to be split and separated through SFC when the chirality is constructed, the loss is reduced, the yield is increased, and a target product is obtained with high chiral selectivity; meanwhile, the cost is relatively reduced, and the cost is saved.

The present invention relates to the technical field of organic synthesis, and specifically relates to a method for constructing the chirality of a pyran ring in Orforglipron by means of enzymatic catalysis, the method comprising the following steps: step S1, by using SM1 and SM2 as starting materials, carrying out a reaction under the action of a palladium catalyst and a ligand to obtain INT-1; step S2, under the catalysis of Pd / C, subjecting INT-1 to double bond hydrogenation reduction to obtain INT-2; step S3, in the presence of a solvent, a buffer salt system and enzymatic catalysis, subjecting INT-2 to hydrolysis and resolution to obtain a chirally pure intermediate INT-3; step S4, subjecting INT-3 to a Grignard reaction for cyclization, so as to synthesize a lactone intermediate INT-4; and step S5, subjecting INT-4 to reduction by means of Dibal-H, quenching same, performing extraction with dichloromethane, drying same with anhydrous sodium sulfate, and then performing reduction by means of triethylsilane to obtain a compound of general formula A. In the present invention, the chirality is constructed by means of enzymatic catalysis without the need of SFC resolution for separating isomeric impurities during the construction of the chirality, thereby reducing losses and improving yield, obtaining the target product at high yield and high chiral selectivity, and further saving expenses and reducing costs.

This invention discloses a method for synthesizing a venetum intermediate, specifically as follows: Step 1: In an organic solvent, 2,4-difluorobenzoic acid and 5-hydroxy-7-azaindole undergo an etherification reaction under the action of an acid-binding agent. After the reaction, post-treatment yields 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid; Step 2: 2-((1h-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-fluorobenzoic acid reacts with 1-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine in… An amination reaction occurs under the action of a base. After the reaction, post-treatment yields 2-(7-azaindole-5-oxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohexene-1-)methyl)piperazine-1-)benzoic acid, i.e., Venetantora intermediate III. The synthetic process provided by this invention avoids Grignard reactions and subsequent hydrolysis reactions, shortens the operation steps, simplifies the synthetic process, and provides a simple and easy-to-operate synthetic process. The raw materials are inexpensive and readily available, while avoiding the use of highly toxic raw materials. The production process is green and environmentally friendly, and suitable for industrial production.

The invention discloses a preparation method of 4-chloro-2-fluoro-3-methoxyphenylboronic acid and a preparation method of the 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The specific implementation process comprises the following steps: by taking 1-bromo-4-chloro-2-fluoro-3-methoxybenzene as a raw material, carrying out Grignard reaction on magnesium chips and an initiator in an organic solvent to synthesize 4-chloro-2-fluoro-3-methoxyphenyl magnesium bromide; and the 4-chloro-2-fluoro-3-methoxyphenyl magnesium bromide and boric acid ester are synthesized into the 4-chloro-2-fluoro-3-methoxyphenylboronic acid, and then the 4-chloro-2-fluoro-3-methoxyphenyl magnesium bromide and boric acid ester are synthesized into the 4-chloro-2-fluoro-3-methoxyphenylboronic acid. The novel synthesis method of 4-chloro-2-fluoro-3-methoxyphenylboronic acid is designed, the total synthesis yield of the method ranges from 88% to 95%, compared with an existing synthesis route, the problems that a traditional route relates to an ultralow temperature condition and strong alkali, is low in safety and high in cost are solved, and the method has the advantages of being simple, environmentally friendly, safe, efficient and the like and is suitable for industrial production. Meanwhile, the method has a relatively good industrialization prospect.

The invention belongs to the technical field of drying equipment for Grignard reaction, and particularly relates to an automatic moisture drying system and method for benzenetetrasolvent in maltol production, and the system comprises a pre-drying storage tank, a first-stage drying storage tank, a first-stage circulating pump and a first-stage drying tower; the bottom of the before-drying storage tank is connected with an upper inlet of a first-stage drying storage tank through a pipeline, a bottom outlet of the first-stage drying storage tank is connected with a first-stage circulating pump, an outlet of the first-stage circulating pump is connected with an upper inlet of a first-stage drying tower, and an outlet of the first-stage drying tower is connected with the upper inlet of the first-stage drying storage tank; an outlet of the first-stage circulating pump is connected with an upper inlet of the second-stage drying storage tank, an outlet of the second-stage drying storage tank is connected with an inlet of the second-stage circulating pump, an outlet of the second-stage circulating pump is connected with an upper inlet of the second-stage drying tower, and a lower outlet of the second-stage drying tower is connected with an upper inlet of the second-stage drying storage tank. According to the invention, the benzene tetrasolvent is automatically dried in maltol production, and manual operation is not needed.

The application provides a preparation method of 2,4,6-trifluorobenzoic acid, which comprises the following steps: 1) subjecting 1,3,5-trifluorobenzene to a bromination reaction to obtain 2,4,6-trifluorobromobenzene; and 2) subjecting the 2,4,6-trifluorobromobenzene to a Grignard reaction to obtain 2,4,6-trifluorobenzoic acid. The method has the advantages of short flow, simple process, high molar yield and high purity of 2,4,6-trifluorobromobenzene, low cost of 2,4,6-trifluorobenzoic acid prepared by the method, and relatively environmentally-friendly and safe operation process, and is suitable for large-scale production.

This invention discloses a method for preparing tetraenestrol, comprising the following steps: S1. Etherification reaction: In a solvent and in the presence of a catalyst, compound I is etherified with methanol to generate compound II, yielding a solution of compound II; S2. Grignard reaction: The solution of compound II obtained in S1 is reacted with a Grignard reagent to generate compound III, yielding a solution of compound III; S3. Hydrolysis reaction: In the presence of an acid, the solution of compound III obtained in S2 is hydrolyzed to generate compound IV, yielding a solution of compound IV; S4. Dehydrogenation reaction: In the presence of a dehydrogenation reagent, the solution of compound IV obtained in S3 is dehydrogenated to generate compound V, yielding tetraenestrol. This preparation route features simple reaction operation, high overall yield, and high product purity, reducing the overall production cost.

The application belongs to the technical field of liquid crystal materials, and relates to a trans-decahydronaphthalene indole liquid crystal compound and a preparation method thereof. The application provides a trans-decahydronaphthalene indole liquid crystal compound, which has a chemical structural formula as shown in formula (I). The preparation of the compound of formula (I) comprises the following steps: obtaining a compound of formula (III) from a compound of formula (II) through a Grignard reaction, oxidizing the compound of formula (III) to obtain a compound of formula (IV), and obtaining the compound of formula (I) from the compound of formula (IV) through a Fischer indole synthesis reaction. The preparation method is simple in operation, high in product yield and purity, and the prepared trans-decahydronaphthalene indole liquid crystal compound can be applied to special liquid crystal materials.

The application discloses a modified polysilane-polysiloxane body type crosslinking copolymer scintillator and a preparation method thereof. The crosslinking copolymer scintillator is a body type crosslinking structure formed by crosslinking of modified polymethylhydrosilane and polymethylphenylsiloxane. In the application, a scintillation group with 2-3 aromatic rings is introduced into a Si-Si main chain through a Grignard reaction, so that an original sigma conjugated system is expanded into a sigma-pi and sigma-pi conjugated system. Correspondingly, introduced pi electrons and lone pair electrons (n electrons) are converted into pi to sigma transition and pi to n to sigma transition, so that the energy gap width is changed, and the fluorescence emission spectrum of the polysilane becomes adjustable. After modification, the conjugated system is expanded, and the intermolecular electron transfer is improved, so that the fluorescence intensity and the quantum yield of the polysilane are improved. The fluorescence intensity of the modified scintillation group is 20-40 times higher than that of the unmodified polysilane-polysiloxane crosslinking copolymer.

The invention discloses a preparation method of vinyl liquid polycarbosilane, which comprises the following steps: preparing a vinyl Grignard reagent through a multi-step Grignard reaction, and reacting with polycarbosilane to construct a vinyl-containing polycarbosilane molecular structure, thereby effectively enhancing the ceramic yield of liquid polycarbosilane and the performance of a subsequent SiC ceramic-based composite material.

The application relates to the technical field of organic synthesis, and provides a synthesis method of chiral allylamine and application thereof, which takes isoegual and chiral tert-butylsulfonamide as initial raw materials, synthesizes an enamine intermediate M1, adopts a silyl ether protecting group to protect a phenolic hydroxyl group to obtain an intermediate M2, then carries out a Grignard reaction on the intermediate M2 to obtain an intermediate M3, then removes a sulfinyl group from the intermediate M3 to obtain an intermediate M4, and then acetylates to obtain an intermediate M5, and finally removes a silyl ether protecting group from the intermediate M5 to obtain the chiral allylamine. The synthesis method can reduce the preparation cost of the chiral allylamine, is beneficial to industrialized production, optimizes stereoselectivity, and omits a chiral resolution step, and the chiral allylamine can be used for synthesizing colchicine.

The invention discloses a preparation method of pentafluorophenyl triethoxy silane, which comprises the following steps: by taking bromopentafluorobenzene and tetraethyl orthosilicate as raw materials, carrying out Grignard reaction under the action of a catalyst to generate pentafluorophenyl triethoxy silane, and carrying out reduced pressure distillation to obtain a pentafluorophenyl triethoxy silane product; the catalyst is magnesium chips, and the Grignard reaction is carried out in an anhydrous organic solvent by taking iodine particles as an initiator; according to the invention, the molar ratio of magnesium chips to bromopentafluorobenzene to tetraethyl orthosilicate to iodine particles is 1: (0.8-1.2): (0.8-1.2): (0.0005-0.001); the magnesium chips and the zeolite are used as a filler layer of the fixed bed reactor, the contact time and the contact area of materials are prolonged, the reaction time is greatly shortened, the purity of the prepared pentafluorophenyltriethoxysilane product can reach 97.0% or above, and the product yield can also reach about 90%.

The utility model belongs to the technical field of chemical production, and particularly relates to a safe Grignard reaction kettle which comprises a reaction kettle body, an initiator feeding pipe penetrates through the left side end of the top of the reaction kettle body, and the input end of the initiator feeding pipe is connected with a flow adjusting mechanism and connected with an initiator storage tank through the flow adjusting mechanism. The initiator storage tank and the flow regulating mechanism are arranged in a flow regulation and control mode, and meanwhile the initiator storage tank is connected with the reaction kettle body through an initiator feeding pipe, the right side end of the top of the reaction kettle body is connected with a magnesium chip feeding mechanism, and a magnesium chip conveying mechanism is arranged on the upper side portion of the magnesium chip feeding mechanism; the magnesium chip conveying mechanism is connected with the reaction kettle body through the magnesium chip feeding mechanism. According to the utility model, the safety problems of overspeed reaction, rapid temperature rise, material flushing and the like caused by improper addition of an initiator are solved, and the stability, the safety and the controllability of the Grignard reaction are ensured.

The application discloses a synthesis method of bifenzhydrylamine intermediate, and relates to the technical field of organic synthesis. The synthesis method comprises the following steps: taking 4-methoxy aniline as a starting material, and obtaining 4-methoxy benzene diazonium salt through a diazotization reaction; decomposing the 4-methoxy benzene diazonium salt to form an aryl free radical, adding a certain amount of benzene to carry out a coupling reaction, and obtaining 4-methoxy biphenyl; then carrying out halogenation reaction on the 4-methoxy biphenyl through a halogenating reagent to obtain 4-methoxy-3-halogen biphenyl; finally, adding a metal amide to carry out nucleophilic substitution, and obtaining 4-methoxy-3-amino biphenyl. The synthesis method of 4-methoxy-3-amino biphenyl provided by the application avoids relatively dangerous and harsh reactions such as nitration reaction and Grignard reaction, the reaction process is relatively safe, raw materials are cheap and easy to obtain, the reaction yield is high, the reaction condition is mild, the synthesis route is short, the equipment investment is small, and the method is easy to industrialize.

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of methylprednisolone and an intermediate compound thereof. The preparation method comprises the following steps: by taking cortisone as a raw material, carrying out 17 and 21 site upper protecting groups and 3 site upper protecting groups, and carrying out reduction, so as to obtain a methylprednisolone intermediate compound shown as a formula V; and carrying out 5 and 6-site epoxidation, Grignard reaction, 3-site protecting group removal, 4 and 5-site dehydration elimination, 1 and 2-site dehydrogenation and 17 and 21-site protecting group removal on the compound in the formula V to obtain methylprednisolone. The structural formula of the compound of formula V is shown in the specification. The preparation process has the advantages of high yield, high purity, low cost, simplicity in operation and suitability for industrial production.

The invention discloses a synthesis method of a diene liquid crystal monomer, which comprises the following steps: S1, Grignard addition reaction: carrying out Grignard addition reaction on substituted cyclohexyl N-methoxy-N-methyl benzamide and a substituted cyclohexyl methyl chloride Grignard reagent to obtain a ketone intermediate; s2, the ketone intermediate sequentially reacts with 5, 5-dibromobarbituric acid for a bromination reaction, then sodium formate is added into an alcohol solvent for a hydroxylation reaction, then sodium borohydride is added for a reduction reaction, and a vicinal diol intermediate is obtained; and S3, carrying out an orthoformate reaction on the vicinal diol intermediate obtained in the step S2 and triethyl orthoformate in a fluorine-containing alcohol solvent, then heating to reflux, and carrying out an elimination reaction to obtain the target diene liquid crystal monomer. According to the invention, a traditional double bond construction strategy of multiple Wittig reactions is abandoned, a new synthesis route which takes the Grignard reaction as a starting point and finally constructs a diene structure by a one-pot method through a low-temperature orthoformate / elimination reaction carried out in a specific fluorine-containing solvent is designed, the route is simple, the total yield is high, and the overall cost is lower.

The invention relates to the technical field of pharmaceutical chemicals, in particular to a preparation method of cholesterol. The method comprises the following steps: 3-position carbonyl ketal protection reaction: uniformly mixing BA, ethylene glycol, p-toluene phosphoric acid and triethyl orthoformate, controlling the temperature to be 40-60 DEG C, reacting for 2-8 hours, cooling to-10-10 DEG C, controlling the temperature to be 1-5 hours, filtering, and drying at 40-70 DEG C to obtain a compound IM1; oxidation of 21-site hydroxyl into aldehyde; s3, carrying out Grignard reaction on the 21-site aldehyde group; carrying out a reaction of oxidizing 21-site hydroxyl into ketone; carrying out a reaction of reducing 21-site carbonyl into methylene; carrying out 3-position carbonyl ester forming reaction; the method disclosed by the invention has the characteristics of good selectivity, low cost and small pollution, and the method is stable and easy to realize industrial production.

The invention relates to a silicon-hydrogen-terminated silicon-containing aryne resin and a preparation method and application thereof, the structural formula of the silicon-hydrogen-terminated silicon-containing aryne resin is as follows: in the formula, R1 and R2 are respectively and independently CH3, CH2 = CH, H or phenyl; n is equal to 1-9. The preparation method comprises the following steps: firstly, carrying out Grignard reaction on 1, 3-diacetylene benzene and a Grignard reagent to obtain a compound 1 as shown in a formula I; carrying out polymerization reaction on the compound 1 and a compound 2 as shown in a formula II to obtain a compound 3 as shown in a formula III; and then carrying out reduction reaction on the compound 3 and lithium aluminum hydride to obtain the silicon-hydrogen-terminated silicon-containing aryne resin. Compared with the prior art, the silicon-hydrogen-terminated silicon-containing aryne resin prepared by the invention has excellent heat resistance, has extremely high thermal decomposition temperature of 5% of cured substance weight loss in nitrogen and air, has excellent processability and has an extremely wide processable temperature window.

The invention provides a preparation method of 4-(4-chlorophenoxy)-2-trifluoromethyl acetophenone, which is characterized in that o-trifluoromethyl aniline is used as a raw material, and the 4-(4-chlorophenoxy)-2-trifluoromethyl acetophenone is obtained through amino protection, bromination reaction, protecting group removal, diazotization reaction, coupling reaction, hydrolysis reaction and etherification reaction. The raw materials of the preparation method are cheap and easy to obtain and are supplied in large scale in China; an acetyl group is obtained by diazotization, coupling and hydrolysis processes, a Grignard reagent and a Grignard reaction are not needed, dangerous reagents, harsh reaction conditions, fluoride-free cracking and other processes are avoided, special equipment is not needed, and magnesium-containing, fluorine-containing and other difficult-to-treat wastewater cannot be generated. The preparation method has the advantages of cheap and easily available raw materials, simple process, mild reaction conditions, safe and controllable preparation process and higher industrial application value, and all reactions can be carried out under normal pressure.

The application belongs to the technical field of raw materials and intermediate preparation in organic synthesis, and relates to a method for preparing a key intermediate of a natural product Brasilicardin A analogue, and the Brasilicardin A is a new immunosuppressive agent, the mechanism of action of which is to inhibit the amino acid transport system L, has strong immunosuppressive activity (IC50=0.057 mu g / ml), and has potential clinical application value. The application belongs to the technical field of raw materials and intermediate preparation in organic synthesis. The preparation method of the key intermediate comprises: Grignard reaction, methylation reaction, iodinated lactone reaction, intramolecular Aldol reaction and the like for preparing a precursor compound of a C ring, and then through diastereoselective alkylation reaction and intramolecular Michael addition reaction, the synthesis of the key intermediate of the Brasilicardin A analogue is completed. The method has the advantages of simplicity and high efficiency, controllable method, high product purity and easy industrial production and the like.

The invention belongs to the field of organic chemistry, particularly relates to a teprenone preparation method adopting a continuous flow process, and improves the existing teprenone synthesis process. The first continuous flow reaction system disclosed by the invention can safely and continuously carry out Carroll reaction at high temperature and high pressure, and the system does not need to adopt a high-boiling-point solvent, so that the reaction efficiency is greatly improved, and the risk of blasting boiling or material flushing in a traditional kettle type reaction process is solved; according to the second continuous flow reaction system, the metal Grignard reagent can be sealed in the pipeline and is not exposed outside, the reaction temperature is increased, the reaction retention time is shortened, and the safety of the Grignard reaction is ensured. The continuous synthesis method provided by the invention can realize safe, stable and continuous amplification reaction, and is more suitable for industrial production of teprenone.

According to the preparation method of the posaconazole key intermediate, 2, 4-difluorobromobenzene serves as a raw material, the target compound (I) is obtained through the Grignard reaction, elimination and substitution reactions, the raw materials are easy to obtain and low in price, the Grignard reaction is mature, the reaction conditions are mild, the yield is high, reagents which have great harm to the environment are not used, and the preparation method is more environmentally friendly and suitable for industrial production. The method is suitable for large-scale industrial production.

The application relates to the technical field of drug intermediate synthesis, in particular to an anti-platelet reduction drug romiplostim intermediate and a preparation method thereof. The method of the application is as follows: starting from compound I, i.e. 2-halogenated phenol, reacting with paraformaldehyde to obtain compound II; the compound II is reacted with a methylating agent and a Grignard reagent in sequence to obtain intermediate IV; the alcohol hydroxyl group in the intermediate IV is oxidized to obtain compound V; the halogen in the compound V is replaced by a cyano group to obtain intermediate VI; the intermediate VI is subjected to asymmetric reduction to obtain intermediate VII; the hydroxyl group in the intermediate VII is continuously protected to obtain intermediate VIII, the cyano group in the intermediate VIII is subjected to a Grignard reaction to obtain intermediate IX; the intermediate IX is subjected to bromination to obtain compound X; and the compound X is ring-closed with thiourea to obtain intermediate XI. The synthesis route of the application avoids column chromatography in each step, is easy to operate, and the reaction yield of each step is relatively high, and can all reach more than 80%.

The application belongs to the technical field of organic synthesis and specifically relates to a preparation method of (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide. The application mixes p-bromoanisole, magnesium, an initiator and an organic solvent to perform a first-stage Grignard reaction, mixes the obtained first-stage Grignard reaction liquid and a compound shown in formula 2 to perform a second-stage Grignard reaction, performs chlorosulfonation reaction on the obtained compound shown in formula 3 and chlorosulfonic acid, mixes the obtained chlorosulfonation reaction liquid and ammonia water to perform an amination reaction, performs reduction reaction on the obtained compound shown in formula 4 in a hydrogen atmosphere, and (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide is obtained. The preparation method provided by the application simplifies the operation process, has less waste, and has high yield in each step, and the obtained (R)-5-(2-aminopropyl)-2-methoxybenzenesulfonamide product has high purity and is suitable for industrial production.

The application discloses a hyperbranched fluorocarbon surfactant and a preparation method thereof. The fluorocarbon surfactant is prepared by using an iodine-substituted alkane as a substrate and through addition, ring opening, quaternary ammonium, Grignard reaction, borohydride oxidation and other steps. The fluorocarbon surfactant has both hydrophilic groups and hydrophobic groups. The fluorocarbon surfactant with the structure has excellent surface performance. When the fluorocarbon surfactant is compounded with other materials into a foam fire extinguishing agent, the fluorocarbon surfactant can effectively isolate the combustion from air, and plays a role of rapid fire extinguishing.

The utility model relates to a reaction device for Grignard reaction, which comprises a reaction kettle, an inlet of the reaction kettle is connected with a diaphragm pump, the reaction kettle is further connected with a nitrogen storage tank through a nitrogen pipe, the nitrogen storage tank is further connected with a material pressing device through a nitrogen pipe, the material pressing device is arranged on a Grignard reagent barrel, and the material pressing device comprises a disc. A liquid phase pipe and a gas phase pipe penetrate through the disc, and the material pressing device is further connected with an inlet of the reaction kettle through a feeding valve and a pneumatic control valve. According to the reaction device for the Grignard reaction, disclosed by the utility model, a Grignard reagent is prevented from being in contact with air in a conveying process, is added into the reaction kettle in a nitrogen atmosphere and reacts in the nitrogen atmosphere, so that the Grignard reagent is prevented from being decomposed.

This invention discloses a curcumin derivative with therapeutic effects on acute lung injury and its preparation method, comprising: dissolving curcumin in tetrahydrofuran, removing air from the reaction apparatus, and adding nitrogen to the reaction apparatus to fill it with nitrogen; then adding ethyl magnesium bromide and refluxing at a first preset temperature for 30 min; then adding succinic anhydride and refluxing at a second preset temperature for 4 h; stopping the reaction by adding water and adjusting the pH to 4 with hydrochloric acid; after extraction with ethyl acetate, purifying the upper layer using a preset method to obtain a yellow oily substance I-1; reacting curcumin succinate monoester I-1 with a 5% sodium bicarbonate solution, and evaporating the solvent to obtain curcumin succinate monoester sodium salt II. The raw material used in this invention has wide clinical applications and is safe and low in toxicity. The hydroxyl group of curcumin is combined with succinic anhydride through a Grignard reaction to form curcumin succinate monoester I-1, which is then reacted with sodium bicarbonate solution to obtain curcumin succinate monoester sodium salt II.

The invention discloses a preparation method of 17-(4 '-phenyl phenyl)-estra-1, 3, 5 (10)-triene-3, 17 beta-diol and an application of the 17-(4'-phenyl phenyl)-estra-1, 3, 5 (10)-triene-3, 17 beta-diol. The method comprises the following steps: by taking estrone as an initial raw material, carrying out hydroxyl protection, carrying out lithium-halogen exchange on n-butyllithium and 4-bromodiphenyl to generate a high-activity biphenyl lithium intermediate, then carrying out nucleophilic addition on the high-activity biphenyl lithium intermediate and a protected estrone derivative, and finally, carrying out hydrolysis deprotection to obtain a target product. According to the method, a traditional and low-efficiency Grignard reaction route is successfully replaced with a lithium-halogen exchange strategy, the technical bottlenecks that the steric hindrance of a substrate is large and the reaction is difficult to carry out are overcome, the method has the advantages of being easy and convenient to operate, mild in reaction condition, high in product yield and good in purity, and a reliable scheme is provided for preparing the key impurity standard substance.

The invention discloses a novel synthesis method of 2, 6-naphthalic acid, and belongs to the technical field of organic synthesis. The method comprises the following steps: taking 2-bromine-6-methoxynaphthalene and methyl magnesium bromide as initial raw materials, firstly preparing an intermediate 2, 6-dimethylnaphthalene through a Grignard reaction / coupling reaction in one step under the action of a nickel catalyst, and then carrying out a catalytic oxidation reaction by taking air as an oxygen source under the action of a manganese-cobalt-bromine catalyst system to obtain a target product. The total yield reaches 85%, and the purity is 99%. The method has the advantages of high total yield, cheap catalyst, few reaction steps, simplicity in operation, high reaction selectivity, easiness in purification, low energy consumption and few three wastes, so that the method is synthesized, the production cost is lower, and the method is suitable for industrial production.

The invention discloses a preparation method of a lultrombopag key intermediate, which comprises the following steps: by taking cheap and easily available 2, 6-dichlorobenzaldehyde as a starting raw material, carrying out Wittig reaction on the starting raw material and phosphorus ylide with ester carbonyl protected by dioxolane to obtain an olefin compound; then carrying out bromination reaction under the catalysis of iron powder to obtain a high-yield brominated compound; and carrying out Grignard reaction, carbon dioxide carboxylation and hydrochloric acid acidification synchronous degreasing protection, and carrying out primary crystallization to obtain the key intermediate of the lutrombopag. According to the method, lithium diisopropylamide and other strong bases are not needed, the reaction temperature is controlled to range from-10 DEG C to 30 DEG C, the requirement of the system for moisture is low, the total yield is high, the single impurity (containing Z-type isomer) of the product is smaller than 0.1%, the method has the advantages of being low in material cost, mild in reaction condition, high in stereoselectivity and easy to industrially produce, and the production cost of the lutrombopag is remarkably reduced.