50 results about "Mitsunobu reaction" patented technology

The invention relates to a method for preparing a nerofloxacin chiral piperidylamine intermediate, which comprises the following steps of: carrying out condensation reaction on 5-hydroxy nicotinic acid which is simple and easy to obtain and is used as a raw material and different alcohols, screening through a series of asymmetric catalytic hydrogenation conditions to obtain optimal reaction conditions, and under the conditions, carrying out reaction on various 3, 3 '-dihydroxy nicotinic acid and 3, 3'-dihydroxy nicotinic acid to obtain the nerofloxacin chiral piperidylamine intermediate. The 2, 5-disubstituted pyridine quaternary ammonium salt is reduced into a tetrahydropyridine product, and the C5 site enantioselectivity of the product is excellent. The preparation method comprises the following steps: selecting methyl (R)-1-benzyl-5-hydroxy-1, 4, 5, 6-tetrahydropyridine-3-carboxylic acid methyl ester as a substrate, completely hydrogenating by using platinum dioxide hydrogen, and then carrying out methyl ester reduction, dehydroxylation, Mitsunobu reaction and protecting group removal to obtain a key chiral intermediate for industrial synthesis of a quinolone antibacterial drug nemonofloxacin with high enantioselectivity and high yield.

The invention provides a preparation method of a suvorexant key intermediate as shown in a formula (I), which comprises the following steps: S5, carrying out Mitsunobu reaction ring closure on a compound 5 to obtain a compound 6; s6, the compound 6 is subjected to a deprotection reaction in the presence of alkali; then, salifying with acid to obtain a compound 7; and S7, dissociating the compound 7 in a salt form in the presence of alkali to obtain the compound as shown in the formula (I). The method has the remarkable advantages that the used raw materials are low in price, wide in source and easy to obtain; meanwhile, the reaction conditions of each step are mild, the process operation is simple and convenient, and the production cost is effectively reduced. In addition, the use of expensive and high-toxicity reaction reagents in the original process route is avoided, so that the safety and environmental protection property of production are improved. Therefore, the method is more suitable for large-scale industrial production and has very high application value and market prospect.

The invention discloses a preparation method of (R)-3-aminotetrahydrofuran hydrochloride, and belongs to the technical field of organic medicine intermediates. The preparation method comprises the following steps: taking (S)-3-hydroxytetrahydrofuran and triphenylmethylamine as raw materials, and reacting in the presence of triphenylphosphine and an azo reagent to generate (R)-N-triphenylmethylhydrofuran-3-amine; and the (R)-N-triphenylmethylhydrofuran-3-amine is subjected to deprotection in an alcohol solvent in the presence of hydrochloric acid to form a salt so as to generate the (R)-3-aminotetrahydrofuran hydrochloride. According to the invention, triphenylphosphine and an azo catalyst are adopted to carry out Mitsunobu reaction, configuration inversion is realized, the conversion rate is high, the method is suitable for industrial production, and reference is provided for synthesis of the compounds.

The invention discloses four-arm polyethylene glycol amine as well as a preparation method and application thereof, relates to the technical field of high polymer materials, and solves the problems of poor comprehensive properties such as strength, fatigue resistance and swelling resistance when traditional dual-network hydrogel is applied to preparation of a cartilage repair material in the prior art. The molecular weight of four-arm polyethylene glycol amine provided by the invention is 10 kDa or 40 kDa, four-arm polyethylene glycol, phthalimide, diisopropyl azodicarboxylate and triphenylphosphine are subjected to a Mitsunobu reaction and hydrazinolysis, and the four-arm polyethylene glycol amine with the molecular weight of 10 kDa is obtained; four-arm polyethylene glycol, phthalimide, diisopropyl azodicarboxylate and triphenylphosphine are subjected to a Mitsunobu reaction and hydrazinolysis, and four-arm polyethylene glycol amine with the molecular weight of 40 kDa is obtained. The double-network hydrogel prepared from the four-arm polyethylene glycol amine has excellent comprehensive performance such as high mechanical strength, fatigue resistance, self-recovery performance and swelling resistance, and can be applied to preparation of cartilage-like materials.

The invention discloses a preparation method of galanthamine and an intermediate thereof, and belongs to the technical field of organic chemical synthesis. The chemical structural formulas of the intermediates for synthesis of galanthamine are as shown in formulas (I)-(IV). According to the invention, 2-cyclohexenone, acrylic ester, 3-hydroxy-2-halo-4-methoxybenzaldehyde and the like are used as starting raw materials, and the intermediate required for preparing the galanthamine is synthesized in sequence through a plurality of reactions such as Sentian-Bellies-Hilmann reaction, Corey-Barksh-Chai-field reaction, Mitsunobu reaction and the like; and then the galanthamine is synthesized by using the intermediates. The synthesis method is low in raw material and reagent price, low in production cost, short in synthesis route, easy and convenient to operate, high in yield and suitable for large-scale production, and the problems that an existing galanthamine synthesis process is complex, high in cost, low in yield and the like are solved.

Four-arm polyethylene glycol amine and preparation method and application thereof, relate to the technical field of high polymer materials, and solve the problem of poor comprehensive performance such as strength, fatigue resistance and swelling resistance when the traditional double network hydrogel is applied to the preparation of cartilage repair materials in the prior art. The four-arm polyethylene glycol amine provided by the application has a molecular weight of 10 kDa or 40 kDa. Four-arm polyethylene glycol, phthalimide, diisopropyl azodicarboxylate and triphenylphosphine are subjected to Mitsunobu reaction and hydrazinolysis to obtain four-arm polyethylene glycol amine with a molecular weight of 10 kDa. Four-arm polyethylene glycol, phthalimide, diisopropyl azodicarboxylate and triphenylphosphine are subjected to Mitsunobu reaction and hydrazinolysis to obtain four-arm polyethylene glycol amine with a molecular weight of 40 kDa. The double network hydrogel prepared from the four-arm polyethylene glycol amine has excellent comprehensive performance such as high mechanical strength, fatigue resistance, self-recovery and swelling resistance, and can be applied to the preparation of cartilage-like materials.

The invention discloses a synthesis method of 2 '-O-methyladenosine, and belongs to the technical field of nucleoside synthesis and medicinal chemistry. According to the method, xylose which is rich in source is taken as an initial raw material, eight-step reaction including acetalation protection, acetylation, glycosylation, deacetylation, methylation, deacetalation protection, Mitsunobu reaction and secondary deacetylation is performed, reaction conditions of each step are accurately controlled, and finally, a target product is synthesized. The method has the advantages of high methylation reaction regioselectivity, mild reaction conditions, cheap and easily available raw materials and controllable cost, and overcomes the problems of poor methylation reaction regioselectivity, harsh reaction conditions and high cost in the existing synthesis method. The obtained product has important application value in the fields of research and development of antiviral drugs, design of nucleic acid probes and the like.

The invention discloses a preparation method of Linzagolix, which comprises the following steps: taking 2, 3-difluoro-6-methoxybenzyl alcohol as a raw material, under the action of alkali and phosphine ligand, carrying out Mitsunobu reaction on 2, 3-difluoro-6-methoxybenzyl alcohol and 2-methoxy-4-fluorophenol to obtain a compound A, sequentially carrying out nitration reaction and reduction reaction on the compound A to obtain a compound C, and carrying out recrystallization on the compound C to obtain the Linzagolix. Under the alkaline condition and the action of triphosgene, the compound C and 4-aminothiophene-2, 3-dimethyl dicarboxylate hydrochloride are subjected to a one-pot condensation reaction to obtain a compound D, and the compound D reacts under the alkaline condition to generate Linzaolix. According to the invention, the synthesis process of Linazagolix is shortened to five steps, the reaction condition is mild, the operation is simpler and more convenient, and the method is suitable for industrial production.

The invention provides atomoxetine hydrochloride and a preparation method thereof, and relates to the technical field of medicinal chemistry and organic synthesis. The method provided by the invention comprises the following steps: adopting acetophenone, methylamine hydrochloride and a formaldehyde aqueous solution as raw materials, carrying out Mannich reaction to construct a beta-amino carbonyl skeleton, reducing carbonyl into hydroxyl by adopting sodium borohydride, then reacting with di-tert-butyl dicarbonate to form an amino protecting group, adopting o-methylphenol as a raw material, and preparing the beta-amino carbonyl skeleton. The method comprises the following steps: adding p-toluenesulfonic acid monohydrate and a (2-hydroxybenzyl) phosphine oxide catalyst to construct an ether bond through a Mitsunobu reaction, then removing a t-butyloxycarboryl protecting group, and carrying out chiral resolution and salinization reaction by using S-mandelic acid to obtain atomoxetine hydrochloride. The method of dropwise adding the formaldehyde aqueous solution in batches and controlling the reaction temperature is adopted, so that the generation of impurities can be reduced, and the yield is effectively improved; the p-toluenesulfonic acid monohydrate and the (2-hydroxybenzyl) phosphine oxide catalyst capable of participating in catalytic circulation are used for catalyzing the Mitsunobu reaction, the economic principle is met, and the purity and the yield of the product are greatly improved.

The present invention relates to a method for preparing a compound of formula I, which is a key intermediate of maralixibat chloride, and a use thereof. The compound of formula I can be synthesised by using a compound of formula IV or a compound of formula IX as a starting substrate, wherein the compound of formula IX undergoes a Mitsunobu reaction with a compound of formula VIII and sulfhydryl deprotection and substitution reactions to obtain the compound of formula IV, and the compound of formula IV then undergoes in sequence a reduction reaction and two oxidation reactions to obtain the compound of formula I, wherein R1, R4, and R5 are as defined in the description. The present invention provides a new method for synthesising a compound of formula I as a key intermediate of maralixibat chloride from different starting substrates; the method of the present invention has the advantages of simple steps, inexpensive raw materials, mild reaction conditions, high total yield, and high product purity, and is suitable for industrial production.

The present invention discloses a method for synthesizing optically pure glabridin. The method uses (R)-3-acetoxy-2-(2,4-dimethoxyphenyl)propanol and 2-isopentenylresorcinol as raw materials to obtain a key intermediate compound I through a Mitsunobu reaction, and then obtains an intermediate compound II through hydrolysis and iodination. The intermediate compound II is then cyclized, reduced, and protected by removal to obtain glabridin. The present invention retains the reactivity of the olefin functional group by introducing an isopentyl side chain, provides a key site for subsequent cyclization, ensures the precise stereoconfiguration of the product, and ultimately obtains optically pure glabridin. The present invention has a short route, low cost, mild reaction conditions, and is suitable for industrial production.

This invention discloses a apigenin-betaine compound and its preparation method. The compound uses apigenin (Api) as its core, with -O-(CH2) at the 7', 4', and / or 5-position hydroxyl groups. n -N + (CH3)2-CH2COO ‑ Fragment substitution (n=2~12, x=1~3) forms an internal salt-type zwitterionic structure. In preparation, apigenin is first reacted with bromool Br(CH2). n A mitsunobu reaction was performed on OH under triphenylphosphine / dialkyl azodicarbonate conditions to obtain mono / polysubstituted bromoalkoxylated apigenin; subsequently, nucleophilic substitution with N,N-dimethylglycine under alkaline conditions yielded the target product. This structure, possessing both a tunable alkyl chain and a betaine cation / anion pair, significantly enhances the solubility and hydration capacity of apigenin in aqueous / alcoholic media, strengthens its affinity and stability for biomembranes, thereby improving in vivo absorption and distribution and potentially maintaining its antioxidant and anti-inflammatory activities. The method is mild, with a wide solvent and temperature range, suitable for scale-up and formulation applications.

The application discloses a trifluoromethyl benzyl ether substituted amino acid derivative, a preparation method and application thereof, and belongs to the technical field of organic compound synthesis and medicine. The synthesis method of the trifluoromethyl benzyl ether substituted amino acid derivative is obtained through two-step reaction, that is, first, a photo extension reaction is carried out between a benzyl alcohol compound and hydroxynaphthaldehyde (or hydroxybenzaldehyde), then a Schiff base is formed after an amino acid ester hydrochloride, and then the Schiff base is reduced by sodium cyanoborohydride, and then simple hydrolysis is carried out to obtain the trifluoromethyl benzyl ether substituted amino acid derivative. The preparation method has the characteristics of simple steps, mild reaction conditions and fast reaction, and meets the requirements of green chemistry. The compound prepared according to the method can selectively adjust S1P1 receptors without exciting S1P3 receptors, and is expected to be developed into a new preparation for treating idiopathic pulmonary fibrosis.

The invention discloses a synthesis method of 1, 4, 7, 10-tetraaza-2, 6-pyridine cyclophane, and relates to the technical field of organic synthesis.The synthesis method comprises the steps that 2, 6-pyridine dimethanol which is low in price and easy to obtain serves as a starting raw material, and the 1, 4, 7, 10-tetraaza-2, 6-pyridine cyclophane is synthesized through a Mitsunobu reaction, a Staudinger reaction and a reductive amination ring closing reaction; the synthesis method has the characteristics of short route, simple operation, mild reaction conditions, high yield and the like, and is suitable for industrial production of 1, 4, 7, 10-tetraaza-2, 6-pyridine cyclophane.

This invention belongs to the field of medicinal chemistry and pharmaceutical technology, specifically relating to a method for preparing a rufiamide impurity reference standard. The method includes the following steps: (1) mixing o-fluorobenzyl alcohol, 1H-1,2,3-triazol-4-nitrile, photocatalytic reaction reagent, triphenylphosphine, and solvent 1, and reacting to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile; (2) mixing 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-nitrile, carbonate, hydrogen peroxide, and solvent 2, and reacting to obtain 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-formamide. This invention is simple to operate, has milder reaction conditions, and does not involve the use or generation of azides; the synthesis method is green and novel, and can rapidly and efficiently prepare 1-(2-fluorobenzyl)-1H-1,2,3-triazol-4-formamide.

The invention discloses a method for preparing chiral R or S 3-methylmorpholine. The method uses chiral S or R propylene oxide as a raw material, reacts it with Boc ethanolamine under the action of a Lewis acid, and then undergoes a Mitsunobu reaction to close the ring to obtain a chiral morpholine compound. The preparation method of the present invention shortens the steps, improves the total yield, and effectively reduces the unit cost.

The present invention belongs to the technical field of DNA synthesis. Provided is a method for synthesizing an N2-C6 amino-modified deoxyguanosine monomer. The synthesis method comprises: performing a silylation protection reaction on deoxyguanosine under the protection of a silanization reagent so as to obtain a first intermediate; performing a Mitsunobu reaction on a second reaction raw material to obtain a second intermediate; performing a nucleophilic substitution reaction on the first intermediate and the second intermediate to obtain a third intermediate; and performing a desilylation protection reaction and a protective group introduction reaction, followed by an activation coupling reaction to obtain a final product. In the synthesis method, the final product is prepared by performing the silylation protection reaction, the Mitsunobu reaction, the nucleophilic substitution reaction, the protective group introduction reaction and the activation coupling reaction on the raw materials. The synthesis method has the advantages of the chemical raw materials used being simple and readily available, and being low cost; having mild reaction conditions, and easy to scale-up production; high stability of the intermediate obtained; and being a simple purification method and easily operated.

Thioesters, thiocarbamates, thiocarbazates, semithiocarbazates, peptides, aza-amino acid conjugates, and azapeptides; and a chemoselective and site-specific functionalization protocol of protected thiocarbazates and semithiocarbazates are described. The protocol features the use of Mitsunobu reaction to alkylate specifically the nitrogen atom close to the acylthiol moiety with alcohols to produce protected mono-substituted thiocarbazates that can be stored for months, activated under mild conditions at low temperature using halonium reagents and integrated orthogonally to make substituted semicarbazides that can be used, e.g., as synthons in synthesis of aza-amino acid conjugates, azapeptides and other peptidomimetics. Methods for preparing and using ureases, carbazides, semicarbazides, beta-peptides, azapeptides, and other peptidomimetics and azapeptide conjugates, and uses of ureases, carbazides, semicarbazides, beta-peptides, azapeptides in drug discovery, diagnosis, inhibition, prevention and treatment of diseases are also described.

The invention relates to the technical field of compound synthesis, in particular to a preparation method of tigorazan, which comprises the following steps: (1) in an organic solvent, carrying out bromination reaction on 4-hydroxy-N, N, 2-trimethyl-1-(benzyl)-1H-benzimidazole-6-formamide and a bromination reagent to obtain a compound I; (2) in an organic solvent, carrying out Mitsunobu reaction on the compound I and (R)-5, 7-difluorochroman-4-ol under the catalysis of a phosphine reagent and an azo compound to prepare a compound II; and (3) carrying out hydrogenation reaction on the compound II in an organic solvent in a hydrogen atmosphere to obtain the tigorazan. A brand new process route is developed, the whole reaction route is short, raw materials are easy to obtain, operation is easy and convenient, reaction conditions are mild and safe, the yield of the obtained tigoran is high, the total yield is 83% or above, and industrial production can be achieved easily.

The application belongs to the field of pharmaceutical chemistry and particularly relates to a synthesis method of besuxidil mesylate. First, 2-chloroquinazoline-4-amine a is used as raw material, and then a nucleophilic substitution reaction with 5-bromoindazole b, a Suzuki coupling reaction with 3-hydroxyphenylboronic acid d, a Mitsunobu reaction with 2-hydroxy-N-isopropylacetamide f and a salt reaction with methanesulfonic acid are sequentially performed to obtain besuxidil mesylate. The main route of the application is short, and compared with the existing route, the yield is higher, and the industrial production is facilitated.

The invention relates to the technical field of medicine synthesis, and particularly discloses a synthesis process of a bemaprost intermediate. According to the method, B is taken as a starting point of a reaction route, a carbon chain skeleton is constructed through a Grignard reaction, stereo enrichment is realized through enzymatic resolution, a byproduct configuration is converted in combination with a Mitsunobu reaction, finally, a target product is obtained through enzyme hydrolysis, the stereoselectivity of the whole process is good in control, and high enantiomer purity of the product is ensured through chiral recognition of an enzyme and overturning of the configuration through an SN2 reaction.

The invention relates to the technical field of antibacterial agents, in particular to an andrographolide derivative and a synthesis method and application thereof.The andrographolide is structurally modified, and a series of 14-site aryloxy / acylamino substituted derivatives are synthesized; the preparation method comprises the following steps: firstly, protecting 3, 19-dihydroxyl to obtain 3, 19-isopropylidene andrographolide; then, carrying out Mitsunobu reaction, so as to obtain a series of compounds of which the configuration at the C-14 site is reversed; and finally, in the presence of p-toluenesulfonic acid monohydrate, removing 3, 19-site protecting groups to obtain the target compound. The andrographolide derivative provided by the technical scheme has an inhibition rate of more than 60% on six test fungi at a concentration of 100 [mu] g / mL, and the activity of the andrographolide derivative is superior to that of a positive control drug azoxystrobin; and meanwhile, the hypha form of the pyrethrum can be obviously destroyed, and the vigna unguiculata seed germination is not influenced, so that high safety is shown.

The application discloses a novel method for preparing an intermediate of an aryl abietane diterpene Plebein C, and specifically comprises the following steps: substituting a carbonyl alpha position of 4,4-dimethyl-2-cyclohexen-1-ketone to obtain compound I; protecting the compound I by TBS to obtain compound II; performing a Luche reduction reaction on the compound II to obtain compound III; performing an iodination reaction on 3-hydroxy-4-methoxybenzaldehyde to obtain compound IV; performing a Wittig reaction on the compound IV to obtain compound V; performing a Mitsunobu reaction between the compound III and the compound V to obtain compound VI; performing a radical cyclization reaction on the compound VI to obtain compound VII; performing an oxidation on a benzyl position of the compound VII to obtain compound VIII; and finally performing an oxidation and a ring closure on the compound VIII to obtain a five-ring intermediate compound IX of a Plebein C molecule; the preparation method has the advantages of simple synthetic route, low-cost and easily-obtained reagents, high yield, favorability for industrial preparation of the intermediate, and strong popularization potential.

The present invention discloses intermediate I and intermediate II that can be used for preparing galanthamine, and its preparation method and a kind of asymmetric total synthesis method of galanthamine and derivatives thereof as shown in structural formula (I) and formula (II) respectively, and a kind of synthetic route is short, high yield galanthamine and its derivatives. The present invention uses simple, cheap and easily available compound 2, vinylcarbamic acid tert-butyl ester and 3 hydroxy 2 iodine 4 methoxybenzaldehyde as starting raw materials, and the intermediate required for preparing galanthamine and its derivatives, i.e. the intermediate shown in formula (I) and formula (II) is synthesized in sequence by multiple reactions such as Suzuki cross-coupling reaction and Mitsunobu reaction, and then galanthamine and its derivatives are prepared using these intermediates. The synthetic route of the preparation method of galanthamine, its derivatives and intermediates provided by the present invention is short, high yield, and it is easy to realize large-scale production.

The invention discloses a tigorazan impurity as well as a preparation method and application thereof. The preparation method of the tigorazan impurity comprises the following steps: taking an intermediate M1 of tigorazan as a raw material, and carrying out alkylation and Mitsunobu reaction on the intermediate M1 and (R)-5, 7-difluorochroman-4-ol to prepare an impurity compound I and an impurity compound II; and removing benzyl from the impurity compound I and the impurity compound II under the catalysis of a catalyst to respectively obtain an impurity compound III and an impurity compound IV. The tigorazan impurity prepared by the method is high in purity, can be used as a reference substance or a standard substance for qualitative and / or quantitative analysis of impurities in all-component analysis of a tigorazan raw material medicine, and further helps to control the impurities in the actual production process, so that the purity and quality of tigorazan are guaranteed, and the medicine quality is guaranteed.

The invention provides a preparation method of a diacylglycerol kinase inhibitor, which comprises the following steps: S1, reacting 4-fluorobenzyl bromide with magnesium under inert gas by taking iodine as an initiator to obtain a Grignard reagent B; s2, the Grignard reagent B and N-tert-butyloxycarbonyl-4-piperidone are subjected to an addition reaction, and an intermediate C is obtained through hydrolysis and deprotection; s3, carrying out Heck coupling reaction on the intermediate C, 4-fluorophenyl trifluoromethanesulfonate and a catalyst in the presence of alkali to obtain an intermediate D; s4, carrying out substitution reaction on the intermediate D and chloroethanol in the presence of alkali to obtain an intermediate E; s5, carrying out Mitsunobu reaction on the intermediate E to obtain an intermediate F; s6, carrying out addition reaction on the intermediate F and N, N '-thiocarbonyldiimidazole to obtain an intermediate G; and S7, carrying out cyclization reaction on the intermediate G, 2-methyl aminobenzoate and alkali to obtain the diacylglycerol kinase inhibitor R59949. The synthesis route disclosed for the first time has the characteristics of mild reaction conditions, reasonable design, cheap and easily available raw materials, high yield and the like, and provides theoretical support for biological evaluation and clinical application of R59949.

The invention belongs to the field of drug synthesis, and particularly relates to an application of a Mitsunobu reagent in the synthesis of ipropam hydrochloride, which is characterized in that an aldehyde group is reduced into benzyl alcohol by sodium borohydride in a protic solvent to obtain an intermediate 1; the intermediate 1 rapidly reacts in BEHT trifluoromethanesulfonate, a high-purity intermediate 2 can be obtained through simple extraction, water washing, recrystallization and filtration, and the BEHT trifluoromethanesulfonate has the characteristic of high conversion rate which is not possessed by other ordinary Mitsunobu reaction reagents in the reaction. The intermediate 2 is hydrolyzed by sodium hydroxide and deprotected by trifluoroacetic acid, and the purity reaches 99% or above under recrystallization. The method is high in reaction conversion rate, high in repeatability, simple in preparation method, low in equipment requirement and easy for industrial production.

Thioesters, thiocarbamates, thiocarbazates, semithiocarbazates, peptides, aza-amino acid conjugates, and azapeptides; and a chemoselective and site-specific functionalization protocol of protected thiocarbazates and semithiocarbazates are described. The protocol features the use of Mitsunobu reaction to alkylate specifically the nitrogen atom close to the acylthiol moiety with alcohols to produce protected mono-substituted thiocarbazates that can be stored for months, activated under mild conditions at low temperature using halonium reagents and integrated orthogonally to make substituted semicarbazides that can be used, e.g., as synthons in synthesis of aza-amino acid conjugates, azapeptides and other peptidomimetics. Methods for preparing and using ureases, carbazides, semicarbazides, beta-peptides, azapeptides, and other peptidomimetics and azapeptide conjugates, and uses of ureases, carbazides, semicarbazides, beta-peptides, azapeptides in drug discovery, diagnosis, inhibition, prevention and treatment of diseases are also described.

The invention relates to a synthesis process of a KRAS inhibitor type antitumor drug MRTX849, which comprises the following steps: by taking a benzyl-protected compound 2 as an initial raw material, firstly carrying out amidation reaction, introducing a piperidine ring into a main chain structure, carrying out cyclization reaction to obtain a compound 6, then directly introducing a nitrogen methyl tetrahydropyrrole ring through Mitsunobu reaction, then removing benzyl protection, introducing a naphthalene ring through SNAr reaction, and finally obtaining the KRAS inhibitor type antitumor drug MRTX849. According to the process disclosed by the invention, the reaction is further reduced to seven steps, a coupling reaction catalyzed by palladium is reduced to one step, an oxidation reaction with relatively high risk is avoided, the overall yield is improved, the process is stable, the operation is simple, the post-treatment is easy, and the process has more advantages on industrial enlarged production.

The invention discloses a synthesis method of 2-bromo-5-fluoro-4-methoxypyridine, which comprises the following steps: by taking 2-bromo-5-fluoropyridine as a raw material, firstly converting into (2-bromo-5-fluoropyridine-4-yl) boric acid, then converting into 2-bromo-5-fluoro-4-hydroxypyridine, and finally under the action of triphenylphosphine, methanol and diisopropyl azodicarboxylate, carrying out a reaction to obtain 2-bromo-5-fluoro-4-methoxypyridine. The target compound 2-bromine-5-fluoro-4-methoxypyridine is obtained after the reaction is completed. According to the synthesis method, in key steps, triphenylphosphine, methanol and diisopropyl azodicarboxylate are adopted to convert a compound 2-bromo-5-fluoro-4-hydroxypyridine into 2-bromo-5-fluoro-4-methoxypyridine through a Mitsunobu reaction, no isomer by-products are generated, post-treatment and purification are simple, the reaction and time cost is greatly reduced, the yield is ideal, and the method is suitable for industrial production. And the defects of easy generation of isomers, difficult purification and the like in the prior art are avoided.