CN116143677A - Preparation method of key intermediate of voronoi fumarate - Google Patents

Preparation method of key intermediate of voronoi fumarate Download PDF

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CN116143677A
CN116143677A CN202111143125.6A CN202111143125A CN116143677A CN 116143677 A CN116143677 A CN 116143677A CN 202111143125 A CN202111143125 A CN 202111143125A CN 116143677 A CN116143677 A CN 116143677A
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hydroxide
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何杰
胡卫东
王鑫
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Beijing Jimeitang Medicine Research Co ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/333—Radicals substituted by oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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 relates to the field of pharmaceutical chemistry, and provides a preparation method of a voronoi fumarate key intermediate. According to the method, the key intermediate 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde is prepared from 5- (2-fluorophenyl) -1H-pyrrole-3-formaldehyde through two steps, and the key intermediate of the voronoi fumarate is prepared through an economic, green and safe method, so that the method is simple and convenient to operate, mild in condition and high in yield and purity of the product.

Description

Preparation method of key intermediate of voronoi fumarate
Technical Field
The invention provides a preparation method of a key intermediate of voronoi fumarate.
Background
Vonoprazan fumarate (Vonoprazan fumarate), trade name
Figure BDA0003284450500000011
The chemical name is 1- [5- (2-fluorobenzene) -1- (pyridine-3-sulfonyl) -1H-pyrrole-3-yl]-N-methyl methylamine monofumarate, the structural information of which is as follows:
Figure BDA0003284450500000012
fumaric acid Fu Nuola is an acid inhibitor with a brand new mechanism of action developed by the chemical industry Co., ltd. The Fu Ma Suanfu Nola tablet was marketed in Japan in 2015, and was formally approved for marketing in NMPA in 2019 in 12, with the batch indication being reflux esophagitis (Reflux Esophagitis, RE for short). Potassium competitive acid blocker (P-CAB) as first approved into the national market by blocking H + ，K + K of ATPase + Channel, competitive block K + The combination of the enzyme can stay in gastric parietal cells for a long time, thereby rapidly inhibiting the secretion of gastric acid, and has obvious pharmaceutical characteristics of rapidness, strong, long time and stability.
Reflux esophagitis is a common disease of the digestive system, and its characteristic symptoms include heartburn and acid regurgitation caused by reflux of gastric contents, which can be accompanied by extraesophageal symptoms, and erosion of esophageal mucosa, which seriously affects life and sleep quality of patients. Epidemiological data show that reflux esophagitis is has a prevalence of up to 6.4% in the general population in china, which has been on the rise in recent years.
According to Newport data statistics, the global sales of the futures vonolamine is 8.9 tons by 2021, 15.4 percent higher than the last year, 804 hundred million yuan higher than the last year, 20 percent higher than the same period, and the future demand of the product market is continuously increased. Therefore, development of a green, economical, cost-effective process for producing voronoi fumarate is particularly urgent to cope with the increasing market demand and the core competitiveness of enterprises.
Looking at Fu Nuola raw fumaric acid preparation-related documents, the preparation routes share several routes:
1. the preparation process of voronoi fumarate disclosed in the examples of the compound patent CN101300229B is as follows:
Figure BDA0003284450500000021
the preparation of the formula III adopts a palladium-carbon catalytic hydrogenation process, the reaction temperature of the formula IV compound for preparing the formula I compound is-78 ℃, the requirement of industrial production on equipment is high, and the energy consumption is high.
2. Another preparation process route of vonolamine fumarate is disclosed in the preparation method published by the wuta pharmacy patent CN102421753B, and is optimized based on the method published by the compound patent thereof, as follows:
Figure BDA0003284450500000022
on the basis of the compound patent, the preparation process of the compound of the formula I is optimized, the deep cooling reaction is avoided, but the catalytic hydrogenation process is still the method for preparing the compound of the formula II and the compound of the formula II. The catalytic hydrogenation method has higher requirements on reaction equipment, reaction workshops and the like, and introduces a certain safety risk for the mass production of the voronoi fumarate.
3. Patent CN201510786974a discloses the route as follows:
Figure BDA0003284450500000031
the route avoids hydrogenation reaction, but expensive reagents are used in the synthetic route, meanwhile, active intermediates in the reaction process are more, process impurities are easy to introduce to cause separation and purification difficulties, the yield is low and other risk points, the process is only at laboratory level, and the process is estimated to be unsuitable as a preparation process of industrialized voronoi fumarate.
The preparation method of the mature voronoi fumarate in the current market is the same as the route 2, but in the route, the preparation of the key intermediate (formula I) involves two-step hydrogenation, and the hydrogenation is a national key supervision dangerous process (the national key supervision dangerous process catalog 2013 edition), because the hydrogenation has the following dangerous characteristics: 1) The reaction material has explosion hazard, the explosion limit of hydrogen is 4-75%, and the reaction material has high explosion hazard characteristic; 2) Hydrogenation is a strong exothermic reaction, hydrogen is contacted with steel at high temperature, carbon molecules in the steel are easy to react with hydrogen to generate hydrocarbon, so that the strength of steel equipment is reduced, and hydrogen embrittlement is formed; 3) Explosion is easily caused in the process of regenerating and activating the catalyst; (4) The hydrogen and other impurities which are not completely reacted in the hydrogenation tail gas are easy to cause ignition and explosion when discharged.
In summary, whether the preparation process of the intermediate I can safely and controllably produce the fumarates in larger batches directly influences the industrialization scale of fumarates, namely, the increase of the production scale of the traditional catalytic hydrogenation process requires the configuration of a large-scale hydrogenation reaction kettle, and the approval, design and construction of potential new chemical land and production factory buildings can definitely cause the production enterprises to increase the investment and the research, development and production cost. Under the large background of collection at the present stage, the control of the production cost of the bulk drug is a key means of collection and collection of 'price change'. Therefore, it is particularly urgent to find a method for preparing a compound of formula I which is inexpensive and has low safety risks.
Disclosure of Invention
Object of the Invention
The invention aims to prepare the key intermediate of the voronoi fumarate as shown in formula I by an economic, green and safe method, and has the advantages of simple and convenient operation, mild conditions and high product purity.
Technical proposal
The preparation method of the intermediate formula I comprises the following steps: comprising the following steps: the compound of the formula III reacts under the existence of triethylsilane, palladium catalyst, alkaline reagent and solvent at a certain temperature to obtain a compound of the formula II, and the compound of the formula II reacts under the existence of triethylsilane, raney nickel, acidic reagent and solvent at a certain temperature to obtain a compound of the formula I, wherein the following steps are shown:
Figure BDA0003284450500000041
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adding a certain proportion of alkali and a certain proportion of palladium catalyst into a mixed solvent of an organic solvent and a certain proportion of purified water by taking a compound shown in a formula III as a substrate, adding a certain proportion of triethylsilane at a certain temperature for reaction, and obtaining a target intermediate compound shown in a formula II after post-treatment; adding acid with a certain proportion and Raney nickel with a certain proportion into a mixed solvent of an organic solvent and purified water with a certain proportion, adding triethylsilane with a certain proportion at a certain temperature for reaction, and obtaining the target intermediate compound of the formula I after post-treatment.
Further, the method comprises the following steps:
the preparation method of the compounds of the formula I and the formula II is characterized in that triethylsilane is used, wherein the mole number of the triethylsilane is 0.5-10.0 equivalents of the mole number of a substrate, and 1.2-4.0 is preferable;
the preparation method of the compound shown in the formula I and the formula II is characterized in that the palladium catalyst comprises palladium carbon, palladium chloride, palladium acetate, tetra (triphenylphosphine bar), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, tris (dibenzylideneacetone) dipalladium, 1, 2-bis (diphenylphosphino) ethane and 1, 3-bis (diphenylphosphino) propane, wherein 10% palladium carbon is preferred.
The organic solvent is alcohols, ethers and water with 1-12 carbon atoms, wherein water or mixed solvent of methanol, ethanol, isopropanol, tertiary butanol, tetrahydrofuran and water with any proportion is preferable;
a process for the preparation of a compound of formula I, formula II according to claim 1, wherein the reaction temperature is-10 to 50 ℃, preferably 10 to 50 ℃, more preferably 20 to 30 ℃;
the preparation method of the compound shown in the formula I and the formula II is characterized in that the alkaline reagent used for preparing the compound shown in the formula II comprises inorganic alkali including sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, magnesium carbonate, barium carbonate, rubidium carbonate and cesium carbonate, wherein sodium bicarbonate is preferred; organic bases include triethylamine, N-diisopropylethylamine, pyridine, lutidine, trimethylamine, tripropylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 4-Dimethylaminopyridine (DMAP), N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine, sodium methoxide, sodium ethoxide, potassium t-butoxide, N-butyllithium, phenyllithium, lithium Diisopropylamide (LDA), lithium hexamethyldisilamide (LiHMDS), with triethylamine, N-diisopropylethylamine being preferred, and triethylamine being more preferred;
the preparation method of the compounds of the formula I and the formula II is characterized in that the acidic reagent for preparing the compounds of the formula I comprises inorganic acid including hydrochloric acid, sulfuric acid, phosphoric acid and manganic acid, wherein hydrochloric acid is preferred; the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid, wherein formic acid and acetic acid are preferred, and formic acid is more preferred;
the preparation method of the compounds of the formula I and the formula II is characterized in that triethylsilane is used as H 2 The source is used in a molar amount of 0.5 to 10.0 equivalents based on the molar amount of the substrate, preferably 1.2 to 4.0;
the innovation points are as follows:
according to the method, triethylsilane is used for reacting with water to generate hydrogen to react with a substrate in situ, so that the method avoids the use of a large amount of hydrogen, and the triethylsilane is quantitatively added to generate hydrogen quantitatively for the reduction reaction of the target compound, so that special equipment is not required, the reaction can be completed at normal temperature and normal pressure, the compound of the formula I can be obtained in high yield and high purity, almost no waste gas is discharged, the safety of the product is improved, and the supervision cost is reduced.
The preparation process route of the compound of the formula II is as follows:
Figure BDA0003284450500000051
/>
the method of similar structure of formula II (halogen reduction) reported in the literature at the present stage is searched and summarized, and the halogen on the pyrrole ring is reduced by a catalytic hydrogenation method only in different reaction pressures. The following are provided:
Figure BDA0003284450500000052
Figure BDA0003284450500000061
the preparation process route of the compound of the formula I is as follows:
Figure BDA0003284450500000062
the methods reported in the literature of the present stage for the reduction of cyano groups to aldehydes of similar structure were searched and summarized, with the catalytic hydrogenation reduction using Raney nickel and with the chemical reduction using DIBAL-H, as follows:
Figure BDA0003284450500000063
in summary, the reduction of chlorine on pyrrole ring is mostly palladium-carbon catalytic hydrogenation, and the reaction pressures of different structures have certain difference. The reaction of cyano group into aldehyde group is not only hydrogenation reaction, but also DIBAL-H reaction temperature used in chemical method requires harsh reaction temperature of-60-20 deg.C, and the reagent has poor stability and is sensitive to air and humidity. Therefore, the current catalytic hydrogenation method and the chemical method have special requirements on reaction equipment, and have certain challenges on the control of production cost.
Based on the safety and supervision controllability of industrial production, a green process condition for reducing halogen and cyano into aldehyde with low cost is developed, the halogen and cyano can be reduced at normal temperature and normal pressure, the equipment has no special requirements, the operation is simple and convenient to perform, and the target intermediate compound of the formula I can be obtained with high yield and high purity.
Meanwhile, the potential impurities in the preparation process of the compound of the formula II and the compound of the formula I are researched, and the table is as follows:
Figure BDA0003284450500000071
/>
Figure BDA0003284450500000081
* : not detected
For reducing halogen and aldehyde groups by using triethylsilane, potential impurities in the compounds of the formula II and the compounds of the formula I are researched, the control limits are established, the impurities in the above table are controlled within the limits, and the related substances of the fumonisin raw material medicines for the subsequent production can be ensured to meet the requirements.
Advantageous effects
The innovation point of the invention is that:
1. there is no literature report on the use of triethylsilane for halogen reduction and cyano reduction to aldehyde groups, and the present invention proposes this process operation for the first time.
2. The use of triethylsilane for halogen and cyano reduction can circumvent the operations involved in hydrogenation, cryogenic reactions, etc. currently reported in this process.
3. The triethylsilane is used for reducing halogen and cyano into aldehyde, the reaction temperature and the reaction pressure are low, the reaction can be completed at normal temperature and normal pressure, the monitoring pressure and the production safety risk caused by hydrogenation and cryogenic technology can be avoided greatly, and the power cost can be controlled remarkably.
4. The triethylsilane is used for reducing halogen and cyano into aldehyde, the influence of factors such as air, moisture and the like is not needed to be avoided, the operation tolerance is strong, and the industrial production control is convenient.
5. The triethylsilane is used for reducing halogen and cyano into aldehyde, the yield and the quality are superior to those of the catalytic hydrogenation preparation process, and the production cost can be obviously reduced.
6. The triethylsilane is used for reducing halogen and cyano into aldehyde, and the triethylsilane can be used quantitatively, so that the potential emission of a large amount of waste gas caused by hydrogen and potential safety hazards are avoided.
Drawings
FIG. 1 is an HPLC plot of the intermediate compound of formula II obtained in example 1;
FIG. 2 is an HPLC plot of the intermediate compound of formula I obtained in example 1;
FIG. 3 is an HPLC plot of the intermediate compound of formula II obtained in comparative example 1;
fig. 4 is an HPLC profile of the intermediate compound of formula I obtained in comparative example 1.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Preparation of the compound of formula II: adding 13.2L of ethanol, 1512g of triethylamine, 2200g of purified water and 2200g of a compound of formula III into a 20L reaction kettle, adding 1380g of triethylsilane under stirring, stirring for 30 minutes, filtering off palladium carbon, concentrating, evaporating to remove a solvent, adding ethanol, stirring to dissolve, adding purified water, cooling, crystallizing, suction-filtering, drying a filter cake to constant weight to obtain 1650g of a compound of formula II, yield 88.6%, and purity of HPLC: 98.15%;
preparation of the compound of formula I: adding 8.7L of tetrahydrofuran, 1180mL of formic acid, 2700g of purified water and 1300g of a compound of formula II into a 20L reaction kettle, adding a mixed solution of 1254g of triethylsilane and 450mL of tetrahydrofuran under stirring of 160g of Raney nickel, stirring for 1 hour, filtering out Raney nickel, adding ethyl acetate and water into an organic phase, extracting and separating liquid, washing the organic phase by using a sodium bicarbonate solution and saturated saline solution, concentrating to remove the organic phase, adding ethyl acetate, pulping, filtering, drying a filter cake to constant weight, and obtaining 1099g of the compound of formula I, wherein the yield is 83.2% and the HPLC purity: 99.08%;
example 2
Preparation of the compound of formula II: adding 132mL of methanol, 13.12g of N, N-diisopropylethylamine, 22.00g of purified water and 22.00g of a compound of formula III in a 250mL reaction flask at 20-30 ℃, adding a mixed solution of 13.80g of triethylsilane and 20mL of dichloromethane under stirring, stirring for 30 minutes after adding, filtering off palladium carbon, concentrating and evaporating the solvent, adding methanol, stirring and dissolving, adding purified water, cooling and crystallizing, filtering, drying a filter cake to constant weight, and obtaining 15.27g of the compound of formula II with the yield of 82.1%;
preparation of the compound of formula I: adding 240mL of tetrahydrofuran, 26g of hydrochloric acid, 27mL of purified water and 26g of a compound of the formula II into a 500mL reaction kettle, adding 12.54g of triethylsilane under stirring, stirring for 0.5 hour, filtering out Raney nickel, concentrating the filtrate to remove the solvent, adding sodium bicarbonate aqueous solution and ethyl acetate, extracting and separating the liquid, washing the organic phase with purified water again, separating the liquid, concentrating and steaming the organic phase to remove ethyl acetate, adding methyl tertiary butyl ether into the residue, pulping, filtering, drying the filter cake to constant weight, and obtaining 21.8g of the compound of the formula I, and 82.6% of yield;
example 3
Preparation of the compound of formula II: adding 132mL of tetrahydrofuran, 16.50g of pyridine, 22.00g of purified water and 40.00g of compound of formula III into a 250mL reaction bottle at 20-30 ℃, adding a mixed solution of 17.20g of triethylsilane and 40mL of tetrahydrofuran under stirring, stirring for 30 minutes after adding, filtering out palladium carbon, concentrating, evaporating to remove a solvent, adding methanol, stirring and dissolving, adding purified water, cooling, crystallizing, carrying out suction filtration, and drying to constant weight to obtain 15.27g of compound of formula II, wherein the yield is 82.1%;
preparation of the compound of formula I: adding 260mL of tetrahydrofuran, 26.00g of acetic acid, 54mL of purified water and 26.00g of a compound of the formula II into a 500mL reaction kettle, adding 16.23g of triethylsilane under stirring, after adding, stirring for 0.5 hour, filtering out Raney nickel, concentrating filtrate to remove a solvent, adding ethyl acetate and a purified water extraction liquid, washing an organic phase by using a sodium carbonate solution, separating the liquid, concentrating the organic phase to remove the ethyl acetate, adding methyl tertiary butyl ether into the residue, heating to dissolve, cooling to room temperature for crystallization, carrying out suction filtration, and drying a filter cake to constant weight to obtain 21.95g of the compound of the formula I, wherein the yield is 83.1%;
comparative example 1
Catalytic hydrogenation process for preparing compound of formula II and formula I
Preparation of the compound of formula II: 160mL of methanol, 13.79g of triethylamine, 20.00g of a compound of formula III and 1.00g of palladium carbon are added into a 250mL reaction bottle at the temperature of 20-30 ℃, stirring, nitrogen substitution and hydrogen substitution are carried out, the pressure in the reaction bottle is kept at 0.3Mpa, the reaction is carried out for 15 hours, palladium carbon is filtered, the organic phase is removed by concentration, 100mL of purified water is added into the residue for pulping, filtering is carried out, and a filter cake is dried to constant weight, thus obtaining 15.37g of the compound of formula II, the yield is 90.8%, and the purity is 89.28%.
Preparation of the compound of formula I: adding 90mL of tetrahydrofuran, 30mL of water, 6mL of acetic acid, 15.00g of a compound of formula II and 12.00g of Raney nickel into a 250mL reaction bottle, stirring, replacing three times with nitrogen and replacing three times with hydrogen, keeping the pressure in the reaction bottle at 0.3MPa, reacting for 9 hours, filtering out Raney nickel, concentrating to remove an organic phase, adding ethyl acetate and purified water solution, washing the organic phase with sodium bicarbonate solution, separating the solution, concentrating to remove the organic phase, adding n-heptane into the residue, stirring for crystallization, filtering, drying a filter cake to constant weight, and obtaining 11.37g of the compound of formula II, wherein the yield is 74.6%, and the purity is 97.60%.
Comparative example 2
DiBAL-H chemistry to reduce cyano groups to aldehydes
Preparation of the compound of formula I: adding 70mL of dichloromethane (with water content controlled less than 0.05%) into a 250mL reaction bottle at 20-30 ℃, adding 3g of a compound shown in a formula II, cooling to-40 ℃, adding a dichloromethane solution of DiBAL-H under the protection of nitrogen, reacting for 5 hours at the temperature not higher than-35 ℃, heating to room temperature, washing an organic phase by using a 5% citric acid aqueous solution, drying the organic phase by using anhydrous sodium sulfate, evaporating the solvent, and obtaining a target intermediate by column chromatography, wherein the yield is 52.3%.
Comparative example 3
Influence of reduction temperature on the reaction
Preparation of the compound of formula II: into a 50mL reaction flask, 14mL of tetrahydrofuran, 1.5g of pyridine, 2.2g of purified water and 4.0g of a compound of formula III, 0.5g of palladium on carbon (5%), stirring and heating to reflux (60-66 ℃), adding a mixed solution of 2.0g of triethylsilane and 4mL of tetrahydrofuran, stirring for 30 minutes after the addition, and detecting the reaction by TLC, wherein the residual compound of formula III is more. When the temperature is judged to be higher, the solubility of the generated hydrogen in the solution is obviously reduced, so that the hydrogen participating in the reaction is insufficient. Therefore, the reaction temperature is not suitable for the reaction at high temperature.
Preparation of the compound of formula II: 14mL of tetrahydrofuran, 1.5g of pyridine, 2.2g of purified water and 4.0g of a compound of formula III, 0.5g of palladium on carbon (5%), stirring and cooling to-15 ℃) are added into a 50mL reaction bottle, a mixed solution of 2.0g of triethylsilane and 4mL of tetrahydrofuran is added, stirring is carried out for 30 minutes after the addition, TLC detection reaction is carried out, more residual compound of formula III is carried out, the reaction is continuously monitored, and partial materials still remain unreacted for 9 hours. Judging that the reaction temperature is not suitable to be lower than-10 ℃ for reaction, otherwise, reducing the production efficiency.

Claims (8)

1. A preparation method of a key intermediate I of voronoi fumarate is characterized by comprising the following steps of: the method comprises the following steps: the compound of the formula III reacts in the presence of triethylsilane, a palladium catalyst, an alkaline reagent and a solvent to obtain a compound of the formula II; the compound of the formula II reacts in the presence of triethylsilane, raney nickel, an acidic reagent and a solvent to obtain a compound of the formula I, wherein the reaction formula is shown as follows:
Figure FDA0003284450490000011
2. the method of claim 1, wherein; the mole number of the triethylsilane is 1.0-10.0 times of the mole number of the substrate.
3. The method of claim 1, wherein the palladium catalyst comprises palladium on carbon, palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium, [1,1' -bis (diphenylphosphino) ferrocene ] dichloride, tris (dibenzylideneacetone) dipalladium, 1, 2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane.
4. The method according to claim 1, wherein the solvent is one or more of alcohols, ethers and water having 1 to 12 carbon atoms.
5. The method according to claim 4, wherein the solvent is a mixed solvent of methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran and water in any ratio.
6. The method of claim 1, wherein the reaction temperature is from-10 ℃ to 50 ℃.
7. The method of claim 1, wherein the basic reagent for preparing the compound of formula II comprises an inorganic base and an organic base;
wherein the inorganic base comprises sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, magnesium carbonate, barium carbonate, rubidium carbonate and cesium carbonate;
the organic base comprises triethylamine, N-diisopropylethylamine, pyridine, dimethylpyridine, trimethylamine, tripropylamine, triethylenediamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, 4-dimethylaminopyridine, N-methylmorpholine, tetramethylethylenediamine, tetramethylguanidine, sodium methoxide, sodium ethoxide, potassium tert-butoxide, N-butyllithium, phenyllithium, lithium diisopropylamide, lithium hexamethyldisilamide.
8. The method of claim 1, wherein the acidic reagent used in the preparation of the compound of formula I comprises an inorganic acid and an organic acid;
wherein the inorganic acid comprises hydrochloric acid, sulfuric acid, phosphoric acid and manganic acid; the organic acid includes formic acid, acetic acid, propionic acid, oxalic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid.
CN202111143125.6A 2021-09-28 2021-09-28 Preparation method of key intermediate of voronoi fumarate Pending CN116143677A (en)

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