CN117126093A - Preparation method of voronoi intermediate - Google Patents

Preparation method of voronoi intermediate Download PDF

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Publication number
CN117126093A
CN117126093A CN202311378364.9A CN202311378364A CN117126093A CN 117126093 A CN117126093 A CN 117126093A CN 202311378364 A CN202311378364 A CN 202311378364A CN 117126093 A CN117126093 A CN 117126093A
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voronoi
compound
preparation
reaction
reacting
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CN117126093B (en
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冯凯瑞
刘斌卓
李法辉
宋伟国
许光昭
甲宗青
钟文达
金峰
丁文硕
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Shandong Daohe Pharmaceutical Co ltd
Weifang Medical University
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Shandong Daohe Pharmaceutical Co ltd
Weifang Medical University
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    • 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
    • C07D207/32—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

Abstract

The application provides a preparation method of a voronoi intermediate, which relates to the technical field of drug synthesis, and comprises the following steps: s1, reacting o-bromofluorobenzene serving as a starting material with a magnesium reagent or a lithium reagent, and then reacting with cyclobutanone to obtain a compound shown in a formula II; s2, after the compound II reacts with p-toluenesulfonic acid, quenching the reaction product by sodium bicarbonate to obtain a compound shown in a formula III; s3, reacting the compound III with ammonium acetate to obtain the voronoi intermediate shown in the formula IV. The preparation method provided by the application has the advantages of low-cost and easily-obtained raw materials, short synthetic route, few byproducts and high product yield, and the route is suitable for industrial production.

Description

Preparation method of voronoi intermediate
Technical Field
The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a voronoi intermediate.
Background
Fu Nuola (Vorinostat, also known as Voronoi praecox) is a potassium competitive acid blocker for the treatment of erosive esophagitis, gastric ulcer, duodenal ulcer, eradication of helicobacter pylori, etc., originally developed by Japanese Wuta Kogyo Co., ltd, and marketed in Japan in 2014, and has the following structural formula:
fumaric acid Fu Nuola is a fumarate salt of voronoi, which has better stability and solubility, and the preparation route of voronoi and its fumarate salt is disclosed in WO2007026916 and CN101300229 by the japan wuta-tsu pharmaceutical industries, ltd:
according to the scheme, 2-fluoro acetophenone is used as a starting material, cyanoethyl acetate is introduced and then is closed, so that an intermediate 2-chloro-5- (2-fluorophenyl) -1H-pyrrole-3-carboxylic acid ethyl ester is obtained, and then the intermediate is subjected to hydrogenation reduction, oxidation and aromatic electrophilic addition and then reacts with fumaric acid to prepare the funolamine fumarate, wherein the yield is 74%.
Subsequently, this company, in patent WO2010098351 and CN102421753 filed 2010, proposes a new route for preparing voronoi fumarate, starting from 2- ((2-fluorophenyl) -2-oxoethyl) malononitrile to obtain the intermediate 2- (2-fluorophenyl) -1H-pyrrole-3-carbonitrile, followed by hydrogenation reduction, oxidation, addition and finally salification of fumaric acid to obtain voronoi fumarate.
The patent CN106366071 filed in 2016 by the Shandong Jincheng medicine Co., ltd discloses the following synthesis method of voronoi fumarate: the 2-fluoro acetophenone is first condensed with allylamine, then ring-closing reaction is carried out under the catalysis of copper catalyst to obtain intermediate 3-methyl-5- (2-fluorophenyl) -1H-pyrrole, and then the intermediate is subjected to sulfonamide, bromination and amination reaction, and then forms salt with fumaric acid to obtain the funolamine fumarate.
In the preparation method, the intermediate 2- (2-fluorophenyl) -1H-pyrrole or the 5- (2-fluorophenyl) -1H-pyrrole key intermediate is used, but the preparation route of the key intermediate is complex, the byproducts are more, the conversion is insufficient, and the yield and the purity of the product are not improved.
Japanese chemical Co., ltd. In WO2019131695 and CN111527067, a process for producing voronoi fumarate, comprising reacting an o-fluorobenzene derivative as a raw material with pyrrole under the catalysis of a palladium catalyst to give an intermediate 2- (2-fluorophenyl) tetrahydropyrrole, further formylating the pyrrole ring nitrogen atom to give a pyrrole-3-carbaldehyde derivative, deprotecting to give 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde, reacting with pyridine-3-sulfonyl chloride or a salt thereof in the presence of a base, subjecting to reductive amination with methylamine to give 1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrol-3-yl ] -N-methylmethylamine, and salifying with fumaric acid to give voronoi fumarate. This route simplifies the original route but requires the use of expensive palladium catalysts for catalysis.
Accordingly, there is a need to provide an improved solution to the above-mentioned deficiencies of the prior art.
Disclosure of Invention
The application aims to provide a preparation method of a voronoi intermediate, which is used for obtaining a voronoi intermediate 2- (2-fluorophenyl) -1H-pyrrole, and has the advantages of short synthetic route, easy purification and high yield, so as to solve the problems of more byproducts and higher cost of the existing synthetic route.
In order to achieve the above object, the present application provides the following technical solutions:
a preparation method of a voronoi intermediate comprises the following steps:
s1, reacting o-bromofluorobenzene serving as a starting material with a magnesium reagent or a lithium reagent, and then reacting with cyclobutanone to obtain a compound shown in a formula II;
s2, after the compound II reacts with p-toluenesulfonic acid, quenching by using sodium bicarbonate to obtain a compound shown in a formula III;
s3, reacting the compound III with ammonium acetate to obtain a voronoi intermediate shown in a formula IV;
the reaction process is as follows:
preferably, in step S1, o-bromofluorobenzene is dissolved in tetrahydrofuran and then reacted with a magnesium reagent or a lithium reagent.
Preferably, in step S1, the magnesium reagent includes at least one of isopropyl magnesium chloride-lithium chloride or magnesium turnings, and the lithium reagent is n-butyl lithium.
Preferably, in step S1, cyclobutanone is added dropwise at a temperature of less than or equal to-5℃and then cooling is stopped.
Preferably, in step S1, the reaction time is not less than 1 hour.
Preferably, in step S1, after the reaction is completed, the compound ii is obtained by quenching with a saturated aqueous ammonium chloride solution, and then subjecting the quenched compound to extraction, washing, drying, filtration, and concentration followed by column chromatography.
Preferably, in step S2, compound ii is dissolved in methanol, p-toluenesulfonic acid monohydrate is added, after the reaction of compound ii is completed, saturated aqueous sodium bicarbonate solution is added for quenching, and then, after extraction, washing, drying and filtration, compound iii is obtained by vacuum concentration.
Preferably, in step S3, compound III is dissolved in an organic solvent and Co (aca) is addedc) 2 Heating and refluxing ammonium acetate and TMSiA, DPEphos, filtering by diatomite, extracting by ethyl acetate, drying by anhydrous magnesium sulfate, concentrating in vacuum, and separating by column chromatography to obtain a compound IV;
the organic solvent is at least one selected from dimethyl ether, toluene, xylene and 1, 4-dioxane.
Preferably, in step S3, the Co (acac) 2 The molar ratio of the ammonium acetate to the TMSiA, DPEphos is 0.1:2:0.2:1.
Preferably, in the step S3, the reaction temperature is 60-100 ℃ and the reaction time is 3-8 hours.
The beneficial effects are that:
the application aims to provide a synthesis method of a key intermediate of voronoi, which adopts commercial raw materials, and can obtain the intermediate 2- (2-fluorophenyl) -1H-pyrrole by three steps of reactions, compared with the existing synthesis route, the method has the advantages that the yield of the product of each step of reaction can reach more than 80%, a noble metal catalyst is not needed in the reaction process, the preparation cost of the voronoi can be obviously reduced, the method has good economic benefit, and has obvious economic advantages compared with the existing method, and the method is suitable for industrial production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. Wherein:
fig. 1 is a synthetic route diagram of a voronoi intermediate of the present application.
FIG. 2 is a chart showing the nuclear magnetic resonance hydrogen spectrum of the compound II prepared in example 1 of the present application.
FIG. 3 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the compound IV prepared in example 3 of the present application.
FIG. 4 is a mass spectrum of the compound IV prepared in example 3 of the present application.
FIG. 5 shows the HPLC detection result of compound IV prepared in example 3 of the present application.
FIG. 6 is a chart showing the hydrogen nuclear magnetic resonance spectrum of the compound V prepared in example 4 of the present application.
FIG. 7 shows a nuclear magnetic resonance hydrogen spectrum of the compound VI prepared in example 5 of the present application.
FIG. 8 is a chart showing the hydrogen nuclear magnetic resonance spectrum of voronoi fumarate prepared in example 6 of the present application.
Detailed Description
The following description of the technical solutions in the embodiments of the present application will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present application, but not all embodiments. All other embodiments, which are derived by a person skilled in the art based on the embodiments of the application, fall within the scope of protection of the application.
The present application will be described in detail with reference to examples. It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other.
Aiming at the problems of long synthetic route and more byproducts in the existing synthesis method of the vonolamine, the application provides a preparation method of a vonolamine intermediate, which comprises the following steps:
s1, reacting o-bromofluorobenzene serving as a starting material with a magnesium reagent or a lithium reagent, and then reacting with cyclobutanone to obtain a compound shown in a formula II;
s2, after the compound II reacts with p-toluenesulfonic acid, quenching by using sodium bicarbonate to obtain a compound shown in a formula III;
s3, reacting the compound III with ammonium acetate to obtain a voronoi intermediate shown in a formula IV;
the reaction process is shown in FIG. 1.
The method takes o-bromofluorobenzene as an initial raw material, activates the o-bromofluorobenzene by a magnesium reagent or a lithium reagent, then reacts with cyclobutanone to obtain 1- (2-fluorophenyl) cyclobutane-1-ol, then further condenses to obtain carbon-carbon double bond, and finally directly converts cyclobutene into pyrrole ring by reacting with ammonium acetate, and the ring closing reaction is not needed in the reaction process, and an expensive palladium catalyst is not needed, thus being suitable for industrial production.
The application provides a preparation method of a voronoi intermediate,
in a preferred embodiment of the present application, in step S1, o-bromofluorobenzene is dissolved in tetrahydrofuran and then reacted with a magnesium reagent or a lithium reagent.
In a preferred embodiment of the present application, in step S1, the magnesium reagent comprises at least one of isopropyl magnesium chloride-lithium chloride or magnesium turnings, and the lithium reagent is n-butyl lithium.
In a preferred embodiment of the application, in step S1, cyclobutanone is added dropwise at a temperature of less than or equal to-5 ℃ (e.g., -5 ℃, -6 ℃, -7 ℃, -13 ℃, -8 ℃, -9 ℃, -10 ℃, -11 ℃), and cooling is stopped.
In a preferred embodiment of the present application, in step S1, the reaction time is not less than 1 hour, preferably 1 to 3 hours (e.g., 1 hour, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours).
In the preferred embodiment of the present application, in step S1, after the reaction is completed, the compound ii is obtained by quenching with a saturated aqueous ammonium chloride solution, followed by extraction, washing, drying, filtration, concentration and column chromatography.
In the preferred embodiment of the application, in the step S2, the compound II is dissolved in methanol, the paratoluenesulfonic acid monohydrate is added, after the compound II is completely reacted, the saturated sodium bicarbonate aqueous solution is added for quenching, and then the compound III is obtained through extraction, washing, drying, filtering and vacuum concentration.
In a preferred embodiment of the present application, in step S3, compound III is dissolved in an organic solvent, co (acac) is added 2 Heating and refluxing ammonium acetate and TMSiA, DPEphos, filtering by diatomite, extracting by ethyl acetate, drying by anhydrous magnesium sulfate, concentrating in vacuum, and separating by column chromatography to obtain a compound IV;
the organic solvent is at least one selected from dimethyl ether, toluene, xylene, and 1, 4-dioxane.
In the preferred embodiment of the present application, co (acac) is used in step S3 2 The molar ratio of the ammonium acetate to the TMSiA, DPEphos is 0.1:2:0.2:1.
In a preferred embodiment of the present application, in step S3, the reaction temperature is 60 to 100 ℃ (e.g. 61 ℃, 65 ℃, 70 ℃, 75 ℃,80 ℃, 85 ℃, 90 ℃, 95 ℃, 99 ℃) and the reaction time is 3 to 8 hours (e.g. 3.5 hours, 4.0 hours, 4.5 hours, 5.0 hours, 5.5 hours, 6.0 hours, 6.5 hours, 7.0 hours, 7.5 hours).
The preparation method of the voronoi intermediate of the present application is described in detail below by way of specific examples.
In the following examples, the sources of the drugs used are as follows:
o-bromofluorobenzene was purchased from Shanghai Bi to medical science and technology Co., ltd;
tetrahydrofuran, available from Shanghai Taitan technologies Co., ltd;
isopropyl magnesium chloride-lithium chloride, available from Shanghai taitan technologies Co., ltd;
cyclobutanone, available from Shanghai Taitan technologies, inc.;
ammonium chloride, available from Shanghai Taitan technologies Co., ltd, was prepared into an aqueous solution having a concentration of 1-5M using deionized water;
ethyl acetate, available from Shanghai taitan technologies, inc;
anhydrous magnesium sulfate, available from Shanghai Taitan technologies Co., ltd;
methanol, available from Shanghai Taitan technologies Co., ltd;
p-toluenesulfonic acid monohydrate, available from Shanghai Taitan technologies Co., ltd;
sodium bicarbonate, available from Shanghai Taitan technologies Co., ltd;
dimethyl ether, available from Shanghai Taitan technologies Co., ltd;
Co(acac) 2 cobalt acetylacetonate, also known as cobalt acetylacetonate, available from Shanghai Taitan technologies, inc.;
DPEphos, also known as bis (2-diphenylphosphinophenyl) ether, is available from Shanghai Taitan technologies Co., ltd;
ammonium acetate, available from Shanghai Taitan technologies Co., ltd;
TMSIA, also known as trimethylsilyl azide, is available from Shanghai Taitan technologies Co., ltd;
4-methyltetrahydropyran available from Shanghai Taitan technologies Co., ltd;
1, 3-dimethyl-2-imidazolidinone, available from Shanghai Taitan technologies Co., ltd;
sodium hydride, available from Shanghai Taitan technologies Co., ltd;
triisopropylchlorosilane, available from Shanghai Taitan technologies Co., ltd;
vilsmeier reagent, available from Shanghai Taitan technologies Co., ltd;
cyclohexane, available from Shanghai Taitan technologies Co., ltd;
DMAP, available from shanghai taitan technologies inc;
3-sulfonylchloropyridine, available from Shanghai Bi De medical technology Co., ltd;
n, N-diisopropylethylamine available from Shanghai Taitan technologies Co., ltd;
acetonitrile, available from Shanghai Taitan technologies Co., ltd;
methylamine-methanol solution with a purity of 30% was produced by the manufacturer of the co-pharmaceutical industry, inc. Of mountain east;
sodium borohydride, manufacturer mountain eastern co-pharmaceutical company limited;
methylene chloride, available from Shanghai Taitan technologies Co., ltd;
fumaric acid, available from Shanghai Taitan technologies Co., ltd;
column chromatography, wherein the stationary phase is 200-300 mesh silica gel, and the mobile phase is petroleum ether and ethyl acetate.
Example 1
Synthesis of 1- (2-fluorophenyl) cyclobutan-1-ol:
o-bromofluorobenzene (1 eq) is dissolved in tetrahydrofuran, stirred for 20 minutes at the temperature of-5 to-8 ℃, then isopropyl magnesium chloride-lithium chloride (1.5 eq) is added, stirring is continued for 10 minutes at the temperature of-5 to-8 ℃, then cyclobutanone (2 eq) is added dropwise, then the mixture is moved to the normal temperature environment, stirring is carried out for 1.5 hours, TLC monitors the reaction, after the o-bromofluorobenzene is reacted completely, saturated ammonium chloride aqueous solution is added dropwise for quenching, ethyl acetate is used for extraction, the organic phases are combined, the organic phases are washed by saturated saline solution, then dried by anhydrous magnesium sulfate and filtered, the filtrate is concentrated in vacuo, and colorless oily liquid is obtained through column chromatography separation, namely the target compound II, and the yield is 87%.
The prepared compound ii was detected using nuclear magnetic resonance as shown in fig. 2.
Example 2
Synthesis of 1- (cyclobut-1-en-1-yl) -2-fluorobenzene:
1- (2-fluorophenyl) cyclobutan-1-ol (1 eq) is dissolved in methanol, p-toluenesulfonic acid monohydrate (2 eq) is added for 3 hours, after TLC detects that the compound II is completely reacted, saturated sodium bicarbonate aqueous solution is added dropwise for quenching reaction, ethyl acetate is used for extraction, organic phases are combined, then the organic phases are washed by saturated saline solution, anhydrous magnesium sulfate is dried and filtered, and filtrate is concentrated in vacuum to obtain colorless oily liquid, namely the target compound III, and the yield is 93%.
The compound III prepared in this example was directly subjected to the subsequent reaction without further purification.
Example 3
Synthesis of 2- (2-fluorophenyl) -1H-pyrrole:
1- (cyclobut-1-en-1-yl) -2-fluorobenzene (1 eq) prepared in example 2 was dissolved in dimethyl ether and 0.1eq Co (acac) was added 2 Reflux reaction of 0.15eq DPEphos, 1eq ammonium acetate, 2.5eq TMSIA at 80 ℃ for 5 hours, after TLC monitoring the complete reaction of the raw materials, filtering through kieselguhr to remove the catalyst, extracting the filtrate through ethyl acetate, drying through anhydrous magnesium sulfate, concentrating in vacuo, separating the residue through column chromatography to obtain pale red oily liquid, namely the target compound IV, the yield is 81%, and the HPLC purity is as follows: 97.03%, ESI-MS (m/z): 160.0523[ M-H ]] - 。
The nuclear magnetic resonance, mass spectrum and HPLC detection results of the compound IV are shown in figures 3, 4 and 5 respectively.
The compound IV can be used for further preparing Fu Nuola and fumarate thereof, and the method for preparing the voronoi fumarate by using the compound IV can be referred to as examples 4-6, and can be performed according to other existing preparation methods.
Example 4
Synthesis of 5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde:
2- (2-fluorophenyl) -1H-pyrrole (1 eq) was dissolved in 4-methyltetrahydropyran, then 1, 3-dimethyl-2-imidazolidinone (3 eq) was added, stirred under ice bath for 3 minutes, then sodium hydride (1.2 eq) was added, stirring under ice bath was continued for 5 minutes, then triisopropylchlorosilane (1.1 eq) was added dropwise, stirred under ice bath until TLC monitored that the 2- (2-fluorophenyl) -1H-pyrrole spot disappeared, vilsmeier reagent was added, gradually heated to 70℃for 5 hours, then the heating was removed, after recovering normal temperature, 2M aqueous sodium hydroxide solution was added for deprotection, then washed with saturated brine, extracted with ethyl acetate, the organic phase was combined, distilled under reduced pressure, then the residue was continued to be added with a proper amount of ethyl acetate, after which much of the residue was dissolved by heat, cyclohexane was added, stirred under ice bath until solid was precipitated, filtered to obtain the objective compound, white solid was obtained in 67% yield.
Example 5
Synthesis of 5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-carbaldehyde:
5- (2-fluorophenyl) -1H-pyrrole-3-carbaldehyde (1 eq), DMAP (0.15 eq) and 3-sulfonylchloropyridine were dissolved in tetrahydrofuran solution, followed by addition of N, N-diisopropylethylamine (0.15 eq), heating to 40℃and stirring for 2 hours. And then cooling the mixture to normal temperature, regulating the pH to 4-5 by using 1M hydrochloric acid, adding deionized water, continuously stirring for 1 hour and filtering after solid precipitation occurs, washing a filter cake by using acetonitrile-water mixed solution, and drying under reduced pressure to obtain the target product with the yield of 87%.
Example 6
Synthesis of voronoi fumarate:
dissolving 5- (2-fluorophenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-formaldehyde (1 eq) by using methanol, then dripping a methylamine-methanol solution (1.3 eq) into a reaction liquid, reacting for 1 hour at normal temperature, then cooling to 0-10 ℃, adding sodium borohydride solid (0.45 eq) into the reaction liquid, continuously reacting for 1 hour at low temperature, after the reaction is complete, adding a 5% hydrochloric acid solution to adjust the pH value to 8-9, washing by saturated sodium chloride, extracting by dichloromethane, merging organic phases, concentrating under reduced pressure to obtain crude voronoi, then directly adding 70% methanol aqueous solution to dissolve the crude product, heating to 70 ℃, adding fumaric acid, stirring for half an hour at 0 ℃, continuously stirring for 2 hours, finally carrying out suction filtration, and vacuum drying on a filter cake to obtain the voronoi solid fumarate, wherein the yield is 92.57%.
The prepared sample of voronoi fumarate was examined using nuclear magnetic resonance and the results are shown in fig. 8.
The synthesis method of the voronoi intermediate provided by the application can obtain the intermediate 2- (2-fluorophenyl) -1H-pyrrole by three steps of reactions, is shorter than the existing synthesis route, has the product yield of each step of reaction of more than 80%, does not need to use a noble metal catalyst in the reaction process, can obviously reduce the preparation cost of the voronoi, has good economic benefit, and is suitable for industrial application.
The above description is only of the preferred embodiments of the present application and is not intended to limit the present application, but various modifications and variations can be made to the present application by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims (10)

1. The preparation method of the voronoi intermediate is characterized by comprising the following steps of:
s1, reacting o-bromofluorobenzene serving as a starting material with a magnesium reagent or a lithium reagent, and then reacting with cyclobutanone to obtain a compound shown in a formula II;
s2, after the compound II reacts with p-toluenesulfonic acid, quenching by using sodium bicarbonate to obtain a compound shown in a formula III;
s3, reacting the compound III with ammonium acetate to obtain a voronoi intermediate shown in a formula IV;
the reaction process is as follows:
。
2. the process for the preparation of a voronoi intermediate according to claim 1, wherein in step S1, o-bromofluorobenzene is dissolved in tetrahydrofuran and then reacted with a magnesium reagent or a lithium reagent.
3. The process for preparing a voronoi intermediate as claimed in claim 1 or 2, wherein in step S1, said magnesium reagent comprises at least one of isopropyl magnesium chloride-lithium chloride or magnesium turnings, and said lithium reagent is n-butyllithium.
4. The process for the preparation of a voronoi intermediate as claimed in claim 1 or 2, wherein in step S1, cyclobutanone is added dropwise at a temperature of less than or equal to-5 ℃ and then cooling is stopped.
5. The process for the preparation of a voronoi intermediate according to claim 1, wherein in step S1, the reaction time is not less than 1 hour.
6. The process for preparing a voronoi intermediate according to claim 1, wherein in step S1, after completion of the reaction, the compound ii is obtained by quenching with a saturated aqueous ammonium chloride solution, followed by extraction, washing, drying, filtration, concentration and column chromatography.
7. The process for preparing a voronoi intermediate as claimed in claim 1, wherein in step S2, compound ii is dissolved in methanol, p-toluenesulfonic acid monohydrate is added, after the reaction of compound ii is completed, saturated aqueous sodium bicarbonate solution is added for quenching, and then extraction, washing, drying, filtration and vacuum concentration are carried out to obtain compound iii.
8. The process for producing a voronoi intermediate as claimed in claim 1, wherein in step S3, compound iii is dissolved in an organic solvent and Co (acac) is added 2 Heating and refluxing ammonium acetate and TMSiA, DPEphos, filtering by diatomite, extracting by ethyl acetate, drying by anhydrous magnesium sulfate, concentrating in vacuum, and separating by column chromatography to obtain a compound IV;
the organic solvent is at least one selected from dimethyl ether, toluene, xylene and 1, 4-dioxane.
9. The method for producing a voronoi intermediate as claimed in claim 8, wherein in step S3, said Co (acac) 2 The molar ratio of the ammonium acetate to the TMSiA, DPEphos is 0.1:2:0.2:1.
10. The process for preparing a voronoi intermediate as claimed in claim 8, wherein in step S3, the reaction temperature is 60 to 100 ℃ and the reaction time is 3 to 8 hours.
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