CN113603670B - Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one - Google Patents
Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one Download PDFInfo
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- -1 [1,3] dioxol-4-yl Chemical group 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000007259 addition reaction Methods 0.000 claims abstract description 6
- 238000005882 aldol condensation reaction Methods 0.000 claims abstract description 6
- 238000005893 bromination reaction Methods 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 34
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 26
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052794 bromium Inorganic materials 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 6
- 229940117975 chromium trioxide Drugs 0.000 claims description 6
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 6
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 238000006138 lithiation reaction Methods 0.000 claims description 4
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 claims description 2
- VXWPONVCMVLXBW-UHFFFAOYSA-M magnesium;carbanide;iodide Chemical compound [CH3-].[Mg+2].[I-] VXWPONVCMVLXBW-UHFFFAOYSA-M 0.000 claims description 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003999 initiator Substances 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/54—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/52—Radicals substituted by halogen atoms or nitro radicals
Abstract
The application relates to the technical field of organic synthesis, and particularly discloses a method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one, which takes 1, 3-benzodioxy-4-formaldehyde as an initiator to obtain a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one shown in a formula (VI) through aldol condensation reaction, bromination reaction, addition reaction and oxidation reaction in sequence. The method simplifies the synthetic route and improves the yield and purity.
Description
Technical Field
The application relates to the technical field of organic synthesis, in particular to a method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one.
Background
1- (7-Bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one (CAS: 1892297-18-6) is an important intermediate in pharmaceutical synthesis, for example: chronic hepatitis C therapeutic drug-cloperavir Hydrochloride (Clopavir Hydrochloride).
However, the synthesis route of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one in the related art is long, the yield is low, and the product purity is low.
Disclosure of Invention
In order to simplify the synthetic route and improve the yield and purity, the application provides a method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one, which adopts the following technical scheme:
a process for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one of formula (V) comprising the steps of:
preparation of a Compound of formula (II): carrying out aldol condensation reaction on a compound shown in a formula (I) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (II), wherein the molar ratio of the compound shown in the formula (I), the ethylene glycol and the catalyst is 1 (1-2) to 0.09-0.11;
preparation of a Compound of formula (IV): carrying out lithiation reaction on a compound shown in a formula (II) and n-butyllithium, and carrying out bromination reaction on the compound shown in the formula (II) and bromine to obtain a compound shown in a formula (III), wherein the molar ratio of the compound shown in the formula (II) to the n-butyllithium to the bromine is 1 (1-1.5) to 1-1.5; carrying out carbonyl deprotection reaction on the compound shown in the formula (III) to obtain a compound shown in a formula (IV);
preparation of a Compound of formula (V): carrying out addition reaction on a compound shown in a formula (IV) and methyl magnesium halide to obtain a compound shown in a formula (V), wherein the molar ratio of the compound shown in the formula (IV) to the methyl magnesium halide is 1 (1.2-1.3);
Preparation of a Compound of formula (VI): the compound shown in the formula (V) is subjected to oxidation reaction in a system of chromium trioxide and sulfuric acid to obtain the compound shown in the formula (VI), wherein the molar ratio of the compound shown in the formula (V) to the chromium trioxide is 1 (0.99-1).
Optionally, in the step of preparing the compound shown in the formula (II), the temperature condition of the aldol condensation reaction is 110 to 115 ℃.
Optionally, in the step of preparing the compound represented by the formula (II), the catalyst is p-toluenesulfonic acid.
Optionally, in the step of preparing the compound represented by the formula (IV), the temperature condition of the lithiation reaction is-80 to-78 ℃.
Alternatively, in the step of preparing the compound represented by the formula (IV), the temperature condition of the bromination reaction is room temperature.
Optionally, in the preparation step of the compound shown in the formula (IV), the molar ratio of n-butyllithium to bromine is 1 (0.99-1.01).
Optionally, in the step of preparing the compound represented by the formula (V), the temperature condition of the addition reaction is-10 to 0 ℃.
Optionally, in the step of preparing the compound represented by formula (V), the methyl magnesium halide is at least one selected from methyl magnesium chloride, methyl magnesium bromide and methyl magnesium iodide.
Optionally, in the step of preparing the compound shown in the formula (VI), the sulfuric acid is an aqueous solution of 25-35% by weight.
Optionally, in the preparation step of the compound shown in the formula (VI), the molar ratio of the chromium trioxide to the sulfuric acid is 1 (5.3-5.7).
In summary, the present application has the following beneficial effects:
the application not only simplifies the synthetic route of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one, but also improves the yield and purity.
Drawings
FIG. 1 is a synthetic scheme of one method of the present application for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one.
Detailed Description
The present application will be described in further detail with reference to examples.
The synthetic route of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one is shown in FIG. 1.
Taking 1, 3-benzodioxyl-4-formaldehyde as an initiator of a compound shown in a formula (I), and sequentially carrying out aldol condensation reaction, bromination reaction, addition reaction and oxidation reaction to obtain a compound 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone shown in a formula (VI).
Preparation of the Compound of formula (II)
Preparation example 1 of Compound represented by formula (II)
Adding 1, 3-benzodioxyl-4-formaldehyde (15.1g, 100.6mmol) shown in the formula (I) and ethylene glycol (9.3g, 150mmol) into a dry flask which is provided with 60mL of toluene and is connected with a water separator in advance, stirring at room temperature, adding p-toluenesulfonic acid (1.7g, 10.1mmol), heating the reaction mixture to 110-115 ℃, stirring for 1 hour, continuously separating water, after the reaction is finished, cooling the mixture to room temperature, filtering, and evaporating the solvent at 70 ℃ under vacuum to obtain a compound (18.1g, 93.2mmol, 92.64% yield and 98.95% purity) shown in the formula (II).
Preparation example 2 of Compound represented by the formula (II)
In contrast to preparation 1, preparation 2 differs in that: the feeding amount of the ethylene glycol is 12.4g and 200mmol, and the rest feeding amounts and reaction conditions are the same. Preparation example 2 the compound represented by the formula (II) (18.2g, 93.7mmol, yield 93.14%, purity 98.97%) was obtained.
Table 1: yield and purity of the compound of formula (II)
Preparation of Compound of formula (IV)
Preparation example 1 of Compound represented by formula (IV)
A compound represented by the formula (II) (18.1g, 93.2mmol) and 200mL of tetrahydrofuran were added to the reactor, and the mixture was stirred. Then, the mixture was cooled to-80 ℃ to-78 ℃, 64.1mL (molar amount of n-butyllithium: 102.6mmol) of a 1.6mol/L n-butyllithium tetrahydrofuran solution was added dropwise thereto, the mixture was stirred for 4 hours while maintaining the temperature and then warmed to room temperature, followed by addition of bromine (16.4g, 102.6mmol), and the mixture was stirred at room temperature for 2 hours. An appropriate amount of saturated aqueous sodium thiosulfate solution was added, and extraction was performed with ethyl acetate and water. The organic layer was concentrated under reduced pressure and then recrystallized to obtain the compound represented by the formula (III).
The compound represented by the formula (III) was dissolved in 200mL of tetrahydrofuran, 20mL of 1N hydrochloric acid was added, and after stirring and heating to reflux for 2 hours, the residue was dissolved in 10mL of ethyl acetate by evaporation under reduced pressure, washed with the same volume of water and a saturated sodium chloride solution, and finally dried over magnesium sulfate and the solvent was evaporated to dryness to obtain the compound represented by the formula (IV) (17.2g, 75.1mmol, yield 80.58%, purity 99.35%).
Preparation of Compound represented by the formula (IV) 2
In contrast to preparation 1, preparation 2 differs in that: 82.1mL of a 1.6mol/L n-butyllithium tetrahydrofuran solution (the molar amount of n-butyllithium was 131.4mmol) and 21.0g and 131.4mmol of bromine were added dropwise; the rest feeding materials and reaction conditions are the same. Preparation example 2 the compound represented by the formula (IV) (17.1g, 74.7mmol, yield 80.15%, purity 99.38%) was obtained.
Preparation example 3 of Compound represented by formula (IV)
Compared with preparation 1, preparation 3 differs in that: 82.1mL of a 1.6mol/L n-butyllithium tetrahydrofuran solution (131.4 mmol as the molar amount of n-butyllithium) was added dropwise thereto; the rest feeding materials and reaction conditions are the same. Preparation example 2 the compound represented by the formula (IV) (16.7g, 72.9mmol, yield 78.22%, purity 98.80%) was obtained.
Preparation of Compound of formula (IV) comparative example 1
Comparative preparation example 1 was prepared in contrast to preparation example 1 except that: replacing n-butyl lithium with equimolar lithium diisopropylamide; the rest feeding materials and reaction conditions are the same. Preparation of comparative example 1 the compound represented by the formula (IV) (15.6g, 68.1mmol, yield 73.07%, purity 84.39%) was obtained.
Table 2: yield and purity of the Compound of formula (IV)
As can be seen from table 2, in the preparation step of the compound represented by formula (IV), the kind of the organolithium reagent and the molar ratio of organolithium and bromine have a great influence on the yield and purity of the compound represented by formula (IV).
Since the purity of the compound represented by the formula (IV) obtained in production example 3 and production comparative example 1 was not 99% or more, it was not used as a raw material in the production step of the compound represented by the formula (V).
Preparation of Compound of formula (V)
The compound represented by the formula (IV) (17.1g, 74.7mmol) was added to 200mL of tetrahydrofuran, stirred and cooled to 0 ℃ or below, followed by dropwise addition of 98.2mL of a 0.93mol/L solution of methylmagnesium bromide in tetrahydrofuran (molar amount of methylmagnesium bromide: 91.3mmol), and after completion of the dropwise addition, the mixture was warmed to room temperature and stirred for 1 hour. After the reaction, 2mol/L hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate. The extracted organic phase was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a compound represented by the formula (V) (16.7g, 68.1mmol, yield 91.16%, purity 99.45%).
Preparation of the Compound of formula (VI)
The compound represented by the formula (V) (16.7g, 68.1mmol) was dissolved in 170mL of acetone, and CrO was added 3 (6.75g, 67.5mmol) in 30mL of a 30% strength by weight aqueous solution of sulfuric acid; then, mixing the two solutions, stirring, controlling the temperature to be 15-25 ℃, reacting for 2 hours, adjusting the solution to be neutral by adopting a sodium hydroxide aqueous solution with the weight percentage concentration of 30% after the reaction is finished, and then adopting CH 2 Cl 2 Extraction IIISeparating to obtain organic phase, washing the organic phase with saturated NaCl aqueous solution, and removing anhydrous Na 2 SO 4 Drying, filtering, and evaporating the solvent under reduced pressure to obtain the compound 1- (7-bromobenzo [ D ] shown in the formula (VI)][1,3]Dioxolen-4-yl) ethan-1-one (14.7g, 60.5mmol, yield 88.84%, purity 99.2%).
Confirmation of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one represented by formula (V):
1 H-NMR(300MHz,DMSO-d 6 )：δ7.47(d,1H),7.133(d,1H),6.07(s,2H),2.62(s,3H)；MZ：m/z:241.96。
in conclusion, the total yield of the 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one prepared by the method provided by the application is more than 60%, and the purity is more than 99%.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (9)
1. A process for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one of formula (V) comprising the steps of:
preparation of a Compound of formula (II): carrying out aldol condensation reaction on a compound shown in a formula (I) and ethylene glycol under the action of a catalyst to obtain a compound shown in a formula (II), wherein the molar ratio of the compound shown in the formula (I), the ethylene glycol and the catalyst is 1 (1-2) to 0.09-0.11; the catalyst is p-toluenesulfonic acid;
Preparation of a Compound of formula (IV): carrying out lithiation reaction on a compound shown in a formula (II) and n-butyllithium, and carrying out bromination reaction on the compound shown in the formula (II) and bromine to obtain a compound shown in a formula (III), wherein the molar ratio of the compound shown in the formula (II) to the n-butyllithium to the bromine is 1 (1-1.5) to 1-1.5; carrying out carbonyl deprotection reaction on the compound shown in the formula (III) to obtain a compound shown in a formula (IV);
preparation of a Compound of formula (V): carrying out addition reaction on a compound shown in a formula (IV) and methyl magnesium halide to obtain a compound shown in a formula (V), wherein the molar ratio of the compound shown in the formula (IV) to the methyl magnesium halide is 1 (1.2-1.3);
preparation of a Compound of formula (VI): the compound shown in the formula (V) is subjected to oxidation reaction in a system of chromium trioxide and sulfuric acid to obtain the compound shown in the formula (VI), wherein the molar ratio of the compound shown in the formula (V) to the chromium trioxide is 1 (0.99-1).
2. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (II), the temperature of the aldol condensation reaction is 110 to 115 ℃.
3. The method according to claim 1, wherein the temperature condition of the lithiation reaction in the preparation step of the compound represented by the formula (IV) is-80 to-78 ℃.
4. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (IV), the temperature condition of the bromination reaction is room temperature.
5. The method according to claim 1, wherein the molar ratio of n-butyllithium to bromine in the step of preparing the compound represented by formula (IV) is 1 (0.99-1.01).
6. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (V), the temperature condition of the addition reaction is-10 to 0 ℃.
7. The method according to claim 1, wherein in the step of preparing the compound represented by formula (V), the methylmagnesium halide is at least one selected from the group consisting of methylmagnesium chloride, methylmagnesium bromide and methylmagnesium iodide.
8. The method according to claim 1, wherein in the step of preparing the compound represented by the formula (VI), the sulfuric acid is an aqueous solution of 25 to 35% by weight of sulfuric acid.
9. The method according to claim 8, wherein the molar ratio of the chromium trioxide to the sulfuric acid in the step of preparing the compound represented by the formula (VI) is 1 (5.3-5.7).
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| WO2004110344A2 (en) * | 2003-06-13 | 2004-12-23 | Astrazeneca Ab | New azetidine compounds |
| CN101203500A (en) * | 2005-01-25 | 2008-06-18 | Epix特拉华公司 | Substituted arylamine compounds and uses as 5-HT6 moderator thereof |
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| WO2004110344A2 (en) * | 2003-06-13 | 2004-12-23 | Astrazeneca Ab | New azetidine compounds |
| CN101203500A (en) * | 2005-01-25 | 2008-06-18 | Epix特拉华公司 | Substituted arylamine compounds and uses as 5-HT6 moderator thereof |
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