CN114014792B - Preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one - Google Patents
Preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one Download PDFInfo
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- CN114014792B CN114014792B CN202111535125.0A CN202111535125A CN114014792B CN 114014792 B CN114014792 B CN 114014792B CN 202111535125 A CN202111535125 A CN 202111535125A CN 114014792 B CN114014792 B CN 114014792B
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- bromobenzoyl
- indol
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- tetrahydrofuran
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- JDSPXIPYMUGSIJ-UHFFFAOYSA-N 7-(4-bromobenzoyl)-1,3-dihydroindol-2-one Chemical compound C1=CC(Br)=CC=C1C(=O)C1=CC=CC2=C1NC(=O)C2 JDSPXIPYMUGSIJ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 54
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 27
- RNXKQFMCSXIADL-UHFFFAOYSA-N (4-bromophenyl)-(1h-indol-7-yl)methanone Chemical compound C1=CC(Br)=CC=C1C(=O)C1=CC=CC2=C1NC=C2 RNXKQFMCSXIADL-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 13
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 28
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 230000002140 halogenating effect Effects 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 claims 1
- 150000005625 indol-2-ones Chemical class 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000005658 halogenation reaction Methods 0.000 abstract description 4
- 238000006722 reduction reaction Methods 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- -1 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one Chemical compound 0.000 description 23
- 239000007787 solid Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000002425 crystallisation Methods 0.000 description 9
- 230000008025 crystallization Effects 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 9
- 239000008213 purified water Substances 0.000 description 9
- 238000000967 suction filtration Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- WIISOMGJWLLMDG-UHFFFAOYSA-N (2-aminophenyl)-(4-bromophenyl)methanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=C(Br)C=C1 WIISOMGJWLLMDG-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- HQSCPPCMBMFJJN-UHFFFAOYSA-N 4-bromobenzonitrile Chemical compound BrC1=CC=C(C#N)C=C1 HQSCPPCMBMFJJN-UHFFFAOYSA-N 0.000 description 1
- 238000003309 Hoesch reaction Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- ANSXAPJVJOKRDJ-UHFFFAOYSA-N furo[3,4-f][2]benzofuran-1,3,5,7-tetrone Chemical compound C1=C2C(=O)OC(=O)C2=CC2=C1C(=O)OC2=O ANSXAPJVJOKRDJ-UHFFFAOYSA-N 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XJDQUPFWVIUWNZ-UHFFFAOYSA-N o-ethyl propanethioate Chemical compound CCOC(=S)CC XJDQUPFWVIUWNZ-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one. The preparation method comprises the following steps: (1) Carrying out halogenation reaction on 7- (4-bromobenzoyl) indole in tetrahydrofuran in the presence of acid to obtain 3, 3-dihalo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one; (2) 3, 3-dihalogenated-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one is prepared by reduction reaction in tetrahydrofuran under the action of acetic acid and zinc powder to obtain 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one. The method has the characteristics of easily obtained raw materials, mild reaction conditions, simple operation, high yield and high purity, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one.
Background
7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one is an important intermediate for the synthesis of sodium bromfenate, which was developed by Japanese Qianshou pharmaceutical Co., ltd. Into eye drops to be marketed, and Japanese PMDA approval was obtained at 3 months of 2000 for the symptomatic treatment of inflammatory diseases of the outer eye and the anterior eye.
The current preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one mainly comprises the following two steps:
in the first method, U.S. Pat. Nos. 4126635 and Journal of Medicinal Chemistry,1990 33 (8), 2296-2304 report that 2-amino-4' -bromobenzophenone and ethyl 2-methylthioacetate are used as raw materials, and are cyclized under the catalysis of pivaloyl chloride and then reduced by Raney nickel or tin, and the cyclization reaction condition of the route requires-70 ℃ and the process is complex.
In the second method, european patent EP0221753, journal of Heterocyclic Chemistry,17 (8), 1663-4,1980 and Journal of Medicinal Chemistry (11), 1379-1388,1984 report that p-bromobenzonitrile and indoline are used as raw materials, a Houben-Hoesch reaction is carried out by using boron trichloride and aluminum trichloride as catalysts, and then the product is prepared by oxidation of active manganese dioxide, halogenation of NBS or N-chlorosuccinimide and acid hydrolysis of phosphoric acid. The disadvantage of this route is that the reaction temperature is high and the time is long during the hydrolysis of phosphoric acid, and the separation and purification are difficult due to the red polymer.
In the prior art, the preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one has various defects, and the searching of a process route which has mild reaction conditions, simple purification operation and easy industrial production is obviously important.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one, which has the characteristics of easily available raw materials, mild reaction conditions, simple operation, high yield and high purity, and is suitable for industrial production.
The invention is realized by the following technical scheme:
the 7- (4-bromobenzoyl) indole is subjected to halogenation reaction to prepare alpha-dihalogenated amide, namely 3, 3-dihalogenated-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one, and the 3, 3-dihalogenated-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one is subjected to reduction reaction to prepare the 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one.
Wherein R is halogen and is selected from F, cl, br, I.
Further, the invention comprises the following steps:
(1) Carrying out halogenation reaction on 7- (4-bromobenzoyl) indole in tetrahydrofuran in the presence of acid to obtain 3, 3-dihalo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
(2) 3, 3-dihalogenated-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one is prepared by reduction reaction in tetrahydrofuran under the action of acetic acid and zinc powder to obtain 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one.
In the step (1), the acid is sulfuric acid or hydrochloric acid, preferably concentrated sulfuric acid or concentrated hydrochloric acid.
In the step (1), the halogenating reagent for the halogenating reaction is N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide.
Preferably the halogenating agent is N-chlorosuccinimide.
In step (1), 7- (4-bromobenzoyl) indole: halogenated reagent: acid: water: the mass ratio of tetrahydrofuran is 1:0.5-2.5:0.1-3:0-5:7-20 parts;
further, in order to secure the safety of the reaction, the present invention preferably uses 7- (4-bromobenzoyl) indole: halogenated reagent: acid: water: the mass ratio of tetrahydrofuran is 1:1.4-2:0.2-1.0:0.5-2:9-11;
in step (2), 3-dihalo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one: acetic acid: the molar ratio of zinc powder is 1:1-4:2-4.
The preferred reaction scheme is as follows:
the invention also relates to a compound 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one and a preparation method thereof.
The 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one has the following structure:
the preparation method comprises the following steps:
the 7- (4-bromobenzoyl) indole is subjected to chlorination reaction in tetrahydrofuran in the presence of acid to obtain 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
wherein the acid is sulfuric acid or hydrochloric acid, preferably concentrated sulfuric acid or concentrated hydrochloric acid.
The chlorinating reagent of the chlorination reaction is N-chlorosuccinimide.
7- (4-bromobenzoyl) indole: chloro reagent: acid: water: the mass ratio of tetrahydrofuran is 1:0.5-2.5:0.1-3:0-5:7-20 parts;
preferably, 7- (4-bromobenzoyl) indole: halogenated reagent: acid: water: the mass ratio of tetrahydrofuran is 1:1.4-2:0.2-1.0:0.5-2:9-11.
The invention provides a preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one, which takes 3, 3-dihalogenated-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one as a key intermediate to synthesize the novel preparation method of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one, has the advantages of easily available raw materials, mild and controllable reaction conditions, simple operation, suitability for industrial production, low cost and simple operation, and is suitable for industrial production, and the novel compound 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one and the preparation method thereof, and the novel compound 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one is used as the intermediate to prepare the 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one.
Drawings
FIG. 1 is an HPLC chart of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
FIG. 2 is a hydrogen spectrum of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
FIG. 3 is a mass spectrum of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
FIG. 4 is an HPLC chart of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
FIG. 5 is a hydrogen spectrum of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
FIG. 6 is a mass spectrum of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one.
Detailed Description
The invention will be further described by way of examples, which are not intended to limit the scope of the invention, but to provide equivalent alternatives or corresponding modifications to the technical features of the invention, which are within the scope of the invention.
Example 1 preparation of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
9kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole and 0.1kg of 36-38% hydrochloric acid are weighed, 0.1kg of water is added, 1.5kg of N-chlorosuccinimide is added, after reaction for 4 hours, purified water is added for crystallization and suction filtration, and a filter cake is dried at 50 ℃ to obtain 1.16kg of pale yellow solid with the yield of 90%. 1 H-NMR(DMSO-D6,600MHz)7.28(t,1H,J＝7.8Hz),7.56(dd,1H,J＝7.9Hz),7.71(d,2H,J＝6.7Hz),7.80(d,2H,J＝6.7Hz),7.96(d,1H,J＝7.4Hz),11.41(s,1H)。HRMS(ESI,neg)[M-H]＝384。
Example 2 preparation of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
9kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole and 0.5kg of 36-38% hydrochloric acid are weighed, 1.0kg of N-chlorosuccinimide is added, after 4 hours of reaction, purified water is added for crystallization and suction filtration, and a filter cake is dried at 50 ℃ to obtain 0.9kg of pale yellow solid with the yield of 70%.
Example 3 preparation of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
weighing 10kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole and 1.0kg of 36-38% hydrochloric acid, 2.0kg of water, adding 2.0kg of N-chlorosuccinimide, reacting for 4 hours, adding purified water for crystallization and suction filtration, and drying a filter cake at 50 ℃ to obtain 1.2kg of pale yellow solid with the yield of 94%.
Example 4 preparation of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
7kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole and 0.2kg of 36-38% hydrochloric acid are weighed, 0.5kg of N-chlorosuccinimide is added, after 4 hours of reaction, purified water is added for crystallization and suction filtration, and a filter cake is dried at 50 ℃ to obtain 1.15kg of pale yellow solid with the yield of 70%.
Example 5 preparation of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
weighing 10kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole, 3.0kg of 36-38% hydrochloric acid and 5.0kg of water, adding 1.4kg of N-chlorosuccinimide, reacting for 4 hours, adding purified water for crystallization and suction filtration, and drying a filter cake at 50 ℃ to obtain 1.21kg of pale yellow solid with the yield of 95%.
Example 6 preparation of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
weighing 20kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole, 0.6kg of 36-38% hydrochloric acid and 1.0kg of water, adding 1.5kg of N-chlorosuccinimide, reacting for 4 hours, adding purified water for crystallization and suction filtration, and drying a filter cake at 50 ℃ to obtain 1.2kg of pale yellow solid with the yield of 94%.
Example 7 preparation of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
weighing 10kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole and 1.0kg of 36-38% hydrochloric acid, adding 1.4kg of N-chlorosuccinimide, reacting for 4 hours, adding purified water for crystallization and suction filtration, and drying a filter cake at 50 ℃ to obtain 1.2kg of pale yellow solid with the yield of 94%.
Example 8 preparation of 3, 3-dibromo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
9kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole, 0.2kg of 36-38% hydrochloric acid and 0.5kg of water are weighed, 1.8kg of N-bromosuccinimide is added, after reaction for 5 hours, purified water is added for crystallization and suction filtration, and a filter cake is dried at 50 ℃ to obtain 1.46kg of pale yellow solid with the yield of 93%.
Example 9 preparation of 3, 3-diiodo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
12kg of tetrahydrofuran, 1.0kg of 7- (4-bromobenzoyl) indole, 0.5kg of 36-38% hydrochloric acid and 0.5kg of water are weighed, 2.25kg of N-iodosuccinimide is added, after reaction for 6 hours, purified water is added for crystallization and suction filtration, and a filter cake is dried at 50 ℃ to obtain 1.8kg of pale yellow solid with the yield of 95%.
Example 10 preparation of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
1kg of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one prepared in example 1, 15kg of tetrahydrofuran and 0.5kg (3.2 equiv.) of acetic acid were dissolved and zinc powder 0 was added with stirring675kg (4 equv.) of insoluble matter was filtered off after reaction at 40℃for 2 hours, and the filtrate was concentrated to recover the solvent, followed by addition of ethyl acetate and beating to give 0.6kg of an off-white solid in 73% yield. 1 H-NMR(DMSO-D6,600MHz)3.59(s,2H),7.05(t,1H,J＝7.5Hz),7.33(d,1H,J＝8Hz),7.48(d,1H,J＝7.3Hz),7.66(d,2H,J＝6.7Hz),7.78(d,2H,J＝6.7Hz),10.36(s,1H)。HRMS(ESI,neg)[M+H]＝316,318。
Example 11 preparation of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
1kg of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one prepared in example 1, 13kg of tetrahydrofuran and 0.156 (1 equiv.) kg of acetic acid are dissolved, 0.7kg of zinc powder (4.1 equiv.) is added under stirring, the mixture is reacted at 35 ℃ for 2 hours, insoluble substances are filtered off, the obtained filtrate is concentrated to recover a solvent, and ethanol is added to pulp the mixture to obtain 0.66kg of off-white solid, and the yield is 80%.
Example 12 preparation of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
1kg of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one prepared in example 1, 10kg of tetrahydrofuran and 0.624kg (4 equiv.) of acetic acid are dissolved, 0.34kg (2.0 equiv.) of zinc powder is added under stirring, the mixture is reacted at 30 ℃ for 2 hours, insoluble substances are filtered off, the obtained filtrate is concentrated to recover a solvent, methanol is added and the solvent is beaten to obtain 0.66kg of off-white solid, and the yield is 80%.
Example 13 preparation of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
1kg of 3, 3-dibromo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one prepared in example 1, 13kg of tetrahydrofuran and 0.3kg (1.9 equiv.) of acetic acid are dissolved, 0.6kg (3.5 equiv.) of zinc powder is added under stirring and reacted at 40 ℃ for 2 hours to remove insoluble substances, and after the obtained filtrate is concentrated to recover a solvent, ethyl acetate is added and slurried to obtain 0.62kg of off-white solid with a yield of 75%.
Example 14 preparation of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one:
1kg of 3, 3-dibromo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one prepared in example 1, 13kg of tetrahydrofuran and 0.8kg (5.1 equiv.) of acetic acid are dissolved, 1.0kg (6 equiv.) of zinc powder is added under stirring and reacted at 40 ℃ for 2 hours to remove insoluble substances, the obtained filtrate is concentrated to recover a solvent, and ethyl acetate is added to pulp to obtain 0.56kg of off-white solid, and the yield is 68%.
The halogenated reagent species, 7- (4-bromobenzoyl) indole in step (1): halogenated reagent: acid: water: effect of mass ratio of tetrahydrofuran on yield of 3, 3-dichloro-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one
3, 3-dihalo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one in step (2): acetic acid: effect of the molar ratio of Zinc powder on the yield of 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one
Claims (1)
1.7- (4-bromobenzoyl) -1, 3-dihydro-2H-process for the preparation of indol-2-ones, characterized in that it comprises the following steps:
(1) Halogenating 7- (4-bromobenzoyl) indole in tetrahydrofuran in the presence of acid to obtain 3, 3-dihalo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
(2) 3, 3-dihalo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one is reduced in tetrahydrofuran with acetic acid and zinc powder to obtain 7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one;
wherein R is halogen selected from Cl and Br;
the acid in the step (1) is sulfuric acid or hydrochloric acid, and the halogenated acidThe halogenated reagent of the reaction isNChlorosuccinimide,N-bromosuccinimide;
in step (1), 7- (4-bromobenzoyl) indole: halogenated reagent: acid: water: the mass ratio of tetrahydrofuran is 1:1.4-2:0.2-1.0:0.5-2:9-11;
in step (2), 3-dihalo-7- (4-bromobenzoyl) -1, 3-dihydro-2H-indol-2-one: acetic acid: the molar ratio of zinc powder is 1:1-4:2-4.
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