CN113045475A - Preparation method of 5-bromo-7-methylindole - Google Patents
Preparation method of 5-bromo-7-methylindole Download PDFInfo
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- CN113045475A CN113045475A CN201911379100.9A CN201911379100A CN113045475A CN 113045475 A CN113045475 A CN 113045475A CN 201911379100 A CN201911379100 A CN 201911379100A CN 113045475 A CN113045475 A CN 113045475A
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- methylindole
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- HOUJSOAXJSBNRH-UHFFFAOYSA-N 5-bromo-7-methyl-1h-indole Chemical compound CC1=CC(Br)=CC2=C1NC=C2 HOUJSOAXJSBNRH-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 57
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- PCHYYOCUCGCSBU-UHFFFAOYSA-N 4-bromo-2-methylaniline Chemical compound CC1=CC(Br)=CC=C1N PCHYYOCUCGCSBU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 238000003477 Sonogashira cross-coupling reaction Methods 0.000 claims abstract description 4
- 238000006192 iodination reaction Methods 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 41
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N NMP Substances CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000002346 iodo group Chemical group I* 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 claims description 5
- 238000005859 coupling reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- QBRVKTCCYSLHTO-UHFFFAOYSA-N 4-bromo-2-iodo-6-methylaniline Chemical compound CC1=CC(Br)=CC(I)=C1N QBRVKTCCYSLHTO-UHFFFAOYSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- 238000010898 silica gel chromatography Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000006159 Bartoli reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Abstract
The invention discloses a preparation method of 5-bromo-7-methylindole, the structure of the intermediate corresponds to a formula V,
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 5-bromo-7-methylindole.
Background
Indole and substituted indole derivatives are important compounds with biological activity, and are widely applied to the research and development of medicines for treating migraine and anticancer active medicines. 5-bromo-7-methylindole is used as an important intermediate in the field of drug research and development, and synthetic documents in the prior art are few in reports.
U.S. patent documents US20070232600a1 and US20070149503a1 disclose a synthesis method, which uses 4-bromo-2-methylaniline as a raw material to obtain 5-bromo-7-methylindole through four steps of coupling, ring closing, hydrolysis and decarboxylation; the specific reaction is shown in scheme one:
scheme one
However, the reaction route of the route is long, particularly quinoline is used as a solvent in the decarboxylation step, so that the cost is high, the post-treatment is complicated, the yield is low, and the method is not suitable for large-scale preparation.
US patent documents US20060166947a1, US2005033113a1 report a method of synthesis of an indole analogue; the specific reaction is shown in scheme two:
scheme two
However, the reduction reaction in the last step of the route needs expensive lithium borohydride, and the reaction yield is low; and the reaction is complex, the purification is difficult, and the method is not suitable for large-scale production.
The literature, Indian Journal of Chemistry, Section B, Organic Chemistry Inclusion Medicinal Chemistry,55B (9), 1117-; 2016 and WO2013/149997 a1 report a Bartoli indole synthesis method, the specific reaction is shown in scheme three:
scheme three
The route is short, the yield is moderate, but the starting material is expensive, more than 3 molar equivalents of Grignard reagent are needed for the reaction, and the reaction is carried out under the condition of low temperature, so the method is not suitable for large-scale preparation.
Therefore, the technology in the field needs to develop a preparation method of 5-bromo-7-methylindole, which has the advantages of low cost, mild reaction conditions, high yield and suitability for large-scale preparation.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a novel method which has the advantages of low cost, mild reaction conditions, simple and convenient purification method and high yield and is suitable for preparing 5-bromo-7-methylindole on a large scale. .
In order to realize the purpose, the invention provides a preparation method of 5-bromo-7-methylindole, which adopts the following technical scheme:
a preparation method of 5-bromo-7-methylindole, the structure of the intermediate corresponds to a formula V,
the method uses 4-bromo-2-methylaniline (formula I) as a starting material, and obtains 5-bromo-7-methylindole (formula V) through three steps of iodination reaction, Sonogashira coupling reaction and ring closing reaction; the synthetic route is as follows:
preferably, the method comprises the steps of:
s1 use of a compound of formula I4-bromo-2-methylaniline
Reacting with an iodo reagent in a solvent to obtain a compound of formula II;
s2, carrying out coupling reaction on the compound of the formula II and the compound of the formula III in the presence of a catalyst
To give a compound of formula IV;
s3, the compound of formula IV is subject to cyclization reaction in solvent under the action of alkali,
5-bromo-7-methylindole (formula V) is obtained.
Further, in step S1, the iodo reagent is NIS or I2。
Further, in step S1, the reaction solvent is any one or a combination of acetic acid, acetonitrile, dichloromethane and chloroform.
Further, in step S1, the molar ratio of the iodo reagent to the compound of formula I is (1-2): 1.
Further, in step S2, the catalyst used in the coupling reaction includes CuI and Pd (PPh)3)4、PdCl2(PPh3)2、Pd2(dba)3Any one or a combination of more of;
further, in step S2, the reaction solvent is any one or a combination of THF, acetonitrile, toluene, and dichloromethane.
Further, in step S2, the reaction temperature is 0-100 ℃.
Further, in step S2, the reaction temperature is 10-40 ℃.
Further, the reaction of step S2 is performed under alkaline conditions, and the base is an organic base.
Further, the base is any one of triethylamine, diisopropylethylamine and DBU.
In step S2, the molar ratio of the base to the compound of formula II is (1.5-5): 1.
In step S2, the molar ratio of the catalyst to the compound of formula II is (0.2-0.4): 1.
In step S2, the molar ratio of the compound of formula III to the compound of formula II is (1-2): 1.
Further, in step S3, the base used in the ring closing reaction is any one or a combination of more of potassium carbonate, potassium phosphate, potassium tert-butoxide, sodium hydride, potassium hydride, LiHMDS, and LDA;
further, in step S3, the solvent in the ring-closing reaction is any one or a combination of DMF, DMAc, NMP, HMPA and THF;
further, in step S3, the reaction temperature is 40-80 ℃.
Further, in step S3, the reaction temperature was 60 ℃.
In step S3, the molar ratio of the base to the compound of formula IV is (1-5): 1.
Compared with the prior art, the invention has the beneficial effects that:
the invention takes 4-bromo-2-methylaniline (formula I) as a starting material, and obtains 5-bromo-7-methylindole (formula V) through three steps of reactions including iodination reaction, Sonogashira coupling reaction and ring closure reaction, wherein the specific route is as follows:
1) the initial raw materials of the synthetic method are cheap and easy to obtain, and the cost is low.
2) The invention has mild reaction conditions and does not relate to low-temperature reaction and high-temperature reaction. .
3) The reverse purification method is simple and convenient, has high yield and is suitable for large-scale production and preparation.
Detailed Description
The present invention is further described below with reference to specific examples, which are only exemplary and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes and modifications may be made without departing from the principles of the invention and these changes and modifications are to be considered within the scope of the invention.
In the embodiment of the invention:
NMR: all nuclear magnetic spectra were detected by Bruker AV400MHz nuclear magnetic resonance apparatus with TMS as internal standard.
MS: all mass spectra were detected by LCMS 2020 (Shimadzu).
Example 1
Step S1: preparation of 4-bromo-2-iodo-6-methylaniline (II)
Adding a compound of formula I (15g, 0.08mol) and glacial acetic acid (75mL) into a 500mL three-neck flask at room temperature, and stirring to dissolve; NIS (19.1g,0.085mol) was added in portions, the temperature being controlled not higher than 30 ℃. After the addition, the reaction was carried out at room temperature for 2 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate (7.5mL) and water (110mL) were added and the mixture was stirred at room temperature for 1 hour.
And (5) performing TLC (thin layer chromatography) control, and finishing the reaction. Filtering, washing with water, and drying at 40 deg.C to obtain compound of formula II.
Yield: 23.9g, yield: 95 percent.
MS(M+1)：312,314。
1H NMR(400MHz,DMSO-d6):δ7.55(d,J＝4Hz,1H),7.17(d,J＝4Hz,1H),5.03(br,2H),2.14(s,3H).
Step 2: preparation of 4-bromo-6- (trimethylsilylacetylene) -2-methylaniline (IV)
A compound of formula II (20g, 0.064mol) was added to a 250mL three-necked flask at room temperature, and anhydrous tetrahydrofuran (100mL) was added and dissolved with stirring. Sequentially adding PdCl2(PPh3)2(0.45g,0.64mmol), CuI (0.245g,1.28mmol), Triethylamine (21.4g,0.212mol), with NitrogenDisplacement is carried out for three times; the compound trimethylsilylacetylene of formula III (6.9g,0.071mol) was then slowly added dropwise over the course of 2 hours at room temperature.
And after the reaction is finished, filtering. The reaction mixture was concentrated to dryness. The crude product is purified by silica gel column chromatography to give the compound of formula IV.
Yield: 16.6g, yield: 92 percent.
MS(M+1)：282,284。
1H NMR(400MHz,CDCl3):δ7.30(d,J＝4Hz,1H),7.12(d,J＝4Hz,1H),4.20(br,2H),2.12(s,3H),0.27(s,9H).
And step 3: preparation of 5-bromo-7-methylindole (V)
Adding potassium tert-butoxide (12.2g, 0.11mol) and NMP (70mL) into a 250mL three-neck flask at room temperature under the protection of nitrogen, and stirring for dissolving; a solution of the compound of formula IV (14g, 0.05mol) dissolved in NMP (30mL) was slowly added dropwise to the potassium tert-butoxide solution. After the addition, the reaction system was heated to 60 ℃ and kept warm for 2 hours.
After the reaction, the reaction mixture was poured into ice water, extracted with methyl tert-butyl ether, and washed with an aqueous sodium bicarbonate solution and brine in this order. Then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography to give the compound of formula V (5-bromo-7-methylindole).
Yield: 8.26g, yield: 79 percent.
MS(M+1)：210,212。
1H NMR(400MHz,CDCl3):δ8.10(br,1H),7.63(s,1H),7.22(t,1H),7.12(s,1H),6.51(q,1H),2.47(s,3H).
Example 2
Step S1: preparation of 4-bromo-2-iodo-6-methylaniline (II)
Adding a compound of formula I (15g, 0.08mol) and acetonitrile (75mL) into a 500mL three-neck flask at room temperature, and stirring to dissolve; adding I in portions2(21.5g,0.085mol), the temperature is controlled not to be higher than 30 ℃. After the addition, the reaction was carried out at room temperature for 2 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate (7.5mL) and water (110mL) were added and the mixture was stirred at room temperature for 1 hour.
And (5) performing TLC (thin layer chromatography) control, and finishing the reaction. Filtering, washing with water, and drying at 50 ℃ to obtain the compound shown in the formula II.
Yield: 23.8g, yield: 94.6 percent.
MS(M+1)：312,314。
1H NMR(400MHz,DMSO-d6):δ7.55(d,J＝4Hz,1H),7.17(d,J＝4Hz,1H),5.03(br,2H),2.14(s,3H).
Step 2: preparation of 4-bromo-6- (trimethylsilylacetylene) -2-methylaniline (IV)
A compound of formula II (20g, 0.064mol) was added to a 250mL three-necked flask at room temperature, and anhydrous tetrahydrofuran (100mL) was added and dissolved with stirring. Sequentially adding Pd (PPh)3)4(0.74g,0.64mmol), CuI (0.245g,1.28mmol), diisopropylethylamine (27.4g,0.212mol), with nitrogen substitution three times; the compound trimethylsilylacetylene of formula III (6.9g,0.071mol) was then slowly added dropwise over the course of 2 hours at room temperature.
And after the reaction is finished, filtering. The reaction mixture was concentrated to dryness. The crude product is purified by silica gel column chromatography to give the compound of formula IV.
Yield: 16.56g, yield: 91.8 percent.
MS(M+1)：282,284。
1H NMR(400MHz,CDCl3):δ7.30(d,J＝4Hz,1H),7.12(d,J＝4Hz,1H),4.20(br,2H),2.12(s,3H),0.27(s,9H).
And step 3: preparation of 5-bromo-7-methylindole (V)
Sodium hydride (2.64g, 0.11mol) and DMF (70mL) are added into a 250mL three-neck flask at room temperature under the protection of nitrogen, and stirred to dissolve; a solution of the compound of formula IV (14g, 0.05mol) dissolved in DMF (30mL) was slowly added dropwise to the potassium tert-butoxide solution. After the addition, the reaction system was heated to 60 ℃ and kept warm for 2 hours.
After the reaction, the reaction mixture was poured into ice water, extracted with methyl tert-butyl ether, and washed with an aqueous sodium bicarbonate solution and brine in this order. Then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography to give the compound of formula V (5-bromo-7-methylindole).
Yield: 8.36g, yield: 80 percent.
MS(M+1)：210,212。
1H NMR(400MHz,CDCl3):δ8.10(br,1H),7.63(s,1H),7.22(t,1H),7.12(s,1H),6.51(q,1H),2.47(s,3H).
Example 3
Step S1: preparation of 4-bromo-2-iodo-6-methylaniline (II)
Adding a compound of formula I (15g, 0.08mol) and glacial acetic acid (75mL) into a 500mL three-neck flask at room temperature, and stirring to dissolve; NIS (35.9g,0.16mol) was added in portions, the temperature being controlled not higher than 30 ℃. After the addition, the reaction was carried out at room temperature for 2 hours. After completion of the reaction, an aqueous sodium thiosulfate solution (9mL) was added, followed by addition of water (120mL) and stirring at room temperature for 1 hour.
And (5) performing TLC (thin layer chromatography) control, and finishing the reaction. Filtering, washing with water, and drying at 40 deg.C to obtain compound of formula II.
Yield: 22.6g, yield: 89.8 percent.
MS(M+1)：312,314。
1H NMR(400MHz,DMSO-d6):δ7.55(d,J＝4Hz,1H),7.17(d,J＝4Hz,1H),5.03(br,2H),2.14(s,3H).
Step 2: preparation of 4-bromo-6- (trimethylsilylacetylene) -2-methylaniline (IV)
A compound of formula II (20g, 0.064mol) was added to a 250mL three-necked flask at room temperature, and anhydrous tetrahydrofuran (100mL) was added and dissolved with stirring. Sequentially adding Pd2(dba)3(1.17g,1.28mmol), CuI (0.245g,1.28mmol), triethylamine (32.3g,0.32mol), with nitrogen replaced three times; the compound trimethylsilylacetylene of formula III (12.4g,0.128mol) was then slowly added dropwise over the course of 2 hours at room temperature.
And after the reaction is finished, filtering. The reaction mixture was concentrated to dryness. The crude product is purified by silica gel column chromatography to give the compound of formula IV.
Yield: 16.38g, yield: 90.8 percent.
MS(M+1)：282,284。
1H NMR(400MHz,CDCl3):δ7.30(d,J＝4Hz,1H),7.12(d,J＝4Hz,1H),4.20(br,2H),2.12(s,3H),0.27(s,9H).
And step 3: preparation of 5-bromo-7-methylindole (V)
Adding potassium tert-butoxide (27.7g, 0.25mol) and NMP (120mL) into a 250mL three-neck flask at room temperature under the protection of nitrogen, and stirring for dissolving; a solution of the compound of formula IV (14g, 0.05mol) dissolved in NMP (50mL) was slowly added dropwise to the potassium tert-butoxide solution. After the addition, the reaction system was heated to 60 ℃ and kept warm for 2 hours.
After the reaction, the reaction mixture was poured into ice water, extracted with methyl tert-butyl ether, and washed with an aqueous sodium bicarbonate solution and brine in this order. Then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography to give the compound of formula V (5-bromo-7-methylindole).
Yield: 8.24g, yield: 78.8 percent.
MS(M+1)：210,212。
1H NMR(400MHz,CDCl3):δ8.10(br,1H),7.63(s,1H),7.22(t,1H),7.12(s,1H),6.51(q,1H),2.47(s,3H).
Example 4
Step S1: preparation of 4-bromo-2-iodo-6-methylaniline (II)
Adding a compound of formula I (15g, 0.08mol) and glacial acetic acid (75mL) into a 500mL three-neck flask at room temperature, and stirring to dissolve; NIS (18g,0.08mol) was added in portions, the temperature being controlled not higher than 30 ℃. After the addition, the reaction was carried out at room temperature for 2 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate (7.5mL) and water (110mL) were added and the mixture was stirred at room temperature for 1 hour.
And (5) performing TLC (thin layer chromatography) control, and finishing the reaction. Filtering, washing with water, and drying at 40 deg.C to obtain compound of formula II.
Yield: 22.3g, yield: 88.7 percent.
MS(M+1)：312,314。
1H NMR(400MHz,DMSO-d6):δ7.55(d,J＝4Hz,1H),7.17(d,J＝4Hz,1H),5.03(br,2H),2.14(s,3H).
Step 2: preparation of 4-bromo-6- (trimethylsilylacetylene) -2-methylaniline (IV)
A compound of formula II (20g, 0.064mol) was added to a 250mL three-necked flask at room temperature, and anhydrous tetrahydrofuran (100mL) was added and dissolved with stirring. Sequentially adding PdCl2(PPh3)2(0.45g,0.64mmol), CuI (0.125g, 0.65mmol), triethylamine (9.69g, 0.096mol), with nitrogen three times; the compound trimethylsilylacetylene of formula III (6.2g,0.064mol) was then slowly added dropwise over the course of 2 hours at room temperature.
And after the reaction is finished, filtering. The reaction mixture was concentrated to dryness. The crude product is purified by silica gel column chromatography to give the compound of formula IV.
Yield: 16.1g, yield: 89.2 percent.
MS(M+1)：282,284。
1H NMR(400MHz,CDCl3):δ7.30(d,J＝4Hz,1H),7.12(d,J＝4Hz,1H),4.20(br,2H),2.12(s,3H),0.27(s,9H).
And step 3: preparation of 5-bromo-7-methylindole (V)
Adding potassium tert-butoxide (6.65g, 0.06mol) and NMP (40mL) into a 250mL three-neck flask at room temperature under the protection of nitrogen, and stirring for dissolving; a solution of the compound of formula IV (14g, 0.05mol) dissolved in NMP (30mL) was slowly added dropwise to the potassium tert-butoxide solution. After the addition, the reaction system was heated to 60 ℃ and kept warm for 2 hours.
After the reaction, the reaction mixture was poured into ice water, extracted with methyl tert-butyl ether, and washed with an aqueous sodium bicarbonate solution and brine in this order. Then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography to give the compound of formula V (5-bromo-7-methylindole).
Yield: 7.86g, yield: 75.2 percent.
MS(M+1)：210,212。
1H NMR(400MHz,CDCl3):δ8.10(br,1H),7.63(s,1H),7.22(t,1H),7.12(s,1H),6.51(q,1H),2.47(s,3H).
Example 5
Step S1: preparation of 4-bromo-2-iodo-6-methylaniline (II)
Adding a compound of formula I (150g, 0.8mol) and glacial acetic acid (750mL) into a 5000mL three-necked flask at room temperature, and stirring to dissolve; NIS (191g,0.85mol) was added in portions, the temperature being controlled not higher than 30 ℃. After the addition, the reaction was carried out at room temperature for 2 hours. After completion of the reaction, an aqueous solution of sodium thiosulfate (75mL) was added, followed by addition of water (1100mL) and stirring at room temperature for 1 hour.
After the reaction is finished, filtering, washing with water, and drying at 40 ℃ to obtain the compound shown in the formula II.
Yield: 240g, yield: 95.4 percent.
MS(M+1)：312,314。
1H NMR(400MHz,DMSO-d6):δ7.55(d,J＝4Hz,1H),7.17(d,J＝4Hz,1H),5.03(br,2H),2.14(s,3H).
Step 2: preparation of 4-bromo-6- (trimethylsilylacetylene) -2-methylaniline (IV)
A compound of formula II (200g, 0.64mol) was added to a 2500mL three-necked flask at room temperature, followed by addition of anhydrous tetrahydrofuran (1000mL) and dissolution with stirring. Sequentially adding PdCl2(PPh3)2(45g,6.4mmol), CuI (2.45g,12.8mmol), triethylamine (214g,2.12mol), replaced three times with nitrogen; the compound trimethylsilylacetylene of formula III (69g,0.71mol) was then slowly added dropwise over the course of 2 hours at room temperature.
And after the reaction is finished, filtering. The reaction mixture was concentrated to dryness. The crude product is purified by silica gel column chromatography to give the compound of formula IV.
Yield: 166.5g, yield: 92.3 percent.
MS(M+1)：282,284。
1H NMR(400MHz,CDCl3):δ7.30(d,J＝4Hz,1H),7.12(d,J＝4Hz,1H),4.20(br,2H),2.12(s,3H),0.27(s,9H).
And step 3: preparation of 5-bromo-7-methylindole (V)
Adding potassium tert-butoxide (123.2g, 1.1mol) and NMP (700mL) into a 250mL three-neck flask at room temperature under the protection of nitrogen, and stirring for dissolving; a solution of the compound of formula IV (140g, 0.5mol) dissolved in NMP (300mL) was slowly added dropwise to the potassium tert-butoxide solution. After the addition, the reaction system was heated to 60 ℃ and kept warm for 2 hours.
After the reaction, the reaction mixture was poured into ice water, extracted with methyl tert-butyl ether, and washed with an aqueous sodium bicarbonate solution and brine in this order. Then dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is purified by silica gel column chromatography to give the compound of formula V (5-bromo-7-methylindole).
Yield: 83.1g, yield: 79.5 percent.
MS(M+1)：210,212。
1H NMR(400MHz,CDCl3):δ8.10(br,1H),7.63(s,1H),7.22(t,1H),7.12(s,1H),6.51(q,1H),2.47(s,3H).
The above description is only a part of the preferred embodiments of the present invention, and the present invention is not limited to the contents of the embodiments. It will be apparent to those skilled in the art that various changes and modifications can be made within the spirit of the invention, and any changes and modifications made are within the scope of the invention.
Claims (10)
1. A preparation method of 5-bromo-7-methylindole, the structure of the intermediate corresponds to a formula V,
the method is characterized in that the compound 5-bromo-7-methylindole of the formula V is obtained by taking 4-bromo-2-methylaniline of the formula I as a starting material and carrying out iodination reaction, Sonogashira coupling reaction and ring closing reaction.
2. The process for preparing 5-bromo-7-methylindole according to claim 1, which comprises the steps of:
s1 use of a compound of formula I4-bromo-2-methylaniline
Reacting with an iodo reagent in a solvent to obtain a compound of formula II;
s2, carrying out coupling reaction on the compound of the formula II and the compound of the formula III in the presence of a catalyst
To give a compound of formula IV;
s3, the compound of formula IV is subject to cyclization reaction in solvent under the action of alkali,
5-bromo-7-methylindole (formula V) is obtained.
3. The method of preparing 5-bromo-7-methylindole according to claim 2, wherein:
in step S1, the iodo reagent is NIS or I2。
4. The method of preparing 5-bromo-7-methylindole according to claim 2, wherein:
in step S1, the reaction solvent is any one or a combination of more of acetic acid, acetonitrile, dichloromethane, and chloroform; and/or the presence of a gas in the gas,
in step S1, the molar ratio of the iodo reagent to the compound of formula I is (1-2): 1.
5. The method of preparing 5-bromo-7-methylindole according to claim 2, wherein:
in step S2, the catalyst used in the coupling reaction includes CuI and Pd (PPh)3)4、PdCl2(PPh3)2、Pd2(dba)3Any one or a combination of more of; and/or the presence of a gas in the gas,
in step S2, the reaction solvent is any one or a combination of more of THF, acetonitrile, toluene, and dichloromethane; and/or the presence of a gas in the gas,
in step S2, the reaction temperature is 0-100 ℃.
6. The method of preparing 5-bromo-7-methylindole according to claim 2, wherein:
the reaction of step S2 is carried out under basic conditions, and the base is an organic base.
7. The method of preparing 5-bromo-7-methylindole according to claim 6, wherein:
in step S2, the molar ratio of the used amount of the alkali to the compound of formula II is (1.5-5): 1.
8. The method of preparing 5-bromo-7-methylindole according to claim 2, wherein:
in the step S2, the molar ratio of the dosage of the catalyst to the compound of the formula II is (0.2-0.4): 1; and/or the presence of a gas in the gas,
in step S2, the molar ratio of the compound of formula III to the compound of formula II is (1-2): 1.
9. The method of preparing 5-bromo-7-methylindole according to claim 2, wherein:
in step S3, the base in the ring closing reaction is any one or a combination of potassium carbonate, potassium phosphate, potassium tert-butoxide, sodium hydride, potassium hydride, LiHMDS, and LDA; and/or the presence of a gas in the gas,
in step S3, the solvent in the ring closing reaction is any one or a combination of DMF, DMAc, NMP, HMPA and THF; and/or the presence of a gas in the gas,
in step S3, the reaction temperature is 40-80 ℃.
10. The method of preparing 5-bromo-7-methylindole according to claim 2, wherein:
in step S3, the molar ratio of the used amount of the base to the compound of formula IV is (1-5): 1.
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