CN114149356A - Preparation method of methyl indolcarbate compound - Google Patents
Preparation method of methyl indolcarbate compound Download PDFInfo
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- CN114149356A CN114149356A CN202111368617.5A CN202111368617A CN114149356A CN 114149356 A CN114149356 A CN 114149356A CN 202111368617 A CN202111368617 A CN 202111368617A CN 114149356 A CN114149356 A CN 114149356A
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- methyl
- indole
- indolcarbate
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- -1 methyl indolcarbate compound Chemical class 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 45
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 35
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 31
- ZPRQXVPYQGBZON-UHFFFAOYSA-N 2-bromo-1h-indole Chemical compound C1=CC=C2NC(Br)=CC2=C1 ZPRQXVPYQGBZON-UHFFFAOYSA-N 0.000 claims abstract description 20
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- 238000005893 bromination reaction Methods 0.000 claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 16
- 238000005886 esterification reaction Methods 0.000 claims abstract description 13
- NQPIEWBAWBFGOB-UHFFFAOYSA-N methyl 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)OC)=CC2=C1 NQPIEWBAWBFGOB-UHFFFAOYSA-N 0.000 claims abstract description 12
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000019253 formic acid Nutrition 0.000 claims abstract description 10
- 239000003446 ligand Substances 0.000 claims abstract description 8
- 239000002184 metal Substances 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 4
- 239000011261 inert gas Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 20
- 238000000605 extraction Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 10
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical group [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 10
- 238000010791 quenching Methods 0.000 claims description 10
- 230000000171 quenching effect Effects 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 6
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- HCUARRIEZVDMPT-UHFFFAOYSA-M 1h-indole-2-carboxylate Chemical compound C1=CC=C2NC(C(=O)[O-])=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-M 0.000 claims description 5
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 3
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 claims description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- FYKVVULXWVRKMP-UHFFFAOYSA-N C(=O)OC.N1C=CC2=CC=CC=C12 Chemical compound C(=O)OC.N1C=CC2=CC=CC=C12 FYKVVULXWVRKMP-UHFFFAOYSA-N 0.000 claims 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 16
- 229910052739 hydrogen Inorganic materials 0.000 description 16
- 239000000047 product Substances 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
- 239000000376 reactant Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 125000001041 indolyl group Chemical group 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000031709 bromination Effects 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- 238000009987 spinning Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 150000004702 methyl esters Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 101150110792 GNRHR gene Proteins 0.000 description 1
- 108050001286 Somatostatin Receptor Proteins 0.000 description 1
- 102000011096 Somatostatin receptor Human genes 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- BWEDPXKFWJUQAD-UHFFFAOYSA-N formic acid 2-methyl-1H-indole Chemical compound C(=O)O.CC=1NC2=CC=CC=C2C1 BWEDPXKFWJUQAD-UHFFFAOYSA-N 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Images
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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention provides a preparation method of a methyl indole formate compound, which is characterized by comprising the following steps: step one, synthesizing bromoindole from indole through bromination reaction; under the protection of inert gas, reacting bromoindole, an organophosphorus ligand, a metal catalyst and formic acid in an organic solvent medium to synthesize carboxylic indole; and step three, synthesizing methyl indolcarbate by carrying out esterification reaction on carboxylic indole and methanol under the action of a catalyst. The preparation method has the advantages of high catalytic efficiency, low substrate cost, simple operation, low equipment requirement, excellent yield and the like.
Description
Technical Field
The invention relates to the technical field of chemical intermediate preparation, in particular to a preparation method of a methyl indolylcarbonate compound.
Background
The methyl indole formate compound is an important organic intermediate and has wide and important application in the chemical field. Indole is an aromatic heterocyclic compound, derivatives of indole are widely distributed in the nature, structures of many natural compounds contain indole rings, and some derivatives of indole are closely related to life activities, so the indole is an important heterocyclic compound. The number of the drugs on the market with 3H-indole as a structural framework is 112, and the targets of the 3H-indole drugs are mostly 5-HT, GnRHR, ADR, SSTR and the like, so the indole compounds are extremely important drug intermediates.
The reported preparation method of the methyl indole formate compound is mainly obtained by metal catalysis and multi-step coupling and oxidation, and has the defects of more reaction steps, low reaction efficiency, low application range and the like.
Disclosure of Invention
The invention aims to solve the technical problems in the prior art. Therefore, the invention provides a preparation method of a methyl indole formate compound, and aims to realize efficient preparation of the methyl indole formate compound and reduce the production cost.
Based on the above purpose, the invention provides a preparation method of a methyl indole carboxylate compound, which is characterized by comprising the following steps:
step one, synthesizing bromoindole from indole through bromination reaction;
under the protection of inert gas, reacting bromoindole, an organophosphorus ligand, a metal catalyst and formic acid in an organic solvent medium to synthesize carboxylic indole;
and step three, synthesizing methyl indolcarbate by carrying out esterification reaction on carboxylic indole and methanol under the action of a catalyst.
The solvent adopted in the first step is dichloromethane, dichloroethane or carbon tetrachloride.
The molar ratio of the indole to the bromination reagent adopted in the bromination reaction is 1: 0.8-1.2.
The brominating reagent is any one of NBS, 1, 3-dibromo-5, 5-dimethylhydantoin, carbon tetrabromide, phenyltrimethyl ammonium tribromide, DBBA and DBI.
The metal catalyst is copper acetate; the mol ratio of bromoindole to organophosphorus ligand to copper acetate to formic acid is 1: 1-3: 0.2-0.6: 1.1-1.5.
The organic phosphine ligand is any one or combination of more of 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine, S- (-) -1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine, triphenylphosphine oxide and tri (dimethylamino) phosphine
In the third step, concentrated sulfuric acid is used as a catalyst, and the molar ratio of the carboxylic acid indole to the methanol to the concentrated sulfuric acid is 1: 1-1.5: 0.5-0.9. Wherein methanol serves as both a solvent and a reactant.
The reaction formula of the invention is as follows:
and (3) after the bromination reaction is finished in the first step, dropwise adding a 3% sodium sulfite aqueous solution for quenching, and then extracting, carrying out rotary drying on an organic phase, and separating a solid through a column to obtain the bromoindole.
And after the reaction in the second step is finished, adding a saturated sodium chloride solution, extracting, concentrating, carrying out chromatography, and carrying out rotary evaporation to obtain the carboxylic indole.
And after the esterification reaction in the third step is finished, extracting, spin-drying an organic phase and recrystallizing to obtain the pure methyl indole formate.
The invention has the beneficial effects that: the raw materials are simple and easy to obtain, and the preparation conditions are mild; the reaction is carried out at a milder temperature, and the requirement on equipment is low; the used solvent is mutually soluble with water, and basically no post-treatment is needed; the catalyst system has wide adaptability, the obtained product has wide application in the field of medicine synthesis, the added value of the process flow is high, and the catalyst is suitable for large-scale industrial production. The invention realizes the high-efficiency preparation of the indole methyl formate compound by adopting cheap copper acetate as a catalyst. Has the advantages of high catalytic efficiency, low substrate cost, simple operation, low requirement on equipment, excellent yield and the like.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a nuclear magnetic spectrum of example 1 of the present invention;
FIG. 2 is a mass spectrum of example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to specific embodiments and the accompanying drawings.
It is to be noted that technical terms or scientific terms used in the embodiments of the present invention should have the ordinary meanings as understood by those having ordinary skill in the art to which the present disclosure belongs, unless otherwise defined.
The invention provides a preparation method of a methyl indole formate compound, which is characterized by comprising the following steps:
step one, synthesizing bromoindole from indole through bromination reaction;
under the protection of inert gas, reacting bromoindole, an organophosphorus ligand, a metal catalyst and formic acid in an organic solvent medium to synthesize carboxylic indole;
and step three, synthesizing methyl indolcarbate by carrying out esterification reaction on carboxylic indole and methanol under the action of a catalyst. The following is a detailed description of specific preferred examples.
Example 1
Step one, synthesizing bromoindole by taking indole as a starting material, dichloromethane as a solvent and NBS as a bromination reagent. The method comprises the following specific steps:
taking a 500ml three-neck flask, adding indole (58.58g,0.5mol) and dichloromethane (250ml), stirring, keeping the temperature at 15 ℃, dropwise adding NBS (71.2g,0.4mol) solution, and finishing the dropwise adding within 30 min; carrying out bromination reaction, detecting the reaction process by using a TLC plate, after the reaction is finished, dropwise adding 3% sodium sulfite aqueous solution into the reactant at a controlled temperature (25-30 ℃) for quenching, and determining that the solution is colorless and the quenching is complete; each time, 100ml of ethyl acetate is added for extraction, three times of combined organic phases are dried by spinning to obtain solid, and the solid is separated by a column to obtain 85g of target product. The mass yield was 80.19%.
Step two, synthesis of carboxylic acid indole
Introducing nitrogen into a 500ml four-neck flask for protection; 53.01g (0.25mol) of bromoindole, 69.5g (0.25mol) of triphenylphosphine oxide and copper acetate (24.95g,0.125mol) were added in one portion. 200ml of DMF was injected with a syringe. After stirring for 30min, 0.275mol of formic acid (12.65g) was injected, the reaction was carried out at 80 ℃ under nitrogen protection, and the progress of the reaction was checked by TLC plate. After the reactant is cooled to room temperature at normal temperature, 100mL of saturated sodium chloride aqueous solution is added into the reactant, then ethyl acetate is used for extraction for 3 times, each time is 100mL, and the extraction liquid is combined; drying the extract with anhydrous sodium sulfate, and rotary drying with rotary evaporator to obtain concentrate; adsorbing the concentrate with column chromatography silica gel, adding into 200-300 mesh chromatography silica gel column, and purifying with n-hexane: and (3) performing flash column chromatography by using ethyl acetate according to a ratio of 2:1, merging eluent, performing rotary drying by using a rotary evaporator, and pumping by using an oil pump to obtain a product 39.3g, wherein the mass yield is 88.8%.
Step three, synthesizing methyl indolcarbate by taking methanol as a raw material and concentrated sulfuric acid as a catalyst
A1L four-necked flask was charged with indole carboxylate (531.5g,3mol) and methanol (144g, 4.5 mol). Heating to 40 ℃, dropwise adding 98% concentrated sulfuric acid (150g, 1.5mol) while stirring, controlling the speed in the dropwise adding process to be not obviously changed in temperature (the temperature is not more than 5 ℃ from top to bottom) to carry out esterification reaction, extracting for 3 times by adding 200ml of dichloromethane and 200ml of water after the esterification reaction is finished, carrying out spin drying on an organic phase to obtain a crude product, and then recrystallizing by using ethanol petroleum ether in a ratio of 1:2 to obtain 512.0g of a pure product, wherein the mass yield is 89.4%.
Unite INVOA form 400 DMSO as solvent, TMS internal standard. As shown in fig. 1, the characteristic hydrogen chemical shifts and integrated areas in the spectra are as follows:
1H-NMR(CF3-COOD，D2O)δ：10.1(S-1H)；7.55(S-1H)；7.27(S-1H)；7.08,(S-1H)；6.55(S-1H)；3.67(S-3H)。
corresponding to the imine hydrogen on the indole ring ((S-1H)), the indole ring internal hydrogen ((S-1H), (S-1H)), the benzene ring hydrogen ((S-1H), (S-1H)) and the methyl hydrogen of the terminal methyl ester ((S-3H)), respectively.
As shown in fig. 2, the mass spectral data are as follows:
ESI-MS:M/Z 192.2[M+H]+。
example 2
A preparation method of methyl indolate comprises the following steps:
step one, synthesizing bromoindole by taking indole as a starting material, dichloromethane as a solvent and NBS as a bromination reagent. The method comprises the following specific steps:
adding indole (58.58g,0.5mol) and dichloroethane (150ml) into a 500ml three-neck flask, stirring, keeping the temperature at 30 ℃, dissolving 1, 3-dibromo-5, 5-dimethylhydantoin (114g,0.4mol) in 100ml of dichloroethane, and finishing dropping for 30 min; carrying out bromination reaction, detecting the reaction process by using a TLC plate, after the reaction is finished, dropwise adding 3% sodium sulfite aqueous solution into the reactant at a controlled temperature (25-30 ℃) for quenching, and determining that the solution is colorless and the quenching is complete; each time, 100ml of ethyl acetate is added for extraction, three times of combined organic phases are dried by spinning to obtain solid, and the solid is separated by a column to obtain 91g of the target product. The mass yield was 85.85%.
Step two, synthesis of carboxylic acid indole
Introducing nitrogen into a 500ml four-neck flask for protection; 53.01g (0.25mol) of bromoindole, 40.8g (0.25mol) of tris (dimethylamino) phosphine and 24.95g (0.125 mol) of copper acetate are added in one portion. 200ml of 1,4 dioxane was injected with a syringe. After stirring for 30min, 0.33mol of formic acid (15.18g) was injected, the reaction was carried out at 100 ℃ under nitrogen, and the progress of the reaction was checked by TLC plates. After the reactant is cooled to room temperature at normal temperature, 100mL of saturated sodium chloride aqueous solution is added into the reactant, then ethyl acetate is used for extraction for 3 times, each time is 100mL, and the extraction liquid is combined; drying the extract with anhydrous sodium sulfate, and rotary drying with rotary evaporator to obtain concentrate; adsorbing the concentrate with column chromatography silica gel, adding into 200-300 mesh chromatography silica gel column, and purifying with n-hexane: and (3) performing flash column chromatography by using ethyl acetate according to a ratio of 2:1, merging eluent, performing rotary drying by using a rotary evaporator, and pumping by using an oil pump to obtain 40.2g of a product, wherein the mass yield is 90.8%.
Step three, synthesizing methyl indolcarbate by taking methanol as a raw material and concentrated sulfuric acid as a catalyst
A1L four-necked flask was charged with indole carboxylate (531.5g,3mol) and methanol (96g, 3 mol). Heating to 40 ℃, dropwise adding 98% concentrated sulfuric acid (270g, 2.7mol) while stirring, controlling the speed in the dropwise adding process to be not obviously changed in temperature (the temperature is not more than 5 ℃ from top to bottom) to carry out esterification reaction, extracting for 3 times by adding 200ml of dichloromethane and 200ml of water after the esterification reaction is finished, carrying out spin drying on an organic phase to obtain a crude product, and then recrystallizing by using ethanol petroleum ether in a ratio of 1:2 to obtain 528.8g of a pure product, wherein the mass yield is 92.3%.
Unite INVOA form 400 DMSO as solvent, TMS internal standard. The characteristic hydrogen chemical shifts and integrated areas in the spectra are as follows:
1H-NMR(CF3-COOD，D2O)δ：10.2(S-1H)；7.58(S-1H)；7.29(S-1H)；7.05,(S-1H)；6.57(S-1H)；3.69(S-3H)。
respectively correspond to: imine hydrogen on the indole ring ((S-1H)), indole ring internal hydrogen ((S-1H), (S-1H)), benzene ring hydrogen ((S-1H), (S-1H)) and terminal methyl ester methyl hydrogen ((S-3H)).
Mass spectral data were as follows:
ESI-MS:M/Z 192.1[M+H]+
example 3
A preparation method of methyl indolate comprises the following steps:
step one, synthesizing bromoindole by taking indole as a starting material, dichloromethane as a solvent and NBS as a bromination reagent. The method comprises the following specific steps:
taking a 500ml three-neck flask, adding indole (58.58g,0.5mol) and dichloromethane (150ml), stirring and maintaining at 30 ℃, dissolving 1, 3-dibromo-5, 5-dimethylhydantoin (171g,0.6mol) in 100ml dichloroethane, and finishing dropping for 30 min; carrying out bromination reaction, detecting the reaction process by using a TLC plate, after the reaction is finished, dropwise adding 3% sodium sulfite aqueous solution into the reactant at a controlled temperature (25-30 ℃) for quenching, and determining that the solution is colorless and the quenching is complete; each time, 100ml of ethyl acetate is added for extraction, three times of combined organic phases are dried by spinning to obtain solid, and the solid is separated by a column to obtain 96g of target product. The mass yield was 90.56%.
Step two, synthesis of carboxylic acid indole
Introducing nitrogen into a 500ml four-neck flask for protection; 53.01g (0.25mol) of bromoindole, 40.8g (0.25mol) of tris (dimethylamino) phosphine and 8.31g (0.042 mol) of copper acetate are added in one portion. 200ml of 1,4 dioxane was injected with a syringe. After stirring for 30min, 0.33mol of formic acid (15.18g) was injected, the reaction was carried out at 100 ℃ under nitrogen, and the progress of the reaction was checked by TLC plates. After the reactant is cooled to room temperature at normal temperature, 100mL of saturated sodium chloride aqueous solution is added into the reactant, then ethyl acetate is used for extraction for 3 times, each time is 100mL, and the extraction liquid is combined; drying the extract with anhydrous sodium sulfate, and rotary drying with rotary evaporator to obtain concentrate; adsorbing the concentrate with column chromatography silica gel, adding into 200-300 mesh chromatography silica gel column, and purifying with n-hexane: and (3) performing flash column chromatography by using ethyl acetate according to a ratio of 2:1, merging eluent, performing rotary drying by using a rotary evaporator, and pumping by using an oil pump to obtain 39.5g of a product, wherein the mass yield is 89.3%.
Step three, synthesizing methyl indolcarbate by taking methanol as a raw material and concentrated sulfuric acid as a catalyst
A1L four-necked flask was charged with indole carboxylate (531.5g,3mol) and methanol (96g, 3 mol). Heating to 40 ℃, dropwise adding 98% concentrated sulfuric acid (150g, 1.5mol) while stirring, controlling the speed in the dropwise adding process to be not obviously changed in temperature (the temperature is not more than 5 ℃ from top to bottom) to carry out esterification reaction, extracting for 3 times by adding 200ml of dichloromethane and 200ml of water after the esterification reaction is finished, carrying out spin drying on an organic phase to obtain a crude product, and then recrystallizing by using ethanol petroleum ether in a ratio of 1:2 to obtain 513.5g of a pure product with a mass yield of 89.6%.
Unite INVOA form 400 DMSO as solvent, TMS internal standard. The characteristic hydrogen chemical shifts and integrated areas in the spectra are as follows:
1H-NMR(CF3-COOD，D2O)δ：10.3(S-1H)；7.59(S-1H)；7.31(S-1H)；7.12,(S-1H)；6.59(S-1H)；3.72(S-3H)。
mass spectral data were as follows:
ESI-MS:M/Z 192.2[M+H]+，
comparative example 1
A preparation method of methyl indolate comprises the following steps:
step one, synthesizing bromoindole by taking indole as a starting material, dichloromethane as a solvent and NBS as a bromination reagent. The method comprises the following specific steps:
adding indole (58.58g,0.5mol) and dichloromethane (150ml) into a 500ml three-neck flask, stirring, keeping the temperature at 30 ℃, dissolving 1, 3-dibromo-5, 5-dimethylhydantoin (86g,0.3mol) in 100ml dichloroethane, and finishing dropping for 30 min; carrying out bromination reaction, detecting the reaction process by using a TLC plate, after the reaction is finished, dropwise adding 3% sodium sulfite aqueous solution into the reactant at a controlled temperature (25-30 ℃) for quenching, and determining that the solution is colorless and the quenching is complete; each time, 100ml of ethyl acetate is added for extraction, three times of combined organic phases are dried by spinning to obtain solid, and the solid is separated by a column to obtain 58g of target product. The mass yield was 57.41%.
The difference between the experimental mixture ratio and the first step of the example 3 is that the molar mixture ratio of the 1, 3-dibromo-5, 5-dimethylhydantoin and other raw materials is out of a limited range, and other conditions are completely consistent; post-reaction treatment also yielded the target molecule but at a much reduced yield. The economic benefit is greatly reduced.
Step two, synthesis of carboxylic acid indole
Introducing nitrogen into a 500ml four-neck flask for protection; 53.01g (0.25mol) of bromoindole, 32.6g (0.20mol) of tris (dimethylamino) phosphine and 8.31g (0.042 mol) of copper acetate are added in one portion. 200ml of 1,4 dioxane was injected with a syringe. After stirring for 30min, 0.33mol of formic acid (15.18g) was injected, the reaction was carried out at 100 ℃ under nitrogen, and the progress of the reaction was checked by TLC plates. After the reactant is cooled to room temperature at normal temperature, 100mL of saturated sodium chloride aqueous solution is added into the reactant, then ethyl acetate is used for extraction for 3 times, each time is 100mL, and the extraction liquid is combined; drying the extract with anhydrous sodium sulfate, and rotary drying with rotary evaporator to obtain concentrate; adsorbing the concentrate with column chromatography silica gel, adding into 200-300 mesh chromatography silica gel column, and purifying with n-hexane: and (3) performing flash column chromatography by using ethyl acetate according to a ratio of 2:1, merging eluent, performing rotary drying by using a rotary evaporator, and pumping by using an oil pump to obtain 39.5g of a product, wherein the mass yield is 61.0%.
The difference between this example and step two of example 3 is that: the molar ratio of the copper acetate to other raw materials is out of the limited range; the rest conditions were completely consistent. The same work-up of the reaction gave a product that was consistent with the target molecular structure, but the yield decreased from 89.3% to 61%.
Step three, synthesizing methyl indolcarbate by taking methanol as a raw material and concentrated sulfuric acid as a catalyst
A1L four-necked flask was charged with indole carboxylate (531.5g,3mol) and methanol (96g, 3 mol). Heating to 40 ℃, dropwise adding 98% concentrated sulfuric acid (300g, 3mol) while stirring, controlling the speed in the dropwise adding process to be not obviously changed in temperature (the temperature is not more than 5 ℃), extracting for 3 times by adding 200ml dichloromethane and 200ml water after the esterification reaction is finished, carrying out spin drying on an organic phase to obtain a crude product, and then recrystallizing by using ethanol petroleum ether in a ratio of 1:2 to obtain 505.6g of a pure product with a mass yield of 88.2%.
The present example differs from step three of example 3 in that: the molar ratio of the concentrated sulfuric acid to other raw materials is out of the limited range; the rest conditions were completely consistent. The product obtained by the same post-treatment of the reaction has the same structure with the target molecule, and the yield is slightly reduced. The proportion of the use amount of the concentrated sulfuric acid exceeding the protection range is shown, so that the yield cannot be improved, and the reaction cost is increased.
The above data indicate that the protection scope of the present patent scale is the result of a large number of experimental demonstrations.
UNITY INVOA 400 type CDCl3As solvent, TMS internal standard. The characteristic hydrogen chemical shifts and integrated areas in the spectra are as follows:
1H-NMR(CF3-COOD，D2O)δ：10.3(S-1H)；7.59(S-1H)；7.31(S-1H)；7.12,(S-1H)；6.59(S-1H)；3.72(S-3H)。
corresponding to the imine hydrogen on the indole ring ((S-1H)), the indole ring internal hydrogen ((S-1H), (S-1H)), the benzene ring hydrogen ((S-1H), (S-1H)) and the methyl hydrogen of the terminal methyl ester ((S-3H)), respectively.
Mass spectral data were as follows:
ESI-MS:M/Z 192.2[M+H]+
those of ordinary skill in the art will understand that: the discussion of any embodiment above is meant to be exemplary only, and is not intended to intimate that the scope of the disclosure, including the claims, is limited to these examples; within the idea of the invention, also features in the above embodiments or in different embodiments may be combined, steps may be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.
The embodiments of the invention are intended to embrace all such alternatives, modifications and variances that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, substitutions, improvements and the like that may be made without departing from the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (9)
1. A preparation method of a methyl indolcarbate compound is characterized by comprising the following steps:
step one, synthesizing bromoindole from indole through bromination reaction;
under the protection of inert gas, reacting bromoindole, an organophosphorus ligand, a metal catalyst and formic acid in an organic solvent medium to synthesize carboxylic indole;
and step three, synthesizing methyl indolcarbate by carrying out esterification reaction on carboxylic indole and methanol under the action of a catalyst.
2. The method for preparing a methyl indolcarbate compound as claimed in claim 1 wherein the molar ratio of indole to brominating reagent used in the bromination reaction is 1: 0.8-1.2.
3. The method for preparing a methyl indolcarbate compound as claimed in claim 2, wherein the brominating reagent is any one of NBS, 1, 3-dibromo-5, 5-dimethylhydantoin, carbon tetrabromide, phenyltrimethylammonium tribromide, DBBA and DBI.
4. The method for producing a methyl indolcarbate compound according to claim 1, wherein the metal catalyst is copper acetate; the mol ratio of bromoindole to organophosphorus ligand to copper acetate to formic acid is 1: 1-3: 0.2-0.6: 1.1-1.5.
5. The method for preparing methyl indolate compound according to claim 1, wherein the organic phosphine ligand is any one or combination of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, S- (-) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, diphenylphosphine, triphenylphosphine oxide, and tris (dimethylamino) phosphine; the organic solvent is one or a combination of N, N-dimethyl sulfoxide, DMF, 1, 4-dioxane and isopropanol.
6. The method for preparing methyl indolcarbate compound according to claim 1, wherein concentrated sulfuric acid is used as a catalyst in the third step, and the molar ratio of indole carboxylate, methanol and concentrated sulfuric acid is 1: 1-1.5: 0.5-0.9.
7. The preparation method of methyl indolcarbamate compound according to claim 1, wherein the bromoindole is obtained by dropwise adding a 3% sodium sulfite aqueous solution for quenching after the bromination reaction is finished in the step one, and then carrying out extraction, organic phase spin drying and solid column separation.
8. The method for preparing indole methyl formate according to claim 1, wherein the carboxylic acid indole is obtained by adding saturated sodium chloride solution, extracting, concentrating, chromatographing, and rotary evaporating after the reaction in step two.
9. The preparation method of methyl indolcarbate compound as claimed in claim 1, wherein the pure methyl indolcarbate is obtained after the esterification reaction in the step three is finished through extraction, organic phase spin drying and recrystallization.
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| CN102558017A (en) * | 2011-12-27 | 2012-07-11 | 郑州凯美克化学有限公司 | Method for preparing 5-bromoindole |
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