CN117820194A - Preparation method of indole-7-methyl formate - Google Patents
Preparation method of indole-7-methyl formate Download PDFInfo
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- CN117820194A CN117820194A CN202211631525.6A CN202211631525A CN117820194A CN 117820194 A CN117820194 A CN 117820194A CN 202211631525 A CN202211631525 A CN 202211631525A CN 117820194 A CN117820194 A CN 117820194A
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- Prior art keywords
- indole
- carboxylic acid
- indoline
- methyl ester
- acid methyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 18
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 14
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 13
- GWAXLDLPPZPQLO-UHFFFAOYSA-N tert-butyl 2,3-dihydroindole-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OC(C)(C)C)CCC2=C1 GWAXLDLPPZPQLO-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 10
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims abstract description 8
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims abstract description 8
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims abstract description 6
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 24
- FTLOEULOTNVCGF-UHFFFAOYSA-N methyl 1h-indole-7-carboxylate Chemical compound COC(=O)C1=CC=CC2=C1NC=C2 FTLOEULOTNVCGF-UHFFFAOYSA-N 0.000 claims description 13
- FLJNKQJTQGASIL-UHFFFAOYSA-N 1-o-tert-butyl 7-o-methyl 2,3-dihydroindole-1,7-dicarboxylate Chemical compound COC(=O)C1=CC=CC2=C1N(C(=O)OC(C)(C)C)CC2 FLJNKQJTQGASIL-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000000377 silicon dioxide Substances 0.000 claims description 12
- -1 3, 3-dimethylbutyl Chemical group 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 235000012239 silicon dioxide Nutrition 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- LFIINZZVXMUCCL-UHFFFAOYSA-N 1-o-tert-butyl 7-o-methyl indole-1,7-dicarboxylate Chemical compound COC(=O)C1=CC=CC2=C1N(C(=O)OC(C)(C)C)C=C2 LFIINZZVXMUCCL-UHFFFAOYSA-N 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 5
- 229910052763 palladium Inorganic materials 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- ORPVVAKYSXQCJI-UHFFFAOYSA-N 1-bromo-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1Br ORPVVAKYSXQCJI-UHFFFAOYSA-N 0.000 description 1
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 description 1
- RDSVSEFWZUWZHW-UHFFFAOYSA-N 7-bromo-1h-indole Chemical compound BrC1=CC=CC2=C1NC=C2 RDSVSEFWZUWZHW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000006713 insertion reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- NJHDBIXFFZVJGZ-UHFFFAOYSA-N methyl 3-methyl-2-nitrobenzoate Chemical compound COC(=O)C1=CC=CC(C)=C1[N+]([O-])=O NJHDBIXFFZVJGZ-UHFFFAOYSA-N 0.000 description 1
- 229910052901 montmorillonite Inorganic materials 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of indole-7-methyl formate, and belongs to the technical field of organic synthesis. Indoline is used as a raw material, di-tert-butyl dicarbonate is used for protecting amino to obtain 1-Boc-indoline, N-butyllithium is reacted with dimethyl carbonate in the presence of N, N-ligand to obtain 1-Boc-indoline-7-methyl carboxylate, the 1-Boc-indole-7-methyl carboxylate is obtained by oxidation with diethyl azodicarboxylate, and finally indole-7-methyl carboxylate is obtained by deprotection. The invention has simple process flow, easily obtained raw materials and low cost, avoids using palladium catalyst, and is more suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of indole-7-methyl formate, belonging to the technical field of organic synthesis.
Background
Indole-7-carboxylic acid methyl ester, english name: methyl 1H-indole-7-carboxylate, CAS 93247-78-0. Indole is one of the most widely separated heterocyclic compounds in nature, and can be used in the fields of natural medicine total synthesis, medicine synthesis, dyes, fragrances, food and feed additives, pesticides and the like. Indole-7-methyl formate is an important pharmaceutical intermediate, and can be synthesized into compounds with physiological and pharmacological activities. The C7 ester group in the indole-7-methyl formate can be further chemically modified, so that the functional compounds such as C7 hydroxyethyl, amide and the like can be prepared. At present, the synthesis of the C7-position indole mainly adopts a Batch o-Leimgruber indole synthesis method, and the synthesis method is suitable for the synthesis of the C4-7-position indole derivative, such as the preparation of the C4-7-position indole derivative by the reaction of o-nitrotoluene and N, N-dimethylformamide dimethyl acetal, and then reduction and cyclization.
The literature [ Journal of Organic Chemistry,1997, vol.62, #17, p.5838-5845] adopts 3-methyl-2-nitrobenzoic acid methyl ester as a raw material, and uses bromination, triphenylphosphine to replace to wittig salt, and adopts formaldehyde gas to eliminate and cyclize to synthesize indole-7-methyl formate in four steps, so that the yield is low, and dangerous solvents such as carbon tetrachloride and expensive reagents such as palladium acetate are used. The reaction equation is as follows:
the literature [ Organic Letters,2006, vol.8, #10, p.2167-2170] uses 1-bromo-2-nitrobenzene as a raw material, reacts with a vinyl grignard reagent to obtain 7-bromoindole, and then undergoes a carbonyl insertion reaction to obtain indole-7-methyl formate, the yield is 56%, a palladium catalyst and a ligand are used, high-pressure synthesis of carbon monoxide is required, and the equipment requirement is high, wherein the cost of the palladium catalyst is high, and the method is not applicable to industrial production. The reaction equation is as follows:
aiming at the defects of the method, the preparation method provided by the invention has the advantages of simple and convenient flow, high product quality, no heavy metal residue and higher total yield, and is suitable for factory production so as to meet the increasing market demands.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a preparation method of indole-7-methyl formate. Indoline is used as a raw material, di-tert-butyl dicarbonate is used for protecting amino to obtain 1-Boc-indoline, N-butyllithium is reacted with dimethyl carbonate in the presence of N, N-ligand to obtain 1-Boc-indoline-7-methyl carboxylate, the 1-Boc-indole-7-methyl carboxylate is obtained by oxidation with diethyl azodicarboxylate, and finally indole-7-methyl carboxylate is obtained by deprotection. The invention has simple process flow, easily obtained raw materials and low cost, avoids using palladium catalyst, and is more suitable for industrial production.
The invention discloses a preparation method of indole-7-methyl formate, which comprises the following steps:
the first step: mixing indoline, di-tert-butyl dicarbonate and an organic solvent, and heating to react to obtain 1-Boc-indoline;
and a second step of: mixing 1-Boc-indoline, N-ligand and tetrahydrofuran, dropwise adding N-butyl lithium solution at ultralow temperature, and then reacting with dimethyl carbonate to obtain 1-Boc-indoline-7-carboxylic acid methyl ester;
and a third step of: mixing 1-Boc-indoline-7-carboxylic acid methyl ester, diethyl azodicarboxylate and 1, 2-dichloroethane, heating to react to obtain 1-Boc-indole-7-carboxylic acid methyl ester, concentrating under reduced pressure, and then adding an organic solvent and silicon dioxide to react to obtain indole-7-carboxylic acid methyl ester.
The reaction equation is expressed as follows:
further, in the above technical scheme, the organic solvent in the first step is selected from acetonitrile or methanol. In the reaction of this step, DMAP catalyst is added to accelerate the reaction, and the catalyst is added in an amount of 2-10mol%.
Further, in the technical scheme, the molar ratio of the indoline to the di-tert-butyl dicarbonate in the first step is 1:1.15-1.20.
Further, in the above technical scheme, in the second step, the N, N-ligand is selected from trans-N, N '-dimethyl-N, N' -bis (3, 3-dimethylbutyl) or trans-1, 3-dimethyl-hexahydro-2H-benzimidazole. The chemical formula is as follows:
further, in the above technical scheme, in the second step, the molar ratio of the 1-Boc-indoline, the N, N-ligand, the N-butyllithium and the dimethyl carbonate is 1:0.1-0.3:1.20-1.25:1.30-1.40.
Further, in the technical scheme, the molar ratio of the 1-Boc-indoline-7-carboxylic acid methyl ester to the azodicarboxylic acid diethyl ester in the third step is 1:1.20-1.25.
Further, in the above technical scheme, the deprotection step three adopts silica or a silica/montmorillonite K-10 mixture (weight ratio of the silica to the montmorillonite is 5/1-1/1). The amount of the used 1-Boc-indoline-7-carboxylic acid methyl ester is 10-20% of the weight of the used 1-Boc-indoline-7-carboxylic acid methyl ester.
Advantageous effects of the invention
A. In the second step, when the butyl lithium is subjected to hydrogen extraction by adding a specific ligand, the 2-position guide is reduced, and the 7-position is mainly extracted, so that the methyl carboxylate is introduced with high selectivity; and the third step of deprotection is finished, and the silicon dioxide can be reused after being dried.
B. The whole process is simple, a palladium catalyst is not used, the excessive heavy metal content of the product is avoided, the product quality is improved, and the intermediate in each step has market demands.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims.
Example 1
Indoline (35.8 g,0.3 mol), di-tert-butyl dicarbonate (78.6 g,0.36 mol) and acetonitrile (250 mL) are added into a reaction bottle under the protection of nitrogen, DMAP (methyl methacrylate) is added under the stirring condition at room temperature, the temperature is raised to 75 ℃ for reaction for 6 hours, the temperature is reduced, the concentration is reduced, the acetonitrile is evaporated under reduced pressure, isopropyl ether is added for replacement, n-heptane is added, the temperature is reduced, and crystallization is carried out to obtain 60g of 1-Boc-indoline, the yield is 91.2%, and the HPLC is 99.4%. 1 HNMR(400MHz,CDCl3)δ:7.81-7.61(m,1H),7.20-7.17(m,1H),7.16-7.12(m,1H),6.93-6.90(m,1H),3.91-3.85(m,2H),3.10-3.03(m,2H),1.48(s,9H).
Example 2
1-Boc-indoline (43.9 g,0.2 mol) and trans-N, N '-dimethyl-N, N' -bis 3, 3-dimethylbutyl (6.2 g,0.02 mo) were added to the flask under nitrogenl) and 300mL of tetrahydrofuran, cooling to-70 ℃, dropwise adding 2.5M n-butyllithium solution (96 mL,0.24 mol), reacting for 1 hour, then dropwise adding dimethyl carbonate (23.4 g,0.26 mol), reacting for 4 hours, slowly heating to 5 ℃, dropwise adding 1M hydrochloric acid to quench and adjust to pH=4.5-5.0, layering and preserving an organic phase, extracting an aqueous phase by ethyl acetate, merging the organic phases, washing by common salt water, concentrating under reduced pressure until no fluid, adding n-heptane, cooling and precipitating solid, filtering to obtain 43.2g of 1-Boc-indoline-7-carboxylic acid methyl ester, obtaining the yield of 77.8%, and carrying out HPLC of 98.6%. 1 HNMR(400MHz,DMSO-d 6 )δ:7.41-7.38(m,1H),7.38-7.34(m,1H),7.08-7.04(m,1H),4.05-4.01(m,2H),3.70(s,3H),3.08-3.05(m,2H),1.43(s,9H).
Example 3
Under nitrogen blowing conditions, 1-Boc-indoline (43.9 g,0.2 mol), trans-1, 3-dimethyl-hexahydro-2H-benzimidazole (6.2 g,0.04 mol) and tetrahydrofuran (300 mL) were added into a reaction flask, the temperature was reduced to-70 ℃, 2.5M n-butyllithium solution (100 mL,0.25 mol) was added dropwise, the reaction was carried out for 1 hour, dimethyl carbonate (24.3 g,0.27 mol) was then added dropwise, the reaction was carried out for 4 hours, the temperature was slowly increased to 5 ℃, 1M hydrochloric acid was added dropwise to quench the mixture to adjust the pH=4.5-5.0, the mixture was layered, the organic phase was retained, ethyl acetate was extracted in aqueous phase, the organic phase was combined, the mixture was washed with saline solution and concentrated under reduced pressure until no liquid was obtained, the mixture was added with n-heptane and cooled down for crystallization, and then filtered to obtain methyl 1-Boc-indoline-7-carboxylate (40.1 g, yield: 72.3%) and HPLC (98.6%).
Example 4
1-Boc-indoline-7-carboxylic acid methyl ester (27.7 g,0.1 mol) and 1, 2-dichloroethane (250 mL) are added into a reaction bottle, diethyl azodicarboxylate (20.9 g,0.12 mol) is dropwise added at room temperature, then the reaction is carried out for 2 hours by heating and refluxing, after cooling, the solvent is distilled off by reduced pressure, anisole is replaced, 5.5g of silicon dioxide is added, the reaction is carried out for 8 hours by heating and refluxing, and cooling is carried out untilThe silicon dioxide is filtered off at room temperature, the filtrate is concentrated to be non-flowing liquid under reduced pressure, and n-heptane is added for cooling and crystallization to obtain 14.2g of indole-7-methyl formate with the yield of 81.3 percent and the HPLC of 99.6 percent. 1 HNMR(400MHz,CDCl 3 )δ:9.91(s,1H),7.93-7.88(m,2H),7.31(s,1H),7.19-7.16(m,1H),6.63(s,1H),3.97(s,3H).
Example 5
1-Boc-indoline-7-carboxylic acid methyl ester (27.7 g,0.1 mol) and 1, 2-dichloroethane are added into a reaction bottle, diethyl azodicarboxylate (21.8 g,0.125 mol) is dropwise added at room temperature, then the reaction bottle is heated and refluxed for 2 hours, the solvent is distilled off by cooling and reduced pressure distillation, diethylene glycol dimethyl ether is replaced, 3g of montmorillonite K-10 and 3g of silicon dioxide are added, the reaction bottle is heated and refluxed for 12 hours, the temperature is reduced to room temperature, montmorillonite K-10 and silicon dioxide are filtered, the filtrate is decompressed and concentrated to no fluid, n-heptane is added for cooling and crystallization to obtain 15.2g of indole-7-carboxylic acid methyl ester, the yield is 86.7%, and HPLC is 99.6%.
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (8)
1. The preparation method of the indole-7-methyl formate is characterized by comprising the following steps of:
the first step: mixing indoline, di-tert-butyl dicarbonate and an organic solvent, and heating to react to obtain 1-Boc-indoline;
and a second step of: mixing 1-Boc-indoline, N-ligand and tetrahydrofuran, dropwise adding N-butyl lithium solution at ultralow temperature, and then reacting with dimethyl carbonate to obtain 1-Boc-indoline-7-carboxylic acid methyl ester;
and a third step of: mixing 1-Boc-indoline-7-carboxylic acid methyl ester, diethyl azodicarboxylate and 1, 2-dichloroethane, heating to react to obtain 1-Boc-indole-7-carboxylic acid methyl ester, concentrating under reduced pressure, and then adding an organic solvent and silicon dioxide to react to obtain indole-7-carboxylic acid methyl ester.
2. The process for preparing indole-7-carboxylic acid methyl ester as claimed in claim 1, wherein: in the first step, the organic solvent is selected from acetonitrile or methanol.
3. The process for preparing indole-7-carboxylic acid methyl ester as claimed in claim 1, wherein: in the first step, the molar ratio of the indoline to the di-tert-butyl dicarbonate is 1:1.15-1.20.
4. The process for preparing indole-7-carboxylic acid methyl ester as claimed in claim 1, wherein: in the second step, the N, N-ligand is selected from trans-N, N '-dimethyl-N, N' -bis (3, 3-dimethylbutyl) or trans-1, 3-dimethyl-hexahydro-2H-benzimidazole.
5. The process for preparing indole-7-carboxylic acid methyl ester as claimed in claim 1, wherein: in the second step, the molar ratio of the 1-Boc-indoline, the N, N-ligand, the N-butyllithium and the dimethyl carbonate is 1:0.1-0.3:1.20-1.25:1.30-1.40.
6. The process for preparing indole-7-carboxylic acid methyl ester as claimed in claim 1, wherein: in the third step, the molar ratio of the 1-Boc-indoline-7-carboxylic acid methyl ester to the azodicarboxylic acid diethyl ester is 1:1.20-1.25.
7. The process for preparing indole-7-carboxylic acid methyl ester as claimed in claim 1, wherein: in the third step, the deprotection is carried out using silica or a silica/montmorillonite K-10 mixture.
8. The process for preparing indole-7-carboxylic acid methyl ester as claimed in claim 1, wherein: in the third step, the organic solvent is selected from anisole or diethylene glycol dimethyl ether.
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