CN114181216A - Preparation method of 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate - Google Patents
Preparation method of 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention provides a preparation method of 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate. The preparation method comprises the following steps: dissolving 4-aldehyde indole and ethyl azidoacetate in methanol, feeding the methanol solution into a module 1 through a pump 1, feeding a sodium methoxide methanol solution into the module 1 through a pump 2, and controlling the reaction temperature to be 20-30 ℃; pouring the material flowing out of the tail end into ice water, filtering, washing with water, and pulping with ethanol to obtain 2-azido-3- (4-indolyl) methyl acrylate; dissolving 2-azido-3- (4-indolyl) methyl acrylate in xylene, and introducing the solution into a module 1 which is preheated to 140 ℃ and 150 ℃; separating the material flowing out of the tail end into liquid through a gas-liquid separation tank, cooling, crystallizing, filtering, and pulping with n-heptane to obtain the 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate. The preparation method of the invention has low danger and convenient operation, and is beneficial to industrial production.
Description
Technical Field
The invention relates to a preparation method of ester, in particular to a preparation method of 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate, belonging to the technical field of compound preparation.
Background
Flow reactors (flow), micro reactors (micro) or medium reactors (meso) are devices named for the purpose of enhancing the continuous performance of chemical reactions. Continuous flow technology has emerged in this context as one is increasingly dissatisfied with the limitations of reaction volumes and vessels in conventional tank reactions. The technology can carry out optimization and adjustment on the size and the performance of the reactor according to specific reaction processes and targets. The key to this technology is that the reaction system should be as small as possible while still meeting the required performance. The fluidization technology shows wide use performance, can meet the requirement of basic debugging of reaction under small scale, and can also meet large-scale industrial production. Therefore, the user can fully feel the advantages and benefits of continuous flow technology, which are really and really different from the tank reaction, in the development stage and the production implementation stage of the process project.
The existing synthesis method of indole ring comprises the following steps:
2-azido-3-aryl acrylate cyclization to synthesize 2-carboxylic acid indole derivatives: 2-azido-3-aryl acrylate can be obtained by condensing azido acetate and aromatic aldehyde, and is heated to cyclize to generate indole 2-carboxylate derivatives, generally, only electron-rich aromatic rings (benzene ring with electron-pushing, furan, thiophene and pyrrole) can be cyclized by the method.
Bartoli indole synthesis reaction: reaction of ortho-substituted nitrobenzenes (or nitrosobenzenes) with alkenyl Grignard reagents to produce 7-substituted indoles
Batco-Leimgruber indole synthesis reaction: condensation of o-nitrotoluene compounds with formamide acetals (e.g. DMFDMA) to give trans- β -dialkylamino-2-nitrostyrene, followed by reduction to give indole compounds.
Cadogan-Sundberg indole synthesis: reaction of o-nitrostyrene or o-nitrostilbene with phosphite triester or trialkylphosphine to generate nitrene, and subsequent cyclization to generate indole. Sundberg indole synthesis reaction is the reaction of o-azido styrene to synthesize indole through nitrene intermediate.
Fischer indole synthesis reaction: the phenylhydrazone is heated and rearranged under the catalysis of acid to eliminate the reaction of one molecule of ammonia to obtain the 2-substituted or 3-substituted indole derivative. In practical operation, aldehyde or ketone and equivalent phenylhydrazine are heated and refluxed in acid to obtain phenylhydrazone, which is immediately rearranged under the catalysis of acid to eliminate ammonia to obtain indole compound. Commonly used catalysts are zinc chloride, boron trifluoride, polyphosphoric acid, AcOH, HCl, trifluoroacetic acid, and the like.
Wherein, the method for synthesizing the 2-carboxylic acid indole derivative by cyclization of the 2-azido-3-aryl acrylate has the characteristics of cheap raw materials, simple and convenient operation and the like. However, the reaction releases nitrogen gas violently because of the use of a large number of equivalents of ethyl azide acetate, and there is a risk of material spraying and explosion.
The synthesis route for methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate disclosed in WO2008103693a2 employs a process for the cyclization of 2-azido-3-arylacrylate to 2-carboxylic acid indole derivatives, wherein in the first step 10 equivalents of ethyl azidoacetate and 8 equivalents of sodium methoxide and a low temperature of-25 ℃ are used. Wherein the use amount of the dangerous material ethyl azide acetate is too large, and the low-temperature operation is complicated. In the second step, all the materials are dissolved in dimethylbenzene to be heated directly. The reaction produces violent gas, and has considerable danger of material spraying and even explosion.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a preparation method of 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate, which has low risk and convenient operation and is beneficial to industrial production.
In order to achieve the technical object, the invention provides a preparation method of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate, which comprises the following steps:
a preparation method of 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate, which comprises the following steps:
dissolving 4-aldehyde indole and ethyl azidoacetate in methanol, feeding the methanol solution into a module 1 through a pump 1, feeding a sodium methoxide methanol solution into the module 1 through a pump 2, and controlling the reaction temperature to be 20-30 ℃; pouring the material flowing out of the tail end into ice water, filtering, washing with water, and pulping with ethanol to obtain 2-azido-3- (4-indolyl) methyl acrylate;
dissolving 2-azido-3- (4-indolyl) methyl acrylate in xylene, and introducing the solution into a module 1 which is preheated to 140 ℃ and 150 ℃; and (3) separating liquid from the material flowing out of the tail end through a gas-liquid separation tank, cooling, crystallizing, filtering, and pulping with n-heptane to obtain the methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate.
In a specific embodiment of the present invention, the mixing equivalent ratio of 4-aldehydic indole to ethyl azidoacetate is 1 eq: 1-2 eq.
In one embodiment of the invention, the mass concentration of the sodium methoxide methanol solution is 15-30 wt%.
In one embodiment of the invention, the flow rate of the sodium methoxide methanol solution is the same as the flow rate of ethyl azidoacetate. Wherein the flow rate of the sodium methoxide methanol solution is 15ml/min-25ml/min (such as 20 ml/min). The flow rate of ethyl azidoacetate is 15ml/min to 25ml/min (e.g., 20 ml/min).
In one embodiment of the present invention, the mixing ratio of methyl 2-azido-3- (4-indolyl) acrylate to xylene is 4 to 5 mol: 50V-60V.
In one embodiment of the invention, methyl 2-azido-3- (4-indolyl) acrylate is dissolved in xylene and passed into module 1 at a flow rate of 80ml/min to 150ml/min (e.g., 100 ml/min).
In one embodiment of the present invention, the feed pump is a plunger rod pump made of various materials.
The preparation method of the 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate does not adopt a traditional kettle type process, but adopts a microchannel continuous flow reaction process, reduces the using amount of dangerous material ethyl azide acetate, improves the reaction temperature to room temperature, is simple to operate, and effectively reduces the risks of reaction spraying and explosion. Compared with the synthesis process in the prior art, the method has low danger and convenient operation, and is beneficial to industrial production.
In the preparation method of the 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate, the advantages of a microchannel reactor in material mixing and heat exchange and the principle of intrinsic safety are fully utilized in the step one, the using amount of dangerous material ethyl azide acetate is effectively reduced, the reaction temperature is controlled at room temperature, and the danger and the operability of the reaction are greatly optimized. In the second step, the principle of intrinsic safety of the microchannel reactor is fully utilized, and the total amount of the reaction liquid stored in the reactor is limited, so that the system has excellent pressure resistance, the danger of the reaction is greatly reduced, and the operability is improved.
Drawings
FIG. 1 is a schematic flow chart of a preparation method of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate according to example 1 of the present invention.
FIG. 2 is an LC-MS of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate of example 1 of the present invention.
FIG. 3 is 3, 6-dihydropyrrolo [3,2-e ] of example 1 of the present invention]Process for preparing indole-2-carboxylic acid methyl ester1H NMR。
Detailed Description
The following examples1The H NMR spectrum was obtained using a Bruker instrument (400MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00ppm) was used.1Method for H NMR expression: s is singlet, d is doublet, t is triplet, q is quartet, m is multiplet, br is broadened, dd is doublet of doublet, dt is doublet of triplet. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode is ESI.
The type of the high performance liquid chromatograph: agilent 1260 and Silmer fly U3000; the type of the chromatographic column: waters xbrige C18(4.6 × 150mm,3.5 μm); mobile phase: a is ACN, B is Water (0.1% H3PO 4); flow rate: 1.0 mL/min; gradient: 5% A for 1min, increment to 20% Awithin 4min, increment to 80% A within 8min, 80% A for 2min, back to 5% Awithin 0.1 min; wavelength: 220 nm; column oven: 35 ℃ is carried out.
TLC: thin layer chromatography. The thin layer chromatography silica gel plate is HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.2mm-0.3mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5 mm.
The column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, the national drug group, the welfare technology limited, the schehia (shanghai) chemical development limited, the shanghai bibi medical technology limited, the shanghai meihel chemical technology limited, and the like.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing agent used for the reaction, a system of eluents for column chromatography employed for purifying compounds or a developing agent system for thin layer chromatography including: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: n-hexane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.
Example 1
This example provides a preparation method of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate (as shown in fig. 1), specifically including the following steps:
the method comprises the following steps: synthesis of 2-azido-3- (4-indolyl) methyl acrylate
4-aldehyde indole (500.0g, 3.4mol) and ethyl azidoacetate (890.0g, 6.9mol) were dissolved in methanol (10L), fed through a stainless steel plunger rod pump, and passed into module 1 at a flow rate of 20 ml/min. 30% wt sodium methoxide methanol solution (1241.0g, 6.9mol) was diluted with methanol (10L) and pumped through a stainless steel plunger rod into module 1 at a flow rate of 20 ml/min. The temperature of the reaction module is set at 20 ℃, and the reaction module is discharged after passing through 5 modules. After 3 retention times, TLC sampling of the end samples was performed to check the reaction was complete and the reaction solution was received. The received reaction solution is poured into ice water for quenching, the mixture is filtered after being stirred for 10min, and after the water washing and the draining, the ethanol is pulped to obtain 581.2g of yellow solid 2-azido-3- (4-indolyl) methyl acrylate, the yield is 69.7 percent.
Step two: synthesis of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate
Methyl 2-azido-3- (4-indolyl) acrylate (1000.0g, 5.0mol) was dissolved in xylene (60L) and the material was passed by means of a stainless steel plunger rod pump into module 1 preheated to 140 ℃ at a flow rate of 100 ml/min. The temperature of the whole reaction module is set at 140 ℃, and the whole reaction module passes through 5 modules and then enters a gas-liquid separation tank to separate liquid and then is discharged. After 3 retention times, TLC sampling of the end samples was performed to check the reaction was complete and the reaction solution was received. Cooling the reaction solution to room temperature for crystallization, and filtering. The filter cake is pulped with n-heptane to obtain 802.3g of brown solid 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylic acid methyl ester, the yield is 90.8 percent, and the purity is 97.9 percent.
As shown in fig. 2, the LC-MS of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate is 215.1[ M + H ] +. 1H NMR (400MHz, DMSO-d6) δ 11.84(s,1H),11.20(s,1H),7.24-7.43(m,3H),7.19(d, J ═ 8Hz,1H),6.68(s,1H),3.87(s,3H) as shown in fig. 3.
Comparative example 1
The comparative example provides a preparation method of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate, which specifically comprises the following steps:
the method comprises the following steps: synthesis of 2-azido-3- (4-indolyl) methyl acrylate
4-aldehyde indole (500.0g, 3.4mol) and ethyl azidoacetate (890.0g, 6.9mol) were dissolved in methanol (10L), fed through a stainless steel plunger rod pump, and passed into module 1 at a flow rate of 20 ml/min. 30% wt sodium methoxide methanol solution (1241.0g, 6.9mol) was diluted with methanol (10L) and pumped through a stainless steel plunger rod into module 1 at a flow rate of 20 ml/min. The temperature of the reaction module is set at 10 ℃, and the reaction module is discharged after passing through 3 modules. After 1 retention time, end sampling TLC detects that the reaction is complete and reaction solution begins to be received. And (3) pouring the received reaction liquid into ice water for quenching, stirring for 10min, filtering, washing with water, draining, and pulping with ethanol to obtain yellow solid 2-azido-3- (4-indolyl) methyl acrylate with the yield of 52.1%.
Step two: synthesis of methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate
Methyl 2-azido-3- (4-indolyl) acrylate (1000.0g, 5.0mol) was dissolved in xylene (60L) and the material was passed by means of a stainless steel plunger rod pump into module 1, previously heated to 180 ℃ at a flow rate of 100 ml/min. The temperature of the whole reaction module is set at 100 ℃, and the whole reaction module enters a gas-liquid separation tank to separate liquid after passing through 3 modules and then is discharged. After 5 retention times, TLC sampling of the end samples was performed to check the reaction was complete and the reaction solution was initially received. Cooling the reaction solution to room temperature for crystallization, and filtering. The filter cake was slurried with n-heptane to give methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate as a brown solid in 76.5% yield and 58.7% purity.
The above embodiments are merely illustrative of the technical ideas and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. A preparation method of 3, 6-dihydropyrrolo [3,2-e ] indole-2-methyl formate, which comprises the following steps:
dissolving 4-aldehyde indole and ethyl azidoacetate in methanol, feeding the methanol solution into a module 1 through a pump 1, feeding a sodium methoxide methanol solution into the module 1 through a pump 2, and controlling the reaction temperature to be 20-30 ℃; pouring the material flowing out of the tail end into ice water, filtering, washing with water, and pulping with ethanol to obtain 2-azido-3- (4-indolyl) methyl acrylate;
dissolving the 2-azido-3- (4-indolyl) methyl acrylate in xylene, and introducing the solution into a module 1 which is preheated to 140 ℃ and 150 ℃; and (3) separating liquid from the material flowing out of the tail end through a gas-liquid separation tank, cooling, crystallizing, filtering, and pulping with n-heptane to obtain the methyl 3, 6-dihydropyrrolo [3,2-e ] indole-2-carboxylate.
2. The preparation method according to claim 1, wherein the mixing equivalent ratio of the 4-aldehydic indole to the ethyl azidoacetate is 1 eq: 1-2 eq.
3. The preparation method according to claim 1, wherein the mass concentration of the sodium methoxide methanol solution is 15-30% wt.
4. The production process according to claim 1 or 3, wherein the flow rate of the sodium methoxide methanol solution is the same as that of ethyl azidoacetate.
5. The method according to claim 1, wherein the flow rate of the sodium methoxide methanol solution is 15ml/min to 25 ml/min.
6. The production method according to claim 1, wherein the flow rate of the sodium methoxide methanol solution is 20 ml/min.
7. The production method according to claim 1, wherein the mixing ratio of methyl 2-azido-3- (4-indolyl) acrylate to xylene is 4 to 5 mol: 50V-60V.
8. The method of claim 1, wherein the methyl 2-azido-3- (4-indolyl) acrylate is dissolved in xylene and is passed through module 1 at a flow rate of 80-150 ml/min.
9. The method of claim 6, wherein the methyl 2-azido-3- (4-indolyl) acrylate is dissolved in xylene and passed through module 1 at a flow rate of 100 ml/min.
10. The method of claim 1, wherein the feeding is performed by a feeding pump, and the feeding pump is a plunger rod pump made of various materials.
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