CN111253297A

CN111253297A - Process method for preparing 5-methoxy-2-methylindole

Info

Publication number: CN111253297A
Application number: CN202010241252.9A
Authority: CN
Inventors: 龙韬; 陈丕证; 顾扬; 邹增龙
Original assignee: SUZHOU BAILING WEICHAO FINE MATERIALS CO Ltd
Current assignee: SUZHOU BAILING WEICHAO FINE MATERIALS CO Ltd
Priority date: 2020-03-31
Filing date: 2020-03-31
Publication date: 2020-06-09

Abstract

The invention discloses a process method for preparing 5-methoxy-2-methylindole, which comprises the following steps: p-methoxyaniline is used as a raw material and reacts with hydroxyacetone under the action of a catalyst to obtain the 5-methoxy-2-methylindole. The reaction yield is high, and the product purity is high.

Description

Process method for preparing 5-methoxy-2-methylindole

Technical Field

The invention relates to the field of medical intermediates, in particular to a process method for preparing 5-methoxy-2-methylindole.

Background

Indole is an aromatic heterocyclic compound, and the chemical structure of the indole is formed by combining a benzene ring and a pyrrole ring. Indole is a most common chemical medicine structural skeleton, and due to high biological activity of indole, indole occupies a place in medicines in multiple treatment fields of hypertension resistance, antiproliferation, virus resistance, tumor resistance, pain relief, inflammation resistance, bacteria resistance and the like. For example, the number of drugs on the market containing indole skeleton is 112 from the recorded drug information in the Bigde database.

5-Methoxy-2-Methylindole (5-Methoxy-2-Methylindole, CAS:1076-74-0) is a very important electron-rich indole building block in indole structures. The positions of 5-methoxy-2-methylindole available for derivatization are very many, and hydrogen on a pyrrole ring, methyl on the pyrrole ring, nitrogen on the pyrrole ring, hydrogen on a benzene ring and oxygen on a benzene ring can be correspondingly derivatized, so that the 5-methoxy-2-methylindole is widely applied to drug synthesis, and the derivatization reaction recorded on Scifinder by light is more than 2000.

The currently reported synthesis routes of 5-methoxy-2-methylindole with practical value mainly comprise two routes, respectively as follows:

the first route is the one reported in pharmaceutical Chemistry (Journal of Medicinal Chemistry; vol.49; nb.1; (2006); p.135-158) in 2006,

the route adopts a 2-step synthesis method, 4-methoxy phenylhydrazine or 4-methoxy phenylhydrazine hydrochloride is taken as an initial raw material, and is condensed with acetone, and then Fisher indole cyclization is carried out by using zinc chloride to obtain the 5-methoxy-2-methylindole.

There are three more serious problems with this approach: firstly, the steps are long, and the operation is complicated; secondly, the raw material 4-methoxy phenylhydrazine or 4-methoxy phenylhydrazine hydrochloride in the first step is obtained by diazotizing p-anisidine and then reducing the diazotization reaction, the diazotization reaction has explosiveness and great hidden danger to the personal safety of operators, the whole life cycle of the raw material does not meet the requirements of green environmental protection, and simultaneously, the raw material has higher price and does not meet the economic principle; thirdly, the second step requires the use of a large amount of zinc chloride, and a large amount of viscous metal salts are generated during the post-treatment of the reaction, which makes the post-treatment difficult. These three problems severely limit the further application of the process and also make the kilogram scale and ten kilogram scale up of the product more difficult.

The second route is the one reported in Journal of the American chemical society, vol.134, nb.22, (2012), p.9098-9101 in 2012,

the route adopts a 1-step synthesis method, wherein p-anisidine is taken as a starting material, and is subjected to ring closure with acetone under the action of palladium acetate, copper acetate and oxygen to obtain the 5-methoxy-2-methylindole.

This method also has two more serious problems: firstly, the expensive noble metal catalyst palladium acetate is used, so that the economic principle is not met, a small amount of heavy metal is remained in the product, and the use of the product in the subsequent drug synthesis is influenced; secondly, oxygen needs to be introduced in the reaction process, so that not only is the operation difficulty increased, but also the explosion risk of the method is increased by more than one order of magnitude when the method is amplified in a larger amount. Both of these problems severely limit further applications of the process and also make kilogram and ten kilogram scale-up of the product difficult.

In order to solve the problems of high price of key raw materials, poor process safety and complex post-treatment of the existing process route of the 5-methoxy-2-methylindole, the method for synthesizing the 5-methoxy-2-methylindole, which has the advantages of reasonable route design, low price of raw materials, convenience in operation and high safety, is very important.

Disclosure of Invention

In order to overcome the defects in the prior art, the embodiment of the invention provides a process method for preparing 5-methoxy-2-methylindole, which has high reaction yield and high product purity.

In order to achieve the above purpose, the embodiments of the present application disclose a process for preparing 5-methoxy-2-methylindole, which comprises the following steps:

p-methoxyaniline is used as a raw material and reacts with hydroxyacetone under the action of a catalyst to obtain the 5-methoxy-2-methylindole.

Preferably, the catalyst is one or more of acetic acid, trifluoroacetic acid, aluminum trichloride, zinc chloride, titanium tetrachloride, stannic chloride, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, eaton's reagent, phosphorus pentoxide and benzenesulfonic acid.

Preferably, the reaction of the methoxyaniline and the hydroxyacetone is carried out in a solvent, which is one or more of dichloromethane, 1, 2-dichloroethane, o-dichlorobenzene, nitrobenzene, chlorobenzene, methanesulfonic acid, acetic acid, trifluoromethanesulfonic acid, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, DMF, DMSO, toluene, xylene, ethyl acetate, propyl acetate, acetonitrile, dioxane.

Preferably, the amount of the hydroxyacetone is as follows: 0.5 to 10 equivalents.

Preferably, the catalyst is used in the following amount: 0.001 to 100 equivalents.

Preferably, the reaction temperature is-20 to 200 ℃.

The invention has the following beneficial effects: all raw materials in the synthetic route adopted by the invention are cheap and easily available; the operation is convenient, the post-treatment is simple, and the process safety is high; the reaction yield is high, the product purity is high, the production cost is greatly reduced, and the requirement of large-scale industrial production of the product can be fully met.

In order to make the aforementioned and other objects, features and advantages of the invention comprehensible, preferred embodiments accompanied with figures are described in detail below.

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 an HPLC chromatogram of example 1 of the present invention;

FIG. 3 is a nuclear magnetic spectrum of example 2 of the present invention;

FIG. 4 is an HPLC chromatogram of example 2 of the present invention;

FIG. 5 is a nuclear magnetic spectrum of example 3 of the present invention;

FIG. 6 is an HPLC chromatogram of example 3 of the present invention;

FIG. 7 is an HPLC chromatogram of example 3 of the present invention.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In order to achieve the purpose, the invention provides a process method for preparing 5-methoxy-2-methylindole.

Example 1

380g of p-anisidine, 250g of hydroxyacetone, 1.5L of toluene and 1Kg of methanesulfonic acid are added in sequence into a 50L glass reaction flask with stirring at room temperature, and the mixture is stirred uniformly.

Further, heating the reaction solution to reflux reaction, and carrying out heat preservation and reflux reaction for 6 hours to finish the reaction.

Further, the reaction solution was distilled under reduced pressure to recover toluene and methanesulfonic acid, and the residue was recrystallized from t-butyl methyl ether, followed by vacuum oven drying to obtain 462g of a white-like solid powdery product with a yield of 92%.

HPLC purity of the product: 99.02 percent.

Nuclear magnetic data: 1H NMR (400MHz, d 6-DMSO): δ 10.68(s, 1H), 7.12(d, 1H), 6.89(d, 1H), 6.60(dd, 1H), 6.01(s, 1H), 3.71(s, 3H), 2.34(s, 3H).

Please refer to fig. 1 for nmr;

please refer to fig. 2 for HPLC spectra;

the structures are shown in Table 1.

Analytical results table

TABLE 1

As can be seen from fig. 1, fig. 2 and table 1, the synthesis route adopted in the present invention has high reaction yield and high product purity.

Example 2

Under stirring at room temperature, 4.2Kg of p-anisidine, 2.9Kg of hydroxyacetone and 25Kg of acetic acid were sequentially added to a 50L glass reaction vessel and stirred uniformly. Heating the reaction solution to reflux reaction, and carrying out heat preservation and reflux reaction for 8 hours to finish the reaction.

The reaction solution is decompressed and distilled to recover acetic acid, and the residue is recrystallized by acetonitrile and then dried by a vacuum oven to obtain 5.2Kg of off-white solid powder product with the yield of 94 percent.

HPLC purity of the product: 99.40 percent.

The nuclear magnetic spectrum is shown in FIG. 3.

The HPLC chromatogram is shown in FIG. 4.

The analytical results are shown in Table 2.

Analytical results table

TABLE 2

As can be seen from fig. 3, fig. 4 and table 2, the synthesis route adopted in the present invention has high reaction yield and high product purity.

Example 3

Under stirring at room temperature, 4.5Kg of p-anisidine, 3.5Kg of hydroxyacetone, 30L of toluene, 2.3Kg of phosphorus pentoxide, and 3.9Kg of phosphoric acid were sequentially added to a 50L glass reaction vessel and stirred uniformly. Heating the reaction solution to reflux reaction, and carrying out heat preservation and reflux reaction for 6 hours to finish the reaction.

The reaction mixture was cooled to room temperature, washed twice with 20L of purified water, once with 20L of a saturated solution of sodium hydrogencarbonate, once with 20L of purified water, and once with 10L of saturated brine. Then, the toluene is recovered by reduced pressure distillation, and the residue is recrystallized by acetonitrile and then dried in a vacuum oven to obtain 5.3Kg of off-white solid powder product with the yield of 90 percent.

HPLC purity of the product: 99.08 percent.

The NMR spectrum is shown in FIG. 5.

The HPLC chromatogram is shown in FIG. 6, and the corresponding analysis results are shown in Table 3.

Detector A Channel 1 230nm

Peak#	Ret.Time	Area	Height	Area％
						1	1.567	15719	565	0.075
2	2.203	68111	1914	0.324
					3	2.971	20871154	1417212	99.359
4	10.364	33463	522	0.159
					5	10.800	1541	129	0.007
6	12.461	15877	447	0.076
					Total		21005865	1420789	100.000

TABLE 3

As can be seen from fig. 5, fig. 6 and table 3, the synthesis route employed in the present invention has high reaction yield and high product purity.

The HPLC chromatogram is shown in FIG. 7, and the corresponding analysis results are shown in Table 4.

Detector A Channel 2 220nm

Peak#	Ret.Time	Area	Height	Area％
						1	2.197	3815	304	0.011
2	2.974	32984492	2231371	99.086
					3	3.863	127057	7921	0.382
4	10.361	66856	904	0.201
					5	14.375	106390	405	0.320
Total		33288610	2240905	100.000

TABLE 4

As can be seen from fig. 5, fig. 7 and table 4, the synthesis route employed in the present invention has high reaction yield and high product purity.

The principle and the implementation mode of the invention are explained by applying specific embodiments in the invention, and the description of the embodiments is only used for helping to understand the method and the core idea of the invention; meanwhile, for a person skilled in the art, according to the idea of the present invention, there may be variations in the specific embodiments and the application scope, and in summary, the content of the present specification should not be construed as a limitation to the present invention.

Claims

1. A process method for preparing 5-methoxy-2-methylindole is characterized by comprising the following steps:

2. The process of claim 1, wherein the catalyst is one or more of acetic acid, trifluoroacetic acid, aluminum trichloride, zinc chloride, titanium tetrachloride, tin chloride, methanesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, sulfuric acid, p-toluenesulfonic acid, eaton's reagent, phosphorus pentoxide, and benzenesulfonic acid.

3. The process of claim 1, wherein the reaction of methoxyaniline with hydroxyacetone is carried out in a solvent selected from the group consisting of dichloromethane, 1, 2-dichloroethane, o-dichlorobenzene, nitrobenzene, chlorobenzene, methanesulfonic acid, acetic acid, trifluoromethanesulfonic acid, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, DMF, DMSO, toluene, xylene, ethyl acetate, propyl acetate, acetonitrile, dioxane.

4. The process for preparing 5-methoxy-2-methylindole according to claim 1, wherein the hydroxyacetone is used in an amount of: 0.5 to 10 equivalents.

5. The process for preparing 5-methoxy-2-methylindole according to claim 1, wherein the catalyst is used in an amount of: 0.001 to 100 equivalents.

6. The process for preparing 5-methoxy-2-methylindole according to claim 1, wherein the reaction temperature is-20 to 200 ℃.