CN106928222A - A kind of preparation method of 3 alkyl Indoli zine derivatives - Google Patents

Abstract

The invention discloses a preparation method of 3-alkylindolizine derivatives. N -alkylpyridinium salts directly prepared from pyridine derivatives and primary halogenated alkanes are mixed with alkali and 2,2,6,6- In the presence of tetramethylpiperidine nitrogen oxides (TEMPO), react with electron-deficient olefins to prepare 3-alkyl indolizine derivatives. The purpose of the present invention is to develop brand-new 3-alkyl indolizine derivatives The raw materials for preparation and the corresponding process methods realize the easy and environmentally friendly synthesis of 3-alkyl indolizine derivatives at a lower production cost under relaxed reaction conditions.

Description

A kind of preparation method of 3-alkyl indolizine derivatives

technical field

The invention relates to organic synthesis chemistry technology, in particular to a preparation method of indolizine derivatives, in particular to a preparation method of 3-alkyl indolizine derivatives.

Background technique

Indolizine derivatives are widely used in the fields of biology, pesticides, medicine and luminescent materials, and are necessary for the production of drugs, dyes and organic luminescent materials. For example: it is an active ingredient in pigments, herbicides, latent phospholipase inhibitors, anti-leishmaniasis and antiviral drugs; in addition, it also exhibits anti-mycobacterial activity; it is a synthetic compound with important physiological activities Key intermediates of alkaloids. In recent years, studies have confirmed that the biological activity of indolizine derivatives has also played a positive role in antitumor, antibacterial, antiviral, acaricidal, anti-inflammatory, antiarrhythmic, antihypertensive and other aspects for humans. Among them, 3-alkylindolizine derivatives are an important compound among indolizine derivatives, which have various special properties and are used in many fields. However, there are certain difficulties in the synthesis of 3-alkylindolizine derivatives in the prior art. Not only is the reaction process long and many steps are required, but expensive metals and ligands are also required. In most cases, an anhydrous and oxygen-free environment is also required. The harsh reaction conditions, while the price of raw materials is high and most of them cannot be purchased directly from the market, thus resulting in its high preparation cost. Therefore, the method for directly synthesizing 3-alkylindolizines by using cheap and bulk chemical products that can be directly purchased in the market as raw materials and using organic reagents as oxidants has a wide market demand.

Contents of the invention

The invention provides a simple preparation method of 3-alkyl indolizine derivatives. The purpose is to realize the easy and environmentally friendly synthesis of 3-alkane under relaxed reaction conditions and at a lower production cost by developing a new raw material for the preparation of 3-alkylindolizine derivatives and a corresponding process method. Indolizine derivatives.

The present invention is realized through the following technical solutions:

A kind of preparation method of 3-alkyl indolizine derivatives, the N -alkylpyridinium salt that will be directly produced by pyridine derivatives and primary halogenated alkanes, in alkali and 2,2,6,6-tetramethylpiper In the presence of pyridine nitrogen oxides (TEMPO), react with electron-deficient olefins to prepare 3-alkyl indolizine derivatives, characterized in that: the preparation method is based on

The chemical reaction formula is prepared by the following process steps:

1) Configure the required raw material components: pyridine, primary halogenated alkanes, electron-deficient olefins, alkalis and TEMPO according to the ratio of 1:1:0.2～5.0:1.0～2.0:0.80～5.0;

2) Put the substituted pyridine (1) and the substituted primary haloalkane (2) into the reaction vessel at a molar ratio of 1:1, add a small amount of solvent 1 or no solvent, and heat at a temperature of 60-120 degrees Stir, and after heating and stirring for 0.5 to 4.0 hours, the synthesized N -alkylpyridinium salt (3) is in the reaction vessel;

3) Then add electron-deficient olefin, alkali and TEMPO into the reaction vessel, then add solvent 2, heat and stir at 100-160 ⁰ C until the reaction is complete, pour the reacted mixture into water, filter, extract, wash, After drying, recrystallization or column chromatography separation, the obtained solid or oil is the target product 3-alkyl indolizine derivative (5).

The technical improvement scheme that the present invention further solves is:

Described preparation step is further set to:

1) 0.60 mmol of substituted pyridine (1) and 0.60 mmol of substituted primary halogenated alkanes (2) are placed in a reaction vessel, and 0.20 ml of solvent 1 or no solvent is added, at a temperature of 60 to 120 degrees Heating and stirring under conditions, heating and stirring for 0.5 to 4.0 hours, the synthesized N -alkylpyridinium salt (3) is in the reaction vessel;

2) Add 0.80 mmol of base, 0.20 mmol of electron-deficient olefin and 0.80 mmol of TEMPO into the reaction vessel in sequence, then add 0.80-3.0 ml of solvent 2, and heat and stir ^at 100-160 °C until the reaction is complete;

3) Pour the reaction mixture in step 2 into water, filter, extract, wash, dry, recrystallize or separate by column chromatography, and the obtained solid is the target product 3-alkylindolizine derivative (5).

The technical improvement scheme that the present invention further solves is:

The selection of the substituted pyridine (1) component: or quinoline, or isoquinoline, or R ₁ = hydrogen, or 2-methyl, or 3-methyl, or 4-methyl, or 4- Carbomethoxy, or 4-phenyl, or 3-phenyl, or 2-phenyl, or 4-benzoyl, or 3,5-dimethyl, or 3,5-diphenyl .

The technical improvement scheme that the present invention further solves is:

The selection of the substituted primary halogenated hydrocarbon (2) component: or bromoethane, or bromopropane, or bromobutane, or bromopentane, or bromohexane, or 3-methyl Oxy-1-bromopropane, or 3-phenoxy-1-bromopropane, or 4-chloro-2,2-diphenylbutyronitrile, or 1-bromo-3-phenylpropane, or 1-chloro-2-phenylethane, or methyl 6-bromohexanoate, or ethyl 4-bromobutyrate, or chloromethylcyclopropane, or 2-ethyl-1-bromo Hexane, or 2-bromomethyl-1,3-dioxolane, or 2-(2-bromoethyl)-1,3-dioxolane, or 2-(3-bromopropane oxy)tetrahydro-2H-pyran.

The technical improvement scheme that the present invention further solves is:

The selection of the base: or lithium tert-butoxide, or potassium phosphate, or cesium carbonate, or potassium hydroxide, or sodium hydride, or lithium hydroxide, or cesium hydroxide.

The technical improvement scheme that the present invention further solves is:

The choice of the solvent 1: or N , N -dimethylformamide, or ethylene glycol dimethyl ether, or 1,4-dioxane, or acetonitrile.

The technical improvement scheme that the present invention further solves is:

The choice of solvent 2: or N , N -dimethylformamide, or N , N -dimethylacetamide, N -methylpyrrolidone, or dimethylsulfoxide, or hexamethylphosphoric triamide.

The technical improvement scheme that the present invention further solves is:

The described preparation step is further set to:

1) 0.60 mmol of substituted pyridine (1) and 0.60 mmol of substituted primary halogenated alkanes (2) were placed in a reaction vessel, and 0.20 ml of N , N -dimethylformamide was added, and placed in a 100-degree Heating and stirring under temperature conditions, heating and stirring for 4.0 hours;

2) Add 0.80 mmol of lithium hydroxide, 0.20 mmol of electron-deficient olefin and 0.80 mmol of TEMPO to the reaction vessel in sequence, and then add 2.8 ml of dimethyl sulfoxide; heat and stir at 140 ⁰ C until the reaction is completed;

3) Pour the reaction mixture in step 2 into water, filter, extract, wash, dry, recrystallize or separate by column chromatography, and the obtained solid is the target product 3-alkylindolizine derivative (5).

Compared with the prior art, the present invention has the following obvious advantages:

The present invention takes the N -alkylpyridinium salt directly prepared from primary halogenated hydrocarbons and pyridine derivatives, reacts with electron-deficient olefins in the presence of alkali and TEMPO, and prepares 3-alkyl indolizine derivatives, The production cost of preparing 3-alkyl indolizine derivatives in the prior art is greatly reduced; all raw materials can be purchased directly, and the price is relatively cheap and easy to obtain; no precious metal catalysts and ligands need to be used in the process flow, and the process flow is also It is simpler and the cost is significantly lower; there is no problem of excessive transition metals in the target product; the whole process is not sensitive to air and moisture, and can be operated under loose reaction conditions without pollution to the environment; it can be used for biological and pesticide Prepare related products in the field of medicine, and provide 3-alkyl indolizine derivatives with abundant sources and low prices.

Description of drawings

Accompanying drawing 1 is a process block diagram of the inventive method:

Accompanying drawing 2 is the NMR spectrum of the target product 3-alkyl indolizine derivative obtained in Example 1 of the present invention;

Accompanying drawing 3 is the carbon nuclear magnetic spectrogram of the target product 3-alkyl indolizine derivative obtained in Example 1 of the present invention;

Accompanying drawing 4 is the NMR spectrum of the target product 3-alkyl indolizine derivative obtained in Example 5 of the present invention;

Accompanying drawing 5 is the NMR spectrum of the target product 3-alkyl indolizine derivative obtained in Example 5 of the present invention.

In addition, the H NMR spectra and C NMR spectra of Examples 2, 3, 4, 6, 7, 8, and 9 of the present invention are not included in the accompanying drawings due to space limitations.

detailed description

Some embodiments are given below and the present invention will be further described in combination with related drawings.

Embodiment one:

As shown in the process flow of accompanying drawing 1, take pyridine as 48 microliters (equivalent to 0.60 mmol), and 1-bromobutane as 65 microliters (equivalent to 0.60 mmol), put them into the reaction vessel together, and add 0.20 milliliters of N , N -dimethylformamide, heated and stirred at 80 degrees for 2.0 hours, then added 19.2 mg of lithium hydroxide (equivalent to 0.80 mmol), 125.0 mg of TEMPO (equivalent to 0.80 mmol), N , N - Add 21 microliters of dimethylacrylamide (equivalent to 0.20 mmol) and 2.8 milliliters of dimethyl sulfoxide into a reaction vessel, heat and stir at 140 degrees Celsius for 24 hours until the reaction is complete, pour the reacted mixture into water, filter, After washing, 32.7 mg of the target product of this example was isolated (71% yield).

The target product in Example 1 was analyzed by a nuclear magnetic resonance spectrometer (model: AVANCE 400MHz, manufacturer: Bruker, Switzerland), and the hydrogen NMR spectrum shown in Figure 2 and the carbon NMR spectrum shown in Figure 3 were obtained. The parameters of the former are 7.91 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 7.0 Hz, 1H), 6.90 – 6.86 (m, 1H), 6.73 (s, 1H), 6.65 (td, J = 6.8, 1.4 Hz, 1H), 3.18 (s, 6H), 2.78 (t, J = 7.5 Hz, 2H), 1.80– 1.75 (m, 2H), 1.04 (t, J = 7.3 Hz, 3H); the latter Its parameters are ¹³ C NMR (CDCl ₃ , 100MHz): 168.1, 134.2, 124.0, 122.0, 120.0, 119.0, 112.6, 111.5, 105.8, 27.8, 20.4, 14.1. This proves that: the target product 3-alkyl indolizine derivatives of the first implementation fully meets the quality requirements.

Embodiment two:

As the process flow of accompanying drawing 1, get 4-phenylpyridine as 93.1 mg (equivalent to 0.60 mmol), 1-bromo-3-methoxypropane is 91.8 mg (equivalent to 0.60 mmol), put into reaction In the vessel, do not add solvent 1, heat and stir at 90 degrees for 1.0 hour, then add 180 mg of cesium hydroxide (equivalent to 1.20 mmol), 156 mg of TEMPO (equivalent to 1.0 mmol), and 13 microliters of acrylonitrile (equivalent to 0.20 mmol) and 2.0 ml of N , N -dimethylformamide into a reaction vessel, heated and stirred at 150 degrees Celsius for 24 hours until the end of the reaction, poured the reacted mixture into water, filtered, washed, and separated Obtained 47.5 mg of the target product of this example (86% yield).

Embodiment three:

As in the process flow of accompanying drawing 1, take 3,5-lutidine as 64.3 mg (equivalent to 0.60 mmol), 2-bromomethyl-1,3-dioxolane as 100 mg (equivalent to 0.60 mmol) mol), put into the same reaction vessel, add 0.2 ml of 1,4-dioxane, heat and stir at 100 degrees for 3.0 hours, then add 80 mg of lithium tert-butoxide (equivalent to 1.00 mmol), 313 Add 43.2 mg of TEMPO (equivalent to 2.0 mmol), 43.2 mg of dimethyl maleate (equivalent to 0.30 mmol) and 3.0 mL of N -methylpyrrolidone into a reaction vessel, heat and stir at 130 degrees Celsius for 36 hours until the end of the reaction, The reacted mixture was poured into water, filtered and washed to obtain 72.0 mg of the target product of this example (72% yield).

Embodiment four:

As in the process flow of accompanying drawing 1, take 2-picoline as 55.9 mg (equivalent to 0.60 mmol), 2-(2-bromoethyl)-1,3-dioxolane as 108.6 mg (equivalent to 0.60 mmol) millimoles), put it into the reaction vessel, add 0.2 ml of ethylene glycol dimethyl ether, heat and stir at 80 degrees for 10 hours, then add 24 mg of sodium hydroxide (equivalent to 0.60 mmol), 188 mg of TEMPO (equivalent to 1.2 mmol), 41.7 mg of chalcone (equivalent to 0.20 mmol) and 1.8 ml of hexamethylphosphonic acid triamide were added to the reaction vessel, and heated and stirred at 150 degrees Celsius for 24 hours until the end of the reaction. The mixture was poured into water, filtered and washed to obtain 73.1 mg of the target product of this example (92% yield).

Embodiment five:

As in the process flow of accompanying drawing 1, get 3,5-lutidine as 64.3 mg (equivalent to 0.60 mmol), 1-bromo-3-methoxypropane as 91.8 mg (equivalent to 0.60 mmol), and Put it into a reaction vessel, add 0.20 ml of N , N -dimethylformamide, heat and stir at 100 degrees for 4.0 hours, then add 293 mg of cesium carbonate (equivalent to 0.90 mmol), 156 mg of TEMPO (equivalent to 1.0 mmol), 13 microliters of acrylonitrile (equivalent to 0.20 mmol) and 2.6 milliliters of dimethyl sulfoxide were added to the reaction vessel, heated and stirred at 150 degrees Celsius for 24 hours until the reaction was completed, and the reacted mixture was poured into water, After filtering and washing, 43.8 mg of the target product of this example was isolated (96% yield).

The five target products in this example were analyzed by a nuclear magnetic resonance spectrometer (model: AVANCE 400MHz, manufacturer: Bruker, Switzerland), and the hydrogen NMR spectrum shown in Figure 4 and the carbon NMR spectrum shown in Figure 5 were obtained. The parameters of the former are ¹ H NMR (CDCl ₃ , 400MHz): 7.63 (s, 1H), 6.80 (s, 1H), 6.64 (s, 1H), 3.73 (t, J = 6.6Hz, 2H), 3.40 (s , 3H), 3.05 (t, J = 6.5 Hz, 2H), 2.68 (s, 3H), 2.29 (s, 3H); the parameter of the latter is ¹³ C NMR (CDCl ₃ , 100MHz): 13C NMR (101 MHz , CDCl3) δ 136.0, 128.3, 124.9, 123.0, 122.4, 119.2, 115.5, 79.8, 70.4, 58.8, 26.5, 18.4, 18.3. This proves that: the target product 3-alkyl indolizine derivatives in the fifth implementation fully meets the quality requirements.

Embodiment six:

As the technological process of accompanying drawing 1, get quinoline and be 77.5 milligrams (corresponding to 0.60 millimoles), 4-chloro-2, 2-diphenylbutyronitrile is 153.5 milligrams (corresponding to 0.60 millimoles), put into reaction In a container, 0.20 ml of acetonitrile was heated and stirred at 90 degrees for 3.0 hours, then 64 mg of tert-butyllithium (equivalent to 1.00 mmol), 156 mg of TEMPO (equivalent to 1.0 mmol), and 25.6 mg of tert-butyl acrylate were added. milligrams (equivalent to 0.20 mmol) and 2.5 milliliters of N , N -dimethylacetamide into a reaction vessel, heated and stirred at 140 degrees Celsius for 24 hours to the end of the reaction, poured the reacted mixture into water, filtered, washed, 83.2 mg of the target product of this example were isolated (88% yield).

Embodiment seven:

As the technological process of accompanying drawing 1, get 4-phenylpyridine as 93.1 milligrams (corresponding to 0.60 millimoles), 2-(3-bromopropoxy) tetrahydro-2H-pyran is 133.9 milligrams (corresponding to 0.60 millimoles) mol), put it into the reaction vessel, add 0.20 ml of ethylene glycol dimethyl ether, heat and stir at 80 degrees for 6.0 hours, then add 112 mg of potassium tert-butoxide (equivalent to 1.00 mmol), 125 mg of TEMPO (equivalent to 0.80 mmol), 29.9 mg of 4-nitrostyrene (equivalent to 0.20 mmol) and 2.8 ml of hexamethylphosphonic acid triamide were put into the reaction vessel, heated and stirred at 140 degrees Celsius for 24 hours until the end of the reaction, The reacted mixture was poured into water, filtered and washed to obtain 74.9 mg of the target product of this example (82% yield).

Embodiment eight:

As the process flow of accompanying drawing 1, get 3-phenylpyridine as 93.1 milligrams (corresponding to 0.60 millimoles), 1-chloro-2-phenylethane is 84.4 milligrams (corresponding to 0.60 millimoles), put into reaction Add 0.20 ml of N , N -dimethylformamide to the vessel, heat and stir at 90 degrees for 2.0 hours, then add 24 mg of lithium hydroxide (equivalent to 1.00 mmol), 156 mg of TEMPO (equivalent to 1.0 mmol mol), 13 microliters of acrylonitrile (equivalent to 0.20 millimoles) and 2.0 milliliters of dimethyl sulfoxide were added to the reaction vessel, heated and stirred at 140 degrees Celsius for 24 hours until the end of the reaction, and the reacted mixture was poured into water, filtered, After washing, 50.0 mg of the target product of this example was isolated (81% yield), and the ratio of the two isomers was 2:1.

Can confirm by above-mentioned embodiment and the nuclear magnetic hydrogen spectrogram and the nuclear magnetic carbon spectrogram that provide: the object prepared by the present invention

The target product 3-alkyl indolizine derivatives all meet the quality requirements, and it has enough room for selection in the compatibility of the component raw materials, but the difference in the amount ratio between the component raw materials and the reaction conditions exists, which brings the target product Comes with varying rates of change.

It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and are not used to limit the protection scope of the present invention. Equivalent replacements or replacements made on the basis of the above-mentioned technical solutions all belong to the protection of the present invention. Scope, the scope of protection of the present invention shall be determined by the claims.

Claims (6)

1. A preparation method of 3-alkyl indolizine derivatives, the N -alkylpyridinium salts directly produced by pyridine derivatives and primary halogenated alkanes, in alkali and 2,2,6,6-tetramethyl In the presence of piperidine nitrogen oxides (TEMPO), react with electron-deficient olefins to prepare 3-alkyl indolizine derivatives, characterized in that: the preparation method is based on The chemical reaction formula is prepared by the following process steps: 1) Configure the required raw material components: pyridine, primary halogenated alkanes, electron-deficient olefins, alkalis and TEMPO according to the ratio of 1:1:0.2～5.0:1.0～2.0:0.80～5.0; 2) Put the substituted pyridine (1) and the substituted primary haloalkane (2) into the reaction vessel at a molar ratio of 1:1, add a small amount of solvent 1 or no solvent, and heat at a temperature of 60-120 degrees Stir, and after heating and stirring for 0.5 to 4.0 hours, the synthesized N -alkylpyridinium salt (3) is in the reaction vessel; 3) Then add electron-deficient olefin, alkali and TEMPO into the reaction vessel, then add solvent 2, heat and stir at 100-160 ⁰ C until the reaction is complete, pour the reacted mixture into water, filter, extract, wash, After drying, recrystallization or column chromatography separation, the obtained solid or oil is the target product 3-alkyl indolizine derivative (5); The selection of the substituted pyridine (1) component: or quinoline, or isoquinoline, or R ₁ = hydrogen, or 2-methyl, or 3-methyl, or 4-methyl, or 4- Carbomethoxy, or 4-phenyl, or 3-phenyl, or 2-phenyl, or 4-benzoyl, or 3,5-dimethyl, or 3,5-diphenyl ; The selection of the substituted primary halogenated hydrocarbon (2) component: or bromoethane, or bromopropane, or bromobutane, or bromopentane, or bromohexane, or 3-methyl Oxy-1-bromopropane, or 3-phenoxy-1-bromopropane, or 4-chloro-2,2-diphenylbutyronitrile, or 1-bromo-3-phenylpropane, or 1-chloro-2-phenylethane, or methyl 6-bromohexanoate, or ethyl 4-bromobutyrate, or chloromethylcyclopropane, or 2-ethyl-1-bromo Hexane, or 2-bromomethyl-1,3-dioxolane, or 2-(2-bromoethyl)-1,3-dioxolane, or 2-(3-bromopropane oxy)tetrahydro- 2H -pyran. 2. the preparation method of a kind of 3-alkyl indolizine derivatives according to claim 1, is characterized in that: described preparation step is further set to: 1) 0.60 mmol of substituted pyridine (1) and 0.60 mmol of substituted primary halogenated alkanes (2) are placed in a reaction vessel, and 0.20 ml of solvent 1 or no solvent is added, at a temperature of 60 to 120 degrees Heating and stirring under conditions, heating and stirring for 0.5 to 4.0 hours, the synthesized N -alkylpyridinium salt (3) is in the reaction vessel; 2) Add 0.80 mmol of base, 0.20 mmol of electron-deficient olefin and 0.80 mmol of TEMPO into the reaction vessel in sequence, then add 0.80-3.0 ml of solvent 2, heat and stir at 100-160 ⁰ C until the reaction is complete; 3) Pour the reaction mixture in step 2 into water, filter, extract, wash, dry, recrystallize or separate by column chromatography, and the obtained solid is the target product 3-alkylindolizine derivative (5). 3. according to the preparation method of a kind of 3-alkyl indolizine derivatives described in claim 1 or 2, it is characterized in that: the selection of described alkali: or lithium tert-butoxide, or potassium phosphate, or cesium carbonate, Or potassium hydroxide, or sodium hydride, or lithium hydroxide, or cesium hydroxide. 4. according to the preparation method of a kind of 3-alkyl indolizine derivatives described in claim 1 or 2, it is characterized in that: the selection of described solvent 1: or N , N -dimethylformamide, or ethyl Glyme, or 1,4-dioxane, or acetonitrile. 5. the preparation method of a kind of 3-alkyl indolizine derivatives according to claim 1 or 2, is characterized in that: the selection of described solvent 2: or N , N -dimethylformamide, or N , N -dimethylacetamide, N -methylpyrrolidone, or dimethylsulfoxide, or hexamethylphosphoric triamide. 6. according to the preparation method of a kind of 3-alkyl indolizine derivatives described in claim 1 or 2, it is characterized in that: described preparation step is further set to: 1) 0.60 mmol of substituted pyridine (1) and 0.60 mmol of substituted primary halogenated alkanes (2) were placed in a reaction vessel, and 0.20 ml of N , N -dimethylformamide was added, and placed in a 100-degree Heating and stirring under temperature conditions, heating and stirring for 4.0 hours; 2) Add 0.80 mmol of lithium hydroxide, 0.20 mmol of electron-deficient olefin and 0.80 mmol of TEMPO to the reaction vessel in sequence, and then add 2.8 ml of dimethyl sulfoxide; heat and stir at 140 ⁰ C until the reaction is completed; 3) Pour the reaction mixture in step 2 into water, filter, extract, wash, dry, recrystallize or separate by column chromatography, and the obtained solid is the target product 3-alkylindolizine derivative (5).