CN106279123B - 3- (benzenesulfonylmethyl) imidazoheterocycles class compound and its synthetic method - Google Patents

Abstract

The invention discloses a kind of 3 (benzenesulfonylmethyl) imidazoheterocycles class compounds and preparation method thereof, include the following steps：Under ar gas environment, imidazoheterocycles class compound and benzenesulfonylmethyl isonitrile analog derivative are added in reaction tube, ferric trichloride is added, green solvent is then added, is reacted 18 ~ 48 hours at 80 ~ 120 DEG C；After reaction extraction, chromatographic isolation, be dried to obtain target product.The reaction is using cheap metal iron (III) as catalyst; water and polyethylene glycol 400 are as reaction dissolvent; imidazoheterocycles class compound is realized to react with the sulfonymethyl of benzenesulfonylmethyl isonitrile analog derivative; the sulfonyl of gained compound can be used as leaving group; realize that the research reacted the sulfonymethylization of imidazoheterocycles class compound and application are of great significance by further function dough reaction, this method.

Description

3-(Benzenesulfonylmethyl) imidazoheterocyclic compound and its synthesis method

technical field

The invention belongs to the technical field of synthesis and application of organic compounds, and in particular relates to a preparation method of 3-(benzenesulfonylmethyl) imidazoheterocyclic compounds.

Background technique

Pyridoimidazole is a very important and common nitrogen heterocyclic compound (ComprehensiveHeterocyclic Chemistry III). Its derivatives have good biological activity: for example, antiviral, antiulcer and antibacterial properties (J. Med. Chem. 2015, 58, 8529; Bioorg. Med. Chem. Lett. 2013, 23, 4996; J. Med. 2015, 58, 9238; Bioorg. Med. Chem. 2011, 19, 4227; ACS Med. Chem. Lett. 2013, 4, 675; J. Med. Chem. 1999, 42, 50). Among them, several types of drugs have been successfully marketed, such as anti-anxiety drugs Alpidem (Alpidem), Saripidem (Saripidem), anesthetic drugs Necopidem (Necopidem) and sedative hypnotics Zolpidem (Zolpidem), etc. ( J. Med. Chem. 2008, 51, 7243; Exp. Ther. 2001, 299, 793; J. Behav. Pharmacol. 1995, 6, 116). At present, the research on the functionalization reaction of pyridoimidazole compounds and imidazoheterocyclic compounds is becoming more and more perfect, but there is no report on the research on the sulfonylmethylation reaction.

p-Toluenesulfonylmethyl isonitrile is widely used in organic synthesis, taking advantage of its high activity and the ease of leaving the sulfonyl group (Angew. Chem., Int. Ed. 2010, 49, 9094, Chem. Rev. 2010 , 110, 5235,Chem. Rev. 2015, 115, 2698), synthesized a series of heterocyclic compounds, such as pyrrole, oxazole, imidazole and other nitrogen heterocyclic compounds (Chem. Commun. 2014, 50, 11837, Chem. Eur. J. 2015, 21, 18949, Org. Lett. 2014, 16, 4004, Adv. Synth. Catal. 2014, 356, 2974). This reaction realizes another reaction mode of p-toluenesulfonylmethylisonitrile, and realizes the sulfonylmethylation reaction with a simple reaction system.

Contents of the invention

The object of the present invention is to provide a kind of synthetic and preparation method of 3-(benzenesulfonylmethyl) imidazoheterocyclic compound, and this method is simple and easy, with low cost and easy to purify.

To achieve the above object, the present invention adopts the following technical solutions:

A 3-(benzenesulfonylmethyl) imidazoheterocyclic compound, its general structural formula is:

where X=C, O or S; n=0 or ¹ ; R1 is hydrogen, alkyl, alkoxy or halogen; Het is thiazole, thiazoline, benzothiazole, quinoline or oxazole heterocyclyl.

The preparation method of the described 3-(benzenesulfonylmethyl) imidazoheterocyclic compound comprises the following steps: under an argon atmosphere, derivatizing the imidazoheterocyclic compound with benzenesulfonylmethyl isocyanide Put the material into the reaction tube, add ferric chloride, then add green solvent, and react at 80~120°C for 18~48 hours; after the reaction is completed, extract, chromatographically separate, and dry to obtain the target product. The reaction equation is as follows:

;

The general formula of the imidazoheterocyclic compound is:

The general structural formula of benzenesulfonylmethyl isonitrile derivatives is:

Where X = C, O or S; n = 0, 1; R ¹ is hydrogen, alkyl, alkoxy or halogen; Het is thiazoles, thiazolines, benzothiazoles, quinolines or oxazoles heterocyclyl.

The molar ratio of the imidazoheterocyclic compound to the benzenesulfonylmethylisonitrile derivative is 1:2 or 1:3.

The amount of the ferric chloride is 0.1-0.3 times of the amount of imidazo heterocyclic compounds.

The green solvent is made by mixing water and polyethylene glycol 400 in a volume ratio of 0~10:10~0, based on the amount of 0.1mmol imidazoheterocyclic compound, the amount of the green solvent is 2mL.

The extractant used in the extraction is dichloromethane.

The eluent used in the chromatographic separation is ethyl acetate and petroleum ether in a volume ratio of 0-100:100-0.

Beneficial effects of the present invention: the present invention provides a simple and easy method for synthesizing imidazoheterocyclic compounds. The reaction uses cheap metal iron (Ⅲ) as a catalyst, green non-toxic water and polyethylene glycol 400 as a reaction solvent, and realizes the sulfonylformation of imidazoheterocyclic compounds and benzenesulfonylmethylisonitrile derivatives. The sulfonyl group of the obtained compound can be used as a leaving group to realize further functionalization reaction, which will provide more feasible ways for the application of this method. The method is simple and efficient, has low cost and is easy to purify, enriches the functional group reaction types of imidazoheterocyclic compounds, and also realizes a new reaction mode of benzenesulfonylmethylisonitrile derivatives. This method will be of great significance to the research and application of the sulfonylmethylation reaction of imidazoheterocyclic compounds.

Detailed ways

The present invention will be further described below in conjunction with specific embodiments. It should be understood that the following examples are only used to illustrate the present invention rather than limit the scope of the present invention, and those skilled in the art can make some non-essential improvements and adjustments based on the content of the above invention.

Example 1

The structure of the compound 2-(furan-2-yl)-3-(tosylmethyl)imidazo[1,2- α ]pyridine of the present embodiment is:

;

Preparation method: Add 0.1 mmol of 2-furylimidazo[1,2-a]pyridine compound, 0.2 mmol of p-toluenesulfonylmethyl isocyanide, 0.02 Mmol of ferric chloride, 2 mL of water, react at 100°C for 36 hours; after the reaction, extract with dichloromethane, concentrate under reduced pressure and then chromatographically separate (silica gel 200-300 mesh), eluent: ethyl acetate/petroleum Gradient elution with ether, the ratio is from 0/100 to 100/0), and drying to obtain a white solid with a yield of 90%. mp = 163-164℃. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.40 (d, J = 6.9 Hz, 1H), 7.60(d, J = 9.1 Hz, 1H), 7.38 (d, J = 8.2 Hz , 2H), 7.32-7.29 (m, 1H), 7.13 (dd, J= 1.6, 0.5 Hz, 1H), 7.06 (d, J = 7.9 Hz, 2H), 6.94 (td, J = 6.8, 1.0 Hz, 1H),6.66 (d, J = 1.1 Hz, 1H), 6.31 (dd, J = 3.4, 1.8 Hz, 1H), 5.08 (s, 2H), 2.27(s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 149.1, 146.3, 145.1, 142.0, 137.8, 133.9, 129.2, 128.4, 126.3, 124.6, 117.3, 112.9, 111.1, 108.4, 108.0, 52.7, 21.5 ^. calcd for C ₁₉ H ₁₇ N ₂ O ₃ S ⁺ : 353.0954, found 353.0961.

Example 2

The structure of the compound 2-(thiophen-2-yl)-3-(tosylmethyl)imidazo[1,2- a ]pyridine of the present embodiment is:

;

Preparation method: Add 0.1 mmol of 2-thienylimidazo[1,2-a]pyridine compound, 0.3 mmol of p-toluenesulfonylmethyl isocyanide, 0.03 Mmol of ferric chloride, polyethylene glycol 400 2mL, react at 100°C for 18 hours; after the reaction, extract with dichloromethane, concentrate under reduced pressure and then chromatographically separate (silica gel 200-300 mesh), eluent: ethyl acetate Gradient elution with ester/petroleum ether, the ratio is from 0/100 to 100/0), and dried to obtain a white solid with a yield of 87%. mp = 161-162℃. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.33 (d, J = 6.9 Hz, 1H),7.64 (d, J = 9.1 Hz, 1H), 7.50 (d, J = 8.3 Hz , 2H), 7.31-7.26 (m, 2H), 7.15(d, J = 8.0 Hz, 2H), 7.02 (dd, J = 3.6, 1.0 Hz, 1H), 6.95 (dd, J = 5.0, 3.7Hz, 1H), 6.90 (td, J = 6.8, 1.0 Hz, 1H), 4.90 (s, 2H), 2.35 (s, 3H). ¹³ C NMR(150 MHz, CDCl ₃ ) δ 146.0, 145.5, 141.7, 135.9, 134.5, 129.9, 128.3, 127.4, 126.3, 126.1, 125.2, 124.6, 117.4, 113.0, 107.5, 53.1, 21.6. HRMS (positiveESI): [M ⁺ H] ⁺ _calcd for C ₁₉ H ₁₇ N ₂ O ₂ S : 369.0726, found 369.0730.

Example 3

The structural formula of the compound 6-phenyl-5-(tosylmethyl)imidazo[2,1- b ]thiazole of the present embodiment is:

;

Preparation method: Add 0.1 mmol of 6-phenylimidazo[2,1- b ]thiazole compound, 0.3 mmol of p-toluenesulfonylmethyl isonitrile, 0.01 Mmol of ferric chloride, water and polyethylene glycol 400 (volume ratio 7:3) 2 mL, react at 120°C for 24 hours; 300 mesh), eluent: ethyl acetate/petroleum ether gradient elution, the ratio is from 0/100 to 100/0), and dried to obtain a white solid with a yield of 85%. mp = 39-40℃. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.71 (d, J = 4.5Hz, 1H), 7.45 (d, J = 8.2 Hz, 2H), 7.24-7.23 (m, 3H) , 7.18-7.14 (m, 4H), 6.90(d, J = 4.5 Hz, 1H), 4.69 (s, 2H), 2.37 (s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ150.9, 148.7, 145.4, _134.1 , _133.2 , ^129.9 , _128.29 , _128.27 , 127.8, 127.6, 119.1, 112.6, 109.8, 53.6, 21.6. ²⁺ : _369.0726 , found 369.0732.

Example 4

The structural formula of the compound 6-phenyl-5-(p-toluenesulfonylmethyl)-2,3-dihydroimidazo[2,1- b ]thiazole of the present embodiment is:

;

Preparation method: Add 0.1 mmol of 6-phenyl-2,3-dihydroimidazo[2,1- b ]thiazole compound and 0.3 mmol of p-toluenesulfonate to a 10 mL Shrek tube under the protection of argon Acylmethyl isonitrile, 0.03 mmol of ferric chloride, water and polyethylene glycol 400 (volume ratio 4:1) 2 mL, react at 80°C for 48 hours; after the reaction, extract with dichloromethane and concentrate under reduced pressure After chromatographic separation (silica gel 200-300 mesh), eluent: ethyl acetate/petroleum ether gradient elution, the ratio is from 0/100 to 100/0), and dried to obtain a white solid with a yield of 95%. mp = 48-49℃. ¹ H NMR (600 MHz, CDCl ₃ ) δ 7.42(d, J = 8.3 Hz, 2H), 7.18-7.15 (m, 3H), 7.10-7.08 (m, 4H), 4.48 ( s, 2H), 4.38(t, J = 7.3 Hz, 2H), 3.86 (t, J = 7.2 Hz, 2H), 2.34 (s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 151.3, 147.9 , 145.3, 133.9, 133.3, _129.8 , ^128.2 , _128.1 , _127.2 , _126.8 , _114.0 , 53.4, 46.3, 34.8, 21.6. ⁺ : 371.0882, found 371.0890.

Example 5

The structural formula of the compound 2-phenyl-3-(p-toluenesulfonylmethyl)benzo[ d ]imidazo[2,1- b ]thiazole of the present embodiment is:

;

Preparation method: Add 0.1 mmol of 2-phenyl-benzo[ d ]imidazo[2,1- b ]thiazole compound, 0.3 mmol of p-toluenesulfonyl to a 10 mL Shrek tube under the protection of argon Methyl isonitrile, 0.03 mmol of ferric chloride, water and polyethylene glycol 400 (volume ratio 3:2) 2 mL, react at 110°C for 24 hours; after the reaction, extract with dichloromethane and concentrate under reduced pressure Chromatographic separation (silica gel 200-300 mesh), eluent: ethyl acetate/petroleum ether gradient elution, ratio from 0/100 to 100/0), and drying to obtain a white solid with a yield of 41%. mp = 179-180℃. ¹ H NMR (600 MHz, CDCl ₃ ) δ8.08 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.52-7.49 (m, 1H ), 7.39(t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.24-7.22 (m, 5H), 5.08 (s,2H), 2.33 (s, 3H). ¹³ C NMR (150 MHz, CDCL ₃ ) Δ 149.7, 148.9, 145.2, 134.0,133.1, 132.9, 130.2, 129.6, 128.2, 127.7, 125.0, 124.7,112.1, 52.8, HRMS (Positive ESI ): [M+H] ⁺ calcd for C ₂₃ H ₁₉ N ₂ O ₂ S ₂ ⁺ :419.0882, found 419.0889.

Example 6

The structural formula of the compound 2-phenyl-1-(tosylmethyl)imidazo[1,2- α ]quinoline of the present embodiment is:

;

Preparation method: Add 0.1 mmol of 2-phenylimidazo[1,2-a]quinoline compound, 0.2 mmol of p-toluenesulfonylmethyl isocyanide to a 10 mL Shrek tube under the protection of argon, 0.02mmol of ferric chloride, 2 mL of water and polyethylene glycol 400 (volume ratio 3:2), reacted at 90°C for 24 hours; after the reaction, extracted with dichloromethane, concentrated under reduced pressure and separated by chromatography (silica gel 200 -300 mesh), eluent: ethyl acetate/petroleum ether gradient elution, the ratio is from 0/100 to 100/0), and dried to obtain a white solid with a yield of 46%. mp = 184-185℃. ¹ H NMR (600 MHz, CDCl ₃ ) δ 8.56 (d, J =8.7 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.71 (t, J = 7.9 Hz , 1H), 7.59 (dd, J= 14.5, 9.3 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7,27 (s, 3H), 7.21-7.19 (m,2H), 7.16 ( d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H), 5.43 (s, 2H), 2.34(s, 3H). ¹³ C NMR (150 MHz, CDCl ₃ ) δ 148.4, 145.9 , 144.9, 134.6, 134.5, 133.1,129.54, 129.49, 128.7, 128.5, 128.3, 128.1, 127.9, 124.8,117.2, 117.1, 54.5, HRMS (Positive ESI): [m+h] ⁺ calcd for C ₂₅ H ₂₁ N ₂ O ₂ S ⁺ : 413.1318, found 413.1318.

The basic principles and main features of the present invention and the advantages of the present invention have been shown and described above. Those skilled in the industry should understand that the present invention is not limited by the above-mentioned embodiments, and what described in the above-mentioned embodiments and the description only illustrates the principles of the present invention, and the present invention will also have other functions without departing from the spirit and scope of the present invention. Variations and improvements are possible, which fall within the scope of the claimed invention. The protection scope of the present invention is defined by the appended claims and their equivalents.

Claims (5)

1. a kind of preparation method of 3- (benzenesulfonylmethyl) imidazoheterocycles class compound, it is characterised in that include the following steps： Under ar gas environment, imidazoheterocycles class compound and benzenesulfonylmethyl isonitrile analog derivative are added in reaction tube, are added three Then green solvent is added in iron chloride, reacted 18 ~ 48 hours under conditions of 80 ~ 120 DEG C；Extraction, chromatography point after reaction From, it is dry that target product, reaction equation are as follows：

；

The general structure of 3- (benzenesulfonylmethyl) the imidazoheterocycles class compound is：

Wherein X=C, O or S；N=0 or 1；R¹For hydrogen, alkyl, alkoxy or halogen；Het is thiazoles, Thiazoling type, benzothiazole Class, quinolines Huo oxazole class heterocycles；

The general formula of the imidazoheterocycles class compound is：

；

The general structure of the benzenesulfonylmethyl isonitrile analog derivative is：

；

Wherein X=C, O or S；N=0 or 1；R¹For hydrogen, alkyl, alkoxy or halogen；Het is thiazoles, Thiazoling type, benzothiazole Class, quinolines Huo oxazole class heterocycles；

The green solvent is water and polyethylene glycol 400 by volume 0 ~ 10:10 ~ 0 are mixed, with 0.1mmol imidazos On the basis of the amount of the substance of heterocycle compound, the dosage of the green solvent is 2mL.

2. the preparation method of 3- (benzenesulfonylmethyl) imidazoheterocycles class compound according to claim 1, feature exist In：The amount ratio of the imidazoheterocycles class compound and the substance of benzenesulfonylmethyl isonitrile analog derivative is 1:2 or 1:3.

3. the preparation method of 3- (benzenesulfonylmethyl) imidazoheterocycles class compound according to claim 1, feature exist In：The dosage of the ferric trichloride is 0.1 ~ 0.3 times of the amount of the substance of imidazoheterocycles class compound.

4. the preparation method of 3- (benzenesulfonylmethyl) imidazoheterocycles class compound according to claim 1, feature exist In：The extractant used that extracts is dichloromethane.

5. the preparation method of 3- (benzenesulfonylmethyl) imidazoheterocycles class compound according to claim 1, feature exist In：The eluant, eluent that the chromatographic isolation uses is 0 ~ 100 for volume ratio：100 ~ 0 ethyl acetate and petroleum ether.