CN106366081A - Green synthesis method for bicyclic pyridone compound - Google Patents

Abstract

The invention discloses a green synthesis method of a bicyclic pyridone compound. The key points of the technical scheme of the present invention are: a kind of green synthesis of bicyclic pyridone compound is to use heterocyclic ketene ketamine and its derivatives and diethyl ethoxymethylene malonate as raw materials in a solvent-free, The catalyst is prepared by one-pot cascading reaction and one-step ring formation under the condition of ultrasonic promotion or microwave promotion, and the specific synthesis steps and the main reaction equation in the preparation process are announced. The invention has the advantages of simple and efficient preparation, safety and environmental protection, mild reaction conditions, etc., conforms to the characteristics of modern green chemistry, and has industrial application prospects.

Description

A kind of green synthetic method of bicyclic pyridone compound

technical field

The invention relates to the field of organic synthesis chemistry, in particular to a green synthesis method of bicyclic pyridone compounds.

Background technique

Bicyclic pyridone compounds are common structural units of drugs and dyes, and are the basic skeletons of many natural alkaloids, purine bases, many natural products with important activities, and intermediates in organic synthesis. Widely distributed in animals and plants, it can also be used as herbicide in pesticides. Bicyclic pyridone heterocyclic compounds play an important role in the field of pharmaceutical industry because of their outstanding biological activities. As a human rhinovirus 3C-protease inhibitor, ACE inhibitor, cyclin kinase inhibitor, calcium channel blocker, etc., it exerts pharmacological effects (Gudmundsson, s.; J. Med. Chem. 2003, 46, 1449 ; Rival, Y.; Omni. Pharm. Bull. 1992, 40, 1170 ; Hranjec , M.; J. Med. Chem. 2007 , 50, 5659 ; Trapani, G.; , F.; Bioorg. Med. Chem. Lett. 2004, 14, 2245 ). However, the synthesis of bicyclic pyridone compounds has certain limitations. The reaction requires heating to reflux or the use of catalysts, specific solvents, etc. The reaction conditions are relatively harsh or the reaction time is long, which does not meet the requirements of environmental friendliness and green chemistry. The optimization of the reaction system and conditions will lay a good foundation for better exerting its practical value.

Contents of the invention

In order to overcome the disadvantages of harsh synthesis reaction conditions and long reaction time of the above-mentioned bicyclic pyridone compounds, the present invention discloses a green and efficient synthesis method of bicyclic pyridone compounds with cheap and easy-to-obtain raw materials and simple operation.

The specific implementation route of the present invention is: take heterocyclic ketene ketamine and its derivatives in the reactor, and take a certain amount of diethyl ethoxymethylene malonate dropwise into the reactor. Under the condition of ultrasonic promotion or microwave promotion of the catalyst, the corresponding bicyclic pyridone products are respectively obtained through one-pot series reaction one-step ring formation, and the pure product of the target product is obtained through silica gel column chromatography, vacuum distillation and recrystallization.

Wherein the reaction formula is as follows:

Wherein, R can be H, alkyl or aryl;

R1 is an electron-withdrawing group, such as a nitro group, a cyano group, an ester group, a halogen atom or an aromatic ketone group, etc.;

The above reaction can take place no matter it is stirred at room temperature, accelerated by ultrasound or accelerated by microwave.

Whether the above reaction is stirred at room temperature, ultrasonically promoted or microwave-promoted, it can be carried out in solvents such as dichloromethane, acetonitrile, 1,4-dioxane, acetone, triethylamine, acetic acid, diphenyl ether, etc. and without When the solvent is used, the corresponding bicyclic pyridone products are obtained to a certain extent, but the reaction yield is higher under solvent-free conditions.

The above reaction can also obtain a small amount of corresponding products in the presence of catalysts NaH, BuOK, triethylamine, acetic acid, etc., but when there is no catalyst, the reaction yield is higher.

The above-mentioned high-temperature reaction can also obtain the expected product to a certain extent, but the reaction system is relatively complicated, and the requirements for separation and purification technology are relatively high.

Among them, all reactions were monitored by TLC spots.

Among them, all the reactions were separated and purified by silica gel column chromatography, and recrystallized to obtain pure bicyclic pyridone products, and the structure of the products was identified by NMR, high-resolution mass spectrometry and other characterization means.

The above reactions all have higher reaction yields under the conditions of solvent-free and catalyst-free conditions, and the use of ultrasonic promotion or microwave promotion shortens the reaction time, and one-step series ring formation does not require intermediate treatment. The raw materials are cheap and easy to obtain, easy to operate, and the reaction conditions are mild. Environmentally friendly, green and efficient, and many other advantages.

The nuclear magnetic resonance data of all above-mentioned reactions were measured by Bruker Ultrashield™ 400 PLUS/BrukerAVANCE III 400M nuclear magnetic spectrometer, TMS was the internal standard, Swiss Bruker company.

The high-resolution mass spectra of all the above reactions were determined by LTQ Orbitrap XL high-resolution liquid chromatography-mass spectrometry, Thermo Fisher Scientific, USA.

detailed description

Example 1 Weigh the compound 2-(benzoylmethylene)imidazolidinidine (1mmol, 188.2mg) in a reaction test tube, and slowly drop into the reaction test tube diethyl ethoxymethylene malonate ( 5mmol, 1081.1mg), reacted at 25-30°C for 5 hours under the promotion of ultrasound, and monitored the reaction by TLC spot plate. After the reaction was complete, the reaction mixture was subjected to silica gel column chromatography and rotary evaporation under reduced pressure to obtain a white solid. Bicyclopyridone compound 1 is the product of white needle crystals. The compound data is:

1

yield 69.8%; White needle-like crystals; ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.32(t, J = 7.04 , 3H,CH ₃ ), 4.06(t, J = 9.64 , 2H, NCH ₂ ) , 4.26-4.33(m, 4H, CONCH ₂ andCOOCH ₂ ), 7.49-7.58(m, 5H, ArH), 8.51 (s, 1H, CH), 8.75 (br, 1H, NH); HRMS(ESI-TOF ⁺ ): m/z Calcd for C ₁₇ H ₁₆ O ₄ N ₂ Na[(M+Na) ⁺ ] 335.1002; found, 335.0995.

Example 2 Weigh 2-(p-methylbenzoylmethylene)imidazolidinidine (1mmol, 202.3mg) into a reaction test tube, and then slowly drop into the reaction test tube diethyl ethoxymethylenemalonate Ester (5mmol, 1081.1mg), reacted at 25-30°C for 5 hours under the promotion of ultrasound, and monitored the reaction by TLC spot plate. After the reaction was complete, the reaction mixture was subjected to silica gel column chromatography, and the white solid was obtained by rotary evaporation under reduced pressure, which was recrystallized to obtain The pure white needle crystal product bicyclopyridone compound 2. The compound data is:

2

yield 71.1%; White needle-like crystals; ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.33(t, J = 7.08 , 3H,CH ₃ ), 2.42(s, 3H,ArCH ₃ ), 4.04(t , J = 9.76 , 2H, NCH ₂ ), 4.26-4.32(m, 4H, CONCH ₂ and COOCH ₂ ), 7.28(d, J = 7.84, 2H, ArH), 7.47(d, J = 7.84, 2H,ArH ), 8.53 (s, 1H, CH), 8.74 (br, 1H, NH); HRMS (ESI-TOF ⁺ ): m/z Calcd for C ₁₈ H ₁₈ O ₄ N ₂ Na[(M+Na) ⁺ ] 349.1159 ; found, 349.1156.

Example 3 Weigh 2-(p-methoxybenzoylmethylene)imidazolinidine (1mmol, 218.2mg) into a reaction test tube, and then slowly drop ethoxymethylenemalonate di Ethyl ester (5mmol, 1081.1mg) was reacted at 25-30°C for 5 hours under the promotion of ultrasound, and the reaction was monitored by TLC spot plate. After the reaction was complete, the reaction mixture was subjected to silica gel column chromatography and rotary evaporation under reduced pressure to obtain a white solid, which was recrystallized The pure white needle-like bicyclopyridone compound 3 was obtained. The compound data is:

3

yield 75.4%; White needle-like crystals; ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.33(t, J = 7.08 , 3H,CH ₃ ), 3.87(s, 3H, OCH ₃ ), 4.03(t , J = 9.56 , 2H, NCH ₂ ), 4.27-4.32(m, 4H, CONCH ₂ and COOCH ₂ ), 6.98(d, J = 8.40, 2H, ArH), 7.58(d, J = 8.40, 2H,ArH ), 8.56 (s, 1H, CH), 8.70 (br, 1H, NH); HRMS (ESI-TOF ⁺ ): m/z Calcd for C ₁₈ H ₁₈ O ₅ N ₂ Na[(M+Na) ⁺ ] 365.1108 ; found, 365.1107.

Example 4 Weigh compound 2-(p-chlorobenzoylmethylene)imidazolidinium (1mmol, 222.7mg) in a reaction test tube, and then slowly drop compound 1 (5mmol, 1081.1mg) into the reaction test tube. Under the promotion of ultrasound, react at 25-30°C for 5 hours, and monitor the reaction by spotting TLC plate. After the reaction is complete, the reaction mixture is subjected to silica gel column chromatography and rotary evaporation under reduced pressure to obtain a white solid, which is recrystallized to obtain pure white needle-shaped bicyclic pyridone Compound 4. The compound data is:

4

yield 67.2%; White needle-like crystals; ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.33(t, J = 7.12 , 3H,CH ₃ ), 4.07(t, J = 9.64 , 2H, NCH ₂ ) , 4.27-4.33(m, 4H, CONCH ₂ andCOOCH ₂ ), 7.47(d, J = 8.08, 2H, ArH), 7.52(d, J = 8.16, 2H, ArH), 8.45 (s, 1H,CH), 8.71 (br, 1H, NH); HRMS (ESI-TOF ⁺ ): m/z Calcd for C ₁₇ H ₁₅ O ₄ N ₂ ClNa[(M+Na) ⁺ ]369.0613; found, 369.0617.

Example 5 Weigh 2-(benzoylmethylene)hexahydropyrimidine (1mmol, 202.3mg) into a reaction test tube, and then slowly drop compound 1 (5mmol, 1081.1mg) into the reaction test tube. React at 25-30°C for 5 hours, and monitor the reaction by spotting on TLC plate. After the reaction is complete, the reaction mixture is subjected to silica gel column chromatography and rotary evaporation under reduced pressure to obtain a white solid, which is recrystallized to obtain pure white needle-shaped bicyclic pyridone compound 5. The compound data is:

5

yield 95.4%; White needle-like crystals; ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.26(t, J = 7.04 , 3H,CH ₃ ), 2.09(s, 2H, CH ₂ ), 3.51(s , 2H, NCH ₂ ), 4.05(d, J = 4.56 , 2H, CONCH ₂ ), 4.23(t, J = 7.00, 2H, COOCH ₂ ), 7.45(d, J = 3.24, 5H, ArH), 8.41 ( s,1H, CH), 11.18 (br, 1H, NH); HRMS (ESI-TOF ⁺ ): m/z Calcd for C ₁₈ H ₁₈ O ₄ N ₂ Na[(M+Na) ⁺ ] 349.1159; found, 349.1155.

Example 6 Weigh compound 2-(p-tolylmethylene)hexahydropyrimidine (1mmol, 216.3mg) into a reaction test tube, and then slowly drop compound 1 (5mmol, 1081.1mg) into the reaction test tube, Under the promotion of ultrasound, react at 25-30°C for 5 hours, and monitor the reaction by TLC spotting. After the reaction is complete, the reaction mixture is subjected to silica gel column chromatography and rotary evaporation under reduced pressure to obtain a white solid, which is recrystallized to obtain pure white needle-shaped bicyclic pyridine Ketone compound 6. The compound data is:

6

yield 84.3%; White needle-like crystals; ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.32(t, J = 7.08 , 3H, CH ₃ ), 2.15(t, J = 5.32, 2H, CH ₂ ) , 2.43(s, 3H, ArCH ₃ ), 3.56(s,2H, NCH ₂ ), 4.11(t, J = 5.76 , 2H, CONCH ₂ ), 4.29(q, J =7.08, 2H, COOCH ₂ ), 7.28 (d, J = 7.08, 2H, ArH), 7.43 (d, J = 7.64, 2H, COArH), 8.50 (s, 1H, CH), 11.24 (br,1H, NH); HRMS (ESI-TOF ⁺ ) : m/z Calcd for C ₁₉ H ₂₀ O ₄ N ₂ Na[(M+Na) ⁺ ] 363.1315; found,363.1313.

Example 7 Weigh compound 2-(p-methoxybenzoylmethylene)hexahydropyrimidine (1mmol, 232.3mg) into a reaction test tube, and slowly drop compound 1 (5mmol, 1081.1mg) into the reaction test tube , reacted at 25-30°C for 5 hours under the promotion of ultrasound, and monitored the reaction by TLC spotting. After the reaction was complete, the reaction mixture was subjected to silica gel column chromatography, and the white solid was obtained by rotary evaporation under reduced pressure, which was recrystallized to obtain pure white needle-shaped bicyclic Pyridone compound 7. The compound data is:

7

yield 85.2%; White needle-like crystals; ¹ H NMR (400 MHz, CDCl ₃ ): δ = 1.34(t, J = 7.04 , 3H, CH ₃ ), 2.16(t, J = 5.52, 2H, CH ₂ ) , 3.90(s, 3H, ArOCH ₃ ), 3.57(s,2H, NCH ₂ ), 4.13(t, J = 5.72 , 2H, CONCH ₂ ), 4.31(q, J =7.16, 2H, COOCH ₂ ), 6.99 (d, J = 8.04, 2H, ArH), 7.54 (d, J = 7.96, 2H, COArH), 8.54 (s, 1H, CH), 11.21 (br,1H, NH); HRMS (ESI-TOF ⁺ ) : m/z Calcd for C ₁₉ H ₂₀ O ₅ N ₂ Na[(M+Na) ⁺ ] 379.1264; found,379.1261.

Example 8 Weigh compound 2-(p-chlorobenzoylmethylene)hexahydropyrimidine (1mmol, 236.7mg) into a reaction test tube, and slowly drop compound 1 (5mmol, 1081.1mg) into the reaction test tube. Under the promotion of ultrasound, react at 25-30°C for 5 hours, and monitor the reaction by TLC spotting. After the reaction is complete, the reaction mixture is subjected to silica gel column chromatography and rotary evaporation under reduced pressure to obtain a white solid, which is recrystallized to obtain pure light yellow flaky crystal bicyclopyridine Ketone compound 8. The compound data is:

8

yield 75.9%; Light yellow flaky crystal; ¹ H NMR (400 MHz, DMSO-d ₆ ): δ =1.15(t, J = 7.04 , 3H, CH ₃ ), 2.01(s, 2H, CH ₂ ), 3.51( s, 2H, NCH ₂ ), 3.90(t, J =5.08 , 2H, CONCH ₂ ), 4.09(q, J =7.00, 2H, COOCH ₂ ), 7.51(d, J = 8.24, 2H, ArH), 7.60 (d, J = 8.20, 2H, COArH), 8.12 (s, 1H, CH), 10.80 (br, 1H, NH); HRMS(ESI-TOF ⁺ ): m/z Calcd for C ₁₈ H ₁₇ O ₄ N ₂ ClNa[(M+Na) ⁺ ] 383.0769; found, 383.0764.

The specific embodiments described above are further descriptions of the invention, and are only for illustration purposes, and are not intended to limit the scope of the invention in any form. All simple modifications, equivalent changes and modifications made to the above embodiments according to the technical essence of the present invention belong to the protection scope of the present invention.

Claims (2)

1. a kind of green synthesis method of bicyclic pyridine assimilation compound it is characterised in that with heterocyclic ketene semiamine and its derivant with Diethyl ethoxymethylenemalonate reacts through one pot of series process and is obtained, and its concrete synthesis step is: (1) is in reaction vessel In solvent-free, no under catalyst, by heterocyclic ketene semiamine and its derivant and diethyl ethoxymethylenemalonate mix and blend, In microwave or ultrasonic lower normal-temperature reaction；(2) tlc monitoring course of reaction, when point plate determines that reaction raw materials point disappears, stops anti- Should, through silica gel column chromatography, it is spin-dried for, recrystallization obtains bicyclic pyridine assimilation compound.

2. a kind of green synthesis method of bicyclic pyridine assimilation compound according to claim 1 was it is characterised in that prepared Key reaction equation solvent-free in journey, that no catalyst occurs is:

n= 1, 2, 3;

z= nh, o, s;

R can be h, alkyl or aromatic radical；

r₁For electron-withdrawing group, such as nitro, cyano group, ester group, halogen atom or fragrant ketone group etc..