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A kind of preparation method of 4-methylene quinazoline (thio) ketone compound

A technology for methylene quinazoline and ketone compounds, which is applied in the field of preparation of 4-methylene quinazoline compounds, can solve the problems of high dependence, multi-step synthesis of raw materials, low yield and the like, and achieves the Diverse structure, avoid heavy metal pollution, good yield effect

Active Publication Date: 2020-10-16
台州同旭生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The second type is the generation of quinazoline-2(1H)-thione compounds after reduction of specific substrates, such as 2-aminobenzonitrile (Arch.Pharm.1983,316:379-381) or 2-amino Benzamide (J.Pharm.Sci.1987,76,633-634) reacts with thiophosgene to prepare the target product ( Figure 10 ), but due to its low yield
[0015] Although the above methods can prepare quinazoline-2(1H)-(thio)ketone, there are some shortcomings, such as highly dependent on metal catalysts, raw materials need multi-step synthesis, etc.

Method used

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  • A kind of preparation method of 4-methylene quinazoline (thio) ketone compound
  • A kind of preparation method of 4-methylene quinazoline (thio) ketone compound
  • A kind of preparation method of 4-methylene quinazoline (thio) ketone compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0049] Embodiment (Ia~Il): the preparation of 4-methylene-quinazoline-2 (1H)-thione (Ia~Il)

[0050] A solution of 2-aminoacetophenone (10 mmol), phenylisothiocyanate (10 mmol) in acetonitrile (10 mL) was stirred and reacted at 85° C. for 90 minutes. TLC plate is carried out detection reaction, after the reaction is carried out completely, decompression distillation removes solvent, and carry out recrystallization with ethyl acetate and sherwood oil (2:1), obtain different 4-methylene-quinazoline-2 (1H) - Thione analog products, as shown in Table 1.

[0051] Table 1

[0052] Example serial number R 1

R 2

state Yield (%) Melting point (°C) Ia H Ph yellow powder 98％ 217～218℃ Ib H 2-CH 3 C 6 h 4

brown powder 58％ 214～215℃ IC H 3-OCH 3 C 6 h 4

yellow powder 41％ 221～225℃ ID H 4-OCH 3 C 6 h 4

White powder 53％ 212～214℃ Ie H 2-ClC 6 h 4

yellow powder 65％ 203～205℃ If ...

Embodiment IAa～I

[0089] Embodiment IAa~IAs: the preparation of 4-methylene-quinazolin-2 (1H)-ketone (IAa~IAs)

[0090] A solution of 2-aminoacetophenone (10 mmol), isocyanate (10 mmol), catalyst (10% mmol) in acetonitrile (10 mL) was stirred and reacted at 85° C. for 60 minutes. TLC plate is carried out detection reaction, after the reaction is carried out completely, decompression distillation removes solvent, and carry out recrystallization with ethyl acetate and sherwood oil (2:1), obtain different 4-methylene-quinazoline-2 (1H) - Ketone analog products, as shown in Table 2.

[0091] Table 2

[0092]

[0093]

[0094] The structural formula of IAa is:

[0095]

[0096] 1 H NMR (400MHz, Chloroform-d) δ8.18(s,1H),7.59–7.49(m,3H),7.47–7.40(m,1H),7.35–7.28(m,2H),7.24(dd,J =7.9,1.3Hz,1H),7.06–6.96(m,1H),6.72(dd,J=8.1,1.2Hz,1H),4.74(d,J=2.2Hz,1H),3.68(d,J= 2.2Hz,1H). 13 C NMR (101MHz, Chloroform-d) δ150.88, 143.31, 138.42, 135.16, 130.27, 129.94, 129.19, 128.34, 123.94, 122.73, 117.0...

Embodiment IBa～IB

[0151] Embodiment IBa~IBe: the preparation of 4-methylene-quinazolin-2 (1H)-ketone (IBa~IBe)

[0152] 2-Amino-5-chloro-acetophenone (10mmol), phenylisocyanate (IIIBa~IIIBe) (10mmol), sodium hydroxide (10%mmol) in acetonitrile solution (10mL) was stirred at 85°C for reaction 60 minutes. TLC plate is carried out detection reaction, after the reaction is carried out completely, decompression distillation removes solvent, and carry out recrystallization with ethyl acetate and sherwood oil (2:1), obtain different 4-methylene-quinazoline-2 (1H) - Keto analog products (Table 3).

[0153] table 3

[0154] Example serial number R 1

R 2

state Yield (%) Melting point (°C) IBa 5-Cl 2-F White powder 98％ 258.9～261.3℃ IBb 5-Cl 3-Cl White powder 80％ 245.6～247.2℃ IBC 5-Cl 3-CH 3

White powder 91％ 201.7～202.4℃ IB 5-Cl 2-CH 3

White powder 40％ 221.2～222.9℃ IBe 5-Cl CH 2 C 6 h 5

White powder 92％ 214....

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Abstract

The invention discloses a preparation method of 4-methylene quinazolinone (thione) derivatives. The preparation method comprises the following steps: dissolving 2-aminoacetophenone derivatives with different substituents and phenyl iso (thio) cyanate derivatives in an organic solvent, and carrying out multi-component reaction under the action of a catalyst (or without a catalyst), so as to preparethe 4-methylene quinazoline-2(1H)-one (thione) derivative (I) shown in the formula (I) by a one-pot method, wherein the yield of most products is more than 70%. Compared with the prior art, the catalyst (or no catalyst) used in the preparation method avoids the use of a metal catalyst from the source, and the derivatives have the characteristics of easily obtained raw materials, various structures, high atom economy, water and air resistance, simple and convenient operation, wide substrate applicability, environmental friendliness and the like, and have better application value and potentialeconomic and social benefits.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical and chemical intermediates, and in particular relates to a preparation method of 4-methylenequinazoline (thio) ketone compounds. Background technique [0002] The nitrogen-containing heterocyclic core structure plays a pivotal role in the core skeleton of drug molecules and natural products. Among them, the nitrogen-containing six-membered heterocyclic quinazolinone compounds play a more important role in the fields of medicine, chemical industry, and materials. important role. Among them, the multi-substituted quinazolinone (thio) ketone compound is an important class of heterocyclic compounds, and is an important structural skeleton of many biologically active compounds. It has a wide range of applications in the fields of biology and medicine. Quinazolinone and its derivatives are the earliest It is derived from higher plants, isolated from microorganisms and animals. Its m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/78C07D239/82C07D239/80
CPCC07D239/78C07D239/80C07D239/82
Inventor 马永敏闫辉辉
Owner 台州同旭生物科技有限公司