CN105384698B - Synthetic method for quinazolinone FPR2 formyl peptide receptor agonist - Google Patents

Abstract

The invention discloses a synthesis method of a quinazolinone FPR2 formyl peptide receptor agonist, which is specifically implemented according to the following steps: according to the ratio of the amount of substances of 1:1:1, isatoic anhydride and aromatic hydrazides are weighed compounds and aromatic aldehyde compounds as raw materials; after mixing the raw materials in a solvent, a one-pot synthesis reaction is carried out with nanometer metal oxides as a catalyst; the reactants after the reaction are separated and purified by column chromatography to prepare A quinazolinone FPR2 formyl peptide receptor agonist was obtained. The invention reduces the complexity of preparation by simplifying the preparation process, and has mild reaction conditions, cheap and easy-to-obtain raw materials, high product yield, non-toxic solvent in the preparation process, and good industrial application prospects.

Description

A kind of synthetic method of quinazolinone FPR2 formyl peptide receptor agonist

technical field

The invention belongs to the field of organic synthesis and relates to a synthesis method of a quinazolinone FPR2 formyl peptide receptor agonist.

Background technique

Quinazolinone compounds are an important nitrogen-containing heterocyclic compound. About 150 alkaloids isolated from natural products have quinazolinone ring skeletons, which exhibit good biological activities in antibacterial and anti-inflammatory. It also has good pharmacological activity in anti-hypertension, anti-tumor, and anti-HIV. The green and efficient synthesis of quinazolinone compounds with medicinal value has become a hot topic of widespread concern. Quin C1 is a non-peptide formyl peptide receptor agonist with quinazolinone as the backbone. Formyl peptide receptor agonists play a key role in the regulation of inflammatory responses and the defense of sensory cell dysfunction. Therefore, non-peptide small molecule agonists have become a better choice for clinical application because of their simple synthesis method and easy management. In 2004, Nanamori et al. screened Quin C1 as a non-peptide formyl peptide agonist from natural products and synthetic small molecules. In 2007, Zhou Caihong and others synthesized Quin C1 compounds with o-nitrobenzene methanesulfonyl chloride and aromatic hydrazide and studied their pharmacological activities, but the synthesis steps were complicated and the synthesis conditions were relatively harsh. The more conventional Quin C1 compounds are synthesized from anthranilyl hydrazide compounds and aromatic aldehydes. The preparation of anthranilyl hydrazide compounds uses acetic acid as a solvent. This method is relatively harsh, and the reaction solvent with aromatic aldehydes is ethanol iso Propanol or DMF, etc., do not conform to the concept of green chemistry.

Contents of the invention

The purpose of the present invention is to provide a synthesis method of quinazolinone FPR2 formyl peptide receptor agonist, which solves the problem of complicated preparation steps in the existing preparation method.

The technical scheme of the present invention is, a kind of synthetic method of quinazolinone FPR2 formyl peptide receptor agonist, specifically implement according to the following steps:

Step 1. Weighing isatoic anhydride, aromatic hydrazide compounds and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances of 1:1:1;

Step 2. After mixing the raw materials weighed in step 1 in a solvent, the nanometer metal oxide is used as a catalyst to carry out a one-pot synthesis reaction;

Step 3, using column chromatography to separate and purify the reactant after the reaction in step 2 to obtain a quinazolinone FPR2 formyl peptide receptor agonist;

The structural formula of aromatic hydrazide compounds is:

The structural formula of aromatic aldehydes is:

R2 ^- CHO;

The structural formula of the quinazolinone FPR2 formyl peptide receptor agonist is:

_{In the structural formulas of aromatic hydrazide compounds, aromatic aldehyde compounds, and quinazolinone FPR2 formyl peptide receptor agonists, R and R are each independently selected from H, C 1 -C 6} ^{alkyl ,} _with Aromatic groups with different substituents; aromatic groups with different substituents include unsubstituted aryl groups, unsubstituted heteroaryl groups, aryl groups with substituents or heteroaryl groups with substituents, the substituents are independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy.

The present invention is also characterized in that,

Aryl is phenyl, naphthyl.

Heteroaryl is furyl, pyridyl, piperidinyl, pyrrolyl, thienyl, pyrazolyl, thiazolyl or piperazinyl.

C ₁ -C ₆ alkyl refers to straight chain or branched chain alkyl with 1-6 carbon atoms, including C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ Alkyl, C ₆ alkyl.

A C ₁ -C ₆ alkoxy group refers to a group in which a C ₁ -C ₆ alkyl group is connected to an oxygen atom.

X is halogen.

Y is CH or N.

In step 2, the solvent is ethanol, and the ratio of the amount of catalyst added to the amount of isatoic anhydride is 1:0.02-0.5; the reaction temperature of the one-pot method is 60-150°C, and the reaction time is 6-30h.

The catalyst is one or more combinations of nanometer copper oxide, nanometer cerium oxide, nanometer ferric oxide and nanometer titanium oxide.

The beneficial effect of the present invention is that, a method for synthesizing a quinazolinone-type FPR2 formyl peptide receptor agonist reduces the complexity of the preparation by simplifying the preparation process, and the reaction conditions of the present invention are mild, and the raw materials are cheap and easy to obtain. The yield of the product is high, the solvent in the preparation process is non-toxic, and has good industrial application prospects.

detailed description

The present invention will be described in detail below in conjunction with examples.

A kind of synthetic method of quinazolinone FPR2 formyl peptide receptor agonist of the present invention, specifically implement according to the following steps: specifically implement according to the following steps:

Step 1. Weighing isatoic anhydride, aromatic hydrazide compounds and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances of 1:1:1;

Step 2, after mixing the raw materials weighed in step 1 in ethanol, one or more mixtures of nano-copper oxide, nano-cerium oxide, nano-ferric oxide, and nano-titanium oxide are used as catalysts, and the amount of catalyst added is the same as The ratio of the amount of isatoic anhydride is 1:0.02-0.5, and the one-pot synthesis reaction is carried out, the reaction temperature is 60-150°C, and the reaction time is 6-30h;

Step 3. Using column chromatography to separate and purify the reactant after the reaction in step 2 to obtain a quinazolinone FPR2 formyl peptide receptor agonist.

Its reaction formula is as follows:

Wherein, the structural formula of aromatic hydrazide compound is:

The structural formula of aromatic aldehydes is:

R2 ^- CHO;

The structural formula of the quinazolinone FPR2 formyl peptide receptor agonist is:

_{In the structural formulas of aromatic hydrazide compounds, aromatic aldehyde compounds, and quinazolinone FPR2 formyl peptide receptor agonists, R and R are each independently selected from H, C 1 -C 6} ^{alkyl ,} _with Aromatic groups with different substituents; aromatic groups with different substituents include unsubstituted aryl groups, unsubstituted heteroaryl groups, aryl groups with substituents or heteroaryl groups with substituents, the substituents are independently selected from C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; aryl is phenyl, naphthyl. Heteroaryl is furyl, pyridyl, piperidinyl, pyrrolyl, thienyl, pyrazolyl, thiazolyl or piperazinyl. C ₁ -C ₆ alkyl refers to straight chain or branched chain alkyl with 1-6 carbon atoms, including C ₁ alkyl, C ₂ alkyl, C ₃ alkyl, C ₄ alkyl, C ₅ Alkyl, C ₆ alkyl. A C ₁ -C ₆ alkoxy group refers to a group in which a C ₁ -C ₆ alkyl group is connected to an oxygen atom. X is halogen. Y is CH or N.

Example 1

Weigh isatoic anhydride, aromatic hydrazide compounds, and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances 1:1:1; mix the weighed raw materials in ethanol, use nano-copper oxide as a catalyst, and add catalyst The ratio of the amount of the isatoic anhydride to the amount of the substance of isatoic anhydride is 1:0.02, and a one-pot synthesis reaction is carried out, the reaction temperature is 60 ° C, and the reaction time is 6 hours; the reactant after the reaction is separated and purified by column chromatography. A quinazolinone FPR2 formyl peptide receptor agonist is prepared.

Example 2

Weigh isatoic anhydride, aromatic hydrazide compounds, and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances 1:1:1; mix the weighed raw materials in ethanol, use nano-cerium oxide as a catalyst, and add catalyst The ratio of the amount to the amount of isatoic anhydride is 1:0.05, and the one-pot synthesis reaction is carried out, the reaction temperature is 70 ° C, and the reaction time is 8 hours; the reactant after the reaction is separated and purified by column chromatography. A quinazolinone FPR2 formyl peptide receptor agonist is prepared.

Example 3

Weigh isatoic anhydride, aromatic hydrazide compounds, and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances 1:1:1; mix the weighed raw materials in ethanol, and use nanometer iron tetroxide as a catalyst, The ratio of the amount of catalyst added to the amount of isatoic anhydride is 1:0.08, a one-pot synthesis reaction is carried out, the reaction temperature is 90 ° C, and the reaction time is 10 h; the reactants after the reaction are separated by column chromatography Purify to obtain quinazolinone FPR2 formyl peptide receptor agonist.

Example 4

Weigh isatoic anhydride, aromatic hydrazide compounds, and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances 1:1:1; mix the weighed raw materials in ethanol, use nano-titanium oxide as a catalyst, and add catalyst The ratio of the amount to the amount of isatoic anhydride is 1:0.11, and a one-pot synthesis reaction is carried out, the reaction temperature is 100 ° C, and the reaction time is 12 hours; the reactant after the reaction is separated and purified by column chromatography. A quinazolinone FPR2 formyl peptide receptor agonist is prepared.

Example 5

Weigh isatoic anhydride, aromatic hydrazide compounds and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances 1:1:1; after mixing the weighed raw materials in ethanol, The mixture is used as a catalyst, the ratio of the amount of catalyst added to the amount of isatoic anhydride is 1:0.2, and a one-pot synthesis reaction is carried out, the reaction temperature is 120°C, and the reaction time is 15h; the reactants after the reaction are analyzed by column chromatography The reactant is separated and purified to obtain a quinazolinone FPR2 formyl peptide receptor agonist.

Example 6

Weigh isatoic anhydride, aromatic hydrazide compounds and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances 1:1:1; after mixing the weighed raw materials in ethanol, use nano-ferric oxide, nano-oxidized Titanium is used as a catalyst, the ratio of the amount of catalyst added to the amount of isatoic anhydride is 1:0.35, a one-pot synthesis reaction is carried out, the reaction temperature is 140 ° C, and the reaction time is 25 hours; the reactant after the reaction is analyzed by column chromatography The reactant is separated and purified to obtain a quinazolinone FPR2 formyl peptide receptor agonist.

Example 7

Weigh isatoic anhydride, aromatic hydrazide compounds and aromatic aldehyde compounds as raw materials according to the ratio of the amount of substances 1:1:1; after mixing the weighed raw materials in ethanol, use nano-copper oxide, nano-cerium oxide, Nano-iron ferric oxide is used as a catalyst, the ratio of the amount of catalyst added to the amount of isatoic anhydride is 1:0.5, and a one-pot synthesis reaction is carried out, the reaction temperature is 150 ° C, and the reaction time is 30h; the reactant after the reaction, The reactant is separated and purified by column chromatography to obtain a quinazolinone FPR2 formyl peptide receptor agonist.

Claims (6)

1. a kind of synthetic method of quinazolinones FPR2 formyl peptide receptor agonist is it is characterised in that specifically according to following step Rapid enforcement：

Step 1, according to material amount ratio 1：1：1 weighs isatoic anhydride, fragrant hydrazide kind compound and aromatic aldehyde compound For raw material；

After step 2, the raw material weighing step 1 mix in a solvent, with nano-metal-oxide as catalyst, carry out one kettle way Synthetic reaction；Described catalyst be nano cupric oxide, nano-cerium oxide, nano ferriferrous oxide, one kind of nano-titanium oxide or Multiple combinations；The reaction temperature of one kettle way is 60-150 DEG C, response time 6-30h；

Step 3, step 2 is reacted the reactant of end, using column chromatography to reactants separate purification, prepared quinazolinones FPR2 formyl peptide receptor agonist；

Described fragrance hydrazide kind compound structural formula be：

Wherein, Y is CH or N；

The structural formula of described aromatic aldehyde compound is：

R²-CHO；

The structural formula of described quinazolinones FPR2 formyl peptide receptor agonist is：

Wherein, X is halogen；

Described fragrance hydrazide kind compound, aromatic aldehyde compound, the structure of quinazolinones FPR2 formyl peptide receptor agonist In formula, R¹And R²It is each independently selected from H, C₁-C₆Alkyl, the aromatic group with different substituents；Described replace with different The aromatic group of base includes unsubstituting aromatic yl, unsubstituted heteroaryl, the aryl with substituent group or the heteroaryl with substituent group； Described substituent group is independently selected from C₁-C₆Alkyl, C₁-C₆Alkoxyl.

2. the synthetic method of a kind of quinazolinones FPR2 formyl peptide receptor agonist according to claim 1, its feature It is, described aryl is phenyl, naphthyl.

3. the synthetic method of a kind of quinazolinones FPR2 formyl peptide receptor agonist according to claim 2, its feature It is, described heteroaryl is furyl, pyridine radicals, piperidyl, pyrrole radicals, thienyl, pyrazolyl, thiazolyl or piperazinyl.

4. the synthesis side of a kind of quinazolinones FPR2 formyl peptide receptor agonist according to any one of claim 1-3 Method is it is characterised in that described C₁-C₆Alkyl, refers to the straight or branched alkyl with 1-6 carbon atom, including C₁Alkane Base, C₂Alkyl, C₃Alkyl, C₄Alkyl, C₅Alkyl, C₆Alkyl.

5. the synthesis side of a kind of quinazolinones FPR2 formyl peptide receptor agonist according to any one of claim 1-3 Method is it is characterised in that described C₁-C₆Alkoxyl, refers to C₁-C₆Alkyl be connected with oxygen atom after group.

6. the synthesis side of a kind of quinazolinones FPR2 formyl peptide receptor agonist according to any one of claim 1-3 It is characterised in that in described step 2, solvent is ethanol, catalyst loading is 1 with the ratio of the amount of the material of isatoic anhydride to method: 0.02-0.5.