CN1386737A - Antifibrosis pyridinone medicine and its prepaing process - Google Patents

Abstract

An anti-fibrosis pyridone drug, characterized in that it is a 1-multi-substituted phenyl-5-methyl-2(IH) pyridone compound with formula (I), the substituent R is a halogen element, and the saturated direct Chain hydrocarbon group, oxo saturated straight chain hydrocarbon group, halogenated saturated straight chain hydrocarbon group, n is 1~2, and the position of R on the benzene ring has the modes of ortho, meta and para. The process method adopts 2-amino-5-picoline as an initial raw material, and in a polar solvent with strong acid, sodium nitrite is used as a diazotization agent to carry out diazotization and other reactions to produce formula (I) The pyridone compound, the strong acid is an inorganic acid or an organic acid such as hydrochloric acid, sulfuric acid, glacial acetic acid, and the polar solvent is glacial acetic acid or water. The pyridone drug of the present invention has a strong anti-fibrosis effect and wide organ applicability; the process method of the present invention adopts readily available and molecularly stable starting materials in the market, the reaction process is simple and easy to control, and is suitable for industrial-scale production.

Description

Anti-fibrosis pyridone drug and its production process

Technical field: The present invention relates to chemically synthesized drugs for the treatment of fibrotic diseases and its production process, especially to the improvement of pyridone-based synthetic drugs and synthetic processes for the treatment of fibrotic diseases.

Background technology: fibrotic diseases such as renal fibrosis, liver cirrhosis, myocardial fibrosis, etc. are a class of important diseases that seriously endanger human life and health. With global industrialization and changes in people's life and diet, the incidence of fibrotic diseases is increasing. Correspondingly, many scholars at home and abroad have conducted a large number of researches on anti-fibrosis drugs from different fields such as chemical drugs, natural drugs, biological agents, and gene therapy. So far, pyridones have been found The compounds are a class of effective anti-fibrosis compounds;

U.S. Patent (6090822), (5789426), International Patent (0044381) and European Patent (1138329A2) have announced some pyridone compounds for the treatment of organ fibrosis respectively, and its structure is the general formula expression of available formula (0) 1-Monosubstituted phenyl-5-methyl-2(IH)pyridinone:

Among them, the number of substituent R is 1, which represents nitro, chlorine atom, and alkyl; the efficacy of such pyridone anti-fibrotic drugs is relatively weak, and the range of action and indications are relatively narrow, and they can only be effective for renal fibrosis. It has a strong therapeutic effect, but has little effect on fibrotic diseases of other organs, and cannot adapt to the requirements of medical clinics.

In addition, U.S. Patent (No. 5789426) discloses a kind of processing method, is to be raw material with the 5-methyl-2 (IH) pyridone of (IV) formula, reacts with the monosubstituent-iodobenzene of (V) formula And generate the 1-benzene series substituting group-5-methyl-2 (1H) pyridones medicine of (0) formula, reaction process is as follows:

U.S. Patent (No. 6090833) improves the reaction conditions of the above-mentioned process, and discloses different preparation methods of the compound of (IV) formula; but its shortcoming is: the reaction starting material is difficult to obtain on the Chinese market, and the price is expensive. And the structure is unstable, it is difficult to popularize.

Chinese patent (1086514A) discloses a method for preparing formula (IV), which is 1-cyano-1-butene of (VI) formula and 1,1-bisdimethylamine-formazine of (VII) formula Ether is used as starting material, reacts to generate the intermediate of 1-dimethylamine-2-methyl-4-cyano-1,3-butadiene of (VIII) formula, and then cyclizes under strong acid conditions, Generate (IV ') formula and the desired compound of (IV) formula, reaction process is as follows:

Although the above-mentioned method has been further improved to some previous methods, it still has the disadvantages that the compound of formula (VI) is unstable and prone to polymerization, and the compound of formula (VII) is not easy to obtain.

Summary of the invention: Aiming at the above-mentioned shortcomings of the prior art, one of the technical solutions of the present invention is to provide an anti-fibrosis pyridone drug with strong anti-fibrosis effect and wide organ applicability; the technical solution of the present invention The second scheme is to provide a process method for producing anti-fibrosis pyridone drugs by using readily available and molecularly stable starting materials on the market.

For this reason, the technical solution of the present invention is a kind of anti-fibrosis pyridone medicine, it is characterized in that: it has 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone compound as formula (I) .

The substituent group R represents a halogen element: F, Cl, Br, I, a saturated straight chain hydrocarbon group, an oxo saturated straight chain hydrocarbon group, a halogenated saturated straight chain hydrocarbon group.

The value of n is 1-2; the position of the substituent group R on the benzene ring has the modes of ortho, meta, and para.

Described processing method is to adopt the 2-amino-5-picoline of (II) formula as initial raw material,

In a polar solvent with a strong acid, sodium nitrite is used as a diazotizing agent to carry out reactions such as diazotization to finally produce a pyridone compound of formula (I).

Described strong acid is inorganic acid or organic acid such as hydrochloric acid, sulfuric acid, glacial acetic acid, wherein preferred sulfuric acid, glacial acetic acid, particularly preferred sulfuric acid; described polar solvent is glacial acetic acid or water, wherein preferred water.

Wherein reaction step and corresponding intermediate product are successively:

A, diazotization reaction generates the 2-diazoamino-5-picoline sulfate of (IX) formula;

B, the 2-diazoamino-5-picoline sulfate of (IX) formula generates the 2-hydroxyl-5-picoline of (IV') formula through hydrolysis reaction;

The 2-hydroxyl-5-picoline of c, (IV ') formula generates the 5-methyl-2 (IH) pyridone of (IV) formula through equilibrium reaction as follows;

D, in the 5-methyl-2 (IH) pyridone solution of (IV) formula, add the multi-substituting group-iodobenzene of (V) formula and carry out nucleophilic substitution reaction,

The resulting product is the desired 1-polysubstituted phenyl-5-methyl-2(IH)pyridone drug of formula (I).

The temperature range of the diazotization reaction is controlled at -20°C to 30°C, preferably -10°C to 10°C, particularly preferably -5°C to 5°C; the temperature range of the hydrolysis and equilibrium reaction is controlled at 50°C to 150°C °C, preferably 90 °C to 100 °C, particularly preferably 100 °C; at the end of the hydrolysis and equilibrium reaction, use anhydrous _Na2CO3 to neutralize the reaction solution and then use extraction, adsorption or cold analysis to obtain the 5-formazan _of formula (III) Crystallization of base-2(IH)pyridone.

The medicine of the present invention and its production process have the following advantages:

Medicine of the present invention is the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), owing to adopting multiple/multiple suitable groups to substitute on benzene ring, make this series The drug has wider adaptability and better curative effect; the production process disclosed by the invention has a stable molecular structure of the starting material, convenient storage and transportation, is easy to obtain in the Chinese market, and the reaction process is simple and easy to control, and is more suitable for industrial scale production.

Detailed ways:

Example 1,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=1, R=Br, such as:

1-(2-Bromophenyl)-5-methyl-2-(IH)pyridinone,

1-(3-Bromophenyl)-5-methyl-2-(IH)pyridone,

1-(4-bromophenyl)-5-methyl-2-(IH)pyridone,

Example 2,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=2, R=Br, Cl, such as:

1-(2,3-Dibromophenyl)-5-methyl-2-(IH)pyridone,

1-(2,4-Dibromophenyl)-5-methyl-2-(IH)pyridone,

1-(2,5-Dibromophenyl)-5-methyl-2-(IH)pyridinone,

1-(2,6-Dibromophenyl)-5-methyl-2-(IH)pyridone,

1-(3,4-Dibromophenyl)-5-methyl-2-(IH)pyridone,

1-(3,5-Dibromophenyl)-5-methyl-2-(IH)pyridone,

1-(2,3-Dibromophenyl)-5-methyl-2-(IH)pyridone,

1-(2,3-dichlorophenyl)-5-methyl-2-(IH)pyridone,

1-(2,4-dichlorophenyl)-5-methyl-2-(IH)pyridone,

1-(2,5-dichlorophenyl)-5-methyl-2-(IH)pyridinone,

1-(2,6-dichlorophenyl)-5-methyl-2-(IH)pyridone,

1-(3,5-dichlorophenyl)-5-methyl-2-(IH)pyridinone,

Example 3,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=1, R=trifluoromethyl, such as:

1-(2-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

1-(4-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

Example 4,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=2, R=trifluoromethyl, such as:

1-(2,3-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,4-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,5-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,6-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

1-(3,4-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,5-trifluoromethylphenyl)-5-methyl-2-(IH)pyridone,

Example 5,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=1, R=methyl, such as:

1-(2-methylphenyl)-5-methyl-2-(IH)pyridone,

1-(3-methylphenyl)-5-methyl-2-(IH)pyridinone,

Example 6,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=2, R=methyl, such as:

1-(2,3-Dimethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,4-Dimethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,5-Dimethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,6-Dimethylphenyl)-5-methyl-2-(IH)pyridone,

1-(3,4-Dimethylphenyl)-5-methyl-2-(IH)pyridone,

1-(2,5-Dimethylphenyl)-5-methyl-2-(IH)pyridone,

Example 7,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=1, R=methoxy group, such as:

1-(2-methoxyphenyl)-5-methyl-2-(IH)pyridinone,

1-(3-methoxyphenyl)-5-methyl-2-(IH)pyridinone,

Example 8,

In the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone of formula (I), n=2, R=methoxy group, such as:

1-(2,3-dimethoxyphenyl)-5-methyl-2-(IH)pyridone,

1-(2,4-dimethoxyphenyl)-5-methyl-2-(IH)pyridone,

1-(2,5-dimethoxyphenyl)-5-methyl-2-(IH)pyridone,

1-(2,6-dimethoxyphenyl)-5-methyl-2-(IH)pyridone,

1-(3,4-dimethoxyphenyl)-5-methyl-2-(IH)pyridone,

1-(3,5-dimethoxyphenyl)-5-methyl-2-(IH)pyridone,

Example 9,

Take 10g (0.1mol) of 2-amino-5-picoline of formula (II), add 17ml of H ₂ O and 17ml of concentrated H ₂ SO ₄ into the solution, cool to below 10°C with ice-salt bath, stir dropwise Add a solution composed of 17.2g (0.25mol/l) NaNO ₂ and 30ml H ₂ O, control the reaction temperature at 0°C to 5°C, after the addition is complete, continue the reaction until complete, add 80ml of water, reflux for about 15min, cool down; Add anhydrous Na ₂ CO ₃ to make the reaction solution neutral, evaporate the solution to dryness, extract the residue with ethanol reflux, decolorize activated carbon and evaporate the ethanol to obtain the 5-methyl-2(IH)pyridone solution of formula (IV). Add the multi-substituting group-iodobenzene of (V) formula to carry out nucleophilic substitution reaction, generate the 1-multi-substituted phenyl-5-methyl-2 (IH) pyridone medicine of desired product namely formula (I).

Claims (7)

1, a kind of anti-fibrosis pyridone medicine is characterized in that: it has suc as formula the polysubstituted phenyl of the 1-of (I)-5-methyl-2 (IH) pyridinone compounds.

2, anti-fibrosis pyridone medicine as claimed in claim 1, it is characterized in that: described substituent group R is represented haloid element: F, Cl, Br, I, saturated straight chain alkyl, oxo saturated straight chain alkyl, halo saturated straight chain alkyl.

3, anti-fibrosis pyridone medicine as claimed in claim 1 or 2, it is characterized in that: described n value is 1～2; The position of described substituent group R on phenyl ring has modes such as ortho position, a position, contraposition.

4, a kind of processing method of producing suc as formula the anti-fibrosis pyridone medicine of (I) is characterized in that: described processing method is to adopt the 2-amido-5-picoline of (II) formula as initial feed,

In the polar solvent that adds strong acid, carry out reactions such as diazotization as diazotization agent with Sodium Nitrite, final production obtains the pyridinone compounds of formula (I).

5, the processing method of production anti-fibrosis pyridone medicine material according to claim 4 is characterized in that: described strong acid is mineral acid or organic acid example hydrochloric acid, sulfuric acid, Glacial acetic acid, wherein preferably sulfuric acid, Glacial acetic acid, special preferably sulfuric acid; Described polar solvent is Glacial acetic acid or water, wherein preferably water.

6,, it is characterized in that wherein reactions steps and corresponding intermediate product are successively according to the processing method of claim 4 or 5 described production anti-fibrosis pyridone medicine materials:

A, diazotization reaction generate the 2-diazonium amido-5-picoline formula vitriol of (III) formula;

The 2-diazonium amido of b, (III) formula-5-picoline formula vitriol generates the 2-hydroxy-5-methyl yl pyridines of (IV ') formula through hydrolysis reaction;

The 2-hydroxy-5-methyl yl pyridines of c, (IV ') formula is as follows through 5-methyl-2 (IH) pyridone that balanced reaction generates (IV) formula;

Multi-substituent-the iodobenzene that adds (V) formula in 5-methyl-2 (IH) the pyridone solution of d, (IV) formula carries out nucleophilic substitution reaction, (wherein n is 1～2)

Generating product is 1-substituted-phenyl-5-methyl-2 (IH) the pyridone medicine of required formula (I).

7, the processing method of production anti-fibrosis pyridone medicine material according to claim 6 is characterized in that: described diazotization reaction temperature range is controlled at-20 ℃～30 ℃, and preferred-10 ℃～10 ℃, preferred-5 ℃～5 ℃ especially; Described hydrolysis and balanced reaction temp scope are controlled at 50 ℃～150 ℃, and preferred 90 ℃～100 ℃, preferred especially 100 ℃; The terminal point of hydrolysis and balanced reaction adopts anhydrous Na ₂CO ₃Adopt extraction, absorption or cold analysis behind the neutralization reaction liquid, obtain 5-methyl-2 (IH) the pyridone crystallization of (III) formula.