CN1218942C

CN1218942C - Anti-fibrosis pyridone compound and its production process

Info

Publication number: CN1218942C
Application number: CN 02114190
Authority: CN
Inventors: 陶立坚; 胡高云; 谭桂山
Original assignee: XIANGYA MEDICAL COLLEGE ZHONGNAN UNIV
Current assignee: Haikou Pharmaceutical Factory Co Ltd
Priority date: 2002-06-11
Filing date: 2002-06-11
Publication date: 2005-09-14
Anticipated expiration: 2022-06-11
Also published as: CN1386737A

Abstract

The present invention relates to an anti-fibrosis pyridone compound, which is 1-(substituent phenyl)-5-methyl-2-(H)pyridone with the structure of formula (I), wherein when n=1 When n=2, R=F, Cl, Br, I, saturated linear hydrocarbon group, oxo saturated linear hydrocarbon group, halogenated saturated linear hydrocarbon group. The compound can use 2-amino-5-picoline as an initial raw material, and in a polar solvent added with a strong acid, a diazotizing agent is subjected to diazotization and other reactions to finally produce a pyridone compound of formula (I). Described strong acid is mineral acid or organic acid such as hydrochloric acid, sulfuric acid, glacial acetic acid. The pyridone compound of the invention has strong anti-fibrosis effect and wide organ adaptability. The synthesis method adopts easily available and 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 pyridinone compounds and producing and manufacturing technique thereof

Technical field

The present invention relates to treat the chemosynthesis compound and the producing and manufacturing technique thereof of fibrotic disease, the synthetic and synthetic process that relates in particular to the pyridine compounds of treatment fibrotic disease improves.

Technical background

Fibrotic disease such as renal fibrosis, liver cirrhosis, myocardial fibrosis etc. are the important diseases of a class serious harm human life health, along with global industrialization and people's life, the change of diet style, the sickness rate of fibrotic disease increases just gradually, correspondingly, domestic and international many scholars have carried out the research of a large amount of anti-fibrosis compounds at the fibrosis link of falling ill from different field such as chemical compound, natural compounds, biotechnological formulation, gene therapies.Up to the present, found that pyridine compounds is the effective anti-fibrosis compound of a class.

U.S. Pat 3839346, US4052509A discloses pyridine compounds, and its structure is 1-monosubstituted phenyl-5-methyl-2 (1H) pyridone that the general formula of available formula (O) is represented.

Wherein, the substituent R number is 0 or 1, and the substituent kind of R is represented nitro, chlorine atom, alkyl, methoxyl group; This type of pyridone have anti-inflammatory, analgesic, reduce serum uric acid level, pain relieving etc.

In addition, United States Patent (USP) (US3839346) discloses a kind of processing method, be that 5-methyl-2 (1H) pyridone with (IV) formula is a raw material, single substituting group iodobenzene with (V) formula, react and generate 1-benzene series substituting group-5-methyl-2 (1H) pyridine compounds of (O) formula, reaction process is as follows:

The method that Chinese patent (1086514A) discloses a kind of preparation formula (IV) is with 1-itrile group-1-butylene of (IV) formula and 1 of (VII) formula, the two dimethyl amine methyl ethers of 1-are as starting raw material, reaction generates the 1-dimethyl amine-2-methyl-4-itrile group-1 of (VIII) formula, the intermediate of 3-divinyl, under strong acid condition, carry out cyclisation again, (IV ') formula of generation reaches (IV) required compound of formula, and reaction process is as follows:

Though aforesaid method had been done further improvement again to former certain methods, but still have the compound instability of (VI) formula, polymerization easily takes place, (VII) compound of formula is difficult for the shortcoming that obtains.

On the other hand, ORGANIC SYNTHESES Vol.78,51 disclose the method for preparing compound (IV) from compound (II)

Summary of the invention

At the above-mentioned shortcoming of prior art, one of technical solution of the present invention is to provide a class anti-fibrosis effect strong, and has the anti-fibrosis pyridinone compounds of organ suitability widely; Two of technical solution of the present invention provides a kind of the employing and is easy to get on the market and processing method that starting raw material that molecule is stable is produced the anti-fibrosis pyridinone compounds.

Anti-fibrosis pyridinone compounds provided by the invention has the molecular structure suc as formula (I).

When n=1, described substituent R is represented F, Br, I.

When n=2, described substituent R is represented F, Cl, Br, I, saturated straight chain alkyl, oxo saturated straight chain alkyl, halo saturated straight chain alkyl.

The position of described substituent group R on phenyl ring has modes such as ortho position, a position, contraposition.

Described processing method adopts the 2-amino-5-picoline of (II) formula as initial feed.

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

Described strong acid is mineral acid or organic acid example hydrochloric acid, sulfuric acid, Glacial acetic acid, wherein preferential sulfuric acid; Described diazotization agent is nitrite, diazoalkane such as Sodium Nitrite, diazoalkane, wherein preferential Sodium Nitrite, and described polar solvent is Glacial acetic acid or water, wherein preferential water.

Reactions steps wherein and corresponding intermediate product are successively:

A. diazotization reaction generates the 2-diazo-5-picoline vitriol of (IX) formula.

B. the 2-diazo of (IX) formula-5-picoline vitriol generates the 2-hydroxy-5-methyl yl pyridines of (IV ') formula through hydrolysis reaction.

C. the 2-hydroxy-5-methyl yl pyridines of (IV ') formula is as follows through 5-methyl-2 (1H) pyridone that the tautomerism reaction generates (IV) formula:

D. the replacement iodobenzene that adds (V) formula in 5-methyl-2 (1H) the pyridone solution of (IV) formula carries out nucleophilic substitution reaction (Ullmann reaction).

Generating product is 1-substituted-phenyl-5-methyl-2 (1H) pyridinone compounds of required formula (I).

Described diazotization reaction temperature range is controlled at-20 ℃～30 ℃, preferential-10 ℃～10 ℃; Described hydrolysis and tautomerism temperature are controlled at 50 ℃～150 ℃, preferential 90 ℃～100 ℃; The terminal point of hydrolysis and tautomerism reaction adopts alkali such as Na ₂CO ₃Adopt extraction, absorption or cold analysis behind the neutralization reaction liquid, obtain 5-methyl-2 (1H) the pyridone crystallization of (III) formula.

Compound provided by the invention has the effect of anti-fibrosis.

Compound provided by the invention and producing and manufacturing technique have following advantage:

Compound of the present invention is 1-substituted-phenyl-5-methyl-2 (1H) pyridone of formula (I), owing to adopted multiple/a plurality of suitable groups on phenyl ring, to replace, make this series compound have wider adaptability, better therapeutic, producing and manufacturing technique disclosed by the invention, starting raw material molecular structure stabilized, the storage convenient transportation, be easy to get on Chinese market, reaction process is simple and easy to control, is more suitable in plant-scale production.

Specific embodiment

Embodiment 1,

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

1-(2-bromophenyl)-5-methyl-2-(1H) pyridone;

1-(3-bromophenyl)-5-methyl-2-(1H) pyridone;

1-(4-bromophenyl)-5-methyl-2-(1H) pyridone.

Embodiment 2,

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

1-(2, the 3-dibromo phenyl)-5-methyl-2-(1H) pyridone

1-(2, the 4-dibromo phenyl)-5-methyl-2-(1H) pyridone

1-(2, the 5-dibromo phenyl)-5-methyl-2-(1H) pyridone

1-(2, the 6-dibromo phenyl)-5-methyl-2-(1H) pyridone

1-(3, the 4-dibromo phenyl)-5-methyl-2-(1H) pyridone

1-(3, the 5-dibromo phenyl)-5-methyl-2-(1H) pyridone

1-(2, the 3-dichlorophenyl)-5-methyl-2-(1H) pyridone

1-(2,4 dichloro benzene base)-5-methyl-2-(1H) pyridone

1-(2, the 5-dichlorophenyl)-5-methyl-2-(1H) pyridone

1-(2, the 6-dichlorophenyl)-5-methyl-2-(1H) pyridone

1-(3, the 5-dichlorophenyl)-5-methyl-2-(1H) pyridone

Embodiment 3,

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

1-(2-trifluoromethyl)-5-methyl-2-(1H) pyridone

1-(4-trifluoromethyl)-5-methyl-2-(1H) pyridone

Embodiment 4,

1-(2, the 3-trifluoromethyl)-5-methyl-2-(1H) pyridone

1-(2, the 4-trifluoromethyl)-5-methyl-2-(1H) pyridone

1-(2, the 5-trifluoromethyl)-5-methyl-2-(1H) pyridone

1-(2, the 6-trifluoromethyl)-5-methyl-2-(1H) pyridone

1-(3, the 4-trifluoromethyl)-5-methyl-2-(1H) pyridone

1-(2, the 5-trifluoromethyl)-5-methyl-2-(1H) pyridone

Embodiment 5,

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

1-(2-aminomethyl phenyl)-5-methyl-2-(1H) pyridone

1-(3-aminomethyl phenyl)-5-methyl-2-(1H) pyridone

Embodiment 6,

1-(2, the 3-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone

1-(2, the 4-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone

1-(2, the 5-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone

1-(2, the 6-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone

1-(3, the 4-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone

1-(2, the 5-3,5-dimethylphenyl)-5-methyl-2-(1H) pyridone

Embodiment 7,

In the 1-substituted-phenyl of formula (I)-5-methyl-2 (1H) pyridone, n=1, the R=methoxyl group, as

1-(2-p-methoxy-phenyl)-5-methyl-2-(1H) pyridone

1-(3-p-methoxy-phenyl)-5-methyl-2-(1H) pyridone

Embodiment 8,

In the 1-substituted-phenyl of formula (I)-5-methyl-2 (1H) pyridone, n=2, the R=methoxyl group, as

1-(2, the 3-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone

1-(2, the 4-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone

1-(2, the 5-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone

1-(2, the 6-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone

1-(3, the 4-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone

1-(3, the 5-Dimethoxyphenyl)-5-methyl-2-(1H) pyridone

Embodiment 9,

Get (II) 2-amino-5-picoline of formula of 10g (0.1mol), add 17ml H ₂The dense H of O and 17ml ₂SO ₄The solution of forming is cooled to below 10 ℃ agitation and dropping 17.2g (0.25mol/l) NaNO with the cryosel bath ₂With 30mlH ₂O mixes the solution of forming, and control reaction temperature is at 0 ℃--and 5 ℃, finish, continue reaction to fully, add 80ml water, about 15min that refluxes, cooling; Stir and add anhydrous Na down ₂CO ₃Make reaction solution present neutrality, evaporate to dryness solution, the residue alcohol reflux, activated carbon decolorizing boils off 5-methyl-2 (1H) the pyridone solution that ethanol obtains (IV) formula, substituting group-the iodobenzene that adds (V) formula in the solution carries out nucleophilic substitution reaction, and generating desired product is 1-multi-substituent-5-methyl-2 (1H) pyridinone compounds of formula (I).

Claims

1. anti-fibrosis pyridone compound, characterized in that it has a structure such as formula (I);

Wherein when n=1, R=F, Br, I;

When n=2, R=F, Cl, Br, I, saturated straight-chain hydrocarbon group, oxo saturated straight-chain hydrocarbon group, halogenated saturated straight-chain hydrocarbon group; the position of the R substituent on the benzene ring has an ortho position and a meta position or counterpoint.

2. A method for producing the anti-fibrosis pyridone compound according to claim 1, characterized in that it consists of the following steps:

(1) adopting 2-amino-5-picoline of formula (II) as initial raw material; In sulfuric acid, with sodium nitrite as diazotization agent, the compound of formula (II) is carried out diazotization reaction;

2-diazo-5-picoline sulfate of formula (III) is obtained:

(2) 2-diazo-5-picoline sulfate of (III) formula generates 2-hydroxyl-5-picoline of formula (IV') through hydrolysis;

(3) 2-hydroxyl-5-picoline of (IV') formula generates 5-methyl-2 (1H) pyridone of (IV) formula through tautomerization as follows:

(4) Add iodobenzene of (V) formula in the 5-methyl-2 (1H) pyridone solution of (IV) formula and carry out nucleophilic substitution reaction;

Generate the pyridone compound shown in product i.e. formula (I).

3. The method for producing anti-fibrosis pyridone compounds according to claim 2, characterized in that: the temperature range of the diazotization reaction is controlled at -20°C to 30°C; the hydrolysis and tautomerization The reaction temperature range is controlled at 50°C to 150°C; at the end point of the hydrolysis and tautomerization reaction, the reaction solution is neutralized with alkali and extracted, adsorbed or cooled to obtain 5-methyl-2(1H ) pyridone crystals.

4. The method for producing anti-fibrosis pyridone compound according to claim 3, characterized in that the diazotization reaction temperature ranges from -10°C to 10°C.

5. The method for producing anti-fibrosis pyridone compound according to claim 3, characterized in that the temperature range of hydrolysis and tautomerization reaction is controlled at 90°C-100°C.

6. An anti-fibrosis pharmaceutical composition, comprising the compound of claim 1 and pharmaceutically acceptable excipients.