CN1218942C - Antifibrosis pyridinone medicine and its prepaing process - Google Patents
Antifibrosis pyridinone medicine and its prepaing process Download PDFInfo
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- CN1218942C CN1218942C CN 02114190 CN02114190A CN1218942C CN 1218942 C CN1218942 C CN 1218942C CN 02114190 CN02114190 CN 02114190 CN 02114190 A CN02114190 A CN 02114190A CN 1218942 C CN1218942 C CN 1218942C
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Abstract
The present invention relates to an anti-fibrosis pyridine medicine which is characterized in that the anti-fibrosis pyridine medicine has a 1-polysubstituted phenyl-5-methyl-2(IH) pyridine compound disclosed in a formula (I). A substitute group R is a halogen element, saturated straight-chain alkyl, oxo-saturated straight-chain alkyl and halogenating saturated straight-chain alkyl, and n is from 1 to 2. The R is positioned on a benzene ring in the modes of adjacency, interjacency, contraposition, etc. 2-amino-5-methylpyridine is adopted as initial raw materials by the technical method, and is added to a polar solvent of strong acid so as to react for diazotization, etc. by using sodium nitrite as a diazotizing agent. The pyridine compound disclosed in the formula (I) is prepared and obtained. The strong acid is inorganic acid or organic acid, such as hydrochloric acid, sulphuric acid and glacial acetic acid. The polar solvent is glacial acetic acid or water. The pyridine medicine has a great anti-fibrosis function and wide organ applicability. The initial raw materials which are easily obtained in a market and have stable molecules are adopted by the technical method. The course of reaction is simple and easily controlled, and the technical method is suitable for industrial scale production.
Description
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,
In the 1-substituted-phenyl of formula (I)-5-methyl-2 (1H) pyridone, n=1, the R=trifluoromethyl, as:
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,
In the 1-substituted-phenyl of formula (I)-5-methyl-2 (1H) pyridone, n=1, the R=methyl, as:
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 (6)
1. the anti-fibrosis pyridinone compounds is characterized in that having the structure suc as formula (I);
Wherein when n=1, R=F, Br, I;
When n=2, R=F, Cl, Br, I, saturated straight chain alkyl, oxo saturated straight chain alkyl, halo saturated straight chain alkyl; The position of R substituting group on phenyl ring has ortho position, a position or contraposition.
2. method of producing the described anti-fibrosis pyridinone compounds of claim 1 is characterized in that being made up of the following step:
(1) adopt the 2-amino-5-picoline of (II) formula as initial feed; In sulfuric acid, as diazotization agent, the compound of formula (II) is carried out diazotization reaction with Sodium Nitrite;
Obtain the 2-diazo-5-picoline formula vitriol of (III) formula:
(2) (III) 2-of formula diazo-5-picoline vitriol generates the 2-hydroxy-5-methyl yl pyridines of (IV ') formula through hydrolysis;
(3) 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:
(4) iodobenzene that (IV) adds (V) formula in 5-methyl-2 (1H) the pyridone solution of formula carries out nucleophilic substitution reaction;
Generating product is the pyridinone compounds shown in the formula (I).
3, the method for production anti-fibrosis pyridinone compounds according to claim 2 is characterized in that: described diazotization reaction temperature range is controlled at-20 ℃～30 ℃; Described hydrolysis and tautomerism range of reaction temperature are controlled at 50 ℃～150 ℃; The terminal point of hydrolysis and tautomerism reaction adopts extraction, absorption or cold analysis behind the employing alkali neutralization reaction liquid, obtains 5-methyl-2 (1H) the pyridone crystallization of (III) formula.
4, the method for production anti-fibrosis pyridinone compounds according to claim 3 is characterized in that the diazotization reaction temperature range is at-10 ℃～10 ℃.
5, the method for production anti-fibrosis pyridinone compounds according to claim 3 is characterized in that hydrolysis and tautomerism range of reaction temperature are controlled at 90 ℃～100 ℃.
6, a kind of pharmaceutical composition of anti-fibrosis contains described compound of claim 1 and available auxiliary material pharmaceutically.
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Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003284808B2 (en) | 2003-11-14 | 2009-01-22 | Catalyst Biosciences, Inc. | The derivatives of pyridone and the use of them |
| CN1846699A (en) * | 2005-04-13 | 2006-10-18 | 中南大学湘雅医院 | Application of 1- (substituted phenyl) -5-methyl-2- (1H) pyridone (I) compound in preparing medicines for resisting fibrosis of other organs or fibrosis of tissues except renal interstitial fibrosis |
| DK1928454T3 (en) | 2005-05-10 | 2014-11-03 | Intermune Inc | PYRIDONE DERIVATIVES FOR MODULATING STRESS-ACTIVATED PROTEINKINATION SYSTEM |
| CN100396669C (en) * | 2006-03-15 | 2008-06-25 | 浙江省医学科学院 | Production of pyriphenanthrenone as anti-fibrosis medicine |
| CN101472588A (en) * | 2007-04-27 | 2009-07-01 | 达瑞科技投资有限公司 | Application of 5-methyl 1-(substituted phenyl group)-2-(1H) pyridinone compound as anti-inflammatory medicament and alpha-tumor necrosis factor (TNF-alpha) |
| MX2007006349A (en) * | 2007-05-29 | 2009-02-18 | Cell Therapy And Technology S | New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same. |
| CN101235013A (en) * | 2008-03-10 | 2008-08-06 | 广东东阳光药业有限公司 | Crystallized 1-(3-fluorophenyl)-5-methyl-2-(1H)pyridine and its preparation method composition and application |
| JP5627574B2 (en) | 2008-06-03 | 2014-11-19 | インターミューン， インコーポレイテッド | Compounds and methods for treating inflammatory and fibrotic diseases |
| CN101918364B (en) * | 2008-10-21 | 2013-02-13 | 史跃年 | Composition and method for treating proteinuria |
| CN101723883B (en) * | 2008-10-24 | 2013-06-05 | 上海睿星基因技术有限公司 | Method for preparing oxycodone |
| US20110313004A1 (en) | 2008-12-04 | 2011-12-22 | Concert Pharmaceuticals, Inc. | Deuterated pyridinones |
| ES2536200T3 (en) * | 2009-05-25 | 2015-05-21 | Central South University | Preparation of compounds of type 1- (substituted benzyl) -5-trifluoromethyl-2- (1H) pyridone, salts thereof and their applications |
| WO2010135972A1 (en) * | 2009-05-25 | 2010-12-02 | 中南大学 | Preparation methods and uses of 1-(substituted aryl)-5-trifluoromethyl-2-(1h)-pyridone compounds and their salts |
| TWI434833B (en) | 2009-06-03 | 2014-04-21 | Intermune Inc | Improved method for synthesizing pirfenidone |
| RU2701156C9 (en) | 2012-07-18 | 2019-12-18 | Саншайн Лейк Фарма Ко., Лтд. | Nitrogen-containing heterocyclic derivatives and use thereof in pharmaceutical preparations |
| AR092742A1 (en) | 2012-10-02 | 2015-04-29 | Intermune Inc | ANTIFIBROTIC PYRIDINONES |
| CA2929394C (en) | 2013-12-19 | 2021-11-16 | Sunshine Lake Pharma Co., Ltd. | Nitrogenous heterocyclic derivatives and their application in drugs |
| RU2692485C2 (en) * | 2014-04-02 | 2019-06-25 | Интермьюн, Инк. | Antifibrous pyridinones |
| CN105130884B (en) * | 2015-07-30 | 2017-09-01 | 四川大学 | 5 methyl 2 (1H) Pyridione derivatives and its production and use |
| CN105175326B (en) * | 2015-08-19 | 2018-02-27 | 四川国康药业有限公司 | 5 methyl 2 (1H) Pyridione derivatives and its production and use |
| CN105085383B (en) * | 2015-08-19 | 2017-09-01 | 四川大学 | 5 methyl 2 (1H) Pyridione derivatives and its production and use |
| ITUB20154832A1 (en) | 2015-10-29 | 2017-04-29 | Procos Spa | PROCESS FOR SYNTHESIS OF PYRPHENING |
| CN105330598B (en) * | 2015-12-02 | 2017-11-14 | 新发药业有限公司 | A kind of preparation method of pirfenidone |
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