CN100396669C - Production of pyriphenanthrenone as anti-fibrosis medicine - Google Patents
Production of pyriphenanthrenone as anti-fibrosis medicine Download PDFInfo
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- CN100396669C CN100396669C CNB2006100498525A CN200610049852A CN100396669C CN 100396669 C CN100396669 C CN 100396669C CN B2006100498525 A CNB2006100498525 A CN B2006100498525A CN 200610049852 A CN200610049852 A CN 200610049852A CN 100396669 C CN100396669 C CN 100396669C
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Abstract
The present invention relates to a novel organic chemistry synthesis method, particularly to a preparation method for pirfenidone as anti-fibrosis drugs used for treating fibrosis diseases. 2-amino-5-methylpyridine is used as initial raw materials, is diazotized and hydrolyzed so as to prepare 5-methyl-2(1H)pyridone, is then nucleophilically substituted with halogen benzene with the existence of a catalyst, and is then purified so as to obtain a pure product of pirfenidone. The preparation method has the advantages of low price of raw materials, scientific and reasonable synthesis route, short reaction time, high product yield and suitable industrialized production, has implementation value, and can generate greater social benefit and economic benefit.
Description
Technical field
The present invention relates to a kind of new organic chemistry synthetic method, especially for the preparation method of the pyriphenanthrenone as anti-fibrosis medicine for the treatment of fibrotic disease.
Background technology
Fibrotic disease such as renal fibrosis, liver cirrhosis, myocardial fibrosiss 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 are at Fibrotic morbidity link, from chemicals, natural drug, biotechnological formulation, different field such as gene therapy have been carried out the research of a large amount of anti-fibrosis medicines, so far, found that pyridine compounds is the effective anti-fibrosis compound of a class, wherein, pirfenidone is the representative compounds in this, abroad study for many years, it is clinical to be in the III phase at present.
The chemical name of pirfenidone is: 5-methyl isophthalic acid-phenyl-2 (1H) pyridone.
English name: Pirfenidone
5-methyl-1-phenyl-2(1H)-pyridone
Outward appearance: white or off-white color crystal
Chemical structural formula:
United States Patent (USP) (3974281), European patent (162464) etc. disclose a kind of processing method, be to be raw material with 5-methyl-2 (1H)-give a tongue-lashing pyridine ketone (III), react and synthetic pirfenidone and analog thereof with single substituting group iodobenzene (IV), but exist the reaction starting raw material on Chinese market, to be difficult to obtain, cost an arm and a leg, reaction process time long (18h), yield and purity is lower, reaction conditions shortcoming such as harshness relatively.
Chinese patent (1086514A) discloses a kind of synthetic method of structure (III), be with 1-itrile group-1-butylene and 1, two dimethyl amido-the methyl ethers of 1-are raw material, reaction generates 1-dimethyl amido-2-methyl-4-itrile group-1, the intermediate of 3-divinyl (V), under strong acid condition, carry out cyclisation more again, get (III).But there are shortcomings such as complex operation, severe reaction conditions, productive rate be low in this method.
United States Patent (USP) (5420284) also discloses the synthetic method of a kind of structure (III) compound, is starting raw material with morpholine and propionic aldehyde, and reaction obtains (III) through 5 steps.This method reaction scheme length, troublesome poeration, yield are also lower.
Chinese patent (1386737A) discloses a kind of synthetic method of structure (III), is to be starting raw material with 2-amino-5-picoline (II), carries out diazotization, hydrolysis and get in the strong acid more than 50%.This method needs the strongly-acid medium, and is relatively more dangerous, also higher to equipment requirements.
Above-mentioned preparation method is long, complex steps, and how expensive starting material are with the reaction agents useful for same, is unsuitable for domestic industry production.
Summary of the invention
The organic synthesis preparation and the purification process that the purpose of this invention is to provide a kind of simple and direct and economic pirfenidone, make preparation method's prices of raw and semifnished materials low, synthetic route science, reasonable, reaction times is short, and the product yield height is fit to suitability for industrialized production, and has implementary value, can produce bigger social benefit and economic benefit, and can be used for prevention and treatment of diseases such as lung, kidney, liver, myocardial fibrosiss.
It is starting raw material that the present invention adopts 2-amino-5-picoline, in acidic medium, carry out diazotization, hydrolysis prepares 5-methyl-2 (1H) pyridone, in the presence of catalyzer, carry out nucleophilic substitution reaction then with halogeno-benzene, generate target compound---pirfenidone, the purified purer product of pirfenidone that get.
Preparation method's step of pirfenidone of the present invention is as follows:
With commercially available industrial chemicals 2-amino-5-picoline (II) cheap and easy to get is initial feed, carries out diazotization in acidic medium, obtains 5-methyl-2 (1H) pyridone (III) after the hydrolysis:
Described acidic medium is the lower concentration mineral acid, example hydrochloric acid, sulfuric acid, phosphoric acid etc., preferably sulfuric acid wherein, its concentration from 1% to 30%, wherein preferred 5% to 10%.Described diazotization reaction is controlled at-20 ℃～30 ℃; Diazo reagent can adopt nitrous acid inorganics or organism such as Sodium Nitrite, potassium nitrite, Isopentyl nitrite, wherein is preferably Sodium Nitrite.
Resulting formula (III) is carried out nucleophilic substitution reaction with the commercially available halogeno-benzene shown in the formula (IV) in the presence of catalyzer, get target product pirfenidone (I) crude product:
X represents halogen atom in the formula, as iodine, bromine, chlorine etc.; Described nucleophilic substitution reaction carries out in the presence of catalyzer, and temperature of reaction is controlled at 50 ℃～250 ℃, wherein preferred 150 ℃～200 ℃; The optional active copper of described catalyzer, cuprous iodide, cuprous chloride, cupric oxide etc., wherein preferred cuprous iodide; According to the difference of catalyzer, its reaction times also changes thereupon, is generally 0.5～12 hour.
The crude product of gained I, through acid fluid dissolves---the operation that alkali lye is separated out obtains pure product.Described acid solution can be a mineral acid commonly used, and example hydrochloric acid, sulfuric acid, phosphoric acid also can be organic acids, as acetate, formic acid etc., and wherein preferred acetate; Described alkali lye can be mineral alkali commonly used, as sodium hydroxide, potassium hydroxide, yellow soda ash, sodium bicarbonate, ammoniacal liquor etc., wherein is preferably sodium hydroxide.
In more detail, the present invention can be by the described method preparation of following reaction scheme.
Reaction scheme:
In the above-mentioned reaction scheme, X represents halogen atom, is preferably chlorine, bromine, and iodine most preferably is iodine.
In this reaction scheme,
Reactions steps A comprises the commercially available industrial chemicals 2-amino-5-picoline (II) shown in the formula (II) is carried out diazotization in acidic medium, obtains 5-methyl-2 (1H) pyridone (III) after the hydrolysis.
Wherein, described diazotization, hydrolytic process can adopt in this area known ordinary method to carry out, and comprise II and nitrite generation diazotization reaction under the low temperature, and diazonium salt is replaced by hydroxyl under the heating condition.
The described nucleophilic substitution reaction of reactions steps B comprises chloro, bromo and iodo, and its reaction can be carried out under the known ordinary method in this area, is included in catalyzer and exists down, and III and halogenating agent be thermal response altogether.Described reaction solvent generally is halogenating agent, comprises iodobenzene, bromobenzene, chlorobenzene etc.Temperature of reaction changes with the difference of reaction system.Preferred reaction conditions is to carry out in the presence of catalyzer with iodobenzene, and temperature of reaction is controlled at 50 ℃～250 ℃, wherein preferred 150 ℃～200 ℃.
Reaction product can obtain with the ordinary method separation, as obtaining product with organic solvent extraction.The purifying of product can be undertaken by ordinary method, as column chromatography, recrystallization etc., also can adopt other method according to the physico-chemical property of product, as acid fluid dissolves---and alkali lye precipitation method etc.
Resulting product is target product pirfenidone (I).
The new method for preparing pirfenidone of the present invention is not limited only to prepare pirfenidone, can also be in order to the polysubstituted pyridine ketone compounds of preparation, as 5-methyl isophthalic acid-(4 '-nitrophenyl)-2 (1H) pyridone, 5-methyl isophthalic acid-(3 '-nitrophenyl)-2 (1H) pyridone, 5-methyl isophthalic acid-(4 '-p-methoxy-phenyl)-2 (1H) pyridone etc. with the pirfenidone structure similar.These preparation method's prices of raw and semifnished materials are low, synthetic route science, reasonable, and the reaction times is short, and the product yield height, is fit to suitability for industrialized production, and has implementary value, can produce bigger social benefit and economic benefit.
Embodiment
Embodiment:
(a) .5-methyl-2 (1H) pyridone
Add 2-amino-5-picoline 10.80g, 5% sulfuric acid 250ml in the there-necked flask successively, drip Sodium Nitrite (12.00g) aqueous solution in 0～5 ℃; Afterwards, reaction solution heating hydrolysis.Reaction is finished, and with the yellow soda ash neutralization, the concentrating under reduced pressure drying gets pale brown look solid, is 5-methyl-2 (1H) pyridone crude product; The dehydrated alcohol recrystallization gets light yellow crystallization 7.90g, yield 72.5%, mp182-183 ℃ (document mp181-182 ℃).IR(cm
-1)：2842.7，2840.0(N-H)，1657.0(C＝O)，1145.1(C-N)。1HNMR(δppmCDCl3)：2.10(3H，s，5-CH3)，6.53(1H，d，H-3)，7.17(1H，d，H-4)，7.33(1H，d，H-6)，13.52(1H，s，N-H)。
(b). pirfenidone
Add 5-methyl-2 (1H) pyridone 5.45g, Anhydrous potassium carbonate 7.66g, iodobenzene 20g, cuprous chloride 0.16g in the there-necked flask successively, back flow reaction 3hr.Use ethyl acetate extraction, be concentrated into dried pale brown look oily matter, add sherwood oil and solidify, pale brown look solid pirfenidone crude product 7.88g, yield 85.1%.
(c). purifying
Add the acetic acid,diluted dissolving in the above-mentioned pirfenidone crude product, stirring drips diluted sodium hydroxide solution down, regulates pH=13, leaves standstill cooling, filters, and gets the pure product 6.38g of white crystals pirfenidone.Yield 81.0%, mp108-109 ℃ (103-105 ℃ of document mp).Purity 99.90% (HPLC).IR (cm
-1): 1675.0 (C=O), 1133.9 (C-N), 765.9,701.8 (single-substituted C-H).1HNMR(δppm?CDCl3)：2.09(3H，s，5-CH3)，6.60(1H，d，H-3)，7.10(1H，d，H-4)，7.27(1H，d，H-4’)，7.36(1H，d，H-6)，7.40(2H，t，H-3’，5’)，7.46(2H，t，H-2’，6’)。MS(M+1)：186.2，158.1，143.1，110.1，95.1，92.1，77.0，65.1。
Claims (3)
1. the preparation method of a pyriphenanthrenone as anti-fibrosis medicine, it is characterized in that adopting 2-amino-5-picoline (structural formula II) to be initial feed, in the inorganic acid medium of 1%-30%, carry out diazotization, obtain 5-methyl-2 (1H) pyridone shown in the structural formula II I after the hydrolysis; Resulting formula (III) is carried out nucleophilic substitution reaction with the halogenated benzene compound shown in the formula (IV) under cuprous iodide or cuprous chloride catalysis, generate target compound---pirfenidone (I), and purified pure product
2. preparation method according to claim 1 is characterized in that described mineral acid is a sulfuric acid.
3. preparation method according to claim 1 is characterized in that described halogeno-benzene is iodobenzene, bromobenzene or chlorobenzene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNB2006100498525A CN100396669C (en) | 2006-03-15 | 2006-03-15 | Production of pyriphenanthrenone as anti-fibrosis medicine |
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| CNB2006100498525A CN100396669C (en) | 2006-03-15 | 2006-03-15 | Production of pyriphenanthrenone as anti-fibrosis medicine |
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| CN100396669C true CN100396669C (en) | 2008-06-25 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11066368B2 (en) | 2016-01-14 | 2021-07-20 | Laurus Labs Limited | Process for the preparation and particle size reduction of pirfenidone |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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. |
| 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 |
| WO2010065755A1 (en) | 2008-12-04 | 2010-06-10 | Concert Pharmaceuticals, Inc. | Deuterated pyridinones |
| TWI434833B (en) | 2009-06-03 | 2014-04-21 | Intermune Inc | Improved method for synthesizing pirfenidone |
| CN101891676A (en) * | 2010-08-03 | 2010-11-24 | 陕西合成药业有限公司 | Novel method for preparing 5-methyl-1-phenyl-2-(1H)-pyridone |
| CN102558040A (en) * | 2011-12-28 | 2012-07-11 | 辰欣药业股份有限公司 | Method for preparing pirfenidone |
| AR092742A1 (en) | 2012-10-02 | 2015-04-29 | Intermune Inc | ANTIFIBROTIC PYRIDINONES |
| KR102373700B1 (en) | 2014-04-02 | 2022-03-11 | 인터뮨, 인크. | Anti-fibrotic pyridinones |
| CN106397408B (en) * | 2015-07-30 | 2019-04-02 | 四川大学 | 5- methyl -2 (1H) Pyridione derivatives and its preparation method and application |
| ITUB20154832A1 (en) | 2015-10-29 | 2017-04-29 | Procos Spa | PROCESS FOR SYNTHESIS OF PYRPHENING |
| CN105315198A (en) * | 2015-11-02 | 2016-02-10 | 重庆康乐制药有限公司 | Crystal form of pirfenidone and preparation method of crystal form |
| CN105330598B (en) * | 2015-12-02 | 2017-11-14 | 新发药业有限公司 | A kind of preparation method of pirfenidone |
| US20180009753A1 (en) | 2016-07-08 | 2018-01-11 | Dipharma Francis S.R.L. | Method for preparing an antifibrotic agent |
| IT201600071672A1 (en) * | 2016-07-08 | 2018-01-08 | Dipharma Francis Srl | METHOD FOR SYNTHESIZING AN IMMUNOSUPPRESSOR DRUG |
| WO2018178996A1 (en) * | 2017-03-28 | 2018-10-04 | Natco Pharma Limited | Improved process for the preparation of pirfenidone |
| CN111039857A (en) * | 2019-12-25 | 2020-04-21 | 苏州雅尼生物科技有限公司 | Preparation method of high-purity pirfenidone |
| US20220251042A1 (en) * | 2020-09-10 | 2022-08-11 | Suzhou Fude Zhaofeng Biochemical Technology Co., Ltd | Total synthesis of pirfenidone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2947755A (en) * | 1959-02-05 | 1960-08-02 | Wallace & Tiernan Inc | Substituted 1-m-aminophenyl-2-pyridones |
| US3839346A (en) * | 1972-12-18 | 1974-10-01 | Affiliated Med Res | N-substituted pyridone and general method for preparing pyridones |
| CN1386737A (en) * | 2002-06-11 | 2002-12-25 | 中南大学湘雅医学院 | Antifibrosis pyridinone medicine and its prepaing process |
-
2006
- 2006-03-15 CN CNB2006100498525A patent/CN100396669C/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2947755A (en) * | 1959-02-05 | 1960-08-02 | Wallace & Tiernan Inc | Substituted 1-m-aminophenyl-2-pyridones |
| US3839346A (en) * | 1972-12-18 | 1974-10-01 | Affiliated Med Res | N-substituted pyridone and general method for preparing pyridones |
| CN1386737A (en) * | 2002-06-11 | 2002-12-25 | 中南大学湘雅医学院 | Antifibrosis pyridinone medicine and its prepaing process |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11066368B2 (en) | 2016-01-14 | 2021-07-20 | Laurus Labs Limited | Process for the preparation and particle size reduction of pirfenidone |
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