CN1386737A - Antifibrosis pyridinone medicine and its prepaing process - Google Patents
Antifibrosis pyridinone medicine and its prepaing process Download PDFInfo
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- CN1386737A CN1386737A CN 02114190 CN02114190A CN1386737A CN 1386737 A CN1386737 A CN 1386737A CN 02114190 CN02114190 CN 02114190 CN 02114190 A CN02114190 A CN 02114190A CN 1386737 A CN1386737 A CN 1386737A
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- fibrosis
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- 239000003814 drug Substances 0.000 title claims abstract description 25
- 230000002300 anti-fibrosis Effects 0.000 title claims abstract description 18
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title abstract description 10
- 230000008569 process Effects 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 9
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 9
- 229960000583 acetic acid Drugs 0.000 claims abstract description 7
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 7
- 239000002798 polar solvent Substances 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 150000007524 organic acids Chemical class 0.000 claims abstract description 3
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000003672 processing method Methods 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 150000003222 pyridines Chemical class 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000012954 diazonium Substances 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- SOHMZGMHXUQHGE-UHFFFAOYSA-N 5-methyl-1h-pyridin-2-one Chemical compound CC1=CC=C(O)N=C1 SOHMZGMHXUQHGE-UHFFFAOYSA-N 0.000 claims description 3
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000013067 intermediate product Substances 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 150000005299 pyridinones Chemical class 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 abstract 2
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical class C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 abstract 1
- 239000004317 sodium nitrate Substances 0.000 abstract 1
- 235000010344 sodium nitrate Nutrition 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
- 201000010099 disease Diseases 0.000 description 6
- 230000003176 fibrotic effect Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- -1 1-monosubstituted phenyl-5-methyl-2 (IH) pyridone Chemical group 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 201000002793 renal fibrosis Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- QLFMOQVBGPZBAY-UHFFFAOYSA-N 1-(2-bromophenyl)-5-methylpyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1Br QLFMOQVBGPZBAY-UHFFFAOYSA-N 0.000 description 1
- MCAAQJLJBILPBZ-UHFFFAOYSA-N 1-(3-bromophenyl)-5-methylpyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC(Br)=C1 MCAAQJLJBILPBZ-UHFFFAOYSA-N 0.000 description 1
- PYZJZGLJFOVHRH-UHFFFAOYSA-N 1-(4-bromophenyl)-5-methylpyridin-2-one Chemical compound C1=C(C)C=CC(=O)N1C1=CC=C(Br)C=C1 PYZJZGLJFOVHRH-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010028594 Myocardial fibrosis Diseases 0.000 description 1
- JXRWUCWQCGMRQQ-UHFFFAOYSA-N NCC1=C(C=CC=C1)N1C(C=CC(=C1)C)=O Chemical compound NCC1=C(C=CC=C1)N1C(C=CC(=C1)C)=O JXRWUCWQCGMRQQ-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 150000005217 methyl ethers Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- HVZWVEKIQMJYIK-UHFFFAOYSA-N nitryl chloride Chemical group [O-][N+](Cl)=O HVZWVEKIQMJYIK-UHFFFAOYSA-N 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
An antifibrosis pyridinone medicine, 1-polysubstituted phenyl-5-methyl-2(IH) pyridinone is prepared from 2-amino-5-methyl pyridine through diazotization reaction in polar solvent containing concentrated acid and sodium nitrate as diazotizing agent. Said concentrated acid may be inorganic acid or organic acid. Said polar solvent is glacial acetic acid or water. Its advantages are high antifibrosis effect, and simple reaction procedure.
Description
Technical field: the present invention relates to treat the chemical synthetic drug and the producing and manufacturing technique thereof of fibrotic disease, relate in particular to the pyridinone synthetic drugs of treatment fibrotic disease and the improvement of synthetic process.
Background technology: 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 live, 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, carried out the research of a large amount of anti-fibrosis medicines from different field such as chemicals, natural drug, biotechnological formulation, gene therapies, so far, found that pyridine compounds is the effective anti-fibrosis compound of a class;
United States Patent (USP) (6090822), (5789426), international monopoly (0044381) and European patent (1138329A2) have announced that respectively some are used for the treatment of the pyridine compounds of organ fibrosis disease, and its structure is 1-monosubstituted phenyl-5-methyl-2 (IH) pyridone that the general formula of available formula (0) is represented:
Wherein, the substituent R number is 1, represents nitro, chlorine atom, alkyl; The drug effect of this type of pyridinone anti-fibrosis medicine a little less than, sphere of action and indication are narrower, only can stronger therapeutic action be arranged to the renal fibrosis disease, and very little to the fibrotic disease effect of other organs, can not adapt to the clinical requirement of medical treatment.
In addition, United States Patent (USP) (No. 5789426) discloses a kind of processing method, be that 5-methyl-2 (IH) pyridone with (IV) formula is a raw material, react with single substituting group-iodobenzene of (V) formula and generate 1-benzene series substituting group-5-methyl-2 (IH) the pyridinone medicine of (0) formula, reaction process is as follows:
United States Patent (USP) (No. 6090833) improves the reaction conditions of above-mentioned processing method, and discloses the different preparation methods of the compound of (IV) formula; But its shortcoming is: the reaction starting raw material is difficult to obtain on Chinese market, cost an arm and a leg, and structural instability, be difficult to promote.
Chinese patent (1086514A) discloses the method for a kind of preparation formula (IV), be with 1-itrile group-1-butylene of (VI) formula and 1 of (VII) formula, two dimethyl amine-the 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, capable again cyclisation under strong acid condition, (IV ') formula that generates 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, easily polymerization take place, (VII) compound of formula is difficult for the shortcoming that obtains.
Summary of the invention: at the above-mentioned shortcoming of prior art, one of technical solution of the present invention is to provide a kind of anti-fibrosis effect strong and have an anti-fibrosis pyridone medicine of organ suitability widely; Two of technical solution of the present invention is to provide a kind of the employing to be easy to get on the market and processing method that starting raw material that molecule is stable is produced anti-fibrosis pyridone medicine.
For this reason, technical solution of the present invention is a kind of anti-fibrosis pyridone medicine, it is characterized in that: it has suc as formula the polysubstituted phenyl of the 1-of (I)-5-methyl-2 (IH) pyridinone compounds.
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.
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.
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).
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.
Reactions steps wherein and corresponding intermediate product are successively:
A, diazotization reaction generate the 2-diazonium amido-5-picoline formula vitriol of (IX) formula;
The 2-diazonium amido of b, (IX) 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,
Generating product is the polysubstituted phenyl of 1--5-methyl-2 (IH) the pyridone medicine of required formula (I).
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.
Medicine of the present invention and producing and manufacturing technique thereof have following advantage:
Medicine of the present invention is the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, owing to adopted multiple/a plurality of suitable groups to replace on phenyl ring, makes this medicine series have wider adaptability, better therapeutic; Producing and manufacturing technique disclosed by the invention, the starting raw material molecular structure stabilized, the storage convenient transportation is easy to get on Chinese market, and reaction process is simple and easy to control, is more suitable in plant-scale production.
Embodiment:
Embodiment 1,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=1, R=Br, as:
1-(2-bromophenyl)-5-methyl-2-(IH) pyridone,
1-(3-bromophenyl)-5-methyl-2-(IH) pyridone,
1-(4-bromophenyl)-5-methyl-2-(IH) pyridone,
Embodiment 2,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=2, R=Br, Cl, as:
1-(2, the 3-dibromo phenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 4-dibromo phenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 5-dibromo phenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 6-dibromo phenyl)-5-methyl-2-(IH) pyridone,
1-(3, the 4-dibromo phenyl)-5-methyl-2-(IH) pyridone,
1-(3, the 5-dibromo phenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 3-dibromo phenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 3-dichlorophenyl)-5-methyl-2-(IH) pyridone,
1-(2,4 dichloro benzene base)-5-methyl-2-(IH) pyridone,
1-(2, the 5-dichlorophenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 6-dichlorophenyl)-5-methyl-2-(IH) pyridone,
1-(3, the 5-dichlorophenyl)-5-methyl-2-(IH) pyridone,
Embodiment 3,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=1, the R=trifluoromethyl, as:
1-(2-trifluoromethyl)-5-methyl-2-(IH) pyridone,
1-(4-trifluoromethyl)-5-methyl-2-(IH) pyridone,
Embodiment 4,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=2, the R=trifluoromethyl, as:
1-(2, the 3-trifluoromethyl)-5-methyl-2-(IH) pyridone,
1-(2, the 4-trifluoromethyl)-5-methyl-2-(IH) pyridone,
1-(2, the 5-trifluoromethyl)-5-methyl-2-(IH) pyridone,
1-(2, the 6-trifluoromethyl)-5-methyl-2-(IH) pyridone,
1-(3, the 4-trifluoromethyl)-5-methyl-2-(IH) pyridone,
1-(2, the 5-trifluoromethyl)-5-methyl-2-(IH) pyridone,
Embodiment 5,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=1, the R=methyl, as:
1-(2-aminomethyl phenyl)-5-methyl-2-(IH) pyridone,
1-(3-aminomethyl phenyl)-5-methyl-2-(IH) pyrrole is than pyridine ketone,
Embodiment 6,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=2, the R=methyl, as:
1-(2, the 3-3,5-dimethylphenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 4-3,5-dimethylphenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 5-3,5-dimethylphenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 6-3,5-dimethylphenyl)-5-methyl-2-(IH) pyridone,
1-(3, the 4-3,5-dimethylphenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 5-3,5-dimethylphenyl)-5-methyl-2-(IH) pyridone,
Embodiment 7,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=1, the R=methoxyl group, as:
1-(2-p-methoxy-phenyl)-5-methyl-2-(IH) pyridone,
1-(3-p-methoxy-phenyl)-5-methyl-2-(IH) pyridone,
Embodiment 8,
In the polysubstituted phenyl of the 1-of formula (I)-5-methyl-2 (IH) pyridone, n=2, the R=methoxyl group, as:
1-(2, the 3-Dimethoxyphenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 4-Dimethoxyphenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 5-Dimethoxyphenyl)-5-methyl-2-(IH) pyridone,
1-(2, the 6-Dimethoxyphenyl)-5-methyl-2-(IH) pyridone,
1-(3, the 4-Dimethoxyphenyl)-5-methyl-2-(IH) pyridone,
1-(3, the 5-Dimethoxyphenyl)-5-methyl-2-(IH) pyridone,
Embodiment 9,
Get (II) 2-amido-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 finishes at 0 ℃～5 ℃, continues reaction to fully, adds 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 (IH) the pyridone solution that ethanol obtains (IV) formula, multi-substituent-the iodobenzene that adds (V) formula in the solution carries out nucleophilic substitution reaction, and generating desired product is the polysubstituted phenyl of 1--5-methyl-2 (IH) the pyridone medicine of 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.
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| CN 02114190 CN1218942C (en) | 2002-06-11 | 2002-06-11 | Antifibrosis pyridinone medicine and its prepaing process |
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|---|---|---|---|
| CN 02114190 CN1218942C (en) | 2002-06-11 | 2002-06-11 | Antifibrosis pyridinone medicine and its prepaing process |
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| CN1218942C CN1218942C (en) | 2005-09-14 |
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Cited By (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005047256A1 (en) * | 2003-11-14 | 2005-05-26 | Shanghai Genomics, Inc. | The derivatives of pyridone and the use of them |
| WO2006108354A1 (en) * | 2005-04-13 | 2006-10-19 | Xiangya Hospital Of Central South University | 1-(substituted phenyl)-5- methyl- 2 - (1h) pyridone in the manufacture of medicaments for treating fibrosis in organs or tissues |
| CN100396669C (en) * | 2006-03-15 | 2008-06-25 | 浙江省医学科学院 | Production of pyriphenanthrenone as anti-fibrosis medicine |
| WO2008131586A1 (en) * | 2007-04-27 | 2008-11-06 | Dieretech Investment Limited | Uses of 5-methyl-1-(substituted phenyl)-2(1h)-pyridones as anti-inflammatory and tnf-alpha-blocking agents |
| WO2008147170A1 (en) * | 2007-05-29 | 2008-12-04 | Cell Therapy Technology, S.A. De C.V. | New process of synthesis for obtaining 5-methyl-1-phenyl-2 (ih) -pyridone, composition and use of the same |
| WO2009111947A1 (en) * | 2008-03-10 | 2009-09-17 | 广东东阳关药业有限公司 | Crystalline 1-(3-fluorophenyl)-5-methyl-2-(1h)pyridone, the preparation methods, compositions and applications thereof |
| WO2010045871A1 (en) * | 2008-10-21 | 2010-04-29 | Dieretech Investment Limited | Composition and method for treating proteinuria |
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2002
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