CN105017138A - Ethylene-glycol-alcoholized 3-pyridinol-4-ketone compound and preparation method and application thereof - Google Patents

Ethylene-glycol-alcoholized 3-pyridinol-4-ketone compound and preparation method and application thereof Download PDF

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CN105017138A
CN105017138A CN201510477926.4A CN201510477926A CN105017138A CN 105017138 A CN105017138 A CN 105017138A CN 201510477926 A CN201510477926 A CN 201510477926A CN 105017138 A CN105017138 A CN 105017138A
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pegylation
ketone
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hydroxypyridin
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张兴元
李军配
罗伯特·海德
文森索·阿巴特
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University of Science and Technology of China USTC
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/69—Two or more oxygen atoms

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Abstract

The invention discloses an ethylene-glycol-alcoholized 3-pyridinol-4-ketone compound and a preparation method and application thereof. The ethylene-glycol-alcoholized 3-pyridinol-4-ketone compound comprises ethylene-glycol-alcoholized 3-pyridinol-4-ketone derivatives and salt of the ethylene-glycol-alcoholized 3-pyridinol-4-ketone derivatives. The structural formula of the ethylene-glycol-alcoholized 3-pyridinol-4-ketone derivatives can be seen in the specification. The ethylene-glycol-alcoholized 3-pyridinol-4-ketone derivatives are designed in an optimized mode, ethylene-glycol-alcoholized groups are introduced, the biological activity of chelation iron ions of the ethylene-glycol-alcoholized 3-pyridinol-4-ketone derivatives is improved, toxic effects are reduced, the high oral activity is achieved, and the iron discharge capacity of the ethylene-glycol-alcoholized 3-pyridinol-4-ketone derivatives is remarkable. Experiments prove that the metabolism effect of the ethylene-glycol-alcoholized 3-pyridinol-4-ketone compound for the iron overload disease is obviously better than that of 3-hydroxy-1,2-dimenthyl-4-(1H)-pyridone, and the ethylene-glycol-alcoholized 3-pyridinol-4-ketone compound can be used for preparing medicine for preventing the iron overload disease.

Description

A kind of PEGylation 3-pyridone-4-ketone compounds and its production and use
One, technical field
The present invention relates to a kind of PEGylation 3-pyridone-4-ketone compounds and its production and use, this compounds is for the signs of toxicity in body caused by ferro element excess accumulation, as thalassemia and other rely on the disease of long-term massive transfusion, and the damage that in local organization, iron ion excess accumulation causes has special pharmaceutical use.
Two, background technology
Since 20 century 70, first PEGylation medicine (PEGylated drug) is developed, the PEGylation protein of modification and small molecules class medicine improve the healing degree of some chronic diseases greatly, as hepatitis C, leukemia, some immunodeficient diseases, rheumatism arthritis and Crohn's disease.Most important PEGylation medicine comprises adenosine deaminase (Pegademasebovine), pegaspargase (Pegaspargase), training filgrastim (Pegfilgrastim), pegvisomant (Pegvisomant) and match trastuzumab (Certolizumab pegol), some PEGylation medicines just in the high speed development stage, as PEGylation uriKoxidase (PEG-uricase) and PEGylation oxyphorase (PEGylated hemoglobin).The adaptability of PEGylation effect (PEGylation) and application will very likely be used for the treatment of many diseases being difficult to cure in the past undoubtedly.The material of PEGylation, containing the ethylene oxy subunit repeated, active low, safety non-toxic, no antigen, have good amphipathic, its biocompatibility has obtained the certification of U.S. food Drug Administration, the hydrodynamic radius of self can be promoted during hyperhydrated effect, and itself be the compound of a series of monodispersity.When protein is after PEG class modifier is modified, many advantageous properties of modifier can be transplanted in adorned albumen thereupon.
Thalassemia is a kind of rare inherited disease, is divided into α type thalassemia (α-thalassemia) and β type thalassemia (β-thalassemia), and its medium and heavy β type thalassemia is fatefulue disease.β type thalassemia causes β subunit to synthesize by the sudden change of beta-globin gene and regulating and controlling sequence thereof or disappearance to reduce or stop completely, cause patient blood hemoglobin level to reduce, cause hemolytic anemia.The ground such as China Guangdong, Hainan, Guangxi, Yunnan are β type thalassemia districts occurred frequently.Modal treatment inherited blood disorders, as β type thalassemia mainly keeps the oxyphorase of high dosage by periodic transfusions.Because human body does not get rid of the mechanism of excessive iron element, cannot renal excretion iron be passed through, repeat blood transfusion and iron level in body can be caused to raise.Unnecessary iron is mainly positioned at liver and other height and inculcates organ (internal organs such as heart, spleen) and cause tissue injury, organ failure, finally causes death.If do not accept treatment, or only accept blood transfusion and do not use de-iron medicine, patient's mortality ratio before growing up is quite high.The medicine of the iron in human overload that current treatment β type thalassemia causes only has Deferiprone (Deferiprone in the world, CP20), desferrioxamine (Desferioxamine) and Deferasirox (Deferasirox) three medicines, (" Orphan drug " refers to the medicine for preventing, treating, diagnose some rare disease all to belong to " Orphan drug ", because rare sick patient groups is few, the market requirement is few, R&D costs are high, pharmacy corporation is seldom had to pay close attention to the research and development of its medicine).Deferiprone is first oral iron chelating agent in the world, at present by the production and sales of Canadian Ao Bei Tyke pharmaceutical Co. Ltd (Apotex Inc.).Deferiprone chemical name is 3-hydroxyl-1,2-dimethyl-4-(1H)-pyridone (3-hydroxy-1,2-dimethylpyridin-4 (1H)-one), belonging to 3-hydroxyl-4-pyridine compounds (HPOs), is one of current main oral iron chelators.Deferiprone is in the news as clinical de-iron medicine and experimental study more.But Deferiprone is easy to glycosylation effect occurs in liver, when therefore patient uses this medicine, dosage need promote greatly, and generally using dosage is 75-100mgkg -1day -1.Because Deferiprone medicine is " Orphan drug ", dosage is large, so its medical expense in China is very high, each patient about needs 14000 yuan of transfuse blood expense and 16000 yuan of de-iron pharmacological agent expenses every year, and patient needs life long treatment.China there is no the de-iron medicine of listing or has the imitation medicine of similar functions, and this also causes its medicine valency to remain high.
Three, summary of the invention
The present invention is directed to thalassemia and cause iron to transship the present situation of disease, in conjunction with the efficient iron affinity of 3-hydroxyl-4-pyridine compounds, Orally active is good, patient dependence is good, myocardial cell can be entered and produce de-iron drug action, and desferrioxamine and do not have this function, and PEGylation material uniqueness is nontoxic, without immune response, the features such as hydrophilic and oleophilic, provide a kind of PEGylation 3-pyridone-4-ketone compounds and its production and use, wherein PEGylation 3-pyridone-4-ketone compounds comprises 1-position, 2-position, 6-position and 2, the 3-hydroxypyridin-4-one derivatives that 6-position is replaced by ethylene glycol compound and salt thereof, by Fourier transform infrared spectrum, nucleus magnetic resonance, mass spectrum and high performance liquid chromatography demonstrate structure and the purity of compound, not glycosylation to obtaining protection drug molecule, extend the effect of its effect transformation period etc.
PEGylation 3-pyridone-4-ketone compounds of the present invention, comprise PEGylation 3-hydroxypyridin-4-one derivatives and salt thereof, wherein the general structure of PEGylation 3-hydroxypyridin-4-one derivatives is as follows:
Wherein, R 1be selected from-CH 2(CH 2oCH 2) 2cH 2nHCOCH 2cH 3,-CH 3,-(CH 2) 2o (CH 2) 2oH ,-(CH 2) 2o (CH 2) 2oCH 3,-CH 2(CH 2oCH 2) 2cH 2nH 2,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-CH 2(CH 2oCH 2) 2cH 2nHCOCH 3or-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nH 2;
R 2be selected from-CH 3,-CH 2cH 3,-CH 2oCH 2o (CH 2) 2oCH 3,-CH 2o (CH 2) 2o (CH 2) 2oCH 3,-H or-CH 2o (CH 2) 2o (CH 2) 2oCH 3;
R 6be selected from-CH 3,-H, CH 2oCH 2o (CH 2) 2oCH 3or CH 2o (CH 2) 2o (CH 2) 2oCH 3.
PEGylation 3-hydroxypyridin-4-one derivatives salt of the present invention refers to the corresponding salt that PEGylation 3-hydroxypyridin-4-one derivatives is formed to acid; Described acid is strong inorganic acid (being generally mineral acid), strong organic acid (being generally alkyl carboxylic acid), saturated or undersaturated dicarboxylic acid or sulfonic acid (be generally alkyl-have substituted or unsubstituted Phenylsulfonic acid), wherein strong inorganic acid comprises sulfuric acid, phosphoric acid or hydrochloric acid, strong organic acid comprises acetic acid, saturated or undersaturated dicarboxylic acid comprises tartrate, citric acid, and sulfonic acid comprises o-methyl-benzene sulfonic acid or p-methyl benzenesulfonic acid.
PEGylation 3-hydroxypyridin-4-one derivatives of the present invention is preferably following structure:
PEGylation 3-hydroxypyridin-4-one derivatives of the present invention is more preferably:
The preparation method of PEGylation 3-pyridone-4-ketone compounds of the present invention, comprise the preparation method of PEGylation 3-hydroxypyridin-4-one derivatives and the preparation method of PEGylation 3-hydroxypyridin-4-one derivatives salt, wherein the preparation method of PEGylation 3-hydroxypyridin-4-one derivatives is specifically divided into the synthetic method of 3-hydroxypyridin-4-one derivatives of 1-position, 2-position, 6-position and 2,6-position PEGylation;
Wherein the synthetic method of the 3-hydroxypyridin-4-one derivatives of 1-position PEGylation comprises the steps:
Methyl maltol or veltol plus and benzyl chlorine are obtained by reacting the voitol of 3-position benzyl protection, obtain the 3-benzyloxypyridine-4-ketones derivant of 1-position PEGylation again with the primary amine reaction of PEGylation, finally under palladium carbon (Pd/C) catalysis, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 1-position PEGylation;
Described saponins is selected from methyl maltol, veltol plus, 3-benzyloxy-2,6-dihydroxymethyl-4H-pyrans-4-ketone or 3-benzyloxy-2-methylol-6-methyl-4H-pyrans-4-ketone;
The primary amine of described PEGylation is NH 2cH 2(CH 2oCH 2) 2cH 2nHCOCH 2cH 3, NH 2(CH 2) 2o (CH 2) 2oH, NH 2(CH 2) 2o (CH 2) 2oCH 3, NH 2cH 2(CH 2oCH 2) 2cH 2nH 2, NH 2(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3, NH 2(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3, NH 2cH 2(CH 2oCH 2) 2cH 2nHCOCH 3or NH 2(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nH 2;
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 1-position PEGylation is as follows:
Wherein R 2be selected from methyl or ethyl;
R 1for PEGylation group, be selected from-CH 2(CH 2oCH 2) 2cH 2nHCOCH 2cH 3,-(CH 2) 2o (CH 2) 2oH ,-(CH 2) 2o (CH 2) 2oCH 3,-CH 2(CH 2oCH 2) 2cH 2nH 2,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-CH 2(CH 2oCH 2) 2cH 2nHCOCH 3or-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nH 2;
Wherein the synthetic method of the 3-hydroxypyridin-4-one derivatives of 2-position PEGylation comprises the steps:
The chlorine or bromine of 3-benzyloxy-2-methylol-6-methyl-4H-pyrans-4-ketone and PEGylation is obtained by reacting the pyranone compounds of 2-position PEGylation for thing, be obtained by reacting the 3-benzyloxypyridine-4-ketone compound of 2-position PEGylation again with methylamine, finally under palladium carbon (Pd/C) catalysis, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 2-position PEGylation;
The chlorine or bromine of described PEGylation is selected from ClCH for thing 2oCH 2o (CH 2) 2oCH 3, ClCH 2o (CH 2) 2o (CH 2) 2oCH 3, BrCH 2oCH 2o (CH 2) 2oCH 3or BrCH 2o (CH 2) 2o (CH 2) 2oCH 3.
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 2-position PEGylation is as follows:
R 2for PEGylation group, be selected from-CH 2oCH 2o (CH 2) 2oCH 3or-CH 2o (CH 2) 2o (CH 2) 2oCH 3.
Wherein the synthetic method of the 3-hydroxypyridin-4-one derivatives of 6-position PEGylation comprises the steps:
The chlorine or bromine of 3-benzyloxy-6-methylol-4H-pyrans-4-ketone and PEGylation is obtained by reacting the pyranone compounds of 6-position PEGylation for thing, be obtained by reacting the 3-benzyloxypyridine-4-ketone compound of 6-position PEGylation again with methylamine, finally under palladium carbon (Pd/C) catalysis, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 6-position PEGylation;
The chlorine or bromine of described PEGylation is selected from ClCH for thing 2oCH 2o (CH 2) 2oCH 3, ClCH 2o (CH 2) 2o (CH 2) 2oCH 3, BrCH 2oCH 2o (CH 2) 2oCH 3or BrCH 2o (CH 2) 2o (CH 2) 2oCH 3.
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 6-position PEGylation is as follows:
R 6for PEGylation group, be selected from-CH 2oCH 2o (CH 2) 2oCH 3or-CH 2o (CH 2) 2o (CH 2) 2oCH 3.
Wherein the synthetic method of the 3-hydroxypyridin-4-one derivatives of 2,6-position PEGylation comprises the steps:
By 3-benzyloxy-2, the chlorine or bromine of 6-dihydroxymethyl-4H-pyrans-4-ketone and PEGylation is obtained by reacting 2 for thing, the pyranone compounds of 6-position PEGylation, 2 are obtained by reacting again with methylamine, 3-benzyloxypyridine-4-the ketone compound of 6-position PEGylation, finally under palladium carbon (Pd/C) catalysis, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 2,6-position PEGylation;
The chlorine or bromine of described PEGylation is ClCH for thing 2o (CH 2) 2o (CH 2) 2oCH 3or BrCH 2o (CH 2) 2o (CH 2) 2oCH 3.
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 2,6-position PEGylation is as follows:
R 2for-CH 2o (CH 2) 2o (CH 2) 2oCH 3, R 6for-CH 2o (CH 2) 2o (CH 2) 2oCH 3.
PEGylation 3-hydroxypyridin-4-one derivatives can be generated corresponding salt to acid-respons, and reaction formula is:
Described acid (HX) is strong inorganic acid, strong organic acid, saturated or undersaturated dicarboxylic acid or sulfonic acid; Wherein strong inorganic acid comprises sulfuric acid, phosphoric acid or hydrochloric acid, and strong organic acid comprises acetic acid, and saturated or undersaturated dicarboxylic acid comprises tartrate, citric acid, and sulfonic acid comprises o-methyl-benzene sulfonic acid or p-methyl benzenesulfonic acid.
PEGylation 3-pyridone-4-ketone compounds of the present invention can be used for the excessive disease drug of preparation iron-resistant ion.The results showed: PEGylation 3-pyridone-4-ketone compounds of the present invention has the ability of the metallic element, particularly ferro element of excess accumulation in the chela merge purge mankind and beasts body, and has good Orally active, its row's iron ability is remarkable.
Wherein the dosage form of the excessive disease drug of iron-resistant ion comprises liquid preparation and solid preparation, relates to granule, tablet or capsule and pill.The administering mode of the excessive disease drug of described iron-resistant ion comprises oral administration or drug administration by injection.
The present invention is optimized design to 3-hydroxypyridin-4-one derivatives emphatically, adds PEGylation group, improves the biological activity of its chelates ferric ions, reduce toxic action simultaneously.PEGylation 3-hydroxypyridin-4-one derivatives of the present invention has good biological activity, has the ability of the metallic element, particularly ferro element of excess accumulation in the chela merge purge mankind and beasts body, and has good Orally active, and its row's iron ability is remarkable.Rat experiment in vivo shows them to the result for the treatment of of Fe supply disease significantly better than the Compound C P20 gone on the market, therefore indivedual preferred compound (6a, 6b, 8a, 8b and 14d) be expected to become the medicine of new treatment Fe supply disease, rely on the disease of long-term massive transfusion for thalassemia and other, and in local organization, iron ion accumulates the damage caused, as the lesion tissue mediated by iron ion in nerve degenerative diseases and tumor disease, as heart, liver etc.
Four, accompanying drawing explanation
Fig. 1 is the synthetic route schematic diagram of the 3-hydroxypyridin-4-one derivatives of 1-position PEGylation.
Fig. 2 is the synthetic route schematic diagram of the 3-hydroxypyridin-4-one derivatives of 2-position PEGylation.
Fig. 3 is the synthetic route schematic diagram of the 3-hydroxypyridin-4-one derivatives of 6-position PEGylation.
Fig. 4 is the synthetic route schematic diagram of the 3-hydroxypyridin-4-one derivatives of 2,6-position PEGylation.
Fig. 5 is the PEGylation 3-hydroxypyridin-4-one derivatives prepared of the embodiment of the present invention and the I phase (white histogram) of CP29 and II phase (black histogram) metabolism test result figure.
Five, embodiment
The present invention is further described in conjunction with specific embodiments.
Embodiment (one)
The synthesis of example 1,3-benzyloxy-2-methyl-4H-pyrans-4-ketone
122.3g NaOH is dissolved in 278mL water, then is added in the 1160mL ethanolic soln containing 390g malt meal, after mixing, under agitation add 422g benzyl chlorine, fully after mixing at 60 DEG C heated and stirred 3.5h.After reaction system cooling, suction filtration removes solid impurity, filter residue is with washing with alcohol, and be spin-dried for after washings and filtrate being merged, surplus materials dissolves with methylene dichloride, then with 5wt%NaOH solution washing, last again with water washing, be spin-dried for solvent after organic over anhydrous dried over sodium sulfate, pale yellowish oil liquid can be obtained, can obtain target product with Diethyl ether recrystallization after cooling, yield is 82%.
MS(ESI,m/z):[M+H] +calcd for C 13H 13O 3217.09；found 217.10. 1H NMR(CDCl 3):δ2.08(s,3H),5.16(s,2H),6.37(d,J＝5.64Hz,1H),7.41-7.30(m,5H),7.60(d,J＝5.64Hz,1H). 13C NMR(CDCl 3):δ175.05,159.71,153.53,143.76,136.86,128.99(2C),128.41(2C),128.31,117.11,73.50,14.77.
The synthesis of example 2,3-benzyloxy-2-ethyl-4H-pyrans-4-ketone
122.3g NaOH is dissolved in 278mL water, then is added in the 1160mL ethanolic soln containing 390g malt meal, after mixing, under agitation add 422g benzyl chlorine, fully after mixing at 60 DEG C heated and stirred 3.5h; After reaction system cooling, suction filtration removes solid impurity, filter residue is with washing with alcohol, and be spin-dried for after washings and filtrate being merged, surplus materials dissolves with methylene dichloride, then with 5wt%NaOH solution washing, last again with water washing, be spin-dried for solvent after organic over anhydrous dried over sodium sulfate, pale yellowish oil liquid can be obtained, can obtain target product with Diethyl ether recrystallization after cooling, yield is 81%.
The synthesis of example 3,3-benzyloxy-6-methylol-4H-pyrans-4-ketone
Keep the reaction conditions of embodiment 1 constant, malt meal is replaced with the kojic acid of equivalent, obtain 3-benzyloxy-6-methylol-4H-pyrans-4-ketone, yield 70%.
MS(ESI,m/z):[M+H] +calcd for C 13H 13O 4233.08；found 233.17. 1H NMR(DMSO-d 6)δ:4.30(s,2H),4.95(s,2H),5.71(br s,1H),6.33(s,1H),7.34-7.44(m,5H),8.19(s,1H). 13C NMR(DMSO-d 6)δ:173.17,168.04,146.58,141.14,136.12,128.41(2C),128.16,128.11(2C),111.12,70.51,59.28.
The synthesis of example 4,3-benzyloxy-2,6-dihydroxymethyl-4H-pyrans-4-ketone
It is in the aqueous sodium hydroxide solution of 1.1M that 17.05g (120mmol) kojic acid is dissolved in 120mL concentration, then keeps 5min under stirring at room temperature; Slow dropping 10.22mL (3.78g, 126mmol) formalin (37%in water) is in reaction system and stirring at room temperature 24 hours, and the pH using concentrated hydrochloric acid (mass concentration 37%) regulation system is afterwards 1; Reaction solution is positioned in cold compartment of refrigerator (4 DEG C) and leaves standstill 8-12h, wash three final vacuum dryings with cold diethyl ether (temperature is-20 to-5 DEG C) after filtering-depositing and obtain white crystalline powder 3-benzyloxy-2,6-dihydroxymethyl-4H-pyrans-4-ketone (14.11g, 81mmol, yield 67.5%).MS(ESI,m/z):[M+H] +calcd for C 7H 9O 5173.04；found 172.91. 1H NMR(DMSO-d 6)δ:4.31(s,2H),4.41(s,2H),6.32(s,1H),6.98(s,1H). 13C NMR(DMSO-d 6)δ:173.94,167.55,149.28,141.62,108.81,59.47,54,97.
The synthesis of example 5,3-benzyloxy-2-methylol-6-methyl-4H-pyrans-4-ketone
Be that 11M aqueous sodium hydroxide solution joins containing 15.61g (100mmol) BH by 10mL concentration 3methanol solution in, be warming up to backflow under agitation condition, by 12.66mL (13.92g, 110mmol, 1.1equiv) benzyl chlorine solution is slowly added drop-wise in above-mentioned reaction solution, keep backflow and agitation condition reaction 8-12h, cooled and filtered removes Sodium chloride deposit in reaction solution, underpressure distillation is removed solvent and is obtained yellowish crude product, crude product is dissolved in methylene dichloride, the aqueous sodium hydroxide solution of 5wt% and distillation is used to wash once respectively, then anhydrous sodium sulfate drying is used, underpressure distillation uses methylene dichloride and sherwood oil (volume ratio is 3:1) recrystallization to obtain pure white solid product 3-benzyloxy-2-methylol-6-methyl-4H-pyrans-4-ketone (14.77g after removing solvent, 60mmol, yield 60%).
MS(ESI,m/z):[M+Na] +calcd for C 14H 14NaO 4269.08；found 269.07. 1H NMR(CDCl 3)δ:2.18(s,3H),4.21(s,2H),5.12(s,2H),6.13(s,1H),7.31-7.20(m,5H). 13C NMR(CDCl 3)δ:176.19,164.91,158.48,142.00,136.46,129.43(2C),128.79,128.71(2C),114.95,73.81,57.60,19.67.
The synthesis of the 3-hydroxypyridin-4-one derivatives of example 6,1-position PEGylation
To 3-benzyloxy-2-methyl-4H-pyrans-4-ketone (2a) (2.16g, 10mmol, methanol aqueous solution (water: methyl alcohol volume ratio 1equiv), 2 are added 50:50mL), 2 '-(ethylene dioxy) two (ethamine) (2.96g, 20mmol, 2equiv), the pH using l0N aqueous sodium hydroxide solution regulation system is 13; Then back flow reaction 12 hours under agitation; Utilize thin-layer chromatographic analysis (TLC) detection reaction, use ethyl acetate is developping agent, shows to react completely; Revolve the solvent steaming half in removing reaction solution, residual reaction liquid uses chloroform (5 × 50mL) extraction, use anhydrous sodium sulfate drying after combining extraction liquid and filter and obtain filtrate, crude product uses layer of silica gel post to analyse separation (ethanol/methylene after removing solvent by underpressure distillation, 1/10, v/v), obtain clean product 1-(2,2 '-(ethylene dioxy) bis-ethylamino)-2-methyl-3-benzyloxy-4-(1H)-pyridone (3a) (1.56g, 45%).
MS(ESI,m/z):[M+H] +calcd for C 19H 27N 2O 4,347.20；found 347.20. 1H NMR(CDCl 3):δ7.43-7.27(m,6H,H-6&Ph),6.41(d,J＝7.6Hz,1H,C-5H),5.22(s,2H,CH 2Ph),3.95(t,J＝5.2Hz,2H,H-7’),3.65(t,J＝5.2Hz,2H,H-2’),3.53(s,4H,H-4’,5’)3.46(q,J＝5.2Hz,2H,H-1’)2.85(t,J＝5.2Hz,2H,H-8’)2.12(s,3H,CH 3-2)1.81(brs,2H,-NH 2). 13C NMR(CDCl 3):δ173.57,145.93,140.87,139.07,137.61,129.12(2C),128.25(2C),127.95,116.97,73.35,72.99,70.95,70.23,69.88,53.12,41.63,12.69.
According to the reaction conditions of above-mentioned preparation 3a, 2a is used to obtain 3b, 7a and 7b respectively with 4,7,10-tri-oxygen-1,13-tridecane diamine, 2-(2-methoxy ethoxy) ethanol or 2-(2-amino ethoxy) ethanol synthesis respectively; Use 2b and 2,2 '-(ethylene dioxy) two (ethamine) obtains 3c;
The Chinese of 3b is 1-(4,7,10-tri-oxygen-1,13-tridecane diamine base)-2-methyl-3-benzyloxy-4-(1H)-pyridone.MS(ESI,m/z):[M+H] +calcd for C 23H 35N 2O 5,419.25；found 419.23. 1H NMR(CDCl 3):δ7.42-7.27(m,6H,H-6&Ph),6.41(d,J＝7.6Hz,1H,C-5H),5.23(s,2H,CH 2Ph),3.92(t,J＝6.8Hz,2H,H-1’),3.65-3.53(m,10H,H-5’,6’,8’&9’),3.35(t,J＝5.6Hz,2H,H-3’),2.78(t,J＝6.8Hz,2H,H-13’),2.09(s,3H,CH 3-2),1.86(m,2H,H-12’),1.72(m,2H,H-2’). 13C NMR(CDCl 3):δ173.40,146.08,140.73,138.98,137.65,129.19(2C),128.21(2C),127.94,117.11,72.91,70.63,70.41,70.27,70.22,69.50,66.11,50.18,39.57,33.34,30.22,12.28.
The Chinese of 7a is 1-(2-(2-methoxy ethoxy) second hydroxyl)-2-methyl-3-benzyloxy-4-(1H)-pyridone.
MS(ESI,m/z):[M+H] +calcd for C 18H 24NO 4,318.17；found 318.17. 1H NMR(CDCl 3):δ7.44-7.29(m,6H,H-6,H-6&Ph),6.41(d,J＝7.6Hz,1H,H-5),5.24(s,2H,CH 2Ph),3.95(t,J＝6.4Hz,2H,H-2’),3.66(t,J＝5.2Hz,2H,H-5’),3.54-3.46(m,4H,H-4’&1’),3.35(s,3H,H-7’),2.13(s,3H,CH 3-2). 13C NMR(CDCl 3):δ173.55,145.97,140.70,138.98,137.70,129.13(2C),128.23(2C),127.93,117.05,72.98,71.92,70.95,69.95,59.13,53.08,12.66.
The Chinese of 7b is 1-(2-(2-amino ethoxy) second hydroxyl)-2-methyl-3-benzyloxy-4-(1H)-pyridone.
MS(ESI,m/z):[M+H] +calcd for C 17H 22NO 4,304.15；found 304.14. 1H NMR(D 2O):δ7.60(d,J＝7.2Hz,1H,H-6),7.28(brs,5H,H-Ph),6.44(d,J＝7.6Hz,1H,H-5)4.92(s,2H,CH 2Ph)4.03(t,J＝5.2Hz,2H,H-5’)3.58(t,J＝5.2Hz,2H,H-2’)3.50(m,2H,H-4’),3.33(m,2H,H-1’)1.97(s,3H,CH 3-2). 13C NMR(D 2O):δ172.18,144.82,143.35,140.45,134.68,128.76(2C),127.82,127.54(2C),114.66,72.96,71.05,67.92,59.27,52.62,11.38.
The Chinese of 3c is 1-(2,2 '-(ethylene dioxy) two (ethamine) base)-2-ethyl-3-benzyloxy-4-(1H)-pyridone.
HRMS(ESI,m/z):[M+H] +calcd for C 20H 29N 2O 4,361.2127；found 361.2129. 1H NMR(CDCl 3):δ7.44-7.26(m,6H,H-6&Ph),6.40(d,J＝7.5Hz,1H,H-5),5.26(s,2H,CH 2Ph),3.96(t,J＝5.2Hz,2H,H-7’),3.67(t,J＝5.2Hz,2H,H-2’),3.53(s,4H,H-4’&5’),3.45(t,J＝5.3Hz,4H,H-1’)2.84(t,J＝5.3Hz,2H,H-8’),2.62(q,J＝7.5Hz,2H,H-11’),1.00(t,3H,J＝7.5Hz,CH 3-2). 13CNMR(CDCl 3):δ173.79,145.74,145.60,139.08,137.94,128.70(2C),128.25(2C),127.83,117.12,73.26,72.84,70.97,70.36,70.24,52.53,41.62,19.39,13.09.
To 3a (2.7g, 5wt% palladium-carbon catalyst (0.25g) is added in the mixing solutions of 10mmol), 90mL methyl alcohol and 10mL water, under this mixture is positioned over atmosphere of hydrogen at ambient temperature (initial hydrogen pressure is by force 2.0bar), react after 6 hours and filter removal catalyzer, underpressure distillation is removed solvent and is obtained yellow oil 1-(2,2 '-(ethylene dioxy) bis-ethylamino)-2-methyl-3-hydroxyl-4-(1H)-pyridone (4a) (1.50g, 80%).Getting 10mL 2M hydrochloric acid soln joins in beaker, by hydrochloric acid and 4a compound mole ratio 1:1, adds 4a in beaker, stirring at room temperature 5-10min, then the hydrochloride that solvent obtains 4a is removed in solution decompression distillation.
HRMS(ESI,m/z):calcd for C 12H 21N 2O 4[M+H] +:257.1501；found:257.1496. 1H NMR(DMSO-d 6):δ7.54(d,J＝7.3Hz,1H,H-6),6.12(d,J＝7.3Hz,1H,H-5),4.12(t,J＝5.2Hz,2H,H-7’),3.67(t,J＝5.2Hz,2H,H-2’),3.52-3.48(m,4H,H-4’,5’),3.44(t,J＝5.6Hz,2H,H-1’),2.77(t,J＝5.6Hz,2H,H-8’),2.30(s,3H,CH 3-2). 13C NMR(D 2O):δ170.35,148.50,137.01,134.93,111.78,69.99,69.32,69.25,69.12,53.71,39.38,11.90.
Keep above-mentioned preparation 4a hydrogenation conditions constant, change initial reactant, use 3b, 7a or 7b respectively, can 4b, 8a or 8b be obtained.
The Chinese of 4b is 1-(4,7,10-tri-oxygen-1,13-tridecane diamine base)-2-methyl-3-hydroxyl-4-(1H)-pyridone, productive rate 85%.
HRMS(ESI,m/z):calcd for C 10H 16NO 4[M+H] +:214.1079；found:214.1076. 1H NMR(D 2O):δ7.95(d,J＝7.0Hz,1H,H-6),6.99(d,J＝7.0Hz,1H,H-5),4.45(t,J＝4.8Hz,1H,H-5’),3.83(t,J＝4.8Hz,1H,H-2’),3.54-3.44(m,4H,H-4’&1’),2.49(s,3H,CH 3-2). 13C NMR(D 2O):δ158.85,142.59,142.47,139.24,110.57,71.98,68.41,60.26,55.64,12.38.
The Chinese of 8a is 1-(2-(2-methoxy ethoxy) second hydroxyl)-2-methyl-3-hydroxyl-4-(1H)-pyridone, productive rate: 90%.HRMS (ESI, m/z): calcd for C 11h 18nO 4[M+H] +: 228.1236; Found:228.1230. 1h NMR (D 2o): δ 7.59 (d, J=7.2Hz, 1H, H-6), 6.46 (d, J=7.2Hz, 1H, H-5), 4.21 (t, J=5.2Hz, 1H, H-2 '), 3.77 (t, J=5.2Hz, 1H, H-5 '), 3.52-3.41 (m, 4H, H-4 ' & 1 '), 3.19 (s, 3H, H-7 '), 2.35 (s, 3H, CH 3-2). 13c NMR (D 2o): δ 168.54,144.50,139.13,135.14,112.05,70.95,69.79,69.08,57.98,53.65,11.70.
The Chinese of 8b is 1-(2-(2-amino ethoxy) second hydroxyl)-2-methyl-3-hydroxyl-4-(1H)-pyridone, productive rate: 90%.HRMS (ESI, m/z): calcd for C 10h 16nO 4[M+H] +: 214.1079; Found:214.1076. 1h NMR (D 2o): δ 7.95 (d, J=7.0Hz, 1H, H-6), (6.99 d, J=7.0Hz, 1H, H-5), 4.45 (t, J=4.8Hz, 1H, H-5 '), 3.83 (t, J=4.8Hz, 1H, H-2 '), 3.54-3.44 (m, 4H, H-4 ' & 1 '), 2.49 (s, 3H, CH 3-2). 13c NMR (D 2o): δ 158.85,142.59,142.47,139.24,110.57,71.98,68.41,60.26,55.64,12.38.
Example 7, acidylate 1-position PEGylation 3-hydroxypyridin-4-one derivatives
At nitrogen atmosphere, to Acetyl Chloride 98Min. (0.34g.4.3mmol under 0 DEG C of condition, 1.5equiv) and 5mL DMF solution in slowly drip 1-(2,2 '-(ethylene dioxy) bis-ethylamino)-2-methyl-3-benzyloxy-4-(1H)-pyridone (3a) (1.0g, 2.9mmol, 1equiv), the mixing solutions of anhydrous methylene chloride (30mL) and triethylamine (1.46g, 25mmol, 5equiv), after being added dropwise to complete, reaction solution is reacted 8-12 hour under nitrogen atmosphere and room temperature condition, then filtering-depositing obtains filtrate, high vacuum Rotary Evaporators is used to obtain crude product by after removal of solvents, crude product is dissolved in 25mL water, then the aqueous sodium hydroxide solution regulator solution pH using 10N concentration is 11, use methylene dichloride (3 × 50mL) extraction, filter after using anhydrous sodium sulfate drying after combining extraction liquid and obtain filtrate, after evaporate to dryness, residual substance is put into layer of silica gel post and analyse analysis (MeOH/DCM, 1/20, v/v) 1-(1-amido-2 is obtained, 2 '-(ethylene dioxy) acetamido)-2-methyl-3-benzyloxy-4-(1H)-pyridone (5a) (0.57g, 51%).
MS(ESI,m/z):[M+H] +calcd for C 21H 29N 2O 5,389.21；found 389.14. 1H NMR(CDCl 3):δ7.42-7.28(m,6H,H-6&Ph),6.41(d,J＝7.6Hz,1H,H-5),6.18(brs,1H,NH)5.21(s,2H,CH 2Ph),3.95(t,J＝5.2Hz,2H,H-7’),3.65(t,J＝5.2Hz,2H,H-2’),3.50(s,4H,H-4’&5’)3.46-3.36(m,4H,H-1’&8’)2.14(s,3H,CH 3-2)1.97(s,3H,COCH 3). 13C NMR(CDCl 3):δ173.57,170.39,145.93,141.00,139.04,137.55,129.09(2C),128.29(2C),128.02,117.00,72.99,70.97,70.10,69.94,69.86,53.14,39.22,23.26,12.74.
Keep above-mentioned preparation 5a condition constant, 3a become 3b, can 5b be obtained,
The Chinese of 5b: 1-(1-amido-4,7,10-tri-oxygen-1,13-tridecane acetamido)-2-methyl-3-benzyloxy-4-(1H)-pyridone, productive rate 45%.
MS(ESI,m/z):[M+H] +calcd for C 25H 37N 2O 6,461.27；found 461.11. 1H NMR(CDCl 3):δ7.45-7.29(m,6H,H-6,Ph),6.43(d,J＝7.6Hz,1H,C-5H),5.22(s,2H,CH 2Ph),3.93(t,J＝6.4Hz,2H,H-1’),3.65-3.53(m,10H,H--5’,6’,8,9’&13’),3.37-3.32(m,4H,H-3’&11’),2.11(s,3H,CH 3-2),1.97(s,3H,COCH 3),1.88-1.76(m,4H,H-12’&2’). 13C NMR(CDCl 3):δ173.42,170.43,146.09,140.74,139.56,137.61,129.13(2C),128.23(2C),127.98,116.94,72.94,70.61,70.41,70.32,70.19,69.89,65.94,50.01,37.63,29.96,29.09,23.25,12.26.
Keep above-mentioned preparation 5a condition constant, Acetyl Chloride 98Min. is changed to propionyl chloride, 1-(1-amido-2,2 '-(ethylene dioxy) propionamido-)-2-methyl-3-benzyloxy-4-(1H)-pyridone (5c) can be obtained; Keep above-mentioned preparation 5a condition constant, Acetyl Chloride 98Min. is changed to propionyl chloride, 3a is changed to 3c and can obtains 1-(1-amido-2,2 '-(ethylene dioxy) propionamido-)-2-ethyl-3-benzyloxy-4-(1H)-pyridone (5d).
The Chinese of 5c: 1-(1-amido-2,2 '-(ethylene dioxy) propionamido-)-2-methyl-3-benzyloxy-4-(1H)-pyridone, productive rate 40%.
HRMS(ESI,m/z):calcd for C 22H 31N 2O 5,403.2233found 403.2253. 1H NMR(CDCl 3):δ7.43-7.27(m,6H,H-6&Ph),6.40(d,J＝7.5Hz,1H,H-5),5.21(s,2H,CH 2Ph),3.96(t,J＝5.1Hz,2H,H-7’),3.65(t,J＝5.1Hz,2H,H-2’),3.50(s,4H,H-4’&5’),3.48-3.37(m,4H,H-1’&8’),2.24-2.14(m,H-11’&CH 3-2),1.14(t,3H,J＝7.6Hz,H-12’). 13C NMR(CDCl 3):δ174.07,173.55,145.95,141.04,139.08,137.55,129.09(2C),128.28(2C),128.02,116.96,73.02,70.94,70.11,70.01,69.86,53.16,39.08,29.62,12.73,9.87.
The Chinese of 5d: 1-(1-amido-2,2 '-(ethylene dioxy) propionamido-)-2-ethyl-3-benzyloxy-4-(1H)-pyridone, productive rate 39%).
HRMS(ESI,m/z):[M+Na +]calcd for C 23H 32N 2NaO 5,439.2209found 439.2224. 1H NMR(CDCl 3):δ7.46-7.27(m,6H,H-6&Ph),6.40(d,J＝7.5Hz,1H,H-5),5.27(s,2H,CH 2Ph),3.97(t,J＝5.2Hz,2H,H-7’),3.67(t,J＝5.2Hz,2H,H-2’),3.51(s,4H,H-4’&5’),3.49-3.38(m,4H,H-1’&8’),2.65(q,J＝7.6Hz,2H,CH 2-2),2.21(q,J＝7.6Hz,2H,H-11’),1.94(brs,2H,-NH 2),1.14(t,3H,J＝7.6Hz,CH 3-2),1.00(t,J＝7.5Hz,2H,H-12’). 13C NMR(CDCl 3):δ174.00,173.83,145.68,139.05,137.85,128.71(2C),128.28(2C),127.89,117.12,72.84,70.96,70.32,70.10,70.00,52.56,39.05,32.59,29.62,19.37,13.10,9.86.
Keep above-mentioned hydrogenation conditions (reaction of preparation 4a) constant, change initial reactant, use 5a, 5b, 5c or 5d respectively, 6a, 6b, 6c or 6d can be obtained respectively.
The Chinese of 6a: 1-(1-amido-2,2 '-(ethylene dioxy) acetamido)-2-methyl-3-hydroxyl-4-(1H)-pyridone, productive rate 90%.
HRMS(ESI,m/z):calcd for C 14H 23N 2O 5[M+H] +:299.1607；found:299.1603. 1H NMR(D 2O):δ7.93(d,J＝7.0Hz,1H,H-6),6.98(d,J＝7.0Hz,1H,H-5),4.44(t,J＝5.0Hz,1H,H-5’),3.82(t,J＝5.0Hz,1H,H-2’),3.52-3.48(m,4H,H-4’&5’),3.40(t,J＝5.5Hz,2H,H-1’),3.19(t,J＝5.5Hz,2H,H-8’),2.50(s,3H,CH 3-2),1.86(s,3H,H-11’). 13C NMR(D 2O):δ174.18,159.28,142.58,142,32,139.16,110.63,69.97,69.27,68.65,68.49,55.50,38.90,21.73,12.38.
The Chinese of 6b: 1-(1-amido-4,7,10-tri-oxygen-1,13-tridecane acetamido)-2-methyl-3-hydroxyl-4-(1H)-pyridone, productive rate 91%.
HRMS(ESI,m/z):calcd for C 18H 31N 2O 6[M+H] +:371.2182；found:371.2177. 1H NMR(CDCl 3):δ7.87(d,J＝7.0Hz,1H,H-6),6.43(d,J＝7.0Hz,1H,H-5),4.33(t,J＝6.4Hz,2H,H-1’),3.66-3.53(m,8H,H--5’,6’,8’&9’),3.39(t,J＝5.5Hz,2H,H-13’),3.33-3.28(m,2H,H-3’),2.52(s,3H,CH 3-2),2.06(m,2H,H-12’),1.98(s,3H,COCH 3),1.78(m,2H,H-2’). 13C NMR(CDCl 3):δ173.42,170.43,146.09,140.74,139.56,137.61,129.13(2C),128.23(2C),127.98,116.94,72.94,70.61,70.41,70.32,70.19,69.89,65.94,50.01,37.63,29.96,29.09,23.25,12.26.
The Chinese of 6c: 1-(1-amido-2,2 '-(ethylene dioxy) propionamido-)-2-methyl-3-hydroxyl-4-(1H)-pyridone, productive rate 93%.
1H NMR(CDCl 3):δ7.35(d,J＝7.3Hz,1H,H-6),6.39(d,J＝7.2Hz,1H,H-5),4.09(t,J＝5.1Hz,2H,H-7’),3.74(t,J＝5.1Hz,2H,H-2’),3.54(s,4H,H-4’&5’),3.49-3.38(m,4H,H-1’&8’),2.41(s,3H,2-CH 3),2.21(q,J＝7.6Hz,2H,H-11’),1.15(t,J＝7.6Hz,3H,H-12’). 13C NMR(CDCl 3):δ174.01,169.43,145.96,137.76,128.81,111.03,70.90,70.14,70.01,69.92,53.31,39.08,29.62,12.20,9.86.
The Chinese of 6d: 1-(1-amido-2,2 '-(ethylene dioxy) propionamido-)-2-ethyl-3-hydroxyl oxygen base-4-(1H)-pyridone, productive rate 92%).
1H NMR(CDCl 3):δ7.33(d,J＝7.3Hz,1H,H-6),6.39(d,J＝7.3Hz,1H,H-5),4.08(t,J＝5.2Hz,2H,H-7’),3.74(t,J＝5.2Hz,2H,H-2’),3.55(s,4H,H-4’&5’),3.50-3.39(m,4H,H-1’&8’),2.83(q,J＝7.5Hz,2H,H-12’),2.21(q,J＝7.5Hz,2H,H-11’),1.22(t,3H,J＝7.6Hz,CH 3-2),1.15(t,J＝7.6Hz,2H,H-12’).. 13C NMR(CDCl 3):δ174.00,169.85,145.52,137.82,133.84,111.08,70.92,70.32,70.12,70.01,52.78,39.06,29.63,19.26,12.62,9.85.
The synthesis of the 3-hydroxypyridin-4-one derivatives of example 8,2-position PEGylation
3-benzyloxy-2-methylol-6-methyl-4H-pyrans-4-ketone (9) (1.06g is added in a 50mL there-necked flask, 4.3mmol) with 20mL N, dinethylformamide, the bromo-2-of 1-(2-methoxy ethoxy) ethane (2.89mL, 21.5mol) is slowly dripped by constant pressure funnel under agitation condition, after being added dropwise to complete, the pale yellow solution in flask is stirred 30min at 25 DEG C, then by sodium hydride (60wt%) (0.34g, 8.6mmol) join in the there-necked flask of another 50mL, use normal hexane (3 × 5mL) to remove mineral oil wherein, the constant pressure funnel of then installing a 50mL is on the flask putting sodium hydride and pass into nitrogen protection, the pale yellow solution of above-mentioned preparation is joined in constant pressure funnel, is then added dropwise to complete in 1.5 hours under nitrogen atmosphere agitation condition, in dropping process, solution colour in flask becomes scarlet, afterwards solution is reacted under room temperature condition the solvent in the Rotary Evaporators removal solution then using condition of high vacuum degree for 48 hours, remaining dissolution of solid is in 100mL water, then methylene dichloride (3 × 20mL) is used to extract, after extracting the organic phase merging obtained, use anhydrous sodium sulfate drying, after filtering, evaporate to dryness obtains crude product, used by crude product layer of silica gel post to analyse (moving phase: ethyl acetate and normal hexane volume ratio are 1:1) to purify and obtain clean product 3-benzyloxy-2-(1-methylol-2-(2-methoxy ethoxy) ethyl group)-6-methyl-4H-pyrans-4-ketone (10b).
MS(ESI,m/z):[M+Na] +calcd for C 19H 24NaO 6371.15；found 371.20. 1H NMR(CDCl 3):δ7.41-7.28(m,5H,H-Ph),6.21(s,1H,C-5H),5.20(s,2H,CH 2Ph),4.32(s,2H,CH 2-2),3.63-3.52(m,8H,(OCH 2CH 2) 2),3.37(s,3H,OCH 3),2.28(s,3H,CH 3-6). 13C NMR(CDCl 3):δ176.00,164.86,156.06,143.72,136.70,129.01(2C),128.47(2C),128.35,114.97,74.05,71.90,70.56,70.38,70.20,64.73,58.99,19.65.
According to the reaction conditions of above-mentioned preparation 13a, 9 are used to obtain compound 10a with 2-methoxvethoxvmethvl chlorine.
The Chinese of 10a: 3-benzyloxy-2-(1-methylol-2-(2-methoxvethoxvmethvl))-6-methyl-4H-pyrans-4-ketone .MS (ESI, m/z): [M+H] +calcd for C 18h 23o 6335.15; Found 335.13. 1h NMR (CDCl 3): δ 7.43-7.31 (m, 5H, H-Ph), 6.23 (s, 1H, C-5H), 5.21 (s, 2H, CH 2ph), 4.72 (s, 2H, OCH 2o), 4.38 (s, 2H, CH 2-2), 3.70-3.51 (m, 4H, OCH 2cH 2o), 3.39 (s, 3H, OCH 3), 2.29 (s, 3H, CH 3-6). 13c NMR (CDCl 3): δ 176.09,164.82,156.04,143.61,136.65,128.96 (2C), 128.48 (2C), 128.36,115.03,95.45,74.06,71.62,67.12,61.20,59.04,19.70.
According to the reaction conditions of above-mentioned preparation 3a, 10a or 10b and methylamine is used to be obtained by reacting 11a or 11c;
The Chinese of 11a: 1-methyl-2-(1-methylol-2-(2-methoxvethoxvmethvl))-3-benzyloxy-6-methyl-4H-pyridone, productive rate: 40%.
MS(ESI,m/z):[M+H] +calcd for C 19H 26NO 5348.18；found 347.98. 1H NMR(CDCl 3):δ7.46-7.31(m,5H,H-Ph),6.39(s,1H,C-5H),5.27(s,2H,CH 2Ph),4.66(s,2H,OCH 2O),4.61(s,2H,CH 2-2),3.67-3.65(m,11H,OCH 2CH 2O),3.60(s,3H,CH 3O),3.50-3.48(m,2H,OCH 2CH 2O),3.37(s,3H,CH 3-1),3.32(s,3H,CH 3-6). 13C NMR(CDCl 3):δ173.75,147.07,146.58,139.20,137.48,128.93(2C),128.33(2C),127.97,118.99,95.21,73.61,71.64,67.51,60.06,59.09,35.76,20.77.
The Chinese of 11c: 1-methyl-2-(1-methylol-2-(2-methoxy ethoxy) ethyl group)-3-benzyloxy-6-methyl-4H-pyridone, productive rate: 26%.
MS(ESI,m/z):[M+H] +calcd for C 20H 28NO 5,362.20；found 362.06. 1H NMR(CDCl 3):δ7.36-7.26(m,5H,H-Ph),6.29(s,1H,C-5H),5.17(s,2H,CH 2Ph),4.45(s,2H,CH 2-2),3.55-3.45(m,11H,(OCH 2CH 2) 2&OCH 3),3.30(s,3H,CH 3-1),2.25(s,3H,CH 3-6). 13C NMR(CDCl 3):δ173.57,147.46,146.48,139.37,137.32,128.90(2C),128.34(2C),128.02,118.68,73.68,71.80,70.35,70.17,69.19,63.04,58.95,35.81,20.69.
Keep above-mentioned preparation 4a hydrogenation conditions constant, change initial reactant, use 11a or 11c respectively, can 11b or 11d be obtained.
The Chinese of 11b: 1-methyl-2-(1-methylol-2-(2-methoxvethoxvmethvl))-3-hydroxyl-6-methyl-4H-pyridone, productive rate: 85%.
HRMS(ESI,m/z):[M+H] +calcd for C 12H 20NO 5258.1341；found 258.1341. 1H NMR(D 2O):δ6.53(s,1H,H-5),4.82(s,2H,OCH 2O),4.74(s,2H,CH 2-2),3.68(s,3H,OCH 3),3.62-3.45(m,4H,(OCH 2CH 2O),3.24(s,3H,CH 3-1),2.33(s,3H,CH 3-6). 13C NMR(D 2O):δ166.95,149.33,144.70,133.18,113.93,95.01,70.92,67.03,59.69,57.99,36.90,20.04.
The Chinese of 11d: 1-methyl-2-(1-methylol-2-(2-methoxy ethoxy) ethyl group)-3-hydroxyl-6-methyl-4H-pyridone, productive rate: 90%.
HRMS(ESI,m/z):[M+H] +calcd for C 13H 22NO 5272.1498；found 272.1495. 1H NMR(CDCl 3):δ6.37(s,1H,C-5H),4.79(s,2H,CH 2-2),3.70(s,3H,OCH 3),3.70-3.54(m,8H,(OCH 2CH 2) 2),3.39(s,3H,CH 3-1),2.37(s,3H,CH 3-6). 13C NMR(CDCl 3):δ169.64,146.48,146.40,127.35,112.78,71.90,70.44,70.31,69.13,62.93,59.04,35.84,20.99.
The synthesis of the 3-hydroxypyridin-4-one derivatives of example 9,6-position PEGylation
According to the reaction conditions of above-mentioned preparation 10b, the kojic acid (12) of benzyl protection and the bromo-2-of 1-(2-methoxy ethoxy) ethane is used to obtain compound 13b.
The Chinese of 13b is: 3-benzyloxy-6-(1-methylol-2-(1-methoxyl group-2-(2-methoxy ethoxy) ethane)-4H-pyrans-4-ketone.
MS(ESI,m/z):[M+H] +calcd for C 18H 23O 6,335.15；found 335.22. 1H NMR(CDCl 3):δ7.53(s,1H,C-6H),7.42-7.33(m,5H,H-Ph),6.51(s,1H,C-3H),5.09(s,2H,CH 2Ph),4.35(s,2H,CH 2-2),3.73-3.64(m,8H,(OCH 2CH 2) 2),3.57-3.55(m,3H,OCH 3). 13C NMR(CDCl 3):δ174.65,164.00,147.12,141.58,135.75,128.71(2C),128.41,127.81(2C),113.64,71.91(2C),70.79,70.71,70.57,68.90,59.08.
The Chinese of 13a is: 3-benzyloxy-6-(1-methylol-2-methoxvethoxvmethvl chlorine)-4H-pyrans-4-ketone.
Compound 12 (8.17g, 35mmol) is dissolved in chloroform (50mL), then adds diisopropylethylamine (8.0mL) and 2-methoxvethoxvmethvl chlorine (3.2mL).After mixture reacts 30min under ice-water bath agitation condition, reaction is positioned over room temperature and reacts and spend the night.5% potassium hydrogen sulfate solution is joined in above-mentioned reaction, then chloroform extraction is used, extraction liquid is merged and uses saturated sodium bicarbonate aqueous solution and sodium chloride aqueous solution washing, remove solvent with underpressure distillation after anhydrous sodium sulfate drying afterwards, use layer of silica gel post to analyse separation (normal hexane: ethyl acetate=4:1-2:1) and obtain clean product 13a.
MS(ESI,m/z):[M+H] +calcd for C 17H 21O 6,321.13；found 321.17. 1H NMR(CDCl 3):δ7.45(s,1H,C-6H),7.34-7.20(m,5H,H-Ph),6.40(s,1H,C-3H),5.00(s,2H,CH 2Ph),4.71(s,2H,OCH 2O),4.31(s,2H,CH 2-2),3.66-3.46(m,4H,OCH 2CH 2O),3.31(s,3H,OCH 3). 13C NMR(CDCl 3):δ174.62,163.74,147.12,141.59,135.73,128.71(2C),128.42,127.80(2C),113.72,95.27,71.91,71.61,67.39,64.78,59.07.
According to the reaction conditions of above-mentioned preparation 3a, 13a or 13b and methylamine is used to be obtained by reacting 14a or 14c;
The Chinese of 14a is: 1-methyl-3-benzyloxy-6-(1-methylol-2-methoxvethoxvmethvl chlorine)-4H-pyridone, productive rate: 38%.
MS(ESI,m/z):[M+H] +calcd for C 18H 24NO 5,334.17；found 334.03. 1H NMR(CDCl 3):δ7.44-7.30(m,5H,H-Ph),6.96(s,1H,C-6H),6.52(s,1H,C-3H),5.20(s,2H,CH 2Ph),4.77(s,2H,OCH 2O),4.44(s,2H,CH 2-2),3.73-3.55(m,7H,OCH 2CH 2O&CH 3-1),3.41(s,3H,OCH 3). 13C NMR(CDCl 3):δ173.34,148.13,143.84,136.82,129.43,128.54(2C),128.04,127.87(2C),118.96,94.75,71.85,71.64,67.54,65.34,59.13,40.46.
The Chinese of 14c is: 1-methyl-3-benzyloxy-6-(1-methylol-2-(1-methoxyl group-2-(2-methoxy ethoxy) ethane)-4H-pyridone, productive rate: 36%.
MS(ESI,m/z):[M+H] +calcd for C 19H 26NO 5,348.18；found 348.20. 1H NMR(CDCl 3):δ7.35-7.23(m,5H,H-Ph),6.99(s,1H,C-6H),6.39(s,1H,C-3H),5.05(s,2H,CH 2Ph),4.33(s,2H,CH 2-2),3.59-3.47(m,11H,(OCH 2CH 2) 2&CH 3-1),3.31-3.30(m,3H,OCH 3). 13C NMR(CDCl 3):δ172.96,162.31,148.16,144.05,136.44,128.53(2C),128.11,127.75(2C),118.62,71.80,71.64,70.45,70.32,69.65,69.60,58.95,40.63.
Keep the hydrogenation conditions of above-mentioned preparation 4a constant, change initial reactant, use 14a or 14c respectively, can 14b or 14d be obtained.
The Chinese of 14b is: 1-methyl-3-hydroxyl-6-(1-methylol-2-methoxvethoxvmethvl chlorine)-4H-pyridone, productive rate: 86%.
HRMS(ESI,m/z):[M+H] +calcd for C 11H 18NO 5,244.1185；found 244.1179. 1H NMR(D 2O):δ7.53(s,1H,H-6),6.56(s,1H,H-3),4.74(s,2H,OCH 2O),4.55(s,2H,CH 2-2),3.69(s,3H,CH 3-1),3.65-3.48(m,4H,OCH 2CH 2O),3.25(s,3H,OCH 3). 13C NMR(D 2O):δ170.42,146.11,144.66,128.78,115.76,94.83,70.89,67.03,65.40,57.99,40.98.
The Chinese of 14d is: 1-methyl-3-hydroxyl-6-(1-methylol-2-(1-methoxyl group-2-(2-methoxy ethoxy) ethane)-4H-pyridone, productive rate: 86%.
HRMS(ESI,m/z):[M+H] +calcd for C 12H 20NO 5,258.1341；found 258.1339. 1H NMR(D 2O):δ7.61(s,1H,H-6),6.68(s,1H,H-3),4.49(s,2H,CH 2-2),3.71(s,3H,CH 3-1),3.64-3.46(m,8H,(OCH 2CH 2) 2),3.23(s,3H,OCH 3). 13C NMR(D 2O):δ169.41,145.85,144.61,128.92,115.44,70.92,69.41,69.34,69.27,68.15,57.94,41.04.
The synthesis of the 3-hydroxypyridin-4-one derivatives of example 9,2,6-position PEGylation
According to the reaction conditions of above-mentioned preparation 10b, 15 are used to obtain compound 16 with the bromo-2-of 1-(2-methoxy ethoxy) ethane.
The Chinese of 16 is: 3-benzyloxy-2,6-bis-(1-methylol-2-(2-methoxy ethoxy) ethyl group)-4H-pyrans-4-ketone .MS (ESI, m/z): [M+H] +calcd for C 24h 35o 9467.23; Found 467.16. 1h NMR (CDCl 3): δ 7.24-7.14 (m, 5H, H-Ph), 6.34 (s, 1H, C-5H), 5.03 (s, 2H, CH 2ph), 4.21 (s, 2H, CH 2-2), 4.14 (s, 2H, CH 2-6), 3.58-3.34 (m, 16H, O CH 2cH 2oCH 2cH 2oCH 2-2 &-6), 3.23 (s, 3H, CH 3-1), 3.20 (s, 3H, CH 3-6). 13c NMR (CDCl 3): δ 175.92,164.22,156.12,144.14,136.56,129.07 (2C), 128.54 (2C), 128.45,113.83,74.09,71.92,71.89,70.92,70.74,70.58,70.56,70.38,70.21,68.73,64.70,59.11,59.07.
According to the reaction conditions of above-mentioned preparation 3a, 16 are used to be obtained by reacting 17a with methylamine.
The Chinese of 17a is: 1-methyl-3-benzyloxy-2,6-bis-(1-methylol-2-(2-methoxy ethoxy) ethyl group)-4H-pyridone, productive rate: 31%.
MS(ESI,m/z):[M+H] +calcd for C 25H 38NO 8480.26；found 479.94. 1H NMR(CDCl 3):δ7.45-7.32(m,5H,H-Ph),6.53(s,1H,C-5H),5.28(s,2H,CH 2Ph),4.55(s,2H,CH 2-2),4.46(s,2H,CH 2-6),3.72(s,3H,CH 3-1),3.69(s,4H,CH 2OCH 3-2&-6),3.66-3.51(m,12H,OCH 2CH 2OCH 2-2&-6),3.40(s,3H,CH 3-1),3.38(s,3H,CH 3-6). 13C NMR(CDCl 3):δ173.65,147.25,145.40,140.06,137.39,128.98(2C),128.40(2C),128.07,119.97,73.71,71.91,71.88,70.60,70.58,70.46(2C),70.26,69.67,69.30,63.02,59.09,59.06,35.43.
Keep the hydrogenation conditions of above-mentioned preparation 4a constant, change initial reactant, use 17a that benzyl deprotection is obtained 17b.The Chinese of 17b is: 1-methyl-3-hydroxyl-2,6-bis-(1-methylol-2-(2-methoxy ethoxy) ethyl group)-4H-pyridone, productive rate: 88%.
HRMS(ESI,m/z):[M+H] +calcd for C 18H 32NO 8390.2128；found 390.2128. 1H NMR(D 2O):δ7.16(s,1H,H-5),4.87(s,4H,CH 2-2&CH 2-6),3.91(s,3H,CH 3-1),3.69-3.47(m,16H,(OCH 2CH 2) 2),3.26(s,3H,OCH 3-2)3.25(s,3H,OCH 3-6). 13C NMR(D 2O):δ161.32,147.40,144.23,138.28,112.76,70.94(2C),69.79,69.42-69.37(5C),68.40,61.63,57.98,57.97,37.73.
The Purificatiou of embodiment (two) 3-hydroxypyridin-4-one derivatives and physico-chemical constant test
The pKa of example 1, PEGylation 3-hydroxypyridin-4-one derivatives and iron affinity coefficient
In order to study part and the iron affinity constant of PEGylation, choosing some parts and testing its iron sequestering power value (pFe iIIvalues).The present invention uses the fluorescence analysis method reported to measure its pFe iIIvalue, fluorescent probe CP691 synthesizes according to bibliographical information and stand-by (reference: Ma, Y. under being stored in room temperature condition; Xie, Y.; Hider, R.C., A novel fluorescencemethod for determination of pFe 3+.Analyst 2013,138 (1), 96-99.).As seen from Table 1, the pyridinone compounds of PEGylation is compared with the pFe of Deferiprone sheet iIIvalue does not have difference clearly.Methylate and slightly can reduce the pFe of compound with amidated pyridinone compounds iIIvalue.1-position end contains the pyridinone compounds pFe of N class iIIbe worth a little more than the pyridinone compounds containing O.But the pFe of compound 14b and 14d iIIvalue, higher than Deferiprone, in iron chelating agent clinical application, has some superiority.Wherein the structural formula of compound 18 is as follows:
The pK of table 1. PEGylation 3-hydroxypyridin-4-one derivatives awith iron affinity coefficient
Glycosylation and the metabolism research of example 2, PEGylation 3-hydroxypyridin-4-one derivatives
Deferiprone is that 3-position hydroxyl is easy at liver glycosylation as the problem that oral de-iron medicine is maximum, is so just difficult to chelated iron further again.In order to probe into the metabolic effects of its PEGylation pyridinone compounds at human body, we have chosen some pyridinone compounds in the hepatomicrosome of people, carry out I phase and II phase metabolism test, I phase and the II phase metabolism test result of 6a in the drug metabolism of synthesis can be found out, be starkly lower than CP20 by the efficiency that metabolism is fallen.
In a word, the present invention has synthesized a series of poly ethyldiol modified 3-hydroxyl-4-pyridine compounds, test the important parameter such as its physico-chemical property and iron affinity, show that these pyridinone compounds synthesizing preparation have very high iron sequestering power and the physico-chemical property as oral pharmaceutical excellence.The synthesis of the macromolecular compound for carrying out below is provided good theoretical basis by this, and it can be used as the high molecular functional unit of synthesis or monomer will to be very effective methods must synthesizing polymer iron chelate.Wherein the structural formula of compound 19 is as follows:

Claims (10)

1. a PEGylation 3-pyridone-4-ketone compounds, comprises PEGylation 3-hydroxypyridin-4-one derivatives and salt thereof, it is characterized in that: the general structure of described PEGylation 3-hydroxypyridin-4-one derivatives is as follows:
R 1be selected from-CH 2(CH 2oCH 2) 2cH 2nHCOCH 2cH 3,-CH 3,-(CH 2) 2o (CH 2) 2oH ,-(CH 2) 2o (CH 2) 2oCH 3,-CH 2(CH 2oCH 2) 2cH 2nH 2,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-CH 2(CH 2oCH 2) 2cH 2nHCOCH 3or-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nH 2;
R 2be selected from-CH 3,-CH 2cH 3,-CH 2oCH 2o (CH 2) 2oCH 3,-CH 2o (CH 2) 2o (CH 2) 2oCH 3,-H or
-CH 2O(CH 2) 2O(CH 2) 2OCH 3；
R 6be selected from-CH 3,-H, CH 2oCH 2o (CH 2) 2oCH 3or CH 2o (CH 2) 2o (CH 2) 2oCH 3.
2. PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that:
Described PEGylation 3-hydroxypyridin-4-one derivatives salt refers to the corresponding salt that PEGylation 3-hydroxypyridin-4-one derivatives is formed to acid; Described acid is strong inorganic acid, strong organic acid, saturated or undersaturated dicarboxylic acid or sulfonic acid.
3. PEGylation 3-pyridone-4-ketone compounds according to claim 2, is characterized in that:
Described strong inorganic acid comprises sulfuric acid, phosphoric acid or hydrochloric acid, and described strong organic acid comprises acetic acid, and described saturated or undersaturated dicarboxylic acid comprises tartrate, citric acid, and described sulfonic acid comprises o-methyl-benzene sulfonic acid or p-methyl benzenesulfonic acid.
4. PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that R 1, R 2, R 6substituent structure is as follows:
5. PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that R 1, R 2, R 6substituent structure is as follows:
6. a preparation method for PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that comprising the following steps:
Methyl maltol or veltol plus and benzyl chlorine are obtained by reacting the voitol of 3-position benzyl protection, obtain the 3-benzyloxypyridine-4-ketones derivant of 1-position PEGylation again with the primary amine reaction of PEGylation, finally under the catalysis of palladium carbon, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 1-position PEGylation;
Described saponins is selected from methyl maltol, veltol plus, 3-benzyloxy-2,6-dihydroxymethyl-4H-pyrans-4-ketone or 3-benzyloxy-2-methylol-6-methyl-4H-pyrans-4-ketone;
The primary amine of described PEGylation is NH 2cH 2(CH 2oCH 2) 2cH 2nHCOCH 2cH 3, NH 2(CH 2) 2o (CH 2) 2oH, NH 2(CH 2) 2o (CH 2) 2oCH 3, NH 2cH 2(CH 2oCH 2) 2cH 2nH 2, NH 2(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3, NH 2(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3, NH 2cH 2(CH 2oCH 2) 2cH 2nHCOCH 3or NH 2(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nH 2;
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 1-position PEGylation is as follows:
R 2be selected from methyl or ethyl;
R 1for PEGylation group, be selected from-CH 2(CH 2oCH 2) 2cH 2nHCOCH 2cH 3,-(CH 2) 2o (CH 2) 2oH ,-(CH 2) 2o (CH 2) 2oCH 3,-CH 2(CH 2oCH 2) 2cH 2nH 2,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nHCOCH 3,-CH 2(CH 2oCH 2) 2cH 2nHCOCH 3or-(CH 2) 2(CH 2oCH 2) 3(CH 2) 2nH 2.
7. a preparation method for PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that comprising the following steps:
The chlorine or bromine of 3-benzyloxy-2-methylol-6-methyl-4H-pyrans-4-ketone and PEGylation is obtained by reacting the pyranone compounds of 2-position PEGylation for thing, be obtained by reacting the 3-benzyloxypyridine-4-ketone compound of 2-position PEGylation again with methylamine, finally under the catalysis of palladium carbon, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 2-position PEGylation;
The chlorine or bromine of described PEGylation is selected from ClCH for thing 2oCH 2o (CH 2) 2oCH 3, ClCH 2o (CH 2) 2o (CH 2) 2oCH 3, BrCH 2oCH 2o (CH 2) 2oCH 3or BrCH 2o (CH 2) 2o (CH 2) 2oCH 3;
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 2-position PEGylation is as follows:
R 2for PEGylation group, be selected from-CH 2oCH 2o (CH 2) 2oCH 3or-CH 2o (CH 2) 2o (CH 2) 2oCH 3.
8. a preparation method for PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that comprising the following steps:
The chlorine or bromine of 3-benzyloxy-6-methylol-4H-pyrans-4-ketone and PEGylation is obtained by reacting the pyranone compounds of 6-position PEGylation for thing, be obtained by reacting the 3-benzyloxypyridine-4-ketone compound of 6-position PEGylation again with methylamine, finally under the catalysis of palladium carbon, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 6-position PEGylation;
The chlorine or bromine of described PEGylation is selected from ClCH for thing 2oCH 2o (CH 2) 2oCH 3, ClCH 2o (CH 2) 2o (CH 2) 2oCH 3, BrCH 2oCH 2o (CH 2) 2oCH 3or BrCH 2o (CH 2) 2o (CH 2) 2oCH 3;
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 6-position PEGylation is as follows:
R 6for PEGylation group, be selected from-CH 2oCH 2o (CH 2) 2oCH 3or-CH 2o (CH 2) 2o (CH 2) 2oCH 3.
9. a preparation method for PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that comprising the following steps:
By 3-benzyloxy-2, the chlorine or bromine of 6-dihydroxymethyl-4H-pyrans-4-ketone and PEGylation is obtained by reacting 2 for thing, the pyranone compounds of 6-position PEGylation, 2 are obtained by reacting again with methylamine, 3-benzyloxypyridine-4-the ketone compound of 6-position PEGylation, finally under palladium carbon (Pd/C) catalysis, carry out the 3-hydroxypyridin-4-one derivatives that hydro-reduction deprotection can obtain 2,6-position PEGylation;
The chlorine or bromine of described PEGylation is selected from ClCH for thing 2o (CH 2) 2o (CH 2) 2oCH 3or BrCH 2o (CH 2) 2o (CH 2) 2oCH 3;
Wherein the structural formula of the 3-hydroxypyridin-4-one derivatives of 2,6-position PEGylation is as follows:
R 2for-CH 2o (CH 2) 2o (CH 2) 2oCH 3, R 6for-CH 2o (CH 2) 2o (CH 2) 2oCH 3.
10. a purposes for PEGylation 3-pyridone-4-ketone compounds according to claim 1, is characterized in that: the application of described PEGylation 3-pyridone-4-ketone compounds in the excessive disease drug of preparation iron-resistant ion.
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Publication number Priority date Publication date Assignee Title
CN112351970A (en) * 2018-05-30 2021-02-09 科莱恩国际有限公司 Method for forming 2-hydroxypyridine-1-oxide or derivative thereof

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Publication number Priority date Publication date Assignee Title
CN1151399A (en) * 1995-09-29 1997-06-11 西巴-盖尔基股份公司 Novel hydroxylpyridinones

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1151399A (en) * 1995-09-29 1997-06-11 西巴-盖尔基股份公司 Novel hydroxylpyridinones

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112351970A (en) * 2018-05-30 2021-02-09 科莱恩国际有限公司 Method for forming 2-hydroxypyridine-1-oxide or derivative thereof
US11753379B2 (en) 2018-05-30 2023-09-12 Clariant International Ltd Process for forming 2-hydroxypyridine-1-oxide or derivatives thereof

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Application publication date: 20151104