CN106748984A - Ketone of 6 methylol, 1 phenylpyridine 2 and preparation method and application - Google Patents
Ketone of 6 methylol, 1 phenylpyridine 2 and preparation method and application Download PDFInfo
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- CN106748984A CN106748984A CN201611029185.4A CN201611029185A CN106748984A CN 106748984 A CN106748984 A CN 106748984A CN 201611029185 A CN201611029185 A CN 201611029185A CN 106748984 A CN106748984 A CN 106748984A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to ketone of 6 methylol, 1 phenylpyridine 2 and preparation method and application, the compound with the ketone pyridine of 2 carboxyl 6 be initiation material, reacted by 3 steps and obtain target compound, the compound is to prepare treatment or the prevention very important part of anaemia disease drug, is with a wide range of applications in anaemia disease is prevented and treated；Its preparation method raw material is cheap and easily-available, and synthetic method is simple, is a kind of completely new approach for synthesizing the ketone of 6 methylol, 1 phenylpyridine 2, the need for being adapted to scale industrial production.
Description
Technical field
The present invention relates to a kind of pyridine compounds and preparation method thereof, especially a kind of 6- methylols -1- phenylpyridines -2-
Ketone and preparation method thereof.
Background technology
Pyridine compounds and their is one of development and application kind widest in area in current heterocyclic compound, important as one kind
Fine chemical material, its derivative mainly has alkyl pyridine, haloperidid, aminopyridine, bromopyridine, picoline, iodine pyrrole
Pyridine, chloropyridine, nitropyridine, pyridone, benzyl pyridine, ethylpyridine, cyanopyridine, fluorine pyridine, dihydropyridine etc..
At this stage, pyrimidine compound includes in the main application of field of medicaments：(1) cancer therapy drug.(2) AIDS drugs
Thing.
The content of the invention
The technical problems to be solved by the invention are to provide a kind of 6- methylols -1- phenylpyridine -2- ketone.
Another technical problem to be solved by this invention is the system for providing above-mentioned 6- methylols -1- phenylpyridine -2- ketone
Preparation Method.
Another technical problem to be solved by this invention is to provide answering for above-mentioned 6- methylols -1- phenylpyridine -2- ketone
With.
In order to solve the above technical problems, the technical scheme is that：
A kind of 6- methylols -1- phenylpyridine -2- ketone, its structural formula is shown (I),
Preferably, above-mentioned 6- methylols -1- phenylpyridine -2- ketone, hydrogen nuclear magnetic resonance modal data is：2.580 (b, 1H),
4.066-4.056(d,2H),6.453-6.433(dd,1H),6.587-6.564(d,1H),7.194-7.173(t,2H),
7.505-7.404(m,4H)。
The preparation method of above-mentioned 6- methylols -1- phenylpyridine -2- ketone, with 2- carboxyl -6- ketone pyridines as initiation material, leads to
Cross the reaction of 3 steps and obtain target compound, comprise the following steps that：
(1) the 2- carboxyl -6- ketone pyridines of compound 1 carry out esterification reaction and obtain compound 2；
(2) compound 2 carries out coupling reaction and obtains compound 3；
(3) compound 3 applies NaBH4Reduction obtains target compound 4；Wherein,
Intermediate compound 3 in the preparation method of above-mentioned 6- methylols -1- phenylpyridine -2- ketone, its structural formula is
(II) shown in,
The specific reaction equation of the preparation method of above-mentioned 6- methylols -1- phenylpyridine -2- ketone is as follows：
Application of the above-mentioned 6- methylols -1- phenylpyridine -2- ketone in terms for the treatment of or prevention anaemia disease drug is prepared.
The beneficial effects of the invention are as follows：
Above-mentioned 6- methylols -1- phenylpyridine -2- ketone is to prepare PHD2 (prolyl hydroxylase domain-
Containing protein 2) inhibitor important intermediate, prepare treatment or prevention anaemia disease drug it is extremely important
Part, prevent and treat anaemia disease in be with a wide range of applications；Its preparation method raw material is cheap and easily-available, closes
It is simple into method, it is a kind of completely new approach of synthesis 6- methylols -1- phenylpyridine -2- ketone, it is adapted to scale industrial production
Need.
Brief description of the drawings
Fig. 1 is the HNMR spectrograms of 6- methylol -1- phenylpyridine -2- ketone.Its hydrogen modal data is：2.580 (b, 1H),
4.066-4.056(d,2H),6.453-6.433(dd,1H),6.587-6.564(d,1H),7.194-7.173(t,2H),
7.505-7.404(m,4H)。
Specific embodiment
In order that those skilled in the art is better understood from technical scheme, with reference to specific embodiment
Technical scheme of the present invention is described in further detail.
Embodiment 1
The preparation method of 6- methylol -1- phenylpyridine -2- ketone, comprises the following steps that：
(1) T=18 DEG C, the 2- carboxyls -6- ketone pyridine of 10.3g compounds 1 and 160mL methyl alcohol are added to 250mL there-necked flasks
In, stirring (system is muddy) is opened, to the 9mL concentrated sulfuric acids are slowly added into system, charging terminates rear system and is warming up to 32 DEG C, now
Still there are a small amount of undissolved solid, heating reflux reaction in system.After 5.5h, T=77 DEG C, TLC detections (DCM:MeOH=1：1 adds
One drop glacial acetic acid) react complete, without starting material left.System lower the temperature, water pump, 55 DEG C be concentrated into out cut it is very slow when, in system
200mL saturated sodium bicarbonate aqueous solutions are dividedly in some parts, 18g sodium acid carbonates are added, system pH to 7-8, system DCM is reconciled
(50mL*3) is extracted, and merges organic phase, and organic phase washed once with 100mL saturated aqueous common salts again, water pump, and 45 DEG C are concentrated to give 5.8g
Faint yellow solid (compound 2).
(2) successively by 2.5g compounds 2,6.0g phenyl boric acids, 6.0g Salicylaldoximes, 2.5g 4A molecular sieves, 40mL1,2-
Dichloroethanes and 5.1g pyridines, are added in 100mL single port bottles, replacement of oxygen three times, 55 DEG C of reaction 17h.After 17h, T=55
DEG C, TLC detections (DCM:MeOH=50：1) fundamental reaction completely, send LC-MS (10-100-0) starting material left 3.6%.System drops
Temperature and 0100-240 system merging treatments, to 40mL water and 40mL DCM is added in system, 20min is again through diatomite mistake for stirring
Filter, filter cake is washed with 20mL DCM, and filtrate point liquid, water is mutually extracted twice with DCM (25mL*2), merges organic phase, is concentrated to give
7.3g crude products, PE is purified to obtain through column chromatography:EA=1：1 goes out preceding intersection 0.7g weak yellow liquids (compound 3).
(3) 2.7g compounds 3 are dissolved in 50mL methyl alcohol, 3.0g sodium borohydrides is dividedly in some parts in system, system is produced
Angry body, aerating ball makes system closed, room temperature reaction 15h.After 15h, T=25 DEG C, LC-MS (10-100-0) 0100-261- is sent
16 reactions are complete, prepare TLC (EA:MeOH=20：1) nuclear-magnetism 0100-260-20CDCl3 (0.7g systems) is sent, LC-MS is confirmed as
Target product, is shown in Fig. 1.To 30mL water and 50mL EA is added in system, hardly possible layering adds 20mL saturated aqueous common salts, water mutually to use again
EA (20mL*2) is extracted twice, and is associated with sign, and organic phase washed once with 30mL saturated aqueous common salts again, concentrates (45 DEG C, water
Pump), obtain 0.1g off-white powders through column chromatography purifying (pure EA).
Above-mentioned specific reaction equation is as follows：
Application test example
Rat 40 is selected in experiment, raises low iron base feed, and consumption 3 weeks makes Anemia Animal, taken through tail vein
Blood, determines content of hemoglobin, when content of hemoglobin is less than 100g/L, is randomly divided into rat by content of hemoglobin scarce
1 group of iron control group and the embodiment of the present invention, every group 20, successive administration 4 weeks.Iron deficiency control group is used raises low iron base feed,
Gavage 2.0ml deionized waters；Using low iron base feed is raised, daily gavage gives of the invention real 1 group of the embodiment of the present invention respectively
Apply target compound (6- methylol -1- phenylpyridine -2- ketone) 20mg/kg in example 1.At the end of experiment, rat is anesthetized with ether,
After through abdominal aortic blood, liver and spleen are won, put -30 DEG C of refrigerators standby.
Hemoglobin determines content of hemoglobin using HemoCue, and big rat-tail blood is taken with 10 μ l quantitative capillary tubes, puts
Enter to fill in the plastic tube of 2.5ml high-potassium ferricyanide reagents, fully vibration makes the complete dissolution of blood, after avoid light place 15min, uses
Hemoglobin Meter is determined, while determining hemoglobin standard and primary standard substance.Packed cell volume HCT is taken with 9 μ l quantitative capillary tubes
Blood, one end is sealed with plasticine, is determined using hematocrit measurement instrument, and result is read after 2min, while measure refers to base
Quasi- blood sample.Free erythrocyte protoporphyrin FEP by droplets of whole blood on special filter paper, it is to be dried after be stored in 4 DEG C of refrigerators standby (time be not
More than 2 months).During measure, the filter paper with drop of blood is squeezed into teat glass with card punch, add 2% tripolite solution, put
Enter 4 DEG C of refrigerator overnight wash-outs, add ethyl acetate: glacial acetic acid (4:1) mixed liquor extraction, is centrifuged 10min, takes supernatant addition
0.5mol/L hydrochloric acid, vibration centrifugation, removes a layer liquid fluorescent spectrophotometer assay.Iron takes about 0.2g in liver, spleen tissue
Tissue is put into the teat glass through hydrochloric acid dry cleansing, adds nitric acid: perchloric acid (4:1) mixed acid 2ml, after digestion, spends
Ionized water is settled to 5ml or 10ml, and iron content in organizing is determined using flame atomization, determines every time with the beef liver powder (U.S.
State Standard Bureau NBS1577a) as Quality Control material.
Result judgement method：1 group of content of hemoglobin of rat of the embodiment of the present invention, packed cell volume, FEP, liver and
Any 2 indexs are less than iron deficiency control group better than iron deficiency control group, i.e. FEP in spleen iron content, can determine that the tested material has
Improve the effect of anemia in rats.Statistical procedures are compared using t inspections to data, inspection level α=0.05.
Experimental result：Before each group rat hemoglobin content Hb, packed cell volume HCT, the experiment of red blood cell FEP comparision contents
The Hb contents of each group rat, packed cell volume, red blood cell FEP content differences are not statistically significant, medicine reality of the present invention after experiment
Apply the Hb contents of 1 group of rat of example, packed cell volume and be all remarkably higher than iron deficiency control group, red blood cell FEP contents are substantially less than iron deficiency
Control group, is shown in Table 1.
The each group rat hemoglobin content of table 1, packed cell volume, the comparing of red blood cell FEP contents
It is above-mentioned the 6- methylol -1- phenylpyridine -2- ketone and preparation method and application is entered with reference to specific embodiment
Capable detailed description, be it is illustrative can include several embodiments according to limited scope rather than limited, therefore
Changing and modifications in the case where present general inventive concept is not departed from, should belong within protection scope of the present invention.
Claims (5)
1. a kind of 6- methylols -1- phenylpyridine -2- ketone, it is characterised in that：Its structural formula is shown (I),
2. 6- methylols -1- phenylpyridine -2- ketone according to claim 1, it is characterised in that：Hydrogen nuclear magnetic resonance modal data
For：2.580 (b, 1H), 4.066-4.056 (d, 2H), 6.453-6.433 (dd, 1H), 6.587-6.564 (d, 1H), 7.194-
7.173(t,2H),7.505-7.404(m,4H)。
3. the preparation method of 6- methylols -1- phenylpyridine -2- ketone described in claim 1, it is characterised in that：With 2- carboxyls -6-
Ketone pyridine is initiation material, is reacted by 3 steps and obtains target compound, is comprised the following steps that：
(1) the 2- carboxyl -6- ketone pyridines of compound 1 carry out esterification reaction and obtain compound 2；
(2) compound 2 carries out coupling reaction and obtains compound 3；
(3) compound 3 applies NaBH4Reduction obtains target compound 4；Wherein,
4. the intermediate compound 3 in the preparation method of 6- methylols -1- phenylpyridine -2- ketone described in claim 3, it is special
Levy and be：Its structural formula is shown (II),
5. 6- methylols -1- phenylpyridine -2- ketone described in claim 1 prepare treatment or prevention anaemia disease drug in terms of should
With.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201611029185.4A CN106748984A (en) | 2016-11-22 | 2016-11-22 | Ketone of 6 methylol, 1 phenylpyridine 2 and preparation method and application |
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| CN201611029185.4A CN106748984A (en) | 2016-11-22 | 2016-11-22 | Ketone of 6 methylol, 1 phenylpyridine 2 and preparation method and application |
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Citations (4)
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|---|---|---|---|---|
| US20080319026A1 (en) * | 2007-06-20 | 2008-12-25 | Auspex Pharmaceuticals, Inc. | Substituted n-aryl pyridinones |
| CN103012254A (en) * | 2005-05-10 | 2013-04-03 | 英特芒尼公司 | Pyridone derivatives for modulating stress-activated protein kinase system |
| CN103561741A (en) * | 2011-03-08 | 2014-02-05 | 奥斯拜客斯制药有限公司 | Substituted N-aryl pyridinones |
| WO2016045125A1 (en) * | 2014-09-28 | 2016-03-31 | Merck Sharp & Dohme Corp. | Inhibitors of hif prolyl hydroxylase |
-
2016
- 2016-11-22 CN CN201611029185.4A patent/CN106748984A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012254A (en) * | 2005-05-10 | 2013-04-03 | 英特芒尼公司 | Pyridone derivatives for modulating stress-activated protein kinase system |
| US20080319026A1 (en) * | 2007-06-20 | 2008-12-25 | Auspex Pharmaceuticals, Inc. | Substituted n-aryl pyridinones |
| CN101842355A (en) * | 2007-06-20 | 2010-09-22 | 奥斯拜客斯制药有限公司 | Substituted n-aryl pyridinones as fibrotic inhibitors |
| CN104892498A (en) * | 2007-06-20 | 2015-09-09 | 奥斯拜客斯制药有限公司 | Substituted n-aryl pyridinones |
| CN103561741A (en) * | 2011-03-08 | 2014-02-05 | 奥斯拜客斯制药有限公司 | Substituted N-aryl pyridinones |
| WO2016045125A1 (en) * | 2014-09-28 | 2016-03-31 | Merck Sharp & Dohme Corp. | Inhibitors of hif prolyl hydroxylase |
Non-Patent Citations (1)
| Title |
|---|
| DAVID G.WORKMAN等: "Synthesis of novel Iron(III) chelators based on triaza macrocycle backbone and 1-hydroxy-2(H)-pyridin-2-one coordinating groups and their evaluation as antimicrobial agents", 《JOURNAL OF INORGANIC BIOCHEMISTRY》 * |
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Inventor after: Tan Wenfei Inventor after: Yao Qingjia Inventor after: Wu Simin Inventor after: Xu Yangjun Inventor before: Yao Qingjia Inventor before: Wu Simin Inventor before: Xu Yangjun |
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Application publication date: 20170531 |