CN103848781B - A method for methylol in high-selectivity oxidation dihydroxymethyl pyridine - Google Patents
A method for methylol in high-selectivity oxidation dihydroxymethyl pyridine Download PDFInfo
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- CN103848781B CN103848781B CN201210504392.6A CN201210504392A CN103848781B CN 103848781 B CN103848781 B CN 103848781B CN 201210504392 A CN201210504392 A CN 201210504392A CN 103848781 B CN103848781 B CN 103848781B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
An a kind of method for methylol in high-selectivity oxidation dihydroxymethyl pyridine, one methylol of pyridine ring selective oxidation that multiple methylols are replaced is carboxaldehyde radicals, and it is oxidant to use DMP or IBX, and raw material is 1 with the mol ratio of oxidant：1~10.The method has selectivity very high, and some in several methylols in compound can be selectively oxidized, and this method is environment-friendly, product yield high, the convenient post-treatment for obtaining.
Description
Technical field：
The present invention relates to an a kind of method for methylol in high-selectivity oxidation dihydroxymethyl pyridine, by multiple methylols
Substituted one methylol of pyridine ring selective oxidation is carboxaldehyde radicals.
Background technology：
, it is necessary to by formula in a kind of pharmaceutical procedures for treating bronchial astehma, chronic bronchitis, pulmonary emphysema are prepared
II compound oxidations are compound of formula I（R is hydroxy-protective group in formula）：
US3700681（Embodiment 1B）A kind of method that Formula II is oxidized to Formulas I is described, is oxidation with manganese dioxide
Agent, after the completion of reaction, by concentration, silica gel column chromatography, is recrystallized to give the target compound Formulas I of yield about 20%.
However, the method there are many defects, be not suitable for industrial production：
1. selectivity is not strong, and two methylols on pyridine ring are oxidized, and cause accessory substance excessive；
2. yield is very low, and only 20%；
3. post processing is bothered, because accessory substance is more, it is necessary to use silica gel column chromatography, recrystallization separation product, high cost, operation
Inconvenience；
4. in addition, a large amount of manganese salts pollution environment produced after reaction.
Therefore, it is necessary to provide a kind of method that high-selectivity oxidation hydroxymethylpyridine is formaldehyde yl pyridines.
The content of the invention：
It is an object of the invention to overcome the deficiencies in the prior art, there is provided one kind is suitable to industrialization large-scale production Formulas I
The method of compound, that is, find and for 6 methylols in Formula II compound to be oxidized to stronger, the in hgher efficiency side of formaldehyde based selective
Method.
The technical scheme is that：
A kind of is the method for compound of formula I by Formula II compound oxidation, it is characterized in that：It is oxidant to use DMP or IBX,
Starting materials of formulae II compounds are 1 with the mol ratio of the oxidant:1 ~ 10, R is hydroxy-protective group in formula.
The research process of the inventive method is as follows：
1st, selective oxidation agent and its consumption are the central factors for influenceing oxidation reaction selectivity
In the oxidation reaction that methylol compound is changed into carbonyls, selectivity is most important.And oxidant
And its consumption turns into the central factor of influence reaction selectivity.In the method for the present invention, the R of prepared product compound of formula I
It is hydroxy-protective group, such as silylation, cycloalkyl or aromatic radical.In Formulas I and Formula II, there are two methylols on pyridine ring,
For this structure, two methylols may be oxidized, and at this moment be accomplished by especially considering the problem of oxidation reaction selectivity：Such as
Methylol on the right side of how only making is oxidized and left side methylol does not produce influence.
1）Oxidant of the prior art is changed
The present invention have selected DMP（1,1,1- triethoxy -1,1- dihydro -1,2- benzenesulfonyl -3- ketone）Or IBX（O- iodoxy
Yl benzoic acid）, belong to iodine reagent high, it is different from oxygen, aluminium isopropoxide, potassium permanganate, manganese dioxide, hydrogen peroxide, dichromic acid
The oxidants such as potassium, nitric acid, sodium hypochlorite, simple substance bromine, iodine.Itself property is gentle, and free from environmental pollution, goes for
Industrial production.
2）Oxidizer to this method has carried out exploratory development
And be 1 in the mol ratio of starting materials of formulae II and oxidant DMP or IBX by showing after experimental exploring：1 ~ 10 scope
It is interior, it can be ensured that this selectivity.
Experiment is proved：When Formula II and the mol ratio with the oxidant are 1：When 1 ~ 7, more preferable effect can be produced.
Using 1 ~ 10 times of DMP or IBX, improve the selectivity of reaction, show yield higher and it is easier after
Process step.
2nd, the research of other reaction conditions
1）Reaction time
Research shows, in the method for the present invention, the reaction time can be not particularly limited, oxidation reaction typically carry out compared with
Hurry up, and i.e. stopping reaction after raw material does not exist can be detected by TLC, the extension reaction time will not produce larger shadow to reaction
Ring.
2）Reaction temperature
Reaction temperature is also without being particularly limited to.Carrying out making reaction at 10 DEG C~150 DEG C is preferably carried out, suitably
Reaction temperature is improved to be favorably improved reaction speed but the side reaction is substantially increased.
3）Reaction dissolvent
In the method for the present invention, conventional organic solvent can be selected as reaction dissolvent.Such as use benzene, toluene, diformazan
Benzene, dichloroethanes, dichloromethane or DMSO equal solvents, then can be such that the selectivity of oxidant is preferably played.
3rd, post processing mode is easy to operate, low cost, is particularly suitable for industrialized mass production
After oxidation reaction is finished, the separation of product, post processing use crystallization mode, very convenient, it is only necessary to add hydrophobic
Solvent（Such as ether）, required product can just crystallized, separated.And need to carry out column chromatography in the prior art just to make product
Separate, this method is because selectivity is good, and accessory substance is few, post processing needs not move through that column chromatography is so time-consuming and separation of high cost
Mode.
The solution have the advantages that：
1st, the selectivity of reaction is high.Such as there are two compounds of methylol for Formula II, can specifically to its right side
Methylol aoxidized, without the other methylols of influence.
2nd, improve product yield.Product yield of the invention can reach more than 50%, far above of the prior art
20%。
3rd, convenient post-treatment.Need to carry out column chromatography in the prior art product can just separated, post processing of the invention is not
Need by column chromatography, it is only necessary to use hydrophobic solvent（Such as ether）Product is set to separate by being crystallized.
4th, it is environment-friendly.The oxidants containing metal such as traditional manganese dioxide are substituted with DMP or IBX, it is possible to reduce to ring
The pollution in border.
Specific embodiment:
Technical scheme is further described with embodiment below, but limits this hair never in any form
It is bright.
In following embodiment：
1. the content of product detects that detecting instrument is as follows with condition using HPLC methods：
Detecting instrument：LC-10ATVP
Testing conditions：Chromatographic column：Lichrospher Si 4.6*250mm 5um
Detection wavelength：254nm
Mobile phase：Acetonitrile:Water（80:20）
Flow velocity：2.0ml/min
Sample size：20μl
Temperature：25℃
2nd, in for detecting whether starting materials of formulae II reacts complete TCL methods, solvent is n-hexane/ethyl acetate=3/
1。
3. the preparation method of starting materials of formulae II is：
2- methylol -3- benzyloxy -6- the pyridine carboxaldehydes of embodiment 1（R is benzyl）Preparation
In the reactor, 2.6-dihydroxymethyl-3- benzyloxypyridines 24.5g is added（0.1mol）, DMSO 425ml, stirring
After making dissolution of raw material complete, IBX 56g are dividedly in some parts（0.2mol）, finishing and reacted at 10~16 DEG C, TLC detects original
After material disappears, plus methyl alcohol is quenched reaction, filters, filtrate concentration, adds crystallizing from ether, obtains target compound 14.1g.Mole
Yield 57.9%, content 97.2%.
Silyloxy -6- the pyridine carboxaldehydes of 2 2- methylols -3- of embodiment three（R is trimethyl silicon substrate）Preparation
In the reactor, the silyloxy pyridine 22.7g of 2.6-dihydroxymethyl-3- three are added（0.1mol）, benzene 800ml, often
The lower stirring of temperature makes dissolution of raw material completely, is dividedly in some parts IBX 196g（0.7mol）, stirring reaction, to TLC detect raw material disappear
Afterwards, plus methyl alcohol is quenched reaction, filtering, filtrate concentration, adds crystallizing from ether, obtains target compound 11.8g.Molar yield
52.3%, content 96.8%.
2- methylol -3- benzyloxy -6- the pyridine carboxaldehydes of embodiment 3（R is benzyl）Preparation
In the reactor, 2.6- dihydroxymethyl -3- benzyloxypyridines 24.5g is added（0.1mol）, toluene 280ml, stirring
Make dissolution of raw material completely, be dividedly in some parts DMP 127g（0.3mol）, finishing and reacted at 40~45 DEG C, TLC detects original
After material disappears, plus methyl alcohol is quenched reaction, filters, filtrate concentration, adds crystallizing from ether, obtains target compound 13.4g.Mole
Yield 54.6%, content 98.3%.
2- methylol -3- cyclopentyloxy -6- the pyridine carboxaldehydes of embodiment 4（R is cyclopenta）Preparation
In the reactor, 2.6- dihydroxymethyl -3- cyclopentyloxy pyridines 22.3g is added（0.1mol）, chloroform 516ml, stir
Mixing and heating up makes dissolution of raw material completely, is dividedly in some parts DMP 42.4g（0.1mol）, finish and reacted at 140~150 DEG C,
After TLC detects raw material disappearance, plus methyl alcohol is quenched reaction, filters, and filtrate concentration adds crystallizing from ether, obtains target chemical combination
Thing 11.4g.Molar yield 51.7%, content 95.6%.
2- methylol -3- tertiary butyl dimethyl Si base -6- the pyridine carboxaldehydes of embodiment 5（R is tert-butyldimethyl silyl
Base）Preparation
In the reactor, 2.6-dihydroxymethyl-3- tertiary butyl dimethyl Sis base-pyridine 26.9g is added（0.1mol）, two
Chloroethanes 623ml, stirring and heating up makes dissolution of raw material completely, is dividedly in some parts IBX 280g（1mol）, finish at 75~80 DEG C
Reacted, after TLC detects raw material disappearance, plus methyl alcohol is quenched reaction, filters, filtrate concentration adds crystallizing from ether, obtains
Target compound 13.5g.Molar yield 50.6%, content 97.7%.
Each embodiment reaction material of table 1 and product are had a guide look of
Claims (5)
1. a kind of is the method for compound of formula I by Formula II compound oxidation,
In Formulas I and Formula II, R is hydroxy-protective group；It is characterized in that：
1) it is oxidant to use DMP or IBX；
2) starting materials of formulae II compounds and the mol ratio of oxidant are 1:1~10；
R is selected from trimethyl silicon substrate, t-Butyldimethylsilyl, cyclopenta or benzyl.
2. the method described in claim 1, after oxidation reaction is finished, using crystallization mode separation product；The crystallization is to add
Hydrophobic solvent makes compound of formula I separate out crystallization.
3. the method described in claim 1, starting materials of formulae II compounds are 1 with the mol ratio of oxidant:1~7.
4. the method described in claim 1, it is characterized in that reaction temperature is 10 DEG C~150 DEG C.
5. the method described in claim 1, it is characterized in that reaction dissolvent is benzene,toluene,xylene, dichloroethanes, dichloromethane
Or DMSO.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3700681A (en) * | 1971-02-16 | 1972-10-24 | Pfizer | 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines |
| CN1732002A (en) * | 2002-12-23 | 2006-02-08 | 诺瓦提斯公司 | Derivatives of aryl-quinazoline/aryl-2amino-phenyl methanone which promote the release of parathyroid hormone |
-
2012
- 2012-11-30 CN CN201210504392.6A patent/CN103848781B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3700681A (en) * | 1971-02-16 | 1972-10-24 | Pfizer | 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines |
| CN1732002A (en) * | 2002-12-23 | 2006-02-08 | 诺瓦提斯公司 | Derivatives of aryl-quinazoline/aryl-2amino-phenyl methanone which promote the release of parathyroid hormone |
Non-Patent Citations (2)
| Title |
|---|
| A chiral pool strategy for the synthesis of enantiopure hydroxymethyl-substituted pyridine derivatives;Christian Eidamshaus等;《Eur. J. Org. Chem.》;20110824;第2011卷;第6061页左栏方案8，第6067页左栏倒数第6－15行 * |
| Benzothiazole- and benzoxazole-substituted pyridine-2-carboxylates as efficient sensitizers f europium luminescence;Nail M. Shavaleev等;《Inorg. Chem.》;20090514;第48卷(第13期);第6178-6191页 * |
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