CN106279011A - A kind of preparation method of 2,4 dihydroxy 6 methylnicotinic acid ethyl esters - Google Patents
A kind of preparation method of 2,4 dihydroxy 6 methylnicotinic acid ethyl esters Download PDFInfo
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- CN106279011A CN106279011A CN201610676503.XA CN201610676503A CN106279011A CN 106279011 A CN106279011 A CN 106279011A CN 201610676503 A CN201610676503 A CN 201610676503A CN 106279011 A CN106279011 A CN 106279011A
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- dihydroxy
- reaction
- acid ethyl
- ester
- methylnicotinic acid
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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
- C07D213/80—Acids; Esters in position 3
-
- 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
- C07D213/803—Processes of preparation
Abstract
The invention discloses a kind of 2, the preparation method of 4 dihydroxy 6 methylnicotinic acid ethyl esters, the method is that 3 amino Ethyl crotonates successively occur the condensation of Clarkson ester gram and diekmann ester condensation reaction to generate product 2,4 dihydroxy 6 methylnicotinic acid ethyl ester with diethyl malonate under the effect of Sodium ethylate.The two-step reaction Clarkson ester gram condensation of the inventive method and diekmann ester condensation reaction are all carried out in same system, significantly shorten the response time, greatly reduce production cost, the preparation method of the present invention is simple, reaction system environmental protection and reaction condition the harshest, thus obtained product purity is up to more than 99%, yield, up to more than 80%, is therefore applicable to industrialization large-scale production.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of 2, the system of 4-dihydroxy-6-methylnicotinic acid ethyl ester
Preparation Method.
Background technology
2,4-dihydroxy-6-methylnicotinic acid ethyl esters, English name: 3-Pyridinecarboxylicacid, 1,6-
Dihydro-4-hydroxy-6-oxo-, ethyl ester, molecular formula is: C7H7NO4, molecular weight is 169.1348, density:
1.555g/cm3, fusing point: 205 DEG C, boiling point: 363.155 DEG C of at 760mmHg, flash-point: 173.43 DEG C, vapour pressure: 0mmHg at
25 DEG C, CAS:70254-52-3, molecular structural formula is:
2,4-dihydroxy-6-methylnicotinic acid ethyl esters are a kind of important organic chemical industry's intermediate, at medicine, dyestuff and pesticide
Have a wide range of applications in field.Its derivant is mainly used in cardiovascular disease, nervous system new drug in field of medicaments
And the synthesis of cancer therapy drug, therefore 2, the synthesis of 4-dihydroxy-6-methylnicotinic acid ethyl ester has highly important market value, is
The preferred product of pharmaceutical manufacturer.Through retrieval, the ring closure reaction that existing synthetic method is mentioned needs to carry out high temperature 140-150 DEG C,
And yield is below 80%, production cost is high, and required production equipment is special, is unfavorable for industrialized production.
Summary of the invention
It is an object of the invention to overcome the shortcoming of prior art, it is provided that a kind of 2,4-dihydroxy-6-methylnicotinic acid ethyl ester
Preparation method, the method is simple to operate, it is convenient to prepare, low cost, environmental protection, be applicable to industrialization large-scale production.
The purpose of the present invention is achieved through the following technical solutions: the system of a kind of 2,4-dihydroxy-6-methylnicotinic acid ethyl ester
Preparation Method, 3-amino Ethyl crotonate and diethyl malonate successively occur under the effect of Sodium ethylate the condensation of Clarkson ester gram and
Diekmann ester condensation reaction generates product 2,4-dihydroxy-6-methylnicotinic acid ethyl ester, and synthetic route is as follows:
Further, the temperature of described reaction is 80～90 DEG C, and the time of reaction is 20～30h.
Further, system solvent is dehydrated alcohol.
Further, described 3-amino Ethyl crotonate, diethyl malonate are 0.8～1.5 with the weight ratio of Sodium ethylate:
1.5～2.5:1.
Further, it also includes the method for product purification, and concrete operations are: after question response terminates, and reaction system is dropped
Temperature, to 50～60 DEG C, by adding basic activated carbon in concentrated solution after concentrating under reduced pressure, filters, and filtrate is cooled to less than 0 DEG C, uses chlorination
The pH value of ammonium regulation filtrate is to 2～3, and gained solid is dried at a temperature of 50～60 DEG C, i.e. prepares 2,4-dihydroxy-6-methyl
Ethyl nicotinate.
The invention have the advantages that the preparation side that the invention provides a kind of 2,4-dihydroxy-6-methylnicotinic acid ethyl ester
Method, successively there is the condensation of Clarkson ester gram and Dick in 3-amino Ethyl crotonate and diethyl malonate under the effect of Sodium ethylate
Graceful ester condensation reaction, two-step reaction is all carried out in same system, significantly shorten the response time, greatly reduces and produce into
This, the preparation method of the present invention is simple, reaction system environmental protection and reaction condition the harshest, be therefore applicable to industrialization big
Large-scale production.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described, and protection scope of the present invention is not limited to following institute
State.
Embodiment 1:
A kind of 2, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, 3-amino Ethyl crotonate and malonic acid diethyl
The condensation of Clarkson ester gram and diekmann ester condensation reaction is successively there is in ester under the effect of Sodium ethylate, after question response terminates, and will be anti-
Answering system to be cooled to 50 DEG C, by adding basic activated carbon in concentrated solution after concentrating under reduced pressure, filter, filtrate is cooled to less than 0 DEG C, uses
The pH value of ammonium chloride regulation filtrate is to 2, and gained solid is dried at a temperature of 50 DEG C, i.e. prepares 2,4-dihydroxy-6-methyl cigarette
Acetoacetic ester.The temperature of described reaction is 80 DEG C, and the time of reaction is 20h, and system solvent is dehydrated alcohol, described 3-amino Fructus Crotonis
Acetoacetic ester, diethyl malonate are 0.8:1.5:1 with the weight ratio of Sodium ethylate.
Embodiment 2:
A kind of 2, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, 3-amino Ethyl crotonate and malonic acid diethyl
The condensation of Clarkson ester gram and diekmann ester condensation reaction is successively there is in ester under the effect of Sodium ethylate, after question response terminates, and will be anti-
Answering system to be cooled to 60 DEG C, by adding basic activated carbon in concentrated solution after concentrating under reduced pressure, filter, filtrate is cooled to less than 0 DEG C, uses
The pH value of ammonium chloride regulation filtrate is to 3, and gained solid is dried at a temperature of 60 DEG C, i.e. prepares 2,4-dihydroxy-6-methyl cigarette
Acetoacetic ester.The temperature of described reaction is 90 DEG C, and the time of reaction is 30h, and system solvent is dehydrated alcohol, described 3-amino Fructus Crotonis
Acetoacetic ester, diethyl malonate are 1.5:2.5:1 with the weight ratio of Sodium ethylate.
Embodiment 3:
A kind of 2, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, 3-amino Ethyl crotonate and malonic acid diethyl
The condensation of Clarkson ester gram and diekmann ester condensation reaction is successively there is in ester under the effect of Sodium ethylate, after question response terminates, and will be anti-
Answering system to be cooled to 53 DEG C, by adding basic activated carbon in concentrated solution after concentrating under reduced pressure, filter, filtrate is cooled to less than 0 DEG C, uses
The pH value of ammonium chloride regulation filtrate is to 2.4, and gained solid is dried at a temperature of 54 DEG C, i.e. prepares 2,4-dihydroxy-6-methyl
Ethyl nicotinate.The temperature of described reaction is 83 DEG C, and the time of reaction is 24h, and system solvent is dehydrated alcohol, described 3-amino bar
Bean acetoacetic ester, diethyl malonate are 1:1.8:1 with the weight ratio of Sodium ethylate.
Embodiment 4:
A kind of 2, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, 3-amino Ethyl crotonate and malonic acid diethyl
The condensation of Clarkson ester gram and diekmann ester condensation reaction is successively there is in ester under the effect of Sodium ethylate, after question response terminates, and will be anti-
Answering system to be cooled to 58 DEG C, by adding basic activated carbon in concentrated solution after concentrating under reduced pressure, filter, filtrate is cooled to less than 0 DEG C, uses
The pH value of ammonium chloride regulation filtrate is to 2.8, and gained solid is dried at a temperature of 58 DEG C, i.e. prepares 2,4-dihydroxy-6-methyl
Ethyl nicotinate.The temperature of described reaction is 87 DEG C, and the time of reaction is 28h, and system solvent is dehydrated alcohol, described 3-amino bar
Bean acetoacetic ester, diethyl malonate are 1.3:2.2:1 with the weight ratio of Sodium ethylate.
Experimental example:
In reactor add 3-amino Ethyl crotonate (100g, 0.7752mol), diethyl malonate (124g,
0.7752mol) Sodium ethylate (65g, 0.9559mol) and dehydrated alcohol (240g), be then to slowly warm up to 80～90 DEG C by system,
System is reflux state, maintains this temperature stirring reaction 24 hours.System is cooled to 50～60 DEG C, and concentrating under reduced pressure goes out 100g second
Alcohol, concentrated solution is slowly added in 1000ml water, adds basic activated carbon 10g, filters after 1 hour.Filtrate is cooled to 0 DEG C
Hereinafter, by ammonium chloride regulation system pH=2～3, a large amount of solids separate out filter, filter, and solid is dried at a temperature of 50～60 DEG C again,
White needle-like crystals is 2,4-dihydroxy-6-methylnicotinic acid ethyl ester, W=125g (Yield=81.85%, HPLC=
99.5%), m.p.210-211.5 °.
Below by way of test explanation beneficial effects of the present invention:
1. reaction dissolvent screening: reaction dissolvent and reaction condition and result are as shown in table 1:
Table 1: reaction dissolvent screening test
Lab scale solvent employs dehydrated alcohol, oxolane and DMF respectively and screens, in the situation that other conditions are identical
Under, as shown in Table 1:
1. too low the causing of reflux temperature using oxolane to make solvent is reacted not exclusively, and yield is relatively low, and solvent cost
High.
When 2. using dehydrated alcohol to make solvent, more thoroughly, yield yield is higher, and cost is minimum for reaction ratio.
3. using DMF to make solvent reaction system dissolubility preferable, system color is relatively deep, and post processing is that decolorizing effect is inconspicuous
Cause finished product color the deepest.
Therefore selection dehydrated alcohol is the optimum selection of reaction dissolvent.
2. the selection in response time: reaction dissolvent and reaction condition and result are as shown in table 2:
Table 2: response time screening conditions and result
Response time (16h, 24h, 48h and 72h) has been carried out following the tracks of and sieve by lab scale (80～90 DEG C) at reflux
Choosing, as shown in Table 2:
1. back flow reaction is after 16 hours, a large amount of starting material left, reacts the most thorough.
2. back flow reaction is reacted after 24 hours thoroughly, and principal product is obvious.
3. back flow reaction after 48 hours system darken and have new impurity to generate.
4. back flow reaction after 72 hours system color become brown, post processing difficulty, yield is minimum.
Therefore return time is chosen as the condition raw material of 24 hours and impurity is minimum, yield is the highest, and energy consumption is relatively low, product
The unit cost of production minimum.
3. the selection of reaction temperature: reaction dissolvent and reaction condition and result are as shown in table 3:
Table 3: reaction temperature screening conditions and result
Respectively reaction temperature is being carried out lab scale, as shown in Table 3:
1. reaction temperature controls a large amount of starting material left when 60～70 DEG C, reacts the most thorough.
2. reaction temperature controls the reaction when 70～80 DEG C the most not thoroughly, has starting material left.
3. reaction temperature controls at 80～90 DEG C of reaction ratios more thoroughly, and yield is the highest.
4., when system maintains 90～100 DEG C of strong inverse flow reactions, there is because temperature is too high impurity to generate and reactant liquor color is inclined
Deeply, product colour is only off-white color.
Therefore controlling the condition that temperature is 80～90 DEG C (system normal reflow temperature) is the most rationally selecting of this technique.
The optimum process condition of synthesis 2,4-dihydroxy-6-methylnicotinic acid ethyl ester is in sum: reaction substrate is anhydrous
Reflux in ethanol (80～90 DEG C) reaction 24 hours.
The features such as the inventive method has that cost of material is cheap, process conditions are gentle, low cost, low energy consumption and low stain,
Thus obtained product purity is up to more than 99%, and yield is up to more than 80%, it is easy to industrialized production.In view of 2,4-dihydroxy
The derivant of base-6-methylnicotinic acid ethyl ester is in the extensive application in the fields such as modern medicine, and this route has high promotional value.
Claims (5)
1. one kind 2, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, it is characterised in that 3-amino Ethyl crotonate and third
Diethyl adipate successively occurs the condensation of Clarkson ester gram and diekmann ester condensation reaction to generate product 2 under the effect of Sodium ethylate,
4-dihydroxy-6-methylnicotinic acid ethyl ester, synthetic route is as follows:
2. one 2 as claimed in claim 1, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, it is characterised in that institute
The temperature stating reaction is 80～90 DEG C, and the time of reaction is 20～30h.
3. one 2 as claimed in claim 1, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, it is characterised in that body
Series solvent is dehydrated alcohol.
4. one 2 as claimed in claim 1, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, it is characterised in that institute
Stating 3-amino Ethyl crotonate, diethyl malonate is 0.8～1.5:1.5～2.5:1 with the weight ratio of Sodium ethylate.
5. one 2 as claimed in claim 1, the preparation method of 4-dihydroxy-6-methylnicotinic acid ethyl ester, it is characterised in that it
The method also including product purification, concrete operations are: after question response terminates, and reaction system is cooled to 50～60 DEG C, reduce pressure dense
By adding basic activated carbon in concentrated solution after contracting, filtering, filtrate is cooled to less than 0 DEG C, with the pH value of ammonium chloride regulation filtrate to 2
～3, gained solid is dried at a temperature of 50～60 DEG C, i.e. prepares 2,4-dihydroxy-6-methylnicotinic acid ethyl ester.
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| CN201610676503.XA CN106279011A (en) | 2016-08-16 | 2016-08-16 | A kind of preparation method of 2,4 dihydroxy 6 methylnicotinic acid ethyl esters |
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| CN201610676503.XA CN106279011A (en) | 2016-08-16 | 2016-08-16 | A kind of preparation method of 2,4 dihydroxy 6 methylnicotinic acid ethyl esters |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001087886A1 (en) * | 2000-05-18 | 2001-11-22 | Neurocrine Biosciences, Inc. | Crf receptor antagonists and methods relating thereto |
| WO2002024650A2 (en) * | 2000-09-19 | 2002-03-28 | Centre National De La Recherche Scientifique (Cnrs) | Pyridinone and pyridinethione derivatives having hiv inhibiting properties |
| WO2003008414A1 (en) * | 2001-07-17 | 2003-01-30 | Sb Pharmco Puerto Rico Inc. | Chemical compounds |
| WO2008129380A1 (en) * | 2007-04-18 | 2008-10-30 | Pfizer Products Inc. | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
-
2016
- 2016-08-16 CN CN201610676503.XA patent/CN106279011A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001087886A1 (en) * | 2000-05-18 | 2001-11-22 | Neurocrine Biosciences, Inc. | Crf receptor antagonists and methods relating thereto |
| WO2002024650A2 (en) * | 2000-09-19 | 2002-03-28 | Centre National De La Recherche Scientifique (Cnrs) | Pyridinone and pyridinethione derivatives having hiv inhibiting properties |
| WO2003008414A1 (en) * | 2001-07-17 | 2003-01-30 | Sb Pharmco Puerto Rico Inc. | Chemical compounds |
| WO2008129380A1 (en) * | 2007-04-18 | 2008-10-30 | Pfizer Products Inc. | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
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