CN108358836A - The method that 2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction prepares vitamin B6 - Google Patents
The method that 2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction prepares vitamin B6 Download PDFInfo
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- CN108358836A CN108358836A CN201810172294.4A CN201810172294A CN108358836A CN 108358836 A CN108358836 A CN 108358836A CN 201810172294 A CN201810172294 A CN 201810172294A CN 108358836 A CN108358836 A CN 108358836A
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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
- C07D213/65—One oxygen atom attached in position 3 or 5
- C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
- C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
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Abstract
The present invention discloses 2 methyl, 3 pyridone 4, the method that 5 dicarboxylic acid esters reduction prepare vitamin B6,2 methyl, 3 pyridone 4,5 dicarboxylic acid esters dissolve in a solvent, then sodium borohydride or potassium borohydride, lewis acid, tertiary amine are sequentially added, then heating 2-4 hours of reaction, after the reaction was complete, system temperature is cooled to less than or equal to 10 DEG C, then 10% ammonium chloride is added, adjusts pH to neutrality, filtering and concentrating, it extracts, be passed through HCl gases, concentration stands crystallization, filtration drying up to the crude product of vitamin B6.By using sodium borohydride or potassium borohydride in the technical program, lewis acid, 3 pyridone 4 of reductase 12 methyl under tertiary amine collective effect, 5 dicarboxylic acid esters prepare vitamin B6, during whole operation, the solvent of use needs not move through Non-aqueous processing, without using high-tension apparatus, carries out under mild conditions.
Description
Technical field
The present invention relates to the preparation methods of vitamin B6, and in particular to 2- methyl -3- pyridones -4,5- dicarboxylic acid esters are also
The method that original prepares vitamin B6.
Background technology
Vitamin B6 exists in nature in the form of three kinds of pyridoxol, pyridoxal and pyridoxamine.Under certain condition three
Person can mutually convert in vivo.The vitamin B6 industrially synthesized is generally pyridoxine hydrochloride.It industrially adopts mostly at present
Yong oxazole forensic chemistries synthesize vitamin B6.
There are mainly two types of the big production vitamin B6 oxazole methods of current commercial：
Method one：It is to use 4- methyl -5- alkane oxygen base oxazole or 4- methyl -5- alkyl siloxy oxazoles and alkyl -4 2-,
7- dihydros -1,3- bis- Evil English in heptan is after Diels-Alder additions and aromatization reaction, then at salt up to vitamin B6, the method
The shortcomings that be：Energy consumption of reaction is high, and the reaction time is longer, and ingredient proportion is big.Bioxin is as dienophile, alkene both ends substituent group
For electron donating group, the relatively low , Yu oxazoles of activity carry out needing higher reaction temperature when D-A cyclizations, and reaction temperature is generally in 80-
Between 160 DEG C, the reaction time needs 8-15 hours；4- methyl -5- alkoxies (or alkoxysilyl group) oxazoles and 2- alkyl -4,7-
The rate of charge of dihydro -1,3- Er Evil English in heptan is 1：11-1：Between 15.Reacted will also recycle excessive object by high temperature rectifying
Material.
Method two：It is using 4- methyl -5- alkane oxygen base oxazole or 4- methyl -5- alkyl siloxy oxazoles and maleic acid diester
Or dimethyl ester is after Diels-Alder additions and aromatization, through reduction, at salt up to vitamin B6.The method
Advantage is：Diels-Alder additions and aromatization time are short, and yield is up between 86-95%；The disadvantage is that：Ester group
Reduction needs to use strong reductant.
Restoring method there are two types of reporting at present：A kind of restoring method is：US3227721 is referred to by Diels-Alder
2- methyl -3- pyridones -4,5- the dicarboxylic acid esters that addition and aromatization reaction generate are restored using Lithium Aluminium Hydride.There are reducing agents
Expensive, dosage is big, the shortcomings of requiring high safety hidden danger big, inconvenient for operation anhydrous to system；Another restoring method is：
The use Raney Ni mentioned in CN103058919 is catalyst, hydrogen is reducing agent, through high-pressure catalytic hydrogenation, at salt get Wei Sheng
Plain B6.The method the disadvantage is that：It is catalyst to need the Raney Ni using expensive and easy spontaneous combustion, and reaction system is high-pressure catalytic
Hydrogenation, needs dedicated catalytic hydrogenation workshop, high to equipment and personnel requirement, and security risk is big.
The shortcomings that based on existing method, is studied and develops design 2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction system
The method of standby vitamin B6.
Invention content
The present invention provides 2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction method for preparing vitamin B6, using
Sodium borohydride or potassium borohydride, lewis acid, tertiary amine collective effect under dicarboxylic ester on reduction pyridine ring, entire reactant
Without doing special Non-aqueous processing, safe operation in system, and the vitamin B6 yield prepared is high, solves in the prior art
Prepare the method operation technical problems such as hidden danger is big of vitamin B6.
The present invention is achieved through the following technical solutions：
The method that 2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction prepares vitamin B6, by 2- methyl -3- hydroxyls
Pyridine -4,5- dicarboxylic acid esters dissolve in a solvent, then sequentially add sodium borohydride or potassium borohydride, lewis acid, tertiary amine,
Then heating 2-4 hour of reaction, after the reaction was complete, system temperature is cooled to less than or equal to 10 DEG C, and 10% chlorination is then added
Ammonium adjusts pH to neutrality, and filtering, liquid separation extraction are passed through HCl gases to being saturated, and concentration stands crystallization, filtration drying up to vitamin
The crude product of B6.
Reaction equation is as follows：
Based on the method for preparing vitamin B6 in the prior art, such as：1) use raw material for 4- methyl -5- alkoxies
Oxazole or 4- methyl -5- alkyl siloxy oxazoles are with two Evil English systems in heptan of 2- alkyl -4,7- dihydros -1,3- for the method for vitamin B6
The big defect of high, time length that there are energy consumption of reaction, ingredient proportion；2) raw material 4- methyl -5- Wan Yang Ji oxazoles or 4- methyl-are used
There is the reduction used in the method that 5- alkyl siloxy oxazoles prepare vitamin B6 with maleic acid diester or dimethyl ester
Agent Lithium Aluminium Hydride higher price, dosage is big, and operation requires the defects of high；3) it for catalyst, hydrogen is reduction to use Raney Ni
Agent using high-pressure catalytic hydrogenation, obtains vitamin B6 preparation method at salt, and there are the technical problems such as security risk is big.
In the technical program mainly use raw material pyridine dicarboxylate, and use in the prior art fat carboxylic ether, virtue
Fragrant carboxylate etc. is required to restore using expensive strong reductant when being raw material, such as lithium aluminium hydride reduction etc., or uses boron
Sodium hydride or potassium borohydride, the methanol or simple monocarboxylic esters of ethanol reduction, but aforementioned used reducing agent such as boron hydrogen
Changing sodium or potassium borohydride, methanol or ethyl alcohol can not be to two ester of the raw material pyridine dicarboxylate used in the technical program simultaneously
It is reduced to alcohol.
And raw material pyridine dicarboxylate is gone back under sodium borohydride, lewis acid, tertiary amine collective effect in the technical program
Originally it was pyridine glycol, i.e. vitamin B6.If individually use the mechanism of the collective effect ester reduction of sodium borohydride, alcohol for：Hydroboration
Sodium is acted on alcohol generates borate to restore, and the reducing power of borate is weaker, can not be by two esters of pyridine dicarboxylate
It restores simultaneously.
The above-mentioned reduction mechanism by taking sodium borohydride, ferrous salt, tertiary amine as an example is as above, sodium borohydride and the ferrous iron of low activity
Salt is initially formed two hydroboration iron of high activity, and then the carbonyl carbon of Borohydride anion and ester forms ion pair, then completes hydrogen
Transfer, while boron is combined with negative oxygen ion, forms alcoxyl boron hydride, under the tertiary amine effect with lone pair electrons simultaneously
The transfer that methoxy anion is left away with second hydrogen is carried out, the fracture of boron-oxygen key is finally hydrolyzed, obtains alcohol, and regenerate tertiary amine.
Further, in order to preferably realize that the present invention, the molar ratio of the reactant are 2- methyl -3- pyridones -
4,5- dicarboxylic acid esters：Sodium borohydride or potassium borohydride：Lewis acid：Tertiary amine=1：2—3：1—1.5：1-1.5, to the reaction
The addition ratio of object carries out preferred, it can be ensured that the abundant progress of reaction.And 4- methyl -5- alcoxyls are used compared with the existing technology
Base oxazole or 4- methyl -5- alkyl siloxy oxazoles are reacted with two Evil English in heptan of 2- alkyl -4,7- dihydros -1,3- prepares vitamin B6
Method in, rate of charge 1:11—1:15, have ingredient proportion big, the features such as reaction time is long, therefore, after completion of the reaction
Also excessive material can be recycled by high temperature rectifying, it is seen then that the advantage of the technical program is ensuring the same of reaction completion
When, the raw material of use is less, greatly reduces cost.
Further, in order to preferably realize that the present invention, the molar ratio of the reactant are 2- methyl -3- pyridones -
4,5- dicarboxylic acid esters：Sodium borohydride or potassium borohydride：Lewis acid：Tertiary amine=1：2：1：1.
Further, in order to preferably realize the present invention, the heating reaction temperature is 40-90 DEG C.In the technical program
It is 40-90 DEG C to react heating temperature, and relative to 80-160 DEG C of reaction temperature in conventional method, reaction is more mild, when reaction
Temperature without so high, then corresponding energy consumption reduces.The reaction time is only 2-4 hours at 40-90 DEG C, and the prior art
In at 80-160 DEG C, the reaction time is 8-15 hours, and there is in this programme the reaction time advantages such as to shorten, higher reaching
While yield, reaction time shortens, and the yield in the unit interval greatly increases, being capable of large-scale production.
Further, in order to preferably realize the present invention, 2- methyl -3- pyridone -4,5- dicarboxylic acid esters dissolving
Solvent be 2- methylfurans, tetrahydrofuran, dioxane, methyl tertiary butyl ether(MTBE), any one in ether.
Further, in order to preferably realize the present invention, the lewis acid is ferrous sulfate, ferrous oxalate, protochloride
Any one in iron.
Further, in order to preferably realize the present invention, the tertiary amine is triethylamine, trimethylamine, dimethylaniline, two different
Any one in propylethylamine.
Further, in order to preferably realize the present invention, the vitamin B6 crude product is using absolute ethyl alcohol recrystallization, mistake
Filter is to get vitamin B6 sterling.
Further, in order to preferably realize the present invention, the temperature after the reaction was complete is cooled to 2-10 DEG C.
Compared with prior art, the present invention having the following advantages and advantages：
By using sodium borohydride or potassium borohydride in the technical program, lewis acid, reductase 12-under tertiary amine collective effect
Methyl -3- pyridone -4,5- dicarboxylic acid esters prepare vitamin B6, and during whole operation, the solvent of use needs not move through nothing
Water process can carry out under mild conditions without using high-tension apparatus.
Specific implementation mode
To make the objectives, technical solutions, and advantages of the present invention clearer, with reference to embodiment, the present invention is made
Further to be described in detail, exemplary embodiment of the invention and its explanation are only used for explaining the present invention, are not intended as to this
The restriction of invention.
Embodiment 1：
150ml 2- methyltetrahydrofurans are added into three-necked flasks of the 500ml with stirring, thermometer and condenser pipe,
25.3g, 0.1mol 2- methyl -3- pyridone -4,5- dicarboxylic acid ethyl esters, 18.1g, 0.15mol dimethylanilines, 11.34g,
Then 0.3mol sodium borohydrides, 21.6g, 0.15mol ferrous oxalates are to slowly warm up to back flow reaction 2 hours, reaction is finished, cooling
To 10 DEG C, 10% ammonium chloride solution tune pH value is added to neutrality, filtering steams 2- methyltetrahydrofurans, is added in residue
Ethyl alcohol 150ml*3 extractions, extraction phase are passed through hydrogen chloride gas to being saturated, and then decompression steams ethyl alcohol to 75ml, and resting solution exists
Crystallization 2-3 hours are stood at room temperature, are filtered, washed the off-white powder 18.91g that drying purity is 98.5%, are as tieed up
Raw element B6.Yield is 92%.
Embodiment 2：
The addition 150ml tetrahydrofurans into three-necked flasks of the 500ml with stirring, thermometer and condenser pipe, 0.1mol,
25.3g2- methyl -3- pyridones -4,5- dicarboxylic acid ethyl ester, 12.1g, 0.10mol dimethylaniline, 7.59g, 0.2mol boron
Sodium hydride, 27.81g, 0.1mol ferrous sulfate, are then to slowly warm up to back flow reaction 4 hours.Reaction, which is finished, is cooled to 8 DEG C, is added
For 10% ammonium chloride solution tune pH value to neutrality, filtering steams tetrahydrofuran and water, and 150ml*3 ethyl alcohol extraction is added in residue
It takes, extraction phase is passed through hydrogen chloride gas to being saturated, and then decompression steams ethyl alcohol to 75ml, and resting solution stands crystallization 2- at room temperature
3 hours, it is filtered, washed the off-white powder 19.2g that drying purity is 98.5%, as vitamin B6.Yield is
93.4%.
Embodiment 3：
The dioxane of addition 150ml into three-necked flasks of the 500ml with stirring, thermometer and condenser pipe, 25.3g,
0.1mol2- methyl -3- pyridone -4,5- dicarboxylic acid ethyl esters, 12.1g, 0.12mol triethylamines, 9.46g, 0.25mol boron hydrogen
Change sodium, 15.21g, then 0.12mol frerrous chlorides are to slowly warm up to 90 DEG C and react 3 hours.Reaction, which is finished, is cooled to 2 DEG C, is added
For 10% ammonium chloride solution tune pH value to neutrality, filtering steams dioxane and water, and 150ml*3 ethyl alcohol extraction is added in residue
It takes, extraction phase is passed through hydrogen chloride gas to being saturated, and then decompression steams ethyl alcohol to 75ml, and resting solution stands crystallization 2- at room temperature
3 hours, it is filtered, washed the off-white powder 18.4g that drying purity is 98.2%, as vitamin B6.Yield is
89.5%.
Comparative example 1：
Using 4- methyl -5- alkane oxygen base oxazole or 4- methyl -5- alkyl siloxy oxazoles and dihydro -1 2- alkyl -4,7-,
3- bis- Evil English in heptan acid adding after Diels-Alder reacts is hydrolyzed, and then at salt up to vitamin B6, reaction temperature is
80-120 DEG C, the reaction time is 8-15 hours, 4- methyl-5- alkoxies (or alkoxysilyl group) oxazoles and 2- alkyl-4,7-
The rate of charge of dihydro -1,3- Er Evil English in heptan is 1：11-1:15, the yield of the vitamin B6 prepared is 75%.
Comparative example 2：
Using 4- methyl -5- alkane oxygen base oxazole or 4- methyl -5- alkyl siloxy oxazoles and maleic acid diester or fumaric acid
Diester after Diels-Alder additions and addition reaction, through reduction, at salt up to vitamin B6, the vitamin for preparing
The yield of B6 is 72%.
It can be obtained by above-described embodiment 1-3 and the comparative analysis of comparative example 1, comparative example 2, using hydroboration
2- methyl -3- pyridone -4,5- dicarboxylic acid ethyl esters are reduced under sodium or potassium borohydride, lewis acid and tertiary amine collective effect
Pyridine glycol, that is, vitamin, 1) operationally, entire reaction process is mild, the time is short, low energy consumption, utilization rate of equipment and installations significantly
It improves, solvent is without doing special Non-aqueous processing, and operation does not need high-tension apparatus, therefore is conducive to without security risk in operating process
Operation；2) for from yield, relative to the preparation method described in comparative example 1-2, yield has greatly embodiment 1-3
It improves.
Above-described specific implementation mode has carried out further the purpose of the present invention, technical solution and advantageous effect
It is described in detail, it should be understood that the foregoing is merely the specific implementation mode of the present invention, is not intended to limit the present invention
Protection domain, all within the spirits and principles of the present invention, any modification, equivalent substitution, improvement and etc. done should all include
Within protection scope of the present invention.
Claims (9)
- The method that 1.2- methyl -3- pyridone -4,5- dicarboxylic acid esters reduction prepares vitamin B6, it is characterised in that：2- methyl- 3- pyridone -4,5- dicarboxylic acid esters dissolve in a solvent, then sequentially add sodium borohydride or potassium borohydride, Louis Acid, tertiary amine, then heating 2-4 hour of reaction, after the reaction was complete, system temperature is cooled to less than or equal to 10 DEG C, is then added 10% ammonium chloride is adjusted pH to neutrality, is filtered, and liquid separation extraction is passed through HCl gases to being saturated, and concentration standing crystallization, filtration drying are Obtain the crude product of vitamin B6.
- 2. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 1 prepares the side of vitamin B6 Method, it is characterised in that：The molar ratio of the reactant is 2- methyl -3- pyridone -4,5- dicarboxylic acid esters：Sodium borohydride or Potassium borohydride：Lewis acid：Tertiary amine=1：2—3：1—1.5：1—1.5.
- 3. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 2 prepares the side of vitamin B6 Method, it is characterised in that：The molar ratio of the reactant is 2- methyl -3- pyridone -4,5- dicarboxylic acid esters：Sodium borohydride or Potassium borohydride：Lewis acid：Tertiary amine=1：2：1：1.
- 4. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 1 prepares the side of vitamin B6 Method, it is characterised in that：The heating reaction temperature is 40-90 DEG C.
- 5. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 1 prepares the side of vitamin B6 Method, it is characterised in that：The solvent of the 2- methyl -3- pyridone -4,5- dicarboxylic acid esters dissolving is 2- methylfurans, tetrahydrochysene furan It mutters, any one in dioxane, methyl tertiary butyl ether(MTBE), ether.
- 6. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 1 prepares the side of vitamin B6 Method, it is characterised in that：The lewis acid is any one in ferrous sulfate, ferrous oxalate, frerrous chloride.
- 7. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 1 prepares the side of vitamin B6 Method, it is characterised in that：The tertiary amine is any one in triethylamine, trimethylamine, dimethylaniline, diisopropylethylamine.
- 8. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 1 prepares the side of vitamin B6 Method, it is characterised in that：The vitamin B6 crude product is using absolute ethyl alcohol recrystallization, filtering to get vitamin B6 sterling.
- 9. 2- methyl -3- pyridones -4,5- dicarboxylic acid esters reduction according to claim 1 prepares the side of vitamin B6 Method, it is characterised in that：The temperature after the reaction was complete is cooled to 2-10 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3227721A (en) * | 1965-05-24 | 1966-01-04 | Merck & Co Inc | Process for preparing 2-methyl-3-hydroxypyridines |
| GB1151252A (en) * | 1965-06-08 | 1969-05-07 | Takeda Chemical Industries Ltd | A process for preparing Pyridoxin |
| CN101391941A (en) * | 2008-11-11 | 2009-03-25 | 江苏技术师范学院 | Method for preparing 3,5-dihydroxybenzylalcohol |
| CN103058919A (en) * | 2012-12-24 | 2013-04-24 | 新发药业有限公司 | One-pot preparation method of vitamin B6 |
-
2018
- 2018-03-01 CN CN201810172294.4A patent/CN108358836B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3227721A (en) * | 1965-05-24 | 1966-01-04 | Merck & Co Inc | Process for preparing 2-methyl-3-hydroxypyridines |
| GB1151252A (en) * | 1965-06-08 | 1969-05-07 | Takeda Chemical Industries Ltd | A process for preparing Pyridoxin |
| CN101391941A (en) * | 2008-11-11 | 2009-03-25 | 江苏技术师范学院 | Method for preparing 3,5-dihydroxybenzylalcohol |
| CN103058919A (en) * | 2012-12-24 | 2013-04-24 | 新发药业有限公司 | One-pot preparation method of vitamin B6 |
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Effective date of registration: 20230923 Address after: Room 505, No.7 and No.9 Qingchun Road, Shangcheng District, Hangzhou City, Zhejiang Province, 310009 Patentee after: Hangzhou Longsheng Pharmaceutical Technology Co.,Ltd. Address before: No. 501, 5th floor, building 2, No. 99, Wuke West 4th Road, Wuhou New Town Management Committee, Wuhou District, Chengdu, Sichuan 610000 Patentee before: CHENGDU PINGHE AN'KANG MEDICAL TECHNOLOGY CO.,LTD. |