CN107652323A - A kind of synthetic method of phosphopyridoxal pyridoxal phosphate - Google Patents
A kind of synthetic method of phosphopyridoxal pyridoxal phosphate Download PDFInfo
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- CN107652323A CN107652323A CN201710850639.2A CN201710850639A CN107652323A CN 107652323 A CN107652323 A CN 107652323A CN 201710850639 A CN201710850639 A CN 201710850639A CN 107652323 A CN107652323 A CN 107652323A
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- pyridoxal
- phosphopyridoxal
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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Abstract
The present invention relates to the present invention relates to chemosynthesis technical field, a kind of synthetic method of phosphopyridoxal pyridoxal phosphate is specifically disclosed.The synthetic method of the phosphopyridoxal pyridoxal phosphate, oxidation reaction is occurred under activated manganese dioxide effect by pyridoxine hydrochloride pyridoxal hydrochloride is made；The pyridoxal hydrochloride and N, N dimethyl-ethylenediamine occur condensation reaction and obtain pyridoxal condensation product；Phosphating reaction occurs in the presence of polyphosphoric acids and obtains phosphopyridoxal pyridoxal phosphate crude product for pyridoxal condensation product condensation product, then obtains phosphopyridoxal pyridoxal phosphate product by purifying, crystallization.There is this method supplementary material to be easy to get, reaction condition is gentle, high income, environment-friendly advantage.
Description
Technical field
The present invention relates to chemosynthesis technical field, more particularly to a kind of synthetic method of phosphopyridoxal pyridoxal phosphate.
Background technology
Phosphopyridoxal pyridoxal phosphate（PLP）For white crystals, chemical name 2- methyl -3- hydroxyl -4- formaldehyde -5- hydroxymethylpyridine phosphoric acid
Ester, it is the coenzyme of transaminase in amino acid metabolism and decarboxylase, glutamic acid decarboxylase can be promoted, promote the life of γ-aminobutyric acid
Into the latter is neural inhibitory transmitter.It is used clinically for treating the medicine of parkinson's syndrome, promotes transaminase to be turned
Ammonia effect improves the content of internal dopamine.In addition, it can also be catalyzed a variety of reactions, a-amino acid and 2-ketoacid common are
Transamination and a-amino acid decarboxylating.
At the beginning of PLP synthesis self-discovery the emphasis, Gusalus etc. of just always many scholar's research with pyridoxal through trichlorine
Barium salt is made in oxygen phosphorus aqueous solution phosphorylation；Peterson and Heyl is mixed using pyridoxamine as raw material with phosphoric acid and phosphorus pentoxide
Phosphorylation obtains phosphopyridoxamine, then is aoxidized to obtain phosphopyridoxal pyridoxal phosphate；Chinese patent discloses one kind and is condensed by pyridoxal
The preparation method of thing, by pyridoxal and N, N- bis- substitutes propane diamine to be condensed to yield intermediate, then makees in phosphorus pentoxide and phosphoric acid
Phosphopyridoxal pyridoxal phosphate product is obtained under.
Preparation report on PLP is a lot, but step is numerous and diverse, and yield is relatively low, it is impossible to meets industrialization production requirements.
The content of the invention
Complicated for existing phosphopyridoxal pyridoxal phosphate preparation method, the problems such as yield is low, the present invention provides a kind of phosphopyridoxal pyridoxal phosphate
Synthetic method.
To achieve the above object of the invention, the embodiment of the present invention employs following technical scheme：
A kind of synthetic method of phosphopyridoxal pyridoxal phosphate, including at least following steps：
Step 1, using activated manganese dioxide as catalyst, pyridoxine hydrochloride is oxidized to pyridoxal hydrochloride；
Step 2, the pyridoxal hydrochloride and N, N- dimethyl-ethylenediamine are subjected to condensation reaction obtain pyridoxal condensation product；
Step 3, the pyridoxal condensation product and polyphosphoric acids are subjected to phosphating reaction prepare phosphopyridoxal pyridoxal phosphate crude product.
Relative to prior art, the inventive method provided by the invention is simple to operate, and raw and auxiliary material is easy to get, and yield is higher,
More than 70%, it is adapted to industrialized production.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, with reference to embodiments, to the present invention
It is further elaborated.It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not used to
Limit the present invention.
The embodiment of the present invention provides a kind of synthetic method of phosphopyridoxal pyridoxal phosphate, including at least following steps：
Step 1, using activated manganese dioxide as catalyst, pyridoxine hydrochloride is oxidized to pyridoxal hydrochloride；
Step 2, the pyridoxal hydrochloride and N, N- dimethyl-ethylenediamine are subjected to condensation reaction obtain pyridoxal condensation product；
Step 3, the pyridoxal condensation product and polyphosphoric acids are subjected to phosphating reaction prepare phosphopyridoxal pyridoxal phosphate crude product.
The inventive method provided in an embodiment of the present invention is simple to operate, and raw and auxiliary material is easy to get, and yield is higher, more than 70%,
It is adapted to industrialized production.
Preferably, in the step 1, the method that pyridoxine hydrochloride is oxidized to pyridoxal hydrochloride is：Concentration is provided
For the hydrochloric acid solution of 10-200g/L pyridoxine hydrochloride, activated manganese dioxide is added, is aoxidized under the conditions of 10 ~ 60 DEG C
Reaction prepares pyridoxal hydrochloride.
Manganese dioxide is a kind of highly stable transition metal oxide, under the conditions of watery hydrochloric acid, manganese dioxide pyrrole
The yield that alcohol of trembling obtains pyridoxal is very high, so the hydrochloric acid solution of pyridoxine hydrochloride is preferably used in the present invention as raw material, with
Manganese dioxide is oxidant and catalyst.
Preferably, the activated manganese dioxide and the mass ratio of the pyridoxine hydrochloride are 1.5-2.0：1；And/or
The mass concentration of the hydrochloric acid is 3-30%.
Preferably, in addition to the pyridoxal hydrochloride to obtaining carries out purification process, the method for the purification process
For：Reaction system is subjected to filtration treatment, filtrate is collected, the filtrate is concentrated to give concentrate 1, into the concentrate 1
Add solvent 1 to be recrystallized, the pyridoxal hydrochloride purified.
Preferably, in the step 2, the pyridoxal hydrochloride and N, N- dimethyl-ethylenediamine is subjected to condensation reaction and obtained
Method to pyridoxal condensation product is：The pyridoxal hydrochloride and N, N- dimethyl-ethylenediamine are added in solvent 2, stirred
Mix, under 85-90 DEG C of counterflow condition, reacted, prepare pyridoxal condensation product.
Preferably, in addition to the pyridoxal condensation product to obtaining carries out purification process, and the purification treating method is：
The pyridoxal condensation product is concentrated to give concentrate 2, solvent 3 is added into the concentrate 2, heating is until dissolve, then
Decrease temperature crystalline, obtain pyridoxal condensation product.
Preferably, the mol ratio of the pyridoxal hydrochloride and N, N- dimethyl-ethylenediamine is 1:2-3；And/or
The concentration condition is to obtain concentrate 2 in 45-50 DEG C of decompression.
Preferably, the mass ratio of pyridoxal condensation product and polyphosphoric acids described in the step 3 is 1：1.3-1.5, reaction
Temperature is 50-90 DEG C.
Preferably, in addition to the phosphopyridoxal pyridoxal phosphate crude product to obtaining carries out purification process, and the purification treating method is：Will
732 ion exchange resin are crossed after the phosphopyridoxal pyridoxal phosphate crude product addition water dissolving to be purified, and are collected desorbed solution, are concentrated under reduced pressure
To concentrate 3, into the concentrate 3, addition solvent 4 is crystallized to obtain phosphopyridoxal pyridoxal phosphate product.
Preferably, the solvent 1 is one kind in methanol, ethanol, glycerine；And/or
The solvent 2 is one kind in toluene, benzene, dimethylbenzene；And/or
The solvent 3 is one kind in normal heptane, dichloromethane.
The solvent 4 is one kind in methanol, ethanol, normal propyl alcohol.
It is provided in an embodiment of the present invention in order to better illustrate, illustrated below by embodiment is further.
Embodiment 1
The present embodiment provides a kind of synthetic method of phosphopyridoxal pyridoxal phosphate, comprises the following steps：
Step 1, prepare pyridoxal hydrochloride
By 50g pyridoxine hydrochlorides it is molten be added to 500mL mass concentrations be 30% hydrochloric acid solution in, add 80g activity dioxies
Change manganese, stir and be warming up to 50 DEG C and reacted, raw material converts completely after reacting 24h, naturally cools to 20-25 DEG C of room temperature, very
Sky, which filters, obtains filtrate, and filtrate control is concentrated under reduced pressure into no liquid under the conditions of 60 DEG C and flows out to obtain concentrate 1, to the concentration
200mL methanol is added in thing 1 to stir, and is cooled：5 DEG C were cooled in 10 hours, obtains turbid solution, filters, dry filter cake
It is dry to obtain 43g pyridoxal hydrochlorides；
Step 2, prepare pyridoxal condensation product
The 43g pyridoxals hydrochloride and 25g N, N- dimethyl-ethylenediamines are added in 400mL toluene, are warming up in stirring
90 DEG C, flow back 8h, is reacted, and after reaction completely, is concentrated in vacuo out toluene and obtains concentrate 2, added into the concentrate 2
200mL normal heptanes, heating is until dissolving, and then decrease temperature crystalline, obtains 42g pyridoxal condensation products；
Step 3, prepare phosphopyridoxal pyridoxal phosphate
42g pyridoxals condensation product and 55g polyphosphoric acids are added in reaction bulb, stirring is warming up to 70 DEG C of reaction 12h to reaction
Completely, then add 30mL water to stir dissolving, cross 250mL 732 resins, parsing flow velocity is 0.2BV/h, and collection purity is big
In 83% desorbed solution, concentrate 3 is concentrated under reduced pressure to give, 160mL methanol dissolving is added into the concentrate 3, slow cooling obtains
To white crystals, drying obtains product phosphopyridoxal pyridoxal phosphate 37g, and gross mass yield is 74%.
Embodiment 2
The present embodiment provides a kind of synthetic method of phosphopyridoxal pyridoxal phosphate, comprises the following steps：
Step 1, prepare pyridoxal hydrochloride
By 100g pyridoxine hydrochlorides it is molten be added to 1000mL mass concentrations be 15% hydrochloric acid solution in, add 200g activity
Manganese dioxide, stir and be warming up to 55 DEG C and reacted, raw material converts completely after reacting 28h, naturally cools to room temperature 20-25
DEG C, vacuum filtration obtains filtrate, and filtrate control is concentrated under reduced pressure into no liquid under the conditions of 60 DEG C and flows out to obtain concentrate 1, to institute
State addition 400mL ethanol in concentrate 1 to stir, cool：5 DEG C were cooled in 10 hours, turbid solution is obtained, filtering, incites somebody to action
Filter cake dries to obtain 88g pyridoxal hydrochlorides；
Step 2, prepare pyridoxal condensation product
The 88g pyridoxals hydrochloride and 55g N, N- dimethyl-ethylenediamines are added in 880mL dimethylbenzene, heated up in stirring
To 90 DEG C, flow back 8h, is reacted, and after reaction completely, is concentrated in vacuo out toluene and obtains concentrate 2, adds into the concentrate 2
Enter 200mL dichloromethane, heating is until dissolving, and then decrease temperature crystalline, obtains 85g pyridoxal condensation products；
Step 3, prepare phosphopyridoxal pyridoxal phosphate
85g pyridoxals condensation product and 120g polyphosphoric acids are added in reaction bulb, stirring is warming up to 70 DEG C of reaction 12h to reaction
Completely, then add 60mL water to stir dissolving, cross 550mL 732 resins, parsing flow velocity is 0.2BV/h, and collection purity is big
In 83% desorbed solution, concentrate 3 is concentrated under reduced pressure to give, 340mL normal propyl alcohol dissolving, slow cooling are added into the concentrate 3
White crystals are obtained, drying obtains product phosphopyridoxal pyridoxal phosphate 76g, and gross mass yield is 76%.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all essences in the present invention
Any modification, equivalent substitution or improvement made within refreshing and principle etc., should be included in the scope of the protection.
Claims (10)
- A kind of 1. synthetic method of phosphopyridoxal pyridoxal phosphate, it is characterised in that：Including at least following steps：Step 1, using activated manganese dioxide as catalyst, pyridoxine hydrochloride is oxidized to pyridoxal hydrochloride；Step 2, the pyridoxal hydrochloride and N, N- dimethyl-ethylenediamine are subjected to condensation reaction obtain pyridoxal condensation product；Step 3, the pyridoxal condensation product and polyphosphoric acids are subjected to phosphating reaction prepare phosphopyridoxal pyridoxal phosphate crude product.
- 2. the synthetic method of phosphopyridoxal pyridoxal phosphate as claimed in claim 1, it is characterised in that：In the step 1, by pyridoxol salt The method that hydrochlorate is oxidized to pyridoxal hydrochloride is：The hydrochloric acid solution for the pyridoxine hydrochloride that concentration is 10-200g/L is provided, added Enter activated manganese dioxide, oxidation reaction is carried out under the conditions of 10 ~ 60 DEG C and prepares pyridoxal hydrochloride.
- 3. the synthetic method of phosphopyridoxal pyridoxal phosphate as claimed in claim 2, it is characterised in that：The activated manganese dioxide with it is described The mass ratio of pyridoxine hydrochloride is 1.5-2.0：1；And/orThe mass concentration of the hydrochloric acid is 3-30%.
- 4. the synthetic method of phosphopyridoxal pyridoxal phosphate as claimed in claim 2, it is characterised in that：Also include trembling to the obtained pyrrole Aldehyde hydrochloride carries out purification process, and the method for the purification process is：Reaction system is subjected to filtration treatment, collects filtrate, will The filtrate is concentrated to give concentrate 1, and solvent 1 is added into the concentrate 1 and is recrystallized, the pyridoxal salt purified Hydrochlorate.
- 5. the synthetic method of phosphopyridoxal pyridoxal phosphate as claimed in claim 1, it is characterised in that：In the step 2, the pyrrole is trembled Aldehyde hydrochloride and N, N- dimethyl-ethylenediamine carry out condensation reaction and obtain the method for pyridoxal condensation product：By the pyridoxal salt Hydrochlorate and N, N- dimethyl-ethylenediamine are added in solvent 2, under stirring, 85-90 DEG C of counterflow condition, are reacted, prepare pyrrole Tremble aldehyde condensate.
- 6. the synthetic method of phosphopyridoxal pyridoxal phosphate as claimed in claim 5, it is characterised in that：Also include trembling to the obtained pyrrole Aldehyde condensate carries out purification process, and the purification treating method is：The pyridoxal condensation product is concentrated to give concentrate 2, to Solvent 3 is added in the concentrate 2, heating is until dissolving, and then decrease temperature crystalline, obtains pyridoxal condensation product.
- 7. the synthetic method of the phosphopyridoxal pyridoxal phosphate as described in claim any one of 5-6, it is characterised in that：The pyridoxal hydrochloric acid The mol ratio of salt and N, N- dimethyl-ethylenediamine is 1:2-3；And/orThe concentration condition is to obtain concentrate 2 in 45-50 DEG C of decompression.
- 8. the synthetic method of phosphopyridoxal pyridoxal phosphate as claimed in claim 1, it is characterised in that：Pyridoxal described in the step 3 The mass ratio of condensation product and polyphosphoric acids is 1：1.3-1.5 reaction temperature is 50-90 DEG C.
- 9. the synthetic method of phosphopyridoxal pyridoxal phosphate as claimed in claim 1, it is characterised in that：Also include trembling to obtained phosphoric acid pyrrole Aldehyde crude product carries out purification process, and the purification treating method is：Will the phosphopyridoxal pyridoxal phosphate crude product add water dissolving after cross 732 from Sub-exchange resin is purified, and is collected desorbed solution, is concentrated under reduced pressure to give concentrate 3, and solvent 4 is added into the concentrate 3 and is entered Row crystallization obtains phosphopyridoxal pyridoxal phosphate product.
- 10. the synthetic method of the phosphopyridoxal pyridoxal phosphate as described in claim any one of 2-9, it is characterised in that：The solvent 1 is first One kind in alcohol, ethanol, glycerine；And/orThe solvent 2 is one kind in toluene, benzene, dimethylbenzene；And/orThe solvent 3 is one kind in normal heptane, dichloromethane;The solvent 4 is one kind in methanol, ethanol, normal propyl alcohol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109021012A (en) * | 2018-08-01 | 2018-12-18 | 江苏理工学院 | A kind of synthesis technology of pyridoxime 5'-phosphate |
| CN111362982A (en) * | 2020-04-07 | 2020-07-03 | 河北美邦工程科技股份有限公司 | Refining method of pyridoxal phosphate |
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| ES8308851A1 (en) * | 1982-10-26 | 1983-10-01 | Targa S A | Pyridoxal-5'-phosphate prodn. |
| CN1199402A (en) * | 1995-09-04 | 1998-11-18 | 施泰格瓦尔德制药有限公司 | Method for production of magnesium pyridoxal-5'-phosphate glutamate and intermediate products obtained thereby |
| CN101525331A (en) * | 2008-03-07 | 2009-09-09 | 上海医药工业研究院 | Phosphopyridoxal intermediates, preparation method of same, application of same, and method for preparing phosphopyridoxal therefrom |
| CN101525330A (en) * | 2008-03-07 | 2009-09-09 | 上海医药工业研究院 | Phosphopyridoxal intermediates, preparation method of same, application of same, and method for preparing phosphopyridoxal therefrom |
| CN106946932A (en) * | 2017-03-21 | 2017-07-14 | 上海津力生物科技股份有限公司 | A kind of preparation method of the phosphate of pyridoxal 5 |
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2017
- 2017-09-20 CN CN201710850639.2A patent/CN107652323A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3644385A (en) * | 1967-11-27 | 1972-02-22 | Tanabe Seiyaku Co | Alpha**5-o-acyl-pyridoxal derivatives |
| ES8308851A1 (en) * | 1982-10-26 | 1983-10-01 | Targa S A | Pyridoxal-5'-phosphate prodn. |
| CN1199402A (en) * | 1995-09-04 | 1998-11-18 | 施泰格瓦尔德制药有限公司 | Method for production of magnesium pyridoxal-5'-phosphate glutamate and intermediate products obtained thereby |
| CN101525331A (en) * | 2008-03-07 | 2009-09-09 | 上海医药工业研究院 | Phosphopyridoxal intermediates, preparation method of same, application of same, and method for preparing phosphopyridoxal therefrom |
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| CN106946932A (en) * | 2017-03-21 | 2017-07-14 | 上海津力生物科技股份有限公司 | A kind of preparation method of the phosphate of pyridoxal 5 |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109021012A (en) * | 2018-08-01 | 2018-12-18 | 江苏理工学院 | A kind of synthesis technology of pyridoxime 5'-phosphate |
| CN109021012B (en) * | 2018-08-01 | 2021-04-20 | 南通香地生物有限公司 | Synthesis process of pyridoxal 5' -phosphate |
| CN111362982A (en) * | 2020-04-07 | 2020-07-03 | 河北美邦工程科技股份有限公司 | Refining method of pyridoxal phosphate |
| CN111362982B (en) * | 2020-04-07 | 2023-01-17 | 河北美邦工程科技股份有限公司 | Refining method of pyridoxal phosphate |
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Application publication date: 20180202 |