CN105906559A - One-step synthesis method of medicinal metadoxine - Google Patents
One-step synthesis method of medicinal metadoxine Download PDFInfo
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- CN105906559A CN105906559A CN201610417171.3A CN201610417171A CN105906559A CN 105906559 A CN105906559 A CN 105906559A CN 201610417171 A CN201610417171 A CN 201610417171A CN 105906559 A CN105906559 A CN 105906559A
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention discloses a one-step synthesis method of medicinal metadoxine. The method comprises the steps that vitamin B6 is adopted as a starting raw material and directly reacts with L-pyroglutamic acid after alkali dissociation to obtain metadoxine through one-step synthesis. The proper solvent, the reaction raw material ratio and the proper reaction temperature are adopted, the medicinal metadoxine with the stable crystal form, the good flowability and high purity can be produced industrially without recrystallization or purification, the preparation steps are simplified, operation is easy, the solvent usage amount is decreased, and the production cost is saved. The medicinal metadoxine can be used for treating acute and chronic alcoholism and alcoholic liver diseases.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to the one-step synthesis of a kind of pharmaceutical grade metadoxine.
Background technology
The chemical name of metadoxine is: metadoxine (1:1), and molecular formula is:
C8H11NO3·C5H7NO3, molecular weight is: 298.29.Metadoxine another name is: vitamin B6 Jiao's paddy ammonia
Hydrochlorate, its structure is:
As accelerating internal alcohol metabolism, improving the medicine of hepatic insufficiency, the appearance of metadoxine medicine is given
Numerous hepatopaths bring Gospel.Metadoxine medicine in December, 2013 in " the 11st middle traditional Chinese medical science
Medicine marketing new master forum " on, it is cited as 2013 ten greatly one of weight pound medicines, can take off improving human body aldehyde
The activity of hydrogen enzyme simultaneously, is accelerated ethanol and the removing of acetaldehyde in blood plasma and urine, thus liver is risen bigger guarantor
Protect effect.Meanwhile, its hepatoprotective effect has other clinical indications possibilities expanding alcoholism related liver disease.
Metadoxine medicines structure is by pyridoxol (vitamin B6 alkali) and pyrrolidone carboxylic acid salt (L-Jiao Gu
Propylhomoserin) the ion pair medicine that formed by salification between two compounds, the particularity of its structure embodies
: 1) structure of vitamin B6 alkali due to the existence of multiple electron-donating groups make it the most oxidized thus not
Stable；2) ion-pair structure formed by non-covalent bond.Due to above reason so that the synthesis of this raw material
Technique report is less, and industrialization difficulty is big.Italian patent IT1131855 uses vitamin B6 and L-
Pyroglutamic acid one reacts, by an ion-exchange chromatogram purification, finally by removed under reduced pressure eluent,
Residual liquid precipitation obtains target product.This prepares the method for metadoxine, needs through an ion exchange chromatography
Purification, and need high-temperature pressure-reduction evaporation of eluate, not only energy consumption is high, and easily causes decomposition product, very
It is unfavorable for industrialized production.Guo Xuefei et al., at " chemical intermediate " 2006, reports use two in 4,19
The method walking synthetically prepared metadoxine, prepares dimension first by vitamin B6 hydrogen chloride salt and sodium hydroxide raw
Element B6 alkali, then prepares metadoxine finished product with L-Glutimic acid reaction, and this prepares the method for metadoxine,
A large amount of sodium chloride will be produced, owing to sodium chloride has similar to product during preparing vitamin B6 alkali
Dissolubility, is very difficult to remove in system, thus affects the carrying out of salt-forming reaction.Additionally vitamin in the method
B6 alkali and two raw materials of L-Glutimic acid are required to grinding and sieve, and need to be sufficiently mixed under solvent-free state, industry
Production takes time and effort, operation inconvenience, it is difficult to industrialization.Patent application WO9419324A and patent application
CN101092394A reports use vitamin B6 alkali and L-Glutimic acid at isopropanol as solvent condition
The lower method preparing metadoxine finished product, although the method can reach to prepare the purpose of metadoxine finished product,
But make it the most oxidized and more unstable owing to vitamin B6 alkali exists multiple electron-donating group, thus more difficult
It is carried out quality control, then cannot ensure the quality of metadoxine finished product, it is more difficult to reach medicinal rank.
Further, since vitamin B6 alkali compares vitamin B6, price, and due to its structural instability, incite somebody to action
The production costs such as special storage condition can be greatly increased, thus limit the industrialization of the method.
Summary of the invention
For the problem overcoming prior art to exist, the invention provides a kind of use vitamin B6 is initiation material,
After alkali is free directly and the one-step method for synthesizing of metadoxine is prepared in L-Glutimic acid reaction.
Compared with prior art, metadoxine one-step method for synthesizing disclosed by the invention has the advantage that
1. selecting vitamin B6 is initiation material, compares vitamin B6 alkali, and low price is easy to get, and character is steady
Fixed, it is simple to transport and store, and vitamin B6 inherently a kind of crude drug, quality can obtain very well
Guarantee.
2. use sodium hydroxide free vitamin B6, through simple post processings such as filtrations, directly in reaction system
Middle addition L-Glutimic acid can generate metadoxine finished product, through simple centrifugal, dry post-processing operation i.e.
Available pharmaceutical grade finished product.Compare two step synthesis, greatly reduce the discharge of waste water, waste residue, meet green
Change production requirement.
3. applicant further found that metadoxine is unstable in the case of high humidity (75%RH), especially high humidity
(75%RH) with under high temperature (40 DEG C) common conditions, product is the most easily degraded.Therefore at metadoxine
The production process of tablet needs avoid using wet granulation and using dry granulation or powder vertical compression, and powder is straight
Pressure is the formulation method having related substance impact minimum on metadoxine crude drug, but powder vertical compression technology pair
The particle diameter of crude drug and the requirement of mobility are higher, and he is many to use U.S. that synthetic method of the present invention prepares
Pungent finished product, have stable crystal form, uniform particle sizes, without finely ground sieving, good fluidity, dissolvent residual are low,
Purity is high, fully meets the feature of formulation requirements.
Concrete technical scheme of the present invention is as follows:
The one-step synthesis of pharmaceutical grade metadoxine of the present invention is with vitamin B6 as raw material, straight after alkali is free
Connect and react with L-Glutimic acid, one-step synthesis method metadoxine, concrete operation step is as follows:
A. vitamin B6 is suspended in isopropanol, flow hydro-oxidation sodium solution, control system pH to 7～
8；
B. it is centrifuged, collects isopropyl alcohol and water mixing mother solution；
C. L-Glutimic acid is added in above-mentioned mixing mother liquor solution, react 10～30 minutes；Cooling makes crystallization,
Keep 30～60 minutes；
D. being centrifuged, a small amount of isopropanol drip washing, gained solid i.e. obtains pharmaceutical grade metadoxine after forced air drying.
Further, described vitamin B6 is 1:1～3 with the mass ratio of isopropanol in described A.
Further, described vitamin B6 is 1:0.94～0.98 with the mass ratio of described sodium hydroxide solution.
Further, the concentration of described sodium hydroxide solution is 20%.
Further, described L-Glutimic acid is 1:1.59 with the mass ratio of described vitamin B6.
Further, in described C, reaction temperature is 25～35 DEG C.
Further, in described C, crystallization temperature is 0～5 DEG C.
Further, in described D, the temperature of forced air drying is 35～45 DEG C, and drying time is 8～12h.
A kind of pharmaceutical grade metadoxine one-step synthesis that the present invention provides, mainly has the advantages that
(1) raw material of the present invention and product are all without grinding, simple to operate, with short production cycle, and solvent load is fitted
When, it is easy to large-scale industrial production operates.
(2) the inventive method synthetic route is short, and waste water and dregs discharge is few, meets greenization production requirement.
(3) yield height, very high purity, yield reaches 92%, and purity is more than 99.9%.
(4) products obtained therefrom stable crystal form, uniform particle sizes, good fluidity, dissolvent residual are low.
Accompanying drawing explanation
Fig. 1 is infrared spectrum (IR) figure of the metadoxine of embodiment 1 preparation.
Fig. 2 is differential scanning calorimetric analysis (XRD) figure of the metadoxine of embodiment 1 preparation.
Fig. 3 be embodiment 1 preparation metadoxine proton nmr spectra (1HNMR) figure.
Fig. 4 be embodiment 1 preparation metadoxine carbon-13 nmr spectra (13CNMR) figure.
Fig. 5 is X-ray powder diffraction spectrum (XRD) figure of the metadoxine of embodiment 1 preparation.
Fig. 6 is X-ray powder diffraction spectrum (XRD) figure of the metadoxine of embodiment 2 preparation.
Fig. 7 is X-ray powder diffraction spectrum (XRD) figure of the metadoxine of embodiment 3 preparation.
Metadoxine sheet prepared by Tu8Shi Yuanyan producer (Baldacci company of Italy, lot number: 0814)
X-ray powder diffraction spectrum (XRD) figure.
Fig. 9 is the grain size distribution of the metadoxine of embodiment 1 preparation.
Figure 10 is the grain size distribution of the metadoxine of embodiment 2 preparation.
Detailed description of the invention
The present invention being explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate this
Bright technical scheme, and non-limiting the spirit and scope of the invention.The most only point out, the present invention uses
Reagent and test equipment, in addition to indicating the source especially, are the commercially available universal product.In the embodiment of the present invention not
Indicate the experimental technique of actual conditions, generally according to normal condition, or make institute of manufacturer according to raw material or commodity
The condition of suggestion.
Main test instrunment used by experiment:
1, DSC spectrum
INSTRUMENT MODEL: Mettler Toledo DSC 1Stare System
2, X-ray powder diffraction spectrum
INSTRUMENT MODEL: D/Max-Bruker D 8Focus X-ray powder diffractometer
3、1HNMR spectrum with13CNMR composes
INSTRUMENT MODEL: Bruker AVANCE III 400
4, elementary analysis
INSTRUMENT MODEL: Elemantar vario EL cube elemental analyser
5, particle diameter distribution
INSTRUMENT MODEL: Malvern mastersizer3000 particle diameter distribution detector
Metadoxine prepared by embodiment involved in the present invention uses following methods to carry out purity testing:
Take this product appropriate, add acetonitrile: water (1:9) dissolves and dilutes to make and contains the molten of 1.0mg in every 1ml
Liquid, as need testing solution；Precision measures in right amount, adds acetonitrile: water (1:9) makes every 1ml containing 5ug
Solution, as contrast solution.With reference to high performance liquid chromatography (Chinese Pharmacopoeia two annex V of version in 2010
D) test, using octadecylsilane chemically bonded silica as filler, with 0.004mol/L octane sulfonate sodium solution
(with phosphoric acid tune pH value to 2.5) is mobile phase A phase, and with acetonitrile for Mobile phase B phase, detection wavelength is
291nm, column temperature 30 DEG C, sample size 20ul, carry out gradient elution by table 1, number of theoretical plate presses metadoxine
Peak calculates and is not less than 2000.Take contrast solution 20ul and inject chromatograph of liquid, regulate detection sensitivity, make main
The peak height of composition chromatographic peak is about the 10% of full scale；Precision measures each 20ul of above two solution, notes respectively
Enter chromatograph of liquid, 3 times of record chromatogram to main constituent peak retention time.
Table 1 gradient elution program
| Time (min) | A phase (%) | B phase (%) |
| 0 | 95 | 5 |
| 30 | 50 | 50 |
| 35 | 50 | 50 |
| 40 | 95 | 5 |
| 55 | 95 | 5 |
Metadoxine prepared by embodiment involved in the present invention uses following methods to carry out dissolvent residual mensuration:
Take this product appropriate, accurately weighed, in top set empty bottle, the accurate DMF 5ml that adds, close
Envelope, shaking makes dissolving, as need testing solution；Precision weighs, isopropanol is each in right amount, adds N, N-dimethyl
Methanamide quantitatively dilutes the solution made in every 1ml containing about isopropanol 2.0mg, and precision measures 5ml top set empty bottle
In, seal, as reference substance solution.According to residual solvent algoscopy (Chinese Pharmacopoeia four general rules of version in 2015
0861 second method) test, with 6% cyanogen propyl group phenyl 94% dimethyl polysiloxane (or polarity is close) be
The capillary tube of fixative is chromatographic column (Agilent DB-624 30m*0.53mm*3.0 μm or equivalence chromatographic column).
Initial temperature is 35 DEG C, maintains 14 minutes, with the ramp of 30 DEG C per minute to 120 DEG C, maintains 3 minutes,
Rise to 200 DEG C with the speed of 100 DEG C per minute again, maintain 4 minutes.Flow 1.5ml/min；Injector temperature is
200 DEG C, split ratio 2:1；Detector is fid detector, and detector temperature is 250 DEG C；Ml headspace bottle equilibrium temperature
It it is 80 DEG C；Equilibration time is 30 minutes.Take reference substance solution headspace sampling, record chromatogram.Take test sample
Solution and reference substance solution headspace sampling respectively, records chromatogram.
Embodiment 1
1, the preparation of metadoxine of the present invention
A. 30.0Kg vitamin B6 is added in 500L reactor, add 90.0Kg isopropanol, under stirring
In system, stream adds the 20% sodium hydroxide solution 29.4Kg (process for preparation: 5.88Kg hydrogen-oxygen prepared in advance
Change sodium to be dissolved in 23.52Kg purified water), adition process feed temperature is maintained at less than 35 DEG C, and 1～2h stream adds
Complete, after finishing, continue stirring 30 minutes；
B. it is centrifuged, collects isopropyl alcohol and water mixing mother solution；
C. the L-Glutimic acid of 18.8Kg is added in above-mentioned mixing mother liquor solution, be sufficiently stirred for, at 25 DEG C
React 30 minutes；It is cooled to 0～5 DEG C, keeps 30～60 minutes；
D. being centrifuged, a small amount of isopropanol drip washing, gained solid is warming up to 45 DEG C after 35 DEG C of dry 2h of air blast again
It is dried 10h, obtains 44.9Kg white solid, it is not necessary to refine and i.e. obtain pharmaceutical grade metadoxine certified products, yield
92%.
2, the structural identification of metadoxine prepared by the embodiment of the present invention 1:
The product that the present embodiment obtains is white odorless crystalline powder, and micro-strip tart flavour is highly soluble in water,
It is slightly soluble in cold ethanol, insoluble in organic solvents such as acetone, ether, chloroform, benzene, with metadoxine character phase
Symbol.The structure of product metadoxine can be confirmed from following several respects:
(1) fusing point of product: 100.6～102.5 DEG C, is consistent with the metadoxine fusing point in document；
(2) as it is shown in figure 1, infrared absorption spectroscopy (IR) figure shows, the feature of metadoxine ion pair salt
Absorb, be different from the characteristic absorption of two starting materials；
(3) as in figure 2 it is shown, differential scanning calorimetric analysis (DSC) figure shows, DSC melts with metadoxine
Point matches；
(4) as it is shown on figure 3, proton nmr spectra (1HNMR) detection: (400MHz, D2O)δ8.06(s,
1H), 4.94 (s, 2H), 4.75 (s, 2H), 4.15 (dd, J=8.9,5.8Hz, 1H), 2.58 (s, 3H),
2.52-2.39 (m, 1H), 2.39-2.29 (m, 2H), 2.05-1.96 (m, 1H), with metadoxine structure phase
Symbol；
(5) as shown in Figure 4, proton nmr spectra (13CNMR) detection: (100MHz, D2O)δ181.65,
179.78,153.51,142.80,140.23,136.56,129.08,58.05,57.97,56.58,29.54,
25.15,14.40, it is consistent with metadoxine structure；
(6) elementary analysis: product analysis result: product formula is C8H11NO3·C5H7NO3
(7) as it is shown in figure 5, use Cu-Ka radiation, the X-ray powder diagram represented with 2 θ angles
Spectrum, about 7.14,14.35,15.41,17.29,18.39,20.09,21.24,22.25,24.30,
24.75, there is characteristic peak at 25.34,26.60,27.55,28.33,34.05, grinds through former with metadoxine
Tablet XRD (Fig. 8) comparison of producer's (Baldacci company of Italy, lot number: 0814), really
Think crystal formation of the same race.
3, purity testing:
The above-mentioned method for detecting purity, the purity of the metadoxine prepared by the embodiment of the present invention 1 is used to be
99.96%.
4, isopropanol residues detecton:
Use the assay method of above-mentioned dissolvent residual, the isopropyl of the metadoxine prepared by the embodiment of the present invention 1
Alcohol residual is 0.033%.
The preparation of embodiment 2 metadoxine of the present invention
A. 10.0Kg vitamin B6 is added in 100L reactor, add 20.0Kg isopropanol, under stirring
In system, stream adds the 20% sodium hydroxide solution 9.5Kg (process for preparation: 1.9Kg hydroxide prepared in advance
Sodium is dissolved in 7.6Kg purified water), adition process feed temperature is maintained at less than 35 DEG C, and 0.5～1h stream adds
Finish, after finishing, continue stirring 30 minutes；
B. it is centrifuged, collects isopropyl alcohol and water mixing mother solution；
C. the L-Glutimic acid of 6.29Kg is added in above-mentioned mixing mother liquor solution, be sufficiently stirred for, at 35 DEG C
React 30 minutes；It is cooled to 0～5 DEG C, keeps 30～60 minutes；
D. being centrifuged, a small amount of isopropanol drip washing, gained solid is warming up to 45 DEG C after 35 DEG C of dry 3h of air blast again
It is dried 7h, obtains 14.8Kg white solid, it is not necessary to refine and i.e. obtain pharmaceutical grade metadoxine certified products, yield
91%, purity is 99.92%, and isopropanol residual is 0.043%.
The preparation of embodiment 3 metadoxine of the present invention
A. 1.0Kg vitamin B6 is added in 10L tri-neck reaction bulb, add 1.0Kg isopropanol, stirring
Lower in system stream add 20% sodium hydroxide solution 0.94Kg (process for preparation: the 0.188Kg prepared in advance
Sodium hydroxide is dissolved in 0.752Kg purified water), adition process feed temperature is maintained at less than 35 DEG C, 20 points
In clock, stream adds complete, after finishing, continues stirring 30 minutes；
B. it is centrifuged, collects isopropyl alcohol and water mixing mother solution；
C. the L-Glutimic acid of 0.63Kg is added in above-mentioned mixing mother liquor solution, be sufficiently stirred for, at 30 DEG C
React 30 minutes；It is cooled to 0～5 DEG C, keeps 30～60 minutes；
D. being centrifuged, a small amount of isopropanol drip washing, gained solid is warming up to 45 DEG C after 35 DEG C of dry 2h of air blast again
It is dried 6h, obtains 1.53Kg white solid, it is not necessary to refine and i.e. obtain pharmaceutical grade metadoxine certified products, yield
94%, purity is 99.92%, and isopropanol residual is 0.039%.
Embodiment 4 stability of crystal form is tested
By former to the metadoxine sample prepared by embodiment 1-3 and metadoxine grind medicine (lot number: 0814,
Baldacci company of Italy) carry out X-ray powder diffraction experiment.
Test result:
(1) as shown in Fig. 5, Fig. 6, Fig. 7, Fig. 8, the X-ray powder of the multiple batches of sample of embodiment 1-3
Diffraction spectrogram is consistent, and with former to grind medicine X-ray powder diffractogram consistent, shows with the present invention side of synthesis
The stable crystal form of metadoxine prepared by method.
(2) as shown in Figure 9, Figure 10, the particle diameter distribution of metadoxine prepared by the present invention is basically identical.
Claims (8)
1. the one-step synthesis of a pharmaceutical grade metadoxine, it is characterised in that: with vitamin B6 as raw material,
Directly reacting with L-Glutimic acid after alkali is free, one-step synthesis method metadoxine, its synthetic reaction formula is as follows:
Concrete operation step is as follows:
A. vitamin B6 is suspended in isopropanol, flow hydro-oxidation sodium solution, control system pH to 7～
8；
B. it is centrifuged, collects isopropyl alcohol and water mixing mother solution；
C. L-Glutimic acid is added in above-mentioned mixing mother liquor solution, react 10～30 minutes；Cooling makes crystallization,
Keep 30～60 minutes；
D. being centrifuged, a small amount of isopropanol drip washing, gained solid i.e. obtains pharmaceutical grade metadoxine after forced air drying.
The one-step synthesis of pharmaceutical grade metadoxine the most according to claim 1, it is characterised in that described
Vitamin B6 is 1:1～3 with the mass ratio of isopropanol in described A.
The one-step synthesis of pharmaceutical grade metadoxine the most according to claim 1, it is characterised in that: described
Vitamin B6 is 1:0.94～0.98 with the mass ratio of described sodium hydroxide solution.
The one-step synthesis of pharmaceutical grade metadoxine the most according to claim 1, it is characterised in that: described
The concentration of sodium hydroxide solution is 20%.
The one-step synthesis of pharmaceutical grade metadoxine the most according to claim 1, it is characterised in that: described
L-Glutimic acid is 1:1.59 with the mass ratio of described vitamin B6.
The one-step synthesis of pharmaceutical grade metadoxine the most according to claim 1, it is characterised in that: described
In C, reaction temperature is 25～35 DEG C.
The one-step synthesis of pharmaceutical grade metadoxine the most according to claim 1, it is characterised in that: described
In C, crystallization temperature is 0～5 DEG C.
The one-step synthesis of pharmaceutical grade metadoxine the most according to claim 1, it is characterised in that: described
In D, the temperature of forced air drying is 35～45 DEG C, and drying time is 8～12h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4313952A (en) * | 1980-06-30 | 1982-02-02 | Massimo Baldacci | Method of treating acute alcoholic intoxication with pyridoxine P.C.A. |
| IT1131855B (en) * | 1980-06-30 | 1986-06-25 | Baldacci Lab Spa | PROCEDURE FOR THE PREPARATION OF PYROLIDON PYRIDEXIN CARBOXYLATE |
| WO1994019324A1 (en) * | 1993-02-23 | 1994-09-01 | Laboratori Baldacci Spa | Process for the preparation of pyridoxine 5-oxo-2-pyrrolidone carboxylate |
| CN101092394A (en) * | 2007-07-17 | 2007-12-26 | 深圳市源兴药业有限公司 | Method for preparing Meixianduoxin |
-
2016
- 2016-06-14 CN CN201610417171.3A patent/CN105906559B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4313952A (en) * | 1980-06-30 | 1982-02-02 | Massimo Baldacci | Method of treating acute alcoholic intoxication with pyridoxine P.C.A. |
| IT1131855B (en) * | 1980-06-30 | 1986-06-25 | Baldacci Lab Spa | PROCEDURE FOR THE PREPARATION OF PYROLIDON PYRIDEXIN CARBOXYLATE |
| WO1994019324A1 (en) * | 1993-02-23 | 1994-09-01 | Laboratori Baldacci Spa | Process for the preparation of pyridoxine 5-oxo-2-pyrrolidone carboxylate |
| CN101092394A (en) * | 2007-07-17 | 2007-12-26 | 深圳市源兴药业有限公司 | Method for preparing Meixianduoxin |
Non-Patent Citations (1)
| Title |
|---|
| 郭雪飞，等: "美他多辛的合成", 《化工中间体》 * |
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