CN105906559B - A kind of one-step synthesis of pharmaceutical grade metadoxine - Google Patents
A kind of one-step synthesis of pharmaceutical grade metadoxine Download PDFInfo
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- CN105906559B CN105906559B CN201610417171.3A CN201610417171A CN105906559B CN 105906559 B CN105906559 B CN 105906559B CN 201610417171 A CN201610417171 A CN 201610417171A CN 105906559 B CN105906559 B CN 105906559B
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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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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
The invention discloses a kind of pharmaceutical grade metadoxine one-step synthesis, using vitamin B6 as starting material, directly react one-step synthesis metadoxine with L pyroglutamic acids after alkali is free.The present invention is by using suitable solvent, reaction raw materials with when suitable reaction temperature, the high pharmaceutical grade metadoxine of stable crystal form, good fluidity, purity can be industrially produced by not needing recrystallizing and refining, not only reduce preparation process, it is easily operated, and reduce solvent usage amount, save production cost.The pharmaceutical grade metadoxine can be used for treating acute and chronic alcoholism and alcoholic liver disease.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to a kind of one-step synthesis of pharmaceutical grade metadoxine.
Background technology
The chemical name of metadoxine is：Metadoxine (1：1), molecular formula is：
C8H11NO3·C5H7NO3, molecular weight is：298.29.Metadoxine alias is：Metadoxine, structure are：
As the drug accelerated internal alcohol metabolism, improve hepatosis, the appearance of metadoxine drug is to vast liver
Patient brings Gospel.Metadoxine drug exists in December, 2013《11st Chinese Medicine marketing new master forum》On,
Be cited as one of 2013 ten big weight pound drug, can the activity for improving human body aldehyde dehydrogenase simultaneously, accelerate in blood plasma and urine
The removing of ethyl alcohol and acetaldehyde, to play larger protective effect to liver.Meanwhile hepatoprotective effect has expansion alcoholism phase
Other clinical indications for closing hepatopathy may.
Metadoxine medicines structure is by pyridoxol (vitamin B6 alkali) and pyrrolidone carboxylic acid salt (L-Glutimic acid) two
The ion pair drug formed by salification between a compound, the particularity of structure are embodied in：1) vitamin B6 alkali
Structure makes it easily by oxidation to unstable due to the presence of multiple electron-donating groups；2) ion formed by non-covalent bond
To structure.Due to above so that the synthesis technology report of the raw material is less, and industrialization difficulty is big.Italian patent
IT1131855 is using reacting vitamin B6 and L-Glutimic acid one, by an ion-exchange chromatogram purification, finally by
Removed under reduced pressure eluent, raffinate precipitate to obtain target product.This prepares the method for metadoxine, needs by an ion exchange
Chromatogram purification, and need high-temperature pressure-reduction evaporation of eluate, not only high energy consumption, but also easily product is caused to decompose, it is highly detrimental to work
Industry metaplasia is produced.Guo Xue fly et al.《Chemical intermediate》It is reported in 2006,4,19 and is synthetically prepared metadoxine using two steps
Method prepares vitamin B6 alkali using vitamin B6 hydrogen chloride salt and sodium hydroxide first, then the system of reacting with L-Glutimic acid
Standby metadoxine finished product, this prepares the method for metadoxine, will will produce a large amount of sodium chloride during preparing vitamin B6 alkali,
It is difficult removal in system, to influence the progress of salt-forming reaction since sodium chloride and product have similar solubility.In addition
Two raw materials of vitamin B6 alkali and L-Glutimic acid are required to be ground up, sieved in this method, need to be sufficiently mixed under solvent-free state,
It is taken time and effort in industrial production, it is inconvenient, it is difficult to industrialization.Patent application WO9419324A and patent application
CN101092394A all report using vitamin B6 alkali and L-Glutimic acid prepared in the case where isopropanol is as solvent condition U.S. he
The method of mostly pungent finished product, although this method can achieve the purpose that prepare metadoxine finished product, since vitamin B6 alkali exists
Multiple electron-donating groups keep it easily more unstable by oxidation, carry out quality control to it to more difficult, can not then ensure
The quality of metadoxine finished product, it is more difficult to reach medicinal rank.In addition, due to vitamin B6 alkali compare vitamin B6, price, and
And due to its structural instability, it will the production costs such as special storage condition are greatly increased, to limit the industry of this method
Change.
Invention content
Of the existing technology to overcome the problems, such as, it is starting material that the present invention provides a kind of using vitamin B6, through alkali
The one-step method for synthesizing for preparing metadoxine is directly reacted with L-Glutimic acid after free.
Compared with prior art, metadoxine one-step method for synthesizing disclosed by the invention has the following advantages：
1. selecting vitamin B6 for starting material, vitamin B6 alkali is compared, cheap to be easy to get, property is stablized, convenient for fortune
Defeated and storage, and inherently a kind of bulk pharmaceutical chemicals of vitamin B6, quality can be ensured well.
2. using sodium hydroxide free vitamin B6, by the simple post-processing such as filtering, directly it is added in the reaction system
L-Glutimic acid produces metadoxine finished product, can be obtained pharmaceutical grade finished product by simply centrifuging, drying post-processing operation.
It is synthesized compared to two steps, greatly reduces the discharge of waste water, waste residue, meet greenization production requirement.
3. applicant further found that metadoxine is unstable in high humidity (75%RH), especially high humidity (75%RH) and
Under high temperature (40 DEG C) common conditions, the very easy degradation of product.Therefore it needs to avoid making in the production process of metadoxine tablet
Dry granulation or powder vertical compression are used with wet granulation, and powder vertical compression is influenced on the related substance of metadoxine bulk pharmaceutical chemicals
Minimum formulation method, but powder vertical compression technology is to the more demanding of the grain sizes of bulk pharmaceutical chemicals and mobility, and use the present invention
The metadoxine finished product that synthetic method is prepared has stable crystal form, uniform particle sizes, without finely ground sieving, good fluidity, molten
Agent residual is low, purity is high, the characteristics of fully meeting formulation requirements.
Specific technical solution of the present invention is as follows：
The one-step synthesis of pharmaceutical grade metadoxine of the present invention is using vitamin B6 as raw material, after alkali is free directly and L-
Pyroglutamic acid reacts, one-step synthesis method metadoxine, and concrete operation step is as follows：
A. vitamin B6 is suspended in isopropanol, stream plus sodium hydroxide solution, the pH to 7~8 of control system；
B. it centrifuges, collects isopropyl alcohol and water mixing mother liquor；
C. L-Glutimic acid is added in above-mentioned mixing mother liquor solution, is reacted 10~30 minutes；Cooling makes crystallization, keeps 30
~60 minutes；
D. it centrifuges, a small amount of isopropanol elution, obtained solid is after forced air drying up to pharmaceutical grade metadoxine.
Further, the mass ratio of the vitamin B6 and isopropanol in the A is 1:1~3.
Further, the mass ratio of the vitamin B6 and the sodium hydroxide solution is 1：0.94~0.98.
Further, a concentration of the 20% of the sodium hydroxide solution.
Further, the mass ratio of the L-Glutimic acid and the vitamin B6 is 1:1.59.
Further, reaction temperature is 25~35 DEG C in the C.
Further, crystallization temperature is 0~5 DEG C in the C.
Further, the temperature of forced air drying is 35~45 DEG C in the D, and drying time is 8~12h.
A kind of pharmaceutical grade metadoxine one-step synthesis provided by the invention, mainly has the advantages that：
(1) raw material and product of the present invention are not necessarily to grinding, and easy to operate, with short production cycle, solvent dosage is appropriate, is easy to big
Technical scale production operation.
(2) the method for the present invention synthetic route is short, and waste water and dregs discharge is few, meets greenization production requirement.
(3) high income, very high purity, for yield up to 92%, purity is 99.9% or more.
(4) products obtained therefrom stable crystal form, uniform particle sizes, good fluidity, dissolvent residual are low.
Description of the drawings
Fig. 1 is infrared spectrum (IR) figure of metadoxine prepared by embodiment 1.
Fig. 2 is differential scanning calorimetric analysis (XRD) figure of metadoxine prepared by embodiment 1.
Fig. 3 be embodiment 1 prepare metadoxine nuclear magnetic resonance spectroscopy (1HNMR) figure.
Fig. 4 be embodiment 1 prepare metadoxine carbon-13 nmr spectra (13CNMR) figure.
Fig. 5 is X-ray powder diffraction spectrum (XRD) figure of metadoxine prepared by embodiment 1.
Fig. 6 is X-ray powder diffraction spectrum (XRD) figure of metadoxine prepared by embodiment 2.
Fig. 7 is X-ray powder diffraction spectrum (XRD) figure of metadoxine prepared by embodiment 3.
Fig. 8 is Yuan Yan producers (Italian Baldacci companies, lot number：0814) the X-ray powder of the metadoxine piece prepared
Last diffraction spectra (XRD) figure.
Fig. 9 is the grain size distribution of metadoxine prepared by embodiment 1.
Figure 10 is the grain size distribution of metadoxine prepared by embodiment 2.
Specific implementation mode
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate the skill of the present invention
Art scheme, and non-limiting the spirit and scope of the invention.Here it only points out, the reagent and test equipment used in the present invention is except spy
It does not indicate the source outer, is the commercially available universal product.Test method without specific conditions in the embodiment of the present invention, is usually pressed
More solito condition, or according to the condition proposed by raw material or commodity making manufacturer.
Experiment main test equipment used：
1, DSC is composed
Instrument model：Mettler Toledo DSC 1Stare System
2, X-ray powder diffraction is composed
Instrument model：D/Max-Bruker D 8Focus X-ray powder diffraction instrument
3、1HNMR compose with13CNMR is composed
Instrument model：Bruker AVANCEⅢ400
4, elemental analysis
Instrument model：Elemantar vario EL cube elemental analysers
5, particle diameter distribution
Instrument model：Malvern mastersizer3000 particle diameter distribution testers
Metadoxine prepared by embodiment involved in the present invention carries out purity testing using following methods：
It takes this product appropriate, adds acetonitrile：Water (1：9) it dissolves and dilutes and the solution containing 1.0mg in every 1ml is made, as examination
Product solution；Precision measures in right amount, adds acetonitrile：Water (1：9) solution of every 1ml containing 5ug is made, as a contrast solution.With reference to efficiently
Liquid chromatography (two V D of annex of Chinese Pharmacopoeia version in 2010) is tested, using octadecylsilane chemically bonded silica as filler,
With 0.004mol/L octane sulfonate sodium solutions (with phosphoric acid tune pH value to 2.5) for mobile phase A phase, using acetonitrile as Mobile phase B phase, inspection
Survey wavelength is 291nm, and 30 DEG C, sample size 20ul of column temperature carries out gradient elution by table 1, and number of theoretical plate is calculated by metadoxine peak
Not less than 2000.It takes contrast solution 20ul to inject liquid chromatograph, adjusts detection sensitivity, make the peak height of principal component chromatographic peak about
It is the 10% of full scale；Precision measures each 20ul of above two solution, is injected separately into liquid chromatograph, record chromatogram to it is main at
3 times of swarming retention time.
1 gradient elution program of table
| Time (min) | A phases (%) | B phases (%) |
| 0 | 95 | 5 |
| 30 | 50 | 50 |
| 35 | 50 | 50 |
| 40 | 95 | 5 |
| 55 | 95 | 5 |
Metadoxine prepared by embodiment involved in the present invention carries out dissolvent residual measurement using following methods：
Take this product appropriate, accurately weighed, in top set empty bottle, n,N-Dimethylformamide 5ml is added in precision, seals, shaking
Make dissolving, as test solution；Precision weighs, isopropanol is each appropriate, adds n,N-Dimethylformamide quantitatively to dilute and is made often
It is measured in 5ml top set empty bottles containing about the solution of isopropanol 2.0mg, precision in 1ml, sealing, as a contrast product solution.It is molten according to remaining
Agent measuring method (four general rules of Chinese Pharmacopoeia version in 2015,0,861 second method) is tested, poly- with 6% cyanogen propyl phenyl, 94% dimethyl
Siloxanes (or similar in polarity) is that the capillary of fixer is chromatographic column (Agilent DB-624 30m*0.53mm*3.0 μm
Or equivalent chromatographic column).Initial temperature is 35 DEG C, is maintained 14 minutes, is warming up to 120 DEG C with 30 DEG C of rate per minute, maintains 3 points
Clock, then 200 DEG C are risen to 100 DEG C of rate per minute, it maintains 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 is 80 DEG C；Equilibration time is
30 minutes.Reference substance solution headspace sampling is taken, chromatogram is recorded.Test solution and reference substance solution is taken to distinguish headspace sampling,
Record chromatogram.
Embodiment 1
1, the preparation of metadoxine of the present invention
A. 30.0Kg vitamin B6s are added in 500L reaction kettles, 90.0Kg isopropanols is added, are flowed into system under stirring
Add advance prepared 20% sodium hydroxide solution 29.4Kg (process for preparation：5.88Kg sodium hydroxides are dissolved in 23.52Kg purified waters
In), adition process feed temperature be maintained at 35 DEG C hereinafter, 1~2h streams add it is complete, after finishing, continue stirring 30 minutes；
B. it centrifuges, collects isopropyl alcohol and water mixing mother liquor；
C. the L-Glutimic acid of 18.8Kg is added in above-mentioned mixing mother liquor solution, is sufficiently stirred, 30 points are reacted at 25 DEG C
Clock；It is cooled to 0~5 DEG C, is kept for 30~60 minutes；
D. it centrifuging, a small amount of isopropanol elution, obtained solid is warming up to 45 DEG C of dry 10h again after 35 DEG C of dry 2h of air blast,
44.9Kg white solids are obtained, need not be refined up to pharmaceutical grade metadoxine certified products, yield 92%.
2, the structural identification of metadoxine prepared by the embodiment of the present invention 1：
The reaction product that the present embodiment obtains is the odorless crystalline powder of white, and micro-strip tart flavour is highly soluble in water, is slightly soluble in
Cold ethyl alcohol is consistent insoluble in organic solvents such as acetone, ether, chloroform, benzene with metadoxine property.Reaction product metadoxine
Structure can be confirmed from following several respects：
(1) fusing point of reaction product：100.6~102.5 DEG C, it is consistent with the metadoxine fusing point in document；
(2) as shown in Figure 1, infrared absorption spectrum (IR) figure is shown, the characteristic absorption of metadoxine ion pair salt is different from
The characteristic absorption of two starting materials；
(3) as shown in Fig. 2, differential scanning calorimetric analysis (DSC) figure shows that DSC matches with metadoxine fusing point；
(4) as shown in figure 3, nuclear magnetic resonance spectroscopy (1HNMR it) detects：(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) are consistent with metadoxine structure；
(5) as shown in figure 4, nuclear magnetic resonance spectroscopy (13CNMR it) detects：(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, with it is beautiful he
More sympletic structures are consistent；
(6) elemental analysis：Reaction product analysis result：Product formula is C8H11NO3·C5H7NO3
(7) as shown in figure 5, being radiated using Cu-Ka, with the X-ray powder diffraction collection that 2 θ angles indicate, about 7.14,
14.35、15.41、17.29、18.39、20.09、21.24、22.25、24.30、24.75、25.34、26.60、27.55、
28.33, have characteristic peak at 34.05, through with metadoxine Yuan Yan producers (Italian Baldacci companies, lot number：0814) piece
Agent XRD (Fig. 8) is compared, and is confirmed as crystal form of the same race.
3, purity testing：
Using above-mentioned method for detecting purity, the purity of the metadoxine prepared by the embodiment of the present invention 1 is 99.96%.
4, isopropanol residues detecton：
Using the assay method of above-mentioned dissolvent residual, the isopropanol of the metadoxine prepared by the embodiment of the present invention 1 remains
It is 0.033%.
The preparation of 2 metadoxine of the present invention of embodiment
A. 10.0Kg vitamin B6s are added in 100L reaction kettles, 20.0Kg isopropanols is added, are flowed into system under stirring
Add advance prepared 20% sodium hydroxide solution 9.5Kg (process for preparation：1.9Kg sodium hydroxides are dissolved in 7.6Kg purified waters),
Adition process feed temperature be maintained at 35 DEG C hereinafter, 0.5~1h streams add it is complete, after finishing, continue stirring 30 minutes；
B. it centrifuges, collects isopropyl alcohol and water mixing mother liquor；
C. the L-Glutimic acid of 6.29Kg is added in above-mentioned mixing mother liquor solution, is sufficiently stirred, 30 points are reacted at 35 DEG C
Clock；It is cooled to 0~5 DEG C, is kept for 30~60 minutes；
D. it centrifuges, a small amount of isopropanol elution, obtained solid is warming up to 45 DEG C of dry 7h after 35 DEG C of dry 3h of air blast, obtains again
14.8Kg white solids need not refine up to pharmaceutical grade metadoxine certified products, yield 91%, purity 99.92%, isopropyl
Alcohol residual is 0.043%.
The preparation of 3 metadoxine of the present invention of embodiment
A. 1.0Kg vitamin B6s are added in tri- neck reaction bulbs of 10L, 1.0Kg isopropanols is added, are flowed into system under stirring
Add advance prepared 20% sodium hydroxide solution 0.94Kg (process for preparation：0.188Kg sodium hydroxides are dissolved in 0.752Kg purifying
In water), adition process feed temperature be maintained at 35 DEG C hereinafter, in 20 minutes stream add it is complete, after finishing, continue stirring 30 minutes；
B. it centrifuges, collects isopropyl alcohol and water mixing mother liquor；
C. the L-Glutimic acid of 0.63Kg is added in above-mentioned mixing mother liquor solution, is sufficiently stirred, 30 points are reacted at 30 DEG C
Clock；It is cooled to 0~5 DEG C, is kept for 30~60 minutes；
D. it centrifuges, a small amount of isopropanol elution, obtained solid is warming up to 45 DEG C of dry 6h after 35 DEG C of dry 2h of air blast, obtains again
1.53Kg white solids need not refine up to pharmaceutical grade metadoxine certified products, yield 94%, purity 99.92%, isopropyl
Alcohol residual is 0.039%.
4 stability of crystal form of embodiment is tested
By prepared by embodiment 1-3 metadoxine sample and metadoxine original grind drug (lot number：0814, Italy
Baldacci companies) 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 diffraction spectrogram of the multiple batches of samples of embodiment 1-3 is consistent,
And grind that drug X-ray powder diffraction spectrogram is consistent with original, show that the crystal form of the metadoxine with synthetic method of the present invention preparation is steady
It is fixed.
(2) as shown in Figure 9, Figure 10, the particle diameter distribution for the metadoxine that prepared by the present invention is almost the same.
Claims (5)
1. a kind of one-step synthesis of pharmaceutical grade metadoxine, it is characterised in that：It is straight after alkali is free using vitamin B6 as raw material
It connects and is reacted with L-Glutimic acid, one-step synthesis method metadoxine, synthetic reaction formula is as follows：
Concrete operation step is as follows：
A. vitamin B6 is suspended in isopropanol, stream plus a concentration of 20% sodium hydroxide solution, the pH to 7 of control system~
8, the mass ratio of the vitamin B6 and the isopropanol is 1:1~3, the matter of the vitamin B6 and the sodium hydroxide solution
Amount is than being 1：0.94~0.98；
B. it centrifuges, collects isopropyl alcohol and water mixing mother liquor；
C. L-Glutimic acid is added in above-mentioned mixing mother liquor solution, is reacted 10~30 minutes；Cooling makes crystallization, keeps 30~60
Minute；
D. it centrifuges, a small amount of isopropanol elution, obtained solid is after forced air drying up to pharmaceutical grade metadoxine.
2. the one-step synthesis of pharmaceutical grade metadoxine according to claim 1, it is characterised in that：The L-Glutimic acid with
The mass ratio of the vitamin B6 is 1:1.59.
3. the one-step synthesis of pharmaceutical grade metadoxine according to claim 1, it is characterised in that：Reaction temperature in the C
It is 25~35 DEG C.
4. the one-step synthesis of pharmaceutical grade metadoxine according to claim 1, it is characterised in that：Crystallization temperature in the C
It is 0~5 DEG C.
5. the one-step synthesis of pharmaceutical grade metadoxine according to claim 1, it is characterised in that：Forced air drying in the D
Temperature be 35~45 DEG C, drying time be 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 |
|---|
| 美他多辛的合成;郭雪飞，等;《化工中间体》;20060430(第4期);第18-19页，尤其是第18-19页 * |
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