EP1578752A1 - Procede de production de pyridoxine ou de son sel d'addition d'acide - Google Patents

Procede de production de pyridoxine ou de son sel d'addition d'acide

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Publication number
EP1578752A1
EP1578752A1 EP03799503A EP03799503A EP1578752A1 EP 1578752 A1 EP1578752 A1 EP 1578752A1 EP 03799503 A EP03799503 A EP 03799503A EP 03799503 A EP03799503 A EP 03799503A EP 1578752 A1 EP1578752 A1 EP 1578752A1
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EP
European Patent Office
Prior art keywords
compound
acid addition
water
addition salt
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03799503A
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German (de)
English (en)
Inventor
Alois Kindler
Thomas Letzelter
Dirk Franke
Katrin Friese
Christian Knoll
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BASF SE
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BASF SE
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Publication date
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Publication of EP1578752A1 publication Critical patent/EP1578752A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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

Definitions

  • the present invention relates to a process for the preparation of pyridoxine and its acid addition salts.
  • Pyridoxine is the commercial form of vitamin B 6 . As is known, this is 2-methyl-3-hydroxy-4,5-bis (hydroxymethyl) pyridine. Pyridoxine, in particular its hydrochloride, is used in a variety of ways in pharmaceutical preparations and as a food and feed supplement.
  • 4-methyloxazoles which carry an alkoxy group or a nitrile substituent in the 5-position are reacted with a suitable dienophile, in particular a derivative of cis-2-butene-1,4-diol.
  • a suitable dienophile in particular a derivative of cis-2-butene-1,4-diol.
  • DOX 4,7-Dihydro-1,3-dioxepins
  • the preparation of pyridoxine via the Diels-Alder reaction of 4-methyloxazoles (MOX) with dioxepins DOX is shown in the following diagram:
  • Y is CN or a group OR 1 , in which R 1 is optionally substituted alkyl.
  • R 2 and R 3 are independently hydrogen or optionally substituted alkyl.
  • the Diels-Alder adduct I aromatizes spontaneously, or in the case of a substituent OR 1 by treatment of I with catalytic amounts of acid to give the compound II.
  • the compound II is then converted to pyridoxine or deprotects its acid addition salt.
  • the purity of the pyridoxine is subject to high requirements.
  • the pyridoxine produced via Diels-Alder reaction of MOX with DOX is purified at the pyridoxine hydrochloride stage.
  • this procedure is technically very complex since the by-products and pyridoxine hydrochloride behave very similar chemically.
  • the object of the present invention is therefore to provide a process for the preparation of pyridoxine which does not have the disadvantages of the processes known from the prior art.
  • the present invention relates to a process for the preparation of pyridoxine and its acid addition salts, comprising:
  • R 1 represents optionally substituted alkyl and R 2 and R 3 independently of one another are hydrogen or optionally substituted alkyl, or together with the carbon atom to which they are attached form a 5- to 8-membered, saturated cycle in one Mixture of an organic solvent which is at least partially miscible with water and water and treating the solution of I thus obtained at elevated temperature, optionally in the presence of a catalytically effective amount of an acid, until at least part of the compound I is in the compound II
  • step ii Precipitation of the compound II or its acid addition salt from that in step i. obtained solution by adding a precipitant and isolating compound II or its acid addition salt;
  • alkyl represents a linear or branched, aliphatic hydrocarbon radical with generally 1 to 10 and in particular 1 to 6 carbon atoms, which may have one or more, for example, 2 or 3, substituents.
  • substituents include halogen, CC ⁇ alkoxy, hydroxy, COOH, dC 4 - alkylthio, nitro, amino and phenyl, where phenyl in turn can have one or more substituents selected from CC 4 alkyl, CrC 4 alkoxy or halogen ,
  • alkyl having 1 to 10 and in particular 1 to 6 carbon atoms are:
  • CC 4 alkoxy examples are: methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1, 1-dimethylethoxy.
  • Substituted alkyl is in particular:
  • C Ce-haloalkyl such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2 , 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl
  • C 1 -C 4 -alkylthio-C ⁇ C -alkyl such as methylthiomethyl, ethylthiomethyl, propylthiomethyl, (I-methylethylthio) methyl, butylthiomethyl, (I-methylpropylthio) methyl, (2-methylpropylthio) methyl, (1, 1-dimethylethylthio) methyl, 2- (methylthio) ethyl, 2- (ethylthio) ethyl, 2- (propylthio) ethyl, 2- (1-methylethylthio) ethyl, 2- (butylthio) ethyl, 2- (1-methylpropylthio) ethyl, 2- (2 -MethyIpropylthio) ethyl, 2- (1, 1-dimethylethylthio) ethyl, 2- (Methylthio) propyl, 2- (Ethy
  • Examples of a 5- to 8-membered cycle are carbocyclic radicals such as cyclohexyl, cycloheptyl, cyclooctyl, and heterocyclic radicals such as 2-oxacyclopentyl, 2-oxacyclohexyl and the like.
  • R 1 in formulas I and MOX preferably represents an unsubstituted CrC 6 alkyl radical, in particular ethyl, n-propyl, n-butyl.
  • the radical R 2 in the formulas DOX, I and II preferably represents hydrogen.
  • the radical R 3 in the formulas DOX I and II is preferably different from hydrogen and is in particular an unsubstituted dC ⁇ alkyl radical, C ⁇ C ⁇ alkoxy-CrC 4 alkyl or CrC-r alkylthio-C C-ralkyl.
  • R 3 stands for unsubstituted C 1 -C 4 -alkyl and especially for isopropyl or 2-butyl.
  • the compound I is in step i. dissolved in a mixture of an organic solvent that is at least partially miscible with water and water.
  • An at least partial miscibility with water means that the solvent is able to absorb at least 10% by weight, in particular at least 20% by weight and particularly preferably at least 50% by weight of water with the formation of a homogeneous phase (room temperature).
  • Suitable solvents are acyclic ethers and ether alcohols, cyclic ethers and C Cs alkanols.
  • acyclic ethers are diethyl ether, 1,2-bismethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether and the like.
  • ether alcohols are 2-methoxyethanol, 2- or 3- Methoxypropanol.
  • cyclic ethers are, in particular, dioxane and tetrahydrofuran (THF).
  • CC 6 alkanols are methanol, ethanol, n-propanol, n-butanol, isopropanol, 2-butanol, tert-butanol and n-pentanol.
  • Preferred, at least partially water-miscible organic solvents are C -C -alkanols and cyclic ethers, in particular cyclic ethers and among these particularly preferably tetrahydrofuran.
  • Organic solvents which are infinitely miscible with water are particularly preferred.
  • the concentration of compound I in the solution is generally in the range from 5 to 60% by weight and in particular in the range from 10 to 50% by weight.
  • step ii. Solvent mixture used 0.5 to 10 mol water, in particular 2 to 6 mol water per mol compound I.
  • the conversion of compound I to the compound II can be achieved by acids, preferably weak acids having a pK value in the range of 1.5 to 6.5, in particular by aliphatic carboxylic acids having preferably have 1 to 4 carbon atoms such as formic acid, acetic acid and propionic acid, and catalyze specifically with acetic acid.
  • the amount of acid is preferably 0.01 to 1 mol, in particular 0.05 to 0.5 and particularly preferably 0.1 to 0.3 mol, per mol of compound I.
  • the temperatures required for the conversion of I to II are generally above 30 ° C., preferably in the range from 40 to 100 ° C. and in particular in the range from 50 to 70 ° C.
  • the conversion of I into II is preferably carried out to such an extent that at least 10% and in particular at least 20% of the compound I have been converted into the compound II. In principle, the conversion can be carried out up to a complete conversion from I to II. However, it has proven to be advantageous if the conversion of I into II is only carried out up to a partial conversion, preferably up to a conversion of 80% and in particular up to a conversion of 50%.
  • the reaction time required to achieve such conversions in acid catalysis, depending on the desired temperature, is generally at least one hour and preferably at least 2 hours and is in particular in the range from 2 hours to 8 hours.
  • the person skilled in the art can determine the progress of the reaction in a manner known per se, for example by means of HPLC.
  • the conversion from I to II can also be achieved in the absence of an acid.
  • a precipitant is added to precipitate compound II.
  • the conversion from I to II surprisingly continues, so that at the end of the precipitation, conversion of at least 90% and in particular at least 95% of the compound I into the compound II is generally achieved.
  • Precipitants are basically all agents that reduce the solubility of compound II in the step i. effect used solvent / water mixture.
  • suitable solubility-reducing agents are, in particular, aliphatic and alicyclic hydrocarbons such as hexane, heptane, isohexane, octane, cyclohexane, aliphatic hydrocarbon fractions, for example petroleum ether or gasoline fractions and mixtures thereof.
  • the precipitant is a mineral acid such as sulfuric acid, phosphoric acid or hydrogen halide, optionally in the form of the aqueous acids.
  • the compounds II then precipitate out as poorly soluble acid addition salts.
  • the preferred acidic precipitant is hydrogen chloride, optionally in the form of its aqueous acid, with gaseous hydrogen chloride being particularly preferred.
  • the amount of acid is measured in such a way that the acid equivalents correspond at least to the number of moles of the compound II.
  • the acid is preferably used in an excess of at least 5 mol%, preferably at least 10 mol%, in particular 10 mol% to 80 mol% and especially 20 mol% to 80 mol%.
  • the addition of the precipitant can be achieved by mixing the in step i. obtained solution with the precipitant in any way.
  • the precipitant is preferably added to that in step i. obtained solution.
  • the precipitant can in principle be added in one portion.
  • the precipitant is preferably added in several portions or over a longer period of time, e.g. B. within 0.5 h to 5 h and especially within 1 to 3 h to that in step i. obtained solution.
  • the addition of the precipitant is usually carried out by mixing the in step i. obtained solution with the precipitant.
  • the apparatus suitable for this purpose is familiar to the person skilled in the art. Examples of suitable apparatus are stirred tanks which can have heat exchangers for removing the heat of crystallization and which are equipped with single-stage or multi-stage stirrers, such as cross-bar stirrers or inclined-blade turbines, and in particular also with disk stirrers in the case of gaseous precipitants.
  • the precipitant is initially at an elevated temperature, e.g. B. in the range of 30 to 100 ° C, preferably in the range of 40 to 80 ° C and in particular in the range of 50 to 70 ° C and during or after the addition of the precipitant the mixture obtained to a lower temperature , for example in the range from -20 to + 30 ° C. and especially to cool in the range from -10 to + 20 ° C and especially in the range from -10 to + 10 ° C.
  • this final temperature is usually maintained for a certain time in order to achieve a complete crystallization of the compound II or its acid addition salt.
  • the cooling rates are preferably in the range from 50 to 5 K / h, in particular in the range from 40 to 10 K / h.
  • the solid compound II thus obtained is then separated from the mother liquor in a manner known per se, for example by filtration or by centrifugation. Belt filtration has also proven itself for continuous reaction control.
  • the crystals can be washed in the usual way. This is particularly useful in step i. organic solvents used.
  • the amount of washing liquid will generally be in the range from 0.5 to 3 and in particular in the range from 1 to 2.5 parts by weight per part by weight of dry crystals.
  • step i. has the additional advantage that a solvent-water azeotrope can be distilled off during the workup, which directly in step i. can be used again.
  • step ii. Compound II obtained can then be converted in a manner known per se into pyridoxine or into its acid addition salt, in particular into its hydrochloride. Methods for this are known in principle from the prior art cited at the beginning and in particular from DE-OS 1445882, US 3,525,749, DE-OS 1545943. Methods analogous to this, as described in DE-OS 1620045 or in GB 1293843, are also suitable.
  • Conversion II into pyridoxine is usually carried out by treating II with a mineral acid.
  • the acid addition salt of II is naturally obtained.
  • the reaction of II or its acid addition salt is preferably carried out in pyri- doxin in an aqueous mineral acid at elevated temperature.
  • the preferred aqueous mineral acid is hydrochloric acid.
  • the concentration of the mineral acid is preferably in the range from 0.01 to 1 mol / l and in particular in the range from 0.05 to 0.5 mol / l.
  • the concentration of compound II (calculated as neutral compound) is generally set to values in the range from 10 to 50% by weight and in particular 15 to 40% by weight.
  • water vapor preferably in a mixture with liquid water
  • the amount of water introduced is generally in the range from 1 to 50 parts by weight, preferably 2 to 20 parts by weight and in particular 4 to 10 parts by weight, based on one part by weight of compound II (calculated as neutral compound).
  • the amount of liquid water will generally be chosen so that the amount of water introduced via the water vapor is at least one part by weight, based on one part by weight of compound II.
  • step iii. at a reduced pressure, preferably a pressure of at most 0.5 x 10 5 Pa, and in particular at a pressure in the range from 0.1 to 0.5 x 10 5 Pa.
  • the temperature required for the reaction is generally above 30 ° C., preferably in the range from 40 to 80 and in particular in the range from 50 to 70 ° C.
  • the pyridoxine then crystallizes out as its acid addition salt, in particular as the hydrochloride.
  • the still hot reaction mixture is concentrated until the content of pyridoxine, calculated as the acid addition salt, is at least 20% by weight and is in particular in the range from 20 to 35% by weight. Higher concentrations, for example until the solubility limit is reached at this temperature or above, are in principle possible, but not advantageous. It is preferably concentrated to such an extent that the solubility limit of the pyridoxine is not exceeded.
  • the pyridoxine as acid addition salt, is obtained from the reaction mixture by crystallization.
  • the crystallization can be carried out both in the vessel in which the conversion of II to pyridoxine was carried out and in a reaction vessel separate from it.
  • the still hot reaction mixture Before the crystallization, the still hot reaction mixture can be subjected to a treatment with activated carbon.
  • the still hot solution is passed, preferably at a temperature of at least 40 ° C and in particular at a temperature of at least 50 ° C, for. B. in the range of 50 to 100 ° C on a column loaded with activated carbon. Colored impurities are adsorbed.
  • the solution of the pyridoxine acid addition salt obtained is cooled.
  • the final temperature is usually below 20 ° C, preferably maintenance 10 ° C and in particular in the range from 10 ° C to 0 ° C.
  • the cooling rate during the crystallization will generally not exceed a value of 20 K / h and in particular 10 K / h in order to ensure uniform crystallization and thus high purity of the crystals.
  • the cooling rate is in the range from 2 K / h to 10 K / h.
  • the crystallization can be carried out in all devices customary for this.
  • devices for carrying out suspension crystallization for example stirred kettles, have proven successful.
  • These stirred tanks preferably have external heat exchangers for dissipating the heat of crystallization.
  • the pyridoxine acid addition salt is obtained in a manner known per se by filtration and / or by centrifugation.
  • the crystals can be subjected to customary cleaning measures, for example a washing step with water, aqueous mineral acid and / or alcohols.
  • the pyridoxine acid addition salt obtained as crystals has an extremely high purity.
  • the yields, based on compound II used, are clearly above the yields obtained when using the methods of the prior art.
  • pyridoxine acid addition salt obtained in this way has a lower purity, but this is sufficient for many applications, in particular for use as a feed additive.
  • the crystals thus obtained are introduced into the step iii. obtained, still hot reaction mixture and in this way increases the yield of primary crystals.
  • the compound of the general formula I is prepared in a manner known per se by reacting DOX with MOX, where Y is OR 1 , in accordance with the reaction scheme given at the beginning at elevated temperature.
  • the reaction temperatures required for the reaction are usually at least 110 ° C., preferably at least 120 ° C. and in particular at least 140 ° C. They are preferably a value of 200 C C, in particular 180 ° C or above specifically 170 ° C.
  • MOX and DOX are therefore preferably fed to the reaction zone in a molar ratio DOX: MOX of at least 2: 1, in particular at least 5: 1 and particularly preferably in the range from 5: 1 to 20: 1.
  • the reaction of MOX with DOX is usually carried out in the liquid phase, since the starting materials are generally liquid under reaction conditions.
  • an organic solvent can be added to the reaction mixture.
  • suitable solvents are aliphatic and cycloaliphatic hydrocarbons, such as hexane, octane, cyclohexane, technical hydrocarbon mixtures, e.g. B.
  • gasoline fractions aromatic hydrocarbons, such as toluene, xylenes, cumene, tert-butylbenzene and the like, furthermore aliphatic and alicyclic ethers, such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and mixtures of these solvents.
  • the process is carried out in the absence of an organic solvent (solvent content ⁇ 10% by weight, in particular ⁇ 5% by weight, based on the total amount of the starting materials).
  • the reaction of MOX with DOX is advantageously carried out as a continuous process by continuously supplying MOX and DOX to a reaction zone and continuously discharging a product stream containing the compound I from the reaction zone.
  • MOX and DOX continuously supplied MOX and DOX to a reaction zone and continuously discharging a product stream containing the compound I from the reaction zone.
  • the reaction zone is designed in such a way that it has little backmixing of product with starting material. This results in a narrower distribution of the reactants in the reaction zone.
  • the reaction zone is designed as an at least 2-stage stirred tank cascade.
  • the reaction zone is designed as a flow tube without product return.
  • the flow tube preferably has a ratio of Length: diameter of at least 5: 1, preferably at least 10: 1, in particular in the range from 10: 1 to 1000: 1.
  • the residence time in the reaction zone is preferably chosen so that the conversion of MOX does not exceed a value of 70% and in particular a value of 60%. Usually, however, the reaction will lead to a conversion of at least 20% and preferably at least 40% MOX.
  • the residence times required for this are generally in the range from 30 minutes to 5 hours and in particular in the range from 60 minutes to 3 hours.
  • the reaction is usually carried out at normal pressure or at elevated pressure, for example up to 200 bar and preferably up to 150 bar. If the reaction zone is in the form of a stirred tank cascade, the reaction is usually carried out at atmospheric pressure or at a slightly increased or reduced pressure, for example at 0.8 bar to 50 bar and preferably at 0.9 bar to 10 bar. If the reaction zone is designed as a flow tube, it has proven useful to carry out the reaction at elevated pressure, for example in the range from 10 bar to 200 bar, preferably in the range from 50 bar to 150 bar and especially in the range from 60 bar to 120 bar.
  • the workup of the reactor discharge containing the compound I can be carried out in a conventional manner, for. B. by distillation.
  • low boilers such as MOX and DOX are separated from the target compound I.
  • target compound I is achieved if the product stream is subjected to flash evaporation in order to remove volatile constituents.
  • the still hot reactor discharge is expanded into a zone with low pressure immediately after leaving the reaction zone, for example a pressure below 500 mbar, preferably below 100 mbar and in particular in the range from 1 to 20 mbar.
  • the temperatures in the evaporator zone are preferably in the range from 30 to 160 ° C. and in particular in the range from 40 to 100 ° C.
  • the flash evaporation is carried out without additional heat input.
  • the flash evaporation can be carried out in a conventional manner, for example in a gas-liquid separator. In flash evaporation, at least 30%, preferably at least 40%, z. B.
  • the residue is preferably used for further purification of a short path distillation, for example in a thin film evaporator, such as falling film evaporators, e.g. B. downdraft evaporator, spiral tube falling film evaporator, further rotor evaporator, z. B. Sambay evaporator.
  • the temperatures in the short path distillation will usually not exceed values of 160 ° C. and in particular 140 ° C. and are preferably in the range from 80 ° C. to 140 ° C.
  • the work-up can also be carried out exclusively by short-path distillation in the manner described here.
  • the residence time in the flash evaporator is generally in the range from 1 minute to 30 minutes and in particular in the range from 2 minutes to 10 minutes.
  • a product I which contains less than 10%, preferably less than 5% and in particular up to 1% low boilers.
  • the low boilers separated in this way consist essentially of MOX and DOX and, where appropriate, organic solvent used and can therefore be returned to the reaction zone.
  • the mother liquor contained further DOPxHCI and small amounts of pyridoxine hydrochloride.
  • Reaction mixture 214 g of gaseous HCl were introduced into the solution over the course of 2 h, metering being carried out under the stirrer. DOPxHCI precipitated out as a solid.
  • the solution was cooled at 30 K / h from 60 ° C to 30 ° C and then at 10 K / h from 30 ° C to 20 ° C.
  • the suspension was cooled further to 0 ° C. at 20 K / h.
  • the solid was then separated off from the mother liquor via a suction filter, washed with 1320 g of cold tetrahydrofuran and dried under vacuum. 850 g of dry, white solid were obtained.
  • step 1 In a reaction vessel with distillation apparatus, the DOPxHCI obtained in step 1 (variant a) was dissolved in 0.1 N hydrochloric acid with heating, a concentration of about 13% by weight being set. The pressure was then lowered to 400 mbar while maintaining the temperature and the temperature was maintained for a further 2 hours. This distilled isobutyraldehyde and
  • the still hot solution was passed over an activated carbon column at temperatures in the range of about 55 to 60 ° C.
  • the still hot solution obtained was then slowly cooled (about 10 o K / h) to a temperature of 0 ° C. using a stirred kettle with a 3-stage inclined blade stirrer (power input 0.25 watt / kg).
  • pyridoxine hydrochloride crystallized out.
  • the mother liquor still contains about 8% by weight of VB6xHCI, which can be partially obtained as a solid by concentrating the mother liquor under reduced pressure and subsequent crystallization.
  • step 1 variant a
  • DOPxHCI crystallized out.
  • the solid was filtered off as described above and washed with a little tetrahydrofuran. In this way, 100 g of crystalline product with a color number of APHA 416 were obtained. Taking into account the product proportions contained in the mother liquor, the selectivity with respect to DOPxHCI was 84%. The monthly recovery was only 84%.
  • the selectivity for the DOPxHCI formation was 95% over the entire batch with a molar recovery of 97% (2% pyridoxine hydrochloride).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention concerne un procédé de production de pyridoxine et de ses sels d'addition d'acide, ledit procédé consistant à: (i) dissoudre le produit (I) obtenu par addition de Diels-Alder de 4-méthyloxazol sur une 4,7-dihydro-1,3-dioxépine dans un mélange constitué d'un solvant organique, au moins en partie miscible à l'eau, et d'eau et traitement de la solution de (I) ainsi obtenue, à température élevée, éventuellement en présence d'une quantité catalytiquement active d'un acide, jusqu'à ce qu'au moins une partie du composé (I) soit transformée en 1,5-dihydro-8-méthyl-[1,3]dioxépine-[5,6c]pyridin-9-ol (II) correspondant; (ii) précipitation du composé (II) ou de son sel d'addition d'acide à partir de la solution obtenue à l'étape (i) par addition d'un précipitant et isolement du composé (ii) ou de son sel d'addition d'acide; et (iii) transformation du composé (ii) obtenu à l'étape (i) ou de son sel d'addition d'acide en pyridoxine ou en un sel d'addition d'acide de pyridoxine.
EP03799503A 2002-12-27 2003-12-23 Procede de production de pyridoxine ou de son sel d'addition d'acide Withdrawn EP1578752A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10261271 2002-12-27
DE2002161271 DE10261271A1 (de) 2002-12-27 2002-12-27 Verfahren zur Herstellung von Pyridoxin oder seines Säureadditionssalzes
PCT/EP2003/014812 WO2004058774A1 (fr) 2002-12-27 2003-12-23 Procede de production de pyridoxine ou de son sel d'addition d'acide

Publications (1)

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EP1578752A1 true EP1578752A1 (fr) 2005-09-28

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EP (1) EP1578752A1 (fr)
CN (1) CN100351257C (fr)
AU (1) AU2003300226A1 (fr)
DE (1) DE10261271A1 (fr)
WO (1) WO2004058774A1 (fr)

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CN101402600B (zh) * 2008-11-17 2010-08-25 江西天新药业有限公司 维生素b6的制备方法
CN102584692B (zh) * 2011-01-14 2013-10-09 浙江天新药业有限公司 盐酸吡哆醇的制备方法
CN102295598B (zh) * 2011-07-12 2012-12-19 湖北惠生药业有限公司 一种维生素b6的结晶方法
CN104710351B (zh) * 2013-12-13 2017-12-26 大丰海嘉诺药业有限公司 一种维生素b6的连续制备方法
CN103739545B (zh) * 2014-01-20 2015-07-15 新发药业有限公司 一种简便的维生素b6的制备方法
CN114149442A (zh) * 2021-12-08 2022-03-08 华中药业股份有限公司 一种杂质ts-3b的制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3250778A (en) * 1962-11-29 1966-05-10 Hoffmann La Roche Intermediates for and synthesis of vitamin b and related compounds
US3227721A (en) * 1965-05-24 1966-01-04 Merck & Co Inc Process for preparing 2-methyl-3-hydroxypyridines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004058774A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108586488A (zh) * 2018-03-29 2018-09-28 浙江新和成股份有限公司 一种维生素B6中间体Diels-Alder加成物的光催化合成方法

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AU2003300226A1 (en) 2004-07-22

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