CN101627017B - Process for the manufacture of a precursor of vitamin b1 - Google Patents
Process for the manufacture of a precursor of vitamin b1 Download PDFInfo
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- CN101627017B CN101627017B CN200780009190.1A CN200780009190A CN101627017B CN 101627017 B CN101627017 B CN 101627017B CN 200780009190 A CN200780009190 A CN 200780009190A CN 101627017 B CN101627017 B CN 101627017B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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Abstract
A process for the preparation of Grewe diamine by treatment of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine in aqueous solution with an ion exchange resin.
Description
The present invention relates to a kind of ion exchange resin that adopts the solution of 4-amino-2-methyl-5-acyl amino methyl-pyrimidine is processed the GD (GD of preparation formula I; GD; Compound I) method.
GD be synthesise vitamins B1 important as precursors (referring to, Moine for example, Ullmann ' the s Encyclopedia of Industrial Chemistry of G. and H.-P.Hohmann etc., VCH, 27A volume, 515-517 (1996)).
According to existing method, can be prepared by the following method GD: expensive method of reducing, for example carry out respectively hydrogenation or reduction amination with corresponding 5-nitrilo or 5-formyl radical-pyrimidine; Perhaps in the presence of catalyzer, corresponding 5-alkoxy methyl-pyrimidine and ammonia reacted under the temperature at least 230 ℃ (referring to EP1138675A and US6,365,740).DE3511273 has described the employing aqueous sodium hydroxide solution and 2-methyl-4-amino-5-formyl radical amino methyl-pyrimidine is hydrolyzed and has adopted methyl-isobutyl-methanol extraction GD.In order to obtain pure products (productive rate is 58.2-65.7%), need under 130-220 ℃/1.5-2mbar, distil.
We find by make spent ion exchange resin can obtain a kind of simple easily but very effectively prepare the method for GD by hydrolysis 5-acyl amino methyl-pyrimidine precursor.
Therefore the present invention relates to a kind of method of the GD for the preparation of formula I:
Described method is characterised in that, adopts ion exchange resin that the solution of the 4-amino-2-methyl of formula II-5-acyl amino methyl-pyrimidine (Compound I I) is processed,
Wherein, R is hydrogen or straight or branched C
1-4Alkyl.
C
1-4Alkyl is methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.Preferred acyl group among the Compound I I is formyl radical, and this is equivalent to substituent R is hydrogen.The preferred solvent of the 4-amino-2-methyl that employing ion exchange resin is processed-5-acyl amino-methyl-pyrimidine is water.Contain in contact before the solution of Compound I I, can for example come the described solution of purifying by filtration or distillation by any usual manner.In distillation, can form azeotropic mixture with water and be removed from the impurity such as ortho-, meta-or p-chloroaniline of the processing step in Compound I I synthetic.Described reaction preferably adopts anionite-exchange resin to implement, and most preferably adopts strong anion-exchange resin, implements such as Quaternary Ammonium Resin.
The basic step of the method is to adopt strong anion-exchange resin to process hydrolysis compound II.Then by any ordinary method with resin and solution separating, and wash resin with water.Washings can merge with the solution that separates.The acylate R-CO-O that generates by being hydrolyzed acyl group R-CO
-Remained by strong anion-exchange resin.Then, after hydrolysis, contain GD but carboxylate-containing R-CO-O not
-Water-based elutriant and/or washings can be used in the form of concentrated solution or non-concentrated solution in the further chemical reaction.Can separate GD by complete concentrated solution.If need even more highly purified GD, can pass through methods known in the art so, for example extraction and/or crystallization are separated it from solution.
Major advantage of the present invention is, can isolate relatively pure GD and not need extra post-processing step by a single operation.Adopt the alkali of NaOH to come hydrolysis compound II (especially 5-formyl radical amino methyl-pyrimidine) although described among the DE3511273; but do not realize the sodium formiate by product is directly separated from required GD, preferably use strong alkali ion exchange resin to have following two effects: the quaternary ammonium group absorption sodium formiate of hydrolysis compound II and resin.Do not have sodium formiate in the GD that obtains thus, and sodium formiate obtains separately by resin regeneration.Therefore according to the details of operational condition, the content of acidylate sodium in the required final product (specifically sodium formiate) can easily be down to<and 10%, preferred<5%, more preferably<2%, most preferably<1% (dry weight based on GD is calculated).And, can avoid with an organic solvent, thereby a kind of environmental friendliness is provided and not need the method for complicated solvent reclamation step.Because the GD aqueous solution is the suitable feedstock of synthesise vitamins B1 subsequently, so obtain another benefit that the GD aqueous solution is present method.Need not carry out exchange of solvent or the compound of solid form be carried out the processing of complexity.
In principle, the ion exchange resin that can be used in this reaction is anionite-exchange resin and Zeo-karb, preferred anionic exchange resin, specifically strongly basic anion exchange resin.Use anionite-exchange resin to have following advantage: resin has kept the acylate that produces by hydrolysis compound II, and GD is present in elutriant and the washings simultaneously.Using in the situation of Zeo-karb, be collected in acylate in elutriant and the washings with the form of corresponding carboxylic acid.Yet, need second step, the GD that namely wash-out keeps from resin.Therefore, use Zeo-karb not too preferred.Can use all known and commercially available ion exchange resin.This is particularly including all strongly basic anion exchange resins and all storng-acid cation exchange resins, such as deriving from BayerAG, Rohm ﹠amp; Haas Comp., Lewatits, Amberlites, Duolite, Dowex and the Diaion resin of the companies such as Dow Chemical Company and MitsubishiChemicals Corp.Can be used for resin of the present invention and be not limited to cited these of this section.
Can under 20-100 ℃ temperature, preferably under 35-90 ℃ temperature, more preferably under 45-80 ℃ temperature, most preferably under 55-75 ℃ temperature, implement according to hydrolysis of the present invention.The concentration of the Compound I I aqueous solution that present method is used is in the scope of 2-30% (w/w), preferably in the scope of 4-25%, more preferably in the scope of 6-20%, most preferably in the scope of 8-16%.The aqueous solution and the resin of Compound I I are kept in touch one period reaction times, and this reaction times depends on the size of reaction vessel, is generally 0.25-6 hour, is preferably 0.5-4 hour, more preferably 0.75-3 hour, most preferably is 1-2 hour.
Resin demand is the 1-10 equivalent with respect to the equivalent of Compound I I, is preferably the 1.1-6 equivalent, and more preferably the 1.2-4 equivalent most preferably is the 1.3-3 equivalent.
Method of the present invention can adopt method known to those skilled in the art to implement with intermittent mode or continuous mode.In batch technology, the solution of Compound I I mixes in the reactor of for example stirred-tank reactor with resin compound.Resin and solution mixed during the reaction times separately, then by removing by filter resin and wash resin with water, thereby obtained whole GD.For this purpose, in operational process once or for several times, usually use with respect to the volume of resin altogether 0.5-15 volume, preferred 1-10 volume, more preferably 1.5-8 volume, the water of 2-5 volume most preferably.Washings can mix with filtrate, perhaps can all or part of recovery be used in the further experiment.When resin almost is acylated thing and fills fully, before described resin capacity is depleted, it must be regenerated according to methods known in the art, adopt the aqueous solution of water-soluble alkali, preferably adopt the aqueous solution of sodium hydroxide to regenerate.The elutriant of regeneration step comprises acylate, comprises acidylate sodium in preferred embodiment, and these materials are suitably collected, processed or abandon.
In continuous processing, in the pre-hot solution adding fixed-bed reactor with Compound I I, for example add in the pillar that adopts resin filling.Elutriant is collected, and adopt the water washing resin of above-mentioned specified quantitative.Then, thereby washings and the elutriant that contains GD the aqueous solution that obtains GD can be made up, perhaps the washings that contains GD can be collected separately.Thereby can reclaim all or part of elutriant or washings is used in the further experiment.In addition, the aqueous solution that employing can water-soluble alkali (preferred NaOH) is regenerated to fixing ion exchange bed.
In the situation of using acidic cation-exchange resin, carry out to adopt identical process after the necessary correction.
Further set forth the present invention by following examples.
Embodiment 1
Batch technology: 60 ℃ of lower hydrolysis
N-formyl radical GD (NFGD, 91.44w/w% with 9.00g; The ortho-, meta-or p-chloro-aniline of 1.04w/w%, 1.80w/w% ethanol) under 60 ℃ temperature, be dissolved in the 103.5g softening water (demineralized water).Add 107.1g Amberlyst in this solution
(OH
-Form, 2 equivalents).This reaction mixture is 60 ℃ of lower stirrings 3 hours.At different time reaction mixture is analyzed.The results are shown in the following table.
Leach resin, and with the 140g softening water resin is washed.Analyze respectively filtrate (110.13g) and washings (137.07g).Analyze GD, NFGD and ortho-, meta-or p-chloroaniline by HPLC; By the ion chromatography sodium formiate.
Filtrate
Washings
In rotatory evaporator, 94.59g filtrate is concentrated into drying.The gained solid is dry in moisture eliminator, obtains the GD that 3.95g contains 0.004w/w% (HPLC) NFGD and 1.82w/w% (chromatography of ions) sodium formiate, and its purity is 90.19w/w% (HPLC).Ortho-, meta-or p-chloro-aniline can't detect.
At room temperature adopt the 1400g NaOH aqueous solution (4w/w%) to come regenerating resin.Resin is leached, and the employing softening water washs to neutrality and is ready to use in next the experiment.
The filtrate that is obtained by regeneration comprises following compound:
Embodiment 2
Batch technology: 75 ℃ of lower hydrolysis
With 230mL wet resin IRA
(Gl-form) shakes three times in the NaOH of the total amount 2000g aqueous solution (4w/w%).Leach resin, and with the softening water washing resin until washings is neutral.
With 15.00g NFGD (93.90w/w%; The ortho-, meta-or p-chloro-aniline of 0.35w/w%) under 75 ℃, be dissolved in the softening water of 85.0g.Add 230mL IRA in this solution
(OH
-Form, 2 equivalents).This reaction mixture is 75 ℃ of lower stirrings 3 hours.At different time reaction mixture is analyzed.The results are shown in the following table.
Leach resin, and with 230g softening water washing resin.Analyze respectively filtrate (90.62g) and washings (217.20g).
Filtrate
Washings
At room temperature adopt the 2036g NaOH aqueous solution (4w/w%) regenerating resin.Resin is leached, and the employing softening water washs to neutrality and is ready to use in next the experiment.
Embodiment 3
Continuous processing: 75 ℃ of lower fixed bed hydrolysis
At room temperature, with the wet ion exchange resin IRA of 200mL
(Cl
-Form) (the 0.8mol CI in the post with heating jacket that packs into
-/ l resin).Pillar adopts the 993.3g NaOH aqueous solution (4w/w%) flushing one hour.Adopt 1962.3g softening water washing resin.The sheath of pillar is heated to 75 ℃.Thus, the preparation resin is OH
-The pillar of form.
With the rough NFGD (89.41w/w% of 14.76g; The ortho-, meta-or p-chloro-aniline of 0.62w/w%) under 75 ℃, be dissolved in the 85.62g softening water.By removing by filter a small amount of soluble material.
With the flow velocity of 3.33ml/min, the filtrate (75 ℃, 82.70g contains 57mmol NFGD) of preheating is loaded on the pillar.Collect the elutriant of pillar with the amount of each 3ml.After loading is finished, (collect 21 batches), adopted 300ml softening water (being preheated to 75 ℃) washing pillar.In addition, collect elutriant with the amount of each 3ml.After beginning to collect 51 times, collecting amount is each 6ml.In the time of 78 times, stop wash-out.
Below listed the analytical results of each fraction of collecting:
Merge fraction 1 to 78.Gained GD solution (324.71g) is analyzed.
Adopt the NaOH aqueous solution (4w/w%) of total amount 1500g that pillar is regenerated.Divide 7 batches of elutriants of collecting regeneration, and it is analyzed.The results are shown in the following table.
(85.58mmol)
With pillar with softening water washing to neutral and be ready to use in next experiment.
Embodiment 4
Continuous processing: 60 ℃ of lower fixed bed hydrolysis
With the rough NFGD (91.40w/w% of 7.40g; The ortho-, meta-or p-chloro-aniline of 0.54w/w%) under 60 ℃, be dissolved in the 79.89g softening water.By removing by filter a small amount of soluble material.
With the flow velocity of 3.33ml/min, the filtrate (60 ℃, 86.10g contains 35mmol NFGD) of preheating is loaded into the pillar (OH that contains 200ml
-The IRA of form
) on.Collect the elutriant of pillar in batches.After loading is finished, adopt 300ml softening water (being preheated to 75 ℃) washing pillar.The elutriant of in batches collecting is analyzed.
Following table has been listed analytical results:
Merge fraction 1 to 4.Gained GD solution (380.43g) is analyzed.
Adopt the NaOH aqueous solution (4w/w%) of total amount 1500g that pillar is regenerated.The analytical results of elutriant is listed in the following table.
With pillar with softening water washing to neutral and be ready to use in next experiment.
Claims (6)
2. the method for claim 1, wherein R is hydrogen.
3. method as claimed in claim 1 or 2 wherein, is implemented described method with intermittent mode.
4. method as claimed in claim 1 or 2 wherein, is implemented described method in the continuous processing mode.
5. method as claimed in claim 1 or 2 wherein, after described reaction is finished, is separated described resin and wash from described solution, and the washings that concentrates separated solution and/or obtain if necessary.
6. method as claimed in claim 4, wherein, described method is carried out in being loaded with the pillar of described resin, and pillar is washed, and concentrated cleaning solution if necessary.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06005262 | 2006-03-15 | ||
EP06005262.8 | 2006-03-15 | ||
PCT/EP2007/001859 WO2007104442A2 (en) | 2006-03-15 | 2007-03-05 | Process for the manufacture of a precursor of vitamin b1 |
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CN101627017A CN101627017A (en) | 2010-01-13 |
CN101627017B true CN101627017B (en) | 2013-02-27 |
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Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102105438B (en) * | 2008-07-22 | 2014-07-16 | 帝斯曼知识产权资产管理有限公司 | Novel synthesis of substituted 4-amino-pyrimidines |
CN103261173B (en) * | 2010-12-10 | 2015-09-23 | 帝斯曼知识产权资产管理有限公司 | The preparation method of 2-methyl-4-amino-5-cyanopyrimidine (I) |
CN104031038B (en) * | 2014-07-04 | 2016-06-08 | 东北制药集团股份有限公司 | The method of vitamin b1 hydrochloride prepared by a kind of sulphur hydroxyl thiamines |
CN104326989B (en) * | 2014-11-26 | 2016-04-27 | 江西天新药业有限公司 | The preparation method of 2-methyl-4-amino-5-(amino methyl) pyrimidine |
CN108546249B (en) * | 2018-02-28 | 2021-10-01 | 东北制药集团股份有限公司 | Method for preparing bisamine pyrimidine |
CN114230488A (en) * | 2021-12-27 | 2022-03-25 | 江苏兄弟维生素有限公司 | Preparation method and application of alpha- (o-chloroaniline) based methine-beta-formamido propionitrile |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
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JPS5946255A (en) * | 1982-09-10 | 1984-03-15 | Ube Ind Ltd | Preparation of 2-alkoxymethylene-3,3-dialkoxy- propanenitriles |
US9108925B2 (en) * | 2005-01-28 | 2015-08-18 | Dsm Ip Assets B.V. | Process for the manufacture of a precursor of vitamin B1 |
-
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- 2007-03-05 CN CN200780009190.1A patent/CN101627017B/en active Active
- 2007-03-05 WO PCT/EP2007/001859 patent/WO2007104442A2/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
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WO2007104442A2 (en) | 2007-09-20 |
CN101627017A (en) | 2010-01-13 |
WO2007104442A3 (en) | 2009-09-11 |
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