CN101627017A - Process for the manufacture of a precursor of vitamin b1 - Google Patents
Process for the manufacture of a precursor of vitamin b1 Download PDFInfo
- Publication number
- CN101627017A CN101627017A CN200780009190A CN200780009190A CN101627017A CN 101627017 A CN101627017 A CN 101627017A CN 200780009190 A CN200780009190 A CN 200780009190A CN 200780009190 A CN200780009190 A CN 200780009190A CN 101627017 A CN101627017 A CN 101627017A
- Authority
- CN
- China
- Prior art keywords
- resin
- solution
- compound
- described method
- washings
- 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.)
- Granted
Links
Classifications
-
- 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
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 Grewe diamines (GD that adopts ion exchange resin the solution of 4-amino-2-methyl-5-acyl amino methyl-pyrimidine to be handled preparation formula I; 5-amino methyl-2-methyl-pyrimidine-4-base-amine; 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 the Grewe diamines: expensive method of reducing, for example carry out hydrogenation or reduction amination respectively with corresponding 5-nitrilo or 5-formyl radical-pyrimidine; Perhaps in the presence of catalyzer, corresponding 5-alkoxy methyl-pyrimidine and ammonia are reacted (referring to EP 1138675A and US 6,365,740) under the temperature at least 230 ℃.DE 3511273 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 Grewe diamines.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 Grewe diamines by hydrolysis 5-acyl amino methyl-pyrimidine precursor.
Therefore the present invention relates to a kind of method that is used for the Grewe diamines of preparation formula I:
Described method is characterised in that, adopts ion exchange resin that the solution of 4-amino-2-methyl-5-acyl amino methyl-pyrimidine (Compound I I) of formula II is handled,
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 a formyl radical, and this is equivalent to substituent R is hydrogen.The preferred solvent of 4-amino-2-methyl-5-acyl amino-methyl-pyrimidine that employing ion exchange resin is handled is a water.Contain in contact before the solution of Compound I I, can for example come the described solution of purifying by any usual manner by filtration or distillation.In distillation, can form azeotropic mixture with water and be removed from the impurity such as neighbour-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 the quaternary ammonium resin.
The basic step of this method is to adopt strong anion-exchange resin to handle hydrolysis compound II.Then by any ordinary method with resin and solution separating, and wash resin with water.Washings can merge with isolating solution.The acylate R-CO-O-that generates by hydrolysis acyl group R-CO is remained by strong anion-exchange resin.Then, after hydrolysis, contain the Grewe diamines but the water-based elutriant of carboxylate-containing R-CO-O-and/or washings can not 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 desired 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 pure relatively 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 DE 3511273; but do not realize the sodium formiate by product is directly separated from required Grewe diamines, 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 Grewe diamines 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 being sodium formiate) can easily be reduced 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, and the preferred anionic exchange resin specifically is a strongly basic anion exchange resin.Use anionite-exchange resin to have following advantage: resin has kept the acylate that is produced by hydrolysis compound II, and GD is present in elutriant and the washings simultaneously.Using under 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, i.e. the GD that 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 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, use usually with respect to the volume of resin 0.5-15 volume, preferred 1-10 volume, more preferably 1.5-8 volume, the water of 2-5 volume most preferably altogether.Washings can mix with filtrate, perhaps can all or part of recovery be used in the further experiment.When resin is almost filled fully by acylate, 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, handled 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 the 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 the fixed ion exchange bed.
Under 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 following hydrolysis
N-formyl radical Grewe diamines (NFGD, 91.44w/w% with 9.00g; 1.04w/w% neighbour-chloro-aniline, 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 stirred 3 hours down at 60 ℃.At different time reaction mixture is analyzed.The results are shown in the following table.
Leach resin, and resin is washed with the 140g softening water.Analyze filtrate (110.13g) and washings (137.07g) respectively.Analyze GD, NFGD and neighbour-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).Neighbour-chloro-aniline detect less than.
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 following hydrolysis
With 230mL wet resin IRA
(Cl
-Form) in the NaOH of the total amount 2000g aqueous solution (4w/w%), shakes three times.Leach resin, and be neutral up to washings with the softening water washing resin.
With 15.00g NFGD (93.90w/w%; 0.35w/w% neighbour-chloro-aniline) 75.Be dissolved under ℃ in the softening water of 85.0g.Add 230mL IRA in this solution
(OH
-Form, 2 equivalents).This reaction mixture stirred 3 hours down at 75 ℃.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 filtrate (90.62g) and washings (217.20g) respectively.
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 following fixed bed hydrolysis
At room temperature, with the wet ion exchange resin IRA of 200mL
(Cl
-Form) (the 0.8mol Cl in the post that has 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; 0.62w/w% neighbour-chloro-aniline) under 75 ℃, is 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 to collect the regenerated elutriant, and it is analyzed.The results are shown in the following table.
With pillar with softening water washing to neutral and be ready to use in next experiment.
Embodiment 4
Continuous processing: 60 ℃ of following fixed bed hydrolysis
With the rough NFGD (91.40w/w% of 7.40g; 0.54w/w% neighbour-chloro-aniline) under 60 ℃, is 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 (10)
1. method that is used to make the Grewe diamines (GD) of formula I:
Described method is characterised in that, adopts ion exchange resin that the solution of 4-amino-2-methyl-5-acyl amino methyl-pyrimidine of formula II is handled,
Wherein, R is hydrogen or straight or branched C
1-4Alkyl.
2. the method for claim 1, wherein use deacidite.
3. method as claimed in claim 1 or 2, wherein, R is a hydrogen.
4. as any described method among the claim 1-3, wherein, implement described method with intermittent mode.
5. as any described method among the claim 1-3, wherein, implement described method in the continuous processing mode.
6. as any described method among the claim 1-4, wherein, after described reaction is finished, described resin is separated and washed from described solution, and concentrate elutriant and/or the washings that contains GD if necessary.
7. as any described method in claim 1-3 and 5, wherein, wash, concentrate solution and/or the washings that contains GD if necessary loading the pillar that uses the back.
The GD that obtains according to any described method among the claim 1-7 as intermediate in preparation as the purposes in the method for the compound of medicine or nutritious supplementary.
9. as the purposes of GD as described in the claim 9, be used to prepare VITMAIN B1.
10. compound, described compound according to Claim 8 or claim 9 described by using GD to prepare as raw material or intermediate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06005262.8 | 2006-03-15 | ||
| EP06005262 | 2006-03-15 | ||
| PCT/EP2007/001859 WO2007104442A2 (en) | 2006-03-15 | 2007-03-05 | Process for the manufacture of a precursor of vitamin b1 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101627017A true CN101627017A (en) | 2010-01-13 |
| CN101627017B CN101627017B (en) | 2013-02-27 |
Family
ID=38509829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200780009190.1A Active CN101627017B (en) | 2006-03-15 | 2007-03-05 | Process for the manufacture of a precursor of vitamin b1 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101627017B (en) |
| WO (1) | WO2007104442A2 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261173A (en) * | 2010-12-10 | 2013-08-21 | 帝斯曼知识产权资产管理有限公司 | Method for preparation of 2-ethyl-4-amtno-5-cyanopyrimidine |
| CN104031038A (en) * | 2014-07-04 | 2014-09-10 | 东北制药集团股份有限公司 | Method for preparing vitamin B1 hydrochloride with thiol thiamine |
| CN104326989A (en) * | 2014-11-26 | 2015-02-04 | 江西天新药业有限公司 | Preparation method of 2-methyl-4-amino-5-(aminomethyl) pyrimidine |
| CN108546249A (en) * | 2018-02-28 | 2018-09-18 | 东北制药集团股份有限公司 | A method of preparing diamine pyrimidine |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010010113A1 (en) * | 2008-07-22 | 2010-01-28 | Dsm Ip Assets B.V. | Novel synthesis of substituted 4-amino-pyrimidines |
| 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5946255A (en) * | 1982-09-10 | 1984-03-15 | Ube Ind Ltd | Preparation of 2-alkoxymethylene-3,3-dialkoxy- propanenitriles |
| DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
| DE602006001394D1 (en) * | 2005-01-28 | 2008-07-17 | Dsm Ip Assets Bv | PROCESS FOR PREPARING VITAMIN B1 |
-
2007
- 2007-03-05 WO PCT/EP2007/001859 patent/WO2007104442A2/en active Application Filing
- 2007-03-05 CN CN200780009190.1A patent/CN101627017B/en active Active
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103261173A (en) * | 2010-12-10 | 2013-08-21 | 帝斯曼知识产权资产管理有限公司 | Method for preparation of 2-ethyl-4-amtno-5-cyanopyrimidine |
| 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) |
| CN104031038A (en) * | 2014-07-04 | 2014-09-10 | 东北制药集团股份有限公司 | Method for preparing vitamin B1 hydrochloride with thiol thiamine |
| CN104326989A (en) * | 2014-11-26 | 2015-02-04 | 江西天新药业有限公司 | Preparation method of 2-methyl-4-amino-5-(aminomethyl) pyrimidine |
| 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 |
| CN108546249A (en) * | 2018-02-28 | 2018-09-18 | 东北制药集团股份有限公司 | A method of preparing diamine 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101627017B (en) | 2013-02-27 |
| WO2007104442A2 (en) | 2007-09-20 |
| WO2007104442A3 (en) | 2009-09-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101627017B (en) | Process for the manufacture of a precursor of vitamin b1 | |
| TW201439331A (en) | Methods of recovering scandium from titanium residue streams | |
| CN1962611B (en) | Process for preparing glycine using hydroxy-acetonitrile method | |
| CN102952126A (en) | Novel method for synthesizing vitamin B1 hydrochloride | |
| EP3733651B1 (en) | Method for producing calcobutrol | |
| JP2001226344A (en) | Method for producing 2-hydroxy-4-methylthiobutanoic acid | |
| KR20220098764A (en) | Arrangement and method for recovering lithium hydroxide | |
| JP3394981B2 (en) | Method for producing free hydroxylamine aqueous solution | |
| CN103241750B (en) | Method for preparing cesium carbonate by ion exchange method | |
| CN111635344B (en) | Post-treatment method of homocystine reaction solution | |
| US6900350B2 (en) | Method for the production of ω-aminoalkylsulphonic acids | |
| JPH11503146A (en) | Method for producing monosodium glutamate | |
| CN101085749A (en) | Method for separating terramycin | |
| JP4517520B2 (en) | Process for producing 2-hydroxy-4-methylthiobutanoic acid | |
| JP2002521365A (en) | Method for producing high-purity nicotinamide | |
| JP3053510B2 (en) | Method for producing D-kilo-inositol | |
| JPH03109358A (en) | Production of dialkyl carbonate | |
| JP2002533316A (en) | Removal of lead from organic diaryl carbonate reaction mixtures | |
| EP1694632B1 (en) | Process for the purification of gabapentin | |
| JP4759828B2 (en) | Process for producing 2-hydroxy-4-methylthiobutanoic acid | |
| CN108690102B (en) | Method for purifying methyl glucoside | |
| JPH0768222B2 (en) | Method for producing 4-methyl-5-[(2-aminoethyl) -thiomethyl-imidazole | |
| JPH0544957B2 (en) | ||
| CN116640086A (en) | Synthesis method of regenamine | |
| JPH0545299B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |