CN104059023B - The environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine - Google Patents
The environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine Download PDFInfo
- Publication number
- CN104059023B CN104059023B CN201310087215.7A CN201310087215A CN104059023B CN 104059023 B CN104059023 B CN 104059023B CN 201310087215 A CN201310087215 A CN 201310087215A CN 104059023 B CN104059023 B CN 104059023B
- Authority
- CN
- China
- Prior art keywords
- amino
- methyl
- poly
- preparation
- formula
- 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.)
- Active
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
The present invention relates to a kind of environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine.Comprise and utilize the functional polymer containing aromatic amine structural unit to substitute highly carcinogenic Ortho-Chloro aniline or other small molecules anils, carry out condensation reaction in acid condition to enol alkali and generate corresponding enamine polymkeric substance, this enamine polymkeric substance generates 2-methyl-4-amino-5-formamido group pyrimidine again with acetamidine hydrochloride condensation, through hydrolysis preparation 2-methyl-4-amino-5-amino methylpyrimidine.Discharge the functional polymer containing aromatic amine structural unit simultaneously, be cycled to used in lower batch reaction.The method technical process is short, and waste water and waste liquids discharge is few, is conducive to the raising of suitability for industrialized production and VITMAIN B1 commercial production levels.
Description
Technical field
The present invention relates to a kind of environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine, belong to VITMAIN B1 and derivative production technical field thereof.
Background technology
People start to understand and use VITMAIN B1 very early, just have relevant record in ancient Chinese medical book, and such as well-known doctor's SUN Si miao utilizes paddy skin to treat vitamin B1 deficiency.VITMAIN B1 is also the earliest by the VITAMIN that people purify, and within 1896, first Dutch scientist Yi Keman finds VITMAIN B1, and the scholar Feng Ke that Polonizes for 1910 extracts and purify out VITMAIN B1 from rice bran.The structural formula of VITMAIN B1 is as follows:
VITMAIN B1, also known as VitB1 or aneurin, is a kind of vitamin B group be combined into by pyrimidine ring and thiazole ring.VITMAIN B1 is white crystals or crystalline powder, has faint characteristic odor, bitter, has to draw moist, and dew is put in atmosphere, easily absorbs moisture, easily decomposes rotten in basic solution, meets light and heat and to tire decline.VITMAIN B1 is very stable in an acidic solution, but unstable in basic solution, and is easy to oxidation and decomposes.
In the crust that VITMAIN B1 is mainly present in seed and plumule, as rice bran and wheat bran, in yeast, content is extremely abundant, and in lean meat, Chinese cabbage and celery, content is also more.VITMAIN B1 has multiple important physiological action: its energy neuroprotective system; can also enterogastric peristalsis be promoted, help carbohydrate digestion, improve mental status; maintain the normal activity of nervous tissue, muscle, heart, VITMAIN B1 contributes to the treatment to zoster in addition.When Vitamin B1 deficiency, by its degree, following reaction can be there is successively: neural system reaction (dry beriberi), cardiovascular systems reaction (beriberi humida), Wernicke (Wei Buddhist nun kirschner) encephalopathic and Korsakoff syndromes (Korakaff's psychosis).
Some derivatives of VITMAIN B1 also obtained extensive concern for over ten years, as Fursutiamine, rosickyite amine and benfotiamine etc. past.VB1 and various derivative thereof, except medicinal, are more used for the additive of feed, food and makeup.
VITMAIN B1 is as a kind of important basal nutrient composition, and its synthesis preparation receives much concern always, and wherein, 2-methyl-4-amino-5-amino methylpyrimidine is the key intermediate of preparation VITMAIN B1 conventional at present.About the synthesis of 2-methyl-4-amino-5-amino methylpyrimidine, mainly contain cyanopyrimidine, formyl pyrimidine, formamido group pyrimidine three kinds of routes.
Cyanopyrimidine route (route 1) take propane dinitrile as starting raw material, ethoxymethylidene base propane dinitrile is prepared with trimethyl orthoformate condensation, ammonia replacement obtains amino methane base propane dinitrile, the latter and the condensation of ethyl inferior amine salt hydrochlorate obtain 2-methyl-4-amino-5-cyanopyrimidine, then under Raney Ni catalysis Hydrogenation for 2-methyl-4-amino-5-amino methylpyrimidine.This route 1 needs to use a large amount of ethyl inferior amine salt hydrochlorate (1.8 to 2 equivalent), this raw material and propane dinitrile expensive, be unfavorable for that product cost reduces.Chinese patent document CN102712602A (CN201080053163.6) discloses a kind of synthetic method preparing 2-methyl-4-amino-5-cyanopyrimidine.Take propane dinitrile as starting raw material, under the effect of alkali, propane dinitrile and ionic salt compound (III) react in certain solvent, product without separation directly in the presence of a base with acetamidine hydrochloride cyclic condensation, obtained 2-methyl-4-amino-5-cyanopyrimidine.
Formyl pyrimidine route (route 2) take vinyl cyanide as starting raw material; with methyl nitrite reaction preparation 3; 3-dimethoxypropionitrile; formylation generates corresponding enol sodium again; the latter and butanols effect generate 3-butoxy-2-(1; 1-Dibutoxymethyl) vinyl cyanide; 2-methyl-4-amino-5-formylpyrimidin is generated again with acetamidine hydrochloride condensation; react to oxammonium hydrochloride and generate corresponding hydroxylamine compound, then under Raney Ni catalysis Hydrogenation for 2-methyl-4-amino-5-amino methylpyrimidine.Japanese Patent 59046274 and WO2009151098 all adopt this route, and this route 2 reactions steps is complicated, and reaction time is long, and autoclave (about 50 kilograms of pressure) will be used to carry out hydrogenation reaction, is difficult to industrializing implementation.
Formamido group pyrimidine route (route 3) with 3-aminopropionitrile for starting raw material; α-formyl radical-3-formamido group propionitrile is prepared with methyl-formiate formylation under sodium methylate effect; the latter and Ortho-Chloro aniline effect generate 2-formyl aminomethyl-3N-(2-chloro-phenyl-) aminoacrylonitrile; 2-methyl-4-amino-5-formamido group pyrimidine is generated again, through hydrolysis preparation 2-methyl-4-amino-5-amino methylpyrimidine with acetamidine hydrochloride condensation.United States Patent (USP) 2377395 and German Patent 2748153 all have employed this route, and this route 3 is that raw material is cheaply easy to get, and each step reaction conditions is relatively gentle, and yield is higher, is conducive to Product Cost Control.But the weak point of this route 3 is: use highly carcinogenic Ortho-Chloro aniline, operating environment requires high, is unfavorable for environment protection; Although and through steam distillation and repeatedly recrystallization, be still difficult to remove the micro-Ortho-Chloro aniline in the finished product VITMAIN B1.
In addition, CN1319592A (CN01112307.9) additionally provides the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine, be make 2-methyl-4-amino-5-(alkoxymethyl)-2 yl pyrimidines and ammonia react in the presence of a catalyst, catalyzer is Lewis acid.The method temperature of reaction is high, and reaction preference is poor, and yield is low, is difficult to industrializing implementation.
In sum, research and development environmental protection and there is the synthetic method of the 2-methyl-4-amino-5-amino methylpyrimidine of cost advantage, be VITMAIN B1 industry and Sustainable development in the urgent need to.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine.
The present invention utilizes the functional polymer containing aromatic amine structural unit to substitute highly carcinogenic Ortho-Chloro aniline or other small molecules anils, prepares VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine.
Term illustrates:
Vapor detection: utilize gas chromatograph to carry out reaction monitoring and purity detecting.
Liquid Detection: utilize liquid chromatograph to carry out reaction monitoring and purity detecting.
Molecular weight characterization: utilize the polymer microballoon of GPC gel chromatograph (THF makees solvent) to preparation to carry out number-average molecular weight and weight-average molecular weight sign.
Functional polymer containing aromatic amine structural unit: be containing aromatic amino and there is the polymkeric substance of specific molecular weight range.
Technical scheme of the present invention is as follows:
A kind of method of preparation formula (1) 2-methyl-4-amino-5-amino methylpyrimidine,
Carry out condensation reaction by what make formula (2) in acid condition containing the functional polymer of aromatic amine structural unit and the enol alkali of formula (3), generate the enamine polymkeric substance of corresponding formula (4),
In formula (2): m=0,1 or 2, X be CH or N, Y be blank (being namely directly connected), O (Sauerstoffatom) or ester group, A represents polyethylene, polypropylene, polyacrylic ester or their substitutive derivative,
M=Na or K in formula (3);
The enamine of this formula (4) after filtration, dry after and acetamidine hydrochloride be obtained by reacting the 2-methyl-4-amino-5-carboxamidomethyl pyrimidine of formula (5), the functional polymer of formula (2) of simultaneously dissociating, recycles;
2-methyl-4-amino-5-carboxamidomethyl the pyrimidine of formula (5) obtains the 2-methyl-4-amino-5-amino methylpyrimidine of formula (1) through hydrolysis.
Preferred according to the present invention, the functional polymer containing aromatic amine structural unit of described formula (2) is selected from poly-2-aminostyryl, poly-4-aminostyryl, poly-3-aminostyryl, poly-3-(2-amino-benzene oxygen) propylene, poly-3-(3-amino-benzene oxygen) propylene, poly-3-(4-amino-benzene oxygen) propylene, poly-2-(2-amino-benzene) ethanol acrylate, poly-2-(3-amino-benzene) ethanol acrylate, poly-2-(4-amino-benzene) ethanol acrylate, poly-4-aminopyridine-2-ethanol acrylate, poly-4-aminopyridine-4-ethanol acrylate, poly-3-amino-4-vinylpridine, poly-4-amino-3-vinyl pyridine, poly-4-amino-2-vinyl pyridine, poly-3-amino-2-vinyl pyridine, poly-4-amino-5-ethene aminomethyl pyrimidine or poly-2-methyl-4-amino-5-ethene aminomethyl pyrimidine.
According to the present invention, below preparation method specifically illustrates.
An environment-friendly preparation method for VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine, comprises step as follows:
Step 1: the enol alkali of formula (3) is dissolved in appropriate water, the aqueous solution of preparation enol alkali,
Step 2: the functional polymer containing aromatic amine structural unit adding solvent and formula (2) in reactor successively, then, adds appropriate acid, 0 ~ 100 DEG C of insulation reaction 30 ~ 40 minutes;
Step 3: prepare enamine polymkeric substance (4)
In the reactor of step 2, add the aqueous solution of the enol alkali that step 1 configures, 0 ~ 100 DEG C of insulation reaction, after having reacted, is cooled to 0 DEG C, filters, and washing, obtains granular enamine polymkeric substance (4), drying for standby;
Step 4: add acetamidine hydrochloride, methanol solution of sodium methylate in reaction vessel, 0 ~ 40 DEG C of reaction, filter, filtrate is the methanol solution of ethanamidine; As acetamidine free base;
Step 5: preparation 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5)
In another reaction vessel, add the ethanamidine methanol solution of the obtained enamine polymkeric substance of step 3, alcoholic solvent, methyl-phenoxide (internal standard substance), step 4 preparation; Stirring reaction at room temperature ~ 80 DEG C;
Utilize the reaction result of vapor detection enamine and acetamidine free base, compare the GC area ratio of this step product 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5) and methyl-phenoxide internal standard substance, tracking reaction proceeds to reaction and completes;
After having reacted, add suitable quantity of water, steam methyl alcohol, be cooled to room temperature, filter, be washed to neutrality, filter formula (2) functional polymer obtaining dissociating, reclaim, be directly used in next batch reaction; Filtrate is for subsequent use;
Step 6: preparation 2-methyl-4-amino-5-amino methylpyrimidine (1)
Aqueous sodium hydroxide solution is added in the filtrate of step 5,80 ~ 100 DEG C of reactions, generate 2-methyl-4-amino-5-amino methylpyrimidine (1), utilize the conversion situation of vapor detection 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5), to having reacted.
After the reaction of step 6 completes, liquid phase external standard method is utilized to confirm the purity of product 2-methyl-4-amino-5-amino methylpyrimidine (1), and calculated yield.
According to the present invention, step 1 enol alkali used is preferably enol sodium.The compound of the M=Na namely in formula (3).
According to the present invention, the functional polymer of step 2 is (1-3) in the mol ratio of amino and step 1 enol alkali used: 1, wherein preferred molar ratio (1.2-1.8): 1.
According to the present invention, step 2 functional polymer used is the combination of one or more with general structure (2), and described polymkeric substance directly adds in solid form.The polymkeric substance that step 5 reclaims can not drying, is directly used in the step 2 of next batch reaction.
According to the present invention, step 2 formula (2) functional polymer used is selected from formula (2-1) ~ formula (2-17) compound, wherein one of preferred formula (2-1) ~ (2-6), formula (2-12) ~ formula (2-15).
According to the present invention, step 2 solvent used is water, methyl alcohol, one of ethanol or below C4 saturated alcohol or combination, wherein preferably water or methyl alcohol.
Preferred according to the present invention, step 2 acid used is hydrochloric acid, sulfuric acid, phosphoric acid, and its concentration is this area typical concentrations.The wherein hydrochloric acid of further preferably 25-30wt%.
According to the present invention, the reaction of step 3, utilizes high performance liquid chromatography (HPLC) to detect the conversion situation of described enol alkali; Monitoring reaction completes.
Preferred according to the present invention, the temperature of reaction of step 3 is room temperature to 50 DEG C.
Preferred according to the present invention, the concentration of the methanol solution of sodium methylate of step 4 is 20-30wt%.
Preferred according to the present invention, the acetamidine hydrochloride of step 4 and the mol ratio of sodium methylate are 1:1-1.1.
Preferred according to the present invention, step 5 alcoholic solvent used is methyl alcohol, one of ethanol or below C4 saturated alcohol or combination, wherein particular methanol or ethanol further.
Preferred according to the present invention, the temperature of reaction that step 5 prepares 2-methyl-4-amino-5-carboxamidomethyl pyrimidine is 30 DEG C ~ 50 DEG C.
Preferred according to the present invention, the concentration of the aqueous sodium hydroxide solution described in step 5 is 25-35wt%.
According to the present invention, above-mentioned 17 kinds of functional polymers containing aromatic amine structural unit distinguish corresponding following formula (2-1) ~ formula (2-17):
A. the functional polymer of the 2-aminostyryl of formula (2-1), number-average molecular weight scope is 2000 to 12000; With 2-kharophen vinylbenzene for monomer radical polymerization, hydrolysis are obtained,
B. the functional polymer of the 4-aminostyryl of formula (2-2), number-average molecular weight scope is 2000 to 12000; With 4-kharophen vinylbenzene for monomer radical polymerization, hydrolysis are obtained,
C. the functional polymer of the 3-kharophen vinylbenzene of formula (2-3), number-average molecular weight scope is 2000 to 12000; With 3-kharophen vinylbenzene for monomer radical polymerization, hydrolysis are obtained,
D. the polymkeric substance of formula (2-4), the replacement propylene shown in formula (2-5) and formula (2-6); Number-average molecular weight scope is 4000 to 12000; (2-4), (2-5) and (2-6) is that monomer radical polymerization is obtained with 3-(2-kharophen phenoxy group) propylene, 3-(3-kharophen phenoxy group) propylene and 3-(4-kharophen phenoxy group) propylene respectively
Corresponding monomer structure is as follows:
E. acrylic ester polymer, such as formula (2-7), formula (2-8), formula (2-9), formula (2-10), shown in formula (2-11), its number-average molecular weight scope is 4000 to 12000, wherein (2-7), (2-8), (2-9) be respectively with 2-(2-is amino) phenylethyl alcohol acrylate, 2-(3-is amino) phenylethyl alcohol acrylate, 2-(4-is amino) phenylethyl alcohol acrylate is that monomer radical polymerization is obtained, (2-10), (2-11) be obtain for monomer radical is polymerized with 4-aminopyridine-2-ethanol acrylate and 3-aminopyridine-4-ethanol acrylate respectively,
F. polyethylene polymer, shown in (2-12), formula (2-13), formula (2-14), formula (2-15), formula (2-16), formula (2-17), its number-average molecular weight scope is 4000 to 12000, be that monomer radical polymerization, hydrolysis are obtained with 3-acetylaminohydroxyphenylarsonic acid 4-vinylpridine, 4-acetylaminohydroxyphenylarsonic acid 3-vinyl pyridine, 4-acetylaminohydroxyphenylarsonic acid 2-vinyl pyridine, 3-acetylaminohydroxyphenylarsonic acid 2-vinyl pyridine, 4-acetylaminohydroxyphenylarsonic acid 5-ethene aminomethyl pyrimidine, 2-methyl-4-acetylaminohydroxyphenylarsonic acid 5-ethene aminomethyl pyrimidine respectively
According to the present invention, the above-mentioned functional polymer containing aromatic amine structural unit is bought by market, also can prepare by prior art.See CN201310082480.6, CN201310081768.1 and CN201310081676.3.The invention provides following methods:
One, the preparation method of formula (2-1), formula (2-2), formula (2-3), (2-4), formula (2-5), formula (2-6), formula (2-12), formula (2-13), formula (2-14), formula (2-15), formula (2-16), formula (2-17):
1) prepare the alcohol-water solution of monomer, this solution is joined in reaction vessel; Alcohol used is the saturated alcohol of methyl alcohol, ethanol and carbon less than 5;
2) be heated to temperature 60-115 DEG C, drip the alcoholic solution of peroxidation octyl ether initiator;
3) 80-130 DEG C of reaction 2.5 ~ 3 hours are warming up to; Reaction system pressure is 3 ~ 6 normal atmosphere.
4) be cooled to interior temperature 80-85 DEG C, add the molecular chain conditioning agent lauryl mercaptan of 0.5 ~ 2wt% of monomer consumption, 80-85 DEG C of insulation reaction 2 ~ 3 hours;
5) filtered while hot, removes a small amount of precipitate; Filtrate cools, and adds sodium hydroxide and is heated to 80 DEG C ~ reflux temperature, hydrolysis reaction 3-4 hour;
6) be cooled to-10 DEG C ~ 30 DEG C, separate out product, filter, obtain functional polymer, dry.
Two, the preparation method of formula (2-7), formula (2-8), formula (2-9), formula (2-10), formula (2-11) polyacrylate(s) functional polymer:
1. prepare the alcohol-water solution of monomer, this solution is joined in reaction vessel; Alcohol used is the saturated alcohol of methyl alcohol, ethanol and carbon less than 5;
2. be heated to temperature 60-115 DEG C, drip the alcoholic solution of peroxidation octyl ether initiator;
3. 80-130 DEG C of reaction 2.5 ~ 3 hours are warming up to; Reaction system pressure is 2 ~ 4 normal atmosphere;
4. be cooled to 80-85 DEG C, add the molecular chain conditioning agent lauryl mercaptan of 0.5 ~ 2wt% of monomer consumption, 80-85 DEG C of insulation reaction 2 ~ 3 hours;
5. filtered while hot, a small amount of high-molecular weight polymer of separating out of removing; Filtrate is cooled to room temperature, filters, dry, obtains containing amino aryl hydrocarbon structure Elementary Function polymkeric substance.
First: explain detailedly for the poly-2-aminostyryl of formula (2-1): in 1000 milliliters of stainless steel cauldrons, add 400 grams of ethanol, 100 grams of deionized waters, 80.5 grams of (0.5 mole) 2-kharophens vinylbenzene (monomer); Be heated to 80-85 DEG C, drip the solution of 1.6 grams of peroxidation octyl ethers and 10 grams of ethanol, drip and finish, be warming up to 115-120 DEG C, react 3 hours, system pressure is 4-5 normal atmosphere; Be cooled to 80-85 DEG C, add 0.8 gram of lauryl mercaptan, insulation reaction 4 hours; Filtered while hot, removes a small amount of precipitate; Filtrate is cooled to 50 DEG C, adds the aqueous sodium hydroxide solution of 100 grams of 25wt%, is heated to 95-100 DEG C of hydrolysis 4 hours; Be cooled to 20 DEG C, filtration, drying, obtain white solid and gather 2-aminostyryl formula (1) 56.5 gram.
The preparation process of formula (2-2), formula (2-3), (2-4), formula (2-5), formula (2-6), formula (2-12), formula (2-13), formula (2-14), formula (2-15), formula (2-16), formula (2-17) is identical with the poly-2-aminostyryl of formula (2-1), and difference is that corresponding initial monomers replaces 2 – kharophen vinylbenzene with such as the monomer described in front b, c, d, f.
Second: it is that example explains detailedly that formula (2-7) gathers 2-(2-is amino) phenylethyl alcohol acrylate: in 1000 milliliters of stainless steel cauldrons, add 400 grams of Virahols, 100 grams of deionized waters, 95.5 grams of (0.5 mole) 2-(2-amino-benzene) ethanol acrylate; Be heated to interior temperature 65-75 degree, drip the solution of 1.6 grams of peroxidation octyl ethers and 10 grams of Virahols, drip and finish, be warming up to 85 ~ 95 DEG C, react 5 hours, now pressure is 2 normal atmosphere; Be cooled to 80-85 DEG C, add 0.8 gram of lauryl mercaptan, insulation reaction 2 hours; Filtered while hot, removes a small amount of high-molecular weight polymer; Filtrate is cooled to room temperature, filters, dry, obtain poly-2-(2-is amino) phenylethyl alcohol acrylate (formula 2-7) 77.4 grams, outward appearance is off-white color solid particulate, and number-average molecular weight scope is 4000 to 12000, swelling in the hot water, dissolve in the alcohol of heat.
The preparation process of formula (2-8), formula (2-9), formula (2-10), formula (2-11) is identical with the poly-2-of formula (2-7) (2-is amino) phenylethyl alcohol acrylate, and difference is that corresponding initial monomers replaces 2-(2-is amino) phenylethyl alcohol acrylate with such as monomer 2-(3-is amino) the phenylethyl alcohol acrylate described in front e. acrylic ester polymer, 2-(4-is amino) phenylethyl alcohol acrylate, 4-aminopyridine-2-ethanol acrylate or 3-aminopyridine-4-ethanol acrylate.
Technical characterstic of the present invention is: utilize the functional polymer containing aromatic amine structural unit to substitute highly carcinogenic Ortho-Chloro aniline or other small molecules anils, prepare VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine.This functional polymer refers to containing aromatic amino and has the polymkeric substance of specific molecular weight range, reaction system can be partially soluble in, Ortho-Chloro aniline and α-formyl radical-3-formamido group propionitrile reaction can be replaced to generate corresponding enamine polymkeric substance (3-aminoacrylonitrile derivative), the latter generates 2-methyl-4-amino-5-formamido group pyrimidine again with acetamidine hydrochloride condensation, through hydrolysis preparation 2-methyl-4-amino-5-amino methylpyrimidine (1), discharge the functional polymer containing aromatic amine structural unit simultaneously, and the feature utilizing this polymkeric substance to be insoluble to cold alcohol-water solution fully reclaims, can recycle after filtering.The method is easy and simple to handle, and yield is high, and wastewater flow rate is few, and environmental protection is easy to industrial applications.
Excellent results of the present invention is: the present invention utilizes the functional polymer containing aromatic amine structural unit to replace highly carcinogenic Ortho-Chloro aniline or other small molecules aniline compound, by the method production VITMAIN B1, the residual of Ortho-Chloro aniline compounds in product fundamentally can be stopped.This route technical process is short simultaneously, and waste water and waste liquids discharge is few, economic environmental protection.2-methyl-4-amino-5-amino methylpyrimidine the purity standby by this functional polymer legal system is high, HPLC purity can reach 99.1-99.9%, yield can up to more than 90%, cost is low, be beneficial to suitability for industrialized production, to improving the commercial production levels of China's VITMAIN B1 and developing in a healthy way significant.
Accompanying drawing explanation
Fig. 1 is the GC ion flow graph of the 2-methyl-4-amino-5-carboxamidomethyl pyrimidine of embodiment 1;
Fig. 2 is the GC mass spectrum of the 2-methyl-4-amino-5-carboxamidomethyl pyrimidine of embodiment 1.
Embodiment
Describe the present invention in detail below in conjunction with embodiment, but the present invention is not only confined to this.
In embodiment, vapor detection carries out reaction monitoring and purity detecting with Shimadzu gas chromatograph, and INSTRUMENT MODEL is GC-1020PLUS; Liquid Detection: utilize Shimadzu liquid chromatograph to carry out reaction monitoring and purity detecting, INSTRUMENT MODEL is LC-20AT, and chromatographic column is C18 post ODS (250mm × 4.6mm × 5 μm), and moving phase is methyl alcohol: water=2:1 (volume ratio); Determined wavelength is 280nm.
Functional polymer containing aromatic amine structural unit, refer to poly-2-aminostyryl such as formula (2-1), its outward appearance is off-white color solid particulate, is insoluble to cold water, is slightly soluble in hot water, and dissolve in the alcohol of heat, its number-average molecular weight scope is 2000 to 12000.
Percentage concentration described in embodiment is mass ratio.
Embodiment 1: with the functional polymer of the 2-aminostyryl of formula (2-1) and enol sodium for initial reactant, reaction formula is as follows:
*: formula (4) compound and acetamidine hydrochloride reaction generate 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5), discharge the functional polymer (2-1) of aromatic amine structural unit simultaneously.
Step is as follows:
In 500 milliliters of four-hole boiling flasks, add 200 grams of water, 150 grams of enol sodium, stirred at ambient temperature dissolves, and obtains the aqueous solution of enol sodium.
200 grams of water are added successively, the dilute hydrochloric acid of 178.5 grams of (1.5 moles) formula (2-1) functional polymers (poly-2-aminostyryl) 150 gram 30%, 20 to 25 DEG C of insulation reaction 30 minutes in another reactor; Then add the aqueous solution of the enol sodium of above preparation, 20 to 30 DEG C of insulation reaction, utilize the conversion situation of Liquid Detection enol sodium; After Liquid Detection reaction, be cooled to 0 DEG C, filter, washing, obtain granular corresponding enamine polymkeric substance (4), drying weighs 288 grams;
Prepare acetamidine free base: in 1000 milliliters of glass reaction containers, add 104.5 grams of acetamidine hydrochloride, 220 grams of 27wt% methanol solution of sodium methylate, 20 ~ 30 DEG C of reactions, filter, filtrate is the methanol solution of ethanamidine; In another reaction vessel, add 300 grams of methyl alcohol, 286.5 gram enamine polymkeric substance, 1 gram of methyl-phenoxide internal standard substance, the ethanamidine methanol solution more than obtained, 30 to 35 DEG C are reacted 2 hours, 40 ~ 50 DEG C are reacted 2 hours, utilize vapor detection result, compare the GC area ratio of this step product 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5) and methyl-phenoxide internal standard substance, follow the tracks of reaction; React complete, add 500 grams of suitable quantity of water, steam methyl alcohol, be cooled to room temperature, filter, be washed to neutrality, (polymkeric substance that filtration obtains is directly used in lower batch reaction, gained intermediate 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5) by GC-MS analysis confirmation, see Fig. 1 and Fig. 2).The aqueous sodium hydroxide solution of 160 grams of 30wt% is added in filtrate, 95 DEG C to 100 DEG C reactions, utilize the conversion situation of vapor detection (5), utilize liquid phase external standard method to confirm purity and the yield of product 2-methyl-4-amino-5-amino methylpyrimidine (1).Product passes through and standard substance comparison, and liquid phase appearance time is identical.Product purity and yield are in table 1.
Embodiment 2
The poly-2-aminostyryl of the functional polymer (2-1) reclaimed with embodiment 1 replaces new poly-2-aminostyryl, the polymkeric substance of 178.5 grams of 2-aminostyryl is got with dry weight basis, react with enol sodium, preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 3
As described in Example 1, difference is, functional polymer selects formula (2-2) to gather 4-aminostyryl, and number-average molecular weight scope is 2000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 178.5 grams of polymkeric substance (2-2), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 4
As described in Example 1, difference is, functional polymer selects formula (2-3) to gather 3-aminostyryl, and number-average molecular weight scope is 2000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 178.5 grams of polymkeric substance (2-3), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 5
As described in Example 1, difference is, functional polymer selects formula (2-4) to gather 2-amino-benzene oxygen propylene, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 223.5 grams of polymkeric substance (2-4), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 6
As described in Example 1, difference is, functional polymer selects formula (2-5) to gather 3-amino-benzene oxygen propylene, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 223.5 grams of polymkeric substance (2-5), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 7
As described in Example 1, difference is, functional polymer selects formula (2-6) to gather 4-amino-benzene oxygen propylene, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 223.5 grams of polymkeric substance (2-6), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 8
As described in Example 1, difference is, functional polymer selects formula (2-7) to gather 2-(2-is amino) phenylethyl alcohol acrylate, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 305.6 grams of polymkeric substance (2-7), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 9
As described in Example 1, difference is, functional polymer selects formula (2-8) to gather 2-(3-is amino) phenylethyl alcohol acrylate, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 305.6 grams of polymkeric substance (2-8), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 10
As described in Example 1, difference is, functional polymer selects formula (2-9) to gather 2-(4-is amino) phenylethyl alcohol acrylate, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 305.6 grams of polymkeric substance (2-9), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 11
As described in Example 1, difference is, functional polymer selects formula (2-10) to gather 4-aminopyridine-2-ethanol acrylate, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 307.2 grams of polymkeric substance (2-10), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 12
As described in Example 1, difference is, functional polymer selects formula (2-11) to gather 3-aminopyridine-4-ethanol acrylate, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 307.2 grams of polymkeric substance (2-11), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 13
As described in Example 1, difference is, functional polymer selects formula (2-12) to gather 3-amino-4-vinylpridine, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 180 grams of polymkeric substance (2-12), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 14
As described in Example 1, difference is, functional polymer selects formula (2-13) to gather 4-amino-3-vinyl pyridine, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 180 grams of polymkeric substance (2-13), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 15
As described in Example 1, difference is, functional polymer selects formula (2-14) to gather 4-amino-2-vinyl pyridine, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 180 grams of polymkeric substance (2-14), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 16
As described in Example 1, difference is, functional polymer selects formula (2-15) to gather 3-amino-2-vinyl pyridine, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 180 grams of polymkeric substance (2-15), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 17
As described in Example 1, difference is, functional polymer selects formula (2-16) to gather 4-amino-5-ethene aminomethyl pyrimidine, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 225 grams of polymkeric substance (2-16), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Embodiment 18
As described in Example 1, difference is, functional polymer selects formula (2-17) to gather 2-methyl-4-amino-5-ethene aminomethyl pyrimidine, and number-average molecular weight scope is 4000 to 12000; Replace the polymkeric substance in embodiment 1 (2-1) to react with 246 grams of polymkeric substance (2-17), preparation process and condition are with embodiment 1, and products obtained therefrom purity and yield are in table 1.
Table 1: the functional polymer legal system of aromatic amine structural unit is for 2-methyl-4-amino-5-amino methylpyrimidine (1)
Claims (11)
1. a method for preparation formula (1) 2-methyl-4-amino-5-amino methylpyrimidine,
Comprise step as follows:
Step 1: the enol alkali of formula (3) is dissolved in appropriate water, the aqueous solution of preparation enol alkali,
Step 2: the functional polymer containing aromatic amine structural unit adding solvent and formula (2) in reactor successively, then, adds appropriate acid, 0 ~ 100 DEG C of insulation reaction 30 ~ 40 minutes;
In formula (2): m=0,1 or 2, X that to be CH or N, Y be is blank, O (Sauerstoffatom) or ester group, A represents polyethylene, polypropylene, polyacrylic ester or their substitutive derivative;
Step 3: prepare enamine polymkeric substance (4)
In the reactor of step 2, add the aqueous solution of the enol alkali that step 1 configures, 0 ~ 100 DEG C of insulation reaction, after having reacted, is cooled to 0 DEG C, filters, and washing, obtains granular enamine polymkeric substance (4), drying for standby;
Step 4: add acetamidine hydrochloride, methanol solution of sodium methylate in reaction vessel, 0 ~ 40 DEG C of reaction, filter, filtrate is the methanol solution of ethanamidine; As acetamidine free base;
Step 5: preparation 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5)
In another reaction vessel, add the ethanamidine methanol solution of the obtained enamine polymkeric substance of step 3, alcoholic solvent, methyl-phenoxide internal standard substance, step 4 preparation; Stirring reaction at room temperature ~ 80 DEG C;
Utilize the reaction result of vapor detection enamine and acetamidine free base, compare the GC area ratio of this step product 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5) and methyl-phenoxide internal standard substance, tracking reaction proceeds to reaction and completes;
After having reacted, add suitable quantity of water, steam methyl alcohol, be cooled to room temperature, filter, be washed to neutrality, filter formula (2) functional polymer obtaining dissociating, reclaim, be directly used in next batch reaction; Filtrate is for subsequent use;
Step 6: preparation 2-methyl-4-amino-5-amino methylpyrimidine (1)
Aqueous sodium hydroxide solution is added in the filtrate of step 5,80 ~ 100 DEG C of reactions, generate 2-methyl-4-amino-5-amino methylpyrimidine (1), utilize the conversion situation of vapor detection 2-methyl-4-amino-5-carboxamidomethyl pyrimidine (5), to having reacted.
2. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, it is characterized in that the functional polymer containing aromatic amine structural unit of described formula (2) is selected from poly-2-aminostyryl, poly-4-aminostyryl, poly-3-aminostyryl, poly-3-(2-amino-benzene oxygen) propylene, poly-3-(3-amino-benzene oxygen) propylene, poly-3-(4-amino-benzene oxygen) propylene, poly-2-(2-amino-benzene) ethanol acrylate, poly-2-(3-amino-benzene) ethanol acrylate, poly-2-(4-amino-benzene) ethanol acrylate, poly-4-aminopyridine-2-ethanol acrylate, poly-4-aminopyridine-4-ethanol acrylate, poly-3-amino-4-vinylpridine, poly-4-amino-3-vinyl pyridine, poly-4-amino-2-vinyl pyridine, poly-3-amino-2-vinyl pyridine, poly-4-amino-5-ethene aminomethyl pyrimidine or poly-2-methyl-4-amino-5-ethene aminomethyl pyrimidine.
3. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that described enol alkali is enol sodium.
4. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that the functional polymer containing aromatic amine structural unit of step 2 in the mol ratio of amino and step 1 enol alkali used for (1-3): 1.
5. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that the functional polymer containing aromatic amine structural unit of step 2 in the mol ratio of amino and step 1 enol alkali used for (1.2-1.8): 1.
6. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that step 2 solvent used is water, one of methyl alcohol or ethanol or combination.
7. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that step 2 acid used is hydrochloric acid, sulfuric acid or phosphoric acid.
8. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that the concentration of the methanol solution of sodium methylate of step 4 is 20-30wt%.
9. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that the acetamidine hydrochloride of step 4 and the mol ratio of sodium methylate are 1:1-1.1.
10. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, is characterized in that step 5 alcoholic solvent used is one of methyl alcohol, ethanol or combination.
The preparation method of 11. 2-methyl-4-amino-5-amino methylpyrimidines as claimed in claim 1, is characterized in that the stirring reaction temperature described in step 5 is 30 DEG C ~ 50 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310087215.7A CN104059023B (en) | 2013-03-18 | 2013-03-18 | The environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310087215.7A CN104059023B (en) | 2013-03-18 | 2013-03-18 | The environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104059023A CN104059023A (en) | 2014-09-24 |
| CN104059023B true CN104059023B (en) | 2016-04-06 |
Family
ID=51546992
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310087215.7A Active CN104059023B (en) | 2013-03-18 | 2013-03-18 | The environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104059023B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105254574B (en) * | 2015-10-31 | 2017-11-14 | 新发药业有限公司 | A kind of simple and convenient process for preparing of the cyanopyrimidine of 2 methyl of vitamin B1 key intermediate, 4 amino 5 |
| CN107602481A (en) * | 2017-09-05 | 2018-01-19 | 常州大学 | A kind of 2 methyl 4 amino 5 (formyl aminomethyl) pyrimidine hydrolysis process |
| CN109503425B (en) * | 2018-12-24 | 2021-11-16 | 江苏兄弟维生素有限公司 | Purification method of alpha-sodium substituted formyl-beta-formamido propionitrile |
| CN111253320B (en) * | 2020-03-11 | 2021-05-04 | 山东新和成精化科技有限公司 | Synthetic method of formyl pyrimidine |
| CN113912551B (en) * | 2021-10-09 | 2023-04-18 | 浙江新和成股份有限公司 | Recyclable aromatic amine reagent and preparation and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2377395A (en) * | 1945-06-05 | Pyrimidine derivatives and peocesb | ||
| US3242138A (en) * | 1961-03-01 | 1966-03-22 | August Jean Van Paesschen | Process for preparing poly |
-
2013
- 2013-03-18 CN CN201310087215.7A patent/CN104059023B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2377395A (en) * | 1945-06-05 | Pyrimidine derivatives and peocesb | ||
| US3242138A (en) * | 1961-03-01 | 1966-03-22 | August Jean Van Paesschen | Process for preparing poly |
Non-Patent Citations (5)
| Title |
|---|
| 2-甲基-4-氨基-5-甲酰胺甲基嘧啶的合成;姬明理,等;《应用化工》;20050831;第34卷(第8期);第513页第1栏反应式、第2栏倒数1-2段，第514页第1栏第1-3段 * |
| 3,4-二氢嘧啶-2-酮衍生物合成研究进展;路军,等.;《有机化学》;20010930;第21卷(第9期);全文 * |
| 3,4-二胺-1氢-吡唑并[5,4-d]嘧啶的固相合成及抗病毒药VP-63843的合成研究;马月龙;《中国优秀硕士期刊全文数据库》;20040430(第4期);正文第11页倒数第1段，第12页图1.3.2 * |
| 固相有机合成小分子化学库;李伟章,等.;《化学进展》;19970930;第9卷(第3期);全文 * |
| 离子交换剂的原理及应用;郭兆同;《中国药学杂志》;19540930;第1卷(第9期);全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104059023A (en) | 2014-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104059023B (en) | The environment-friendly preparation method of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine | |
| CN103435556B (en) | Simple and quick method for synthesizing improved vitamin B1 intermediate 2-methyl-4-amino-5-aminomethylpyrimidine | |
| CN103420918B (en) | Simple and convenient preparation method of key intermediate (2-methyl-4-amino-5-amino methyl pyrimidine) for vitamin B1 | |
| CN105017260A (en) | Preparation method of sitagliptin intermediate triazolopyrazine derivative | |
| CN102503825A (en) | Preparation method of medicine intermediate butanone diacid diester compound | |
| CN104478790A (en) | Preparation method of S-type apremilast | |
| CN103420881B (en) | A kind of preparation method of medicinal racemization hydroxyl Methionine calcium salt newly | |
| CN105254575A (en) | Synthetic method for sulfadiazine | |
| CN105801587B (en) | A kind of method that environmental friendly catalysis prepares pyrans simultaneously [2,3 d] pyrimidone derivatives | |
| CN102267983B (en) | Sym-triazine derivative compounds containing sym-tetrazine rings and preparation method thereof | |
| CN109516960B (en) | Preparation method of urapidil hydrochloride | |
| CN101463011A (en) | Process for synthesizing 3,4-dihydropyrimidine-2-keto | |
| CN102924362B (en) | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride | |
| CN103739545B (en) | Simple preparation method of vitamin B6 | |
| CN110452181A (en) | The synthetic method of 2- methyl -4- amino -5- formamide methylpyrimidine | |
| CN109180628A (en) | A kind of preparation method of apiolin | |
| CN105732518B (en) | A kind of method that trisulfonic acid radical ion liquid catalyst prepares pyrimidone derivatives | |
| CN102924473A (en) | Preparation method of 2-chlorine-7-iodothieno[3,2-D] pyrimidine | |
| SHALLU et al. | First total synthesis of a guanidine alkaloid Nitensidine D using immobilized ionic liquid, microwaves and formamidinesulfinic acid | |
| CN101230065B (en) | Method for producing 9-[2(hydroxyl)propyl] adenine | |
| CN109761910B (en) | Synthetic method of ideprop | |
| CN104334561B (en) | compound JK12A and preparation thereof | |
| CN108640822B (en) | Preparation method of 4-vinyl guaiacol and 4-vinyl guaiacol | |
| CN104610180A (en) | Oteracil potassium preparation method | |
| CN105418507A (en) | Preparation method for 1-(3-methyl-1-phenyl-1H-pyrazole-5-yl)piperazine |
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 | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Environmentally friendly preparation of 2-methyl-4-amino-5-aminomethylpyrimidine, a key intermediate of vitamin B1 Effective date of registration: 20211130 Granted publication date: 20160406 Pledgee: Zhejiang Commercial Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2021980013546 |