CN104059023A - Environment-friendly preparation method for key intermediate 2-methyl-4-amino-5-aminomethyl pyrimidine of vitamin B1 - Google Patents
Environment-friendly preparation method for key intermediate 2-methyl-4-amino-5-aminomethyl pyrimidine of vitamin B1 Download PDFInfo
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Abstract
The invention relates to an environment-friendly preparation method for a key intermediate 2-methyl-4-amino-5-aminomethyl pyrimidine of vitamin B1. The method comprises the following steps: substituting highly oncogenic o-chloroaniline or other micromolecular aniline derivatives with a functional polymer containing an aromatic amine structural unit; carrying out a condensation reaction with enol alkali under an acidic condition so as to produce a corresponding enamine polymer; subjecting the enamine polymer and ethanamidine hydrochloride to condensation so as to produce 2-methyl-4-amino-5-formylamino-pyrimidine; and carrying out hydrolysis so as to prepare 2-methyl-4-amino-5-aminomethyl pyrimidine; wherein the functional polymer containing the aromatic amine structural unit is released at the same time and is cyclically used for next batch of reactions. The method has short process flow, discharges a small amount of waste water and waste liquid and is beneficial for industrial production and for improvement of the industrial production level of vitamin B1.
Description
Technical field
The environment-friendly preparation method that the present invention relates to a kind of VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine, belongs 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, such as well-known doctor Sun Simiao utilizes paddy skin treatment vitamin B1 deficiency.VITMAIN B1 is also the VITAMIN of being purified by people the earliest, and within 1896, first Dutch scientist Yi Keman finds VITMAIN B1, the scholar Feng Ke that Polonizes for 1910 VITMAIN B1 of extracting and purify out from rice bran.The structural formula of VITMAIN B1 is as follows:
VITMAIN B1 claims again VitB1 or aneurin, is a kind of vitamin B group being combined into by pyrimidine ring and thiazole ring.VITMAIN B1 is white crystals or crystalline powder, has faint characteristic odor, and bitter has and draws moistly, reveals and to put in air, easily absorbs moisture, easily decomposes rottenly in basic solution, meets the light and heat decline of tiring.VITMAIN B1 is very stable in acidic solution, but unstable in basic solution, and is easy to oxidation and decomposes.
VITMAIN B1 is mainly present in the crust and plumule of seed, and 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 promote enterogastric peristalsis, 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, can there is following reaction successively: neural system reaction (dry beriberi), cardiovascular systems reaction (beriberi humida), Wernicke(Wei Nikeshi) encephalopathic and Korsakoff syndromes (Korakaff's psychosis).
Past, some derivatives of VITMAIN B1 also obtained extensive concern, as Fursutiamine, rosickyite amine and benfotiamine etc. for over ten years.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 basic nutrition, and its synthetic preparation receives much concern always, and wherein, 2-methyl-4-amino-5-amino methylpyrimidine is the key intermediate of current conventional preparation VITMAIN B1.About synthesizing of 2-methyl-4-amino-5-amino methylpyrimidine, mainly contain cyanopyrimidine, formyl pyrimidine, three kinds of routes of formamido group pyrimidine.
Cyanopyrimidine route (route 1) be take propane dinitrile as starting raw material, ethoxymethylidene base propane dinitrile is prepared in condensation with trimethyl orthoformate, ammonia replacement obtains amino methane base propane dinitrile, the latter and the condensation of ethyl acetimide hydrochloride obtain 2-methyl-4-amino-5-cyanopyrimidine, then under Raney Ni catalysis Hydrogenation for 2-methyl-4-amino-5-amino methylpyrimidine.This route 1 need to be used a large amount of ethyl acetimide hydrochloride (1.8 to 2 equivalent), and this raw material and propane dinitrile are expensive, is unfavorable for that product cost reduces.Chinese patent document CN102712602A(CN201080053163.6) a kind of synthetic method of the 2-of preparation methyl-4-amino-5-cyanopyrimidine is disclosed.Take propane dinitrile as starting raw material, and under the effect of alkali, propane dinitrile and ion salt compound (III) are reacting in certain solvent, product without separation directly under alkali exists with acetamidine hydrochloride cyclic condensation, make 2-methyl-4-amino-5-cyanopyrimidine.
Formyl pyrimidine route (route 2) is to take vinyl cyanide as starting raw material; with methyl nitrite reaction preparation 3; 3-dimethoxy propionitrile; formylation generates corresponding enol sodium again; the latter and butanols effect generate 3-butoxy-2-(1,1-dibutoxy methyl) vinyl cyanide, then generate 2-methyl-4-amino-5-formyl radical pyrimidine with acetamidine hydrochloride condensation; react with 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 these route 2 reactions steps are complicated, and reaction time is long, and will use autoclave (approximately 50 kilograms of pressure) to carry out hydrogenation reaction, is difficult to industrializing implementation.
Formamido group pyrimidine route (route 3) be take 3-aminopropionitrile as starting raw material; under sodium methylate effect, with methyl-formiate formylation, prepare α-formyl radical-3-formamido group propionitrile; the latter and Ortho-Chloro aniline effect generate 2-formyl aminomethyl-3N-(2-chloro-phenyl-) aminoacrylonitrile; generate 2-methyl-4-amino-5-formamido group pyrimidine with acetamidine hydrochloride condensation again, through hydrolysis preparation 2-methyl-4-amino-5-amino methylpyrimidine.United States Patent (USP) 2377395 and German Patent 2748153 have all adopted this route, and this route 3 is that raw material is cheaply easy to get, and it is relatively gentle that each walks reaction conditions, 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 recrystallization repeatedly, be still difficult to remove the micro-Ortho-Chloro aniline in the finished product VITMAIN B1.
In addition, CN1319592A (CN01112307.9) also provides the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine, be to make 2-methyl-4-amino-5-(alkoxymethyl)-2 yl pyrimidines and ammonia react under catalyzer exists, 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 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 functional polymer that utilization of the present invention contains aromatic amine structural unit substitutes highly carcinogenic Ortho-Chloro aniline or other small molecules anils, prepares VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine.
Term explanation:
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 GPC gel chromatograph (THF makees solvent) to carry out number-average molecular weight and weight-average molecular weight sign to the polymer microballoon of preparation.
The functional polymer that contains aromatic amine structural unit: be the polymkeric substance that contains aromatic amino and there is specific molecular weight range.
Technical scheme of the present invention is as follows:
A method for preparation formula (1) 2-methyl-4-amino-5-amino methylpyrimidine,
By what make formula (2), containing the functional polymer of aromatic amine structural unit and the enol alkali of formula (3), under acidic conditions, carry out condensation reaction, generate the enamine polymkeric substance of corresponding formula (4),
In formula (2): m=0,1 or 2, X be CH or N, Y is blank (being 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, react 2-methyl-4-amino-5-formamido group methylpyrimidine of the formula of obtaining (5) after dry with acetamidine hydrochloride, the functional polymer of formula (2) of simultaneously dissociating, recycles;
Formula (5)
2-methyl-4-amino-5-formamido group methylpyrimidine of formula (5) obtains 2-methyl-4-amino-5-amino methylpyrimidine of formula (1) through hydrolysis.
Preferred according to the present invention, the functional polymer that contains aromatic amine structural unit of described formula (2) is selected from poly-2-amino-benzene ethene, poly-4-amino-benzene ethene, poly-3-amino-benzene ethene, 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 more detailed preparation method illustrates.
An environment-friendly preparation method for VITMAIN B1 key intermediate 2-methyl-4-amino-5-amino methylpyrimidine, comprises that step is 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 that contains aromatic amine structural unit to adding successively solvent and formula (2) in reactor, then, adds appropriate acid, 0～100 ℃ of insulation reaction 30～40 minutes;
Step 3: prepare enamine polymkeric substance (4)
To the aqueous solution that adds the enol alkali of step 1 configuration in the reactor of step 2,0～100 ℃ of insulation reaction, after react, is cooled to 0 ℃, filters, and washes, and obtains granular enamine polymkeric substance (4), drying for standby;
Step 4: add acetamidine hydrochloride, methanol solution of sodium methylate in reaction vessel, 0～40 ℃ of reaction, filters the methanol solution that filtrate is ethanamidine; As ethanamidine free alkali;
Step 5: preparation 2-methyl-4-amino-5-formamido group methylpyrimidine (5)
In another reaction vessel, add the ethanamidine methanol solution of enamine polymkeric substance that step 3 makes, alcoholic solvent, methyl-phenoxide (internal standard substance), step 4 preparation; Stirring reaction at room temperature～80 ℃;
Utilize the reaction result of vapor detection enamine and ethanamidine free alkali, relatively the GC Area Ratio of this step product 2-methyl-4-amino-5-formamido group methylpyrimidine (5) and methyl-phenoxide internal standard substance, follows the tracks of to react to proceed to and has reacted;
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 that obtains dissociating and, reclaim, be directly used in next batch reaction; Filtrate for later use;
Step 6: preparation 2-methyl-4-amino-5-amino methylpyrimidine (1)
In the filtrate of step 5, add aqueous sodium hydroxide solution, 80～100 ℃ of reactions, generate 2-methyl-4-amino-5-amino methylpyrimidine (1), utilize the conversion situation of vapor detection 2-methyl-4-amino-5-formamido group methylpyrimidine (5), to having reacted.
After the reaction of step 6 completes, utilize liquid phase external standard method 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.It is the compound of the M=Na in formula (3).
According to the present invention, it is (1-3) that the functional polymer of step 2 be take the mol ratio of amino and step 1 enol alkali used: 1, and preferred molar ratio (1.2-1.8) wherein: 1.
According to the present invention, step 2 functional polymer used is one or more the combination with general structure (2), and described polymkeric substance directly adds with solid form.The polymkeric substance that step 5 reclaims is drying not, 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 one of water, methyl alcohol, ethanol or the following saturated alcohol of C4 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 further preferably hydrochloric acid of 25-30wt% wherein.
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 has been reacted.
Preferred according to the present invention, the temperature of reaction of step 3 is room temperature to 50 ℃.
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 one of methyl alcohol, ethanol or the following saturated alcohol of C4 or combination, wherein further particular methanol or ethanol.
Preferred according to the present invention, the temperature of reaction of step 5 preparation 2-methyl-4-amino-5-formamido group methylpyrimidine is 30 ℃～50 ℃.
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 that contain aromatic amine structural unit are corresponding following formula (2-1)～formula (2-17) respectively:
A. the amino cinnamic functional polymer of the 2-of formula (2-1), number-average molecular weight scope is 2000 to 12000; Be take 2-kharophen vinylbenzene as monomer radical polymerization, hydrolysis make,
2-kharophen styrene monomer structural formula formula (2-1) is gathered 2-amino-benzene ethene
B. the amino cinnamic functional polymer of the 4-of formula (2-2), number-average molecular weight scope is 2000 to 12000; Be take 4-kharophen vinylbenzene as monomer radical polymerization, hydrolysis make,
4-kharophen styrene monomer structural formula formula (2-2) is gathered 4-amino-benzene ethene
C. the functional polymer of the 3-kharophen vinylbenzene of formula (2-3), number-average molecular weight scope is 2000 to 12000; Be take 3-kharophen vinylbenzene as monomer radical polymerization, hydrolysis make,
3-kharophen styrene monomer structural formula formula (2-3) is gathered 3-amino-benzene ethene
D. the polymkeric substance of the replacement propylene shown in formula (2-4), formula (2-5) and formula (2-6); Number-average molecular weight scope is 4000 to 12000; (2-4), (2-5) and (2-6) be to take respectively 3-(2-kharophen phenoxy group) propylene, 3-(3-kharophen phenoxy group) propylene and 3-(4-kharophen phenoxy group) propylene makes as monomer radical polymerization,
Formula (2-4) is gathered 3-(2-amino-benzene oxygen) propylene
Formula (2-5) is gathered 3-(3-amino-benzene oxygen) propylene
Formula (2-6) is gathered 3-(4-amino-benzene oxygen) propylene
Corresponding monomer structure is as follows:
3-(2-kharophen phenoxy group) propylene 3-(3-kharophen phenoxy group) propylene 3-(4-kharophen phenoxy group) propylene
E. acrylic ester polymer, suc 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 amino with 2-(2-respectively) phenylethyl alcohol acrylate, 2-(3-is amino) phenylethyl alcohol acrylate, 2-(4-amino) phenylethyl alcohol acrylate is that monomer radical polymerization makes, (2-10), (2-11) be to take respectively 4-aminopyridine-2-ethanol acrylate and 3-aminopyridine-4-ethanol acrylate to make as monomer radical polymerization,
Amino is that ortho position: 2-(2-is amino) poly-2-(2-is amino for phenylethyl alcohol acrylate formula (2-7)) phenylethyl alcohol acrylate
Between position: 2-(3-amino) poly-2-(3-is amino for phenylethyl alcohol acrylate formula (2-8)) phenylethyl alcohol acrylate
Contraposition: 2-(4-is amino) poly-2-(4-is amino for phenylethyl alcohol acrylate formula (2-9)) phenylethyl alcohol acrylate
4-aminopyridine-2-ethanol acrylate formula (2-10) is gathered 4-aminopyridine-2-ethanol acrylate
3-aminopyridine-4-ethanol acrylate formula (2-11) is gathered 3-aminopyridine-4-ethanol acrylate
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, to take respectively 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 to make as monomer radical polymerization, hydrolysis
3-acetylaminohydroxyphenylarsonic acid 4-vinylpridine formula (2-12) is gathered 3-amino-4-vinylpridine
4-acetylaminohydroxyphenylarsonic acid 3-vinyl pyridine formula (2-13) is gathered 4-amino-3-vinyl pyridine
4-acetylaminohydroxyphenylarsonic acid 2-vinyl pyridine formula (2-14) is gathered 4-amino-2-vinyl pyridine
3-acetylaminohydroxyphenylarsonic acid 2-vinyl pyridine formula (2-15) is gathered 3-amino-2-vinyl pyridine
4-acetylaminohydroxyphenylarsonic acid 5-ethene aminomethyl pyrimidine formula (2-16) is gathered 4-amino-5-ethene aminomethyl pyrimidine
2-methyl-4-acetylaminohydroxyphenylarsonic acid 5-ethene aminomethyl pyrimidine formula (2-17) is gathered 2-methyl-4-amino-5-ethene aminomethyl pyrimidine
According to the present invention, the above-mentioned functional polymer that contains aromatic amine structural unit can be bought by market, also can prepare by prior art.Referring to 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) alcohol-water solution of preparation monomer, joins this solution in reaction vessel; Alcohol used is methyl alcohol, ethanol and the carbon saturated alcohol below 5;
2) be heated to temperature 60-115 ℃, drip the alcoholic solution of peroxidation octyl ether initiator;
3) be warming up to 80-130 ℃ of reaction 2.5～3 hours; Reaction system pressure is 3～6 normal atmosphere.
4) be cooled to interior temperature 80-85 ℃, add the molecular chain conditioning agent lauryl mercaptan of 0.5～2wt% of monomer consumption, 80-85 ℃ of insulation reaction 2～3 hours;
5) filtered while hot, removes a small amount of precipitate; Filtrate is cooling, adds sodium hydroxide to be heated to 80 ℃～reflux temperature, hydrolysis reaction 3-4 hour;
6) be cooled to-10 ℃～30 ℃, 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 methyl alcohol, ethanol and the carbon saturated alcohol below 5;
2. be heated to temperature 60-115 ℃, drip the alcoholic solution of peroxidation octyl ether initiator;
3. be warming up to 80-130 ℃ of reaction 2.5～3 hours; Reaction system pressure is 2～4 normal atmosphere;
4. be cooled to 80-85 ℃, add the molecular chain conditioning agent lauryl mercaptan of 0.5～2wt% of monomer consumption, 80-85 ℃ of insulation reaction 2～3 hours;
5. filtered while hot, removes the high-molecular weight polymer of separating out on a small quantity; Filtrate is cooled to room temperature, filters, dry, obtains containing amino aromatic hydrocarbons structural unit functional polymer.
First: the poly-2-amino-benzene ethene of the formula (2-1) of take explains detailedly as example: 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-kharophen vinylbenzene (monomer); Be heated to 80-85 ℃, 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 ℃, react 3 hours, system pressure is 4-5 normal atmosphere; Be cooled to 80-85 ℃, 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 ℃, adds the aqueous sodium hydroxide solution of 100 grams of 25wt%, is heated to 95-100 ℃ of hydrolysis 4 hours; Be cooled to 20 ℃, filter, be dried, obtain (1) 56.5 gram of the poly-2-amino-benzene ethene formula of white solid.
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-amino-benzene ethene of formula (2-1), and difference is that corresponding initial monomers replaces 2 – kharophen vinylbenzene with the monomer described in front b, c, d, f.
Second: poly-2-(2-is amino for formula (2-7)) phenylethyl alcohol acrylate is that example explains detailedly: 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-benzenes) 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 ℃, react 5 hours, now pressure is 2 normal atmosphere; Be cooled to 80-85 ℃, 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, obtains poly-2-(2-amino) 77.4 grams of phenylethyl alcohol acrylate (formula 2-7), outward appearance is off-white color solid particulate, and number-average molecular weight scope is 4000 to 12000, and swelling in hot water dissolves in hot alcohol.
Poly-2-(2-is amino for the preparation process of formula (2-8), formula (2-9), formula (2-10), formula (2-11) and formula (2-7)) phenylethyl alcohol acrylate is identical, difference be corresponding initial monomers with as front e. acrylic ester polymer described in monomer 2-(3-amino) phenylethyl alcohol acrylate, 2-(4-be amino) phenylethyl alcohol acrylate, 4-aminopyridine-2-ethanol acrylate or 3-aminopyridine-4-ethanol acrylate replace the 2-(2-amino) phenylethyl alcohol acrylate.
Technical characterstic of the present invention is: utilize the functional polymer that contains 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 the polymkeric substance that contains aromatic amino and have specific molecular weight range, can be partially soluble in reaction system, to can replace Ortho-Chloro aniline and α-formyl radical-3-formamido group propionitrile reaction to generate corresponding enamine polymkeric substance (3-aminoacrylonitrile derivative), the latter generates 2-methyl-4-amino-5-formamido group pyrimidine with acetamidine hydrochloride condensation again, through hydrolysis preparation 2-methyl-4-amino-5-amino methylpyrimidine (1), discharge the functional polymer that contains aromatic amine structural unit simultaneously, and the feature of 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 that contains aromatic amine structural unit to replace highly carcinogenic Ortho-Chloro aniline or other small molecules aniline compound, by the method production VITMAIN B1, can fundamentally stop the residual of Ortho-Chloro aniline compounds in product.This route technical process is simultaneously short, and waste water and discharging of waste liquid are few, economic environmental protection.2-methyl-4-amino-5-amino methylpyrimidine the purity standby by this functional polymer legal system is high, HPLC purity 99.1-99.9%, yield can be up to more than 90%, and 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 2-methyl-4-amino-5-formamido group methylpyrimidine of embodiment 1;
Fig. 2 is the GC mass spectrum of 2-methyl-4-amino-5-formamido group methylpyrimidine of embodiment 1.
Embodiment
Below in conjunction with embodiment, describe the present invention in detail, but the present invention is not only confined to this.
In embodiment, vapor detection is to carry out reaction monitoring and purity detecting with Shimadzu gas chromatograph, and instrument model is GC-1020 PLUS; Liquid Detection: utilize Shimadzu liquid chromatograph to carry out reaction monitoring and purity detecting, instrument model is LC-20AT, chromatographic column is C18 post ODS (250mm * 4.6mm * 5 μ m), moving phase is methyl alcohol: water=2:1 (volume ratio); Detection wavelength is 280nm.
The functional polymer that contains aromatic amine structural unit, refers to poly-2-amino-benzene ethene suc as formula (2-1), and its outward appearance is off-white color solid particulate, is insoluble to cold water, is slightly soluble in hot water, dissolves in hot alcohol, and its number-average molecular weight scope is 2000 to 12000.
Percentage concentration described in embodiment is mass ratio.
Embodiment 1: the amino cinnamic functional polymer of 2-and the enol sodium of formula (2-1) of take is initial reactant, and reaction formula is as follows:
*: formula (4) compound and acetamidine hydrochloride reaction generate 2-methyl-4-amino-5-formamido group methylpyrimidine (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, stirring and dissolving under room temperature, obtains the aqueous solution of enol sodium.
In another reactor, add successively 200 grams of water, the dilute hydrochloric acid that 178.5 grams of (1.5 moles) formulas (2-1) functional polymer (poly-2-amino-benzene ethene) is 150 gram 30%, 20 to 25 ℃ of insulation reaction 30 minutes; Then the aqueous solution that adds the enol sodium of above preparation, 20 to 30 ℃ of insulation reaction, utilize the conversion situation of Liquid Detection enol sodium; After Liquid Detection reaction, be cooled to 0 ℃, filter, washing, obtains granular corresponding enamine polymkeric substance (4), is dried and weighs 288 grams;
Prepare ethanamidine free alkali: 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 ℃ of reactions, filter the methanol solution that filtrate is 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 obtaining, 30 to 35 ℃ are reacted 2 hours, 40～50 ℃ are reacted 2 hours, utilize vapor detection result, relatively the GC Area Ratio of this step product 2-methyl-4-amino-5-formamido group methylpyrimidine (5) and methyl-phenoxide internal standard substance, follows 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, and gained intermediate 2-methyl-4-amino-5-formamido group methylpyrimidine (5) is by GC-MS analysis confirmation, referring to Fig. 1 and Fig. 2).To the aqueous sodium hydroxide solution that adds 160 grams of 30wt% in filtrate, 95 ℃ to 100 ℃ 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 process and standard substance comparison, liquid phase appearance time is identical.Product purity and yield are in Table 1.
Embodiment 2
The poly-2-amino-benzene ethene of functional polymer (2-1) reclaiming with embodiment 1 replaces new poly-2-amino-benzene ethene, with dry weight basis, get the amino cinnamic polymkeric substance of 178.5 grams of 2-, 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-amino-benzene ethene, and number-average molecular weight scope is 2000 to 12000; With 178.5 grams of polymkeric substance (2-2), replace the polymkeric substance (2-1) in embodiment 1 to react, 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-amino-benzene ethene, and number-average molecular weight scope is 2000 to 12000; With 178.5 grams of polymkeric substance (2-3), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 223.5 grams of polymkeric substance (2-4), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 223.5 grams of polymkeric substance (2-5), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 223.5 grams of polymkeric substance (2-6), replace the polymkeric substance (2-1) in embodiment 1 to react, 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 that functional polymer is selected the poly-2-(2-amino of formula (2-7)) phenylethyl alcohol acrylate, number-average molecular weight scope is 4000 to 12000; With 305.6 grams of polymkeric substance (2-7), replace the polymkeric substance (2-1) in embodiment 1 to react, 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 that functional polymer is selected the poly-2-(3-amino of formula (2-8)) phenylethyl alcohol acrylate, number-average molecular weight scope is 4000 to 12000; With 305.6 grams of polymkeric substance (2-8), replace the polymkeric substance (2-1) in embodiment 1 to react, 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 that functional polymer is selected the poly-2-(4-amino of formula (2-9)) phenylethyl alcohol acrylate, number-average molecular weight scope is 4000 to 12000; With 305.6 grams of polymkeric substance (2-9), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 307.2 grams of polymkeric substance (2-10), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 307.2 grams of polymkeric substance (2-11), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 180 grams of polymkeric substance (2-12), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 180 grams of polymkeric substance (2-13), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 180 grams of polymkeric substance (2-14), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 180 grams of polymkeric substance (2-15), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 225 grams of polymkeric substance (2-16), replace the polymkeric substance (2-1) in embodiment 1 to react, 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; With 246 grams of polymkeric substance (2-17), replace the polymkeric substance (2-1) in embodiment 1 to react, 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 (10)
1. a method for preparation formula (1) 2-methyl-4-amino-5-amino methylpyrimidine,
By what make formula (2), containing the functional polymer of aromatic amine structural unit and the enol alkali of formula (3), under acidic conditions, carry out condensation reaction, generate the enamine polymkeric substance of corresponding formula (4),
In formula (2): m=0,1 or 2, X be CH or N, Y is blank (being 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, react 2-methyl-4-amino-5-formamido group methylpyrimidine of the formula of obtaining (5) after dry with acetamidine hydrochloride, the functional polymer of formula (2) of simultaneously dissociating, recycles;
2-methyl-4-amino-5-formamido group methylpyrimidine of formula (5) obtains 2-methyl-4-amino-5-amino methylpyrimidine of formula (1) through hydrolysis.
2. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, the functional polymer that contains aromatic amine structural unit that it is characterized in that described formula (2) is selected from poly-2-amino-benzene ethene, poly-4-amino-benzene ethene, poly-3-amino-benzene ethene, 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 step is 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 that contains aromatic amine structural unit to adding successively solvent and formula (2) in reactor, then, adds appropriate acid, 0～100 ℃ of insulation reaction 30～40 minutes;
Step 3: prepare enamine polymkeric substance (4)
To the aqueous solution that adds the enol alkali of step 1 configuration in the reactor of step 2,0～100 ℃ of insulation reaction, after react, is cooled to 0 ℃, filters, and washes, and obtains granular enamine polymkeric substance (4), drying for standby;
Step 4: add acetamidine hydrochloride, methanol solution of sodium methylate in reaction vessel, 0～40 ℃ of reaction, filters the methanol solution that filtrate is ethanamidine; As ethanamidine free alkali;
Step 5: preparation 2-methyl-4-amino-5-formamido group methylpyrimidine (5)
In another reaction vessel, add the ethanamidine methanol solution of enamine polymkeric substance that step 3 makes, alcoholic solvent, methyl-phenoxide internal standard substance, step 4 preparation; Stirring reaction at room temperature～80 ℃; Preferable reaction temperature is 30 ℃～50 ℃;
Utilize the reaction result of vapor detection enamine and ethanamidine free alkali, relatively the GC Area Ratio of this step product 2-methyl-4-amino-5-formamido group methylpyrimidine (5) and methyl-phenoxide internal standard substance, follows the tracks of to react to proceed to and has reacted;
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 that obtains dissociating and, reclaim, be directly used in next batch reaction; Filtrate for later use;
Step 6: preparation 2-methyl-4-amino-5-amino methylpyrimidine (1)
In the filtrate of step 5, add aqueous sodium hydroxide solution, 80～100 ℃ of reactions, generate 2-methyl-4-amino-5-amino methylpyrimidine (1), utilize the conversion situation of vapor detection 2-methyl-4-amino-5-formamido group methylpyrimidine (5), to having reacted.
5. the preparation method of 2-methyl-4-amino-5-amino methylpyrimidine as claimed in claim 1, it is (1-3) that the functional polymer that contains aromatic amine structural unit that it is characterized in that step 2 be take the mol ratio of amino and step 1 enol alkali used: 1; Preferred molar ratio (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 one of water, methyl alcohol, ethanol or the following saturated alcohol of C4 or combination; Wherein preferably water or methyl alcohol.
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, the concentration that it is characterized in that 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 the following saturated alcohol of C4 or combination, wherein particular methanol or ethanol.
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| 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 |
| CN105254574A (en) * | 2015-10-31 | 2016-01-20 | 新发药业有限公司 | Simple preparation method of vitamin B1 key intermediate 2-methyl-4-amidogen-5-cyanopyrimidine |
| 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 |
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