CN108546249B - Method for preparing bisamine pyrimidine - Google Patents
Method for preparing bisamine pyrimidine Download PDFInfo
- Publication number
- CN108546249B CN108546249B CN201810165802.6A CN201810165802A CN108546249B CN 108546249 B CN108546249 B CN 108546249B CN 201810165802 A CN201810165802 A CN 201810165802A CN 108546249 B CN108546249 B CN 108546249B
- Authority
- CN
- China
- Prior art keywords
- pyrimidine
- methyl
- acylaminomethyl
- amino
- bisamine
- 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
Abstract
The invention belongs to the technical field of compound synthesis, and relates to a method for preparing diaminopyrimidine, which comprises the following steps of treating a 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution by using cation exchange resin to obtain a diaminopyrimidine alkali solution, and further obtaining a pure diaminopyrimidine product by post-treatment. The method has the characteristics of simple and convenient operation, economy and feasibility, higher yield, safety and environmental protection, direct application of the product bisamine pyrimidine solution to the next reaction without treatment, suitability for industrial production and the like.
Description
Technical Field
The invention belongs to the technical field of compound synthesis, and particularly relates to a method for preparing bisamine pyrimidine.
Background
Bisamidopyrimidine, chemical name 5-aminomethyl-2-methyl-pyrimidin-4-yl-amine, is an important precursor for the synthesis of vitamin B1.
The structural formula of the bisamidopyrimidine is as follows:
the bisamine pyrimidines can be prepared according to the prior art by expensive reduction methods, for example by hydrogenation or reductive amination of the corresponding 5-nitrilo or 5-formyl-pyrimidine, respectively; or reacting the corresponding 5-alkoxymethyl-pyrimidine with ammonia in the presence of a catalyst at a temperature of at least 230 ℃, see EP1138675A and US 6365740. DE3511273 describes the hydrolysis of 2-methyl-4-amino-5-formylaminomethyl-pyrimidine with aqueous sodium hydroxide and the extraction of the bisaminopyrimidine with methylisobutyl-methanol, which requires a distillative purification at 130-. Although DE3511273 describes the use of aqueous NaOH solution for the hydrolysis of the compound 2-methyl-4-amino-5-formylaminomethyl-pyrimidine, no direct separation of sodium formate or formic acid by-product from the desired bisaminopyrimidine has been achieved; in addition, an extracting agent methyl isobutyl-methanol used in the post-treatment stimulates a respiratory system, is inflammable and explosive, is not environment-friendly, and has low post-treatment yield. Therefore, the development of a new method for preparing bisamine pyrimidine is a new problem to be solved urgently at present.
Disclosure of Invention
The invention aims to provide a method for preparing bisamine pyrimidine, which has the characteristics of simple and convenient operation, economy, feasibility, higher yield, safety, environmental protection, direct application of a product bisamine pyrimidine solution to the next reaction without treatment, suitability for industrial production and the like.
The object of the present invention is achieved by a process for preparing a solution of a bisamidopyrimidine base, said process comprising the steps of:
treating 4-amino-2-methyl-5-acylaminomethyl-pyrimidine water solution shown in formula I by adopting cation exchange resin,
wherein R is hydrogen or C1-4An alkyl group.
The weight ratio of the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine to the cation exchange resin is 1: 1-8, preferably 1: 1.5-5, and more preferably 1: 2-3; the method for treating the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution shown in the formula I by adopting the cation exchange resin comprises the steps of pouring the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution into a cation exchange resin column for adsorption, washing the resin column by using first purified water, and eluting the resin column by using an alkali aqueous solution to obtain a dipyridamole alkali solution; the cation exchange resin is strong-acid cation exchange resin, and the strong-acid cation exchange resin is 732 strong-acid cation exchange resin; the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine contains o-chloroaniline impurities, the liquid phase content of the o-chloroaniline impurities contained in the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine is 0.01-8%, and the preferable liquid phase content of the o-chloroaniline impurities is 1-5%; said 4-amino-2-methyl-5-acylaminomethyl-pyrimidine has a liquid phase purity of 85-99.9%, preferably 4-amino-2-methyl-5-acylaminomethyl-pyrimidine has a liquid phase purity of 90-99.9%; the alkali is selected from alkali metal hydroxide, and the alkali metal hydroxide is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide; the mass concentration of the alkali aqueous solution is 3-20%, and the mass concentration of the preferable alkali aqueous solution is 10-15%; the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution is prepared by dissolving 4-amino-2-methyl-5-acylaminomethyl-pyrimidine in second purified water at 40-60 ℃, and the concentration of the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution is 5-10%, preferably 7%; the diameter and height ratio of the cation exchange resin column is 1:3-70, and the preferred diameter and height ratio is 1: 5-61; the mass ratio of the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine to the first purified water is 3:50-300, and the preferred mass ratio is 3: 100-240; and eluting the resin column by using an aqueous solution of alkali until the eluting solution cannot detect the bisamidopyrimidine by using thin layer chromatography.
A method for preparing pyraclostrobin, the pyraclostrobin alkali solution, through the after treatment, get pyraclostrobin; the post-treatment method comprises extraction and distillation.
The reaction formula is shown as follows:
wherein R is hydrogen or C1-4An alkyl group.
The gist of the invention resides in a process for preparing bisaminopyrimidines. The principle is as follows: (1) the sulfonic group in 732 strong acid cation exchange resin is used for adsorbing the amine functional group in the structural formula of the pyrimidine derivative. (2) The purified water washes the resin column to remove inorganic or organic compounds not adsorbed onto the resin. (3) Then eluting the resin with 3-15% sodium hydroxide solution for displacement reaction to obtain the alkaline aqueous solution of the bisamine pyrimidine. (4) Relatively pure bisamine pyrimidines can be isolated in a single operation without additional work-up steps.
Compared with the prior art, the method for preparing the bisamine pyrimidine has the characteristics of greatly improving the quality of the bisamine pyrimidine, effectively removing the o-chloroaniline impurity, being simple and convenient to operate, being economic and feasible, having high purity and yield of the bisamine pyrimidine, being safe and environment-friendly, directly using the product bisamine pyrimidine solution for the next reaction without treatment, being beneficial to recycling the by-product formic acid, directly separating the formic acid by-product from the required bisamine pyrimidine, having low industrial price and easy obtainment of 732 resin, having less resin consumption, being suitable for industrial production and the like, and being widely used in the technical field of medicines.
Detailed Description
For a further understanding of the present invention, the following examples are provided to illustrate the preparation of 5-aminomethyl-2-methyl-pyrimidin-4-yl-amine, a bisamidopyrimidine, in accordance with the present invention. It is to be understood that these examples are described merely to illustrate the features of the present invention in further detail, and not as limitations of the invention or of the scope of the claims appended hereto.
The first embodiment is as follows: preparation of bisamine pyrimidines
Dissolving 10g of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine (liquid phase purity 93.6%, 3.2% o-chloroaniline) in 120g of purified water at 50 ℃ to obtain an aqueous solution of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine, pouring the aqueous solution into a resin column containing 20g of 732 strong acid cation exchange resin for adsorption, wherein the inner diameter of the resin column is 18mm, the height is 1.1m, and the outlet flow rate is about 7-10mL/min, washing the resin with about 800mL of purified water, collecting formic acid water, performing environment-friendly treatment or recovering formic acid, finally performing dissociation and exchange by using a 10% sodium hydroxide aqueous solution to elute the resin column, wherein the outlet flow rate is about 2-3mL/min, eluting until the eluate does not detect the bisaminopyrimidine by Thin Layer Chromatography (TLC), about 600mL of the solution of the bisamine pyrimidine alkali is obtained (the purity of the bisamine pyrimidine is higher than 95% through liquid chromatography detection, and the yield is 85% -90%), the solution does not need to be purified, and the solution can be directly subjected to condensation reaction with gamma-chloro-gamma-acetyl propanol acetate, and a contrast test shows that the yield of the condensation reaction between the solution of the bisamine pyrimidine alkali and the yield of the condensation reaction between the pure product of the bisamine pyrimidine and the gamma-chloro-gamma-acetyl propanol acetate are equivalent. The solution of the dipyridamole base can not detect the existence of the o-chloroaniline by liquid chromatography. The used resin column is washed to be neutral by purified water, and then 5 percent hydrochloric acid is added to activate the resin for repeated use. The diamine pyrimidine alkali solution can be extracted and distilled by methyl isobutyl-methanol to obtain diamine pyrimidine.
Example two: preparation of bisamine pyrimidines
Dissolving 30g of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine (liquid phase purity 93.6%, 3.2% o-chloroaniline) in 400g of purified water at 50 ℃ to obtain an aqueous solution of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine, pouring the aqueous solution into a resin column containing 90g of 732 strong acid cation exchange resin for adsorption, wherein the inner diameter of the resin column is 18mm, the height is 1.1m, and the outlet flow rate is about 5-8mL/min, washing the resin with about 1000mL of purified water, collecting formic acid water, performing environment-friendly treatment or recovering formic acid, finally performing dissociation and exchange by using a 15% sodium hydroxide aqueous solution to elute the resin column, wherein the outlet flow rate is about 2-3mL/min, until the eluate cannot detect the bisaminopyrimidine by Thin Layer Chromatography (TLC), about 450mL of the solution of the bisamine pyrimidine alkali is obtained (the purity of the bisamine pyrimidine is higher than 95% through liquid chromatography detection, and the yield is 85% -90%), the solution does not need to be purified, and the solution can be directly subjected to condensation reaction with gamma-chloro-gamma-acetyl propanol acetate, and a contrast test shows that the yield of the condensation reaction between the solution of the bisamine pyrimidine alkali and the yield of the condensation reaction between the solution of the bisamine pyrimidine alkali and the gamma-chloro-gamma-acetyl propanol acetate are equivalent. The solution of the dipyridamole base can not detect the existence of the o-chloroaniline by liquid chromatography. The used resin column is washed to be neutral by purified water, and then 5 percent hydrochloric acid is added to activate the resin for repeated use.
It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.
Claims (12)
1. A process for preparing a solution of a bisamidopyrimidine base, the process comprising the steps of:
treating 4-amino-2-methyl-5-acylaminomethyl-pyrimidine water solution shown in formula I by adopting cation exchange resin,
I
wherein R is hydrogen;
the cation exchange resin is strong-acid cation exchange resin, and the strong-acid cation exchange resin is 732 strong-acid cation exchange resin;
the weight ratio of the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine to the cation exchange resin is 1: 1.5-5;
the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine contains o-chloroaniline impurities, and the liquid phase content of the o-chloroaniline impurities contained in the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine is 1-5%;
the method for treating the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution shown in the formula I by adopting the cation exchange resin comprises the steps of pouring the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution into a cation exchange resin column for adsorption, washing the resin column by using first purified water, and eluting the resin column by using an alkali aqueous solution to obtain the bisaminopyrimidine alkali solution.
2. The method for preparing a bisamine pyrimidine base solution as claimed in claim 1, wherein the weight ratio of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine to cation exchange resin is 1:2 to 3.
3. The method for preparing a bisamine pyrimidine base solution as claimed in claim 1, wherein the base is selected from alkali metal hydroxides selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide; the mass concentration of the alkali aqueous solution is 3-20%.
4. A process for preparing a bisamine pyrimidine base solution as claimed in claim 3 wherein the aqueous base solution has a mass concentration of 10 to 15%.
5. The process for preparing a bisamine pyrimidine base solution as claimed in claim 1, wherein the aqueous solution of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine is prepared by dissolving 4-amino-2-methyl-5-acylaminomethyl-pyrimidine in second purified water at 40-60 ℃, and the concentration of the aqueous solution of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine is 5-10%.
6. The process for preparing a bisamine pyrimidine base solution, as claimed in claim 5, wherein the concentration of the aqueous solution of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine is 7%.
7. The process for preparing a bisamine pyrimidine base solution as claimed in claim 1, wherein the cation exchange resin column has a diameter to height ratio of 1:3 to 70; the mass ratio of the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine to the first purified water is 3: 50-300; and eluting the resin column by using an aqueous solution of alkali until the eluting solution cannot detect the bisamidopyrimidine by using thin layer chromatography.
8. The process for preparing a bisamine pyrimidine base solution, as claimed in claim 7, wherein the cation exchange resin column has a diameter to height ratio of 1:5 to 61; the mass ratio of the 4-amino-2-methyl-5-acylaminomethyl-pyrimidine to the first purified water is 3: 100-240.
9. A process for preparing a bisamine pyrimidine, characterized in that the bisamine pyrimidine base solution prepared by the process according to claim 1 is subjected to a post-treatment to obtain a bisamine pyrimidine.
10. The process for preparing bisamine pyrimidines as claimed in claim 9, wherein the work-up is by extraction, distillation.
11. A process for preparing a solution of a bisamidopyrimidine base, the process comprising the steps of:
10g of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine with a liquid phase purity of 93.6% and 3.2% o-chloroaniline were dissolved in 120g of purified water at 50 ℃, obtaining 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution, pouring the aqueous solution into a resin column containing 20g of 732 strong acid cation exchange resin for adsorption, wherein the inner diameter of the resin column is 18mm, the height of the resin column is 1.1m, the outlet flow rate is about 7-10mL/min, washing the resin with about 800mL of purified water, collecting formic acid water, eluting the resin column with 10% sodium hydroxide aqueous solution for dissociation and exchange, the outlet flow rate is about 2-3mL/min, and eluting until the eluent cannot detect the bisamine pyrimidine through thin layer chromatography to obtain the bisamine pyrimidine alkali solution.
12. A process for preparing a solution of a bisamidopyrimidine base, the process comprising the steps of:
30g of 4-amino-2-methyl-5-acylaminomethyl-pyrimidine with a liquid phase purity of 93.6% and 3.2% o-chloroaniline were dissolved in 400g of purified water at 50 ℃, obtaining 4-amino-2-methyl-5-acylaminomethyl-pyrimidine aqueous solution, pouring the aqueous solution into a resin column containing 90g of 732 strong acid cation exchange resin for adsorption, wherein the inner diameter of the resin column is 18mm, the height of the resin column is 1.1m, the outlet flow rate is about 5-8mL/min, washing the resin with 1000mL of purified water, collecting formic acid water, eluting the resin column with 15% sodium hydroxide aqueous solution for dissociation and exchange, the outlet flow rate is about 2-3mL/min, and eluting until the eluent cannot detect the bisamine pyrimidine through thin layer chromatography to obtain the bisamine pyrimidine alkali solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810165802.6A CN108546249B (en) | 2018-02-28 | 2018-02-28 | Method for preparing bisamine pyrimidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810165802.6A CN108546249B (en) | 2018-02-28 | 2018-02-28 | Method for preparing bisamine pyrimidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108546249A CN108546249A (en) | 2018-09-18 |
| CN108546249B true CN108546249B (en) | 2021-10-01 |
Family
ID=63515823
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810165802.6A Active CN108546249B (en) | 2018-02-28 | 2018-02-28 | Method for preparing bisamine pyrimidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108546249B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
| US4794182A (en) * | 1986-07-14 | 1988-12-27 | Takeda Chemical Industries, Ltd. | 2-Alkyl-4-amino-5-aminomethylpyrimidines |
| CN101111484A (en) * | 2005-01-28 | 2008-01-23 | 帝斯曼知识产权资产管理有限公司 | Process for the manufacture of a precursor of vitamin b* |
| CN101627017A (en) * | 2006-03-15 | 2010-01-13 | 帝斯曼知识产权资产管理有限公司 | Process for the manufacture of a precursor of vitamin b1 |
| 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 |
-
2018
- 2018-02-28 CN CN201810165802.6A patent/CN108546249B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3511273A1 (en) * | 1985-03-28 | 1986-10-09 | Basf Ag, 6700 Ludwigshafen | Improved process for the preparation of 2-methyl-4-amino-5-aminomethylpyrimidine |
| US4794182A (en) * | 1986-07-14 | 1988-12-27 | Takeda Chemical Industries, Ltd. | 2-Alkyl-4-amino-5-aminomethylpyrimidines |
| CN101111484A (en) * | 2005-01-28 | 2008-01-23 | 帝斯曼知识产权资产管理有限公司 | Process for the manufacture of a precursor of vitamin b* |
| CN101627017A (en) * | 2006-03-15 | 2010-01-13 | 帝斯曼知识产权资产管理有限公司 | Process for the manufacture of a precursor of vitamin b1 |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| Lewis Acid-Catalyzed Synthesis of 4-Aminopyrimidines: A Scalable Industrial Process;Ulla Létinois et al.;《Organic Process Research & Development》;20130207;第427-431页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108546249A (en) | 2018-09-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102766185A (en) | Method for respectively recovering ursodesoxycholic acid and chenodeoxycholic acid from ursodesoxycholic acid waste mother liquor | |
| CN103724261A (en) | Novel industrial production method for hydroxychloroquine sulfate | |
| CN111039832A (en) | Method for producing taurine and method for removing impurities from reaction system for preparing taurine | |
| CN103073439B (en) | Synthesis method of ambroxol hydrochloride compound | |
| CN108546249B (en) | Method for preparing bisamine pyrimidine | |
| CN102603603B (en) | Method for preparing (S)-oxiracetam | |
| CN103709221A (en) | Preparation method for cordycepin | |
| CN102718662A (en) | Method for preparing cinacalcet hydrochloride | |
| CN106316935B (en) | A kind of preparation method of Abemaciclib intermediate | |
| CN106749098B (en) | A kind of preparation method preparing dioxopromethazine hydrochloride using oxygen as oxidant | |
| CN109438276A (en) | A kind of preparation method of Oseltamivir phosphate | |
| CN103387511B (en) | A kind of preparation method of Sancycline | |
| CN108147988B (en) | Preparation method of lactam compound with high chiral purity | |
| CN102531935B (en) | Method for synthesizing N-methyl-D-aspartate | |
| CN104045567A (en) | Method for recovering triethylamine from aqueous solution | |
| CN104892501A (en) | Aftertreatment purification method for 3-[(3-amino-4-methylamino benzoyl)(pyridine-2-yl)amino]ethyl propionate | |
| CN102718664A (en) | Preparation method of N-allyl aniline compound | |
| CN107383076A (en) | A kind of synthetic method of the chlorophenylboronic acid pinacol ester of 3 amino 4 | |
| CN102603600A (en) | Method for preparing (S)-oxiracetam | |
| CN107652191B (en) | Purification method of venlafaxine intermediate | |
| CN108976182A (en) | A method of preparing Dapagliflozin five-membered ring impurity | |
| CN102649771A (en) | Method of preparing capsaicine | |
| CN115368278B (en) | Method for preparing benzenesulfonic acid compound by hydrolyzing benzenesulfonamide compound | |
| KR101383246B1 (en) | Novel method for prepararing voglibose | |
| CN104592134A (en) | Method for purifying 2-(2-flourine-4-chlorine-5-aminophenyl)-4-difluromethylation-5-methyl-1,2,4-triazole-3-ketone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |