CN102199146A - Preparation method for N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine - Google Patents
Preparation method for N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine Download PDFInfo
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- CN102199146A CN102199146A CN2010101295257A CN201010129525A CN102199146A CN 102199146 A CN102199146 A CN 102199146A CN 2010101295257 A CN2010101295257 A CN 2010101295257A CN 201010129525 A CN201010129525 A CN 201010129525A CN 102199146 A CN102199146 A CN 102199146A
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Abstract
The invention discloses a preparation method for N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, which comprises the following steps: (a) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine in an ester solvent under the action of a reducing reagent selected from Pd-C/ammonium formate, Pd-C/formic acid and Pd-C/ammonium formate/formic acid; and (b) collecting N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine from the reaction liquid. The product acquired by using the preparation method has a yield above 90% and purity above 99.5% detected by HPLC (high-performance liquid chromatography). The preparation method realizes easy control on the process operation, thereby being suitable for industrial production.
Description
Technical field
The invention belongs to the pharmaceutical chemistry technical field, be specifically related to the preparation method of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE.
Background technology
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is an important intermediate of antitumor drug imatinib.Imatinib is developed by Novartis Co.,Ltd, its chemistry 4-[(4-methyl isophthalic acid-piperazinyl by name) methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl] amino] phenyl] benzamide, its structural formula is as follows:
What use clinically is the mesylate of imatinib.Imatinib mesylate all can suppress the Bcr-Abl Tyrosylprotein kinase in vivo and in vitro on cell levels, can selectivity suppress the chronic myelocytic leukemia of Bcr-Abl positive cell line cell, Ph chromatin-positive and acute lymphoblastic leukemia patient new fresh cell propagation and induce its apoptosis.Clinically, imatinib mesylate is used for the treatment of alpha-interferon administration failure protoblast crisis stadium, chronic stadium, quickens the myelomatosis of stadium, after extensive clinical trial, obtained the high evaluation of medical circle, and, be described as in recent years the oral cancer therapy drug of " important breakthrough is arranged " in the line medication of approval on December 20 calendar year 2001 as chronic lymphocytic leukemia.
At present, the synthetic route of Chang Yong imatinib is a disclosed synthetic route (as shown in Scheme 1) among the US5521184:
Route 1
In this synthetic route, the 3rd step was crucial single step reaction by the reaction that N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE reduction obtains N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE.
About this step reduction reaction, the method for bibliographical information has four kinds:
The one, as reductive agent, make reductive agent with 10% palladium charcoal/hydrogen with palladium charcoal/hydrogen such as the US5521184 report, the crude product that obtains methylene dichloride recrystallization, but do not report yield.
The 2nd, what WO2004074502 reported makes solvent with tetrahydrofuran (THF), tindichloride is made the aqueous hydrochloric acid of reductive agent or tindichloride as reduction system, what obtain is the xanchromatic crude product, and specific embodiment is not reported yield, only mentions in summary of the invention and yield can be brought up to 65～70%.
The 3rd, what WO2006071130 reported makes solvent with methyl alcohol, and Raney nickel and hydrazine hydrate mixture are made reductive agent, and yield brings up to 80%, and product purity can reach 99.8%.
The 4th, WO2008117298 report make reductive agent with sodium sulphite and sulphur, yield brings up to 88%, can obtain fusing point with re-crystallizing in ethyl acetate is 142～147 ℃ solid, does not report purity.
The contriver is easy to produce the situation of over reduction when finding to make reductive agent with palladium charcoal/hydrogen under study for action, can obtain being respectively following two kinds of by products more than 1% (structural formula suc as formula 1 and formula 2 shown in), and if these two kinds of by products only be difficult to remove by the crystalline method.
Formula 1 formula 2
When reducing with tindichloride, post-reaction treatment bothers very much, and it is very difficult to filter by product metastannic acid salt, produces a large amount of waste residue and waste liquid, and the yield of product has only about 60%, and what obtain is crude product.
When using hydrazine hydrate reduction, the consumption of hydrazine hydrate is very big among the embodiment of WO2006071130 report, needs with 8 normal hydrazine hydrates, and hydrazine hydrate belongs to highly toxic product, use with so big amount, being used to handle the cost that contains the hydrazine hydrate waste liquid during suitability for industrialized production can be quite high.
During with sodium sulphite and sulphur reduction, the transformation efficiency that the inventor discovers and reports not as WO2008117298 is so high, and HPLC detection reaction solution has only the product about 60%.
Therefore, this area presses for the preparation method who improves intermediate N (5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, so as can heavy industrialization ground with high yield and prepared in high purity imatinib mesylate.
Summary of the invention
Technical problem to be solved by this invention is to disclose the method for a kind of N-of preparation (5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, to overcome above-mentioned weak point.
The method for preparing N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE of the present invention comprises the steps:
(a) in esters solvent, under the effect of going back original reagent that is selected from palladium charcoal/ammonium formiate, palladium charcoal/formic acid or palladium charcoal/ammonium formiate/formic acid, N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is reduced;
(b) collection obtains N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE from reaction solution.
N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE obtains with reference to US5521184 is synthetic.
In preferred embodiment, the described original reagent of going back is selected from 10% palladium charcoal/ammonium formiate.
In preferred embodiment, in step (a), also add anhydrous sodium sulphate.
In preferred embodiment, be benchmark in the weight of N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, the weight of described 10% palladium charcoal is 2%～10%.
In preferred embodiment, the mol ratio of ammonium formiate and N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is 3～4.5: 1, more preferably 3～3.5: 1.
In preferred embodiment, described esters solvent is selected from methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate, ethyl acetate.
In preferred embodiment, the temperature of reaction of step (a) is 60～85 ℃, and the reaction times is 2～6 hours.
In preferred embodiment, step (a) specifically describes: in ethyl acetate solvent, add 1 normal N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, the 10% palladium charcoal of 2 weight %～10 weight %, 3～3.5 normal ammonium formiates, 1～2 normal anhydrous sodium sulphate, be warming up to 70～80 ℃, reacted 2～3 hours, wherein the weight of 10% palladium charcoal is benchmark for the weight in N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE.
In preferred embodiment, step (b) specifically describes and is: be cooled to room temperature, filter; Wash filtrate with water, filtrate is concentrated into dried, obtains N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE with the mixed solvent recrystallization of ethyl acetate and normal hexane.
In preferred embodiment, the volume ratio of described recrystallization solvent ethyl acetate and normal hexane is 1: 1～9: 1, preferred 1: 1～2: 1.
In the research of step (a), the contriver finds when selecting to reduce reagent when being 10% palladium charcoal/ammonium formiate, when the mol ratio of ammonium formiate and substrate N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is 3～4.5: in the time of 1, analyze through reaction product being carried out HPLC, by product N-(5-formamido--2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (structural formula as shown in Equation 3) has only 0.1%～0.5%, and the yield of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE can reach more than 90%.Especially when mol ratio be 3～3.5: in the time of 1, the by product of formula 3 can be reduced to below 0.1%, and the product purity of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is up to more than 99.8%, and yield is also up to more than 95%.
Formula 3
The contriver also finds, when 10% palladium charcoal add-on be substrate weight 2%～10% the time, 2 two by products of formula 1 and formula detect through HPLC and all do not detect.
The contriver also finds, in step (a), adds in reactant with the substrate mol ratio and be 1～3: 1 that (preferred 1～2: during 1) anhydrous sodium sulphate, the reaction times can be shortened to 2～3 hours by 6 hours, this also has positive influence to reducing production of by-products.
Palladium carbon catalyst can repeat to apply mechanically 10 times in the step (b), can reduce raw materials cost greatly.
The inventive method technological operation is easy to control, and yield can be brought up to more than 90%, and the product purity that obtains is fit to suitability for industrialized production more than 99.5%.
Embodiment
The present invention is further detailed explanation below in conjunction with embodiment.
Herein, for reductive agent palladium charcoal/ammonium formiate or palladium charcoal/formic acid or palladium charcoal/ammonium formiate/formic acid, "/" expression wherein " and ", the material before and after the expression "/" exists simultaneously.
Embodiment 1
20g N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (65.2mmol) is joined in the 1000ml four-hole boiling flask, the 10%Pd/C that adds 0.9g again, add the 500ml ethyl acetate, stir and add 12.8g (203.2mmol) ammonium formiate and 18.5g (130.3mmol) anhydrous sodium sulphate down, be warming up to backflow, refluxed the slowly blackening of reaction system color 2 hours.TLC follows the tracks of reaction (developping agent is a toluene: acetone=6: 4, volume ratio), after reacting completely, is cooled to room temperature, filtered and recycled palladium charcoal.Water (200ml * 2) wash filtrate, anhydrous sodium sulfate drying filters, filtrate is concentrated into dried, mixed solvent (1: 1, volume ratio) recrystallization with 400ml ethyl acetate and normal hexane obtains white solid 17.4g (yield 96.5%), and it is 99.8% that HPLC detects purity.
1H-NMR(DMSO-d
6)δ：2.03(s，3H)，6.29-6.33(m，1H)，6.75-6.76(m，1H)，6.83-6.85(d，1H)，7.32-7.33(m，1H)，7.48-7.43(m，1H)，8.37-8.45(m，1H)，8.52-8.56(m，2H)，8.65-8.68(m，1H)，9.22-9.23(d，1H)。
Embodiment 2
10g N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (32.6mmol) is joined in the 500ml four-hole boiling flask, the 10%Pd/C that adds 0.2g again, add the 300ml ethyl acetate, stir and add 7.2g (114.1mmol) ammonium formiate and 4.6g (32.6mmol) anhydrous sodium sulphate down, be warming up to backflow, refluxed 6 hours.TLC follows the tracks of reaction, after reacting completely, is cooled to room temperature, filtered and recycled palladium charcoal.Water (100ml * 2) wash filtrate, anhydrous sodium sulfate drying filters, filtrate is concentrated into dried, mixed solvent (3: 1, volume ratio) recrystallization with 150ml ethyl acetate and normal hexane obtains white solid 8.2g (yield 91.1%), and it is 99.6% that HPLC detects purity.
1Identical among H-NMR data and the embodiment 1.
Embodiment 3
5g N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (16.3mmol) is joined in the 250ml four-hole boiling flask, the 10%Pd/C that adds 0.5g again, add the 150ml isopropyl acetate, stir and add 2.5ml (54.4mmol) formic acid and 3.0g (21.1mmol) anhydrous sodium sulphate down, be warming up to 85 ℃, reacted 2 hours.TLC follows the tracks of reaction, after reacting completely, is cooled to room temperature, filtered and recycled palladium charcoal.Water (100ml * 2) wash filtrate, anhydrous sodium sulfate drying filters, filtrate is concentrated into dried, mixed solvent (6: 1, volume ratio) recrystallization with 60ml ethyl acetate and normal hexane obtains white solid 3.9g (yield 86.7%), and it is 99.1% that HPLC detects purity.
1Identical among H-NMR data and the embodiment 1.
Embodiment 4
5g N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (16.3mmol) is joined in the 250ml four-hole boiling flask, the 10%Pd/C that adds 0.5g again, add the 150ml ethyl acetate, stir and add 1.3ml (28.3mmol) formic acid, 1.8g (28.6mmol) ammonium formiate and 2.5g (17.6mmol) anhydrous sodium sulphate down, be warming up to backflow, refluxed 2 hours.TLC follows the tracks of reaction, after reacting completely, is cooled to room temperature, filtered and recycled palladium charcoal.Water (100ml * 2) wash filtrate, anhydrous sodium sulfate drying filters, filtrate is concentrated into dried, mixed solvent (5: 1, volume ratio) recrystallization with 120ml ethyl acetate and normal hexane obtains white solid 4.2g (yield 93.3%), and it is 99.2% that HPLC detects purity.
1Identical among H-NMR data and the embodiment 1.
Embodiment 5
10g N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (32.6mmol) is joined in the 500ml four-hole boiling flask, the 10%Pd/C that adds 0.6g again, add the 300ml ethyl acetate, stir and add 9.0g (142.9mmol) ammonium formiate and 5.0g (35.2mmol) anhydrous sodium sulphate down, be warming up to backflow, refluxed 3 hours.TLC follows the tracks of reaction, after reacting completely, is cooled to room temperature, filtered and recycled palladium charcoal.Water (100ml * 2) wash filtrate, anhydrous sodium sulfate drying filters, filtrate is concentrated into dried, mixed solvent (2: 1, volume ratio) recrystallization with 200ml ethyl acetate and normal hexane obtains white solid 8.6g (yield 95.5%), and it is 99.7% that HPLC detects purity.
1Identical among H-NMR data and the embodiment 1.
Embodiment 6
1g N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE (3.26mmol) is joined in the 500ml four-hole boiling flask, the 10%Pd/C that adds 0.1g again, add the 50ml ethyl acetate, stir and add 1.0g (15.9mmol) ammonium formiate and 1.0g (7.0mmol) anhydrous sodium sulphate down, be warming up to 60 ℃, reacted 4 hours.TLC follows the tracks of reaction, after reacting completely, is cooled to room temperature, filtered and recycled palladium charcoal.Water (10ml * 2) wash filtrate, anhydrous sodium sulfate drying filters, filtrate is concentrated into dried, mixed solvent (9: 1, volume ratio) recrystallization with 30ml ethyl acetate and normal hexane obtains white solid 0.7g (yield 77.6%), and it is 99.1% that HPLC detects purity.
1Identical among H-NMR data and the embodiment 1.
Claims (10)
1. the preparation method of a N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is characterized in that, comprises the steps:
(a) in esters solvent, under the effect of going back original reagent that is selected from palladium charcoal/ammonium formiate, palladium charcoal/formic acid or palladium charcoal/ammonium formiate/formic acid, N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is reduced;
(b) collection obtains N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE from reaction solution.
2. method according to claim 1 is characterized in that, the described original reagent of going back is selected from 10% palladium charcoal/ammonium formiate.
3. method according to claim 1 is characterized in that, also adds anhydrous sodium sulphate in step (a).
4. method according to claim 2 is characterized in that, is benchmark in the weight of N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE, and the weight of described 10% palladium charcoal is 2%～10%.
5. method according to claim 2 is characterized in that, the mol ratio of ammonium formiate and N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE is 3～4.5: 1, more preferably 3～3.5: 1.
6. method according to claim 1 is characterized in that described esters solvent is selected from methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butylacetate, isobutyl acetate, ethyl acetate.
7. method according to claim 1 is characterized in that, the temperature of reaction of step (a) is 60～85 ℃, and the reaction times is 2～6 hours.
8. method according to claim 1, it is characterized in that, step (a) specifically describes: in ethyl acetate solvent, add 1 normal N-(5-nitro-2-aminomethyl phenyl) 4-(3-pyridyl)-2-PYRIMITHAMINE, the 10% palladium charcoal of 2 weight %～10 weight %, 3～3.5 normal ammonium formiates, 1～2 normal anhydrous sodium sulphate, be warming up to 70～80 ℃, reacted 2～3 hours, wherein the weight of 10% palladium charcoal is benchmark for the weight in N-(5-nitro-2-aminomethyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE.
9. according to each described method in the claim 1～7, it is characterized in that step (b) specifically describes and is: be cooled to room temperature, filter; Wash filtrate with water, filtrate is concentrated into dried, obtains N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-PYRIMITHAMINE with the mixed solvent recrystallization of ethyl acetate and normal hexane.
10. method according to claim 8 is characterized in that, the volume ratio of described recrystallization solvent ethyl acetate and normal hexane is 1: 1～9: 1, preferred 1: 1～2: 1.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250062A (en) * | 2010-05-19 | 2011-11-23 | 江苏豪森药业股份有限公司 | Preparation method of imatinib mesilate intermediate |
| CN110003129A (en) * | 2019-04-18 | 2019-07-12 | 济南立德医药技术有限公司 | A kind of preparation method of zolmitriptan intermediate |
-
2010
- 2010-03-22 CN CN2010101295257A patent/CN102199146A/en active Pending
Non-Patent Citations (3)
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| KARUNAKARAN A. KALESH ET AL.: "Small molecule probes that target Abl kinase", 《CHEM. COMMUN.》 * |
| SIYA RAM ET AL.: "A GENERAL PROCEDURE FOR MILD AND RAPID REDUCTION OF ALIPHATIC AND AROMATIC NITRO COMPOUNDS USING AMMONIUM FORMATE AS A CATALYTIC HYDROGEN TRANSFER AGENT", 《TETRAHEDRON LETTERS》 * |
| SIYA RAM ET AL.: "Ammonium Formate in Organic Synthesis: A Versatile Agent in Catalytic Hydrogen Transfer Reductions", 《SYNTHESIS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102250062A (en) * | 2010-05-19 | 2011-11-23 | 江苏豪森药业股份有限公司 | Preparation method of imatinib mesilate intermediate |
| CN102250062B (en) * | 2010-05-19 | 2015-04-22 | 江苏豪森药业股份有限公司 | Preparation method of imatinib mesilate intermediate |
| CN110003129A (en) * | 2019-04-18 | 2019-07-12 | 济南立德医药技术有限公司 | A kind of preparation method of zolmitriptan intermediate |
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