CN110317194A - A kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand - Google Patents
A kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand Download PDFInfo
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- CN110317194A CN110317194A CN201910744963.5A CN201910744963A CN110317194A CN 110317194 A CN110317194 A CN 110317194A CN 201910744963 A CN201910744963 A CN 201910744963A CN 110317194 A CN110317194 A CN 110317194A
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- molecular sieve
- buddhist nun
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- catalytic synthesis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The present invention relates to organic synthesis fields, more particularly to a kind of molecular sieve catalytic synthesis uncommon new method for Buddhist nun difficult to understand, N-1- [2- (dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indole -3- base) -2- pyrimidine radicals] -1,2,4- benzene triamines and acrylic acid are raw material, in alcohols solvent, acrylic acid is added, through molecular sieve catalytic, microwave heating is reacted, after reaction, post-treated to obtain difficult to understand wish for Buddhist nun.Reaction condition of the present invention is mild, is convenient for industrialized production, and raw material use is more green, reduces hypertoxic raw material and uses, high income, and reaction is efficient.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular to a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand.
Background technique
AZD9291 is a kind of activation for resistant mutation EGFR, the irreversible EGF-R ELISA network ammonia of the third generation
Acid kinase inhibitor.In April, 2014, Food and Drug Administration (FDA) authorize the title of " breakthrough therapeutic agent "
AZD9291, the medicine category oral class medicine object, and the shortcomings that targeted drug before is improved, hence it is evident that reduce and such as causes abdomen
It rushes down, the targeted drug of the side effects such as fash.
AZD9291 chemical name are as follows: N- { 2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4-
(1- Methyl-1H-indole -3- base) -2- pyrimidine radicals] amino] phenyl } -2- acrylamide, structural formula are as follows:
Aniline Austria is uncommon to replace Buddhist nun's intermediate N1- [2- (dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1-
Methyl-1H-indole -3- base) -2- pyrimidine radicals] -1,2,4- benzene triamine synthesized with 3- chlorpromazine chloride it is difficult to understand uncommon for Buddhist nun N- { 2- [[2- (two
Methylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- Methyl-1H-indole -3- base) -2- pyrimidine radicals] amino] benzene
Base } -2- acrylamide mainly realized by the route of F-C acylation reaction.
A kind of uncommon synthetic method for Buddhist nun difficult to understand is reported in patent WO2013014448A1, F-C is acylated anti-in the route
The reaction equation answered is as follows:
The complicated condition of this method, raw materials used toxicity and volatility are larger, product yield highest 90%, and need in height
It is completed under the conditions of temperature, energy consumption is big, and the process is not environmentally friendly enough, and post-processing difficulty is larger, and not environmentally.
Chinese patent CN104817541A reports a kind of 2- (N, N, N,-trimethyl ethylenediamine base) -4- methoxyl group -5-
T-butyl carbamate aniline is reacted with acryloyl chloride, obtains 2- methoxyl group -4-N, N, N,-trimethyl ethylenediamine base -5- propylene
Amide groups aniline, synthetic route:
The complicated condition of this method, 3- chlorpromazine chloride toxicity used and volatility are larger, price is high, and lead to production cost
Increase, and post-processing difficulty is larger, is not suitable for large-scale industrial production.
Chinese patent CN104910049A, which is reported, a kind of carries out F-C acyl with the fluoro- 4- aminoanisole of 2- and acryloyl chloride
Change reaction, synthetic route:
The complicated condition of this method, 3- chlorpromazine chloride toxicity used and volatility are larger, price is high, and lead to production cost
Increase, and post-processing difficulty is larger, is not suitable for large-scale industrial production.
Summary of the invention
According to above situation, the present invention provides a kind of molecular sieve catalytic synthesis uncommon methods for Buddhist nun difficult to understand, with N-1- [2-
(dimethylamino) ethyl] -5- methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indole -3- base) -2- pyrimidine radicals] -1,2,
4- benzene triamine is raw material with acrylic acid, and in alcohols solvent, through molecular sieve catalytic, microwave heating carries out difficult to understand wish of reaction preparation and replaces
Buddhist nun, this method reaction condition is mild, and raw material use is more green, reduces hypertoxic raw material and uses, and high income is suitble to industry metaplasia
It produces.
The present invention is achieved by the following technical solutions:
A kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand, N-1- [2- (dimethylamino) ethyl] -5- methoxyl group -
N1- methyl-N4- [4- (1- Methyl-1H-indole -3- base) -2- pyrimidine radicals] -1,2,4- benzene triamines and acrylic acid are raw material, in alcohol
In class solvent, acrylic acid is added, through molecular sieve catalytic, microwave heating is reacted, after reaction, post-treated to obtain Ao Xi
For Buddhist nun；
The reaction equation is as follows:
Wherein, the alcohols solvent is one of isopropanol, n-butanol, normal propyl alcohol, isobutanol, n-amyl alcohol；
Wherein, the dosage of the alcohols solvent is 5.0-10.0ml/g, preferable amount 6.0-8.0ml/g；
Wherein, the molecular sieve is one of HY molecular sieve, 13XAPG molecular sieve, 10X molecular sieve, and preferred molecular sieve is
HY molecular sieve, 13XAPG molecular sieve；
Wherein, the dosage of the molecular sieve is 0.001-0.006mol, preferable amount 0.002-0.005mol；
Wherein, the microwave heating is to be reacted using the microwave heating of 2350-2550MHz to 15-45 DEG C, when reaction
Between 3-8h, preferably microwave heating reacted to 20-40 DEG C, preferred reaction time 4-6h.
The beneficial effects of the present invention are: (1) reaction condition is mild, it is convenient for industrialized production；(2) raw material use is greener
Color reduces hypertoxic raw material and uses；(3) high income, reaction are efficient.
Specific embodiment
Here is that the present invention is further described in conjunction with the embodiments.
Embodiment 1
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), HY type molecular sieve (0.44g, 0.002mol), isopropanol (32mL, 7.2ml/g), microwave heating is to 35 DEG C, reaction
4h, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.07g of foamy off-white, yield
81.6%.
Embodiment 2
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), HY type molecular sieve (0.66g, 0.003mol), isopropanol (32mL, 7.2ml/g), microwave heating is to 35 DEG C, reaction
4h, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.88g of foamy off-white, yield
97.9%.
Embodiment 3
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), HY type molecular sieve (0.66g, 0.003mol), isopropanol (32mL, 7.2ml/g), microwave heating is to 30 DEG C, reaction
4h, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.78g of foamy off-white, yield
95.9%.
Embodiment 4
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), HY type molecular sieve (0.66g, 0.003mol), isopropanol (32mL, 7.2ml/g), microwave heating is to 35 DEG C, reaction
5h, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.88g of foamy off-white, yield
97.9%.
Embodiment 5
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), HY type molecular sieve (0.66g, 0.003mmol), isopropanol (30mL, 6.7ml/g), microwave heating is to 35 DEG C, instead
4h is answered, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.85g of foamy off-white, receive
Rate 97.3%.
Embodiment 6
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), 10X type molecular sieve (0.66g, 0.003mmol), isopropanol (32mL, 7.2ml/g), microwave heating is to 35 DEG C, instead
4h is answered, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.86g of foamy off-white, receive
Rate 97.5%.
Embodiment 7
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), HY type molecular sieve (0.66g, 0.003mmol), normal propyl alcohol (32mL, 7.2ml/g), microwave heating is to 35 DEG C, instead
4h is answered, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.83g of foamy off-white, receive
Rate 96.9%.
Embodiment 8
N-2- [[2- (dimethylamino) ethyl] methylamino] -4- methoxyl group -5- [[4- (1- first is added into reaction flask
Base -1H- indol-3-yl) -2- pyrimidine radicals] amino] aniline (4.45g, 0.010mol), be added acrylic acid (0.86g,
0.012mol), HY type molecular sieve (0.66g, 0.003mmol), n-butanol (32mL, 7.2ml/g), microwave heating is to 35 DEG C, instead
4h is answered, dry using anhydrous sodium sulfate, finally revolving, which removes solvent, can be obtained the solid 4.84g of foamy off-white, receive
Rate 97.1%.
Claims (8)
1. a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand, which is characterized in that N-1- [2- (dimethylamino) ethyl] -5-
Methoxyl group-N1- methyl-N4- [4- (1- Methyl-1H-indole -3- base) -2- pyrimidine radicals] -1,2,4- benzene triamines and acrylic acid are original
Material, in alcohols solvent, through molecular sieve catalytic, microwave heating is reacted, after reaction, post-treated to obtain difficult to understand uncommon replace
Buddhist nun；
The reaction equation is as follows:
2. a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand according to claim 1, which is characterized in that the alcohols is molten
Agent is one of isopropanol, n-butanol, normal propyl alcohol, isobutanol, n-amyl alcohol.
3. a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand according to claim 1 or claim 2, which is characterized in that the alcohol
The dosage of class solvent is 5.0-10.0ml/g.
4. a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand according to claim 3, which is characterized in that the alcohols is molten
The dosage of agent is 6.0-8.0ml/g.
5. a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand according to claim 1, which is characterized in that the molecular sieve
For one of HY molecular sieve, 13XAPG molecular sieve, 10X molecular sieve.
6. according to claim 1 or a kind of 5 described molecular sieve catalytic synthesis Austria wish the methods for Buddhist nun, which is characterized in that described point
The dosage of son sieve is 0.001-0.006mol.
7. a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand according to claim 6, which is characterized in that the molecular sieve
Dosage be 0.002-0.005mol.
8. a kind of molecular sieve catalytic synthesis uncommon method for Buddhist nun difficult to understand according to claim 1, which is characterized in that the microwave adds
Heat is reacted for the microwave heating using 2350-2550MHz to 15-45 DEG C, reaction time 3-8h.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358468A (en) * | 2020-11-10 | 2021-02-12 | 德州德药制药有限公司 | Industrial synthesis method of AZD9291 |
| CN112430231A (en) * | 2020-11-06 | 2021-03-02 | 德州德药制药有限公司 | Industrial preparation method of AZD9291 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363603A (en) * | 2011-11-24 | 2012-02-29 | 江苏汉光实业股份有限公司 | Method for preparing 4-acrylamido benzenesulfonic acid sodium salt |
| CN106967050A (en) * | 2017-05-11 | 2017-07-21 | 北京工业大学 | A kind of AZD9291 preparation method |
-
2019
- 2019-08-13 CN CN201910744963.5A patent/CN110317194A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102363603A (en) * | 2011-11-24 | 2012-02-29 | 江苏汉光实业股份有限公司 | Method for preparing 4-acrylamido benzenesulfonic acid sodium salt |
| CN106967050A (en) * | 2017-05-11 | 2017-07-21 | 北京工业大学 | A kind of AZD9291 preparation method |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112430231A (en) * | 2020-11-06 | 2021-03-02 | 德州德药制药有限公司 | Industrial preparation method of AZD9291 |
| CN112358468A (en) * | 2020-11-10 | 2021-02-12 | 德州德药制药有限公司 | Industrial synthesis method of AZD9291 |
| CN112358468B (en) * | 2020-11-10 | 2022-03-22 | 德州德药制药有限公司 | Industrial synthesis method of AZD9291 |
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Application publication date: 20191011 |