CN103694227A - Erlotinib derivative, and preparation method and application thereof - Google Patents
Erlotinib derivative, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to an erlotinib derivative, a preparation method and application thereof in preparation of antineoplastic drugs. The new erlotinib derivative having anticancer activity, provided by the invention, is characterized by performing triazolyl derivation on erlotinib, thus being beneficial to enhance the antineoplastic activity; the erlotinib derivative can be used in preparation of antineoplastic drugs, and is of far reaching importance in discovery of new antineoplastic drugs; and the preparation method adopted by the invention is simple and easy to implement, and has the characteristics of high yield and the like.
Description
Technical field
The present invention relates to a kind of erlotinib derivative and preparation method thereof, and the application in preparing antitumor drug.
Background technology
Erlotinib, English name Erlotinib, Chinese another name N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine, by 3 company's joint developments such as Genetech OSI Roche Roche Holding Ags, a kind of cancer treatment drugs of being produced by Roche is the original new drug being used for the treatment of the local late period of at least one chemotherapy regimen failure or Metastatic Nsclc NSCLC.Erlotinib is epidermal growth factor recipient tyrosine kinase (epidermal growth factor receptor tyrosine kinase, EGFR-TK) inhibitor, it can optionally block Human epidermal growth factor receptor, suppress EGFR Tyrosylprotein kinase and reduce the autophosphorylation of EGFR, thereby cause Growth of Cells to stop and apoptosis, the phosphate cpd of the tumour cell of EGFR overexpression is had to obvious inhibitor effect.The expression of all right inducing cell cycle arrestin P27 of erlotinib, makes cancer cells retardance, and then cancer cell specific induction of apoptosis.Although its clinical effectiveness is more satisfactory, still exist certain resistance, toxic side effect, therefore the important work that is still is modified, transformed to its structure.
And 1,2,3-triazole compounds is from find to enjoy so far pharmaceutical chemistry and biological chemistry worker's attention always, years of researches show, this compounds is because its unique structure and chemical property have broad application prospects at numerous areas such as organometallic chemistry, pharmaceutical chemistry and materials chemistries.Particularly aspect pharmaceutical chemistry, the metabolic balance of anti HIV-1 virus, the antitumor and potassium that control is relevant with cardiovascular disorder for example, they are also successfully applied at aspects such as weedicide, antifungal drugs simultaneously.
The present invention is based on above-mentioned research, erlotinib is carried out to triazolyl and derive, contribute to improve its anti-tumor activity, significant to finding new antitumor drug.
Summary of the invention
The object of the present invention is to provide a kind of new erlotinib derivative with antitumour activity feature and preparation method thereof and the application in preparing antitumor drug.
The invention provides the erlotinib derivative of a kind of structural formula as shown in (I):
Wherein, R
1a kind of in hydrogen base, methyl, methoxyl group, amino, chloro, nitro, phenyl, R
2for benzyl or ethyl methyl ether base.
Preferably, described R
1a kind of in hydrogen base, methyl, chloro, R
2for ethyl methyl ether base.
Preferably, described R
1for hydrogen base, R
2for benzyl.
The present invention also provides the preparation method of the erlotinib derivative of a kind of structural formula as shown in (I), comprises the steps:
(1) the m-aminophenyl acetylene of structural formula as shown in (II) and (III) shown in 4-chloro-6,7-bis-(2-replacement) quinazoline, in alcoholic solution, at 20 ℃～70 ℃ temperature, stirring reaction prepares the erlotinib intermediate shown in formula (IV); Wherein, described m-aminophenyl acetylene, 4-are chloro-6, and the mol ratio of 7-bis-(2-replacement) quinazoline is 1.0:0.95～1.25;
(2) in alcoholic solution, add aryl azide and the structural formula erlotinib intermediate as (IV) as shown in of structural formula as shown in (V), under cupric sulfate pentahydrate and the effect of VC sodium, at 20 ℃～70 ℃ temperature, be stirred to and react completely; Wherein, the mol ratio of described aryl azide, erlotinib intermediate, cupric sulfate pentahydrate, VC sodium is 1.0:0.95～1.15:0.95～1.35:1.95～2.85;
In step (1), (2), described alcoholic solution is one of following: methyl alcohol, ethanol, Virahol, the trimethyl carbinol or its corresponding alcohol solution, wherein, in alcohol solution, the volume ratio of alcohol and water is 1.0:0.5～2.0.
Its syntheti c route is as follows:
Can be chloro-6 by m-aminophenyl acetylene as shown in the formula (II) and 4-as shown in the formula (III), 7-bis-(2-replacement) quinazoline reacts the erlotinib intermediate preparing suc as formula shown in (IV) in alcoholic solution; Then at alcoholic solution, add aryl azide as shown in formula V and suc as formula the erlotinib intermediate shown in (IV), a certain amount of cupric sulfate pentahydrate and VC sodium, stirring reaction at 20 ℃～70 ℃ temperature, in alcoholic solution, add TLC to follow the tracks of detection reaction to reacting completely, in preparation method of the present invention, comparatively crucial is the selection of reaction solvent alcohol.
Preferably, in step (2), described alcoholic solution is butanol/water solution, and wherein the volume ratio of the trimethyl carbinol and water is 1:1; Described temperature of reaction is 20～40 ℃, and described reaction adopts TLC to follow the tracks of and detects.
Preferably, the amount of substance of described aryl azide, erlotinib intermediate, cupric sulfate pentahydrate, VC sodium is than being 1.0:1.0:1.08:2.14.
Preferably, reaction finishes by extraction, dry, filtration is spin-dried for, recrystallization obtains the product after purifying.
Preferably, the preparation method of erlotinib derivative comprises the steps:
(1) in methyl alcohol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) in methyl alcohol, add aziminobenzene and N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine, under cupric sulfate pentahydrate and the effect of VC sodium, at 30 ℃ of temperature, be stirred to and react completely; Wherein, the mol ratio of described aziminobenzene, N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine, cupric sulfate pentahydrate, VC sodium is 1.0:1.0:1.08:2.14;
(3) aftertreatment: with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, after filtration is spin-dried for, obtain target product with ethyl alcohol recrystallization.
Preferably, the preparation method of erlotinib derivative comprises the steps:
(1) in ethanol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1:1,7-bis-(2-methoxy ethoxy) quinazoline, at 70 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-benzyloxy)] quinazoline-4-amine;
(2) in butanol/water solution, add aziminobenzene and N-(3-acetylene phenyl)-[6,7-bis-(benzyloxy)] quinazoline-4-amine, under cupric sulfate pentahydrate and the effect of VC sodium, at 40 ℃ of temperature, be stirred to and react completely; Wherein, the volume ratio of the described trimethyl carbinol and water is 1:1, and the mol ratio of base aziminobenzene, N-(3-acetylene phenyl)-[6,7-bis-(benzyloxy)] quinazoline-4-amine, cupric sulfate pentahydrate, VC sodium is 1.0:1.0:1.08:2.14;
(3) aftertreatment: with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, after filtration is spin-dried for, obtain target product with ethyl alcohol recrystallization.
The application of the erlotinib derivative of structural formula as shown in (I) in preparing antitumor drug.
Structural formula involved in the present invention erlotinib derivative as shown in (I), it can also prepare by following method:
In alcoholic solution, add the aryl azide as shown in formula V, m-aminophenyl acetylene as shown in the formula (II), the cupric sulfate pentahydrate of catalytic amount and VC sodium, stirring reaction at 20 ℃～70 ℃ temperature, TLC follows the tracks of detection reaction to reacting completely, and reaction solution separating treatment obtains suc as formula triazole compounds intermediate shown in (VI); Then chloro-6 with described 4-as shown in the formula (III), 7-bis-(2-replacement) quinazoline reacts the erlotinib derivative preparing as shown in the formula (I) in alcoholic solution.
Involved in the present invention to the purity grade of alcohol be more than chemical pure (CP), cupric sulfate pentahydrate is purchased from blue sky, Huai’an Chemical Co., Ltd., so VC sodium is purchased from Henan Province Chemical Co., Ltd., aziminobenzene, m-aminophenyl acetylene, 4-are chloro-6, and 7-bis-(2-replacement) quinazoline is purchased from Hangzhou Ke Ju Chemical Co., Ltd..
In addition, the present invention also can be directly from being raw material suc as formula the erlotinib intermediate shown in (IV) and aziminobenzene, in alcoholic solution, a certain amount of cupric sulfate pentahydrate and VC sodium, at 20 ℃～70 ℃ temperature, stirring reaction prepares erlotinib derivative as shown in the formula (I).Erlotinib intermediate shown in its Chinese style (IV) can be purchased from Hangzhou Ke Ju Chemical Co., Ltd..
The erlotinib derivative of preparation is applied to human liver cancer cell (BEL-7402), carries out antitumour activity test, measure the propagation situation of above-mentioned tumour cell with mtt assay, experimental result shows that it has certain restraining effect to BEL-7402 cell.
Erlotinib derivative of the present invention can be applicable to prepare in antitumor drug.
The invention provides a kind of new erlotinib derivative with antitumour activity, erlotinib is carried out to triazolyl and derive, contribute to improve its anti-tumor activity, can be applicable to prepare in antitumor drug, significant to finding new antitumor drug; The preparation method that the present invention adopts has the realization of being simply easy to, productive rate high.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
Embodiment 1
The preparation of erlotinib derivative I-a:
A preparation method for the erlotinib derivative of structural formula as shown in (I-a), comprises the steps:
(1) in methyl alcohol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) under certain temperature (20 ℃), in single neck flask of 15ml, add successively aziminobenzene (II-a) 121mg (1.0mmol), N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine (III-a) 393mg (1.0mmol), trimethyl carbinol 10ml, cupric sulfate pentahydrate (270mg, 1.08mmol), VC sodium (424.5mg, 2.14mmol), open magnetic stirring apparatus, temperature is controlled at 20 ℃, and TLC follows the tracks of reaction to complete;
(3) reaction finishes to obtain yellow solution, with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, filters and is spin-dried for to obtain yellow solid, with ethyl alcohol recrystallization, obtains faint yellow solid 860 mg, and productive rate is 95%; Mp 126-128 ℃.
Its syntheti c route is as follows:
1H NMR(400 MHz, DMSO)δ: 3.37 (s, 6H), 3.78-3.80 (m, 4H), 4.30 (s, 1H), 4.33-4.35 (m, 2H), 4.38-4.40 (m, 2H), 7.39 (s, 1H), 7.42 (m, J =7.6 Hz, 3H), 7.51 (m, J=7.9 Hz, 3H), 7.79 (d, J = 9.0 Hz, 1H), 7.88 (s, 1H), 8.40 (s, 1H), 8.86 (s, 1H), 11.46 (s, 1H)。
Embodiment 2
The preparation of erlotinib derivative I-b
A preparation method for the erlotinib derivative of structural formula as shown in (I-b), comprises the steps:
(1) in methyl alcohol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) under certain temperature (30 ℃), in single neck flask of 15ml, add successively p-methylphenyl nitrine (II-b) 135mg (1.0mmol), N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine (III-b) 393mg (1.0mmol), Virahol 5ml, distilled water 5ml, cupric sulfate pentahydrate (270mg, 1.08mmol), VC sodium (424.5mg, 2.14mmol), open magnetic stirring apparatus, temperature is controlled at 30 ℃, and TLC follows the tracks of reaction to complete;
(3) reaction finish rear with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, filtration is spin-dried for and by recrystallizing methanol, obtains white solid afterwards, productive rate is 92%; Mp 126-128 ℃.
1H NMR(400 MHz, DMSO)δ: 3.37 (s, 6H), 3.53 (s, 3H), 3.78-3.82 (m, 4H), 4.34 (s, 1H), 4.33-4.36 (m, 2H), 4.38-4.43 (m, 2H), 7.34 (s, 1H), 7.42 (m, J = 7.6 Hz, 3H), 7.56 (m, J = .9 Hz, 3H), 7.70 (d, J = 9.0 Hz, 1H), 7.82 (s, 1H), 8.45(s, 1H), 8.87 (s, 1H), 11.43 (s, 1H)。
Embodiment 3
The preparation of erlotinib derivative I-c
A preparation method for the erlotinib derivative of structural formula as shown in (I-c), comprises the steps:
(1) in methyl alcohol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) under certain temperature (25 ℃), in single neck flask of 15ml, add successively rubigan nitrine (II-c) 155mg (1.0mmol), N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine (III-c) 393mg (1.0mmol), methyl alcohol 10ml, cupric sulfate pentahydrate (270mg, 1.08mmol), VC sodium (424.5mg, 2.14mmol), open magnetic stirring apparatus, temperature is controlled at 25 ℃, and TLC follows the tracks of reaction to complete;
(3) reaction finishes to obtain deep yellow solution, with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, filters and is spin-dried for to obtain light yellow solid, with ethyl alcohol recrystallization, obtains light yellow solid, and productive rate is 93%; Mp 166-168 ℃.
Its syntheti c route is as follows:
1H NMR(400 MHz, DMSO)δ: 3.35 (s, 6H), 3.78-3.85 (m, 4H), 4.35 (s, 1H), 4.33-4.37(m, 2H), 4.37-4.43 (m, 2H), 7.34 (s, 1H), 7.42 (m, J = 7.6 Hz, 3H), 7.56 (m, J = .9 Hz, 3H), 7.70 (d, J = 9.0 Hz, 1H), 7.82 (s, 1H), 8.45(s, 1H), 8.85 (s, 1H), 11.44 (s, 1H)。
Embodiment 4
The preparation of erlotinib derivative I-d
A preparation method for the erlotinib derivative of structural formula as shown in (I-d), comprises the steps:
(1) in ethanol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1:1,7-bis-(2-methoxy ethoxy) quinazoline, at 70 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-benzyloxy)] quinazoline-4-amine;
(2) under certain temperature (40 ℃), in single neck flask of 15ml, add successively aziminobenzene (II-a) 121mg (1.0 mmol), N-(3-acetylene phenyl)-[6,7-bis-(benzyloxy)] quinazoline-4-amine (III-d) 457mg (1.0mmol), trimethyl carbinol 5ml, distilled water 5mL, cupric sulfate pentahydrate (270mg, 1.08mmol), VC sodium (424.5mg, 2.14mmol), open magnetic stirring apparatus, temperature is controlled at 40 ℃, and TLC follows the tracks of reaction to complete;
(3) reaction finishes to obtain deep yellow solution, with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, filters and is spin-dried for to obtain yellow solid, and productive rate is 90%; Mp 196-198 ℃.
Its syntheti c route is as follows:
[0031] 1H NMR(400 MHz, DMSO)δ: 3.37 (s, 6H), 3.53 (s, 3H), 3.78-3.82 (m, 4H), 4.34 (s, 1H), 4.33-4.36 (m, 2H), 4.38-4.43 (m, 2H), 7.34 (s, 1H), 7.42 (m, J = 7.6 Hz, 6H), 7.56 (m, J = .9 Hz, 4H), 7.70 (m, J = 9.0 Hz, 4H), 7.82 (s, 1H), 8.45(s, 1H), 8.85 (s, 1H), 11.42 (s, 1H)。
Biological activity test:
For the biologic activity of this compound, the human liver cancer cell (BEL-7402) of take is research object, the growing state of observation of cell under the effect of erlotinib derivative, and with mtt assay, measure the propagation situation of tumour cell.
Concrete operations are as follows: BEL-7402 tumour cell is inoculated in 96 well culture plates by certain cell concentration, and cell density is 2 * 104/ml; 37 ℃, CO
2after spending the night in the incubator of concentration 5%, (sample concentration is with reference to table 1 to add sieved sample, dosing group adds 10 μ l/ hole respective concentration medicines, control group adds 10 μ l/ hole PBS), cultivate after 44h, add 10 μ l/ hole MTT to continue to cultivate 4h, with DMSO, dissolve, jolt, under 570nm microplate reader, detect.
The half-inhibition concentration IC of the erlotinib derivative that embodiment 1～4 makes to BEL-7402 cell (human liver cancer cell) test experiments
50, and control group positive drug Cisplatin, erlotinib are as shown in table 1 to BEL-7402 cell (human liver cancer cell) test result.
Table 1
We find that synthetic erlotinib derivative has and suppress BEL-7402(human liver cancer cell by experiment) function of tumour cell, although with the current general positive drug Cisplatin comparison that suppresses this tumour cell, there is a certain distance, but the erlotinib of take compares as control group, find erlotinib derivative for the restraining effect of cancer cells and be not less than erlotinib, can reflect our the erlotinib derivative of design and have inhibit feature aspect antitumor cell, there is certain application prospect.
Claims (10)
1. the erlotinib derivative of structural formula as shown in (I):
Wherein, R
1a kind of in hydrogen base, methyl, methoxyl group, amino, chloro, nitro, phenyl, R
2for benzyl or ethyl methyl ether base.
2. erlotinib derivative according to claim 1, is characterized in that: described R
1a kind of in hydrogen base, methyl, chloro, R
2for ethyl methyl ether base.
3. erlotinib derivative according to claim 1, is characterized in that: described R
1for hydrogen base, R
2for benzyl.
4. the preparation method of erlotinib derivative described in claim 1, is characterized in that comprising the steps:
(1) the m-aminophenyl acetylene of structural formula as shown in (II) and (III) shown in 4-chloro-6,7-bis-(2-replacement) quinazoline, in alcoholic solution, at 20 ℃～70 ℃ temperature, stirring reaction prepares the erlotinib intermediate shown in formula (IV); Wherein, described m-aminophenyl acetylene, 4-are chloro-6, and the mol ratio of 7-bis-(2-replacement) quinazoline is 1.0:0.95～1.25;
(2) in alcoholic solution, add aryl azide and the structural formula erlotinib intermediate as (IV) as shown in of structural formula as shown in (V), under cupric sulfate pentahydrate and the effect of VC sodium, at 20 ℃～70 ℃ temperature, be stirred to and react completely; Wherein, the mol ratio of described aryl azide, erlotinib intermediate, cupric sulfate pentahydrate, VC sodium is 1.0:0.95～1.15:0.95～1.35:1.95～2.85;
In step (1), (2), described alcoholic solution is one of following: methyl alcohol, ethanol, Virahol, the trimethyl carbinol or its corresponding alcohol solution, wherein, in alcohol solution, the volume ratio of alcohol and water is 1.0:0.5～2.0.
5. the preparation method of erlotinib derivative according to claim 4, is characterized in that: in step (2), described alcoholic solution is butanol/water solution, and wherein the volume ratio of the trimethyl carbinol and water is 1:1; Described temperature of reaction is 20～40 ℃, and described reaction adopts TLC to follow the tracks of and detects.
6. according to the preparation method of the erlotinib derivative described in claim 4 or 5, it is characterized in that: the mol ratio of described aryl azide, erlotinib intermediate, cupric sulfate pentahydrate, VC sodium is 1.0:1.0:1.08:2.14.
7. the preparation method of erlotinib derivative according to claim 4, is characterized in that: reaction finishes by extraction, dry, filtration is spin-dried for, recrystallization obtains the product after purifying.
8. the preparation method of erlotinib derivative according to claim 4, is characterized in that comprising the steps:
(1) in methyl alcohol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) in methyl alcohol, add aziminobenzene and N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine, under cupric sulfate pentahydrate and the effect of VC sodium, at 30 ℃ of temperature, be stirred to and react completely; Wherein, the mol ratio of described aziminobenzene, N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine, cupric sulfate pentahydrate, VC sodium is 1.0:1.0:1.08:2.14;
(3) aftertreatment: with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, after filtration is spin-dried for, obtain target product with ethyl alcohol recrystallization.
9. the preparation method of erlotinib derivative according to claim 4, is characterized in that comprising the steps:
(1) in ethanol, adding mol ratio is m-aminophenyl acetylene and the 4-chloro-6 of 1:1,7-bis-(2-methoxy ethoxy) quinazoline, at 70 ℃ of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-benzyloxy)] quinazoline-4-amine;
(2) in butanol/water solution, add aziminobenzene and N-(3-acetylene phenyl)-[6,7-bis-(benzyloxy)] quinazoline-4-amine, under cupric sulfate pentahydrate and the effect of VC sodium, at 40 ℃ of temperature, be stirred to and react completely; Wherein, the volume ratio of the described trimethyl carbinol and water is 1:1, and the mol ratio of base aziminobenzene, N-(3-acetylene phenyl)-[6,7-bis-(benzyloxy)] quinazoline-4-amine, cupric sulfate pentahydrate, VC sodium is 1.0:1.0:1.08:2.14;
(3) aftertreatment: with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, after filtration is spin-dried for, obtain target product with ethyl alcohol recrystallization.
10. the application of erlotinib derivative in preparing antitumor drug described in claim 1.
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| CN104817542A (en) * | 2015-03-16 | 2015-08-05 | 南方医科大学南方医院 | EGFR positron tracer, preparation method and application thereof |
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| CN106632271A (en) * | 2016-11-18 | 2017-05-10 | 河南师范大学 | Erlotinib derivative with antitumor activity, and preparation method and application thereof |
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| CN113493443A (en) * | 2020-04-21 | 2021-10-12 | 侯延生 | Erlotinib derivative with killing performance on wild lung cancer tumor cells and preparation method thereof |
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