CN103694227B - Erlotinib derivative and its preparation method and application - Google Patents
Erlotinib derivative and its preparation method and application Download PDFInfo
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Abstract
The present invention relates to a kind of erlotinib derivative and preparation method thereof, and prepare the application in antitumor drug.The invention provides a kind of erlotinib derivative with antitumour activity newly, carry out triazolyl to erlotinib and derive, contribute to improving its anti-tumor activity, can be applicable to prepare in antitumor drug, to finding, new antitumor drug is significant; The present invention adopt preparation method have simply be easy to realize, productive rate high.
Description
Technical field
The present invention relates to a kind of erlotinib derivative and preparation method thereof, and prepare the application in 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 GenetechOSIRoche 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 Locally Advanced to the failure of at least one chemotherapy regimen or Metastatic Nsclc NSCLC.Erlotinib is epidermal growth factor recipient tyrosine kinase (epidermalgrowthfactorreceptortyrosinekinase, EGFR-TK) inhibitor, it optionally can block Human epidermal growth factor receptor, suppress EGFR Tyrosylprotein kinase and reduce the autophosphorylation of EGFR, thus cause Growth of Cells to stop and apoptosis, to the phosphate cpd of the tumour cell of EGFR overexpression, there is obvious inhibitor effect.The expression of all right induced cell cycle arrestin P27 of erlotinib, makes cancer cells block, and then cancer cell specific induction of apoptosis.Although its clinical effectiveness is more satisfactory, still there is certain resistance, toxic side effect, therefore its structure is modified, transform and be still an important job.
And 1,2,3-triazole compounds is from finding the attention enjoying pharmaceutical chemistry and biochemist so far always, years of researches show, this compounds, because the structure of its uniqueness and chemical property, has broad application prospects at numerous areas such as organometallic chemistry, pharmaceutical chemistry and materials chemistries.Particularly in pharmaceutical chemistry, such as anti HIV-1 virus, antitumor and control the metabolic balance of the potassium relevant with cardiovascular disorder, while they are also successfully applied in weedicide, antifungal drug etc.
The present invention is based on above-mentioned research, carry out triazolyl to erlotinib and derive, contribute to improving its anti-tumor activity, to finding, new antitumor drug is significant.
Summary of the invention
The object of the present invention is to provide a kind of erlotinib derivative with antitumour activity feature newly and preparation method thereof and preparing the application in antitumor drug.
The invention provides the erlotinib derivative of a kind of structural formula as shown in (I):
Wherein, R
1for the one in hydrogen base, methyl, methoxyl group, amino, chloro, nitro, phenyl, R
2for benzyl or ethyl methyl ether base.
Preferably, described R
1for the one in hydrogen base, methyl, chloro, R
2for ethyl methyl ether base.
Preferably, described R
1for hydrogen base, R
2for benzyl.
Present invention also offers the preparation method of the erlotinib derivative of a kind of structural formula as shown in (I), comprise the steps:
(1) 3-aminophenylacetylene of structural formula as shown in (II) and 4-chloro-6,7-bis-(2-replacement) quinazoline shown in (III), in alcoholic solution, at 20 DEG C ~ 70 DEG C temperature, stirring reaction prepares the erlotinib intermediate shown in formula (IV); Wherein, the mol ratio of described 3-aminophenylacetylene, 4-chloro-6,7-bis-(2-replacement) quinazoline is 1.0:0.95 ~ 1.25;
(2) in alcoholic solution, add the aryl azide of structural formula as shown in (V) and the erlotinib intermediate of structural formula as shown in (IV), under cupric sulfate pentahydrate and the effect of VC sodium, be stirred at 20 DEG C ~ 70 DEG C temperature 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:
The erlotinib intermediate prepared such as formula shown in (IV) can be reacted in alcoholic solution by 3-aminophenylacetylene as shown in the formula (II) and 4-as shown in the formula (III) chloro-6,7-bis-(2-replacement) quinazoline; Then at alcoholic solution, add aryl azide as shown in formula V and such as formula the erlotinib intermediate shown in (IV), a certain amount of cupric sulfate pentahydrate and VC sodium, stirring reaction at 20 DEG C ~ 70 DEG C temperature, the reaction of TLC tracing detection is added to reacting completely in alcoholic solution, in preparation method of the present invention, the comparatively crucially 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 DEG C, and described reaction adopts TLC tracing detection.
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 terminate after through extraction, dry, filter be spin-dried for, recrystallization obtains the product after purifying.
Preferably, the preparation method of erlotinib derivative comprises the steps:
(1) in methyl alcohol, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 DEG C 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, be stirred at 30 DEG C of temperature 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, filter after being spin-dried for, obtain target product with ethyl alcohol recrystallization.
Preferably, the preparation method of erlotinib derivative comprises the steps:
(1) in ethanol, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1:1,7-bis-(2-methoxy ethoxy) quinazoline, at 70 DEG C 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, be stirred at 40 DEG C of temperature and react completely; Wherein, the volume ratio of the described trimethyl carbinol and water is 1:1, 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, filter after being spin-dried for, obtain target product with ethyl alcohol recrystallization.
The erlotinib derivative of structural formula as shown in (I) is preparing the application in antitumor drug.
Structural formula involved in the present invention erlotinib derivative as shown in (I), it can also be prepared by following method:
In alcoholic solution, add the aryl azide as shown in formula V, 3-aminophenylacetylene as shown in the formula (II), the cupric sulfate pentahydrate of catalytic amount and VC sodium, stirring reaction at 20 DEG C ~ 70 DEG C temperature, the reaction of TLC tracing detection is to reacting completely, and reaction solution separating treatment obtains such as formula triazole compounds intermediate (VI) Suo Shi; Then chloro-6,7-bis-(2-replaces) quinazoline reacts the erlotinib derivative prepared as shown in the formula (I) in alcoholic solution with described 4-as shown in the formula (III).
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., VC sodium purchased from Henan Province so Chemical Co., Ltd., aziminobenzene, 3-aminophenylacetylene, 4-chloro-6,7-bis-(2-replacement) quinazoline is purchased from Hangzhou Ke Ju Chemical Co., Ltd..
In addition, the present invention also can directly from being raw material such 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 DEG C ~ 70 DEG C 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 proliferative conditions 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 erlotinib derivative with antitumour activity newly, carry out triazolyl to erlotinib and derive, contribute to improving its anti-tumor activity, can be applicable to prepare in antitumor drug, to finding, new antitumor drug is significant; The present invention adopt preparation method have simply be easy to realize, 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:
The preparation method of the erlotinib derivative of a kind of structural formula as shown in (I-a), comprises the steps:
(1) in methyl alcohol, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 DEG C of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) under certain temperature (20 DEG C), aziminobenzene (II-a) 121mg (1.0mmol), N-(3-acetylene phenyl)-[6 is added successively in single neck flask of 15ml, 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 controls at 20 DEG C, and TLC follows the tracks of reaction to complete;
(3) react end and obtain yellow solution, with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, filter and be spin-dried for obtain yellow solid, obtain faint yellow solid 860mg with ethyl alcohol recrystallization, productive rate is 95%; Mp126-128 DEG C.
Its syntheti c route is as follows:
1HNMR(400MHz,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=7.6Hz,3H),7.51(m,J=7.9Hz,3H),7.79(d,J=9.0Hz,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
The preparation method of the erlotinib derivative of a kind of structural formula as shown in (I-b), comprises the steps:
(1) in methyl alcohol, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 DEG C of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) under certain temperature (30 DEG C), p-methylphenyl nitrine (II-b) 135mg (1.0mmol), N-(3-acetylene phenyl)-[6 is added successively in single neck flask of 15ml, 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 controls at 30 DEG C, and TLC follows the tracks of reaction to complete;
(3) reaction terminates rear dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, and filtration is spin-dried for rear recrystallizing methanol and obtains white solid, and productive rate is 92%; Mp126-128 DEG C.
1HNMR(400MHz,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=7.6Hz,3H),7.56(m,J=.9Hz,3H),7.70(d,J=9.0Hz,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
The preparation method of the erlotinib derivative of a kind of structural formula as shown in (I-c), comprises the steps:
(1) in methyl alcohol, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 DEG C of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-methoxy ethoxy)] quinazoline-4-amine;
(2) under certain temperature (25 DEG C), rubigan nitrine (II-c) 155mg (1.0mmol), N-(3-acetylene phenyl)-[6 is added successively in single neck flask of 15ml, 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 controls at 25 DEG C, and TLC follows the tracks of reaction to complete;
(3) react end and obtain deep yellow solution, with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, filter and be spin-dried for obtain light yellow solid, obtain light yellow solid with ethyl alcohol recrystallization, productive rate is 93%; Mp166-168 DEG C.
Its syntheti c route is as follows:
1HNMR(400MHz,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=7.6Hz,3H),7.56(m,J=.9Hz,3H),7.70(d,J=9.0Hz,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
The preparation method of the erlotinib derivative of a kind of structural formula as shown in (I-d), comprises the steps:
(1) in ethanol, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1:1,7-bis-(2-methoxy ethoxy) quinazoline, at 70 DEG C of temperature, stirring reaction prepares N-(3-acetylene phenyl)-[6,7-bis-(2-benzyloxy)] quinazoline-4-amine;
(2) under certain temperature (40 DEG C), aziminobenzene (II-a) 121mg (1.0mmol), N-(3-acetylene phenyl)-[6 is added successively in single neck flask of 15ml, 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 controls at 40 DEG C, and TLC follows the tracks of reaction to complete;
(3) react end and obtain deep yellow solution, with dichloromethane extraction twice, organic phase anhydrous magnesium sulfate drying, filter and be spin-dried for obtain yellow solid, productive rate is 90%; Mp196-198 DEG C.
Its syntheti c route is as follows:
1HNMR(400MHz,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=7.6Hz,6H),7.56(m,J=.9Hz,4H),7.70(m,J=9.0Hz,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, with human liver cancer cell (BEL-7402) for research object, the growing state of observation of cell under the effect of erlotinib derivative, and the proliferative conditions measuring tumour cell with mtt assay.
Concrete operations are as follows: be inoculated in 96 well culture plates by BEL-7402 tumour cell by certain cell concentration, and cell density is 2 × 104/ml; 37 DEG C, CO
2after spending the night in the incubator of concentration 5%, (with reference to table 1, dosing group adds 10 μ l/ hole respective concentration medicines to sample concentration to add sieved sample, control group adds 10 μ l/ hole PBS), after cultivating 44h, add 10 μ l/ hole MTT and continue to cultivate 4h, dissolve with DMSO, jolt, detect under 570nm microplate reader.
The erlotinib derivative that embodiment 1 ~ 4 obtains is to the half-inhibition concentration IC of 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 the erlotinib derivative synthesized has and suppress BEL-7402(human liver cancer cell by experiment) function of tumour cell, although compare with suppressing the positive drug Cisplatin general at present of this tumour cell, there is a certain distance, but be that control group compares with erlotinib, find that erlotinib derivative is not less than erlotinib for the restraining effect of cancer cells, our the erlotinib derivative of design can be reflected in antitumor cell, there is inhibit feature, there is certain application prospect.
Claims (10)
1. the erlotinib derivative of structural formula as shown in (I):
Wherein, R
1for the one 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
1for the one 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) 3-aminophenylacetylene of structural formula as shown in (II) and 4-chloro-6,7-bis-(2-replacement) quinazoline shown in (III), in alcoholic solution, at 20 DEG C ~ 70 DEG C temperature, stirring reaction prepares the erlotinib intermediate shown in formula (IV); Wherein, the mol ratio of described 3-aminophenylacetylene, 4-chloro-6,7-bis-(2-replacement) quinazoline is 1.0:0.95 ~ 1.25;
(2) in alcoholic solution, add the aryl azide of structural formula as shown in (V) and the erlotinib intermediate of structural formula as shown in (IV), under cupric sulfate pentahydrate and the effect of VC sodium, be stirred at 20 DEG C ~ 70 DEG C temperature 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), and 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 DEG C, and described reaction adopts TLC tracing detection.
6. the preparation method of the erlotinib derivative according to claim 4 or 5, 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: after reaction terminates through extraction, dry, filter be 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, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1.0:1.1,7-bis-(2-methoxy ethoxy) quinazoline, at 50 DEG C 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, be stirred at 30 DEG C of temperature 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, filter after being 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, add 3-aminophenylacetylene and 4-chloro-6 that mol ratio is 1:1,7-bis-(2-methoxy ethoxy) quinazoline, at 70 DEG C 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, be stirred at 40 DEG C of temperature and react completely; Wherein, the volume ratio of the described trimethyl carbinol and water is 1:1, and the mol ratio of 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, filter after being spin-dried for, obtain target product with ethyl alcohol recrystallization.
10. erlotinib derivative described in claim 1 is preparing the application in antitumor drug.
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