CN104945332A - Preparation method of erlotinib - Google Patents
Preparation method of erlotinib Download PDFInfo
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- CN104945332A CN104945332A CN201410127452.6A CN201410127452A CN104945332A CN 104945332 A CN104945332 A CN 104945332A CN 201410127452 A CN201410127452 A CN 201410127452A CN 104945332 A CN104945332 A CN 104945332A
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- erlotinib
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- methoxy ethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
Abstract
The invention discloses a preparation method of erlotinib and belongs to the technical field of medicament preparation. In the preparation method, 4,5-di(2-methoxylethoxy)-2-nitrobenzonitrile is used as a raw material and is subjected to reduction and hydrolysis to obtain an intermediate namely 2-amino-4,5-di(2-methoxylethoxy) benzamide which is subjected to cyclization with triethyl orthoformate directly to obtain an erlotinib key intermediate namely 6,7-di(2-methoxylethoxy)-3H-quinazoline-4-one, and a chlorinated product of quinazoline reacts with aminophenylacetylene to obtain erlotinib. By adopting the preparation method disclosed by the invention, the defects that an expensive catalyst is used by nitryl reduction in the conventional synthetic method and the temperature during cyclization is relatively high are overcome, a process with a formamidine intermediate is also avoided, the reaction step is shortened, the reaction cost is reduced, and the yield is improved. Moreover, all reaction conditions in the preparation method are very mild, so that the preparation method is particularly suitable for industrial production.
Description
Technical field
The invention belongs to field of medicine preparing technology, particularly relate to a kind of preparation method of erlotinib.
Background technology
Erlotinib (Erlotinib), commodity are called Erlotinib (Tarceva), are a kind of Urogastron EGFR Tyrosylprotein kinase type small molecular inhibitor cancer therapy drugs of Osi Pharm Inc. of U.S. research and development.Within 2004, first in U.S.'s listing, be mainly used in treating nonsmall-cell lung cancer.The chemical name of erlotinib is N-(3-acetylene phenyl)-6,7-bis-(2-methoxy ethoxy)-4-quinazoline amine, mechanism of action is combined with substrate competition to suppress EGFR phosphorylation in cell, block the transduction of tumour cell signal, thus the growth of inhibition tumor cell, induce it dead.The structure of erlotinib is such as formula shown in V.
In erlotinib synthetic method, key step relates to the synthesis of key intermediate 6,7-pairs-(2-methoxy ethoxy)-3H-quinazoline-4-one.In prior art, have the bibliographical information synthetic method of this intermediate, in these methods, main Problems existing is that nitrated productive rate and purity are lower, and nitroreduction uses expensive catalyst, and during cyclization, temperature is more high.These factors have impact on productive rate and the purity of erlotinib, are unfavorable for suitability for industrialized production.
For the problems referred to above, bibliographical information is also had to adopt 4, two (2-the methoxy ethoxy)-2-nitrobenzonitrile of 5-is raw material, through palladium charcoal/hydrazine hydrate reduction nitro while, cyan-hydrolysis obtains 4, two (2-the methoxy ethoxy)-2-aminobenzamide intermediate of 5-, this intermediate and DMF-DMA addition obtain carbonamidine intermediate, then obtain erlotinib key intermediate 6,7-pairs-(2-methoxy ethoxy)-3H-quinazoline-4-one through cyclization.Synthetic route is as follows:
The method synthesis 6,7-pair-(2-methoxy ethoxy) is though-3H-quinazoline-4-one can carry out suitability for industrialized production, and cyclization need through carbonamidine intermediate, and reactions steps is long, adds reaction cost, also affects the yield of erlotinib simultaneously.
Summary of the invention
Based on this, the object of the invention is to the defect overcoming prior art, provide a kind of preparation method of erlotinib, the method has the advantages that building-up reactions step is short, cost is low and productive rate is high.
For achieving the above object, the present invention takes following technical scheme:
A preparation method for erlotinib, comprises the following steps:
1) with 4,5-bis-(2-methoxy ethoxy)-2-p-nitrile for raw material, under the effect of reductive agent, through reduction, hydrolysis reaction obtains 2-amido-4,5-bis-(2-methoxy ethoxy) benzamide;
2) 2-amido-4,5-bis-(2-methoxy ethoxy) benzamide above-mentioned steps obtained and triethyl orthoformate react under lewis acidic catalysis, directly close ring and obtain intermediate 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-one;
3) 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-ones above-mentioned steps obtained and phosphorus oxychloride are reacted, and obtain 6,7-bis-(2-methoxy ethoxy)-quinazoline-4-chlorine;
4) 6,7-bis-(2-methoxy ethoxy)-quinazoline-4-chlorine above-mentioned steps obtained and an amido phenylacetylene react, and obtain erlotinib.
The preparation method of erlotinib of the present invention, with 4,5-bis-(2-methoxy ethoxy)-2-p-nitrile is raw material, through reduction, be hydrolyzed intermediate 2-amido-4,5-bis-(2-methoxy ethoxy) benzamide that obtains directly and triethyl orthoformate close ring and obtain erlotinib key intermediate 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-one, chloro-product and the amido phenylacetylene of this quinazoline react, and obtain erlotinib.This preparation method avoids, through carbonamidine intermediate, shortening reactions steps, reducing reaction cost, and improve productive rate.
Wherein in some embodiments, in step 1), reaction solvent is water, water-dioxane or water-ethanol; Reductive agent is V-Brite B, iron, zinc, palladium carbon or Raney Ni-hydrazine hydrate; Temperature of reaction is 0 DEG C-40 DEG C.Wherein, Raney Ni is Raney's nickel, is a kind of machine metallic compound as hydrogen activity catalytic reducer; Above-mentioned water-dioxane represents the mixed solvent of water and dioxane; Equally, water-ethanol represents the mixed solvent of water and ethanol; Raney Ni-hydrazine hydrate represents the mixing reductive agent of Raney Ni and hydrazine hydrate.Adopt above-mentioned processing condition, overcome nitroreduction in prior synthesizing method and use expensive catalyst, and temperature more high defect during reaction.
Wherein in some embodiments, in step 1), reaction solvent is water; Reductive agent is Raney Ni-hydrazine hydrate; Temperature of reaction is 20 DEG C-40 DEG C.
Wherein in some embodiments, step 2) in, described Lewis acid is trifluoroacetic acid or boron trifluoride diethyl etherate; Reaction solvent is ethyl acetate, methylene dichloride, ethanol, at least one in methyl alcohol.Ethyl acetate.
Wherein in some embodiments, step 2) in, described 2-amido-4,5-bis-(2-methoxy ethoxy) benzamide, triethyl orthoformate, lewis acidic consumption mol ratio is 1:1-1.5:0.05-0.15, preferred 1:1.2:01; Temperature of reaction is 70-80 DEG C, preferably 77 DEG C.Under the above-described reaction conditions, sufficient reacting can be impelled to carry out, can avoid again the waste to raw material, meanwhile, this reaction conditions is gentle, is particularly suitable for suitability for industrialized production.
Wherein in some embodiments, in step 3), reaction solvent is ethyl acetate, methylene dichloride, at least one in dioxane.Ethyl acetate.
Wherein in some embodiments, in step 3), the consumption mol ratio of described 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-ones and phosphorus oxychloride is 1:2-4, preferred 1:3; Temperature of reaction is 60-80 DEG C, preferably 70 DEG C.Under the above-described reaction conditions, sufficient reacting can be impelled to carry out, the waste to raw material can be avoided again.
Wherein in some embodiments, in step 4), reaction solvent is methyl alcohol, ethanol, Virahol, at least one in propyl carbinol.Preferred alcohol.
Wherein in some embodiments, in step 4), the consumption mol ratio of 6,7-bis-(2-methoxy ethoxy)-quinazoline-4-chlorine and an amido phenylacetylene is 1:1-1.3, preferred 1:1.1; Temperature of reaction is 60-80 DEG C, preferably 70 DEG C.Sufficient reacting can be impelled to carry out, the waste to raw material can be avoided again.
Wherein in some embodiments, in step 4), adopt the method purifying erlotinib of recrystallization, the solvent of described recrystallization is ethanol, Virahol, propyl carbinol, the one in n-propyl alcohol.Preferred propyl carbinol.Adopt above-mentioned solvent, the recrystallization product that purity is higher can be obtained.
Compared with prior art, the present invention has following beneficial effect:
The preparation method of a kind of erlotinib of the present invention, with 4,5-bis-(2-methoxy ethoxy)-2-p-nitrile is raw material, through reduction, is hydrolyzed the intermediate 2-amido-4 obtained, 5-bis-(2-methoxy ethoxy) benzamide directly and triethyl orthoformate close ring and obtain erlotinib key intermediate 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-one, avoids, through carbonamidine intermediate, shortening reactions steps, reduce reaction cost, and improve productive rate.
Further, this preparation method also overcomes nitroreduction in prior synthesizing method and uses expensive catalyst, and temperature more high defect during ring-closure reaction.Meanwhile, reaction conditionss all in this preparation method is all very gentle, is particularly suitable for suitability for industrialized production.
Embodiment
Describe the present invention in detail below in conjunction with specific embodiment, but any restriction is not caused to the present invention.
Following examples are with 4,5-bis-(2-methoxy ethoxy)-2-p-nitrile is raw material, through reduction, be hydrolyzed the intermediate 2-amido-4 obtained, 5-bis-(2-methoxy ethoxy) benzamide directly and triethyl orthoformate close ring and obtain 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-one, chloro-product and the amido phenylacetylene of this quinazoline react, and obtain erlotinib.Synthetic line is as follows:
Embodiment 1
(1) synthesis of compound ii (2-amido-4,5-bis-(2-methoxy ethoxy) benzamide).
At 0 DEG C, by chemical compounds I (4,5-bis-(2-methoxy ethoxy)-2-p-nitrile) 214g, Raney Ni50g is suspended in about 2L water, mechanical stirring, drips the aqueous solution 500mL containing 141mL hydrazine hydrate, dropwise, rise to room temperature (about 20-30 DEG C), reaction 3h, TLC monitoring is to reacting complete.Add sodium hydroxide solution to adjust between Ph value to 11-12, add about 2L dichloromethane extraction 2 times, organic phase saturated common salt is washed, and anhydrous sodium sulfate drying, revolves steaming, obtains the crude product of 170g compound ii, and yield is 83%.
The characterization data of this compound ii is:
1h-NMR (400MHz, DMSO-d6): 7.15 (1H, s), 6.40 (2H, s), 6.27 (1H, s), 5.73 (1H, s), 4.01-4.03 (2H, J=4.8Hz, t), 3.95-3.98 (2H, J=4.8Hz, t), 3.64-3.66 (2H, J=4.8Hz, t), 3.58-3.60 (2H, J=4.8Hz, t), 3.30 (3H, s), 3.31 (3H, s).
(2) synthesis of compound III (6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-one).
By compound ii (2-amido-4,5-bis-(2-methoxy ethoxy) benzamide) 170g, triethyl orthoformate 106.3g, trifluoroacetic acid 7g, be added in about 1.7L ethyl acetate, reflux, about 4h, TLC monitoring is to reacting complete, stopped reaction.Reaction solution is cooled to room temperature, has a large amount of solid to separate out, suction filtration, collect solid, vacuum-drying, obtains compound III solid 158g, carries out purity testing with HPLC, and purity is 99%, and yield is 90%.
The characterization data of this compound III is: 1H-NMR (400MHz, DMSO-d6): 12.02 (1H, brs), 7.97 (1H, s), 7.46 (1H, s), 7.14 (1H, s), 4.23-4.25 (2H, J=4.8Hz, t), 4.17-4.20 (2H, J=4.8Hz, t), 3.69-3.72 (4H, J=4.8Hz, t), 3.32 (6H, s).
(3) synthesis of compounds Ⅳ (6,7-bis-(2-methoxy ethoxy)-quinazoline-4-chlorine).
By compound III (6; 7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-one) 5g is added in about 50mL ethyl acetate; nitrogen protection; add about 4.7mL phosphorus oxychloride; drip 1gDMF(N, dinethylformamide), be then heated to 70 DEG C; react about 2h, TLC monitoring to reacting complete.Reaction solution is cooled to room temperature, drips 100mL frozen water, separatory, aqueous phase is extracted with ethyl acetate 2 × 100mL, collect ethyl acetate phase, saturated common salt is washed, anhydrous sodium sulfate drying, revolve steaming ethyl acetate, vacuum-drying, obtain the compounds Ⅳ solid 4.4g of yellowish, yield is 83%, carry out purity testing with HPLC, purity is 98%.
The characterization data of this compounds Ⅳ is:
1h-NMR (400MHz, DMSO-d6): 8.85 (1H, s), 7.44 (1H, s), 4.34-4.36 (4H, br), 3.75-3.77 (4H, br), 3.34 (6H, s).
(4) synthesis of erlotinib (compound V).
Compounds Ⅳ 2.02g is added in 20mL dehydrated alcohol, is heated to 40 DEG C, form homogeneous suspension liquid, add the ethanolic soln 10mL of 3-aminophenylacetylene at this temperature, slowly be warming up to 70 DEG C, after about 1h, solution is clarified, after about 2h, TLC monitors raw material and disappears, stopped reaction.
Reaction solution is cooled to room temperature, and have a large amount of solid to separate out, solid collected by filtration, vacuum-drying obtains white solid and is about 2.6g, and propyl carbinol recrystallization obtains erlotinib sterling, and yield is 95.2%, carries out purity testing with HPLC, purity 99.89%.
The characterization data of this compound V is:
1h-NMR (400MHz, D
2o-d6): 8.43 (1H, s), 7.42-7.42 (2H, J=9.6Hz, d), 7.34 (1H, s), 7.08-7.12 (1H, J=6.8Hz, t), 6.99-7.00 (1H, J=6.8Hz, d), 6.89 (1H, s), 4.20-4.25 (4H, m), 3.86-3.88 (4H, m), 3.55 (1H, s) 3.50 (6H, s).
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (10)
1. a preparation method for erlotinib, is characterized in that, comprises the following steps:
1) with 4,5-bis-(2-methoxy ethoxy)-2-p-nitrile for raw material, under the effect of reductive agent, through reduction, hydrolysis reaction obtains 2-amido-4,5-bis-(2-methoxy ethoxy) benzamide;
2) 2-amido-4,5-bis-(2-methoxy ethoxy) benzamide above-mentioned steps obtained and triethyl orthoformate react under lewis acidic catalysis, directly close ring and obtain intermediate 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-one;
3) 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-ones above-mentioned steps obtained and phosphorus oxychloride are reacted, and obtain 6,7-bis-(2-methoxy ethoxy)-quinazoline-4-chlorine;
4) 6,7-bis-(2-methoxy ethoxy)-quinazoline-4-chlorine above-mentioned steps obtained and an amido phenylacetylene react, and obtain erlotinib.
2. the preparation method of erlotinib according to claim 1, is characterized in that, in step 1), reaction solvent is water, water-dioxane or water-ethanol; Reductive agent is V-Brite B, iron, zinc, palladium carbon or Raney Ni-hydrazine hydrate; Temperature of reaction is 0 DEG C-40 DEG C.
3. the preparation method of erlotinib according to claim 2, is characterized in that, in step 1), reaction solvent is water; Reductive agent is Raney Ni-hydrazine hydrate; Temperature of reaction is 20 DEG C-40 DEG C.
4. the preparation method of erlotinib according to claim 1, is characterized in that, step 2) in, described Lewis acid is trifluoroacetic acid or boron trifluoride diethyl etherate; Reaction solvent is ethyl acetate, methylene dichloride, ethanol, at least one in methyl alcohol.
5. the preparation method of erlotinib according to claim 1, is characterized in that, step 2) in, described 2-amido-4,5-bis-(2-methoxy ethoxy) benzamide, triethyl orthoformate, lewis acidic consumption mol ratio is 1:1-1.5:0.05-0.15; Temperature of reaction is 70-80 DEG C.
6. the preparation method of erlotinib according to claim 1, is characterized in that, in step 3), reaction solvent is ethyl acetate, methylene dichloride, at least one in dioxane.
7. the preparation method of erlotinib according to claim 1, is characterized in that, in step 3), the consumption mol ratio of described 6,7-bis-(2-methoxy ethoxy)-3H-quinazoline-4-ones and phosphorus oxychloride is 1:2-4; Temperature of reaction is 60-80 DEG C.
8. the preparation method of erlotinib according to claim 1, is characterized in that, in step 4), reaction solvent is methyl alcohol, ethanol, Virahol, at least one in propyl carbinol.
9. the preparation method of erlotinib according to claim 1, is characterized in that, in step 4), the consumption mol ratio of 6,7-bis-(2-methoxy ethoxy)-quinazoline-4-chlorine and an amido phenylacetylene is 1:1-1.3; Temperature of reaction is 60-80 DEG C.
10. the preparation method of erlotinib according to claim 1, is characterized in that, in step 4), adopt the method purifying erlotinib of recrystallization, the solvent of described recrystallization is ethanol, Virahol, propyl carbinol, the one in n-propyl alcohol.
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Cited By (6)
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| CN105646374A (en) * | 2015-12-31 | 2016-06-08 | 山东罗欣药业集团股份有限公司 | Preparation method of erlotinib hydrochloride |
| CN106279585A (en) * | 2016-08-26 | 2017-01-04 | 宁波圣达精工智能科技有限公司 | A kind of preparation method of fire-retardant intelligent compact bookshelf |
| CN106361007A (en) * | 2016-08-26 | 2017-02-01 | 宁波圣达精工智能科技有限公司 | Smart compact bookshelf |
| CN107337648A (en) * | 2016-05-03 | 2017-11-10 | 南京理工大学 | A kind of method for synthesizing Tarceva |
| CN108047144A (en) * | 2018-01-26 | 2018-05-18 | 中国科学院化学研究所 | The preparation method of Tarceva |
| CN113603650A (en) * | 2021-08-03 | 2021-11-05 | 杭州职业技术学院 | Catalytic cyclization preparation method and application of erlotinib key intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105646374A (en) * | 2015-12-31 | 2016-06-08 | 山东罗欣药业集团股份有限公司 | Preparation method of erlotinib hydrochloride |
| CN105646374B (en) * | 2015-12-31 | 2018-11-27 | 山东罗欣药业集团恒欣药业有限公司 | A kind of preparation method of erlotinib Hydrochloride |
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| CN106361007A (en) * | 2016-08-26 | 2017-02-01 | 宁波圣达精工智能科技有限公司 | Smart compact bookshelf |
| CN108047144A (en) * | 2018-01-26 | 2018-05-18 | 中国科学院化学研究所 | The preparation method of Tarceva |
| CN113603650A (en) * | 2021-08-03 | 2021-11-05 | 杭州职业技术学院 | Catalytic cyclization preparation method and application of erlotinib key intermediate |
| CN113603650B (en) * | 2021-08-03 | 2023-03-10 | 杭州职业技术学院 | Catalytic cyclization preparation method and application of erlotinib key intermediate |
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