CN102321076B - Preparation method of lapatinib intermediate and analogues thereof - Google Patents

Preparation method of lapatinib intermediate and analogues thereof Download PDF

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CN102321076B
CN102321076B CN2011101890543A CN201110189054A CN102321076B CN 102321076 B CN102321076 B CN 102321076B CN 2011101890543 A CN2011101890543 A CN 2011101890543A CN 201110189054 A CN201110189054 A CN 201110189054A CN 102321076 B CN102321076 B CN 102321076B
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benzyloxy
quinazoline
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CN102321076A (en
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汪志勇
万常峰
王晔
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University of Science and Technology of China USTC
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Abstract

The invention discloses a compound preparation method, which comprises the following steps: a) a compound disclosed in formula I and 4-chlorine-6-iodine-quinazoline are in backflow reaction in isopropanol; b) kieselguhr, stannous chloride, trifluoroacetic acid, H2PdCl4 and polyvinylpyrrolidone are mixed in water and heated to 100-150 DEG C, and a Pd catalyst is obtained after reaction; c) the products obtained in step a), the Pd catalyst, 5-formyl furanboronic acid and K2CO3 are mixed to be reacted in a first organic solvent; and d) reaction products obtained in step c), organic base and 2-(methyl sulfone) ethylamine hydrochloride are mixed in a second organic solvent, and lapatinib basic groups or analogues thereof are obtained after reaction. The heterogeneous Pd catalyst is adopted, and because the heterogeneous Pd catalyst is easy to recycle, the preparation method provided by the invention protects the environment at the time of saving raw materials. Formula (I) is disclosed in the specification.

Description

The preparation method of lapatinibditosylate intermediate and analogue thereof
Technical field
The present invention relates to the chemical pharmaceutical technical field, more particularly, relate to the preparation method of a kind of lapatinibditosylate intermediate and analogue thereof.
Background technology
Along with the development of human social economy and the progress of science and technology, people have also had significant progress to the research of disease.Even so, but diseases such as cancer and tumour remain the threat of present human life and the healthy maximum that faces.
As a kind of anti-tumor drug; lapatinibditosylate (lapatinib) chemical name is N-(3-chloro-4-((3-fluorophenyl) methoxyl group) phenyl)-6-(5-(((2-(methylsulfonyl) ethyl) amino) methyl)-2-furyl)-4-quinazoline amine two tosilate; gone on the market by drugs approved by FDA in March, 2007; it is a kind of 4-anilinoquinazoline receptoroid tyrosine kinase inhibitor; can effectively block the Tyrosine kinases to its downstream signal transmission; and then stop the quick growth of cancer cells, thereby effectively slow down the progress of cancer.
The lapatinibditosylate base is the key intermediate of synthetic lapatinibditosylate, the synthetic method of lapatinibditosylate base and derivative thereof is reported by GlaxoSmithKline PLC company at first, the said firm is starting raw material with 4-chloro-6-iodine quinazoline (3), under the effect of homogeneous phase noble metal catalyst, synthetic lapatinibditosylate base and derivatives thereof such as nucleo philic substitution reaction, Suzuki linked reaction and reductive amination process.In addition, pertinent literature Bioorganic ﹠amp; Medicinal Chemistry Letters 16 (2006) 4686-4691 have also reported a kind of synthetic method of lapatinibditosylate base, this synthetic method is starting raw material with 4-nitro ortho chloro phenol, under the condition of homogeneous phase noble metal catalyst, steps such as nucleo philic substitution reaction, Suzuki linked reaction have realized synthesizing the lapatinibditosylate base.
But the lapatinibditosylate base of reporting in the prior art and the synthetic method of analogue thereof all adopt homogeneous catalyst, because there is the shortcoming that is difficult for recovery in this homogeneous catalyst, therefore, have polluted environment when causing wastage of material.The inventor considers, the preparation method of a kind of lapatinibditosylate intermediate and analogue thereof is provided, and this method adopts the homogeneous catalyst that easily reclaims, and prepares lapatinibditosylate intermediate and analogue thereof.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is to provide a kind of preparation method of compound, and this method adopts the heterogeneous catalyst that easily reclaims, and prepares lapatinibditosylate intermediate or its analogue.
The invention provides a kind of preparation method of compound, may further comprise the steps:
Step a) is back flow reaction in Virahol with the compound shown in the formula I and 4-chloro-6-iodo-quinazoline,
Figure BDA0000074242790000021
Formula I,
Wherein, R is methyl, halogenic substituent, ester group or cyano group;
Step b) is with diatomite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with polyvinylpyrrolidone, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction;
The product that step c) obtains step a), described Pd catalyzer, 5-formylfuran boric acid and K 2CO 3Hybrid reaction in first organic solvent, temperature of reaction are 70～90 ℃;
The reaction product that step d) obtains step c), organic bases and 2-(methylsulfonyl) ethylamine hydrochloride mixes in second organic solvent, obtains lapatinibditosylate intermediate or its analogue after the reaction.
Preferably, the compound shown in the described formula I is 3-chloro-4-(3-fluoro-benzyloxy)-aniline.
Preferably, described 3-chloro-4-(3-fluoro-benzyloxy)-aniline prepares as follows:
Orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1,2-, two chloro-4-oil of mirbane after the reaction;
With described 1,2-two chloro-4-oil of mirbane and a fluorophenyl methanol place in 2, the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane after the reaction;
Described 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane, ammonium chloride, iron powder and water are mixed, obtain 3-chloro-4-(3-fluoro-benzyloxy)-aniline after the reaction.
Preferably, described fluorophenyl methanol prepares as follows:
Fluorobenzaldehyde mixes in methyl alcohol with sodium borohydride between inciting somebody to action, and the extraction of reaction back, drying obtain a fluorophenyl methanol.
Preferably, the described temperature of reaction that obtains 1,2-, two chloro-4-oil of mirbane steps is 50～70 ℃, and the reaction times is 2～4 hours.
Preferably, the temperature of reaction of the described 3-of obtaining chloro-4-(3-fluoro-benzyloxy)-aniline step is 70～90 ℃, and the reaction times is 1～2 hour.
Preferably, described 4-chloro-6-iodo-quinazoline prepares as follows:
5-iodo-2-benzaminic acid is placed methane amide, mix with phosphorus oxychloride then, obtain 6-iodo-3H-quinazoline-4-one after the reaction;
Described 6-iodo-3H-quinazoline-4-one, triethylamine, phosphorus oxychloride are mixed in toluene, obtain 4-chloro-6-iodo-quinazoline after the reaction.
Preferably, described step b) is specially:
Step b1) diatomite, tindichloride and trifluoroacetic acid are placed water, obtain mixture after the stirring;
Step b2) in described mixture, adds H 2PdCl 4The aqueous solution and polyvinylpyrrolidone, be heated to 100～150 ℃ of reactions, be incubated and obtain the Pd catalyzer after 1～3 hour.
Preferably, the reaction times of described step c) is 1～3 hour.
Preferably, described organic bases is triethylamine or diisopropylethylamine.
The invention provides a kind of preparation method of compound, may further comprise the steps: step a) is back flow reaction in Virahol with the compound shown in the formula I and 4-chloro-6-iodo-quinazoline; Step b) is with diatomite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with polyvinylpyrrolidone, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction; The product that step c) obtains step a), described Pd catalyzer, 5-formylfuran boric acid and K 2CO 3Hybrid reaction in first organic solvent; The reaction product that step d) obtains step c), organic bases and 2-(methylsulfonyl) ethylamine hydrochloride mixes in second organic solvent, obtains lapatinibditosylate base or its analogue after the reaction.Compared with prior art, the present invention has adopted heterogeneous Pd catalyzer, reclaims because this heterogeneous Pd catalyzer exists easily, and therefore, preparation method provided by the invention has protected environment when having saved raw material.Experimental result shows that the present invention prepares lapatinibditosylate intermediate and analogue thereof.
Figure BDA0000074242790000031
Formula I
Description of drawings
In order to be illustrated more clearly in the embodiment of the invention or technical scheme of the prior art, to do to introduce simply to the accompanying drawing of required use in embodiment or the description of the Prior Art below, apparently, accompanying drawing in describing below only is some embodiments of the present invention, for those of ordinary skills, under the prerequisite of not paying creative work, can also obtain other accompanying drawing according to these accompanying drawings.
Fig. 1 is the nucleus magnetic hydrogen spectrum of the lapatinibditosylate intermediate of the embodiment of the invention 1 preparation;
Fig. 2 is the nucleus magnetic hydrogen spectrum of the lapatinibditosylate intermediate analogue of the embodiment of the invention 2 preparations;
Fig. 3 is the nucleus magnetic hydrogen spectrum of the lapatinibditosylate intermediate analogue of the embodiment of the invention 3 preparations.
Embodiment
Below the technical scheme in the embodiment of the invention is clearly and completely described, obviously, described embodiment only is the present invention's part embodiment, rather than whole embodiment.Based on the embodiment among the present invention, those of ordinary skills belong to the scope of protection of the invention not making the every other embodiment that obtains under the creative work prerequisite.
The invention discloses a kind of preparation method of compound, may further comprise the steps:
Step a) is back flow reaction in Virahol with the compound shown in the formula I and 4-chloro-6-iodo-quinazoline,
Figure BDA0000074242790000041
Formula I,
Wherein, R is methyl, halogenic substituent, ester group or cyano group;
Step b) is with diatomite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with polyvinylpyrrolidone, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction;
The product that step c) obtains step a), described Pd catalyzer, 5-formylfuran boric acid and K 2CO 3Hybrid reaction in first organic solvent, temperature of reaction are 70～90 ℃;
The reaction product that step d) obtains step c), organic bases and 2-(methylsulfonyl) ethylamine hydrochloride mixes in second organic solvent, obtain lapatinibditosylate intermediate or its analogue after the reaction, described lapatinibditosylate intermediate or its analogue have the structure shown in the formula II
Figure BDA0000074242790000051
Formula II,
Wherein, R is methyl, halogenic substituent, ester group or cyano group.According to the present invention, the compound shown in the described formula I is preferably 3-chloro-4-(3-fluoro-benzyloxy)-aniline, 3-chloro-4-(4-fluoro-benzyloxy)-aniline or 3-chloro-4-(4-methyl-benzyloxy)-aniline.Wherein, when the compound shown in the described formula I was 3-chloro-4-(3-fluoro-benzyloxy)-aniline, the product that finally prepares was the lapatinibditosylate intermediate; When the compound shown in the described formula I was 3-chloro-4-(4-fluoro-benzyloxy)-aniline or 3-chloro-4-(4-methyl-benzyloxy)-aniline, the product that finally prepares was the analogue of lapatinibditosylate intermediate.
Above-mentioned 3-chloro-4-(3-fluoro-benzyloxy)-aniline preferably is prepared as follows: orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1,2-, two chloro-4-oil of mirbane after the reaction; With described 1,2-two chloro-4-oil of mirbane and a fluorophenyl methanol place in 2, the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane after the reaction; Described 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane, ammonium chloride, iron powder and water are mixed, obtain 3-chloro-4-(3-fluoro-benzyloxy)-aniline after the reaction.Described fluorophenyl methanol prepares as follows: fluorobenzaldehyde mixes in methyl alcohol with sodium borohydride between inciting somebody to action, and the extraction of reaction back, drying obtain a fluorophenyl methanol.
In the process of above-mentioned preparation 3-chloro-4-(3-fluoro-benzyloxy)-aniline, the described temperature of reaction that obtains 1,2-, two chloro-4-oil of mirbane steps is preferably 50～70 ℃, more preferably 60～70 ℃; Reaction times is preferably 2～4 hours, more preferably 3～4 hours.The reaction times of the described 2-of obtaining chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane step is preferably 1～5 hour, more preferably 2～3 hours.The temperature of reaction of the described 3-of obtaining chloro-4-(3-fluoro-benzyloxy)-aniline step is preferably 70～90 ℃, more preferably 80～85 ℃; Reaction times is preferably 1～2 hour, more preferably 1 hour.
In addition, described 3-chloro-4-(4-fluoro-benzyloxy)-aniline preferably is prepared as follows: orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1,2-, two chloro-4-oil of mirbane after the reaction; With described 1,2-two chloro-4-oil of mirbane with fluorophenyl methanol is placed in 2, the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(4-fluoro-benzyloxy)-4-oil of mirbane after the reaction; Described 2-chloro-1-(4 fluoro-benzyloxy)-4-oil of mirbane, ammonium chloride, iron powder and water are mixed, obtain 3-chloro-4-(3-fluoro-benzyloxy)-aniline after the reaction.
Above-mentioned 3-chloro-4-(4-methyl-benzyloxy)-aniline preferably is prepared as follows: orthodichlorobenzene mixes with sulfuric acid, nitric acid, obtains 1,2-, two chloro-4-oil of mirbane after the reaction; With described 1,2-two chloro-4-oil of mirbane with methylbenzyl alcohol is placed in 2, the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(4-methyl-benzyloxy)-4-oil of mirbane after the reaction; Described 2-chloro-1-(4-methyl-benzyloxy)-4-oil of mirbane, ammonium chloride, iron powder and water are mixed, obtain 3-chloro-4-(4-methyl-benzyloxy)-aniline after the reaction.
Preparation process by the compound shown in the above-mentioned formula I as can be seen, the present invention is raw material with orthodichlorobenzene and a fluorobenzaldehyde, by nitrated, reduction and nucleophilic substitution three go on foot, and have obtained the compound shown in the formula I.And preparation method provided by the invention has also overcome the shortcoming that is not easy to derive that has of reported method.In addition, from economic angle, fluorobenzyl bromide was comparatively cheap between fluorobenzaldehyde compared between the present invention's employing; In addition, the nitrated productive rate of the orthodichlorobenzene in the raw material is higher, has overcome the shortcoming of nitro regioselectivity difference on the prior art raw material ortho chloro phenol commonly used.
In step a), described 4-chloro-6-iodo-quinazoline can adopt method preparation well known to those skilled in the art, the present invention preferably adopts following method preparation: 5-iodo-2-benzaminic acid is placed methane amide, mix with phosphorus oxychloride then, obtain 6-iodo-3H-quinazoline-4-one after the reaction; Described 6-iodo-3H-quinazoline-4-one, triethylamine, phosphorus oxychloride are mixed in toluene, obtain 4-chloro-6-iodo-quinazoline after the reaction.The time of described back flow reaction is preferably 2～5 hours, more preferably 2～3 hours.In this step, compound shown in the formula I is as a kind of nucleophilic reagent, amino in the compound shown in this formula I replaces the chlorine atom in the 4-chloro-6-iodo-quinazoline under 70～90 ℃ of conditions, thereby has realized linking of the compound shown in the formula I and 4-chloro-6-iodo-quinazoline.
Described step b) provides Pd Preparation of catalysts process, and described step b) is specially: step b1) diatomite, tindichloride and trifluoroacetic acid are placed water, obtain mixture after the stirring; Step b2) in described mixture, adds H 2PdCl 4The aqueous solution and polyvinylpyrrolidone, be heated to 100～150 ℃ of reactions, be incubated and obtain the Pd catalyzer after 1～3 hour.The Pd catalyzer that this step prepares is heterogeneous catalyst, and this catalyzer has the characteristics of easy recovery, thereby has protected environment when having saved raw material.
After preparing the Pd catalyzer, product, described Pd catalyzer, 5-formylfuran boric acid and K that step a) is obtained 2CO 3Hybrid reaction in first organic solvent, temperature of reaction are 70～90 ℃.In this step, under the katalysis of the Pd catalyzer that step b) prepares, the product that step a) obtains and 5-formylfuran boric acid generation linked reaction.Temperature of reaction described in this step is preferably 75～85 ℃, and more preferably 80～85 ℃, the reaction times is preferably 1～3 hour, more preferably 2～3 hours.
First organic solvent in the described step c) can be identical with second organic solvent described in the step d), also can be different, and it is dehydrated alcohol that the present invention preferably adopts first organic solvent, second organic solvent is dehydrated alcohol.In described step d), described organic bases is preferably triethylamine or diisopropylethylamine.
In addition, described step d) also comprises: add sodium borohydride in described second organic solvent, thereby realize the tracking of some plate, the reaction times in the step d) is preferably 1～5 hour, more preferably 2～3 hours.
From above-mentioned preparation method as can be seen, preparation method's reaction conditions gentleness provided by the invention, the consumption of the organic solvent that this method adopts is less, simple to operate, easily scale operation.In addition, preparation method provided by the invention is suitable equally for preparation lapatinibditosylate intermediate analogue.
In order to further specify technical scheme of the present invention, be described below in conjunction with the preferred embodiment of the invention of embodiment, but should be appreciated that these describe just to further specifying the features and advantages of the present invention, rather than to the restriction of claim of the present invention.
The chemical reagent that adopts in the embodiment of the invention is commercial.
Embodiment 1
The preparation of 5-iodo-2-benzaminic acid:
With anthranilic acid (10mmol, 1.37g), sodium periodate (10mmol, 2.14g) and sodium-chlor (10mmol, 1.90g) be dissolved in the aqueous acetic acid of 30mL (wherein acetic acid 27mL, water 3mL), slowly add potassiumiodide (20mmol then, 1.18g) the aqueous solution (10mL), temperature control adds afterreaction and stirred at ambient temperature 8 hours, then stopped reaction in 50 ℃, reaction system is poured in the frozen water, suction filtration, the upper strata filter cake is with a large amount of water and a spot of ethanol elution, with solid vacuum-drying under 60 ℃ of conditions of suction filtration gained, get 2.52g 5-iodo-2-benzaminic acid, yield:95.7%. at last 1HNMR (300MHz, DMSO-d 6) δ 9.50-8.13 (s, 2H), 7.91 (s, 1H), 7.45 (d, J=7.8Hz, 1H), 6.61 (d, J=7.8Hz, 1H). the reaction formula of said process is as follows:
Figure BDA0000074242790000071
The preparation of 6-iodo-3H-quinazoline-4-one:
5-iodo-2-benzaminic acid (14mmol with above-mentioned preparation, 3.70g) be dissolved in the methane amide of 15mL, after being heated to 90 ℃ of dissolvings, the slow phosphorus oxychloride (control rate of addition) of Dropwise 5 ml with this understanding then, and make temperature of reaction maintain 90 ℃, drip the back and under this temperature, continue reaction 1 hour, stopped reaction is poured reaction system in the frozen water into after the cooling, treat the precipitation separate out fully after, suction filtration, use N, dinethylformamide (being called for short DMF) recrystallization gets light gray solid 3.25g, be 6-iodo-3H-quinazoline-4-one, yield:86%. 1HNMR (300MHz, DMSO-d 6δ 12.35 (s, 1H), 8.38 (s, 1H), 8.07-8.00 (m, 2H), 7.41d, J=7.8Hz, 1H). the reaction formula of said process is as follows:
The preparation of 4-chloro-6-iodo-quinazoline:
In the round-bottomed flask of 50ml, add 6-iodo-3H-quinazoline-4-one (5mmol successively, 1.36g), triethylamine (6.5mmol, 618mg), add the toluene of 20mL then as solvent, slowly drip phosphorus oxychloride then at ambient temperature, after adding, reaction system continues at room temperature to react 1h, be warming up to 90 ℃ then, reacted two hours, add water cancellation behind the stopped reaction, suction filtration, filtrate is used ethyl acetate extraction, anhydrous sodium sulfate drying, spin off solvent after, get 4-chloro-6-iodo-quinazoline 1.22g, yield:84%. 1HNMR (300MHz, CDCl 3) δ 9.06 (s, 1H), 8.65 (d, J=1.5Hz 1H), 8.20 (dd, J=1.5Hz, J=6.0Hz, 1H), 7.79 (1H), the reaction formula of said process is as follows for d, J=6.0Hz:
Figure BDA0000074242790000082
The preparation of 1,2-, two chloro-4-oil of mirbane:
3.2ml sulfuric acid and 2.5ml nitric acid are put in the round-bottomed flask of 50ml, under 60 ℃ and agitation condition, dripped orthodichlorobenzene (20mmol lentamente, 2.92g), after dropwising, continue under this condition, to react 3 hours, stopped reaction is poured reaction system in the frozen water into then, treat its precipitation separate out fully after, suction filtration washes with water repeatedly, reduced pressure at room temperature, get light yellow solid 3.72g, namely 1,2-two chloro-4-oil of mirbane, yield:97.4%.The reaction formula of said process is as follows:
Figure BDA0000074242790000091
The preparation of 3-fluoro-phenylcarbinol:
(10mmol 1.24g) is dissolved in the 25ml methyl alcohol fluorobenzaldehyde, adds sodium borohydride (10mmol then in batches between inciting somebody to action, 0.37g), add the afterreaction system and continue at room temperature to react stopped reaction 6 hours, spin off methyl alcohol, add water, use ethyl acetate extraction, anhydrous sodium sulfate drying then, spin off solvent, colourless liquid 1.257g, i.e. 3-fluoro-phenylcarbinol, yield:99.8%.The reaction formula of said process is as follows:
Figure BDA0000074242790000092
The preparation of 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane:
With 1,2-, two chloro-4-oil of mirbane (5mmol, 0.960g) and a fluorophenyl methanol (6mmol, 0.75g) with DMF (5mL) dissolving after, at room temperature add lentamente then in batches sodium hydride (7.5mmol, 180mg), after adding, reaction system is continued reaction 2 hours, stopped reaction, then system is poured in the frozen water, after precipitation is separated out, suction filtration, oven dry, yellow solid 1.15g, i.e. 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane, Yield:82.4%. 1HNMR (300MHz, CDCl 3) δ 8.32 (d, J=2.7Hz, 1H), 8.13 (dd, J=9.3Hz, J=2.7Hz, 1H), 7.43-7.35 (m, 1H), 7.26-7.17 (m, 2H), 7.09-6.99 (m, 2H), 5.26 (s, 2H). the reaction formula of said process is as follows:
Figure BDA0000074242790000093
The preparation of 3-chloro-4-(3-fluoro-benzyloxy)-aniline:
With 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane (2mmol, 0.562g) with after EtOH (30mL) dissolving, add ammonium chloride (16mmol then, 864mg) with 8mL water, add (6mmol, iron powder 336mg) at last, after adding, reaction system is continued reaction 1 hour under 80 ℃ of conditions, stopped reaction is then with the system suction filtration, filtrate spins off, use ethyl acetate extraction, anhydrous sodium sulfate drying spins off solvent, get thick product yellow solid and get yellow solid 0.464g, be 3-chloro-4-(3-fluoro-benzyloxy)-aniline, Yield:92.4% 1HNMR (300MHz, CDCl 3) δ 7.32-7.15 (and m, 3H), 6.98 (t, J=7.8Hz, 1H), 6.76-6.73 (m, 2H), 6.46 (dd, J=8.7Hz, J=2.4Hz, 1H), 5.00 (s, 2H) .3.47 (s, 2H). the reaction formula of said process is as follows:
Figure BDA0000074242790000101
The preparation of N-(3-chloro-4-(3-fluorine benzyloxy) phenyl)-6-iodine quinazoline-4-amine:
Under nitrogen protection; with 3-chloro-4-(3-fluoro-benzyloxy)-aniline (138mg; 0.55mmol) and 4-chloro-6-iodo-quinazoline (145mg; 0.5mmol) stirring and refluxing 3h in Virahol (5mL); filter; obtain yellow crystal solid 231mg, i.e. N-(3-chloro-4-(3-fluorine benzyloxy) phenyl)-6-iodine quinazoline-4-amine, yield:91.3%. 1HNMR (300MHz, CDCl 3) δ 9.06 (s, 1H), 8.65 (d, J=1.5Hz 1H), 8.20 (dd, J=1.5Hz, J=6.0Hz, 1H), 7.79 (1H), the reaction formula of said process is as follows for d, J=6.0Hz:
N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-preparation of 4-quinazoline amine:
Under condition of nitrogen gas, with N-(3-chloro-4-(3-fluorine benzyloxy) phenyl)-6-iodine quinazoline-4-amine (101mg, 0.2mmol), 5-formylfuran boric acid (52mg, 0.3mmol), the Pd catalyzer of 10mg tripolite loading, K 2CO 3(27.6mg; 0.2mmol) be dissolved in the dehydrated alcohol (5mL); stir 1h under 80 ℃ of conditions, be spin-dried for solvent behind the stopped reaction, use ethyl acetate extraction; anhydrous sodium sulfate drying; spin off extraction liquid, get yellow thick product 85mg, yield:90%; be N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine 1HNMR (300MHz, DMSO) δ 10.21 (s, 1H), 9.77 (s, 1H), 9.06 (s, 1H), 8.69 (s, 1H), 8.38 (d, J=8.7Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=8.7Hz, 1H), 7.85-7.78 (m, 2H), 7.51 (d, J=3.6Hz, 1H), 7.51-7.37 (m, 4H), 7.27-7.25 (m, 1H), 5.29 (s, 2H), 2.44 (s, 3H). the reaction formula of said process is as follows:
Figure BDA0000074242790000111
The preparation of lapatinibditosylate base:
With N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-(120mg 0.25mmol) is dissolved in the anhydrous methanol (5mL) 4-quinazoline amine, adds triethylamine (Et 3N) (40.4mg, 0.30mmol), 2-(methylsulfonyl) ethylamine hydrochloride (44mg, 0.30mmol); under nitrogen protection, stir 2h under the room temperature condition, add sodium borohydride (12mg) then in batches; the point plate is followed the tracks of, and stopped reaction after raw material disappears is spin-dried for solvent then; use ethyl acetate extraction, anhydrous sodium sulfate drying spins off extraction liquid; get yellow thick product 127mg; yield:86%, i.e. lapatinibditosylate base, the reaction formula of said process is as follows:
Figure BDA0000074242790000121
As shown in Figure 1, be the nucleus magnetic hydrogen spectrum of the lapatinibditosylate base of present embodiment preparation. 1HNMR(400MHz，DMSO)δ10.04(s，1H)，8.83(s，1H)，8.55(s，1H)，8.12(dd，J＝6.8Hz，J＝2.0Hz，1H)，8.05(s，1H)，7.80-7.78(m，2H)，7.49-7.45(m，1H)，7.35-7.27(m，3H)，7.19-7.15(m，1H)，7.12(d，J＝3.2Hz，1H)，6.48(d，J＝3.2Hz，1H)，5.23(s，2H)，3.84(s，2H)，3.29(t，J＝6.8Hz，2H)，3.03(s，3H)，3.00(t，J＝6.8Hz，2H)。
Embodiment 2
The preparation of 4-fluoro-phenylcarbinol:
(10mmol 1.24g) is dissolved in the 25ml methyl alcohol, adds sodium borohydride (10mmol then in batches with p-Fluorobenzenecarboxaldehyde, 0.37g), add the afterreaction system and continue at room temperature to react stopped reaction 6 hours, spin off methyl alcohol, add water, use ethyl acetate extraction, anhydrous sodium sulfate drying then, get colourless liquid 1.19g after spinning off solvent, yield:94%, i.e. 4-fluoro-phenylcarbinol, the reaction formula of said process is as follows:
Figure BDA0000074242790000122
The preparation of 2-chloro-1-(4-fluoro-benzyloxy)-4-oil of mirbane:
With 1 of embodiment 1 preparation, 2-two chloro-4-oil of mirbane (5mmol, 0.960g) and to fluorophenyl methanol (6mmol, 0.75g) with after DMF (5mL) dissolving, at room temperature add lentamente then in batches sodium hydride (7.5mmol, 180mg), after adding, reaction system is continued reaction 2 hours, stopped reaction is poured system in the frozen water into then, after precipitation is separated out, suction filtration, oven dry gets yellow solid 1.05g, Yield:74%, be 2-chloro-1-(4-fluoro-benzyloxy)-4-oil of mirbane, the reaction formula of said process is as follows:
Figure BDA0000074242790000131
The preparation of 3-chloro-4-(4-fluoro-benzyloxy)-aniline:
With 2-chloro-1-(4-fluoro-benzyloxy)-4-oil of mirbane (2mmol, 0.561g) with ethanol (EtOH) (30mL) dissolve after, add ammonium chloride (16mmol then, 864mg) with 8ml water, add the iron powder of 6mmol at last, after adding, reaction system is continued reaction 1 hour under 80 ℃ of conditions, stopped reaction is then with the system suction filtration, filtrate spins off, and uses ethyl acetate extraction, anhydrous sodium sulfate drying, spin off solvent, get thick product yellow solid and get yellow solid 0.453g, Yield:90.8% 1HNMR (300MHz, CDCl 3) δ 9.06 (s, 1H), 8.65 (d, J=1.5Hz 1H), 8.20 (dd, J=1.5Hz, J=6.0Hz, 1H), 7.79 (1H), the reaction formula of said process is as follows for d, J=6.0Hz:
The preparation of N-(3-chloro-4-(4-fluorine benzyloxy) phenyl)-6-iodine quinazoline:
Under nitrogen protection, with 3-chloro-4-(4-fluoro-benzyloxy)-aniline (138mg, 0.55mmol) and
(145mg, 0.5mmol) stirring and refluxing 3h in Virahol (5mL) filter the 4-chloro-6-iodo-quinazoline of embodiment 1 preparation, obtain yellow crystal solid 93mg, yield:92%, i.e. N-(3-chloro-4-(4-fluorine benzyloxy) phenyl)-6-iodine quinazoline. 1HNMR (300MHz, DMSO) δ 11.73 (s, 1H), 9.35 (s, 1H), 8.93 (s, 1H), 8.34 (d, J=8.1Hz, 1H), 7.88 (s, 1H), 7.74 (d, J=7.2Hz, 1H), 7.64 (d, J=7.2Hz, 1H), 7.55-7.50 (m, 2H), 7.34 (d, J=8.7Hz, 1H), 7.27-7.21 (m, 2H), 5.23 (s, 2H), 2.33 (s, 3H). the reaction formula of said process is as follows:
Figure BDA0000074242790000141
N-[3-chloro-4-[(4-fluorophenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-preparation of 4-quinazoline amine:
Under condition of nitrogen gas, with N-(3-chloro-4-(3-fluorine benzyloxy) phenyl)-6-iodine quinazoline-4-amine (101mg, 0.2mmol), 5-formylfuran boric acid (52mg, 0.3mmol), the Pd catalyzer of 10mg tripolite loading, K 2CO 3(27.6mg; 0.2mmol) be dissolved in the dehydrated alcohol (5mL); stir 1h under 80 ℃ of conditions, stopped reaction is spin-dried for solvent then; use ethyl acetate extraction; anhydrous sodium sulfate drying spins off extraction liquid, gets yellow thick product 87mg; yield:91%, i.e. N-[3-chloro-4-[(4-fluorophenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine.The reaction formula of said process is as follows:
Figure BDA0000074242790000142
N-[3-chloro-4-[(4-fluorophenyl) methoxyl group] phenyl]-6-[5 ((2-methylsulfonyl) ethylamine methyl) furans-2-yl]-preparation of 4-quinazoline amine:
With N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (95mg; 0.2mmol) be dissolved in the anhydrous methanol (5mL); add diisopropylethylamine (DIPEA) (51.6mg; 0.40mmol); 2-(methylsulfonyl) ethylamine hydrochloride (64mg; 0.4mmol); under nitrogen protection; stir 5h under the room temperature condition; add sodium triacetoxy borohydride then (84.4mg 0.4mmol), puts plate and follows the tracks of in batches; after the raw material disappearance; stopped reaction is spin-dried for solvent then, uses ethyl acetate extraction, anhydrous sodium sulfate drying; spin off extraction liquid; get yellow thick product 85mg, yield:78%, i.e. N-[3-chloro-4-[(4-fluorophenyl) methoxyl group] phenyl]-6-[5 ((2-methylsulfonyl) ethylamine methyl) furans-2-yl]-4-quinazoline amine.The reaction formula of said process is as follows:
Figure BDA0000074242790000151
As shown in Figure 2, be the nucleus magnetic hydrogen spectrum of the lapatinibditosylate base analogue of present embodiment preparation. 1HNMR(400MHz，DMSO)δ10.04(s，1H)，8.87(s，1H)，8.55(s，1H)，8.12(dd，J＝6.8Hz，J＝1.6Hz，1H)，8.05(s，1H)，7.80-7.78(m，2H)，7.58-7.54(m，2H)，7.31-7.24(m，3H)，7.11(d，J＝3.2Hz，1H)，6.48(d，J＝3.2Hz，1H)，5.23(s，2H)，3.84(d，J＝4.4Hz，2H)，3.30(t，J＝6.8Hz，2H)，3.04(s，3H)，2.99(t，J＝6.8Hz，2H).
Embodiment 3
The preparation of 4-methyl-phenylcarbinol:
(10mmol 1.20g) is dissolved in the 25mL methyl alcohol, adds sodium borohydride (10mmol then in batches with p-tolyl aldehyde, 0.37g), add the afterreaction system and continue at room temperature to react stopped reaction 6 hours, spin off methyl alcohol, add water, use ethyl acetate extraction, anhydrous sodium sulfate drying then, spin off solvent, get colourless liquid 1.21g, yield:99.2%, i.e. 4-methyl-phenylcarbinol.The reaction formula of said process is as follows:
The preparation of 2-chloro-1-(4-methyl-benzyloxy)-4-oil of mirbane:
With 1 of embodiment 1 preparation, (5mmol is 0.960g) with to methylbenzyl alcohol (6mmol for 2-two chloro-4-oil of mirbane, 0.732g) with after the DMF of the 5mL dissolving, at room temperature add lentamente then in batches sodium hydride (7.5mmol, 180mg), after adding, reaction system is continued reaction 2 hours, stopped reaction, then system is poured in the frozen water, after precipitation is separated out, suction filtration, oven dry, get yellow solid 1.098g, Yield:79.3%, i.e. 2-chloro-1-(4-methyl-benzyloxy)-4-oil of mirbane.The reaction formula of said process is as follows:
Figure BDA0000074242790000161
The preparation of 3-chloro-4-(4-methyl-benzyloxy)-aniline:
With 2-chloro-1-(4-methyl-benzyloxy)-4-oil of mirbane (2mmol, 0.554g) with after EtOH (30mL) dissolving, add ammonium chloride (16mmol then, 180mg) with 8mL water, the iron powder that adds 6mmol at last, after adding, reaction system is continued reaction 1 hour, stopped reaction under 80 ℃ of conditions, then with the system suction filtration, filtrate spins off, and uses ethyl acetate extraction, anhydrous sodium sulfate drying, spin off solvent, get thick product yellow solid and get yellow solid 462mg, Yield:93.5%, i.e. 3-chloro-4-(4-methyl-benzyloxy)-aniline.The reaction formula of said process is as follows:
Figure BDA0000074242790000162
The preparation of N-(3-chloro-4-(4-methyl benzyloxy) phenyl)-6-iodine quinazoline-4-amine:
Under nitrogen protection, (494mg is 2mmol) with 4-chloro-6-iodo-quinazoline (578mg, 2mmol) stirring and refluxing 3h in Virahol (5mL) with 3-chloro-4-(4-methyl benzyloxy)-aniline.To be cooled to room temperature, suction filtration obtains yellow solid 466mg, Yield:93%, i.e. N-(3-chloro-4-(4-methyl benzyloxy) phenyl)-6-iodine quinazoline-4-amine. 1HNMR (300MHz, DMSO) δ 11.58 (s, 1H), 9.34 (s, 1H), 8.92 (s, 1H), 8.34 (d, J=8.1Hz, 1H), 7.92 (s, 1H), 7.74 (d, J=7.2Hz, 1H), 7.66 (d, J=7.2Hz, 1H), 7.35-7.29 (m, 4H), 7.17 (s, 1H), 5.22 (s, 2H), 2.33 (s, 3H). the reaction formula of said process is as follows:
Figure BDA0000074242790000171
N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-preparation of 4-quinazoline amine:
Under condition of nitrogen gas, with N-(3-chloro-4-(4-methyl benzyloxy) phenyl)-6-iodine quinazoline-4-amine (102mg, 0.2mmol), 5-formylfuran boric acid (52mg, 0.3mmol), the Pd catalyzer of 10mg tripolite loading, K 2CO 3(27.6mg; 0.2mmol) be dissolved in the dehydrated alcohol (5mL), stir 1h, stopped reaction under 80 ℃ of conditions; be spin-dried for solvent then; use ethyl acetate extraction, anhydrous sodium sulfate drying spins off extraction liquid; get yellow thick product 87mg; yield:92%, i.e. N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine 1HNMR (300MHz, DMSO) δ 10.21 (s, 1H), 9.77 (s, 1H), 9.06 (s, 1H), 8.69 (s, 1H), 8.38 (d, J=8.7Hz, 1H), 8.06 (s, 1H), 7.95 (d, J=8.7Hz, 1H), 7.85-7.78 (m, 2H), 7.51 (d, J=3.6Hz, 1H), 7.51-7.37 (m, 4H), 7.27-7.25 (m, 1H), 5.29 (s, 2H), 2.44 (s, 3H). the reaction formula of said process is as follows:
Figure BDA0000074242790000172
N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-6-[5 ((2-methylsulfonyl) ethylamine methyl) furans-2-yl]-preparation of 4-quinazoline amine:
With N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-the 6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (94mg; 0.2mmol) be dissolved in the anhydrous methanol (5mL); add diisopropylethylamine (DIPEA) (51.6mg; 0.40mmol); 2-(methylsulfonyl) ethylamine hydrochloride (64mg; 0.4mmol); under nitrogen protection; stir 5h under the room temperature condition, add then in batches sodium triacetoxy borohydride (84.4mg, 0.4mmol); the point plate is followed the tracks of; after raw material disappeared, stopped reaction was spin-dried for solvent then, uses ethyl acetate extraction; anhydrous sodium sulfate drying; spin off extraction liquid, get yellow thick product 91mg, yield:79%; be N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-6-[5 ((2-methylsulfonyl) ethylamine methyl) furans-2-yl]-4-quinazoline amine, the reaction formula of said process is as follows:
Figure BDA0000074242790000181
As shown in Figure 3, be the nucleus magnetic hydrogen spectrum of the lapatinibditosylate base analogue of present embodiment preparation. 1HNMR(400MHz，DMSO)δ10.15(s，1H)，8.91(s，1H)，8.52(s，1H)，8.12(dd，J＝6.8Hz，J＝2.0Hz，1H)，8.05(s，1H)，7.78-7.75(m，2H)，7.31-7.25(m，2H)，7.17-7.13(m，1H)，7.12(d，J＝3.2Hz，1H)，6.47(d，J＝3.2Hz，1H)，5.18(s，2H)，3.82(d，J＝5.6Hz，2H)，3.29(t，J＝6.8Hz，2H)，3.03(s，3H)，2.99(t，J＝6.8Hz，2H)，2.34(s，3H).
To the above-mentioned explanation of the disclosed embodiments, make this area professional and technical personnel can realize or use the present invention.Multiple modification to these embodiment will be apparent concerning those skilled in the art, and defined General Principle can realize under the situation that does not break away from the spirit or scope of the present invention in other embodiments herein.Therefore, the present invention will can not be restricted to these embodiment shown in this article, but will meet the wideest scope consistent with principle disclosed herein and features of novelty.

Claims (9)

1. the preparation method of a lapatinibditosylate intermediate or its analogue may further comprise the steps:
Step a) is back flow reaction in Virahol with the compound shown in the formula I and 4-chloro-6-iodo-quinazoline,
Figure FDA00003371156600011
The formula I,
Wherein, R is methyl, halogenic substituent, ester group or cyano group;
Step b) is with diatomite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with polyvinylpyrrolidone, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction;
The product that step c) obtains step a), described Pd catalyzer, 5-formylfuran boric acid and K 2CO 3Hybrid reaction in dehydrated alcohol, temperature of reaction are 70～90 ℃, and the reaction times is 1～3h;
The reaction product that step d) obtains step c), organic bases and 2-(methylsulfonyl) ethylamine hydrochloride mixes in second organic solvent, obtains lapatinibditosylate intermediate or its analogue after the reaction;
Described lapatinibditosylate intermediate or its analogue have the structure shown in the formula II:
The formula II.
2. preparation method according to claim 1 is characterized in that, the compound shown in the described formula I is 3-chloro-4-(3-fluoro-benzyloxy)-aniline.
3. preparation method according to claim 2 is characterized in that, described 3-chloro-4-(3-fluoro-benzyloxy)-aniline prepares as follows:
Orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1,2-, two chloro-4-oil of mirbane after the reaction;
With described 1,2-two chloro-4-oil of mirbane and a fluorophenyl methanol place in 2, the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(3-fluoro-benzyloxy after the reaction)-4-oil of mirbane;
With described 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane, ammonium chloride, iron powder and water mixes, and obtains 3-chloro-4-(3-fluoro-benzyloxy after the reaction)-aniline.
4. preparation method according to claim 3 is characterized in that, described fluorophenyl methanol prepares as follows:
Fluorobenzaldehyde mixes in methyl alcohol with sodium borohydride between inciting somebody to action, and the extraction of reaction back, drying obtain a fluorophenyl methanol.
5. preparation method according to claim 3 is characterized in that, the described temperature of reaction that obtains 1,2-, two chloro-4-oil of mirbane steps is 50～70 ℃, and the reaction times is 2～4 hours.
6. preparation method according to claim 3 is characterized in that, the described 3-of obtaining chloro-4-(3-fluoro-benzyloxy)-temperature of reaction of aniline step is 70～90 ℃, the reaction times is 1～2 hour.
7. preparation method according to claim 1 is characterized in that, described 4-chloro-6-iodo-quinazoline prepares as follows:
5-iodo-2-benzaminic acid is placed methane amide, mix with phosphorus oxychloride then, obtain 6-iodo-3H-quinazoline-4-one after the reaction;
Described 6-iodo-3H-quinazoline-4-one, triethylamine, phosphorus oxychloride are mixed in toluene, obtain 4-chloro-6-iodo-quinazoline after the reaction.
8. preparation method according to claim 1 is characterized in that, described step b) is specially:
Step b1) diatomite, tindichloride and trifluoroacetic acid are placed water, obtain mixture after the stirring;
Step b2) in described mixture, adds H 2PdCl 4The aqueous solution and polyvinylpyrrolidone, be heated to 100～150 ℃ of reactions, be incubated and obtain the Pd catalyzer after 1～3 hour.
9. preparation method according to claim 1 is characterized in that, described organic bases is triethylamine or diisopropylethylamine.
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