CN102321076A - The preparation method of lapatinibditosylate midbody and analogue thereof - Google Patents

The preparation method of lapatinibditosylate midbody and analogue thereof Download PDF

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CN102321076A
CN102321076A CN201110189054A CN201110189054A CN102321076A CN 102321076 A CN102321076 A CN 102321076A CN 201110189054 A CN201110189054 A CN 201110189054A CN 201110189054 A CN201110189054 A CN 201110189054A CN 102321076 A CN102321076 A CN 102321076A
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reaction
chloro
preparation
benzyloxy
quinazoline
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CN102321076B (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 kind of preparation method of compound, may further comprise the steps: step a) is with the compound shown in the formula I and 4-chloro-6-iodo-quinazoline back flow reaction in Virahol; Step b) is with zeyssatite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with Vinylpyrrolidone polymer, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction; The product that step c) obtains step a), said 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.The present invention has adopted heterogeneous Pd catalyzer, is prone to reclaim because this heterogeneous Pd catalyzer exists, and therefore, preparation method provided by the invention has protected environment when having saved raw material.

Description

The preparation method of lapatinibditosylate midbody 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 midbody 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 is faced.
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; Go 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 compound method of lapatinibditosylate base and verivate thereof is reported by GlaxoSmithKline PLC company at first; The said firm is a starting raw material with 4-chloro-6-iodine quinazoline (3); Under the effect of homogeneous phase noble metal catalyst, synthetic lapatinibditosylate base and verivates thereof such as nucleo philic substitution reaction, Suzuki linked reaction and reductive amination process.In addition; Pertinent literature Bioorganic & Medicinal Chemistry Letters 16 (2006) 4686-4691 have also reported a kind of compound method of lapatinibditosylate base; This compound method is a 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 compound method of analogue thereof all adopt homogeneous catalyst, because there is the shortcoming that is difficult for recovery in this homogeneous catalyst, therefore, when causing wastage of material, have polluted environment.The inventor considers, the preparation method of a kind of lapatinibditosylate midbody and analogue thereof is provided, and this method adopts the homogeneous catalyst that is prone to recovery, prepares lapatinibditosylate midbody and analogue thereof.
Summary of the invention
In view of this, the technical problem that the present invention will solve is to provide a kind of preparation method of compound, and this method adopts the heterogeneous catalyst that is prone to recovery, prepares lapatinibditosylate midbody or its analogue.
The present invention provides a kind of preparation method of compound, may further comprise the steps:
Step a) is the compound shown in the formula I and 4-chloro-6-iodo-quinazoline back flow reaction in Virahol,
Formula I,
Wherein, R is methyl, halogenic substituent, ester group or cyanic acid;
Step b) is with zeyssatite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with Vinylpyrrolidone polymer, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction;
The product that step c) obtains step a), said 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 midbody or its analogue after the reaction.
Preferably, the compound shown in the said formula I is 3-chloro-4-(3-fluoro-benzyloxy)-aniline.
Preferably, said 3-chloro-4-(3-fluoro-benzyloxy)-aniline prepares as follows:
Orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1 after the reaction, 2-two chloro-4-oil of mirbane;
With said 1,2-two chloro-4-oil of mirbane and a fluorophenyl methanol place 2, in the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane after the reaction;
Said 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, said fluorophenyl methanol prepares as follows:
Fluorobenzaldehyde mixes in methyl alcohol with Peng Qinghuana between inciting somebody to action, and the extraction of reaction back, drying obtain a fluorophenyl methanol.
Preferably, saidly obtain 1, the temperature of reaction of 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 said 3-of obtaining chloro-4-(3-fluoro-benzyloxy)-aniline step is 70～90 ℃, and the reaction times is 1～2 hour.
Preferably, said 4-chloro-6-iodo-quinazoline prepares as follows:
5-iodo-2-benzaminic acid is placed methane amide, mix with POCl3 then, obtain 6-iodo-3H-quinazoline-4-one after the reaction;
Said 6-iodo-3H-quinazoline-4-one, triethylamine, POCl3 are mixed in toluene, obtain 4-chloro-6-iodo-quinazoline after the reaction.
Preferably, said step b) is specially:
Step b1) zeyssatite, tindichloride and trifluoroacetic acid are placed water, obtain mixture after the stirring;
Step b2) in said mixture, adds H 2PdCl 4The aqueous solution and Vinylpyrrolidone polymer, be heated to 100～150 ℃ of reactions, be incubated and obtain the Pd catalyzer after 1～3 hour.
Preferably, the reaction times of said step c) is 1～3 hour.
Preferably, said organic bases is triethylamine or diisopropylethylamine.
The present invention provides a kind of preparation method of compound, may further comprise the steps: step a) is with the compound shown in the formula I and 4-chloro-6-iodo-quinazoline back flow reaction in Virahol; Step b) is with zeyssatite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with Vinylpyrrolidone polymer, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction; The product that step c) obtains step a), said 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, is prone to reclaim because this heterogeneous Pd catalyzer exists, 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 midbody 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; Obviously, the 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 midbody of the embodiment of the invention 1 preparation;
Fig. 2 is the nucleus magnetic hydrogen spectrum of the lapatinibditosylate midbody analogue of the embodiment of the invention 2 preparations;
Fig. 3 is the nucleus magnetic hydrogen spectrum of the lapatinibditosylate midbody analogue of the embodiment of the invention 3 preparations.
Embodiment
Carry out clear, intactly description in the face of the technical scheme in the embodiment of the invention down, 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 are not making the every other embodiment that is obtained under the creative work prerequisite, all belong to the scope of the present invention's protection.
The invention discloses a kind of preparation method of compound, may further comprise the steps:
Step a) is the compound shown in the formula I and 4-chloro-6-iodo-quinazoline back flow reaction in Virahol,
Figure BDA0000074242790000041
Formula I,
Wherein, R is methyl, halogenic substituent, ester group or cyanic acid;
Step b) is with zeyssatite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with Vinylpyrrolidone polymer, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction;
The product that step c) obtains step a), said 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 midbody or its analogue after the reaction; Said lapatinibditosylate midbody or its analogue have the structure shown in the formula II
Figure BDA0000074242790000051
Formula II,
Wherein, R is methyl, halogenic substituent, ester group or cyanic acid.According to the present invention, the compound shown in the said 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 said formula I was 3-chloro-4-(3-fluoro-benzyloxy)-aniline, the product that finally prepares was the lapatinibditosylate midbody; When the compound shown in the said 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 midbody.
Above-mentioned 3-chloro-4-(3-fluoro-benzyloxy)-aniline is preferably according to following method preparation: orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1 after the reaction, 2-two chloro-4-oil of mirbane; With said 1,2-two chloro-4-oil of mirbane and a fluorophenyl methanol place 2, in the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane after the reaction; Said 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.Said fluorophenyl methanol prepares as follows: fluorobenzaldehyde mixes in methyl alcohol with Peng Qinghuana 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, saidly obtain 1, the temperature of reaction of 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 said 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 said 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, said 3-chloro-4-(4-fluoro-benzyloxy)-aniline is preferably according to following method preparation: orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1 after the reaction, 2-two chloro-4-oil of mirbane; With said 1,2-two chloro-4-oil of mirbane with fluorophenyl methanol is placed 2, in the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(4-fluoro-benzyloxy)-4-oil of mirbane after the reaction; Said 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 is preferably according to following method preparation: orthodichlorobenzene mixes with sulfuric acid, nitric acid, obtains 1 after the reaction, 2-two chloro-4-oil of mirbane; With said 1,2-two chloro-4-oil of mirbane with methylbenzyl alcohol is placed 2, in the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(4-methyl-benzyloxy)-4-oil of mirbane after the reaction; Said 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 through the compound shown in the above-mentioned formula I can find out that the present invention is a raw material with an orthodichlorobenzene and a fluorobenzaldehyde, through nitrated, reduction and three steps of nucleophilic substitution, has obtained the compound shown in the formula I.And, preparation method provided by the invention also overcome one reported method have be not easy the deutero-shortcoming.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); Said 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 POCl3 then, obtain 6-iodo-3H-quinazoline-4-one after the reaction; Said 6-iodo-3H-quinazoline-4-one, triethylamine, POCl3 are mixed in toluene, obtain 4-chloro-6-iodo-quinazoline after the reaction.The time of said 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.
Said step b) provides Pd Preparation of catalysts process, and said step b) is specially: step b1) zeyssatite, tindichloride and trifluoroacetic acid are placed water, obtain mixture after the stirring; Step b2) in said mixture, adds H 2PdCl 4The aqueous solution and Vinylpyrrolidone polymer, 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 a heterogeneous catalyst, and this catalyzer has the advantages that to be prone to recovery, thereby when having saved raw material, has protected environment.
After preparing the Pd catalyzer, product, said 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, 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 said step c) can be identical with second organic solvent described in the step d), also can be different, and it is absolute ethyl alcohol that the present invention preferably adopts first organic solvent, second organic solvent is an absolute ethyl alcohol.In said step d), said organic bases is preferably triethylamine or diisopropylethylamine.
In addition, said step d) also comprises: in said second organic solvent, add Peng Qinghuana, thereby realize the tracking of some plate, the reaction times in the step d) is preferably 1～5 hour, more preferably 2～3 hours.
Can find out that from above-mentioned preparation method preparing method's reaction conditions provided by the invention is gentle, the consumption of the organic solvent that this method adopts is less, simple to operate, is prone to scale operation.In addition, preparation method provided by the invention is suitable equally for preparation lapatinibditosylate midbody analogue.
In order to further specify technical scheme of the present invention; Below in conjunction with embodiment the preferred embodiment of the invention is described; Describe just to further specifying feature and advantage of the present invention but should be appreciated that these, 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, aqueous solution 1.18g) (10mL) then; Temperature is controlled in 50 ℃, adds afterreaction and stirs at ambient temperature 8 hours, then stopped reaction; 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 following:
Figure BDA0000074242790000071
The preparation of 6-iodo-3H-quinazoline-4-one:
With the 5-iodo-2-benzaminic acid of above-mentioned preparation (14mmol 3.70g) is dissolved in the methane amide of 15mL, be heated to 90 ℃ of dissolvings after; The slow POCl3 (control rate of addition) of Dropwise 5 ml with this understanding then, and make maintain at 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 deposition separate out fully after; Suction filtration is used N, dinethylformamide (being called for short DMF) recrystallization; Light gray solid 3.25g, i.e. 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 following:
Figure BDA0000074242790000081
The preparation of 4-chloro-6-iodo-quinazoline:
In the round-bottomed flask of 50ml, add successively 6-iodo-3H-quinazoline-4-one (5mmol, 1.36g), triethylamine (6.5mmol, 618mg); The toluene that adds 20mL then slowly drips POCl3 then at ambient temperature as solvent, and after adding, reaction system continues at room temperature to react 1h; Be warming up to 90 ℃ then, reacted two hours, add shrend behind the stopped reaction and go out; Suction filtration, filtrating is used ethyl acetate extraction, anhydrous sodium sulfate drying; After spinning off solvent, 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 following for d, J=6.0Hz:
Figure BDA0000074242790000082
1, the preparation of 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, 60 ℃ with agitation condition under, drip lentamente orthodichlorobenzene (20mmol, 2.92g); After dropwising, continue under this condition, to react 3 hours, stopped reaction is poured reaction system in the frozen water into then; After treating that its deposition is separated out fully, suction filtration is repeatedly with washing, reduced pressure at room temperature; Light yellow solid 3.72g, promptly 1,2-two chloro-4-oil of mirbane, yield:97.4%.The reaction formula of said process is following:
Figure BDA0000074242790000091
The preparation of 3-fluoro-phenylcarbinol:
Will between fluorobenzaldehyde (10mmol 1.24g) is dissolved in the 25ml methyl alcohol, add then in batches Peng Qinghuana (10mmol, 0.37g); Add the afterreaction system and continue at room temperature to react 6 hours, stopped reaction spins off methyl alcohol, adds entry; Use ethyl acetate extraction then, anhydrous sodium sulfate drying spins off solvent; Colourless liquid 1.257g, i.e. 3-fluoro-phenylcarbinol, yield:99.8%.The reaction formula of said process is following:
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 is 0.75g) with after DMF (5mL) dissolving; At room temperature add sodium hydride then lentamente (7.5mmol 180mg), after adding, continues reaction 2 hours with reaction system in batches; Stopped reaction is poured system in the frozen water into then, after deposition is separated out, and 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 following:
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, (16mmol is 864mg) with 8mL water to add ammonium chloride then; (6mmol, iron powder 336mg) after adding, continue reaction 1 hour with reaction system under 80 ℃ of conditions in adding at last; Stopped reaction, with the system suction filtration, filtrating spins off then, uses ethyl acetate extraction; Anhydrous sodium sulfate drying spins off solvent, gets thick product yellow solid and gets 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 following:
Figure BDA0000074242790000101
The preparation of N-(3-chloro-4-(3-fluorine benzyloxy) phenyl)-6-iodine quinazoline-4-amine:
Under nitrogen protection; (138mg is 0.55mmol) with 4-chloro-6-iodo-quinazoline (145mg, 0.5mmol) stirring and refluxing 3h in Virahol (5mL) with 3-chloro-4-(3-fluoro-benzyloxy)-aniline; Filter; Obtain yellow crystal property 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 following for d, J=6.0Hz:
Figure BDA0000074242790000102
The preparation of N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-[(5-formyl radical) furans-2-yl]-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) is dissolved in the absolute ethyl alcohol (5mL), stirs 1h under 80 ℃ of conditions; Revolve dried 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]-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 following:
The preparation of lapatinibditosylate base:
(120mg 0.25mmol) is dissolved in the anhydrous methanol (5mL), adds triethylamine (Et with N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine 3N) (40.4mg, 0.30mmol), 2-(methylsulfonyl) ethylamine hydrochloride (44mg, 0.30mmol), under nitrogen protection; Room temperature condition stirs 2h down, adds Peng Qinghuana (12mg) then in batches, and the some plate is followed the tracks of, raw material disappearance back stopped reaction; Revolve dried solvent then, use ethyl acetate extraction, anhydrous sodium sulfate drying spins off extraction liquid; Yellow thick product 127mg, yield:86%, i.e. lapatinibditosylate base, the reaction formula of said process is following:
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:
With p-Fluorobenzenecarboxaldehyde (10mmol 1.24g) is dissolved in the 25ml methyl alcohol, add then in batches Peng Qinghuana (10mmol, 0.37g); Add the afterreaction system and continue at room temperature to react 6 hours, stopped reaction spins off methyl alcohol, adds entry; Use ethyl acetate extraction then, anhydrous sodium sulfate drying, spin off behind the solvent colourless liquid 1.19g; Yield:94%, i.e. 4-fluoro-phenylcarbinol, the reaction formula of said process is following:
Figure BDA0000074242790000122
The preparation of 2-chloro-1-(4-fluoro-benzyloxy)-4-oil of mirbane:
With 1 of embodiment 1 preparation, and 2-two chloro-4-oil of mirbane (5mmol, 0.960g) and to fluorophenyl methanol (6mmol is 0.75g) with after DMF (5mL) dissolving; At room temperature add sodium hydride then lentamente (7.5mmol 180mg), after adding, continues reaction 2 hours with reaction system in batches; Stopped reaction is poured system in the frozen water into then, after deposition is separated out; Suction filtration, oven dry gets yellow solid 1.05g; Yield:74%, i.e. 2-chloro-1-(4-fluoro-benzyloxy)-4-oil of mirbane, the reaction formula of said process is following:
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 then ammonium chloride (16mmol, 864mg) with 8ml water; The iron powder that adds 6mmol at last after adding, continues reaction 1 hour, stopped reaction with reaction system under 80 ℃ of conditions; With the system suction filtration, filtrating spins off then, 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 following for d, J=6.0Hz:
Figure BDA0000074242790000132
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) with
(145mg, 0.5mmol) stirring and refluxing 3h in Virahol (5mL) filter the 4-chloro-6-iodo-quinazoline of embodiment 1 preparation, obtain yellow crystal property 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 following:
Figure BDA0000074242790000141
The preparation of N-[3-chloro-4-[(4-fluorophenyl) methoxyl group] phenyl]-6-[(5-formyl radical) furans-2-yl]-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) is dissolved in the absolute ethyl alcohol (5mL), under 80 ℃ of conditions, stirs 1h; Stopped reaction revolves dried solvent then, uses 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]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine.The reaction formula of said process is following:
Figure BDA0000074242790000142
The preparation of N-[3-chloro-4-[(4-fluorophenyl) methoxyl group] phenyl]-6-[5 ((2-methylsulfonyl) ethylamine methyl) furans-2-yl]-4-quinazoline amine:
(95mg 0.2mmol) is dissolved in the anhydrous methanol (5mL), adds diisopropylethylamine (DIPEA) (51.6mg with N-[3-chloro-4-[(3-fluorophenyl) methoxyl group] phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine; 0.40mmol), 2-(methylsulfonyl) ethylamine hydrochloride (64mg, 0.4mmol), under nitrogen protection; Room temperature condition stirs down 5h, add then in batches sodium triacetoxy borohydride (84.4mg, 0.4mmol); The point plate is followed the tracks of, wait raw material to disappear after, stopped reaction revolves dried solvent then; Use ethyl acetate extraction, anhydrous sodium sulfate drying spins 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 following:
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:
With p-tolyl aldehyde (10mmol 1.20g) is dissolved in the 25mL methyl alcohol, add then in batches Peng Qinghuana (10mmol, 0.37g); Add the afterreaction system and continue at room temperature to react 6 hours, stopped reaction spins off methyl alcohol, adds entry; Use ethyl acetate extraction then, anhydrous sodium sulfate drying spins off solvent; Get colourless liquid 1.21g, yield:99.2%, i.e. 4-methyl-phenylcarbinol.The reaction formula of said process is following:
Figure BDA0000074242790000152
The preparation of 2-chloro-1-(4-methyl-benzyloxy)-4-oil of mirbane:
With 1 of embodiment 1 preparation, and 2-two chloro-4-oil of mirbane (5mmol, 0.960g) and to methylbenzyl alcohol (6mmol is 0.732g) after the DMF dissolving with 5mL; At room temperature add sodium hydride then lentamente (7.5mmol 180mg), after adding, continues reaction 2 hours with reaction system in batches; Stopped reaction is poured system in the frozen water into then, after deposition is separated out, and suction filtration; Oven dry gets 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 following:
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, (16mmol is 180mg) with 8mL water to add ammonium chloride then; The iron powder that adds 6mmol at last after adding, continues reaction 1 hour with reaction system under 80 ℃ of conditions; Stopped reaction, with the system suction filtration, filtrating spins off then; Use ethyl acetate extraction, anhydrous sodium sulfate drying spins 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 following:
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 following:
Figure BDA0000074242790000171
The preparation of N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-6-[(5-formyl radical) furans-2-yl]-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) is dissolved in the absolute ethyl alcohol (5mL), stirs 1h under 80 ℃ of conditions; Stopped reaction revolves dried solvent then, uses ethyl acetate extraction; Anhydrous sodium sulfate drying spins off extraction liquid, gets yellow thick product 87mg; Yield:92%, i.e. N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-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 following:
Figure BDA0000074242790000172
The preparation of N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-6-[5 ((2-methylsulfonyl) ethylamine methyl) furans-2-yl]-4-quinazoline amine:
With N-[3-chloro-4-[(4-aminomethyl phenyl) methoxyl group] phenyl]-6-[(5-formyl radical) furans-2-yl]-4-quinazoline amine (94mg 0.2mmol) is dissolved in the anhydrous methanol (5mL), add diisopropylethylamine (DIPEA) (51.6mg, 0.40mmol), 2-(methylsulfonyl) ethylamine hydrochloride (64mg; 0.4mmol), under nitrogen protection, room temperature condition stirs 5h down; Add sodium triacetoxy borohydride then (84.4mg 0.4mmol), puts plate and follows the tracks of in batches; After raw material disappeared, stopped reaction revolved dried solvent then, uses ethyl acetate extraction; Anhydrous sodium sulfate drying spins off extraction liquid, gets yellow thick product 91mg; Yield:79%, i.e. 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 following:
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 conspicuous 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 among this paper.Therefore, the present invention will can not be restricted to these embodiment shown in this paper, but will meet and principle disclosed herein and features of novelty the wideest corresponding to scope.

Claims (10)

1. the preparation method of a compound may further comprise the steps:
Step a) is the compound shown in the formula I and 4-chloro-6-iodo-quinazoline back flow reaction in Virahol,
Figure FDA0000074242780000011
Formula I,
Wherein, R is methyl, halogenic substituent, ester group or cyanic acid;
Step b) is with zeyssatite, tindichloride, trifluoroacetic acid, H 2PdCl 4Mix in water with Vinylpyrrolidone polymer, be heated to 100～150 ℃, obtain the Pd catalyzer after the reaction;
The product that step c) obtains step a), said 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 midbody or its analogue after the reaction.
2. preparation method according to claim 1 is characterized in that, the compound shown in the said formula I is 3-chloro-4-(3-fluoro-benzyloxy)-aniline.
3. preparation method according to claim 2 is characterized in that, said 3-chloro-4-(3-fluoro-benzyloxy)-aniline prepares as follows:
Orthodichlorobenzene is mixed with sulfuric acid, nitric acid, obtain 1 after the reaction, 2-two chloro-4-oil of mirbane;
With said 1,2-two chloro-4-oil of mirbane and a fluorophenyl methanol place 2, in the 5-dimethyl furan, add sodium hydride then, obtain 2-chloro-1-(3-fluoro-benzyloxy)-4-oil of mirbane after the reaction;
Said 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.
4. preparation method according to claim 3 is characterized in that, said fluorophenyl methanol prepares as follows:
Fluorobenzaldehyde mixes in methyl alcohol with Peng Qinghuana 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, saidly obtains 1, and the temperature of reaction of 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 temperature of reaction of the said 3-of obtaining chloro-4-(3-fluoro-benzyloxy)-aniline step is 70～90 ℃, and the reaction times is 1～2 hour.
7. preparation method according to claim 1 is characterized in that, said 4-chloro-6-iodo-quinazoline prepares as follows:
5-iodo-2-benzaminic acid is placed methane amide, mix with POCl3 then, obtain 6-iodo-3H-quinazoline-4-one after the reaction;
Said 6-iodo-3H-quinazoline-4-one, triethylamine, POCl3 are mixed in toluene, obtain 4-chloro-6-iodo-quinazoline after the reaction.
8. preparation method according to claim 1 is characterized in that, said step b) is specially:
Step b1) zeyssatite, tindichloride and trifluoroacetic acid are placed water, obtain mixture after the stirring;
Step b2) in said mixture, adds H 2PdCl 4The aqueous solution and Vinylpyrrolidone polymer, 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, the reaction times of said step c) is 1～3 hour.
10. preparation method according to claim 1 is characterized in that, said organic bases is triethylamine or diisopropylethylamine.
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