N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-preparation method of acrylic amide
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl-preparation method of acrylic amide.
Background technology
Protein tyrosine kinase (PTK) is one type of enzyme that in normal cell growth, plays an important role, and it can be transferred on the residue of protein substrate from ATP by the catalysis phosphate group.Many EGF-R ELISAs (EGFR) albumen all has the effect of protein tyrosine kinase, and the interaction of these acceptors and growth factor also is that the growth of normal regulating cell is necessary.Yet the over-expresses of EGFR through the effect of himself Tyrosylprotein kinase, can cause the hyper-proliferative of cell, finally causes the generation of tumour.
Epidermal Growth Factor Receptor Family can be divided into EGFR (Erb-B1), Erb-B2 (HER-2/neu), ErB-B3 and Erb-B4 by its structure difference.These EGF-R ELISAs all have been proved relevant with most Cancerous disease at present.
The vital role that in cancer pathology, risen of receptor kinase based on imbalance; Specific ptk inhibitor is the research focus of present carcinostatic agent as the exploitation of potential anticancer therapeutic agent, and wherein quinazoline derivant has caused people's extensive concern as ptk inhibitor and then the research that is used for cancer therapy.
WO96/30347 (Chinese patent CN96102992), WO96/33980 relate to some 4-(substituted anilinic)-quinazoline derivant, its prodrug and its pharmacy acceptable salt, and their application in the disease that the treatment cell hyperplasia causes.
The verivate that WO99/06378, WO2000/31048 and WO2000/06555 (Chinese patent CN99808949) also relate to some substituted quinazoline has irreversible ptk inhibitor activity.
Traditional quinazoline derivant needs a very big dosage just can reach efficacious therapy in the disease that causes of treatment cell hyperplasia, and this tends to aggravate the spinoffs such as dysentery and fash of its generation.Need further study the medicine of seeking effective and low toxic side effect for this reason.
PCT/CN2006/002786 discloses one type of novel 4-(substituted anilinic)-quinazoline derivant, with and as the application of ptk inhibitor.Wherein, The compound that embodiment 8 relates to is N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-acrylic amide; It has effect of better inhibited growth to people's epiderm-like squamous cell carcinoma A431, human breast cancer cell BT-474 experiment proof, and is obvious to transplanting in the tumor-inhibiting action of the human epidermal cancer A431 of nude mice.In addition, experiment in vitro shows that this compound has predominant suppressing active to the Erb-B2 kinases.Because N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-acrylic amide is as the prospect of medicinal application, so be necessary its synthesis technique is carried out deep research.
WO2006/071017 has partly related to N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl at embodiment }-preparation of acrylic amide, with N
4-[3-chlorine 4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4; 6-diamines (compound IV) and acrylic acid are raw material; With O-(1H-124 Triazole-1-yl)-N, N, N '; N '-tetramethyl-urea a tetrafluoro borate is for contracting and agent, in the presence of acid scavenger through contracting and reaction obtains N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl-acrylic amide.What this reaction needed price comparison was expensive contracts and agent, and needs the long period just to accomplish reaction, and the aftertreatment that should react in addition is not easy, needs be unfavorable for suitability for industrialized production through column chromatography purification.Product through this prepared does not have crystalline form, and quality product is not high, need be further purified, and this also further makes troubles it to follow-up as medicinal research., need further improve it, a kind of agents useful for same price is cheaper, operation is more easy, product is easy to purifying in the hope of finding, the method for suitable suitability for industrialized production for this reason.
Summary of the invention
Technical problem to be solved by this invention is to the synthetic N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino] of above-mentioned prior art-quinazoline-6-yl }-the existing defective of method of acrylic amide, a kind of cheapness, operation is more easy, product is easy to purifying, suitable suitability for industrialized production method are provided.
The present invention provides a kind of N-{4-of preparation [3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-method of acrylic amide, be with N
4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4; 6-diamines (compound IV) is a raw material; Obtain compound I I with the compound generation acylation reaction shown in the general formula III earlier, compound I I obtains described N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl through eliminating reaction again under alkaline condition }-acrylic amide (compound I).
Wherein X can be a halogen, is preferably chlorine, bromine; Y can be halogen or hydroxyl, is preferably halogen, more preferably chlorine.The used reaction solvent of described acylation reaction is a common solvent well known in the art, is preferably THF, methylene dichloride, chloroform or mixed solvent, and said acylation reaction temperature can be preferably room temperature for the boiling point of 0 ℃~reaction solvent for use.Said elimination reaction can be carried out in the presence of alkali, and suitable alkali comprises organic bases such as triethylamine, and mineral alkali such as alkali-metal carbonate, hydrogenate or oxyhydroxide are preferably sodium hydroxide, and the solvent of said elimination reaction is proton polar solvent such as ethanol.
In preparation method of the present invention, said acylation reaction is reacted and can be carried out in position with eliminating, and promptly carries out with the single jar of synthesis mode that does not separate intermediate product; Also can, acylation reaction, under the alkali existence condition, intermediate product be eliminated reaction again after finishing with the intermediate product separation and purification.In a preferred version of the present invention, said acylation reaction is carried out with single jar of synthesis mode with eliminating to react, thereby makes operation more easy, reaches higher yield.
In the present invention, N
4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4; 6-diamines (compound IV) can be through the preparation of following method: promptly react in proton polar solvent such as Virahol by 3-chloro-4-(3-fluoro-benzyloxy)-aniline (compound VI) and 4-chloro-6-nitro-quinazoline (compound VI I) and make N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-nitro-quinazoline-4-amine (compound V), compound V uses always through this area goes back original reagent and reduces and obtain compound IV.
Above-mentioned 4-chloro-6-nitro-quinazoline (compound VI I) can be through the preparation of following method: with anthranilic acid and methane amide is raw material, under 140~150 ℃ of conditions, contracts and reaction obtains compound I X; The nitrating agent reaction commonly used of compound I X and this area obtains compound VIII; Compound VIII makes said compound VI I through the halogen substitution reaction again.Said nitration reaction can be carried out under the condition known in the art, and nitrating agent can be the nitration mixture that strong acid and concentrated nitric acid form, and is preferably the nitration mixture that the vitriol oil and concentrated nitric acid form; Said halogen substitution reaction reagent is preferably oxalyl chloride, and temperature of reaction is preferably 0~50 ℃, more preferably 20~30 ℃.
N-{4-provided by the invention [3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-preparation method of acrylic amide is with respect to prior art; Avoid the use of expensive O-(1H-124 Triazole-1-yl)-N; N; N ', N '-tetramethyl-urea a tetrafluoro borate adopts 3-chlorpromazine chloride cheap and easy to get as acylating reagent as contracting and agent; This acylation reaction just can be accomplished at comparatively gentle condition (like room temperature) reaction 2~3h; Can not separate the purifying acylate then, it directly is dissolved in common solvents such as ethanol, under alkaline condition (as in the presence of the sodium hydroxide etc.) obtain N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl through eliminating reaction-acrylic amide.The method that the relative prior art of this method provides, reaction conditions is fast gentle, and yield is higher.In addition, the method for prior art has been taked the method for column chromatography on purifying products, and fails to obtain good crystal type product.Method aftertreatment provided by the invention is easy; Need not pass through column chromatography; Can obtain the crystal formation better products through the method for recrystallization, simplify its purification process, make its suitable suitability for industrialized production; And the quality product for preparing through this method is higher, helps further as medicinal research.
The preparation method of the 4-chloro-6-nitro-quinazoline (compound VI I) that adopts among the present invention; Relative prior art; Adopting anthranilic acid cheap and easy to get and methane amide is raw material; In follow-up nitrated and halogenating reaction process, adopt respectively nitration mixture that the vitriol oil commonly used and concentrated nitric acid form as nitrating agent, oxalyl chloride as halogenating reaction reagent, reaction conditions is gentle, does not need special reagent, low, the suitable suitability for industrialized production of cost.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Wherein, DMF refers to N, dinethylformamide; TLC refers to thin-layer chromatography; THF refers to THF.
Embodiment
Embodiment 1
The 3H-quinazoline-4-one
The 50mL methane amide stirs and is warming up to 145 ℃, slowly adds anthranilic acid 60g then, behind reinforced the finishing; Insulation is to there being a large amount of solids to separate out, and termination reaction is in reaction solution impouring frozen water; Suction filtration, the filter cake washing is to colourless, and vacuum-drying gets 3H-quinazoline-4-one 40g; Productive rate 62.6%, Mp215 ℃.
Embodiment 2
6-nitro-3H-quinazoline-4-one
The 60mL vitriol oil is cooled to 0 ℃, slowly adds the 3H-quinazoline-4-one 30g (charge temperature is controlled in 10 ℃) of step gained, finish; Continue to stir 10min; Slowly drip 60mL concentrated nitric acid (dropping temperature is controlled in 10 ℃), slowly be warming up to about 98 ℃ insulation reaction 3h then.Be cooled to room temperature, in reaction solution impouring 600mL frozen water, stir, have a large amount of yellow solids to separate out, suction filtration, the filter cake washing is to neutral, and vacuum-drying gets 6-nitro-3H-quinazoline-4-one 32.6g, productive rate 83.2%.
1H-NMR(DMSO-d
6,400MHz):δ10.21(1H,d),9.11(1H,s),8.39(1H,d),8.03(1H,d),7.65(3H,d).
Embodiment 3
4-chloro-6-nitro-quinazoline
6-nitro-3H-quinazoline-4-one the 30g of gained of last step is added in the 400mL methylene dichloride logical argon shield, ice-water bath cooling.After adding 30mL DMF then, slowly drip the 60mL oxalyl chloride, have a large amount of gases to produce.After dropwising, be warming up to 25 ℃, be incubated to the liquid clarification, TLC confirms reaction end.Then under agitation with in the slow impouring frozen water of reaction solution.Leave standstill, layering, organic layer is used saturated Na successively
2CO
3Solution, saturated NaCl solution are washed anhydrous Na
2SO
4Drying, suction filtration, concentrating under reduced pressure is as for getting 4-chloro-6-nitro-quinazoline 28.0g, productive rate 84.8%.
1H-NMR(DMSO-d
6,400MHz):δ9.18(1H,m),8.60(1H,s),8.39(1H,dd),7.89(1H,dd),7.65(3H,d).
Embodiment 4
N-[3-chloro-4-(3-fluorine benzyloxy)-phenyl]-6-nitro-quinazoline-4-amine
The 4-chloro-6-nitro-quinazoline 25g of gained of last step is dissolved in the 750mL Virahol, adds 3-chloro-4-(3-fluoro-benzyloxy)-aniline 30g, refluxing and stirring 2h; Cooling; Have a large amount of yellow solids to separate out, suction filtration, filter cake are washed with Virahol, ETHYLE ACETATE and methylene dichloride successively.Vacuum-drying gets N-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-6-nitro-quinazoline-4-amine 50.0g, productive rate 98.7%.
1H-NMR(DMSO-d
6,400MHz):δ10.37(1H,s),9.56-9.55(1H,d),8.67(1H,s),8.52-8.49(1H,dd),7.98-7.97(1H,d),7.89-7.87(1H,d),7.72-7.69(1H,dd),7.48-7.42(1H,m),7.32-7.25(3H,m),7.19-7.14(1H,m),5.24(2H,s).
Embodiment 5
N
4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4, the 6-diamines
N-[3-chloro-4-(3-fluorine benzyloxy)-the phenyl]-6-nitro-quinazoline-4-amine 20g of gained of last step is dissolved in the 1.2L absolute ethyl alcohol, adds Pd/C2.1g, be warming up to 60 ℃, feed hydrogen (normal pressure).TLC confirms reaction end, after reacting completely, filters, filtrating is concentrated into a large amount of solids separate out after, cooling, suction filtration.Filter cake is washed with ethanol, vacuum-drying, and after mother liquor concentrated, crystallization obtained N altogether once more
4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamines 16.0g, productive rate 86.1%.
1H-NMR(DMSO-d
6,400MHz):δ9.32(1H,s),8.29(1H,s),8.02(1H,s),7.72-7.69(1H,dd),7.51-7.49(1H,d),7.48-7.42(1H,m),7.32-7.28(2H,m),7.21-7.18(2H,dd),7.16-7.14(1H,m),5.57(2H,s),5.22(2H,s).
Embodiment 6
N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-acrylic amide
N with gained of last step
4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamines 11g is dissolved among the 700mL THF, adds the 6.55mL triethylamine, and temperature is controlled at below-15 ℃.Slowly drip the THF solution (volume content 10%) of 1.96mL3-chlorpromazine chloride, have smog to produce.After dropwising, be warmed up to 25 ℃, continue to stir 3h.Be concentrated to dried, must about 13g bullion, it is dissolved in the 700mL ethanol.Add NaOH solid 1.1g (temperature is controlled at below-10 ℃).Then reaction solution is warming up to 50 ℃, continues to stir 3h.Concentrating under reduced pressure is to doing, and recrystallization in the mixed solvent of THF and methyl alcohol gets N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-acrylic amide 8.1g, productive rate 64.8%, Mp234 ℃.
1H-NMR(DMSO-d
6,400MHz):δ10.49(1H,s),9.81(1H,s),8.76(1H,s),8.50(1H,s),7.96(1H,d),7.87-7.84(1H,d),7.77-7.75(1H,d),7.70-7.68(1H,d),7.67-7.43(1H,m),7.33-7.17(3H,m),6.54-6.47(1H,m),6.34-6.30(1H,d),5.84-5.81(1H,d),5.24(2H,s).
Embodiment 7
N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-anilino]-quinazoline-6-yl }-3-chloro-propionic acid amide
With N
4-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamines 1.08g is dissolved among the 70mL THF, adds 655 μ L triethylamines, and temperature is controlled at below-15 ℃.Slowly drip the THF solution (volume content 10%) of 196 μ L3-chlorpromazine chlorides, have low smoke to produce.After dropwising, be warmed up to 25 ℃, stir 3h.Be concentrated to driedly, recrystallization gets N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline]-quinazoline-6-yl }-3-chloro-propionic acid amide 1.26g, productive rate 94.9%.
Embodiment 8
N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline]-quinazoline-6-yl }-acrylic amide
N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline]-quinazoline-6-yl with gained of last step }-3-chloro-propionic acid amide 300mg is dissolved in it in 18mL ethanol.Add sodium hydrate solid 30mg (temperature is controlled at below-10 ℃).Then reaction solution is warming up to 50 ℃, continues to stir 3h.Concentrating under reduced pressure is to doing, and recrystallization in the mixed solvent of THF and methyl alcohol gets N-{4-[3-chloro-4-(3-fluoro-benzyloxy)-aniline]-quinazoline-6-yl }-acrylic amide 180mg, productive rate 65.0%, Mp234 ℃.
1H-NMR(DMSO-d
6,400MHz):δ10.49(1H,s),9.81(1H,s),8.76(1H,s),8.50(1H,s),7.96(1H,d),7.87-7.84(1H,d),7.77-7.75(1H,d),7.70-7.68(1H,d),7.67-7.43(1H,m),7.33-7.17(3H,m),6.54-6.47(1H,m),6.34-6.30(1H,d),5.84-5.81(1H,d),5.24(2H,s).