CN102827087B - Synthetic method of erlotinib - Google Patents
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Abstract
The invention relates to a synthetic method of N-(3-ethynylphenyl)-6,7-di(2-methoxyethoxy)-4-amidoquinazoline (erlotinib) and its hydrochloride. The method comprises a step that an intermediate 6,7-substituted-4-amidoquinazoline (II) is obtained through ring closure of 4,5-disubstituted-2-amidobenzonitrile (I) and formamidine acetate or formamide. The method has the advantages of simple operation, mild condition and high yield, and has an industrial application prospect.
Description
Technical field
The present invention relates to a kind of N-(3-ethynyl phenyl) synthetic method of-6,7-bis-(2-methoxy ethoxy)-4-amido quinazoline (Tarceva) and hydrochloride thereof.
Background technology
Erlotinid hydrochloride (Erlotinib Hydrochloride), have another name called Erlotinib (Tarceva), Locally Advanced or Metastatic Nsclc (NSCLC is treated as one, Non-Small-CellLung Cancer) newtype drug, that first selectively acting is in the inhibitor of EGF EGFR-TK, multinomial clinical research shows its determined curative effect, toxic and side effect is little, the life quality of patient can be improved significantly, extend life cycle, and cancer of pancreas late, certain clinical value has all been manifested in the treatment of head-neck malignant tumor.
The chemical structural formula of erlotinid hydrochloride is as follows:
Synthetic method bibliographical information about erlotinid hydrochloride is a lot, but sum up get up nothing more than two kinds of strategies: a kind of be as patent US 5747498, CN1860105A, WO2011076813A1, WO2007006091, CN101735157A etc. report obtain Tarceva (Scheme 1) by 4-substituted quinazoline and aromatic amine generation nucleophilic displacement of fluorine, another kind is as Organic ProcessResearch & Development 2007, Tarceva (Scheme 2) is synthesized in being reset by Dimroth of 11,813-816 report.
Wherein R is hydroxyl, benzyloxy, methoxyl group or 2-methoxyethoxy.
Summary of the invention
The object of the present invention is to provide the N-(3-ethynyl phenyl that is brand-new) synthetic method of-6,7-bis-(2-methoxy ethoxy)-4-amido quinazoline (Tarceva) and hydrochloride thereof.The method comprises important midbody compound 6,7-disubstituted quinazoline-4-amine II, and the method is easy and simple to handle, mild condition, and yield is high, has industrial applications prospect.
The object of the invention is to be realized by following concrete technical scheme:
A.4,5-bis-replaces-2-amido benzonitrile I and formamidine acetate or formamide generation ring closure reaction, obtains 6,7-disubstituted quinazoline-4-amine II;
B.6, halobenzene formolite reaction between 7-disubstituted quinazoline-4-amine II and a fluorobenzaldehyde or protection, obtains important intermediate compound N-(3-substituted-phenyl)-6,7-bis-and replaces-4-amido quinazoline III;
C.N-(3-substituted-phenyl)-6,7-bis-replace-4-amido quinazoline III de-acetal protecting group and tertbutyloxycarbonyl in acid condition, or debenzylation obtains N-(3-Fonnylphenyl under catalytic hydrogenation)-6,7-bis-replace-4-amido quinazoline IV;
D. with Bestmann Ohira reagent or Wittig reagent, the formoxyl of compound IV is changed into alkynyl, obtain the precursor compound V of Tarceva or Tarceva;
If E. 6, the 7-substituting groups of the precursor compound V of Tarceva are the hydroxyls of hydroxyl or protection, also need by having reacted methoxy ethyl further, to synthesize Tarceva or erlotinid hydrochloride.
Particular compound structure involved in above-mentioned preparation method and synthetic route as follows:
Wherein R
1hydroxyl, benzyloxy, methoxyl group or 2-methoxyethoxy; R
2hydrogen, benzyl or tertbutyloxycarbonyl; R
3it is the formoxyl of formoxyl or protection.
Further; steps A is carried out as follows: under normal pressure, nitrogen protection; 1.0 ~ 6.0eq formamidine acetate and 4; 5-bis-replace-2-amido benzonitrile I in EGME in room temperature to counterflow condition under reaction close ring; after reacting completely, filter, be spin-dried for filtrate and obtain 6; 7-disubstituted quinazoline-4-amine II, also can occur to close ring with formamide at 170 ~ 280 DEG C or under microwave radiation technology.
Step B be 6,7-disubstituted quinazoline-4-amine II under metallic catalyst and alkali acting in conjunction and between protection the coupling reaction that occurs of halobenzene formaldehyde obtain R
3the midbody compound N-(3-substituted-phenyl of formoxyl of protection)-6,7-bis-replace-4-amido quinazoline III or under the effect of alkali and fluorobenzaldehyde generation aromatic nucleophilic substitution reaction-S
nar, obtains R
3the midbody compound N-(3-substituted-phenyl of formoxyl)-6,7-bis-replace-4-amido quinazoline III.
Further; wherein in step B, coupling reaction is carried out as follows: under normal pressure, nitrogen protection; by halobenzene formaldehyde and 6 between protection; 7-disubstituted quinazoline-4-amine II dissolves in a solvent; at 25 ~ 150 DEG C of reaction 5 ~ 24h under the effect of metal, part and alkali, after reacting completely, cross and filter insoluble matter; filtrate is spin-dried for and namely obtains midbody compound N-(3-substituted-phenyl)-6,7-bis-replace-4-amido quinazoline III.
Wherein said solvent is glycol dimethyl ether, toluene or oxolane.
Further, wherein in step B, coupling reaction is by palladium, three (dibenzalacetone) two one or more catalyst and 1 in palladium or palladium bichloride, the two Diphenyl phosphino ferrocene, 2 of 1'-, the two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene or 4, a kind of alkali acting in conjunction in the complex compound that one or more parts in two diphenylphosphine-9, the 9-dimethyl xanthene of 5-are formed and potash, tertiary fourth potassium, cesium carbonate or sodium methoxide realizes.
Further, wherein in step B, in coupling reaction, the mol ratio of catalyst and midbody compound II is 0.001:1 ~ 0.1:1, the mol ratio of part and midbody compound II is 0.01:1 ~ 0.5:1, the mol ratio of alkali and midbody compound II is 1:1 ~ 10:1, and reaction dissolvent is glycol dimethyl ether, toluene or oxolane.
In addition, in step B, aromatic nucleophilic substitution reaction carries out under the effect of one or more alkali in cesium carbonate, potash, sodium acetate or triethylamine; The mol ratio of alkali and midbody compound II is 2:1 ~ 10:1, and reaction temperature is 50 ~ 120 DEG C, and solvent is toluene or dimethyl formamide.
Particularly; in step B, aromatic nucleophilic substitution reaction carries out as follows: under normal pressure, nitrogen protection; fluorobenzaldehyde and 6 between inciting somebody to action; 7-disubstituted quinazoline-4-amine II is dissolved in toluene or dimethyl formamide, adds 1.0 ~ 4.0eq Anhydrous potassium carbonate or triethylamine, at 50 ~ 120 DEG C of reaction 0.5 ~ 4h; after reacting completely; cross and filter insoluble matter, filtrate is spin-dried for and namely obtains midbody compound N-(3-substituted-phenyl)-6,7-bis-replace-4-amido quinazoline III.
Step C carries out as follows: N-(3-substituted-phenyl)-6,7-bis-replace-4-amido quinazoline III or derivatives thereof react with 2.0 ~ 5.0eq trifluoracetic acid in chloroform or in methyl alcohol with 2.0 ~ 6.0eq 1N ~ 5N hydrochloric acid reaction, temperature all controls at 25 ~ 80 DEG C, the tertbutyloxycarbonyl that the aldehyde radical of protection is hydrolyzed and removes on nitrogen by reaction 2 ~ 5h; If R2 is benzyl, then obtain N-(3-Fonnylphenyl by catalytic hydrogenation debenzylation)-6,7-bis-replace-4-amido quinazoline IV.
Step D carries out as follows: under normal pressure, nitrogen protection, N-(3-Fonnylphenyl)-6,7-bis-replaces-4-amido quinazoline IV and is dissolved in absolute methanol, adds 1.0 ~ 10.0eq Anhydrous potassium carbonate, 1.0 ~ 5.0eq Bestmann Ohira reagent, room temperature reaction 2 ~ 3h, react complete, filter, be spin-dried for organic solvent, obtain N-(3-ethynyl phenyl)-6,7-bis-replaces-4-amido quinazoline, i.e. the precursor compound V of Tarceva or Tarceva; Also N-(3-Fonnylphenyl can be made)-6,7-bis-replace-4-amido quinazoline IV and Wittig reagent reacting, convert aldehyde groups is become alkynyl.
Step e is carried out as follows: under normal pressure, nitrogen protection; by 6; 7-substituting group is that the precursor compound V of the Tarceva of the hydroxyl of hydroxyl or protection and 2.0 ~ 5.0eq 2-Chloroethyl methyl ether are dissolved in acetone, acetonitrile or dimethyl formamide; add 2.0 ~ 5.0eq potash; under reflux conditions react 5 ~ 24h, after question response is complete, filter; filtrate is spin-dried for, and namely obtains Tarceva with t-butyl methyl ether recrystallization.
The invention still further relates to a kind of method of synthesizing Tarceva hydrochloride, the method is at room temperature obtained by reacting with said method synthesis Tarceva and hydrogen chloride gas.
Beneficial effect of the present invention is:
Application 4,5-bis-replaces-2-amido benzonitrile I and formamidine acetate or formamide and obtains to complete Guan Huan the 4-amido quinazoline II that intermediate 6,7-replaces, and mild condition, easy and simple to handle, yield is high.
Detailed description of the invention
Help specifically understand the present invention below by specific embodiment, all just illustrate below, but be not only.The amendment made under other any similar principle of the invention and modification, substitute, combine, simplify and all should be simple substitute of the present invention, all in protection scope of the present invention.
Embodiment 1
(1) 6, the preparation of 7-bis-(2-methoxy ethoxy) quinazoline-4-amine: at normal pressure, under nitrogen protection, by 4, 5-dimethoxyethoxy-2-amido benzonitrile (5.32g, 20mmol) (its synthesis is see Heterocycles 2007, 71, 39 ~ 48) with formamidine acetate (8.33g, 80mmol) be added in a 100mL round-bottomed flask, then 50mL EGME is added, under reflux conditions react 3h, TLC monitors reaction, after question response is complete, be cooled to room temperature, filter, filtrate is spin-dried for, crude product recrystallizing methanol obtains pale solid 3.81g, yield is 65%.1H NMR(300MHz,CDCl3):δ(ppm)=8.32(s,1H),7.63(brs,2H),7.62(s,1H),7.12(s,1H),4.18~4.15(m,4H),3.70~3.67(m,4H),3.28(s,6H).
(2) N-[3-(1, 1-enedioxy methyl) phenyl]-6, 7-bis-(2-methoxy ethoxy)-4-amido quinazoline: at normal pressure, under nitrogen protection, by 6, 7-bis-(2-methoxy ethoxy) quinazoline-4-amine (3.66g, 12.5mmol), 3-bromobenzaldehyde (the 11.4g of ethylene glycol protection, 50mmol), palladium bichloride (230.5mg, 1.3mmol), 4, the two diphenylphosphine-9 of 5-, 9-dimethyl xanthene (3.62g, 6.25mmol), sodium tert-butoxide (9.61g, 100mmol) add in 150mL round-bottomed flask, then 50mL toluene is added, 17h is reacted at 50 DEG C.TLC monitors reaction, after question response is complete, reactant liquor slowly cools to room temperature, filter, be spin-dried for by solution with Rotary Evaporators, the crude product carrene recrystallization obtained obtains N-[3-(1,1-enedioxy methyl) phenyl]-6,7-bis-(2-methoxy ethoxy)-4-amido quinazoline 4.21g, yellow solid, yield is 76%.1H NMR(300MHz,DMSO-d6):δ(ppm)=9.55(s,1H),8.45(s,1H),7.98(d,1H,J=8.1Hz),7.90(s,1H),7.79(s,1H),7.40(dd,1H,J=8.0,7.8Hz),7.22(s,1H),7.17(d,1H,J=7.6Hz),5.75(s,1H),4.30~4.27(m,4H),4.08~4.05(m,4H),3.78-3.37(m,4H),3.35(s,6H).
(3) N-(3-Fonnylphenyl)-6, the preparation of 7-bis-(2-methoxy ethoxy)-4-amido quinazoline: at normal pressure, under nitrogen protection, by N-[3-(1, 1-enedioxy methyl) phenyl]-6, 7-bis-(2-methoxy ethoxy)-4-amido quinazoline (4.43g, 10mmol) be dissolved in 50mL chloroform, be chilled to 0 DEG C, under agitation slowly drip trifluoroacetic acid (3mL, 40mmol), after dripping, mixed liquor is warming up to 25 DEG C of reaction 8h, TLC monitors reaction, question response is complete, be spin-dried for and can obtain N-(3-Fonnylphenyl)-6, 7-bis-(2-methoxy ethoxy)-4-amido quinazoline 3.63g, orange solids, yield is 91%.1H NMR(300MHz,CDCl3)：δ(ppm)=10.05(s,1H),8.68(s,1H),8.24(s,1H),8.13(d,1H,J=8.0Hz),7.66(dd,1H,J=8.0,7.8Hz),7.59(d,1H,J=7.8Hz),7.41(s,1H),7.23(s,1H),4.33~4.27(m,4H),3.87~3.84(m,4H),3.47(s,3H),3.36(s,3H).
(4) synthesis of erlotinid hydrochloride: at normal pressure, under nitrogen protection, by Anhydrous potassium carbonate (0.48g, 3.5mmol) be placed in the flask of a 50mL, then 15mL absolute methanol is added, N-(3-Fonnylphenyl)-6, 7-bis-(2-methoxy ethoxy)-4-amido quinazoline (0.4g, 1mmol), Bestmann Ohira reagent (0.96g, 5.0mmol) (its synthesis is see Tetrahedron2006, 62 (28), 6673-6680), at 20 DEG C of reaction 0.5h, reactant liquor diatomite filtration, filtrate is spin-dried for obtain Tarceva 0.36g, yield is 92%.Tarceva is dissolved in absolute methanol, passes into hydrogen chloride gas, at room temperature react 1.5h, separate out solid, filter, solid is dried and obtains erlotinid hydrochloride 0.39g, white solid, yield 98%.1H NMR(300MHz,DMSO-d6)：δ(ppm)=11.42(s,1H),8.86(s,1H),8.38(s,1H),7.88(s,1H),7.78(d,1H,J=8.0Hz),7.38~7.55(m,3H),4.32~4.38(m,4H),4.29(s,1H),3.77(m,4H),3.36(s,6H).
Embodiment 2
(1) N-tertbutyloxycarbonyl-6, the preparation of 7-bis-(2-methoxy ethoxy) quinazoline-4-amine: at normal pressure, under nitrogen protection, by 4, 5-dimethoxyethoxy-2-amido benzonitrile (13.31g, 50mmol) be added in a 250mL round-bottomed flask with formamide 100mL, 2h is reacted under microwave radiation technology, TLC monitors reaction, after question response is complete, with Rotary Evaporators, most solutions is spun off, add 100mL water again, extracted with diethyl ether (3 × 50mL), organic phase anhydrous magnesium sulfate drying, filter, filtrate is spin-dried for, crude product recrystallizing methanol obtains 6, 7-bis-(2-methoxy ethoxy) quinazoline-4-amine 11.87g, gray solid, yield is 81%.6,7-bis-(2-methoxy ethoxy) quinazoline-4-amine (7.33g, 25mmol) is dissolved in the mixed solvent of 100mL dioxane and 100mL water, be chilled to 0 DEG C, drip the NaOH aqueous solution 5mL of 40%, then add di-tert-butyidicarbonate (10.91g, 50mmol), stirred at ambient temperature.After question response is complete (TLC monitoring), decompression steams partial solvent, uses extracted by ether.Ethyl acetate 100mL is added in aqueous phase, ice bath cooling is lower is 1 ~ 2 with 6N hcl acidifying to pH value, be separated organic phase, aqueous phase ethyl acetate extracts, and merges organic phase, wash with saturated common salt, anhydrous magnesium sulfate drying, is spin-dried for solvent, obtains flaxen N-tertbutyloxycarbonyl-6,7-bis-(2-methoxy ethoxy) quinazoline-4-amine 9.44g, yield is 96%.
(2) N-tertbutyloxycarbonyl-N-[3-(1, 1-enedioxy methyl) phenyl]-6, the preparation of 7-bis-(2-methoxy ethoxy)-4-amido quinazoline: at normal pressure, under nitrogen protection, N-tertbutyloxycarbonyl-6, 7-bis-(2-methoxy ethoxy)-4-amido quinazoline (1.97g, 5mmol), m chlorobenzaldehyde (the 2.76g of ethylene glycol protection, 15mmol), three (dibenzalacetone) two palladium (4.58mg, 0.005mmol), 1, two Diphenyl phosphino ferrocene (the 27.72mg of 1'-, 0.05mmol), cesium carbonate (16.29g, 50mmol) be added in a 100mL round-bottomed flask, then 30mL toluene is added, at 100 DEG C of reaction 8h.TLC monitors reaction, after question response is complete, reactant liquor slowly cools to room temperature, solution is spin-dried for by filtration Rotary Evaporators, the crude product recrystallization obtained obtains N-tertbutyloxycarbonyl-N-[3-(1,1-enedioxy methyl) phenyl]-6,7-bis-(2-methoxy ethoxy)-4-amido quinazoline 2.33g, yield is 86%.
(3) N-(3-Fonnylphenyl)-6, the preparation of 7-bis-(2-methoxy ethoxy)-4-amido quinazoline: at normal pressure, under nitrogen protection, N-tertbutyloxycarbonyl-N-[3-(1, 1-enedioxy methyl) phenyl]-6, 7-bis-(2-methoxy ethoxy)-4-amido quinazoline (6.52g, 12mmol) be dissolved in 40mL methyl alcohol, 3.5N hydrochloric acid (6.8mL is slowly dripped under stirring, 24mmol), after dripping, mixed liquor is at 35 DEG C of reaction 3h, TLC monitors reaction, question response is complete, be spin-dried for and can obtain N-(3-Fonnylphenyl)-6, 7-bis-(2-methoxy ethoxy)-4-amido quinazoline 4.22g, it is an orange solids, yield is 88%.
(4) synthesis of erlotinid hydrochloride: under normal pressure, nitrogen protection, is dissolved in triphenylphosphine methyl ylide (0.54g, 1.25mmol) in 10mL THF; be chilled to-78 DEG C; add potassium tert-butoxide (0.56g, 5mmol) in batches, and remain on-78 DEG C of reactions 30 minutes; slowly instill the N-(3-Fonnylphenyl dissolved with 5mL THF again)-6; 7-bis-(2-methoxy ethoxy)-4-amido quinazoline (0.40g, 1mmol), after dripping off; mixed liquor slowly heats up, and at 50 DEG C of reaction 2h.After TLC monitoring reacts completely, filter, filtrate is spin-dried for, and washes can obtain Tarceva 0.36g with pure benzinum, and yield is 91%.Be dissolved in by Tarceva in absolute methanol, pass into hydrogen chloride gas, at room temperature reaction 3h, separate out solid, filtering and solid oven dry is obtained erlotinid hydrochloride 0.38g, is white solid, yield 98%.
Triphenylphosphine methyl ylide can business be bought, and following methods also can be taked to prepare: under normal pressure, nitrogen protection, and methylene bromide (7mL, 100mmol) and triphenylphosphine (26.2g, 100mmol) are dissolved in 100mL toluene, under reflux conditions react.After TLC monitoring reacts completely, filter, filter cake acetone (3 × 100mL) is washed, and dry under infrared lamp and can obtain white solid 42.29g, yield is 97%.
Embodiment 3
(1) N-benzyl-6, the preparation of 7-benzyloxy quinazoline-4-amine: at normal pressure, under nitrogen protection, by 4, 5-benzyloxy-2-amido benzonitrile (8.25g, 25mmol) (its synthesis is see Heterocycles 2007, 71, 39 ~ 48) with formamidine acetate (4.12g, 40mmol) be added in a 150mL round-bottomed flask, then 50mL EGME is added, at 30 DEG C of reaction 10h, TLC monitors reaction, after question response is complete, filter, with Rotary Evaporators, solution is spin-dried for, crude product recrystallization obtains 6, 7-benzyloxy quinazoline-4-amine 5.98g, it is a gray solid, yield is 67%.Under argon shield, 6,7-benzyloxy quinazoline-4-amine (1.25g; 3.5mmol), benzaldehyde (0.5mL, 5.3mmol) and sodium cyanoborohydride (0.33g, 5.3mmol) are dissolved in toluene; add sodium bicarbonate solid (1.47g, 17.5mmol) and molecular sieve 2g, stirring at room temperature 24h; with diatomite filtration; washed with dichloromethane, is spin-dried for, and product recrystallization in the mixed solution of benzinum and ethyl acetate obtains N-benzyl-6; 7-benzyloxy quinazoline-4-amine 1.17g, yield is 98%.
(2) N-benzyl-N-(3 Fonnylphenyl)-6; the preparation of 7-benzyloxy-4-amido quinazoline: under normal pressure, nitrogen protection; N-benzyl-6; 7-benzyloxy quinazoline-4-amine (5.81g; 13mmol); between fluorobenzaldehyde (3.87g, 31.2mmol) be dissolved in 50mL dimethyl formamide, 120 DEG C reaction 5h.After TLC monitoring reacts completely, spin off most of solvent, add 100mL water, dichloromethane extraction (3 × 50mL); merge organic phase, anhydrous magnesium sulfate drying, filter; be spin-dried for obtain N-benzyl-N-(3-Fonnylphenyl)-6,7-benzyloxy-4-amido quinazoline 3.80g, yield is 53%.
(3) N-(3-Fonnylphenyl)-6; the preparation of 7-dihydroxy-4-amido quinazoline: under normal pressure, nitrogen protection; by N-benzyl-N-(3-Fonnylphenyl)-6; 7-benzyloxy-4-amido quinazoline (4.85g; 8.8mmol) be dissolved in 50mL ethanol; add 30%Pd/C(1.44g); nitrogen is replaced into hydrogen, and under 28 DEG C of hydrogen effects, catalytic reaction removes benzyl, after TLC monitoring reacts completely; filter; rotary evaporated to dryness, obtains N-(3-Fonnylphenyl)-6,7-dihydroxy-4-amido quinazoline 2.45g; for orange solids, yield is 99%.
(4) synthesis of erlotinid hydrochloride: under normal pressure, nitrogen protection; potash (3.31g; 24mmol), N-(3-Fonnylphenyl)-6; 7-dihydroxy-4-amido quinazoline (3.37g; 12mmol), Bestmann Ohira reagent (3.46g; 18mmol) be added in a 100mL three-necked bottle, 28 DEG C of reactions with 30mL absolute methanol.After TLC monitoring reacts completely, filter, reduced pressure concentration, obtains N-(3-ethynyl phenyl)-6,7-dihydroxy-4-amido quinazoline 2.69g, yield is 81%.Again by N-(3-ethynyl phenyl)-6,7-dihydroxy-4-amido quinazoline and 2-chloroethyl methyl ether (2.3mL, 24mmol), potash (3.31g, 24mmol) be dissolved in 50mL acetone, after back flow reaction 10h, TLC monitoring has been reacted, filter, filtrate is spin-dried for, and obtains erlotinid hydrochloride 4.29g with recrystallisation from isopropanol, and yield is 83%(tri-step yield).
Embodiment 4
(1) 6, the preparation of 7-dimethoxyquinazoline-4-amine: at normal pressure, under nitrogen protection, 4, 5-dimethoxy-2-amido benzonitrile (2.81g, 15.8mmol) (with 3, 4-dimethoxy benzaldehyde is initiation material, with reference to Heterocycles 2007, 71, the method of 39 ~ 48., dewater through aldehyde radical condensation, nitrated and reduction is total to three-step reaction and obtains, yield 86.8%) be added in 50mL formamide, 0.5h is reacted under microwave radiation technology, TLC monitors reaction, after question response is complete, with Rotary Evaporators, most of solvent is spun off, add 100mL water again, extracted with diethyl ether (3 × 50mL), organic phase anhydrous magnesium sulfate drying, filter, filtrate is spin-dried for, crude product recrystallizing methanol obtains 6, 7-dimethoxyquinazoline-4-amine 2.82g, gray solid, yield is 87%.
(2) N-[3-(1; 1-dimethoxy-methyl) phenyl]-6; the preparation of 7-dimethoxy-4 '-amido quinazoline: under normal pressure, nitrogen protection; palladium (38mg; 0.17mmol), 2; the two diphenyl phosphine-1 of 2'-; 1'-dinaphthalene (1.06g, 1.7mmol) is added in toluene, first flows down activation 10 minutes at room temperature under nitrogen; add 6 subsequently; the contracting methyl ether (5.73g, 20.6mmol) of 7-dimethoxyquinazoline-4-amine (3.53g, 17.2mmol), a benzaldehyde iodine and potash (9.49g; 68.8mmol), mixed liquor is 110 DEG C of reactions.After TLC monitoring reacts completely, filter, filtrate reduced in volume, crude product re-crystallizing in ethyl acetate obtains N-[3-(1,1-dimethoxy-methyl) phenyl]-6, the 7-dimethoxy-4 's-amido quinazoline solid 4.39g of white, and yield is 72%.
(3) N-(3-ethynyl phenyl)-6; the preparation of 7-dimethoxy-4 '-amido quinazoline: under normal pressure, nitrogen protection; N-[3-(1; 1-dimethoxy-methyl) phenyl]-6; 7-dimethoxy-4 '-amido quinazoline (19.53g; 55mmol) dissolve with 100mL methyl alcohol; slowly drip 24mL3.5N HCl solution; after dripping; at 25 DEG C of reaction 2h, after reacting completely, be spin-dried for and obtain N-(3-Fonnylphenyl)-6; 7-dimethoxy-4 '-amido quinazoline 14.96g, yield is 88%.By N-(3-Fonnylphenyl)-6,7-dimethoxy-4 's-amido quinazoline (7.73g, 25mmol), potash (6.9g, 50mmol) and Bestmann Ohira reagent (5.76g, 30mmol) be dissolved in methyl alcohol, 30 DEG C of reactions.After TLC monitoring reacts completely, filter, filtrate reduced in volume, crude product re-crystallizing in ethyl acetate obtains the N-(3-ethynyl phenyl of white)-6,7-dimethoxy-4 's-amido quinazoline solid 7.02g, yield is 92%.
(4) N-(3-ethynyl phenyl)-6; the preparation of 7-dihydroxy-4-amido quinazoline: under normal pressure, nitrogen protection; N-(3-ethynyl phenyl)-6; 7-dimethoxy-4 '-amido quinazoline (5.7g; 18.7mmol) be dissolved in 40% hydrobromic acid solution (25mL); 55 DEG C of reaction 5h; after TLC monitoring reacts completely, saturated sodium carbonate solution adjusts pH=8 ~ 9, extracts with ethyl acetate; anhydrous sodium sulfate drying; filter, remove solvent under reduced pressure, obtain the N-(3-ethynyl phenyl of white)-6; 7-dihydroxy-4-amido quinazoline solid 5.08g, yield is 98%.
(5) preparation of erlotinid hydrochloride: N-(3-ethynyl phenyl under normal pressure, nitrogen protection)-6; 7-dihydroxy-4-amido quinazoline (1.72g; 6.2mmol), potash (2.14g; 15.5mmol), 2-chloroethyl methyl ether (1.5mL; 15.5mmol) be added in 30mL acetonitrile, at 80 DEG C of reaction 6h.After TLC monitoring reacts completely, filter out insoluble matter, be spin-dried for solvent, the mixed solvent recrystallization of crude product benzinum and carrene, obtain white Tarceva 2.32g, yield is 95%.Be dissolved in by Tarceva in absolute methanol, pass into hydrogen chloride gas, at room temperature react 1.5h, separate out solid, filter, dried by solid and obtain erlotinid hydrochloride, altogether 2.35g, yield is 93%.
Claims (7)
1. synthesize a method of the precursor compound V of Tarceva or Tarceva, it is characterized in that described method is synthesized by the midbody compound II shown in following formula,
Wherein R
1for hydroxyl, benzyloxy, methoxyl group or 2-methoxyethoxy, R
2for hydrogen, benzyl or tertbutyloxycarbonyl.
2. method according to claim 1, is characterized in that, the method comprises halobenzene formaldehyde generation coupling reaction between midbody compound II and protection and obtains R
3it is the intermediate compound III of the formoxyl of protection; Or under the effect of alkali and fluorobenzaldehyde generation aromatic nucleophilic substitution reaction-S
nar, obtains R
3the intermediate compound III of formoxyl,
The structure of the compound III wherein related to is:
Wherein R
1, R
2as defined in claim 1; R
3it is the formoxyl of formoxyl or protection.
3. method according to claim 2, it is characterized in that, coupling reaction is carried out under the acting in conjunction of catalyst and alkali, wherein said catalyst is palladium, three (dibenzalacetone) two one or more and ligand 1 in palladium or palladium bichloride, the two Diphenyl phosphino ferrocene of 1'-, 2,2'-two diphenyl phosphine-1,1'-dinaphthalenes or 4, one or more complex compounds formed in two diphenylphosphine-9, the 9-dimethyl xanthene of 5-; Alkali is potash, potassium tert-butoxide or sodium methoxide.
4. the method according to any one of claim 2-3, is characterized in that, coupling reaction is carry out in glycol dimethyl ether, toluene or oxolane at reaction dissolvent.
5. method according to claim 2, is characterized in that, aromatic nucleophilic substitution reaction carries out under the effect of one or more alkali in cesium carbonate, potash, sodium acetate or triethylamine.
6. method according to claim 5, is characterized in that, the mol ratio of alkali and midbody compound II is 2:1 ~ 10:1, and reaction temperature is 50 ~ 120 DEG C, and reaction dissolvent is toluene or dimethyl formamide.
7. method according to claim 1 and 2, is characterized in that, midbody compound II by Compound I and formamide or formamidine acetate Reactive Synthesis,
Wherein R
1identical with the definition in claim 1.
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