CN102827087A - Synthetic method of erlotinib - Google Patents
Synthetic method of erlotinib Download PDFInfo
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- CN102827087A CN102827087A CN2012101999926A CN201210199992A CN102827087A CN 102827087 A CN102827087 A CN 102827087A CN 2012101999926 A CN2012101999926 A CN 2012101999926A CN 201210199992 A CN201210199992 A CN 201210199992A CN 102827087 A CN102827087 A CN 102827087A
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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)-6, the compound method of 7-two (2-methoxy ethoxy)-4-amido quinazoline (Tarceva) and hydrochloride thereof.
Background technology
Hydrochloric acid Tarceva (Erlotinib Hydrochloride); Have another name called Te Luokai (Tarceva), as the newtype drug of local late period of a kind of treatment or transitivity nonsmall-cell lung cancer (NSCLC, Non-Small-Cell Lung Cancer); Be the suppressor factor of first selectively acting in the Urogastron Tyrosylprotein kinase; Multinomial clinical study shows its determined curative effect, and toxic side effect is little, can improve patient's life quality significantly; Prolong lifetime, and all manifested certain clinical value in the treatment of carcinoma of the pancreas, head-neck malignant tumor late.
The chemical structural formula of hydrochloric acid Tarceva is following:
Compound method bibliographical information about the hydrochloric acid Tarceva is a lot; But sum up nothing more than two kinds of strategies: a kind of be as reports such as patent US 5747498, CN1860105A, WO2011076813A1, WO2007006091, CN101735157A pass through the 4-substituted quinazoline and aromatic amine generation nucleophilic substitution obtains Tarceva (Scheme 1); Another kind is like Organic Process Research&Development 2007; 11, the Dimroth that passes through of 813-816 report resets synthetic Tarceva (Scheme 2).
Wherein R is hydroxyl, benzyloxy, methoxyl group or 2-methoxyethoxy.
Summary of the invention
The object of the present invention is to provide a brand-new N-(3-ethynyl phenyl)-6, the compound method of 7-two (2-methoxy ethoxy)-4-amido quinazoline (Tarceva) and hydrochloride thereof.This method comprises important midbody compound 6,7-disubstituted quinazoline-4-amine II, and this method is easy and simple to handle, mild condition, and yield is high, has the industrial applications prospect.
The objective of the invention is to realize through following concrete technical scheme:
A.4,5-two replacement-2-amido cyanobenzene I and FORMAMIDINE ACETATE or methane amide generation ring closure reaction obtain 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-two replacement-4-amido quinazoline III;
C.N-(3-substituted-phenyl)-6,7-two replacement-4-amido quinazoline III take off acetal protection base and tertbutyloxycarbonyl under acidic conditions, or debenzylation obtains N-(3-formyl radical phenyl)-6 under catalytic hydrogenation, 7-two replacement-4-amido quinazoline IV;
D. with Bestmann Ohira reagent or Wittig reagent the formyl radical of compound IV is changed into alkynyl, obtain the precursor compound V of Tarceva or Tarceva;
E. if the precursor compound V of Tarceva 6, the 7-substituting group is the hydroxyl of hydroxyl or protection, also need accomplish methoxy ethylization through further reaction, with synthetic Tarceva or hydrochloric acid Tarceva.
Particular compound structure and synthetic route involved among the above-mentioned preparation method are following:
R wherein
1Be hydroxyl, benzyloxy, methoxyl group or 2-methoxyethoxy; R
2Be hydrogen, benzyl or tertbutyloxycarbonyl; R
3It is the formyl radical of formyl radical or protection.
Further, steps A is carried out as follows: under normal pressure, nitrogen protection, and 1.0 ~ 6.0eq FORMAMIDINE ACETATE and 4; 5-two replacement-2-amido cyanobenzene I react under room temperature to reflux conditions in EGME and close ring; After reacting completely, filter, revolve dried filtrating and obtain 6; Ring also can take place to close with methane amide in 7-disubstituted quinazoline-4-amine II under 170 ~ 280 ℃ or under microwave-assisted.
Step B is 6,7-disubstituted quinazoline-4-amine II under metal catalyst and the alkali acting in conjunction and protection between the linked reaction that takes place of halobenzene formaldehyde obtain R
3Be the midbody compound N-(3-substituted-phenyl)-6 of formyl radical of protection, 7-two replacement-4-amido quinazoline III or under the effect of alkali and a fluorobenzaldehyde fragrant nucleophilic substitution reaction-S takes place
NAr obtains R
3Be the midbody compound N-(3-substituted-phenyl)-6 of formyl radical, 7-two replacement-4-amido quinazoline III.
Further, wherein linked reaction is to carry out as follows among the step B: under normal pressure, nitrogen protection, with halobenzene formaldehyde and 6 between protection; 7-disubstituted quinazoline-4-amine II is dissolved in the solvent; Under the effect of metal, part and alkali,, after reacting completely, remove by filter insolubles at 25 ~ 150 ℃ of reaction 5 ~ 24h; Filtrating is revolved to do and is promptly obtained midbody compound N-(3-substituted-phenyl)-6,7-two replacement-4-amido quinazoline III.
Wherein said solvent is glycol dimethyl ether, toluene or THF.
Further; Wherein linked reaction is through one or more catalyzer and 1 in palladium, three (dibenzalacetone) two palladiums or the Palladous chloride among the step B; The two diphenylphosphine ferrocene, 2 of 1'-, the two diphenyl phosphines-1 of 2'-, 1'-dinaphthalene or 4; The two diphenylphosphines-9 of 5-, complex compound that one or more parts in the 9-dimethyl-oxa-anthracene form and a kind of alkali acting in conjunction in salt of wormwood, uncle's fourth potassium, cesium carbonate or the sodium methylate realize.
Further; Wherein among the step B in the linked reaction mol ratio of catalyzer and midbody compound II be 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 solvent is glycol dimethyl ether, toluene or THF.
In addition, fragrant nucleophilic substitution reaction is to carry out under the effect of one or more alkali in cesium carbonate, salt of wormwood, sodium-acetate or triethylamine among the step B; The mol ratio of alkali and midbody compound II is 2:1 ~ 10:1, and temperature of reaction is 50 ~ 120 ℃, and solvent is toluene or N.
Particularly, fragrant nucleophilic substitution reaction carries out as follows among the step B: under normal pressure, nitrogen protection, and fluorobenzaldehyde and 6 between inciting somebody to action; 7-disubstituted quinazoline-4-amine II is dissolved in toluene or the N, adds 1.0 ~ 4.0eq Anhydrous potassium carbonate or triethylamine, at 50 ~ 120 ℃ of reaction 0.5 ~ 4h; After reacting completely; Remove by filter insolubles, filtrating is revolved to do and is promptly obtained midbody compound N-(3-substituted-phenyl)-6,7-two replacement-4-amido quinazoline III.
Step C carries out as follows: N-(3-substituted-phenyl)-6; 7-two replacement-4-amido quinazoline III or derivatives thereofs in chloroform with 2.0 ~ 5.0eq trifluoracetic acid reaction or in methyl alcohol with 2.0 ~ 6.0eq 1N ~ 5N hydrochloric acid reaction; Temperature all is controlled at 25 ~ 80 ℃, and reaction 2 ~ 5h is with the aldehyde radical hydrolysis of protecting and remove the tertbutyloxycarbonyl on the nitrogen; If R2 is a benzyl, then obtain N-(3-formyl radical phenyl)-6,7-two replacement-4-amido quinazoline IV through the catalytic hydrogenation debenzylation.
Step D carries out as follows: under normal pressure, nitrogen protection, and N-(3-formyl radical phenyl)-6,7-two replacement-4-amido quinazoline IV are dissolved in the anhydrous methanol; Add 1.0 ~ 10.0eq Anhydrous potassium carbonate, 1.0 ~ 5.0eq Bestmann Ohira reagent, room temperature reaction 2 ~ 3h, reaction finishes; Filter, revolve dried organic solvent, obtain N-(3-ethynyl phenyl)-6; 7-two replacement-4-amido quinazolines, i.e. the precursor compound V of Tarceva or Tarceva; Also can make N-(3-formyl radical phenyl)-6,7-two replacement-4-amido quinazoline IV and Wittig reagent reacts change into alkynyl with aldehyde radical.
Step e is carried out as follows: under normal pressure, nitrogen protection, with 6, the 7-substituting group is that precursor compound V and 2.0 ~ 5.0eq 2-chloro ethyl-methyl ether of Tarceva of the hydroxyl of hydroxyl or protection is dissolved in acetone, acetonitrile or the N; Add 2.0 ~ 5.0eq salt of wormwood; Under refluxad react 5 ~ 24h, after question response is complete, filter; Filtrating is revolved dried, promptly obtains Tarceva with the t-butyl methyl ether recrystallization.
The invention still further relates to a kind of method of synthetic Tarceva hydrochloride, this method is to obtain at room temperature reacting with synthetic Tarceva of aforesaid method and hydrogen chloride gas.
Beneficial effect of the present invention is:
Use 4,5-two replacement-2-amido cyanobenzene I and FORMAMIDINE ACETATE or methane amide are accomplished to close to encircle and are obtained midbody 6, the substituted 4-amido of 7-quinazoline II, and mild condition, easy and simple to handle, yield is high.
Embodiment
Help specifically understand the present invention through specific embodiment below, below all just illustrate, but be not only.Modification of being made under other any similar principle of the invention and modification, substitute, combination, simplify and all should be simple substitute of the present invention, all in protection scope of the present invention.
Embodiment 1
The preparation of (1) 6,7-two (2-methoxy ethoxy) quinazoline-4-amine: under normal pressure, nitrogen protection, with 4,5-dimethoxy oxyethyl group-2-amido cyanobenzene (5.32g; 20mmol) (its synthetic referring to Heterocycles 2007,71,39 ~ 48) (8.33g 80mmol) is added in the 100mL round-bottomed flask with FORMAMIDINE ACETATE; Add the 50mL EGME then, under refluxad react 3h, the TLC monitoring reaction; After question response is complete, be cooled to room temperature, filter; Filtrating is revolved dried, bullion obtains pale solid 3.81g with recrystallizing methanol, and 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-two (2-methoxy ethoxy)-4-amido quinazoline: under normal pressure, nitrogen protection; With 6, and 7-two (2-methoxy ethoxy) quinazoline-4-amine (3.66g, 12.5mmol), the 3-bromobenzaldehyde (11.4g of terepthaloyl moietie protection; 50mmol), Palladous chloride (230.5mg, 1.3mmol), 4, the two diphenylphosphines-9 of 5-; 9-dimethyl-oxa-anthracene (3.62g, 6.25mmol), (9.61g 100mmol) adds in the 150mL round-bottomed flask sodium tert-butoxide; Add 50mL toluene then, react 17h down at 50 ℃.The TLC monitoring reaction, after question response was complete, reaction solution slowly cooled to room temperature; Filter, with Rotary Evaporators solution is revolved driedly, the bullion that obtains obtains N-with the methylene dichloride recrystallization, and [3-(1; 1-enedioxy methyl) phenyl]-6; 7-two (2-methoxy ethoxy)-4-amido quinazoline 4.21g, yellow solid, yield are 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-formyl radical phenyl)-6, the preparation of 7-two (2-methoxy ethoxy)-4-amido quinazoline: under normal pressure, nitrogen protection, with N-[3-(1,1-enedioxy methyl) phenyl]-6; (4.43g 10mmol) is dissolved in the 50mL trichloromethane 7-two (2-methoxy ethoxy)-4-amido quinazoline, is chilled to 0 ℃, under agitation slowly drips trifluoroacetic acid (3mL; 40mmol), after dripping, mixed solution is warming up to 25 ℃ of reaction 8h; The TLC monitoring reaction, question response is complete, revolves to do to obtain N-(3-formyl radical phenyl)-6; 7-two (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) the hydrochloric acid Tarceva is synthetic: under normal pressure, nitrogen protection, (0.48g 3.5mmol) places the flask of a 50mL with Anhydrous potassium carbonate; Add 15mL anhydrous methanol, N-(3-formyl radical phenyl)-6 then, and 7-two (2-methoxy ethoxy)-4-amido quinazoline (0.4g, 1mmol), Bestmann Ohira reagent (0.96g; 5.0mmol) (it is synthetic referring to Tetrahedron2006, and 62 (28), 6673-6680); At 20 ℃ of reaction 0.5h; Reaction solution is used diatomite filtration, and filtrating is revolved dried Tarceva 0.36g, and yield is 92%.Tarceva is dissolved in the anhydrous methanol, feeds hydrogen chloride gas, at room temperature react 1.5h, separate out solid, filter, the solid oven dry is obtained hydrochloric acid Tarceva 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-two (2-methoxy ethoxy) quinazoline-4-amine: under normal pressure, nitrogen protection, with 4,5-dimethoxy oxyethyl group-2-amido cyanobenzene (13.31g; 50mmol) be added in the 250mL round-bottomed flask with methane amide 100mL, reaction 2h under microwave-assisted, the TLC monitoring reaction is after question response is complete; With Rotary Evaporators most solutions is spun off, add 100mL water again, (3 * 50mL), organic phase is used anhydrous magnesium sulfate drying to extracted with diethyl ether; Filter, filtrating is revolved dried, bullion obtains 6 with recrystallizing methanol; 7-two (2-methoxy ethoxy) quinazoline-4-amine 11.87g, gray solid, yield is 81%.6, (7.33g 25mmol) is dissolved in the mixed solvent of 100mL dioxane and 100mL water 7-two (2-methoxy ethoxy) quinazoline-4-amine; Be chilled to 0 ℃, drip 40% NaOH aqueous solution 5mL, add the tertiary butyl two carbonic ether (10.91g then; 50mmol), stir under the room temperature.The intact back of question response (TLC monitoring), decompression steams partial solvent, uses ether extraction.Aqueous phase adds ETHYLE ACETATE 100mL, and it is 1 ~ 2 to the pH value that the ice bath cooling is used the 6N hcl acidifying down, separates organic phase; Water is used ethyl acetate extraction, merges organic phase, washes with saturated common salt; Anhydrous magnesium sulfate drying revolves dried solvent, obtains flaxen N-tertbutyloxycarbonyl-6; 7-two (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-two (2-methoxy ethoxy)-4-amido quinazoline: under normal pressure, nitrogen protection; N-tertbutyloxycarbonyl-6, and 7-two (2-methoxy ethoxy)-4-amido quinazoline (1.97g, 5mmol), the m chlorobenzaldehyde (2.76g of terepthaloyl moietie protection; 15mmol), three (dibenzalacetones), two palladiums (4.58mg, 0.005mmol), 1, the two diphenylphosphine ferrocene (27.72mg of 1'-; 0.05mmol), cesium carbonate (16.29g; 50mmol) be added in the 100mL round-bottomed flask, add 30mL toluene then, at 100 ℃ of reaction 8h.The TLC monitoring reaction; After question response was complete, reaction solution slowly cooled to room temperature, filtered and solution was revolved dried with Rotary Evaporators; The bullion recrystallization that obtains obtains N-tertbutyloxycarbonyl-N-, and [3-(1; 1-enedioxy methyl) phenyl]-6,7-two (2-methoxy ethoxy)-4-amido quinazoline 2.33g, yield is 86%.
(3) N-(3-formyl radical phenyl)-6, the preparation of 7-two (2-methoxy ethoxy)-4-amido quinazoline: under normal pressure, nitrogen protection, N-tertbutyloxycarbonyl-N-[3-(1,1-enedioxy methyl) phenyl]-6; (6.52g 12mmol) is dissolved in the 40mL methyl alcohol 7-two (2-methoxy ethoxy)-4-amido quinazoline, stirs slowly to drip 3.5N hydrochloric acid (6.8mL down; 24mmol), after dripping, mixed solution is at 35 ℃ of reaction 3h; The TLC monitoring reaction, question response is complete, revolves to do to obtain N-(3-formyl radical phenyl)-6; 7-two (2-methoxy ethoxy)-4-amido quinazoline 4.22g is an orange solids, and yield is 88%.
(4) the hydrochloric acid Tarceva is synthetic: under normal pressure, nitrogen protection, (0.54g 1.25mmol) is dissolved among the 10mL THF, is chilled to-78 ℃ with triphenylphosphine methyl ylide; Add potassium tert.-butoxide (0.56g 5mmol), and remains on-78 ℃ of reactions 30 minutes in batches; Slowly splash into again with 5mL THF dissolved N-(3-formyl radical phenyl)-6, and 7-two (2-methoxy ethoxy)-4-amido quinazoline (0.40g, 1mmol); After dripping off, mixed solution slowly heats up, and at 50 ℃ of reaction 2h.After the TLC monitoring reaction is complete, filter, filtrating is revolved dried, washes with pure sherwood oil and can obtain Tarceva 0.36g, and yield is 91%.Tarceva is dissolved in the anhydrous methanol, feeds hydrogen chloride gas,, separate out solid, filter the solid oven dry is obtained hydrochloric acid Tarceva 0.38g, be white solid, yield 98% at room temperature reaction 3h.
Triphenylphosphine methyl ylide can commercially be bought, and also can take following method preparation: under normal pressure, nitrogen protection, (7mL, 100mmol) (26.2g 100mmol) is dissolved in the 100mL toluene methylene bromide, under refluxad reaction with triphenylphosphine.After the TLC monitoring reaction is complete, filter, (3 * 100mL) wash filter cake, and oven dry can get white solid 42.29g under ir lamp, and yield is 97% with acetone.
Embodiment 3
(1) N-benzyl-6, the preparation of 7-benzyloxy quinazoline-4-amine: under normal pressure, nitrogen protection, with 4,5-benzyloxy-2-amido cyanobenzene (8.25g; 25mmol) (its synthetic referring to Heterocycles 2007,71,39 ~ 48) (4.12g 40mmol) is added in the 150mL round-bottomed flask with FORMAMIDINE ACETATE; Add the 50mL EGME then, at 30 ℃ of reaction 10h, the TLC monitoring reaction is after question response is complete; Filter, with Rotary Evaporators solution is revolved driedly, the bullion recrystallization obtains 6; 7-benzyloxy quinazoline-4-amine 5.98g is a gray solid, and yield is 67%.Under argon shield, 6,7-benzyloxy quinazoline-4-amine (1.25g, 3.5mmol), phenyl aldehyde (0.5mL; 5.3mmol) and sodium cyanoborohydride (0.33g 5.3mmol) is dissolved in the toluene, and (1.47g is 17.5mmol) with molecular sieve 2g to add sodium bicarbonate solid; Stirring at room 24h uses diatomite filtration, and washed with dichloromethane is revolved dried; Product recrystallization in the mixing solutions of sherwood oil and ETHYLE ACETATE obtains N-benzyl-6,7-benzyloxy quinazoline-4-amine 1.17g, and yield is 98%.
(2) N-benzyl-N-(3 formyl radical phenyl)-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) is dissolved in the 50mL N, 120 ℃ the reaction 5h.After the TLC monitoring reaction is complete, spin off most of solvent, add 100mL water, dichloromethane extraction (3 * 50mL); Merge organic phase, anhydrous magnesium sulfate drying filters; Revolve dried N-benzyl-N-(3-formyl radical phenyl)-6,7-benzyloxy-4-amido quinazoline 3.80g, yield is 53%.
(3) N-(3-formyl radical phenyl)-6, the preparation of 7-dihydroxyl-4-amido quinazoline: under normal pressure, nitrogen protection, with N-benzyl-N-(3-formyl radical phenyl)-6; (4.85g 8.8mmol) is dissolved in the 50mL ethanol 7-benzyloxy-4-amido quinazoline, adds 30%Pd/C (1.44g); With nitrogen replacement is hydrogen, and catalyzed reaction removes benzyl under 28 ℃ of hydrogen effects, after the TLC monitoring reaction is complete; Filter, rotary evaporation gets N-(3-formyl radical phenyl)-6 to doing; 7-dihydroxyl-4-amido quinazoline 2.45g is orange solids, and yield is 99%.
(4) the hydrochloric acid Tarceva is synthetic: under normal pressure, nitrogen protection; Salt of wormwood (3.31g; 24mmol), N-(3-formyl radical phenyl)-6,7-dihydroxyl-4-amido quinazoline (3.37g, 12mmol), Bestmann Ohira reagent (3.46g; 18mmol) be added in the 100mL three-necked bottle, 28 ℃ of reactions with the 30mL anhydrous methanol.After the TLC monitoring reaction is complete, filter, concentrating under reduced pressure obtains N-(3-ethynyl phenyl)-6,7-dihydroxyl-4-amido quinazoline 2.69g, and yield is 81%.Again with N-(3-ethynyl phenyl)-6, and 7-dihydroxyl-4-amido quinazoline and 2-chloroethyl methyl ether (2.3mL, 24mmol), salt of wormwood (3.31g; 24mmol) be dissolved in the 50mL acetone, back flow reaction 10h is after the TLC monitoring reaction is intact; Filter; Filtrating is revolved dried, obtains hydrochloric acid Tarceva 4.29g with the Virahol recrystallization, and yield is 83% (three step yield).
Embodiment 4
The preparation of (1) 6,7-dimethoxyquinazoline-4-amine: under normal pressure, nitrogen protection, 4,5-dimethoxy-2-amido cyanobenzene (2.81g; 15.8mmol) (with 3, the 4-dimethoxy benzaldehyde is a starting raw material, with reference to Heterocycles 2007,71; 39 ~ 48. method, through aldehyde radical condensation dehydration, nitrated and reduction altogether three-step reaction obtain yield 86.8%) be added in the 50mL methane amide, under microwave-assisted, react 0.5h; The TLC monitoring reaction after question response is complete, spins off most of solvent with Rotary Evaporators, adds 100mL water again; (3 * 50mL), organic phase is used anhydrous magnesium sulfate drying to extracted with diethyl ether, filters, and filtrating is revolved dried; Bullion obtains 6 with recrystallizing methanol, 7-dimethoxyquinazoline-4-amine 2.82g, and gray solid, yield is 87%.
(2) N-[3-(1, the 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 phosphines-1 of 2'-; (1.06g 1.7mmol) is added in the toluene 1'-dinaphthalene, activation 10 minutes under the room temperature nitrogen gas stream earlier; Add 6 subsequently, and 7-dimethoxyquinazoline-4-amine (3.53g, 17.2mmol), the methyl ether (5.73g that contracts of a benzaldehyde iodine; 20.6mmol) and salt of wormwood (9.49g, 68.8mmol), mixed solution is 110 ℃ of reactions.After the TLC monitoring reaction is complete, filter, filtrate decompression concentrates, and bullion obtains white N-[3-(1, the 1-dimethoxy-methyl) phenyl]-6 with re-crystallizing in ethyl acetate, 7-dimethoxy-4 '-amido quinazoline solid 4.39g, 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, the 1-dimethoxy-methyl) phenyl]-6; (19.53g 55mmol) uses the 100mL dissolve with methanol to 7-dimethoxy-4 '-amido quinazoline, slowly drips 24mL3.5N HCl solution; After dripping, at 25 ℃ of reaction 2h, after reacting completely; Revolve the dried N-of obtaining (3-formyl radical phenyl)-6,7-dimethoxy-4 '-amido quinazoline 14.96g, yield is 88%.With N-(3-formyl radical phenyl)-6, and 7-dimethoxy-4 '-amido quinazoline (7.73g, 25mmol), (6.9g, 50mmol) (5.76g 30mmol) is dissolved in the methyl alcohol salt of wormwood, 30 ℃ of reactions with Bestmann Ohira reagent.After the TLC monitoring reaction is complete, filter, filtrate decompression concentrates, and bullion obtains white N-(3-ethynyl phenyl)-6 with re-crystallizing in ethyl acetate, 7-dimethoxy-4 '-amido quinazoline solid 7.02g, and yield is 92%.
(4) N-(3-ethynyl phenyl)-6, the preparation of 7-dihydroxyl-4-amido quinazoline: under normal pressure, nitrogen protection, N-(3-ethynyl phenyl)-6; (5.7g 18.7mmol) is dissolved in 40% hydrobromic acid solution (25mL) to 7-dimethoxy-4 '-amido quinazoline, 55 ℃ of reaction 5h; After the TLC monitoring reaction was complete, saturated sodium carbonate solution was transferred pH=8 ~ 9, extracts with ETHYLE ACETATE; Anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure; Obtain the N-(3-ethynyl phenyl)-6 of white, 7-dihydroxyl-4-amido quinazoline solid 5.08g, yield is 98%.
(5) preparation of hydrochloric acid Tarceva: N-under normal pressure, nitrogen protection (3-ethynyl phenyl)-6; 7-dihydroxyl-4-amido quinazoline (1.72g; 6.2mmol), salt of wormwood (2.14g; 15.5mmol), the 2-chloroethyl methyl ether (1.5mL 15.5mmol) is added in the 30mL acetonitrile, 80 ℃ the reaction 6h.After the TLC monitoring reaction is complete, filter out insolubles, revolve dried solvent, bullion obtains white Tarceva 2.32g with the mixed solvent recrystallization of sherwood oil and methylene dichloride, and yield is 95%.Tarceva is dissolved in the anhydrous methanol, feeds hydrogen chloride gas, at room temperature react 1.5h, separate out solid, filter, the solid oven dry is obtained the hydrochloric acid Tarceva, be total to 2.35g, yield is 93%.
Claims (10)
1. the method for the precursor compound V of synthetic Tarceva or Tarceva is characterized in that said method is to come synthetic through the midbody compound II shown in the following formula,
R wherein
1Be hydroxyl, benzyloxy, methoxyl group or 2-methoxyethoxy, R
2Be hydrogen, benzyl or tertbutyloxycarbonyl.
2. method according to claim 1 is characterized in that, this method comprise midbody compound II and protection between halobenzene formaldehyde generation linked reaction obtain R
3Be the midbody compound N-(3-substituted-phenyl)-6 of the formyl radical of protection, 7-two replacement-4-amido quinazoline III; Or under the effect of alkali and a fluorobenzaldehyde fragrant nucleophilic substitution reaction-SNAr takes place, obtain R
3Be the midbody compound N-(3-substituted-phenyl)-6 of formyl radical, 7-two replacement-4-amido quinazoline III,
The structure of the compound III that wherein relates to is:
R wherein
1, R
2Such as in the claim 1 definition; R
3It is the formyl radical of formyl radical or protection.
3. method according to claim 2 is characterized in that, linked reaction is under the acting in conjunction of metal catalyst and alkali, to carry out.
4. method according to claim 3; It is characterized in that metal catalyst is one or more and the ligand 1 in palladium, three (dibenzalacetone) two palladiums or the Palladous chloride, the two diphenylphosphine ferrocene, 2 of 1'-; The two diphenyl phosphines-1 of 2'-; 1'-dinaphthalene or 4, the two diphenylphosphines-9 of 5-, the complex compound of one or more formation in the 9-dimethyl-oxa-anthracene; Alkali is salt of wormwood, potassium tert.-butoxide or sodium methylate.
5. method according to claim 4 is characterized in that, linked reaction is to carry out as follows: under normal pressure, nitrogen protection; With halobenzene formaldehyde and 6 between protection, 7-disubstituted quinazoline-4-amine II is dissolved in the solvent, under the effect of metal, part and alkali, reacts 5 ~ 24h at 25 ~ 150 ℃; After reacting completely; Remove by filter insolubles, filtrating is revolved to do and is promptly obtained midbody compound N-(3-substituted-phenyl)-6,7-two replacement-4-amido quinazoline III.
6. method according to claim 5; It is characterized in that; The mol ratio of metal and midbody compound II is 0.001:1 ~ 0.1:1, and the mol ratio of part and midbody compound II is 0.01:1 ~ 0.5:1, and the mol ratio of alkali and midbody compound II is 1:1 ~ 10:1.
7. according to each described method among the claim 2-6, it is characterized in that linked reaction is to carry out in glycol dimethyl ether, toluene or the THF at reaction solvent.
8. method according to claim 2 is characterized in that, fragrant nucleophilic substitution reaction is to carry out under the effect of one or more alkali in cesium carbonate, salt of wormwood, sodium-acetate or triethylamine.
9. method according to claim 8 is characterized in that, the mol ratio of alkali and midbody compound II is 2:1 ~ 10:1, and temperature of reaction is 50 ~ 120 ℃, and reaction solvent is toluene or N.
10. method according to claim 1 and 2 is characterized in that, midbody compound II is through compound I and methane amide or FORMAMIDINE ACETATE reaction synthetic,
R wherein
1Identical with the definition in the claim 1.
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| CN105968103A (en) * | 2016-07-18 | 2016-09-28 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis method of anti-tumor medicine afatinib |
| CN110317221A (en) * | 2019-06-24 | 2019-10-11 | 华南理工大学 | A kind of polysubstituted alkynes amidine compound and its preparation method and application |
| CN110684000A (en) * | 2019-10-18 | 2020-01-14 | 上海皓元医药股份有限公司 | Process for preparing benzofuran derivatives |
| CN110894189A (en) * | 2019-11-14 | 2020-03-20 | 山东罗欣药业集团股份有限公司 | Preparation method of erlotinib hydrochloride |
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| CN110317221A (en) * | 2019-06-24 | 2019-10-11 | 华南理工大学 | A kind of polysubstituted alkynes amidine compound and its preparation method and application |
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