CN102746242A - Synthesis method of 6, 7-substituted-4-aniline quinazoline - Google Patents

Synthesis method of 6, 7-substituted-4-aniline quinazoline Download PDF

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CN102746242A
CN102746242A CN2012102395779A CN201210239577A CN102746242A CN 102746242 A CN102746242 A CN 102746242A CN 2012102395779 A CN2012102395779 A CN 2012102395779A CN 201210239577 A CN201210239577 A CN 201210239577A CN 102746242 A CN102746242 A CN 102746242A
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nitro
oxygen
quinazoline
aniline
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施凯翔
谢幼容
刘清维
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OMEGA CO Ltd
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OMEGA CO Ltd
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Abstract

The invention relates to a synthesis method of 6, 7-substituted-4-aniline quinazoline. The reaction path of the synthesis method comprises the following steps of: performing esterification, oxygen-alkylation reaction or nitration reaction on 3-methoxyl-4-hydroxybenzoic acid serving as an initiator,, performing hydrolysis-demethylation reaction, esterification, oxygen-alkylation reaction, nitroreduction reaction, cycling reaction, two-in-one reaction and other steps after nitration so as to prepare the 6, 7-substituted-4-aniline quinazoline. The invention provides the preparation way of a 4-aniline quinazoline derivative, which has the advantages of lower cost of the initiator and higher yield, so that the production cost can be effectively reduced and the competitiveness of products of 4-aniline quinazoline derivatives can be improved.

Description

6, the compound method of 7-substituting group-4-aniline quinazoline
Technical field
The invention relates to a kind of compound method of quinazoline derivant, and particularly relevant for 6, the compound method of 7-substituting group-4-aniline quinazoline.The present invention is dividing an application of one Chinese patent application CN200910133962.3.
Background technology
EGF-R ELISA (EGFR; Epidermal Growth Factor Receptor) in cancer development, plays the part of a key player; And 6; 7-substituting group-4-aniline quinazoline also is widely used in and is mainly used in nonsmall-cell lung cancer (Non-small-cell lung cancer clinically; NSCLC) treatment for Buddhist nun (Erlotinib) and be used to treat lung cancer and thyroid carcinoma (Thyroid cancer) medicine ZD6474 (Vandetanib), is used for the treatment of myelomatosis (Myeloid leukemia) or the medullization bad syndrome of life (Myelodysplasia) such as marketed drug ZD1939 (Gefitinib), your Lip river in addition in the clinical second phase; All replace Buddhist nun (Tandutinib) such as carbon, its structure is as follows:
Figure BDA00001874119700011
Relevant for 6,7-substituting group-4-aniline quinazoline Improvement type compound method has been disclosed in many reported literatures, such as:
One, WO2004024703
With Isovanilln is initiator, utilizes HCO 2Na/HCO 2H/ (HCONH 2) 2.H 2SO 4Transfer aldehyde radical to itrile group (CN), via oxygen-alkylated reaction, nitration reaction, transfer itrile group to acid amides behind the nitro-reduction reaction after, by HCO 2H/HCONH 2Cyclisation gets quinazoline (quinazoline) and promptly makes ZD1939 (Gefitinib) with chlorination and amino benzenes compounds replacement at last.
Two, WO9633980
With 6,7-dimethoxy-3, (6,7-dimethoxy-3 is an initiator 4-dihydroquinazolin-4-one) to 4-dihydroquinazoline-4-ketone, utilizes L-methionine(Met) (L-Methionine) in the 6th position demethylation reaction and with Ac 2After the O protection, go chlorination and phenyl amines substitution reaction again will protect base to remove at last, and carry out oxygen-alkylated reaction and can make ZD1939 (Gefitinib).
Three, Organic Process Research&Development2007,11,813-816
Utilize Isovanilln to transfer aldehyde radical to itrile group for initiator; Oxygen-alkylated reaction; Behind nitration reaction and the nitro-reduction reaction, (N (DMF)-DMA) forms N, N-dimethylformamidine verivate to borrow dimethylformamide-dimethylacetal; Last and amino benzenes compounds carries out the Dimroth rearrangement reaction and makes ZD1939 (Gefitinib), and same method also can be applicable to the method for making that Buddhist nun (Erlotinib) is replaced in your Lip river.
Four, CN1733738
With 3,4-dimethoxybenzoic acid (3,4-dimethoxybenzoic acid) is that initiator is via nitration reaction; Demethyl-nitro-reduction reaction; Cyclization, chlorination reaction and aniline substitution reaction are carried out oxygen-alkylated reaction at last again and are made ZD1939 (Gefitinib).
Five, CN101148439A
With 3-hydroxyl-4-methoxyl methyl benzoate (methyl3-hydroxy-4-methoxybenzoate) is that initiator is via oxygen-alkylated reaction; Nitration reaction; Nitro-reduction reaction, cyclization, chlorination reaction and aniline substitution reaction make ZD1939 (Gefitinib).
Yet above-mentioned preparation 6 in the method for 7-substituting group-4-aniline quinazoline, has but that expensive raw material price, reactions step are complicated, intermediate product is unstable or productive rate is crossed problems such as low.Therefore the present invention desires by different starting raw materials, proposes other a kind of preparation 6, the method for 7-substituting group-4-aniline quinazoline.
Summary of the invention
The object of the invention is exactly to provide a kind of 6, the compound method of 7-substituting group-4-aniline quinazoline.
A purpose more of the present invention provides a kind ofly utilizes lower-cost initiator synthetic 6, the compound method of 7-substituting group-4-aniline quinazoline.
Another purpose of the present invention provides a kind ofly utilizes lower-cost initiator synthetic 6,7-substituting group-4-aniline quinazoline and the good method of productive rate.
It is a kind of 6 that the present invention proposes, and the compound method of 7-substituting group-4-aniline quinazoline is said 6, and the chemical formula of 7-substituting group-4-aniline quinazoline is following,
Figure BDA00001874119700031
Said 6, the compound method of 7-substituting group-4-aniline quinazoline comprises following steps:
A. be initiator with 3-methoxyl group-4-hydroxy-benzoic acid, row esterification for the first time obtains 3-methoxyl group-4-methyl hydroxybenzoate, and the oxygen that defines respectively on described 3-methoxyl group and the 4-hydroxyl is first oxygen and second oxygen;
B. in the step of said second up oxygen-alkylated reaction of oxygen, make 3-methoxyl group-4-methoxy ethoxy oil of Niobe;
C. be 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe with 3-methoxyl group-capable nitration reaction of 4-methoxy ethoxy oil of Niobe;
D. with 2-nitro-capable hydrolysis of 5-methoxyl group-4-methoxy ethoxy oil of Niobe-demethylation reaction and for the second time esterification so that the 5-methoxyl group demethylation of 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe, thereby make 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe;
E. in the step of the up oxygen-alkylated reaction of said first oxygen, make 2-nitro-4,5-dimethoxy ethoxy-benzoic acid methyl ester;
F. with 2-nitro-4, the capable nitro-reduction reaction of 5-dimethoxy ethoxy-benzoic acid methyl ester is to make 2-amido-4,5-dimethoxy ethoxy-benzoic acid methyl ester;
G. with 2-amido-4, the capable cyclization reaction of 5-dimethoxy ethoxy-benzoic acid methyl ester is to make 6,7-two 2-methoxy ethoxy quinazoline-4-ones; And
H. with 6,7-two 2-methoxy ethoxy quinazoline-4-ones carry out chlorination and the substituted two-in-one reaction of aniline can make 6,7-substituting group-4-aniline quinazoline.
The present invention provides the 4-anilinoquinazoline derivatives that a kind of initiator cost is lower and productive rate is higher preparation method, therefore can reduce production costs effectively, to improve 4-anilinoquinazoline derivatives competitiveness of product.
Description of drawings
Fig. 1 is embodiment of the invention manufacturing process chemical structural formula figure.
Fig. 2 is another embodiment of the present invention manufacturing process chemical structural formula figure.
Fig. 3 is further embodiment of this invention manufacturing process chemical structural formula figure.
Embodiment
For let above-mentioned and other purposes of the present invention, feature and advantage can be more obviously understandable, hereinafter will cooperate institute's accompanying drawing to elaborate.
The present invention discloses and a kind ofly utilizes 3, and 4-substituting group phenylformic acid (3,4-subsituted benzoic acid) starting raw material synthesizes 6, the method for 7-substituting group-4-aniline quinazoline; Wherein, One synthesis mode is without hydrolysis-demethylation reactions step; (one-pot reaction) can make 6 via esterification, oxygen-alkylated reaction, nitration reaction, nitro-reduction reaction, cyclization reaction and two-in-one reaction, 7-substituting group-4-aniline quinazoline; Another route of synthesis then must be through hydrolysis-demethylation reaction; Its synthesis step comprises esterification, oxygen-alkylated reaction or nitration reaction, hydrolysis-demethylation reaction, esterification, oxygen-alkylated reaction, nitro-reduction reaction, cyclization reaction and two-in-one reaction; To make 6,7-substituting group-4-aniline quinazoline; Wherein, via above-mentioned steps institute synthetic 6,7-substituting group-4-aniline quinazoline can be Gefitinb, Erotinib, Vandetanib and Tandutinib, and its structural formula is as follows:
Figure BDA00001874119700051
Fig. 1 synthesizes 6, the manufacturing process chemical structural formula figure of 7-substituting group-4-aniline quinazoline embodiment for the present invention.As shown in Figure 1; Present embodiment is with 3-hydroxyl-4-methoxybenzoic acid (3-hydroxy-4-methoxybenzoic acid) 1 or 3; 4-resorcylic acid (3; 4-dihydroxybenzoic acid) 11 is starting raw material, via alkylated reaction, nitration reaction, reduction reaction, cyclization reaction and two-in-one reaction (one-pot reaction) on esterification, the oxygen to make 6,7-substituting group-4-aniline quinazoline.
The preparation process of present embodiment is described below:
1. esterification: with compound 3,4-substituted benzoic acid I, such as 3-hydroxyl-4-methoxybenzoic acid 1 or 3,4-resorcylic acid 11 is via Fei Xier esterification (Fischer esterification) or SOCl 2In alcohols, can make compound ii, i.e. 3-hydroxyl-4-methoxyl methyl benzoate (Methyl3-hydroxy-4-methoxybenzoate) 2 and 3,4-dihydric ethyl benzoate (Ethyl 3,4-dihydroxy benzoate) 12.
2. oxygen-alkylated reaction: with 3-hydroxyl-4-methoxyl methyl benzoate 2 or 3,4-dihydric ethyl benzoate 12 is dissolved in organic solvent N (DMF), acetone, CH with side chain chlorination 3-morpholine propoxy-(3-morpholinopropoxy chloride) and 2-bromotrifluoromethane methyl ether (2-bromoethyl methyl ether) respectively 3CN or organic solvent and water; In weak base or KI condition; 25 ~ 150 ℃ of following reactions of temperature can make the compound III; Be 4-methoxyl group-3-(3-morpholine propoxy-) oil of Niobe (Methyl4-methoxy-3-(3-morpholinopropoxy) benzoate) 3 and 3, and 4-dimethoxy ethoxy benzonitrile acetoacetic ester (Ethyl 3, and 4-dimethoxyethoxybenzoate) 13.
3. nitration reaction: with 4-methoxyl group-3-(3-morpholine propoxy-) oil of Niobe 3 and 3,4-dimethoxy ethoxy benzonitrile acetoacetic ester 13 is dissolved in the acetic acid, and adds 70%H 2SO 4And 45%HNO 3Temperature is under 25 ~ 150 ℃ condition; Carry out nitration reaction and can make the compound IV; Be 2-nitro-4-methoxyl group-5-(3-morpholine propoxy-) oil of Niobe (Methyl2-nitro-4-methoxy-5-(3-morpholinopropoxy) benzoate) 4 and 2-nitro-4,5-dimethoxy ethoxy benzonitrile acetoacetic ester (Ethyl 2-nitro-4,5-dimethoxyethoxybenzoate) 14.
4. nitro-reduction reaction: with 2-nitro-4-methoxyl group-5-(3-morpholine propoxy-) oil of Niobe 4 and 2-nitro-4,5-dimethoxy ethoxy benzonitrile acetoacetic ester 14 is dissolved in the strong base solution and adds Na 2S 2O 4Carried out reduction reaction; Or with 10%Pd-C as catalyzer; In machine solvents such as ETHYLE ACETATE or alcohols are arranged; In temperature is 25 ~ 100 ℃ of capable hydrogenations of hydrogen that feed pressure condition at 30 ~ 60psi; Reaction can make the compound VI; Be 2-amido-5-methoxyl group-4-(3-morpholine propoxy-) oil of Niobe (Methyl2-amino-5-methoxy-4-(3-morpholinopropoxy) benzoate) 5 and 2-amido-4,5-dimethoxy ethoxy benzonitrile acetoacetic ester (Ethyl 2-amino-4,5-dimethoxyethoxybenzoate) 15.
5. cyclization reaction: with 2-amido-5-methoxyl group-4-(3-morpholine propoxy-) oil of Niobe 5 and 2-amido-4,5-dimethoxy ethoxy benzonitrile acetoacetic ester 15 adds ammonium acetate and HCONH 2Temperature is that 100 ~ 200 ℃ condition is carried out the cyclization reaction and can be made quinazoline compound VII; Be 7-methoxyl group-6-(3-morpholine propoxy-)-3,4-dihydroquinazoline-4-ketone (7-Methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one) 6 and 6; 7-two (2-methoxy ethoxy) quinazoline-4-one (6,7-bis (2-methoxyethoxy) quinazolin-4-one) 16.
6. two-in-one reaction (chlorination-aniline substitution reaction): with 7-methoxyl group-6-(3-morpholine propoxy-)-3,4-dihydroquinazoline-4-ketone 6 and 6,7-two (2-methoxy ethoxy) quinazoline-4-one 16 adds in the organic solvent, utilizes SOCl 2, POCl 3, PCl 5Carry out chlorination reaction with 2 ~ 20 equivalents, the direct and anils row aniline substitution reaction in alcohols of gained chlorizate, the high purity product ZD1939 (Gefitinib) that can make more than 99.7% replaces Buddhist nun (Erlotinib) with your Lip river.
Synthesize 6 at this embodiment, in the step of 7-substituting group-4-aniline quinazoline, with 3-hydroxyl-4-methoxybenzoic acid 1 or 3; 4-resorcylic acid 11 is a starting raw material; Under the situation of the step of hydrolysis-demethylation-esterification, synthetic 6,7-substituting group-4-aniline quinazoline.
Fig. 2 synthesizes 6 for the present invention, and the manufacturing process chemical structural formula figure of 7-substituting group-another embodiment of 4-aniline quinazoline is as shown in Figure 2; Present embodiment is with 3; 4-dimethoxybenzoic acid (3,4-dimethoxybenzoic acid) 7 is a starting raw material, through esterification, nitration reaction, hydrolysis-demethylation reaction, esterification, oxygen-alkylated reaction, nitro-reduction reaction, cyclization reaction and two-in-one reaction; To make 6,7-substituting group-4-aniline quinazoline.
1. esterification: with 3,4-dimethoxybenzoic acid 7 is via Fei Xier esterification (Fischer esterification) or SOCl 2In alcohols, can make compound ii, promptly 3,4-dimethoxy p-methyl (Methyl3,4-dimethoxybenzoate) 8.
2. nitration reaction: with 3,4-dimethoxy p-methyl 8 is dissolved in the acetic acid, adds 70%H 2SO 4And 45%HNO 3, under the condition of 25 ~ 150 ℃ of temperature, carry out nitration reaction and can make the compound IV, be i.e. 2-nitro-4,5-dimethoxy p-methyl (Methyl2-nitro-4,5-dimethoxybenzoate) 9.
3. hydrolysis-demethylation-esterification: with 2-nitro-4; 5-dimethoxy p-methyl 9 is dissolved in the strong alkali aqueous solution; Under 25 ℃ ~ 100 ℃ temperature condition; In advance hydrolysis reaction is gone the demethylation reaction again, and wherein strong alkali aqueous solution can be alkaline substance solutions such as KOH or NaOH, and above-mentioned reaction formula it is following:
Figure BDA00001874119700081
Carry out esterification subsequently again, to be prepared into compound V, i.e. 2-nitro-5-hydroxyl-4-methoxyl methyl benzoate (Methyl 2-nitro-5-hydroxy-4-methoxybenzoate) 10.
4. oxygen-alkylated reaction: 2-nitro-5-hydroxyl-4-methoxyl methyl benzoate 10 is dissolved in CH with side chain chlorination 3-morpholine propoxy-(3-morpholinopropoxy chloride) 3CN, N (DMF), acetone and other organic solvent or CH 3CN-H 2O, N (DMF)-H 2In the O equal solvent, add K 2CO 3, KHCO 3, NaHCO 3, Na 2CO 3Deng the weak base material, and, can make compound VI, i.e. 2-nitro-4-methoxyl group-5-(3-morpholine propoxy-) oil of Niobe (Methyl 2-nitro-4-methoxy-5-(3-morpholinopropoxy) benzoate) 4 with 25 ℃ to 150 ℃ reactions.
5. nitro-reduction reaction: 2-nitro-4-methoxyl group-5-(3-morpholine propoxy-) oil of Niobe 4 profits are dissolved in the strong base solution, and add Na 2S 2O 4Carry out reduction reaction; Or be catalyzer with 10%Pd-C; In organic solvents such as ETHYLE ACETATE or alcohols; In temperature is that temperature is 25 ~ 100 ℃; Pressure is to feed the capable hydrogenation of hydrogen under the condition of 30 ~ 60psi, and reaction can make the compound VI, i.e. 2-amido-5-methoxyl group-4-(3-morpholine propoxy-) oil of Niobe (Methyl2-amino-5-methoxy-4-(3-morpholinopropoxy) benzoate) 5.
6. cyclization reaction: 2-amido-5-methoxyl group-4-(3-morpholine propoxy-) oil of Niobe 5 is dissolved in ammonium acetate and HCONH 2Carry out the cyclization reaction with 100 ~ 200 ℃ temperature and can make quinazoline compound (VII); Be 7-methoxyl group-6-(3-morpholine propoxy-)-3,4-dihydroxyl quinazoline-4-one (7-Methoxy-6-(3-morpholinopropoxy)-3,4-dihydroquinazolin-4-one) 6.
7. two-in-one reaction (chlorination-aniline substitution reaction): with 7-methoxyl group-6-(3-morpholine propoxy-)-3,4-dihydroxyl quinazoline-4-one 6 is dissolved in organic solvent, utilizes SOCl 2, POCl 3, PCl 5Carry out chlorination reaction with 2 ~ 20 equivalents, the direct and anils row aniline substitution reaction in alcohols of gained chlorizate can make the high purity product ZD1939 (Gefitinib) more than 99.7%.
Synthesizing 6 at the foregoing description, in the step of 7-substituting group-4-aniline quinazoline, is with 3; 4-dimethoxybenzoic acid (3,4-dimethoxybenzoic acid) 7 is a starting raw material, through the step of hydrolysis-demethylation-esterification; Synthesize 6,7-substituting group-4-aniline quinazoline.
Wherein above-mentioned " hydrolysis-demethylation-esterification " also can be under temperature be 25 ℃ ~ 150 ℃ condition, at toluene, oil of mirbane, CH 2Cl 2In the equal solvent by 1 ~ 10 normal AlCl 3Optionally the methoxyl group to nitro contraposition in the compound IV carries out the demethylation reaction and makes compound V; In the present embodiment; Promptly be with 2-nitro-4,5-dimethoxy p-methyl (9) reaction becoming 2-nitro-5-hydroxyl-4-methoxyl methyl benzoate 10.
Fig. 3 synthesizes 6, the manufacturing process chemical structural formula figure of 7-substituting group-another embodiment of 4-aniline quinazoline for the present invention.As shown in Figure 3; Present embodiment is to be starting raw material with 3-methoxyl group-4-hydroxy-benzoic acid (3-methoxy-4-hydroxybenzoic acid) 17; Through esterification, oxygen-alkylated reaction, nitration reaction, hydrolysis-demethylation-esterification, oxygen-alkylated reaction, nitro-reduction reaction, cyclization reaction and two-in-one reaction; To make 6,7-substituting group-4-aniline quinazoline.
1. esterification: with 3-methoxyl group-4-hydroxy-benzoic acid 17 via Fei Xier esterification (Fischer esterification) or SOCl 2In alcohols, can make compound ii, i.e. 3-methoxyl group-4-methyl hydroxybenzoate (Methyl3-methoxy-4-hydroxybenzoate) 18.
2. alkylated reaction on the oxygen: will get 3-methoxyl group-4-methyl hydroxybenzoate 18 and be dissolved in organic solvent N (DMF), acetone, CH with side chain 2-bromotrifluoromethane methyl ether (2-bromoethyl methyl ether) 3CN or organic solvent and water can make the compound III at weak base or 25 ~ 150 ℃ of following reactions of KI condition temperature, i.e. 3-methoxyl group-4-methoxy ethoxy oil of Niobe (Methyl3-methoxy-4-methoxyethoxybenzoate) 19.
3. nitration reaction: 3-methoxyl group-4-methoxy ethoxy oil of Niobe 19 is dissolved in the acetic acid, adds 70%H 2SO 4And 45%HNO 3, under the condition of 25 ~ 150 ℃ of temperature, carry out nitration reaction and can make the compound IV, be i.e. 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe (Methyl2-nitro-5-methoxy-4-methoxyethoxybenzoate) 20.
4. hydrolysis-demethylation-esterification: 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe 20 is dissolved in the strong alkali aqueous solution; Go the demethylation reaction again with 25 ℃ ~ 100 ℃ the temperature hydrolysis reaction of going ahead of the rest; Wherein strong alkali aqueous solution can be alkaline substance solutions such as KOH or NaOH, and above-mentioned reaction formula it is following:
Figure BDA00001874119700101
Carry out esterification subsequently again, to be prepared into compound V, i.e. 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe (Methyl 2-nitro-5-hydroxy-4-methoxyethoxybenzoate) 21.
5. alkylated reaction on the oxygen: 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe 21 is dissolved in organic solvent N (DMF), acetone, CH with side chain 2-bromotrifluoromethane methyl ether 3CN or organic solvent and water can make compound VI at weak base or 25 ~ 150 ℃ of following reactions of KI condition temperature, i.e. 2-nitro-4,5-dimethoxy ethoxy-benzoic acid methyl ester (Methyl2-nitro-4,5-dimethoxyethoxybenzoate) 22.
6. nitro-reduction reaction:, in 5-dimethoxy ethoxy-benzoic acid methyl ester 22 strong base solutions, add Na with 2-nitro-4 2S 2O 4To carry out reduction reaction; Or with 10%Pd-C as catalyzer; In the organic solvent of ETHYLE ACETATE or alcohols was, with 25 ~ 100 ℃ temperature, pressure carried out hydrogenation in the condition of 30 ~ 60psi; Can make the compound VI; Be 2-amido-4,5-dimethoxy ethoxy-benzoic acid methyl ester (Methyl2-amino-4,5-dimethoxyethoxybenzoate) 23.
7. cyclization reaction: with 2-amido-4,5-dimethoxy ethoxy-benzoic acid methyl ester 23 places ammonium acetate and HCONH 2, carry out the cyclization reaction with 100 ~ 200 ℃ temperature and can make quinazoline compound VII, promptly 6,7-two 2-methoxy ethoxy quinazoline-4-ones (6,7-bis (2-methoxyethoxy) quinazolin-4-one) 16.
8. two-in-one reaction (chlorination-aniline substitution reaction): compound 6,7-two 2-methoxy ethoxy quinazoline-4-ones 16 utilize SOCl at organic solvent 2, POCl 3, PCl 5Carry out chlorination reaction with 2 ~ 20 equivalents, the direct and anils row aniline substitution reaction in alcohols of gained chlorizate, Buddhist nun (Erlotinib) is replaced in your Lip river of high purity product that can make more than 99.7%.
At this embodiment synthetic 6; In the step of 7-substituting group-4-aniline quinazoline, be to be starting raw material, through the step of hydrolysis-demethylation-esterification with 3-methoxyl group-4-hydroxy-benzoic acid 17; Synthesize 6,7-substituting group-4-aniline quinazoline replaces Buddhist nun (Erlotinib) like your Lip river.If without the step of hydrolysis-demethylation-esterification, synthesize 6,7-substituting group-4-aniline quinazoline then can make Vandetanib and Tandutinib.
Wherein above-mentioned " hydrolysis-demethylation-esterification " also can be under temperature be 25 ℃ ~ 150 ℃ condition, at toluene, oil of mirbane, CH 2Cl 2In the equal solvent, by 1 ~ 10 normal AlCl 3Optionally the methoxyl group of nitro contraposition carries out the demethylation reaction and makes compound V in compound IV; In the present embodiment, promptly be that 2-nitro-5-methoxyl group-4 methoxy ethoxy oil of Niobe 20 reactions are become 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe 21.
In sum, disclosed by the invention 6,7-substituting group-4-aniline quinazoline Improvement type synthetic synthesis mode all has quite high overall yield, and its overall yield is 30-42%; Moreover, above-mentioned compound method has the characteristic of being convenient to reclaim with purifying, and the purity of its final product is at least more than 99.7%; Moreover the final step of processing procedure accomplishes the preparation of product with two-in-one step (One-Pot), and the initiator price of using is comparatively cheap; By above-mentioned characteristic sight, the present invention has the advantage of commercial production.
What should explain is: above embodiment is only in order to technical scheme of the present invention to be described but not limit it; Although the present invention has been carried out detailed explanation with reference to preferred embodiment; Those of ordinary skill in the art is to be understood that: it still can make amendment or be equal to replacement technical scheme of the present invention, also can not make amended technical scheme break away from the spirit and the scope of technical scheme of the present invention and these are revised or be equal to replacement.
Below just specify the condition and the reaction intermediate NMR result of each reactions step:
(1) alkylated reaction on the oxygen
1.4-the preparation of methoxyl group-3-(3-morpholine propoxy-) oil of Niobe (3):
(25.5g 0.1401mol) is dissolved in 255ml CH to get 3-hydroxyl-4-methoxyl methyl benzoate 2 3CN, (27.54g, 0.1684mol), other gets K to add chlorination 3-morpholine propoxy- 2CO 3(32.78g 0.2375mol) is dissolved in 76.5ml H 2O is added to above-mentioned solution again and reacted 3 hours down in 80 ℃.Add 255ml H 2O uses 255ml ethyl acetate extraction twice again, and the combined ethyl acetate layer is used MgSO 4Dry, filtration, concentrated get pale yellow solid chemical compound 3,43.5g (100%); Its 1H – NMR (CDCl 3) be 1.95 (m, 2H), 2.39 (brs, 4H), 2.46 (m, 2H), 3.62 (m, 4H) 3.78 (s, 3H), 3.82 (s, 3H), 4.12 (m, 2H), 6.78 (dd, 1H, J=8.8Hz, J=2.0Hz), 7.48 (s, 1H), 7.58 (dd, 1H, j=8.8Hz, J=2.0Hz).
2.2-the preparation of nitro-4-methoxyl group-5-(3-morpholine propoxy-) oil of Niobe 4:
(1g 0.0044mol) is dissolved in 10ml N (DMF), and (0.83g, 5.269mmol), other gets K to add chlorination 3-morpholine propoxy-(3-morpholinopropoxy chloride) to get 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe 10 2CO 3(1.21g 8.768mmol) reacted 1 hour down at 50-100 ℃, added 20ml H 2O uses the 20ml ethyl acetate extraction three times again, and the combined ethyl acetate layer is used MgSO 4Dry, filtration, concentrated get pale yellow solid chemical compound 4,1.5g (96.18%); Its 1HNMR (CDC1 3) be 2.02 (t, 2H, J=6.8Hz), 2.42 (brs, 4H), 2.51 (m, 2H), 3.68 (m, 4H), 3.87 (s, 3H), 3.92 (s, 3H), 4.16 (t, 2H, J=6.8Hz), 7.07 (s, 1H), 7.42 (s, 1H).
3.3, the preparation method of 4-dimethoxy ethoxy benzonitrile acetoacetic ester (13):
Get 3, (5g 27.45mmol) places the 250ml two-neck bottle to 4-dihydric ethyl benzoate 12, at room temperature logical N 2Add acetone (Acetone) (100ml), salt of wormwood (Potassium carbonate) (9.48g; 68.63mmol), potassiumiodide (Potassium iodide) (0.5g) and 2-bromine oxethyl methyl ether (2-Bromoethyl methyl ether) (7.84ml; 82.35mmol), move to 60 ℃ of following heating reflux reactions 19 hours.After reaction finishes, cool off and place 5 ℃ to stir 30 minutes, filter, filtrating is concentrated into dried, solid drying (oil free type pump) 22 hours, khaki yellow solid compound 13,8.19g (100%); Its 1HNMR (CDCl 3) be 1.32 (t, 3H, J=7Hz), 3.41 (s, 6H), 3.76 (m, 4H), 4.15 (m, 4H); 4.29 (q, 2H, J=7Hz), 6.85 (d, 1H, J=8.4Hz), 7.53 (dd, 1H; J=8.4Hz, J=2.3Hz), 7.53 (m, 1H), 7.63 (dd, 1H, J=8.4Hz, J=2.3Hz).
4.3-the preparation method of methoxyl group-4-methoxy ethoxy oil of Niobe 19:
Close with aforesaid way, its starting raw material is that 3-hydroxyl-4-methoxy ethoxy oil of Niobe 18 can make milk yellow solid chemical compound 19, and productive rate is 97.8%, its 1H – NMR (CDCl 3) be 3.41 (s, 3H), 3.77 (m, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 4.19 (m, 2H), 6.87 (d, 1H, J=8.48Hz), 7.51 (s, 1H), 7.61 (dd, 1H, J=8.48Hz, J=2.0Hz).
5.2-nitro-4, the preparation method of 5-dimethoxy ethoxy-benzoic acid methyl ester 22:
Close with above-mentioned method, its starting raw material is that 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe 21 can make milk yellow solid chemical compound 22, and productive rate is 95.2%. 1H – NMR (CDCl 3) be 3.34 (s, 6H), 3.76 (m, 4H), 3.86 (s, 3H), 4.21 (m, 4H), 7.08 (s, 1H), 7.48 (s, 1H).
(2) nitration reaction
1.2-the preparation method of nitro-4-methoxyl group-5-(3-morpholine propoxy-) oil of Niobe 4:
Get 4-methoxyl group-3-(3-morpholine propoxy-) oil of Niobe (3) (43.5g, 0.1408mol) in dissolved in 117ml acetic acid, and move to 5 ℃ and splashed into 45.5%HNO in following 10 minutes again 3(21.75ml) reaction is 30 minutes, splashes into 70%H again 2SO 4(44ml) drip off after reaction 2 hours under the dislocation room temperature again.Reaction finishes the back and adds 300ml frozen water, 170ml H down at 5 ℃ 2O washes round-bottomed bottle, splashes into about 280ml50%NaOH furnishing alkali again, stirs 1 hour (under 5 ℃), with twice of 770ml ethyl acetate extraction.The combined ethyl acetate layer is used MgSO 4Dry, filter, concentrate, dry 16 hours aureus solid chemical compound 4,46g (92.3%).
2.2-nitro-4, the preparation method of 5-dimethoxy p-methyl 9:
Close with above-mentioned method, its starting raw material is 3, and 4-dimethoxy p-methyl 8 can make yellow solid compound 9, and productive rate is 95%; Its 1HNMR (CDCl 3) be 3.84 (s, 3H), 3.99 (s, 6H), 7.27 (s, 1H), 7.57 (s, 1H).
3.2-nitro-4, the preparation method of 5-dimethoxy (ethoxymethyl) acetoacetic ester 14:
Close with above-mentioned method, its starting raw material is 3, and 4-dimethoxy (ethoxymethyl) acetoacetic ester compound (13) can make brown liquid compound 14, and productive rate is 81%.Its 1H – NMR (CDCl 3) be 1.31 (t, 2H, J=7Hz), 3.41 (s, 6H), 3.77 (m, 4H), 4.20 (m, 4H), 4.33 (q, 2H, J=7Hz), 7.08 (s, 1H), 7.47 (s, 1H).
4.2-the preparation method of nitro-5-methoxyl group-4 methoxyl group ethoxy oil of Niobe 20:
Close with above-mentioned method, its starting raw material is that 3-methoxyl group-4 methoxyl group ethoxy oil of Niobe compound 19 can make yellow solid compound 20, and productive rate is 93%; Its 1H – NMR (CDCl 3) be 3.42 (s, 3H), 3.78 (m, 2H), 3.87 (s, 3H), 3.93 (s, 3H), 4.22 (m, 2H), 7.04 (s, 1H), 7.48 (s, 1H).
(3) hydrolysis-demethylation reaction/esterification
1.2-the preparation method of nitro-5-hydroxyl-4-methoxyl methyl benzoate 10:
Get 2-nitro-4, (3g 0.0124mol) adds 20ml20%KOH to 5-dimethoxy p-methyl compound 9, reacts 5 hours down in 100 ℃.Be cooled to room temperature and place again under the room temperature to stir and add 50ml 1N HCl, with 30ml ethyl acetate extraction three times.The combined ethyl acetate layer is used MgSO 4Dry, filter, concentrate light yellow solid 2.8g.Add 28ml methyl alcohol and under room temperature, splash into the 1.0ml vitriol oil, reaction is 6 hours under the logical nitrogen reflux.Be cooled to room temperature and add 28ml water termination reaction again, splash into 145ml NaHCO again 3 (sat)Furnishing alkali is used the 28ml ethyl acetate extraction three times again.The combined ethyl acetate layer is used MgSO 4Dry, filter, concentrate milk yellow solid chemical compound 10,2.64g (93.5%), its 1HNMR (CDCl 3) be 3.96 (s, 3H), 7.06 (s, 1H), 7.55 (s, 1H).
2.2-the preparation method of nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe 21:
Close with above-mentioned method, its starting raw material starting raw material is that 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe compound 20 can make yellow solid compound 21, and productive rate is 94%; Its 1H-NMR (CDCl 3) be 3.44 (s, 3H), 3.75 (m, 2H), 3.87 (s, 3H), 4.22 (m, 2H), 7.08 (s, 1H), 7.58 (s, 1H).
(4) demethylation reaction
The preparation method of 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe 21:
(11.68g 87.65mmol) places the single neck bottle of 500ml, logical N under room temperature to take by weighing aluminum chloride (Aluminum chloride) 2, add CH 2Cl 2(5g 17.53mmol) moves to 40 ℃ of following heating reflux reactions 1 hour (50ml), slowly to splash into 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe 20.After reaction finishes, cool off and place 5 ℃ to add ETHYLE ACETATE (50ml), again with H 2O (50ml) termination reaction concentrates and takes out CH 2Cl 2,, merge organic layer with H with ETHYLE ACETATE (50ml x2) extraction 2O (100ml) cleans, and gets organic layer and adds anhydrous MgSO 4Drying is filtered, and filtrating is concentrated into dried yellow solid compound 21,4.78g (100%).
(5) nitro-reduction reaction
1.2-the preparation method of amido-5-methoxyl group-(3-morpholine propoxy-) oil of Niobe 5:
(46g 0.1299mol) is dissolved in 430ml ETHYLE ACETATE entirely and returns normal temperature under 50 ℃ to get 2-nitro-5-methoxyl group-(3-morpholine propoxy-) oil of Niobe compound 4.Other takes by weighing 4.6g10%Pd-C and places beaker, slowly adds 30ml ETHYLE ACETATE, slowly adds in the above-mentioned solution again, injects 50psi hydrogen down in normal temperature, reacts 3 hours.Reaction finishes after-filtration, washes once with 230ml ETHYLE ACETATE again.Filter, concentrate shallow khaki color solid chemical compound 5,41.6g (98.8%), its 1H – NMR (CDCl 3) be 1.93 (m, 2H), 2.44 (m, 4H), 2.51 (m, 2H), 3.69 (m, 4H), 3.80 (s, 6H), 3.96 (m, 2H), 5.55 (brs, 1H), 6.09 (s, 1H), 7.30 (s, 1H).
2.2-amido-4, the preparation method of 5-dimethoxy ethoxy benzonitrile acetoacetic ester 15:
Take by weighing 2-nitro-4, (7g 20.40mmol) places the 500ml two-neck bottle to 5-dimethoxy ethoxy benzonitrile acetoacetic ester 14, adds THF (30ml), H 2O (140ml) and 28 ~ 30%NH 4OH (4ml), (3.88g 28.04mmol), leads to N down in 75 ℃ to add potassium hydrosulfide (Sodium hydrosulfite) at last 2, heating reflux reaction 2 hours.Add 4ml conc.HCl again, continued heating reflux reaction 2 hours.After reaction finishes, cool off and place 5 ℃ to transfer to pH＞9,, merge organic layer and clean, get organic layer and add anhydrous MgSO with H2O (200ml) again with ETHYLE ACETATE (200ml x2) extraction with 18ml20%NaOH 4Drying is filtered, filtrating concentrate brown liquid compound 15,5.34g (85.1%), its 1H-NMR (CDCl 3) be 1.33 (t, 2H, J=7.1Hz), 3.41 (s, 6H), 3.68 ~ 3.71 (m, 4H), 4.04 ~ 4.25 (m, 4H), 4.26 (q, 2H, J=7.1Hz), 6.14 (s, 1H), 7.42 (s, 1H).
3.2-amido-4, the preparation method of 5-dimethoxy ethoxy-benzoic acid methyl ester 23:
Close with above-mentioned method, its starting raw material is a 2-nitro-4, and 5-dimethoxy ethoxy-benzoic acid methyl ester compound 22 can make faint yellow mucous modification compound 23, and productive rate is 93%; Its 1H-NMR (CDCl 3) be 3.41 (s, 6H), 3.68 ~ 3.74 (m, 4H), 3.82 (s, 3H), 4.03 ~ 4.10 (m, 4H), 5.55 (brs, 1H), 6.12 (s, 1H), 7.38 (s, 1H).
(6) cyclization reaction
1.7-methoxyl group-6-(3-morpholine propoxy-)-3, the preparation method of 4-dihydroquinazoline-4-ketone 6:
(41.6g 0.1284mol) adds HCONH in round-bottomed bottle to get 2-amido-5-methoxyl group-4-(3-morpholine propoxy-) oil of Niobe compound 5 2(108ml) and HCO 2NH 4(9.8g 0.0762mmol) in 170 ℃ of down reactions 3 hours,, filters to drain and washes solid with the 83.2ml frozen water again and get ivory buff solid chemical compound 6,14.8g (71.1%) to normal temperature from temperature; Its 1H – NMR (DMSO) 2.07 (m, 2H), 2.58 (brs, 4H), 2.61 (t, 2H, J=6.8Hz), 3.71 (m, 4H), 3.98 (s, 3H), 4.18 (t, 2H, J=6.8Hz), 7.15 (s, 1H), 7.59 (s, 1H), 8.00 (s, 1H).
2.6, the preparation method of 7-two (2-methoxy ethoxy) quinazoline-4-one 16:
Close with above-mentioned method, its starting raw material is a 2-amido-4,5-dimethoxy ethoxybenzoic acid ethyl ester compound 15 or 2-amido-4, and 5-dimethoxy ethoxy-benzoic acid methyl ester compound 23 can make pale solid compound 16, and productive rate is 77%, its 1H – NMR (CDCl 3) be 3.71 (s, 6H), 3.82 (brs, 4H), 3.90 (brs, 4H), 6.26 (s, 1H), 6.57 (s, 1H), 7.58 (s, 1H).
(7) two-in-one reaction
1. the preparation method of ZD1939 (Gefitinib):
7-methoxyl group-6-(3-morpholine propoxy-)-3, (29.12g 0.0913mol) in 190ml toluene, adds Et down at 5 ℃ to 4-dihydroquinazoline-4-ketone compound 6 3(19ml 0.1366mol) gets POCl to N in addition 3(17.8ml,, 0.1824mol) splash in the aforementioned solution, move to 70 ℃ again and reacted 3 hours down.Other gets 3-chloro-4-fluoroaniline (3-chloro-4-fluoroaniline), and (15.9g 0.1093mol) is mixed in and splashes in the 10ml Virahol in the above-mentioned solution, stirs 1 hour down at 70 ℃.Cross and filter khaki color solid solid, add 380ml H again 2O dissolves entirely, splashes into about 30ml20%NaOH and stirs filtration in 1 hour.Solid is separated out, and filters.Can make white solid ZD1939 (Gefitinib) compound 25.65g (62.86%).It is more than 99.9% that product purity is analyzed through HPLC, its 1H – NMR (DMSO) be 2.21 (brs, 2H), 2.84 (brs, 4H), 2.92 (brs, 2H), 3.80 (brs, 4H), 3.99 (s, 3H), 4.28 (brs, 2H), 7.15 (s, 1H), 7.24 (t, 1H, J=8.9Hz), 7.71 (m, 2H) 8.00 (m, 1H), 8.44 (s, 1H).
2. Buddhist nun's (Erlotinib) preparation method is replaced in your Lip river:
Take by weighing 6, (0.53g 1.80mmol) places the 50ml two-neck bottle to 7-two (2-methoxy ethoxy) quinazoline-4-one compound 16; Logical N2 under room temperature, add toluene (Toluene) (5.3ml) and triethylamine (Triethylamine) (0.39ml=0.28g, 2.77mmol); Splash into Phosphorus Oxychloride (Phosphorusoxychloride) (0.57ml=0.94g again; 6.12mmol), stirred 10 minutes, move to 65 ℃ of down logical N again 2, reacted 3 hours.(0.22g 1.84mmol) is dissolved in Virahol (Isopropanol) (1ml), under 65 ℃, splashes in the aforementioned solution, continues reaction 2.5 hours to take by weighing 3-amido phenylacetylene (3-Aminophenylacetylen).After the reaction end, cooling is filtered, and solid drying (60 ℃ of baking ovens) 17 hours gets your Lip river of white solid compound and replaces Buddhist nun (Erlotinib) 0.5g (64%).It is more than 99.7% that product purity is analyzed through HPLC, its 1H-NMR (DMSO) be 3.35 (s, 6H), 3.77 (brs, 4H), 4.28 (s, 1H); 4.32 (brs, 2H), 4.38 (brs, 2H), 7.41 (m, 2H); 7.49 (m, 1H), 7.78 (m, 1H), 7.87 (s, 1H); 8.44 (s, 1H), 8.85 (s, 1H), 11.56 (s, 1H).

Claims (10)

1. one kind 6, the compound method of 7-substituting group-4-aniline quinazoline, said 6,7-substituting group-4-aniline quinazoline chemical formula is following,
Figure FDA00001874119600011
Said 6, the compound method of 7-substituting group-4-aniline quinazoline comprises following steps:
A. be initiator with 3-methoxyl group-4-hydroxy-benzoic acid, row esterification for the first time obtains 3-methoxyl group-4-methyl hydroxybenzoate, and the oxygen that defines respectively on described 3-methoxyl group and the 4-hydroxyl is first oxygen and second oxygen;
B. in the step of said second up oxygen-alkylated reaction of oxygen, make 3-methoxyl group-4-methoxy ethoxy oil of Niobe;
C. be 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe with 3-methoxyl group-capable nitration reaction of 4-methoxy ethoxy oil of Niobe;
D. with 2-nitro-capable hydrolysis of 5-methoxyl group-4-methoxy ethoxy oil of Niobe-demethylation reaction and for the second time esterification so that the 5-methoxyl group demethylation of 2-nitro-5-methoxyl group-4-methoxy ethoxy oil of Niobe, thereby make 2-nitro-5-hydroxyl-4-methoxy ethoxy oil of Niobe;
E. in the step of the up oxygen-alkylated reaction of said first oxygen, make 2-nitro-4,5-dimethoxy ethoxy-benzoic acid methyl ester;
F. with 2-nitro-4, the capable nitro-reduction reaction of 5-dimethoxy ethoxy-benzoic acid methyl ester is to make 2-amido-4,5-dimethoxy ethoxy-benzoic acid methyl ester;
G. with 2-amido-4, the capable cyclization reaction of 5-dimethoxy ethoxy-benzoic acid methyl ester is to make 6,7-two 2-methoxy ethoxy quinazoline-4-ones; And
H. with 6,7-two 2-methoxy ethoxy quinazoline-4-ones carry out chlorination and the substituted two-in-one reaction of aniline can make 6,7-substituting group-4-aniline quinazoline.
2. according to claim 16; The compound method of 7-substituting group-4-aniline quinazoline; The step of said second up oxygen-alkylated reaction of oxygen is to carry out under the environment of 25 ~ 150 ℃ of temperature with the organic solvent with weak base material, water and catalyzer, and wherein said weak base material is K 2CO 3, KHCO 3, NaHCO 3Or Na 2CO 3, and said organic solvent is CH 3CN, N or acetone, said catalyzer are side chain 2-bromotrifluoromethane methyl ethers.
3. according to claim 16; The compound method of 7-substituting group-4-aniline quinazoline; Wherein said hydrolysis-demethylation reaction is the temperature condition at 25 ℃ ~ 100 ℃, and with carrying out in water-soluble solution of highly basic material or the aqueous solutions of organic solvent, wherein said highly basic material is KOH or NaOH;
Esterification was to use the alcoholic solvent of C1 ~ C6 in mineral acid, to react or utilized SOCl said second time 2In the alcoholic solvent of C1 ~ C6, react, its temperature of reaction is 25 ~ 100 ℃;
And the said oxygen-alkylated reaction of said first oxygen is under the environment with 25 ~ 150 ℃ of weak base material, organic solvent, water and a spot of catalyzer and temperature, to carry out, and wherein said weak base material is K 2CO 3, KHCO 3, NaHCO 3Or Na 2CO 3, and said organic solvent is CH 3CN, N or acetone, said catalyzer are side chain 2-bromotrifluoromethane methyl ethers.
4. according to claim 16, the compound method of 7-substituting group-4-aniline quinazoline, wherein said hydrolysis-demethylation reaction is with 1 ~ 10 normal AlCl 3Organic solvent, be to carry out under 25 ~ 150 ℃ the condition in temperature, wherein said organic solvent is toluene, oil of mirbane or CH 2Cl 2Esterification was to use the alcoholic solvent of C1 ~ C6 in mineral acid, to react or utilized SOCl said second time 2In the alcoholic solvent of C1 ~ C6, react, its temperature of reaction is 25 ~ 100 ℃.
5. according to claim 16, the compound method of 7-substituting group-4-aniline quinazoline, esterification was to use alcoholic solvent in mineral acid, to react or utilized SOCl wherein said first time 2In alcoholic solvent, react, its temperature of reaction is 25 ~ 100 ℃.
6. according to claim 16, the compound method of 7-substituting group-4-aniline quinazoline, wherein said nitration reaction are to utilize acetic acid, sulfuric acid and nitric acid to carry out.
7. according to claim 16, the compound method of 7-substituting group-4-aniline quinazoline, wherein said nitro-reduction reaction is in strong base solution, to add Na 2S 2O 4Carrying out reduction reaction or in organic solvent, to add catalytic amount 10%Pd-C, logical hydrogen reaction under pressure 30 ~ 60psi, temperature is 25 ~ 100 ℃, wherein said organic solvent is ETHYLE ACETATE or alcohols.
8. according to claim 16, the compound method of 7-substituting group-4-aniline quinazoline, wherein said cyclization reaction is at HCO at 100 ~ 200 ℃ 2NH 4And HCONH 2In react.
9. according to claim 16, the compound method of 7-substituting group-4-aniline quinazoline, the chlorination reaction in the wherein said two-in-one reaction is in organic solvent, to add PCl 5, POCl 3And SOCl 2Carry out at 25 ~ 160 ℃, wherein said organic solvent is benzene, toluene, N.
10. according to claim 16, the compound method of 7-substituting group-4-aniline quinazoline, the aniline substitution reaction in the wherein said two-in-one reaction is in alcohols, anils to be added reaction.
CN2012102395779A 2009-04-16 2009-04-16 Synthesis method of 6, 7-substituted-4-aniline quinazoline Pending CN102746242A (en)

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CN106397401A (en) * 2016-08-30 2017-02-15 山东罗欣药业集团股份有限公司 Crystal compound of anticancer medicament and preparation method thereof
CN108358798A (en) * 2018-02-12 2018-08-03 黑龙江鑫创生物科技开发有限公司 A kind of method of micro passage reaction synthesis Tarceva intermediate

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