CN101402610A - Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline - Google Patents
Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline Download PDFInfo
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Abstract
The invention discloses a method for synthesizing 4-(3-chloro-4-fluorophenylamino)-7-methoxy -6-[3-(4-morpholinyl)-propoxy] quinoline. The method comprises the following steps: 1) 3-hydroxide radical-4-methoxybenzaldehyde is used as a raw material to prepare 3-hydroxide radical-4-methoxy-benzonitrile; 2) the 3-hydroxide radical-4-methoxy-benzonitrile and 3- chloropropy morpholinehydrochloride are heated to have reflux reaction to obtain 4- methoxy-3-[3-(4- morpholinyl) propoxy] benzonitrile; 3) the 4- methoxy-3-[3-(4-morpholinyl) propoxy] benzonitrile is subjected to nitration to obtain 2- nitryl-4- methoxy -5-[3-(4-morpholinyl) propoxy] benzonitrile; 4) the 2- nitryl-4- methoxy -5-[3-(4-morpholinyl) propoxy] benzonitrile is subjected to reduction to obtain 2-amido-4- methoxy-5-[3-(4-morpholinyl) propoxy] benzonitrile; and 5) the 2-amido-4- methoxy-5-[3-(4-morpholinyl) propoxy] benzonitrile and an azomethine intermediate of 3-chloro-4-fluoroaniline have rearrangement reaction to obtain 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline. The method has characteristics of environmental protection and high production rate.
Description
Technical field
The present invention relates to 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] (Gefitinib, preparation method Gefitinib) belong to the technical field of medication preparation to quinoline.
Background technology
Gefitinib (Gefitinib) is a kind of new type antineoplastic medicine by the exploitation of Astra Zeneca company, it is the oral micromolecular inhibitor at the EGFR protein tyrosine kinase, went on the market in Japan first in 2002, be used for the treatment of and perform the operation or the nonsmall-cell lung cancer of transfer and relapse, got permission as three-way single therapy late period nonsmall-cell lung cancer (NSCLC) medicine in the U.S. and Australia in May, 2003, and it is first small molecular protein tyrosine kinase inhibitor class targeted anticancer medicine that is used for treatment of solid tumors.Nikkei State Food and Drug Administration (SFDA) approval February 25 in 2005 is formally in China's listing (trade(brand)name: Gefitinib), be used for previously accepting chemotherapeutical local late period or transitivity nonsmall-cell lung cancer.Its structural formula is as follows:
Preparation method of gefitinib mainly contains following four kinds:
Method one (WO9742187) synthetic route is as follows for EP0566226, WO9633980:
This route is with 6; 7-dimethoxyquinazoline-4 (3H)-ketone is raw material; obtain 6-hydroxyl-7-methoxyl group quinazoline-4 (3H)-ketone through the selectivity demethoxylation; hydroxyl is obtained the 4-chloro-quinazoline with aceticanhydride protection back chloro; through the nucleophilic substitution of arylamine, deprotection and side chain alkoxylate obtain target compound again.This synthetic route raw material costliness, the regioselectivity demethyl need consume more L-methionine(Met) and expendable methanesulfonic, and chlorination need be used the halide reagent such as the thionyl chloride of high risk, high pollution, phosphorus oxychloride etc.And in the building-up process, hydroxyl needs protection and goes protection, thereby makes that the entire reaction route is longer, is not suitable for industrialized production.
Method two (CN1733738) synthetic route is as follows:
This route is with 3, the 4-mesitylenic acid be raw material through nitrated, the nucleophilic substitution of demethylation, reduction, pass ring, chloro, arylamine, and seven steps reaction such as the alkoxylate of pendant hydroxyl group obtains Gefitinib.This synthetic route reactions steps is long, and chloro is still used the halide reagent thionyl chloride of high risk, high pollution, phosphorus oxychloride etc., and the side reaction in this step of chloro is more, and yield is low.
Method three (CN101148439A) synthetic route is as follows:
This route is a raw material with 3-hydroxyl-4-methoxyl methyl benzoate, at first by the side chain alkoxylate, introduces 3-morpholine propoxy-, and then synthesizes Gefitinib through the six-step processes such as nucleophilic substitution of nitrated, reduction, pass ring, chloro, arylamine.But, not eco-friendly synthetic route because this building-up process still will be used the halide reagent of high risk such as more thionyl chloride, phosphorus oxychloride and high pollution.
Method four (Bioorganic﹠amp; Medicinal Chemistry Letters, 2006,16 (15): 4102; WO2004024703) synthetic route is as follows:
This route is a raw material with 3-hydroxyl-4-methoxybenzaldehyde, through reduction condensation, oxidation, side chain alkoxylate, nitrated, reduction, close ring, obtain the 4-chloro-quinazoline through chloro, again with 3-chloro-4-fluoroaniline generation nucleophilic substitution, altogether through the synthetic Gefitinib of eight steps reaction.Though this route has passed through pilot scale, but still do not break away from the halide reagent of high-risk, high pollution, as the chlorine sulfoxide, the use of phosphorus oxychloride etc.And reactions steps is long, and total recovery is on the low side.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of environmental friendliness, reactions steps is few, productive rate is high 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] preparation method of quinoline.
In order to solve the problems of the technologies described above, the invention provides a kind of 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-Nei oxygen base] synthetic method of quinoline, may further comprise the steps:
1), be raw material with 3-hydroxyl-4-methoxybenzaldehyde, in solvent, carry out single step reaction with oxammonium sulfate, sodium formiate; Arrive 3-hydroxyl-4-anisole nitrile; The mol ratio of 3-hydroxyl-4-methoxybenzaldehyde, oxammonium sulfate and sodium formiate is 1: 1～2: 1.9～4,25～100 ℃ of temperature of reaction, 3～6 hours reaction times;
2), 3-hydroxyl-4-anisole nitrile and 3-chloropropyl morpholine hydrochloride under catalyzer and effect as the mineral alkali of acid binding agent, in solvent, carry out heating reflux reaction, obtain 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] the benzene nitrile; The mol ratio of 3-hydroxyl-4-anisole nitrile and 3-chloropropyl morpholine hydrochloride is 1: 1～1.5, the mol ratio of catalyzer and 3-hydroxyl-4-anisole nitrile is 1%～6%, the mol ratio of mineral alkali and 3-hydroxyl-4-anisole nitrile is 1～3: 1,4～8 hours reaction times;
3), 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] the benzene nitrile after nitrated, obtain 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen;
4), 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen through the reduction after; Obtain 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen;
5), mol ratio is 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-of 1: 1～1.5] the western fluorine alkali intermediate generation rearrangement reaction of benzene cyanogen and 3-chloro-4-fluoroaniline, obtain 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] quinoline; 100～150 ℃ of temperature of reaction, 3～6 hours reaction times.
Improvement as synthetic method of the present invention: the catalyzer step 2) is potassiumiodide or sodium iodide, and mineral alkali is salt of wormwood, yellow soda ash or Quilonum Retard, and solvent is an acetonitrile, temperature of reaction 25-100 ℃.
As the further improvement of synthetic method of the present invention, step 4) is: mol ratio is 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-of 1: 1.5～3.1] benzene cyanogen and reductive agent carry out reduction reaction, 25～100 ℃ of temperature of reaction in solvent.Reductive agent is iron powder, zinc powder, sodium sulfite, or reduces with the palladium carbon that is reduced amount 5～10% (weight percent is 10%) catalytic hydrogenation under 3～4 normal atmosphere, and solvent is water, methyl alcohol, ethanol, ethyl acetate, methylene dichloride or acetic acid.
Further improvement as synthetic method of the present invention: step 3) is: with 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] benzene cyanogen in solvent and nitration mixture (1: 1～3 compositions of sulfuric acid and nitric acid volume ratio) at room temperature carry out nitration reaction, 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] mol ratio of benzene cyanogen and nitric acid is 1: 1～4, the reaction times is 30～50 hours.
Further improvement as synthetic method of the present invention: the western Buddhist alkali intermediates preparation of the 3-chlorine 4-fluoroaniline in the step 5) is as follows: with 3-chloro-4-fluoroaniline and N, the dinethylformamide dimethylacetal carries out back flow reaction under the effect of acetic acid (as catalyzer) in solvent; Reaction times is 2～5 hours, 3-chloro-4-fluoroaniline and N, and the mol ratio of dinethylformamide dimethylacetal is 1: 1～2; The mol ratio of acetic acid and 3-chloro-4-fluoroaniline is 1～10%; This solvent can be selected benzene,toluene,xylene etc. for use.
Further improvement as synthetic method of the present invention: step 5) is: with 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] the benzene nitrile is dissolved in the acetic acid, the western Buddhist alkali intermediate that adds 3-chloro-4-fluoroaniline again, after the mixed heating, carry out the stirring and refluxing reaction.
Further improvement as synthetic method of the present invention: the preferable reaction temperature of step 1) is 50～100 ℃, most preferably is 70～90 ℃; Step 2) preferable reaction temperature is 50～100 ℃; The preferable reaction temperature of step 5) is 120～140 ℃.
Synthetic route of the present invention is as follows:
Synthetic method of the present invention is a raw material with 3-hydroxyl-4-methoxybenzaldehyde, in step 1), be cyano group at first with the aldehyde radical reduction condensation, then in step 2) on 3 hydroxyl oxygen atoms, introduce 3-morpholine propoxy-, obtain 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] the benzene nitrile; Thereby the protection of having avoided hydroxyl in the building-up process in the past with go protection.
The synthetic route of present existing Gefitinib mostly adopts first synthetic intermediate 4-chloro-quinazoline, and then obtain target product with 3-chloro-4-fluoroaniline reaction, because synthetic 4-chloro-quinazoline will be used the halide reagent of high-risk, high pollution inevitably, as chlorine sulfoxide, phosphorus oxychloride etc., this brings very big inconvenience for the aftertreatment of suitability for industrialized production.
In sum, the present invention has following beneficial effect:
1, avoided the halide reagent of high-risk, high pollution fully, the use as chlorine sulfoxide, phosphorus oxychloride etc. greatly reduces environmental pollution, makes production environment friendly more;
2, in building-up process, directly on its 3 Sauerstoffatoms, introduce 3-morpholine propoxy-, thereby avoided the protection and the de-protected loaded down with trivial details process of hydroxyl; Therefore has advantage such as simplify the operation, reduce cost;
3, short, simple to operate, the economic environmental protection of synthesis step of the present invention, total recovery obviously improve, and are fit to industrialized production.
Embodiment
Embodiment 1, a kind of 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthetic method of quinoline, carry out following steps successively:
1), the preparation of 3-hydroxyl-4-anisole nitrile (structural formula is 2):
With 3-hydroxyl-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formiate (89.4g, 1.31mol) and formic acid (480ml) stirring, mix and be heated to 80 ℃, add oxammonium sulfate (114.8g, 0.70mol), oxammonium sulfate is divided into six parts, and every interval added a in 30 minutes; Add the back in 80 ℃ of heated and stirred 5 hours.
To react the miscellany cool to room temperature of gained, add saturated common salt aqueous solution 250ml, stir, filter, separate the throw out of separating out, and wash with water, the dry pale solid that gets is 3-hydroxyl-4-anisole nitrile (79.0g, yield 80%).
1H?NMR(DMSO-d
6，300MHz)：3.83(s，3H)，7.00-7.13(m，2H)，7.24(dd，J＝2.2，8.1Hz，1H)，9.78(s，1H)。
2), 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 3):
With 3-hydroxyl-4-anisole nitrile (80.0g, 0.54mol), salt of wormwood (130.0g, 0.94mol), potassiumiodide (5.0g, 0.030mol), 3-chloropropyl morpholine hydrochloride (92.1g, 0.56mol) mixed being dissolved in the dry acetonitrile (500ml), be heated to 80 ℃, refluxed 6 hours.
After reaction finishes, cool to room temperature, filter, filtrate decompression steams acetonitrile recovery set usefulness, and resistates is dissolved in the 400mL ethyl acetate, washing, anhydrous sodium sulfate drying filters, and the evaporated under reduced pressure ethyl acetate gets viscous liquid, be 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] benzene nitrile (141.6g, yield 95%).
1H?NMR(DMSO-d
6，300MHz)：1.85(q，J＝6.6Hz，2H)，2.43(m，6H)，3.55(t，J＝5.9Hz，4H)，3.82(s，3H)，4.03(t，J＝5.9Hz，2H)，7.09(d，J＝8.8Hz，1H)，7.33-7.43(m，2H).
3), 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 4):
With 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] (40.0g 0.14mol) is dissolved in methylene dichloride (400ml) to the benzene nitrile, and 0-5 ℃ of dropping is chilled to nitration mixture (the 50ml 70%H of room temperature
2SO
4Be woven into 50ml 70%HNO
3And get), reaction mixture is warmed up to room temperature naturally, stirring reaction 40 hours.
After reaction finishes, add 800ml cold water, the NaOH with 40% regulates PH to 11, dichloromethane extraction (300ml * 2), merge organic phase, be washed to neutrality, anhydrous sodium sulfate drying filters, the evaporated under reduced pressure methylene dichloride gets yellow solid, get product with re-crystallizing in ethyl acetate again, be 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene nitrile (42.7g, yield 95%).
1H?NMR(DMSO-d
6，300MHz)：1.90(q，J＝6.6，2H)，2.27-2.44(m，6H)，3.56(t，J＝4.4Hz，4H)，3.96(s，3H)，4.22(t，J＝5.9Hz，2H)，7.69(s，1H)，7.84(s，1H)，
4), 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 5):
With compound 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene nitrile (25g, 0.078mol) be dissolved in the 300ml methyl alcohol, add the Pd/C of 2.5g 10% (weight ratio), in 25 ℃, hydrogenating reduction under 3～4 normal atmosphere is not till having hydrogen to absorb again.Filter, 100mL methanol wash palladium carbon, the recyclable usefulness again of palladium carbon, the filtrate decompression evaporate to dryness gets viscous liquid, is 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene nitrile (21.5g, yield 95%).
1H?NMR(DMSO-d
6，300MHz)：1.77(q，J＝6.6Hz，2H)，2.26-2.40(m，6H)，3.55(t，J＝4.4Hz，4H)，3.72(s，3H)，3.84(t，J＝6.6Hz，2H)，5.63(s，2H)，6.38(s，1H)，6.88(s，1H)。
5), 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] preparation of quinoline:
1., carry out the preparation of the western Buddhist alkali intermediate of 3-chlorine 4-fluoroaniline earlier:
With 3-chloro-4-fluoroaniline (13.1g, 0.09mol), toluene (100ml), acetic acid (2ml) and N, (14ml 0.11mol) mixedly is heated to 110 ℃ to the dinethylformamide dimethylacetal, stirring and refluxing 3 hours, the evaporated under reduced pressure solvent gets colourless liquid, is the western Buddhist alkali intermediate (18.0g, yield 98%) of 3-chlorine 4-fluoroaniline.
1H?NMR(DMSO-d
6，300MHz)：2.53(s，6H)，6.45(s，1H)，6.68(m，1H)，7.51(s，1H)，7.67(m，1H).
2., carry out 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-again] preparation of quinoline
With 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene nitrile (21.5g, 0.074mol) be dissolved in the acetic acid (200ml), the western Buddhist alkali intermediate of adding 3-chloro-4-fluoroaniline (16.0g, 0.08mol), mix and be heated to 120-130 ℃, stirring and refluxing 3 hours.
After back flow reaction finishes, boil off most of acetic acid (recoverys),, pour in the frozen water, with about ammoniacal liquor adjusting PH to 9, add the 50mL ethyl acetate then, stirred 1 hour, separate out solid the reactant cool to room temperature, filter crude product.This crude product is suspended in the 400ml methyl alcohol, stirs, be cooled to 20 ℃, stir and slowly add the 19ml concentrated hydrochloric acid down, separate out white solid, filter, with the cold methanol wash of 200ml, arrive crude product Gefitinib hydrochloride.Again resulting crude product Gefitinib hydrochloride is suspended in the 500ml water, stirring at room 1 hour, be cooled to 5 ℃ again, filter, obtain the off-white color solid with the 100ml cold water washing, with this type of white group solid resuspending in 200ml water, regulate about PH to 8 with ammoniacal liquor, filter dry mp:193-195 ℃ of the elaboration Gefitinib (23.1g, yield 70%) that get; Purity: 99% (HPLC) MS (m/z): [M+1]
+=447.1;
1H NMR (DMSO-d
6, 300MHz): 1.93-2.11 (m, 2H), 2.34-2.59 (m, 6H), 3.74 (dd, J=4.4,4,5Hz, 4H), 3.98 (s, 3H), 4.17 (t, J=6.5Hz, 2H), 7.24 (s, 1H), 7.48 (t, J=8.8Hz, 1H), 7.82 (s, 2H), 8.13 (s, 1H), 8.53 (s, 1H), 9.58 (br, 1H)
Embodiment 2, a kind of 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthetic method of quinoline, carry out following steps successively:
1), the preparation of 3-hydroxyl-4-anisole nitrile (structural formula is 2):
With 3-hydroxyl-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formiate (135.1g, 1.98mol) and formic acid (600ml) stirring, mix and be heated to 85 ℃, add oxammonium sulfate (162.4g, 0.99mol), oxammonium sulfate is divided into six parts, and every interval added part in 30 minutes; Add the back in 85 ℃ of heated and stirred 6 hours.
The miscellany of reaction gained is handled according to the mode that is equal to embodiment 1, got white solid (86.5g, yield 88%).
2), 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 3):
With 3-hydroxyl-4-anisole cyanogen (80.0g, 0.54mol), yellow soda ash (138.9g, 1.35mol), sodium iodide (4.5g, 0.030mol), 3-chloropropyl morpholine hydrochloride (133.2g, 0.81mol) mixed being dissolved in the dry acetonitrile (500ml), be heated to 80 ℃, refluxed 5 hours.
The reaction gains are handled according to the mode that is equal to embodiment 1, got viscous liquid (140.0g, yield 94%).
3), 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 4):
With 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] (20.0g 0.072mol) is dissolved in acetic acid (100ml) to the benzene nitrile, and 0-5 ℃ of dropping is chilled to the nitration mixture (50ml70%H of room temperature
2SO
4Be woven into 50ml 70%HNO
3And get), reaction mixture is warmed up to room temperature naturally, stirring reaction 30 hours.
The reaction gains are handled according to the mode that is equal to embodiment 1, are got 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen (21.5g, yield 93%).
4), 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 5):
With compound 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] (25g 0.078mol) joins in the 200ml water benzene nitrile, and (27.1g 0.16mol), stirs, and 40～50 ℃ were reacted 2 hours to add V-Brite B again; Be warmed up to 70 ℃ then, in 30 minutes, add the 60mL concentrated hydrochloric acid, finish, be incubated 20 minutes, reaction solution cooling room temperature, the NaOH aqueous solution that drips mass concentration 40% is regulated pH value to 8, dichloromethane extraction (3 * 100mL), merge organic phase, be washed to neutrality, anhydrous sodium sulfate drying filters, the evaporated under reduced pressure solvent gets viscous liquid (21.3g, yield 94%).
5), 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] preparation of quinoline:
1., carry out the preparation of the western Buddhist alkali intermediate of 3-chlorine 4-fluoroaniline earlier: with embodiment 1.
2., carry out 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-again] preparation of quinoline
With 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene nitrile (21.5g, 0.074mol) be dissolved in the acetic acid (200ml), the western Buddhist alkali intermediate of adding 3-chloro-4-fluoroaniline (22.0g, 0.11mol), mix and be heated to 130 ℃, stirring and refluxing reaction 4 hours.
The reaction gains are handled according to the mode that is equal to embodiment 1, got product Gefitinib (22.4g, yield 68%)
Embodiment 3, a kind of 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthetic method of quinoline, carry out following steps successively:
1), the preparation of 3-hydroxyl-4-anisole nitrile (structural formula is 2):
With 3-hydroxyl-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formiate (130.0g, 1.91mol) and formic acid (600ml) stirring, mix and be heated to 90 ℃, add oxammonium sulfate (162.4g, 0.99mol), oxammonium sulfate is divided into six parts, and every interval added part in 30 minutes; Add the back in 90 ℃ of heated and stirred 5 hours.
The miscellany of reaction gained is handled according to the mode that is equal to embodiment 1, got white solid (84.6g, yield 86%).
2), 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 3):
With 3-hydroxyl-4-anisole cyanogen (80.0g, 0.54mol), Quilonum Retard (90.4g, 1.35mol), sodium iodide (4.5g, 0.030mol), 3-chloropropyl morpholine hydrochloride (133.2g, 0.81mol) mixed being dissolved in the dry acetonitrile (500ml), be heated to 85 ℃, refluxed 5 hours.
The reaction gains are handled according to the mode that is equal to embodiment 1, got viscous liquid (141.6g, yield 95%).
3), 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 4):
With 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] (60.0g 0.22mol) is dissolved in acetic acid (100ml) to the benzene nitrile, and 0-5 ℃ of dropping is chilled to the nitration mixture (150ml70%H of room temperature
2SO
4Be woven into 150ml 70%HNO
3And get), reaction mixture is warmed up to room temperature naturally, stirs 40 hours.
The reaction gains are handled according to the mode that is equal to embodiment 1, are got 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen (56.5g, 93%).
4), 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] preparation of benzene nitrile (structural formula is 5):
With compound 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene nitrile (25g, 0.078mol) be dissolved in the 300ml acetic acid, add under the room temperature in batches zinc powder (15.2g, 0.24mol), stir, finish, 60-70 ℃ was reacted 4 hours, then the reaction solution cool to room temperature, filter, the most acetic acid of reclaim under reduced pressure, resistates are dissolved in the 200mL methylene dichloride, and 40% the NaOH aqueous solution is regulated pH value to 10, tell organic phase, dichloromethane extraction (2 * 100mL), merge organic phase, be washed to neutrality, anhydrous sodium sulfate drying, filter, the evaporated under reduced pressure solvent gets viscous liquid (21.3g, yield 94%).
5), 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] preparation of quinoline:
1., carry out the preparation of the western Buddhist alkali intermediate of 3-chlorine 4-fluoroaniline earlier: with embodiment 1.
2., carry out 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-again] preparation of quinoline
With 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-that obtains previously] benzene nitrile (21.5g, 0.074mol) be dissolved in the acetic acid (250ml), the western Buddhist alkali intermediate of adding 3-chloro-4-fluoroaniline (18.0g, 0.09mol), mix and be heated to 135 ℃, stirring and refluxing reaction 4 hours.
The reaction gains are handled according to the mode that is equal to embodiment 1, got product Gefitinib (22.4g, yield 65%)
At last, it is also to be noted that what more than enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (9)
1, a kind of 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that may further comprise the steps:
1), be raw material with 3-hydroxyl-4-methoxybenzaldehyde, in solvent, carry out single step reaction with oxammonium sulfate, sodium formiate; Arrive 3-hydroxyl-4-anisole nitrile; The mol ratio of 3-hydroxyl-4-methoxybenzaldehyde, oxammonium sulfate and sodium formiate is 1: 1～2: 1.9～4,25～100 ℃ of temperature of reaction, 3～6 hours reaction times;
2), 3-hydroxyl-4-anisole nitrile and 3-chloropropyl morpholine hydrochloride under catalyzer and effect as the mineral alkali of acid binding agent, in solvent, carry out heating reflux reaction, obtain 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] the benzene nitrile; The mol ratio of 3-hydroxyl-4-anisole nitrile and 3-chloropropyl morpholine hydrochloride is 1: 1～1.5, the mol ratio of catalyzer and 3-hydroxyl-4-anisole nitrile is 1%～6%, the mol ratio of mineral alkali and 3-hydroxyl-4-anisole nitrile is 1～3: 1,4～8 hours reaction times;
3), 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] the benzene nitrile after nitrated, obtain 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen;
4), 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen through the reduction after; Obtain 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] benzene cyanogen;
5), mol ratio is 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-of 1: 1～1.5] the western fluorine alkali intermediate generation rearrangement reaction of benzene cyanogen and 3-chloro-4-fluoroaniline, obtain 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] quinoline; 100～150 ℃ of temperature of reaction, 3～6 hours reaction times.
2,4-according to claim 1 (3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that: step 2) in catalyzer be potassiumiodide or sodium iodide, mineral alkali is salt of wormwood, yellow soda ash or Quilonum Retard, solvent is an acetonitrile, 25～100 ℃ of temperature of reaction.
3,4-according to claim 2 (3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that described step 4) is: mol ratio is 2-nitro-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-of 1: 1.5～3.1] benzene cyanogen and reductive agent carry out reduction reaction, 25～100 ℃ of temperature of reaction in solvent.
4,4-according to claim 3 (3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that: the reductive agent in the described step 4) is iron powder, zinc powder, palladium carbon or V-Brite B.
5, according to claim 3 or 4 described 4-(3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that: the solvent in the described step 4) is water, methyl alcohol, ethanol, ethyl acetate, methylene dichloride or acetic acid.
6,4-according to claim 5 (3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that: described step 3) is: with 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] benzene cyanogen in solvent and nitration mixture at room temperature carry out nitration reaction, described nitration mixture is made up of the sulfuric acid and the nitric acid of volume ratio 1: 1～3; 4-methoxyl group-3-[3-(4-morpholinyl) propoxy-] mol ratio of benzene cyanogen and nitric acid is 1: 1～4, the reaction times is 30～50 hours.
7,4-according to claim 6 (3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that, the western Buddhist alkali intermediates preparation of the 3-chlorine 4-fluoroaniline in the described step 5) is as follows: with 3-chloro-4-fluoroaniline and N, the dinethylformamide dimethylacetal carries out back flow reaction under the effect of acetic acid in solvent; Reaction times is 2～5 hours, 3-chloro-4-fluoroaniline and N, and the mol ratio of dinethylformamide dimethylacetal is 1: 1～2; The mol ratio of acetic acid and 3-chloro-4-fluoroaniline is 1%～10%, and solvent is benzene, toluene or dimethylbenzene.
8,4-according to claim 7 (3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that: described step 5) is: with 2-amino-4-methoxyl group-5-[3-(4-morpholinyl) propoxy-] the benzene nitrile is dissolved in the acetic acid, the western Buddhist alkali intermediate that adds 3-chloro-4-fluoroaniline again, after the mixed heating, carry out the stirring and refluxing reaction.
9,4-according to claim 8 (3-chloro-4-fluoroanilino)-7-methoxyl group-6-[3-(4-morpholinyl)-propoxy-] synthesis method of quinoline, it is characterized in that: the temperature of reaction of step 1) is 50～100 ℃, step 2) temperature of reaction is 50～100 ℃, and the temperature of reaction of step 5) is 120～140 ℃.
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