WO2011147102A1 - Procédé de synthèse d'une 4-aniline-quinazoline substituée aux positions 6 et 7 - Google Patents

Procédé de synthèse d'une 4-aniline-quinazoline substituée aux positions 6 et 7 Download PDF

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WO2011147102A1
WO2011147102A1 PCT/CN2010/073364 CN2010073364W WO2011147102A1 WO 2011147102 A1 WO2011147102 A1 WO 2011147102A1 CN 2010073364 W CN2010073364 W CN 2010073364W WO 2011147102 A1 WO2011147102 A1 WO 2011147102A1
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reaction
substituted
carried out
synthesizing
nitro
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PCT/CN2010/073364
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施凯翔
谢幼容
刘清维
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翔真生物科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a method for synthesizing a quinazoline derivative, and in particular to a method for synthesizing a 6,7-substituted 4-anilinoquinazoline. Background technique
  • Epidermal growth factor receptor plays an important role in cancer development, and 6,7-substituted-4-aniline quinazoline is also widely used clinically for non-small cells.
  • Treatment of lung cancer Non-small-cell lung cancer, NSCLC
  • NSCLC non-small-cell lung cancer
  • Gefitinib marketed drugs Gefitinib, Erlotinib
  • thyroid cancer thyroid cancer Vandetanib
  • myeloid leukemia or Myelodysplasia such as Tandutinib
  • Tandutinib has the following structure:
  • the aldehyde group is converted to a nitrile group by using Isovanilln as a starting material, and after oxy-alkylation reaction, nitration reaction and nitro reduction reaction, hydrazine is formed by dimethylformamide-dimethylacetal (dimethylformamide (DMF)-DMA).
  • DMF dimethylformamide
  • DMF-DMA dimethylformamide-dimethylacetal
  • the ⁇ -dimethylformamidine derivative is finally subjected to Dimroth rearrangement reaction with an aniline compound to obtain Gefitinib.
  • the same method can be applied to the preparation of Erlotinib.
  • 3,4-dimethoxybenzoic acid (3,4-11 11 ( ⁇ 61120 ⁇ acid) as a starting material by nitration reaction, demethylation-nitro reduction reaction, cyclization reaction, chlorination reaction The aniline substitution reaction, and finally the oxy-alkylation reaction to obtain Gefitinib.
  • An object of the present invention is to provide a method for synthesizing a 6,7-substituted-4-aniline quinazoline.
  • a further object of the present invention is to provide a method for synthesizing 6,7-substituted-4-aniline quinazolines using lower cost starting materials.
  • a further object of the present invention is to provide a process for synthesizing 6,7-substituted-4-aniline quinazolines using lower cost starting materials in good yields.
  • the present invention provides a method for synthesizing 6,7-substituted-4-aniline quinazolines, wherein the chemical formula of the 6,7-substituted-4-anilinoquinazoline is as follows.
  • 2-nitro-4,5-substituted benzoate is subjected to a nitro reduction reaction to obtain 2-amino-4,5-substituted benzoic acid vinegar (alkyl 2-amino-4, 5- Subsituted benzoate);
  • 6,7-Substituted-3,4-dihydroquinazolin-4-one is subjected to a two-in-one reaction between chlorination and amine substitution to obtain 6,7-substituted-4-substituted amine quinquin Oxazoline.
  • the step of the reaction is a hydrolysis-demethylation-esterification reaction or an oxygen-alkylation reaction.
  • the invention provides a preparation method of a 4-anilinoquinazoline derivative having a lower starting cost and a higher yield, thereby effectively reducing the production cost and improving the product of the 4-anilinoquinazoline derivative product. Competing. DRAWINGS
  • FIG. 1 is a diagram showing the chemical structure of a manufacturing process according to an embodiment of the present invention.
  • FIG. 2 is a diagram showing the chemical structure of a manufacturing process according to another embodiment of the present invention.
  • FIG. 3 is a diagram showing the chemical structure of a manufacturing process according to still another embodiment of the present invention. detailed description
  • the invention discloses a method for synthesizing 6,7-substituted-4-aniline quinazoline by using a starting material of 3,4-subsituted benzoic acid; wherein, a synthetic method Is not going through
  • the hydrolysis-demethylation reaction step can be obtained by an esterification reaction, an oxy-alkylation reaction, a nitration reaction, a nitro reduction reaction, a cyclization reaction, and a one-pot reaction.
  • Figure 1 shows an example of the synthesis of 6,7-substituted-4-anilinoquinazolines of the present invention. Manufacturing process chemical structure diagram. As shown in Fig. 1, this example uses 3-hydroxy-4-methoxybenzoic acid 1 or 3,4-dihydroxybenzoic acid. As a starting material, an esterification reaction, an alkylation reaction on an oxygen, a nitration reaction, a reduction reaction, a cyclization reaction, and a one-pot reaction to obtain a 6,7-substituent-4- Aniline quinazolines.
  • Nitration reaction methyl 4-methoxy-3-(3-morpholinepropoxy)benzoate 3 and ethyl 3,4-dimethoxyethoxybenzoate 13 are dissolved in acetic acid. And adding 70% H 2 SO 4 and 45% HN0 3 , the temperature is between 25 and 150 ° C, the nitration reaction can be carried out to obtain the compound IV, namely 2-nitro-4-methoxy_5-( 3-Methyl 2-nitro-4-methoxy-5-(3-morpholinopropoxy)benzoate 4 and 2-Shisalki-4, 5-dimethoxyethoxybenzoic acid Ethyl 2-nitro-4, 5-dimethoxyethoxybenzoate 14.
  • step of synthesizing 6,7-substituted-4-aniline quinazoline in this embodiment starting with 3-hydroxy-4-methoxybenzoic acid 1 or 3,4-dihydroxybenzoic acid 1 1
  • the starting material was synthesized without the hydrolysis-demethylation-esterification reaction, and the 6,7-substituted-4-anilinoquinazoline was synthesized.
  • Figure 2 is a diagram showing the chemical structure of a manufacturing process for synthesizing a 6,7-substituted-4-anilinoquinazoline of the present invention.
  • this example is a 3,4-dimethoxy group.
  • 3,4-dimethoxybenzoic acid 7 is the starting material, after esterification, nitration, hydrolysis-demethylation, esterification, oxy-alkylation, nitro reduction, cyclization The reaction and the two-in-one reaction are carried out to obtain a 6,7-substituted-4-anilinoquinazoline.
  • 3,4-dimethoxybenzoic acid 7 can be prepared in the alcohol by Fischer esterification or S0C1 2 , ie, 3,4-dimethoxy Methyl 3 , 4-dimethoxybenzoate 8 .
  • Nitrification reaction Dissolve methyl 3,4-dimethoxybenzoate 8 in acetic acid, add 70% H 2 SO 4 and 45% HNO 3 , and carry out the nitration reaction at a temperature of 25-150 ° C.
  • Compound IV, methyl 2-nitro-4,5-dimethoxybenzoate 9, can be obtained.
  • Hydrolysis-demethylation-esterification reaction Dissolve methyl 2-nitro-4,5-dimethoxybenzoate 9 in a strong aqueous alkali solution at a temperature of 25 ° C to 100 ° C.
  • the strong alkali aqueous solution may be an alkaline solution aqueous solution such as KOH or NaOH, and the above reaction formula is as follows:
  • Oxygen-alkylation reaction Dissolving methyl 2-nitro-5-hydroxy-4-methoxybenzoate 10 with 3-morpholinopropoxy chloride in CH 3 CN, dimethylformamide
  • chlorination-stupamine substitution reaction 7-decyloxy-6-(3-morpholinepropoxy)-3,4-dihydroxyquinazolin-4-one 6 is dissolved In an organic solvent, chlorination reaction is carried out by using 2 to 20 equivalents of S0C1 2 , P0C1 3 and PC1 5 , and the obtained chlorinated product is directly substituted with an aniline derivative in an alcohol. More than 99.7% of the high purity product Gefitinib can be obtained.
  • the starting material of 3,4-dimethoxybenzoic acid 7 is used as a starting material.
  • the step of hydrolysis-demethylation-esterification is carried out to synthesize 6,7-substituted-4-anilinoquinazolines.
  • hydrolysis-demethylation-esterification reaction can also be carried out in a solvent such as toluene, nitrobenzene or CH 2 C1 2 at a temperature of 25 ° C to 150 ° C for 1 to 10
  • a solvent such as toluene, nitrobenzene or CH 2 C1 2
  • A1C1 3 selectively demethylates the methoxy-para-methoxy group in compound IV to produce compound V, which in this embodiment is 2-nitro-4,5-di Methyl methoxybenzoate (9) is reacted to methyl 2-nitro-5-hydroxy-4-methoxybenzoate 10.
  • Fig. 3 is a structural diagram showing the chemical flow of a process for the synthesis of a 6,7-substituted-4-anilinoquinazoline of the present invention.
  • this example is based on 3-methoxy-4-hydroxybenzoic acid 17 as a starting material, undergoing esterification reaction, oxy-alkylation reaction, Nitrification reaction, hydrolysis-demethylation-esterification reaction, oxy-alkylation reaction, nitro reduction reaction, cyclization reaction and 2-in-1 reaction to obtain 6,7-substituted-4-aniline Quinazoline.
  • 3-methoxy-4-hydroxy-benzoic acid 17 can be obtained by Fischer esterification or SOCl 2 in an alcohol, ie, 3-methoxy- Methyl 3-methoxy-4-hydroxybenzoate) 18.
  • Nitrification reaction Dissolve methyl 3-methoxy-4-methoxyethoxybenzoate 19 in acetic acid, add 70% H 2 S0 4 and 45% HN0 3 at a temperature of 25-150 ° C Under the conditions of the nitration reaction, the compound IV, Methyl 2-nitro-5-methoxy-4-methoxyethoxybenzoate, can be obtained. 20. 4.
  • Methyl 2-nitro-5-methoxy-4-methoxyethoxybenzoate 20 is dissolved in a strong aqueous alkali solution at 25 °C ⁇
  • the temperature of 100 ° C is first subjected to a hydrolysis reaction followed by a demethylation reaction, wherein the strong alkali aqueous solution may be an aqueous solution of a basic agent such as KOH or NaOH, and the above reaction formula is as follows:
  • Oxygen alkylation reaction dissolving methyl 2-nitro-5-hydroxy-4-methoxyethoxybenzoate 21 and branched 2-bromoethyl methyl ether in organic solvent dimethyl
  • the compound VI ie 2-nitro-4,5-dimethoxy group, can be obtained by reacting amide (DMF), acetone, CH 3 CN or organic solvent with water at a weak base or KI temperature of 25-150 ° C.
  • Methyl 2-nitro-4, 5-dimethoxyethoxybenzoate 22 can be obtained by reacting amide (DMF), acetone, CH 3 CN or organic solvent with water at a weak base or KI temperature of 25-150 ° C.
  • Nitro reduction reaction a solution of methyl 2-nitro-4,5-dimethoxyethoxybenzoate 22 in a strong base, adding Na 2 S 2 0 4 for reduction; or 10% Pd-C is used as a catalyst in a solvent such as ethyl acetate or an alcohol, and hydrogenation reaction is carried out at a temperature of 25 to 100 ° C under a pressure of 30 to 60 psi to obtain a compound VI, that is, a 2-amino group.
  • Methyl 2-amino-4, 5-dimethoxyethoxybenzoate 23 (Methyl 2-amino-4, 5-dimethoxyethoxybenzoate).
  • step of synthesizing 6,7-substituted-4-anilinoquinazoline in this embodiment 3-methoxy-4-hydroxybenzoic acid 17 is used as a starting material, and hydrolysis-demethylation is carried out.
  • step of the esterification reaction a 6,7-substituted 4-aniline quinazoline such as Erlotinib is synthesized. Vandetanib and Tandutinib can be obtained by synthesizing 6,7-substituted-4-anilinoquinazolines without the hydrolysis-demethylation-esterification step.
  • hydrolysis-demethylation-esterification reaction can also be carried out in a solvent such as toluene, nitrobenzene or CH 2 C1 2 at a temperature of 25 ° C to 150 ° C by means of 1 ⁇ 10 equivalents of A1C1 3 are selectively subjected to demethylation of the methoxy-position methoxy group in compound IV to obtain compound V, which in this embodiment is 2-nitro-5-methoxy Methyl 4-methoxyethoxybenzoate 20 is reacted to methyl 2-nitro-5-hydroxy-4-methoxyethoxybenzoate 21.
  • a solvent such as toluene, nitrobenzene or CH 2 C1 2
  • A1C1 3 is selectively subjected to demethylation of the methoxy-position methoxy group in compound IV to obtain compound V, which in this embodiment is 2-nitro-5-methoxy Methyl 4-methoxyethoxybenzoate 20 is reacted to methyl 2-nitro-5-hydroxy-4-methoxyeth
  • the synthetic methods of the improved synthesis of 6,7-substituted-4-anilinoquinazolines disclosed in the present invention all have a relatively high total yield, and the total yield is 30-42%;
  • the above synthesis method has the characteristics of being convenient for recovery and purification, and the purity of the final product is at least 99.7% or more;
  • the final step of the process is to complete the preparation of the product by a one-Pot step, and the start of use.
  • the price of the product is relatively low; from the above characteristics, the invention has the advantage of commercial mass production.
  • Methyl 2-nitro-5-hydroxy-4-methoxyethoxybenzoate 10 (lg, 0.0044 mol) was dissolved in 10 ml of dimethylformamide (DMF), and 3-morpholinepropane chloride was added. 3-morpholinopropoxy chloride (0.83 g, 5.269 mmol), and further K 2 C03 ( 1.21 g, 8.768 mmol) was reacted at 50-100 ° C for 1 hour, 20 ml of H 2 O was added, and 20 ml of ethyl acetate was added. extracted three times with ethyl acetate layers were dried M g S0 4, filtered, and concentrated to give a pale yellow solid compound 4, 1.5g (96.18%); which -NMR (CDC1 3) is
  • the starting material was methyl 3-hydroxy-4-methoxyethoxybenzoate 18, and a yellow solid compound 19 was obtained in a yield of 97.8%.
  • ⁇ -NMI ⁇ CDCls is 3.34(s,6H), 3.76(m,4H), 3.86(s,3H), 4.21(m,4H), 7.08(s,lH), 7.48(s,lH).
  • the starting material is methyl 3,4-dimethoxybenzoate 8 to obtain a yellow solid compound 9 in a yield of 95%; its -NMR (CDC1 3 ) is
  • the starting material is ethyl 3,4-dimethoxyethoxycarboxylate
  • the compound (13) was obtained as a brown liquid compound 14 in a yield of 81%.
  • Methyl 2-nitro-4,5-dimethoxybenzoate 9 (3 g, 0.0124 mol) was added to 20 ml of 20% KOH, and the mixture was reacted at 100 ° C for 5 hours. After cooling to room temperature and stirring at room temperature, 50 ml of IN HCl was added and extracted three times with 30 ml of ethyl acetate. The combined ethyl acetate layer was dried over MgS0 4, filtered, and concentrated to give a pale yellow solid 2.8g. After adding 28 ml of methanol, 1.0 ml of concentrated gram acid was added dropwise at room temperature, and the reaction was carried out under reflux with nitrogen for 6 hours.
  • Aluminium chloride (1 1.68 g, 87.65 mmol) was weighed into a 500 ml single In a flask, pass N 2 at room temperature, add CH 2 Cl 2 (50 ml), and slowly add dropwise 2-nitro-5-methoxy-4-methoxyethoxybenzoate 20 (5) g, 17.53 mmol) The reaction was heated to reflux at 40 ° C for 1 hour.
  • Ethyl 2-nitro-4,5-dimethoxyethoxybenzoate 14 (7 g, 20.40 mmol) was weighed into a 500 ml flask, and THF (30 ml), H 2 O ( 140 ml) and 28 ⁇ 30% NH 4 OH (4 ml). Finally, sodium hydrosulfite (3.88 g, 28.04 mmol) was added, and N 2 was passed at 75 ° C, and the reaction was refluxed for 2 hours. Again. Into 4 ml cone. HC1, continue to force. The reaction was refluxed for 2 hours.
  • the starting material is 2-amino-4,5-dimethoxyethoxybenzoic acid ethyl ester compound 15 or 2-amino-4,5-dimethoxyethoxy group.
  • the benzoic acid methyl ester compound 23 was obtained as an off-white solid compound (yield: 77%).
  • NMR (CDC1 3 ) was 3.71 (s, 6H), 3.82 (brs, 4H), 3.90 (brs, 4H), 6.26 (s, lH), 6.57 (s, lH), 7.58 (s, lH) o
  • a white solid gefitinib compound can be obtained 25.65g (62.86%).
  • 3-Aminophenylacetylene (3-eight 11 ⁇ 110 11611 13.61 1611) (0.228, 1.84 mmol) was weighed and dissolved in isopropanol (1 ml), and dropped into the above solution at 65 ° C. , continue to react for 2.5 hours. After completion of the reaction, it was cooled, filtered, and dried in a solid (60 ° C oven) for 17 hours to obtain a white solid compound of erlotinib (Erlotinib) 0.5 g (64%).

Abstract

La présente invention concerne un procédé de synthèse d'une 4-aniline-quinazoline substituée aux positions 6 et 7, dans lequel l'acide benzoïque substitué aux positions 3 et 4 est utilisé comme produit de départ et la 4-aniline-quinazoline substituée aux positions 6 et 7 est produite à partir de celui-ci par le biais d'une estérification, d'une O-alkylation, d'une nitration, d'une réduction du groupe nitro, d'une cyclisation, et d'une réaction deux en un de chloration et de substitution de l'amine, ou par estérification, O-alkylation ou nitration, hydrolyse-déméthylation, estérification, O-alkylation, réduction du groupe nitro, cyclisation, et réaction deux en un de chloration et de substitution de l'amine.
PCT/CN2010/073364 2010-05-28 2010-05-28 Procédé de synthèse d'une 4-aniline-quinazoline substituée aux positions 6 et 7 WO2011147102A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102584720A (zh) * 2012-02-02 2012-07-18 瑞阳制药有限公司 高纯度吉非替尼的制备工艺
CN103130760A (zh) * 2011-11-29 2013-06-05 中国科学院大连化学物理研究所 一种新型靶向性抗肿瘤药物及其制备方法与应用
CN103242245A (zh) * 2013-05-22 2013-08-14 苏州明锐医药科技有限公司 坦度替尼的制备方法
WO2013156835A1 (fr) * 2012-04-16 2013-10-24 Laurus Labs Private Limited Procédé amélioré de préparation d'une forme a de chlorhydrate d'erlotinib
WO2014118737A1 (fr) 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Sels d'erlotinib
CN104130199A (zh) * 2013-08-07 2014-11-05 安徽安腾药业有限责任公司 制备7-甲氧基-6-(3-吗啉-4-基丙氧基)喹唑啉-4(3h)-酮的方法
CN104725327A (zh) * 2015-03-03 2015-06-24 山东大学 一种高收率盐酸厄洛替尼的环保制备方法
CN106916067A (zh) * 2015-12-24 2017-07-04 江苏豪森药业集团有限公司 盐酸厄罗替尼关键中间体的制备方法
CN106928069A (zh) * 2017-03-21 2017-07-07 上海玉函化工有限公司 一种4,5‑二(2‑甲氧基乙氧基)‑2‑硝基苯甲酸乙酯的制备方法
CN108358798A (zh) * 2018-02-12 2018-08-03 黑龙江鑫创生物科技开发有限公司 一种微通道反应器合成厄洛替尼中间体的方法
CN110747489A (zh) * 2019-11-07 2020-02-04 湖南大学 抗癌药吉非替尼及其类似物中间体电还原制备方法

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CN101863844A (zh) * 2009-04-16 2010-10-20 翔真生物科技股份有限公司 6,7-取代基-4-苯胺类喹唑啉的合成方法

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WO2008122776A2 (fr) * 2007-04-04 2008-10-16 Cipla Limited Procédé de préparation de l'erlotinib et de ses sels pharmaceutiquement acceptables
CN101863844A (zh) * 2009-04-16 2010-10-20 翔真生物科技股份有限公司 6,7-取代基-4-苯胺类喹唑啉的合成方法

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103130760A (zh) * 2011-11-29 2013-06-05 中国科学院大连化学物理研究所 一种新型靶向性抗肿瘤药物及其制备方法与应用
CN103130760B (zh) * 2011-11-29 2015-06-17 中国科学院大连化学物理研究所 一种新型靶向性抗肿瘤药物及其制备方法与应用
CN102584720B (zh) * 2012-02-02 2014-12-17 瑞阳制药有限公司 高纯度吉非替尼的制备工艺
CN102584720A (zh) * 2012-02-02 2012-07-18 瑞阳制药有限公司 高纯度吉非替尼的制备工艺
WO2013156835A1 (fr) * 2012-04-16 2013-10-24 Laurus Labs Private Limited Procédé amélioré de préparation d'une forme a de chlorhydrate d'erlotinib
WO2014118737A1 (fr) 2013-01-31 2014-08-07 Ranbaxy Laboratories Limited Sels d'erlotinib
CN103242245B (zh) * 2013-05-22 2015-05-20 苏州明锐医药科技有限公司 坦度替尼的制备方法
CN103242245A (zh) * 2013-05-22 2013-08-14 苏州明锐医药科技有限公司 坦度替尼的制备方法
CN104130199A (zh) * 2013-08-07 2014-11-05 安徽安腾药业有限责任公司 制备7-甲氧基-6-(3-吗啉-4-基丙氧基)喹唑啉-4(3h)-酮的方法
CN104725327A (zh) * 2015-03-03 2015-06-24 山东大学 一种高收率盐酸厄洛替尼的环保制备方法
CN106916067A (zh) * 2015-12-24 2017-07-04 江苏豪森药业集团有限公司 盐酸厄罗替尼关键中间体的制备方法
CN106916067B (zh) * 2015-12-24 2021-07-06 江苏豪森药业集团有限公司 盐酸厄罗替尼关键中间体的制备方法
CN106928069A (zh) * 2017-03-21 2017-07-07 上海玉函化工有限公司 一种4,5‑二(2‑甲氧基乙氧基)‑2‑硝基苯甲酸乙酯的制备方法
CN108358798A (zh) * 2018-02-12 2018-08-03 黑龙江鑫创生物科技开发有限公司 一种微通道反应器合成厄洛替尼中间体的方法
CN110747489A (zh) * 2019-11-07 2020-02-04 湖南大学 抗癌药吉非替尼及其类似物中间体电还原制备方法
CN110747489B (zh) * 2019-11-07 2021-05-07 湖南大学 抗癌药吉非替尼及其类似物中间体电还原制备方法

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