厄洛替尼及其中间体的合成工艺研究
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摘要
厄洛替尼(Erlotinib)是由OSI、Genetech和Roche共同开发的一种表皮生长因子受体抑制剂(Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor,EGFR-TKI)。现在临床上主要用于非小细胞肺癌(Non-small Cell Lung Cancer,NSCLC)和胰腺癌的治疗。
本文根据文献资料确定了6步反应合成厄洛替尼的方法:由3,4-二羟基苯甲酸乙酯和2-氯乙基甲基醚烷基化得到3,4-二-(2-甲氧乙氧)苯甲酸乙酯(1);经过硝化、铁粉还原并成盐制得2-氨基-4,5-二-(2-甲氧乙氧)-苯甲酸乙酯盐酸盐(3);(3)与甲酰胺环合得到6,7-二-(2-甲氧乙氧)-4(3H)-喹唑啉酮(4);以POCl3为氯化剂,N,N-二甲基苯胺为催化剂进行氯代反应得到4-氯-6,7-二-(2-甲氧乙氧)-喹唑啉(5);最后,化合物(5)与3-乙炔苯胺在N2保护下反应得到厄洛替尼的盐酸盐。在合成厄洛替尼的同时,还参照文献及相关专利,以间硝基苯甲醛和丙二酸为起始原料,通过Knoevenagel缩合反应、溴加成、除溴-脱羧、消除、还原等一系列步骤得到了中间体3-乙炔苯胺。
在合成方法上主要作了如下改进:采用较为廉价的2-氯乙基甲基醚,通过加强缚酸剂的碱性、提高反应温度合成(1),缩短了反应时间,减少了卤代烃的用量;硝化时适当提高反应温度,提高转化率;在(3)的合成中,采用95%乙醇-冰乙酸的反应体系,克服了铁泥过滤难的问题,不仅收率高,而且后处理容易;确定了合成(5)的卤代剂、最佳反应时间和后处理方法,使反应更加完全,后处理操作简便。
通过本文方法合成的厄洛替尼(以3,4-二羟基苯甲酸乙酯为基准物料)的总收率为44.8%,并用IR,1HNMR、MS确证了其结构。结果证明此方法操作简便,条件温和,适合较大规模生产。
Erlotinib is an epidermal growth factor receptor inhibitor (EGFR-TKI) which was developed by OSI,Genetech and Roche. It is used for the treatment of Non-Small Cell Lung Cancer (NSCLC) and Pancreatic Cancer in clinic.
The thesis determined a six-step route to synthesize Erlotinib by the methods of literature. O-alkylation between ethyl 3,4-dihydroxybenzoate and 1-Chloro-2- methoxy-ethane gaved Ethyl 3 , 4-bis(2-methoxyethoxy)benzoate(1). Ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate hydrochloride(3) was obtained from (1) via nitration,reduction and salt formation. Cyclization between (3) and formamide gaved 6,7-Bis-(2-methoxyethoxy)-quinazolin-4(3H)-one(4). (4) is chloro-substituted by POCl3 and N,N-dimethylaniline as the catalyzer. At last,the hydrochloride salt of Erlotninb can be obtained from (5) and 3-ethynylphenylamine via N-alkylation. By the way,3-ethynylphenylamine was synthesized via Knoevenagel condensation,bromine addition,debromination-decarboxylation,elimination and reduction from m-nitrobenzaldehyde and malonate.
The main improvements of the method are:reaction time is shortened and feed capacity of halohydrocarbon is reduced because of the reinforce of alkalinity of acid-binding and increase the temperature;the conversion rate of (2) is increased by the higher reaction temperature;raising the yield and reducing the cost of the synthesis of compound(3) due to changing the reaction system;Determine the best reaction time and the way of purification during the synthesis of compound (5).
The overall yield of Erlotinib synthesized by the method is 44.8% on the basis of ethyl 3,4-dihydroxybenzoate. The structure of Erlotinib was confirmed by IR,1HNMR,MS. The result indicates that the method is simple,convenient.
本文根据文献资料确定了6步反应合成厄洛替尼的方法:由3,4-二羟基苯甲酸乙酯和2-氯乙基甲基醚烷基化得到3,4-二-(2-甲氧乙氧)苯甲酸乙酯(1);经过硝化、铁粉还原并成盐制得2-氨基-4,5-二-(2-甲氧乙氧)-苯甲酸乙酯盐酸盐(3);(3)与甲酰胺环合得到6,7-二-(2-甲氧乙氧)-4(3H)-喹唑啉酮(4);以POCl3为氯化剂,N,N-二甲基苯胺为催化剂进行氯代反应得到4-氯-6,7-二-(2-甲氧乙氧)-喹唑啉(5);最后,化合物(5)与3-乙炔苯胺在N2保护下反应得到厄洛替尼的盐酸盐。在合成厄洛替尼的同时,还参照文献及相关专利,以间硝基苯甲醛和丙二酸为起始原料,通过Knoevenagel缩合反应、溴加成、除溴-脱羧、消除、还原等一系列步骤得到了中间体3-乙炔苯胺。
在合成方法上主要作了如下改进:采用较为廉价的2-氯乙基甲基醚,通过加强缚酸剂的碱性、提高反应温度合成(1),缩短了反应时间,减少了卤代烃的用量;硝化时适当提高反应温度,提高转化率;在(3)的合成中,采用95%乙醇-冰乙酸的反应体系,克服了铁泥过滤难的问题,不仅收率高,而且后处理容易;确定了合成(5)的卤代剂、最佳反应时间和后处理方法,使反应更加完全,后处理操作简便。
通过本文方法合成的厄洛替尼(以3,4-二羟基苯甲酸乙酯为基准物料)的总收率为44.8%,并用IR,1HNMR、MS确证了其结构。结果证明此方法操作简便,条件温和,适合较大规模生产。
Erlotinib is an epidermal growth factor receptor inhibitor (EGFR-TKI) which was developed by OSI,Genetech and Roche. It is used for the treatment of Non-Small Cell Lung Cancer (NSCLC) and Pancreatic Cancer in clinic.
The thesis determined a six-step route to synthesize Erlotinib by the methods of literature. O-alkylation between ethyl 3,4-dihydroxybenzoate and 1-Chloro-2- methoxy-ethane gaved Ethyl 3 , 4-bis(2-methoxyethoxy)benzoate(1). Ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate hydrochloride(3) was obtained from (1) via nitration,reduction and salt formation. Cyclization between (3) and formamide gaved 6,7-Bis-(2-methoxyethoxy)-quinazolin-4(3H)-one(4). (4) is chloro-substituted by POCl3 and N,N-dimethylaniline as the catalyzer. At last,the hydrochloride salt of Erlotninb can be obtained from (5) and 3-ethynylphenylamine via N-alkylation. By the way,3-ethynylphenylamine was synthesized via Knoevenagel condensation,bromine addition,debromination-decarboxylation,elimination and reduction from m-nitrobenzaldehyde and malonate.
The main improvements of the method are:reaction time is shortened and feed capacity of halohydrocarbon is reduced because of the reinforce of alkalinity of acid-binding and increase the temperature;the conversion rate of (2) is increased by the higher reaction temperature;raising the yield and reducing the cost of the synthesis of compound(3) due to changing the reaction system;Determine the best reaction time and the way of purification during the synthesis of compound (5).
The overall yield of Erlotinib synthesized by the method is 44.8% on the basis of ethyl 3,4-dihydroxybenzoate. The structure of Erlotinib was confirmed by IR,1HNMR,MS. The result indicates that the method is simple,convenient.
引文
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[5]邹燕梅.非小细胞肺癌分子靶向治疗的现状和展望.中国肿瘤临床与康复,2008,15(1):83~86
[6]王章桂,孙国平.表皮生长因子受体酪氨酸激酶抑制剂的研究进展.现代肿瘤医学,2007,15(12):1857~1858
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[8] GHOSH S. LIU XP. et al. Rational design of potent and selective EGFR tyrosine kinase inhibitors as anticancer agents. Current Cancer Drug Targets,200l,1(2):129~140
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[10] YARDEN Y. the EGFR familyand its lignds in human cancer:Sigaling mechanisms and therapeutic opportunities. Eur J center,2001,37(4):3~8
[11] JANMAT ML. Giaccone G. Small~Molecule Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. Oncologist. 2003,8(18):576~586
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[20]王尔兵,王肇.分子靶抗癌药:埃洛替尼治疗非小细胞肺癌的新进展.癌症进展杂志,2005,3(5):477~450
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[23] Petr Knesl,Dirk R?seling and Ulrich Jordis. Improved Synthesis of Substituted 6,7-Dihydroxy-4-quinazolineamines : Tandutinib , Erlotinib and Gefitinib. Molecules ,2006(11):286~297
[24] Rao,Dharmaraj,Ramchandra,Kankan,Rajendra,Narayanrao. Process for preparation of erlotinib and its pharmaceutically acceptable salts : WO2008122776[P]. 2008-12-27. (CA2008,149:440345)
[25]李铭东,曹萌,吉民.盐酸埃洛替尼的合成.中国医药工业杂志,2007,38(4):257~259
[26] Jyothi Prasad,Ramanadham,Nageshwar Rao,Bollepalli,et al.A novel process for the preparation of erlotinib:WO2007060691[P]. 2007-05-31. (CA2007,147:385925)
[27] TUNG,Roger. Quinazoline derivatives and methods of treatment:WO2008076949[P]. 2008-06-28. (CA2008,149:104744)
[28] Chandregowda,Venkateshappa; Rao,Gudapati Venkateswara. One-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones and synthesis of gefitinib and erlotinib hydrochloride. Heterocycles. 2007,71(1):39~48
[29] Chandregowda,Venkateshappa; Rao,Gudapati Venkateswara. A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride (erlotinib hydrochloride)[P]. IN2005CH01483(CA2008,148:495978)
[30] Venkateshappa Chandregowda,Gudapati Venkateswara Rao,et al. Convergent Approach for Commercial Synthesis of Gefitinib and Erlotinib. Organic Process Research & Development. 2007,11:813~816
[31] Chandregowda,Venkateshappa. A Process For Synthesis Of [6,7-bis-(2-methoxyethoxy)- quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride[P]. WO2007138613,2007-12-06. (CA2008,148:239235)
[32] Chandregowda,Venkateshappa. Process For Synthesis Of [6,7-bis-(2-meth-oxyethoxy)- quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride[P]. WO2007138612,2007-12-06. (CA2008,148:331708)
[33]刘林,刘智勇,单书香.苯乙炔衍生物的合成.四川化工,1995,4:2~6
[34] Yamakawa,Kazuyoshi,Sato,et al. Preparation of aminophenylacetylenes as antifogging agents for photothermographic copying materials[P]. JP10036325,1996-07-18. (CA1996,128:167246)
[35] Shannon D.,Zanatta. The Bestmann–Ohira Reagent for the Conversion of Aldehydes into Terminal Alkynes. J. Chem. 2007,60:963
[36] Feng Runliang,Song Zhimei. Process for preparation of 3-nitrophenylacetylene[P]. CN 101270053,2008~05~05(CA2008,149:448031)
[37]刘林,刘智勇,单书香.取代苯乙炔类化合物的合成.四川化工,1994,3:6~7
[38]刘林,刘智勇,单书香.取代苯乙炔的简便合成方法.化学试剂,1996,18(6):370~371
[39] Shen Yongjia,Xu Xi,Hu, Yingyu,et al. Preparation of m-aminophenylacetylene[P]. CN1313274,2001-02-20(CA2002,137:294762)
[40] E. D. Matveeva,A. S. Erin,A. L. Kurz. Synthesis of the Substituted Z-1-Bromo-1-alkenes and Arylacetylenes from 2,3-Dibromocarboxylic Acids. Russian Journal of Organic Chemistry,1997,33(8):1065~1067
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[2] Fry D W. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy:progression from reversible to irreversible inhibitors. Pharmacol ther. 1999,82:207
[3] Klapper LN,Kirschbaum MH,et al. Biochemical and clinical implications of the ErbB/HER signaling network of growth factor receptors. Adv Cancer Res,2000,77:25~79
[4] Arteaga CL. Overview of epidermal growth factor receptor biology and its role as a therapeutic target in human neoplasia. Semin Oncol,2002,29(5Suppl14):3~9
[5]邹燕梅.非小细胞肺癌分子靶向治疗的现状和展望.中国肿瘤临床与康复,2008,15(1):83~86
[6]王章桂,孙国平.表皮生长因子受体酪氨酸激酶抑制剂的研究进展.现代肿瘤医学,2007,15(12):1857~1858
[7]邓超,胡春宏.非小细胞肺癌分子靶向治疗研究进展.中国处方药,2006,8:49~53
[8] GHOSH S. LIU XP. et al. Rational design of potent and selective EGFR tyrosine kinase inhibitors as anticancer agents. Current Cancer Drug Targets,200l,1(2):129~140
[9]何伍,凌霄.小分子EGFR酪氨酸激酶抑制剂研究进展.中国药学杂志,2007,42(2):1685~1688
[10] YARDEN Y. the EGFR familyand its lignds in human cancer:Sigaling mechanisms and therapeutic opportunities. Eur J center,2001,37(4):3~8
[11] JANMAT ML. Giaccone G. Small~Molecule Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors. Oncologist. 2003,8(18):576~586
[12] HEYMACH JV. ZD6474-clinical experience to date. Br J Cancer,2005,92(Suppll):14~20
[13]蒋毅,郭宗儒.表皮生长因子受体的ATP竞争抑制剂.有机化学,2004,24(12):1640~1643
[14] David S.,Lawrence,Jinkui Niu. Protein Kinase Inhibitors:The Tyrosine-Specific Protein Kinases . Pharmacol. Ther.,1998,77(2):81~114
[15] Peter Traxler,Pascal Furet. Strategies toward the Design of Novel and Selective Protein Tyrosine Kinase Inhibitors . Pharmacol. Ther.,1999,82(2~3):195~206
[16] David W.,Fry. Mechanism of action of erbB tyrosine kinase inhibitors . Experimental Cell Research,2003(284):131~139
[17] Jennifer Stamos,Mark X. Sliwkowski et al. Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4~Anilinoquinazoline Inhibitor . THE JOURNAL OF BIOLOGICAL CHEMISTRY,2002,8(23):46265~46272
[18]陈喆，戴媛媛，汤致强.小分子EGFR酪氨酸激酶抑制剂盐酸埃罗替尼.中国新药杂志,2005,14(10):1227~1229
[19]刘小玲,李慧林.分子靶向抗癌药物埃洛替尼的研究进展.杭州师范学院学报(医学版),2006,5:336~338
[20]王尔兵,王肇.分子靶抗癌药:埃洛替尼治疗非小细胞肺癌的新进展.癌症进展杂志,2005,3(5):477~450
[21] Schnur RC,Arnold LD. Quinazoline derivatives:WO1996030347[P]. 1996-10-03. (CA 1996,125:328728)
[22] Schnur RC , Arnold LD. Alkynyl and azid-o-substitubed 4-anilinoquinazolines :US5747498[P]. 1998-05-05. (CA1998,128:321653)
[23] Petr Knesl,Dirk R?seling and Ulrich Jordis. Improved Synthesis of Substituted 6,7-Dihydroxy-4-quinazolineamines : Tandutinib , Erlotinib and Gefitinib. Molecules ,2006(11):286~297
[24] Rao,Dharmaraj,Ramchandra,Kankan,Rajendra,Narayanrao. Process for preparation of erlotinib and its pharmaceutically acceptable salts : WO2008122776[P]. 2008-12-27. (CA2008,149:440345)
[25]李铭东,曹萌,吉民.盐酸埃洛替尼的合成.中国医药工业杂志,2007,38(4):257~259
[26] Jyothi Prasad,Ramanadham,Nageshwar Rao,Bollepalli,et al.A novel process for the preparation of erlotinib:WO2007060691[P]. 2007-05-31. (CA2007,147:385925)
[27] TUNG,Roger. Quinazoline derivatives and methods of treatment:WO2008076949[P]. 2008-06-28. (CA2008,149:104744)
[28] Chandregowda,Venkateshappa; Rao,Gudapati Venkateswara. One-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones and synthesis of gefitinib and erlotinib hydrochloride. Heterocycles. 2007,71(1):39~48
[29] Chandregowda,Venkateshappa; Rao,Gudapati Venkateswara. A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride (erlotinib hydrochloride)[P]. IN2005CH01483(CA2008,148:495978)
[30] Venkateshappa Chandregowda,Gudapati Venkateswara Rao,et al. Convergent Approach for Commercial Synthesis of Gefitinib and Erlotinib. Organic Process Research & Development. 2007,11:813~816
[31] Chandregowda,Venkateshappa. A Process For Synthesis Of [6,7-bis-(2-methoxyethoxy)- quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride[P]. WO2007138613,2007-12-06. (CA2008,148:239235)
[32] Chandregowda,Venkateshappa. Process For Synthesis Of [6,7-bis-(2-meth-oxyethoxy)- quinazolin-4-yl]-(3-ethynylphenyl) amine hydrochloride[P]. WO2007138612,2007-12-06. (CA2008,148:331708)
[33]刘林,刘智勇,单书香.苯乙炔衍生物的合成.四川化工,1995,4:2~6
[34] Yamakawa,Kazuyoshi,Sato,et al. Preparation of aminophenylacetylenes as antifogging agents for photothermographic copying materials[P]. JP10036325,1996-07-18. (CA1996,128:167246)
[35] Shannon D.,Zanatta. The Bestmann–Ohira Reagent for the Conversion of Aldehydes into Terminal Alkynes. J. Chem. 2007,60:963
[36] Feng Runliang,Song Zhimei. Process for preparation of 3-nitrophenylacetylene[P]. CN 101270053,2008~05~05(CA2008,149:448031)
[37]刘林,刘智勇,单书香.取代苯乙炔类化合物的合成.四川化工,1994,3:6~7
[38]刘林,刘智勇,单书香.取代苯乙炔的简便合成方法.化学试剂,1996,18(6):370~371
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