培美曲塞二钠的合成
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摘要
本文着重研究培美曲塞二钠的化学合成方法。确定了以对溴苯甲酸为起始原料经酯化、缩合、溴代、环合、水解、成盐等反应制得培美曲塞二钠的合成工艺,进行了小试及中试放大工艺的研究,小试总收率为13.9% ,中试总收率12.7%。各中间体及目标化合物经核磁共振氢谱、红外及质谱确证结构。
对主要中间体及目标物的合成工艺进行了改进与优化,由中间体2(对溴苯甲酸甲酯)制备中间体4(1-羟基-4-(4-甲酯基苯基)丁磺酸钠盐)采用“一锅烩”的方法简化了操作,并将中间体4制备过程中所用的3A醇与水的混合溶剂改为水;在由中间体4制备中间体5(4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酸甲酯)时,一方面通过采用“一锅烩”的方法简化操作,另一方面将文献报道的反应所用溶剂由二氯甲烷/水改为乙腈/水,使两相反应变成均相反应,结果收率比文献的方法提高了10%,;在该步中试中,省去了小试工艺中二氯甲烷提取的步骤,操作得到了进一步简化,中试收率则提高了12%;在由中间体6(4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酸)制备中间体7(N-[4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸二乙酯)的过程中,反复试验尝试多种混合溶剂重结晶,最终发现采用丙酮-乙醇混合溶剂精制粗产物可以直接得到足够纯度的目标产物,避免了文献所采用的柱层析纯化或制成中间7的对甲苯磺酸盐(该物质在空气中不稳定);在培美曲塞二钠的制备中,将中间体7的水解及N-[4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸的成盐合为一步进行,简化了操作。此外,将反应的监测方法由HPLC法改为简便易行的薄层层析法。多批小试研究及中试放大表明,本文所述合成工艺适宜工业化生产。
In this paper, We put special emphasise on the synthesize methods of pemetrexed disodium. . A reasonable route was developed that pemetrexed disodium was prepared by 4-bromobenzoic acid via esterification, condensation, bromination, cyclization reaction and so on The overall yield of lab research was 13.9% and 12.7% with the scale-up. The structure of pemetrexed disodium and all intermediates was verified by 1H-NMR ,IR and MS.
Process of pemetrexed disodium and intermediates were improved and optimized. water was used as solvent instead of 3A alcohol/water and“one pot”synthesis was adopted which was more easy to be handled in the preparation of intermediate 4(1-Hydroxy-4-(4-caromethyoxyphenyl)butanesulfonic Acid Sodium). Acetonitrile was used as solvent instead of dichloromethane and“one pot”synthesis was adopted in the preparation of intermediate 5 (4-[2-(2-Amino-4,7-Dihydro-4-Oxo-1H-Pyrrolo[2,3-d] pyrimidin-5-yl)ethyl]benzoic Acid Methyl Ester), and the reaction was performed in homogeneous system. At the same time, The manipulation was more easily to be handled and the yield increased. Ethanol-acetone combined solvent was used to purify intermediate 7(N-(4-[2-(2-Amino-4,7-Dihydro-4-Oxo-1H-Pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl)-L-Glutamic Acid Diethyl), avoiding column chromatography or the transformation to unstable toluenesulfonate. Hydrolyzation of intermediate 7 and preparation of pemetrexed disodium were combined into“one step”and manipulation was simplified . Additionally, HPLC method which was used to monitor reaction was changed into TLC which was more easy to handle.
The improved synthesis reduced the process steps . lab research and scale-up research showed synthesize methods of pemetrexed disodium which was described in this paper was suitable for industrial producing.
对主要中间体及目标物的合成工艺进行了改进与优化,由中间体2(对溴苯甲酸甲酯)制备中间体4(1-羟基-4-(4-甲酯基苯基)丁磺酸钠盐)采用“一锅烩”的方法简化了操作,并将中间体4制备过程中所用的3A醇与水的混合溶剂改为水;在由中间体4制备中间体5(4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酸甲酯)时,一方面通过采用“一锅烩”的方法简化操作,另一方面将文献报道的反应所用溶剂由二氯甲烷/水改为乙腈/水,使两相反应变成均相反应,结果收率比文献的方法提高了10%,;在该步中试中,省去了小试工艺中二氯甲烷提取的步骤,操作得到了进一步简化,中试收率则提高了12%;在由中间体6(4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酸)制备中间体7(N-[4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸二乙酯)的过程中,反复试验尝试多种混合溶剂重结晶,最终发现采用丙酮-乙醇混合溶剂精制粗产物可以直接得到足够纯度的目标产物,避免了文献所采用的柱层析纯化或制成中间7的对甲苯磺酸盐(该物质在空气中不稳定);在培美曲塞二钠的制备中,将中间体7的水解及N-[4-[2-(2-氨基-4,7-二氢-4-氧-1H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酰基]-L-谷氨酸的成盐合为一步进行,简化了操作。此外,将反应的监测方法由HPLC法改为简便易行的薄层层析法。多批小试研究及中试放大表明,本文所述合成工艺适宜工业化生产。
In this paper, We put special emphasise on the synthesize methods of pemetrexed disodium. . A reasonable route was developed that pemetrexed disodium was prepared by 4-bromobenzoic acid via esterification, condensation, bromination, cyclization reaction and so on The overall yield of lab research was 13.9% and 12.7% with the scale-up. The structure of pemetrexed disodium and all intermediates was verified by 1H-NMR ,IR and MS.
Process of pemetrexed disodium and intermediates were improved and optimized. water was used as solvent instead of 3A alcohol/water and“one pot”synthesis was adopted which was more easy to be handled in the preparation of intermediate 4(1-Hydroxy-4-(4-caromethyoxyphenyl)butanesulfonic Acid Sodium). Acetonitrile was used as solvent instead of dichloromethane and“one pot”synthesis was adopted in the preparation of intermediate 5 (4-[2-(2-Amino-4,7-Dihydro-4-Oxo-1H-Pyrrolo[2,3-d] pyrimidin-5-yl)ethyl]benzoic Acid Methyl Ester), and the reaction was performed in homogeneous system. At the same time, The manipulation was more easily to be handled and the yield increased. Ethanol-acetone combined solvent was used to purify intermediate 7(N-(4-[2-(2-Amino-4,7-Dihydro-4-Oxo-1H-Pyrrolo[2,3-d] pyrimidin-5-yl) ethyl] benzoyl)-L-Glutamic Acid Diethyl), avoiding column chromatography or the transformation to unstable toluenesulfonate. Hydrolyzation of intermediate 7 and preparation of pemetrexed disodium were combined into“one step”and manipulation was simplified . Additionally, HPLC method which was used to monitor reaction was changed into TLC which was more easy to handle.
The improved synthesis reduced the process steps . lab research and scale-up research showed synthesize methods of pemetrexed disodium which was described in this paper was suitable for industrial producing.
引文
[1]预防与控制癌症,世界卫生组织第114届会议临时议程项目报告
[2]朱赓伯,癌症发病机理新说,家庭医学, 2006, 1:35
[3]龚忠发,宋艳艳,恶性癌症发病机理研究新进展,癌症防治杂志, 2001,8(5):449-451
[4]胥彬,抗癌药物研究的新进展,实用癌症杂志, 2001,16(5): 289-291
[5]孙居锋郭志雄等叶酸拮抗剂类药物研究进展化学通报2006, 69: 1-12
[6] Curtin N J and Hughes A N Pemetrexed disodium, a novel antifolate with multiple targets THE LANCET Oncology 2001, 2:298-306
[7] Kristan D. Rollins and Celeste Lindley, Pemetrexed: A Multitargeted Antifolate, Clinical Therapeutic, 2005, 27(9):1343-1382
[8] Laurent P. Rivory , Stephen J. Clarke,et al, Highly sensitive analysis of the antifolate pemetrexed sodium, a new cancer agent in human plasma and urine by high-performance liquid chromatography, Journal of Chromatography B, 2001 765:135–140
[9] ALIMTA? LABLE http://www.fda.gov/cder/foi/label/2004/021462lbl.pdf
[10] Pieter E. Postmus Activity of pemetrexed (alimta), a new antifolate, against non-small cell lung cancer Lung Cancer ,2002,38:S3-S7
[11] Novello S. , ChevalieT. le r, ALIMTA? (pemetrexed disodium, LY231514, MTA): clinical experience in non-small cell lung cancer, Lung Cancer 34 (2001) :S107–S109
[12] Mark R. Green. Alimta (pemetrexed disodium): a multitargeted antifolate for the treatment of mesothelioma Lung Cancer ,2002,38 :S55-S57
[13] Scasliotti G.V. Pemetrexed: a new cytotoxic agent in the development for first-line non-small-cell lung cancer Lung Cancer ,2005,50 (Suppl. 1): S18-S19
[14]王晓光李金瀚等,培美曲塞治疗非小细胞性肺癌临床研究进展[J]中国肺癌杂志2005,8(3):254-256
[15]美国FDA批准培美曲塞加顺铂联合治疗恶性胸膜间皮瘤,世界临床药物, 2004,25(4):194
[16]黄世杰,新药研究与开发,国外医学药学分册,2004,31(6):381
[17] Barnett Charles Jackson, Wilson Thomas Michael. Process for preparing 5-substituted pyrrolo-[2,3-d]pyrimidines [P]. EP: 0589720 1994-03-30
[18] Kjell Dougls Patton ,Slattery Brian James , Barnett Charles Jackson. Processes and intermediates useful to make antifolates [P] US:6013828 2000-01-11
[19] Taylor Edward C, Kuhnt Dietmar G, Shih Chuan. N -(pyrrolo[2,3-d] pyrimidin-3-ylacyl)-glutamic acid derivatives EP:0432677,1991-06-19
[20] Barnett C J, Wilson T M, Kobierski M E et al. A Practical Synthesis of Multitargeted Antifolate LY231514 Organic Process Resarch & Development, 1999, 3: 184~188.
[21] Talyor E C, Young W B. Pyrrolo[3,2-d]pyrimidine Folate Analogues:“Inverted”Analogues of the Cytotoxic Agent LY231514 J. Org. Chem., 1995, 60: 7947~7952.
[22] Talyor E C, Mao Z et al. Synthesis of Conformationally-Constrained Glutamate Analogues of the Antitumor Agents DDATHF, LY254155, and LY231514 J. Org. Chem., 1997, 62: 5392~5403.
[23] Gangjee A, Yu J et al. Synthesis of Classical, Three-Carbon-Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d] pyrimidine Analogues as Antifolates1 J. Med. Chem., 2000, 43: 3837~3851.
[24] Talyor E C, Liu B. A New and Efficient Synthesis of Pyrrolo [2,3-d]pyrimidine Anticancer Agents: Alimta (LY231514, MTA), Homo-Alimta, TNP-351, and Some Aryl 5-Substituted Pyrrolo[2,3-d] pyrimidines J. Org. Chem., 2003, 68: 9938~9947
[25] Miwa T, Hitaka T, Akimoto H. A Novel Synthetic Approach to Pyrrolo [2,3-d] pyrimidine Antifolated J. Org. Chem., 1993, 58: 1696~1701.
[26] Gangje A, Zeng Y, McGuire J J et al. J. Med. Chem., 2004, 47: 6893~6901.
[27] Taylor Edward C, Patel Hemantkumar H . Process for the preparation of pyrrolo [2,3-d]pyrimidines. EP0549886 1996-07-07
[28] Taylor Edward C ; Liu Bin. Process for the preparation of pyrrolo[2,3-d] pyrimidines . [P].WO2000011004,2000-03-02
[29] Chelius Erik Christopher , Reutzel-Edens Susan Marie, et al. A novel crystallineform of disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo [2,3-D]–pyrimidin-5-yl)ethyl]benzoly]–L-glutamic acid salt and processes therefore WO0114379, 2001-03-01
[30] Sigma-Aldrich corporation. Aldrich2003-2004 ( Handbook of Fine Chemicals and Laboratory Equipment), P1218:40,759-3
[31] Nasser Hanna, Frances A. Shepherd, Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy JCO 2004: 1589-1597.
[2]朱赓伯,癌症发病机理新说,家庭医学, 2006, 1:35
[3]龚忠发,宋艳艳,恶性癌症发病机理研究新进展,癌症防治杂志, 2001,8(5):449-451
[4]胥彬,抗癌药物研究的新进展,实用癌症杂志, 2001,16(5): 289-291
[5]孙居锋郭志雄等叶酸拮抗剂类药物研究进展化学通报2006, 69: 1-12
[6] Curtin N J and Hughes A N Pemetrexed disodium, a novel antifolate with multiple targets THE LANCET Oncology 2001, 2:298-306
[7] Kristan D. Rollins and Celeste Lindley, Pemetrexed: A Multitargeted Antifolate, Clinical Therapeutic, 2005, 27(9):1343-1382
[8] Laurent P. Rivory , Stephen J. Clarke,et al, Highly sensitive analysis of the antifolate pemetrexed sodium, a new cancer agent in human plasma and urine by high-performance liquid chromatography, Journal of Chromatography B, 2001 765:135–140
[9] ALIMTA? LABLE http://www.fda.gov/cder/foi/label/2004/021462lbl.pdf
[10] Pieter E. Postmus Activity of pemetrexed (alimta), a new antifolate, against non-small cell lung cancer Lung Cancer ,2002,38:S3-S7
[11] Novello S. , ChevalieT. le r, ALIMTA? (pemetrexed disodium, LY231514, MTA): clinical experience in non-small cell lung cancer, Lung Cancer 34 (2001) :S107–S109
[12] Mark R. Green. Alimta (pemetrexed disodium): a multitargeted antifolate for the treatment of mesothelioma Lung Cancer ,2002,38 :S55-S57
[13] Scasliotti G.V. Pemetrexed: a new cytotoxic agent in the development for first-line non-small-cell lung cancer Lung Cancer ,2005,50 (Suppl. 1): S18-S19
[14]王晓光李金瀚等,培美曲塞治疗非小细胞性肺癌临床研究进展[J]中国肺癌杂志2005,8(3):254-256
[15]美国FDA批准培美曲塞加顺铂联合治疗恶性胸膜间皮瘤,世界临床药物, 2004,25(4):194
[16]黄世杰,新药研究与开发,国外医学药学分册,2004,31(6):381
[17] Barnett Charles Jackson, Wilson Thomas Michael. Process for preparing 5-substituted pyrrolo-[2,3-d]pyrimidines [P]. EP: 0589720 1994-03-30
[18] Kjell Dougls Patton ,Slattery Brian James , Barnett Charles Jackson. Processes and intermediates useful to make antifolates [P] US:6013828 2000-01-11
[19] Taylor Edward C, Kuhnt Dietmar G, Shih Chuan. N -(pyrrolo[2,3-d] pyrimidin-3-ylacyl)-glutamic acid derivatives EP:0432677,1991-06-19
[20] Barnett C J, Wilson T M, Kobierski M E et al. A Practical Synthesis of Multitargeted Antifolate LY231514 Organic Process Resarch & Development, 1999, 3: 184~188.
[21] Talyor E C, Young W B. Pyrrolo[3,2-d]pyrimidine Folate Analogues:“Inverted”Analogues of the Cytotoxic Agent LY231514 J. Org. Chem., 1995, 60: 7947~7952.
[22] Talyor E C, Mao Z et al. Synthesis of Conformationally-Constrained Glutamate Analogues of the Antitumor Agents DDATHF, LY254155, and LY231514 J. Org. Chem., 1997, 62: 5392~5403.
[23] Gangjee A, Yu J et al. Synthesis of Classical, Three-Carbon-Bridged 5-Substituted Furo[2,3-d]pyrimidine and 6-Substituted Pyrrolo[2,3-d] pyrimidine Analogues as Antifolates1 J. Med. Chem., 2000, 43: 3837~3851.
[24] Talyor E C, Liu B. A New and Efficient Synthesis of Pyrrolo [2,3-d]pyrimidine Anticancer Agents: Alimta (LY231514, MTA), Homo-Alimta, TNP-351, and Some Aryl 5-Substituted Pyrrolo[2,3-d] pyrimidines J. Org. Chem., 2003, 68: 9938~9947
[25] Miwa T, Hitaka T, Akimoto H. A Novel Synthetic Approach to Pyrrolo [2,3-d] pyrimidine Antifolated J. Org. Chem., 1993, 58: 1696~1701.
[26] Gangje A, Zeng Y, McGuire J J et al. J. Med. Chem., 2004, 47: 6893~6901.
[27] Taylor Edward C, Patel Hemantkumar H . Process for the preparation of pyrrolo [2,3-d]pyrimidines. EP0549886 1996-07-07
[28] Taylor Edward C ; Liu Bin. Process for the preparation of pyrrolo[2,3-d] pyrimidines . [P].WO2000011004,2000-03-02
[29] Chelius Erik Christopher , Reutzel-Edens Susan Marie, et al. A novel crystallineform of disodium N-[4-[2-(2-amino-4,7-dihydro-4-oxo-3H-pyrrolo [2,3-D]–pyrimidin-5-yl)ethyl]benzoly]–L-glutamic acid salt and processes therefore WO0114379, 2001-03-01
[30] Sigma-Aldrich corporation. Aldrich2003-2004 ( Handbook of Fine Chemicals and Laboratory Equipment), P1218:40,759-3
[31] Nasser Hanna, Frances A. Shepherd, Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy JCO 2004: 1589-1597.