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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Tagraxofusp タグラクソフスプ

(disulfide bridge: 187-202, 407-475)

Image result for Tagraxofusp US FDA APPROVAL

methionyl (1)-Corynebacterium diphtheriae toxin fragment (catalytic and transmembrane domains) (2-389, Q388R variant)-His390-Met391-human interleukin 3 (392-524, natural P399S variant) fusion protein, produced in Escherichia coli antineoplastic,



CAS: 2055491-00-2
C2553H4026N692O798S16, 57694.4811

FDA 2018/12/21, Elzonris APPROVED

Antineoplastic, Immunotoxin, Peptide

DT-3881L3 / DT388IL3 / Molecule 129 / Molecule-129 / SL-401


Diphteria toxin fusion protein with peptide and interleukin 3 Treatment of blastic plasmacytoid dendritic cell neoplasm (CD123-directed)

FDA approves first treatment for rare blood disease


December 21, 2018


The U.S. Food and Drug Administration today approved Elzonris (tagraxofusp-erzs) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients, two years of age and older.

“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia. The disease is more common in men than women and in patients 60 years and older.

The efficacy of Elzonris was studied in two cohorts of patients in a single-arm clinical trial. The first trial cohort enrolled 13 patients with untreated BPDCN, and seven patients (54%) achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc). The second cohort included 15 patients with relapsed or refractory BPDCN. One patient achieved CR and one patient achieved CRc.

Common side effects reported by patients in clinical trials were capillary leak syndrome (fluid and proteins leaking out of tiny blood vessels into surrounding tissues), nausea, fatigue, swelling of legs and hands (peripheral edema), fever (pyrexia), chills and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin and calcium, and increases in glucose and liver enzymes (ALT and AST). Health care providers are advised to monitor liver enzyme levels and for signs of intolerance to the infusion. Women who are pregnant or breastfeeding should not take Elzonris because it may cause harm to a developing fetus or newborn baby.

The labeling for Elzonris contains a Boxed Warning to alert health care professionals and patients about the increased risk of capillary leak syndrome which may be life-threatening or fatal to patients in treatment.

The FDA granted this application Breakthrough Therapy and Priority Reviewdesignation. Elzonris also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Elzonris to Stemline Therapeutics.

Tagraxofusp is an IL-3 conjugated truncated diphtheria toxin.[4] It is composed by the catalytic and translocation domains of diphtheria toxin fused via Met-His linker to a full-length human IL-3.[67] Tagraxofusp was developed by Stemline Therapeutics Inc and FDA approved on December 21, 2018, as the first therapy for blastic plasmacytoid dendritic cell neoplasm.[3] This drug achieved approval after being designed with the title of breakthrough therapy, priority review, and orphan drug status.[2] Tagraxofusp has been designed as an orphan drug in EU since November 2015.[7]

Tagraxofusp is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients over 2 years old. This treatment allows an alternative for the previous intense treatment which consisted of intensive chemotherapy followed by bone marrow transplantation.[2]

BPDCN is a rare hematologic malignancy derived from plasmacytoid dendritic cells. It is characterized by the significantly increased expression of cells expressing CD4/CD56/CD123 and other markers restricted to plasmacytoid dendritic cells and a lack of expression of lymphoid, natural killer or myeloid lineage-associated antigens.[1] A key feature of the malignant cells is the overexpression of CD123, also known as interleukin-3 receptor, and the constant requirement of IL-3 for survival.[6]

Associated Conditions

PharmacodynamicsIn vitro studies showed that BPDCN blasts are ultrasensitive to tagraxofusp by presenting IC50 values in the femtomolar scale.[6] One of the main physiological changes of BPDCN is the presence of elevated interferon alpha and to produce an inflammatory response. In trials with tagraxofusp and following cell depletion, there was observed a significant reduction in the levels of interferon alpha and interleukin 6.[5]

In clinical trials, tagraxofusp reported complete remission and complete remission with a skin abnormality not indicative of active disease in 54% of the treated patients.[2]

Mechanism of actionTagraxofusp binds to cells expressing the IL-3 receptor and delivers in them the diphtheria toxin after binding. This is very useful as the malignant cells in BPDCN present a particularly high expression of IL-3 receptor (CD123+ pDC).[5] To be more specific, tagraxofusp gets internalized to the IL-3 receptor-expressing cell allowing for diphtheria toxin translocation to the cytosol and followed by the binding to ADP-ribosylation elongation factor 2 which is a key factor for protein translation. Once the protein synthesis is inhibited, the cell goes under a process of apoptosis.[4,6]

As the apoptosis induction requires an active state of protein synthesis, tagraxofusp is not able to perform its apoptotic function in dormant cells.[6]


The reported Cmax in clinical trials was of around 23 ng/ml.[6] After a 15 min infusion of a dose of 12 mcg/kg the registered AUC and Cmax was 231 mcg.h/L and 162 mcg/L respectively.[Label]

Volume of distributionIn BPDCN patients, the reported volume of distribution is of 5.1 L.[Label]

Protein bindingTagraxofusp is not a substrate of p-glycoprotein and other efflux pump proteins associated with multidrug resistance.[6]

MetabolismFor the metabolism, as tagraxofusp is a fusion protein, it is expected to get processed until small peptides and amino acids by the actions of proteases.

Route of eliminationTagraxofusp is eliminated as small peptides and amino acids. More studies need to be performed to confirm the main elimination route.

Half lifeThe reported half-life of tagraxofusp is of around 51 minutes.[6]

ClearanceThe clearance of tagraxofusp was reported to fit a mono-exponential model.[6] The reported clearance rate is reported to be of 7.1 L/h.[Label]

ToxicityThere haven’t been analysis observing the carcinogenic, mutagenic potential nor the effect on fertility. However, in studies performed in cynomolgus monkeys at an overdose rate of 1.6 times the recommended dose, it was observed severe kidney tubular degeneration. Similar studies at the recommended dose reported the presence of degeneration and necrosis of choroid plexus in the brain were. This effect seems to be progressive even 3 weeks after therapy withdrawal.[Label]

  1. Kharfan-Dabaja MA, Lazarus HM, Nishihori T, Mahfouz RA, Hamadani M: Diagnostic and therapeutic advances in blastic plasmacytoid dendritic cell neoplasm: a focus on hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Jul;19(7):1006-12. doi: 10.1016/j.bbmt.2013.01.027. Epub 2013 Feb 5. [PubMed:23396213]
  2. FDA news [Link]
  3. FDA approvals [Link]
  4. Oncology nursing news [Link]
  5. Stemline therapeutics news [Link]
  6. Blood journal [Link]
  7. NHS reports [Link]

FDA label, Download (455 KB)

/////////Antineoplastic, Immunotoxin, Peptide, Tagraxofusp, Elzonris, タグラクソフスプ  , Stemline Therapeutics, Breakthrough Therapy,  Priority Review designation,  Orphan Drug designation, fda 2018, DT-3881L3 , DT388IL3 ,  Molecule 129 ,  Molecule-129 ,  SL-401, 

Eribulin, エリブリンメシル酸塩 an Antineoplastic


Eribulin mesylate


CAS 441045-17-6 MESYLATE

C41H63NO14S, 826.00222 g/mol

halichrondrin B analog, B1939, E7389, ER-086526,Halaven

CAS 253128-41-5  FREE FORM

(1S,3S,4R)-3-tert-butoxycarbonylamino-4-hydroxycyclopentanecarboxylic acid methyl ester;


2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one

(2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-2-((2S)-3-amino-2-hydroxypropyl)-3-methoxy-26-methyl-20,27-dimethylidenehexacosahydro-11,15:18,21:24,28-triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′:5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5(4H)-one methanesulfonate (salt)

11,15:18,21:24,28-Triepoxy-7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′:5,6)pyrano(4,3-b)(1,4)dioxacyclopentacosin-5(4H)-one, 2-((2S)-3- amino-2-hydroxypropyl)hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, 2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt)

Eribulin Mesilate

C40H59NO11▪CH4O3S : 826

Eribulin mesylate is the mesylate salt of a synthetic analogue of halichondrin B, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity.

E7389 is the mesylate salt of a synthetic analogue of halichondrin B, a substance derived from a marine sponge (Lissodendoryx sp.) with antineoplastic activity. Eribulin binds to the vinca domain of tubulin and inhibits the polymerization of tubulin and the assembly of microtubules, resulting in inhibition of mitotic spindle assembly, induction of cell cycle arrest at G2/M phase, and, potentially, tumor regression.

Halichondrin B, a large polyether macrolide, was isolated 25 years ago from the marine sponge Halichondria okadai

Halichondria okadaiHalaven.png


The anti-cancer drug made from a sea-spongeEribulin is an anticancer drug marketed by Eisai Co. under the trade name Halaven. Eribulin mesylate was approved by the U.S. Food and Drug Administration on November 15, 2010, to treat patients with metastatic breast cancer who have received at least two prior chemotherapy regimens for late-stage disease, including both anthracycline– and taxane-based chemotherapies.[1] It was approved by Health Canada on December 14, 2011 for treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. [2]

Eribulin is also being investigated by Eisai Co. for use in a variety of other solid tumors, including non-small cell lung cancer, prostate cancer and sarcoma.[3]

Eribulin has been previously known as E7389 and ER-086526, and also carries the US NCI designation NSC-707389.

Eribulin mesylate is an analogue of halichondrin B, which in 1986 was isolated from the marine sponge Halichondria okadai toxic Pacific.Halichondrin B has a significant anti-tumor activity. The Eribulin synthetically obtained has a simpler but still complex molecular structure.Taxanes such as to inhibit the spindle apparatus of the cell, but it is engaged in other ways.

Drug substance, eribulin mesylate, is a It is a structurally simplified synthetic analogue of halichondrin B, a natural product isolated from the marine sponge Halichondira okadai. Eribulin mesylate is a white powder which is freely soluble in water, methanol, ethanol, 1-octanol, benzyl alcohol, dichloromethane, dimethylsulfoxide, N-methylpyrrolidone and ethyl acetate. It is soluble in acetone, sparingly soluble in acetonitrile, and practically insoluble in tertbutyl methyl ether, n-heptane and n-pentane. Eribulin mesylate is characterized by ion chromatography for counter ion content, and spectroscopic analyses (mass, ultraviolet, nuclear magnetic resonance, single crystal X-ray crystallography, and circular dichroism) for molecular structure and absolute configuration. Bulk drug substance is hygroscopic and sensitive to light, heat, and acid hydrolysis,,,,,,……..



Melvin Yu received his B.S. from MIT, and both his M.A. and Ph.D. degrees from Harvard University while studying under Professor Yoshito Kishi. In 1985, he joined Eli Lilly, and in 1993 he relocated to Eisai Inc. where he led the chemistry team that discovered Halaven. He was then responsible for the initial route nding and synthesis scale-up effort that ultimately provided the rst multi-gram batch of eribulin mesylate. Mel retains a strong interest in natural products as the inspiration of new chemotherapeutic agents, and in this context recently expanded his area of research to include cheminformatics and compound library design.


Wanjun Zheng received a Ph.D. in organic chemistry from Wesleyan University in 1994 under the direction of Professor Peter A. Jacobi working on synthetic methodology development and its application in natural product synthesis. He spent over two years as a postdoctoral research fellow in Harvard University under Professor Yoshito Kishi working on the complete structure determination of maitotoxin. He joined Eisai in 1996 and has since been contributing and leading many drug discovery projects including project in the discovery of Halaven.


Boris M. Seletsky earned his PhD in 1987 from Shemyakin Institute of Bioorganic Chemistry in Moscow, Russia working on new methods in steroid synthesis under direction of Dr George Segal and Professor Igor Torgov. Aer several years of natural product research at the same Institute, he moved on to postdoctoral studies in stereoselective synthesis with Professor Wolfgang Oppolzer at the University of Geneva, Switzerland, and Professor James A. Marshall at the University of South Carolina. Boris joined Eisai in 1994, and has contributed to many oncology drug discovery projects with considerable focus on natural products as chemical leads, culminating in the discovery of Halaven.


Volume 14, Issue 22, 15 November 2004, Pages 5551–5554

Macrocyclic ketone analogues of halichondrin B

This paper is dedicated to memory of Bruce F. Wels, our friend and colleague
  • a Department of Medicinal Chemistry, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA
  • b Department of Anticancer Research, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA
  • c Advisory Board, Eisai Research Institute, 4 Corporate Drive, Andover, MA 01810, USA

Image for unlabelled figure


From micrograms to grams: scale-up synthesis of eribulin mesylate

*Corresponding authors
aEisai Inc., Andover, USA
Nat. Prod. Rep., 2013,30, 1158-1164

DOI: 10.1039/C3NP70051H,!divAbstract

Covering: 1993 to 2002

The synthesis of eribulin mesylate from microgram to multi-gram scale is described in thisHighlight. Key coupling reactions include formation of the C30a to C1 carbon–carbon bond and macrocyclic ring closure through an intramolecular Nozaki–Hiyama–Kishi reaction.

Graphical abstract: From micrograms to grams: scale-up synthesis of eribulin mesylate

The synthesis of the C27–C35 tetrahydrofuran fragment.

The synthesis of the C14–C21 aldehyde subfragment.


In 1986, two Japanese chemists Hirata and Uemura [Y. Hirata, D. Uemura, Pure Appl. Chem. 58 (1986) 701.] isolated a naturally-occurring compound from the marine sponge Halichondria okadai (picture above, right). The compound was named Halichondrin B, and it immediately began to generate great excitement when it was realised that it was extremely potent at killing certain types of cancer cells in small-scale tests. As a result of this discovery, it was immediately given top priority to be tested against a wide range of other cancers, and became one of the first compounds to be evaluated using the novel 60-cell line method developed by the US National Cancer Institute (NCI). In this technique, 60 different types of human tumor cells (including leukemia, melanoma and cancers of the lung, colon, brain, ovary, breast, prostate, and kidney) are tested with the potential anti-cancer molecule delivered at a single dose of 10 μM concentration. This process can be run in parallel, with dozens of different molecules being tested against all 60 cancer cell lines at the same time in a huge array. Any molecules which exhibit significant growth inhibition are prioritised, and the test repeated on them, but this time at five different concentration levels.

Halichondrin B
Halichondrin B – the part of the molecule used to make Eribulin is shown in blue.

Unfortunately, the concentration of Halichondrin B in the sea sponge wasn’t enough to enable commercial production for use in chemotherapy. For example, a ton of sea sponges could only produce 300 mg of Halichondrin B! The race was on to try to synthesise Halichondrin B in the lab, which wasn’t easy due to its large size (molecular weight 1110) and complex structure. However, only 6 years later, chemists at Harvard University published the complete chemical synthesis of this molecule………..T.D. Aicher, K.R. Buszek, F.G. Fang, C.J. Forsyth, S.H. Jung, Y. Kishi, M.C. Matelich, P.M. Scola, D.M. Spero, S.K. Yoon, J. Am. Chem. Soc. 114 (1992) 3162

Although this was a great achievement, Halichondrin B was still far too complex and the sythesis route too expensive to do on a large scale. The molecule needed to be stripped down to its essential components, while keeping, or even improving, its anti-cancer efficacy. Many tests were performed, but eventually the work led to te development of the structurally-simplified and pharmaceutically-optimized analog, which was named Eribulin [3,4]. Eribulin mesylate was approved by the U.S. Food and Drug Administration in 2010, to treat patients with metastatic breast cancer [5], and it is currently being marketed by Eisai Co. under the trade nameHalaven . It is also being investigated for use in a variety of other solid tumors, including lung cancer, prostate cancer and sarcoma .


M.J. Towle, K.A. Salvato, J. Budrow, B.F. Wels, G. Kuznetsov, K.K. Aalfs, S. Welsh, W. Zheng, B.M. Seletsk, M.H. Palme, G.J. Habgood, L.A. Singer, L.V. Dipietro, Y. Wang, J.J. Chen, D.A. Quincy, A. Davis, K. Yoshimatsu, Y. Kishi, M.J. Yu, B.A. Littlefield, Cancer Res. 61 (2001) 1013.

M.J. Yu, Y. Kishi, B.A. Littlefield, in D.J. Newman, D.G.I. Kingston, G.M. Cragg, Anticancer agents from natural products, Washington, DC, Taylor and Francis (2005).

M.A. Jordan, L. Wilson, Nature Revs: Cancer 4 (2004) 253.


Patent Data

Appl No Prod No Patent No Patent
Drug Substance
Drug Product
Patent Use
N201532 001 6214865 Jul 20, 2023 Y
N201532 001 6469182 Jun 16, 2019 U – 1096
N201532 001 7470720 Jun 16, 2019 Y
N201532 001 8097648 Jan 22, 2021 U – 1096

Exclusivity Data

Appl No Prod No Exclusivity Code Exclusivity Expiration
N201532 001 NCE Nov 15, 2015

The substance inhibits the polymerization of tubulin into microtubules and encapsulates tubulin molecules in non-productive aggregates from. The lack of training of the spindle apparatus blocks the mitosis and ultimately induces apoptosis of the cell. Eribulin differs from known microtubule inhibitors such as taxanes and vinca alkaloids by the binding site on microtubules, also it does not affect the shortening. This explains the effectiveness of the new cytostatic agent in taxane-resistant tumor cell lines with specific tubulin mutations.

Structure and mechanism

Structurally, eribulin is a fully synthetic macrocyclic ketone analogue of the marine sponge natural product halichondrin B,[4][5] the latter being a potent naturally-occurring mitotic inhibitor with a unique mechanism of action found in the Halichondria genus of sponges.[6][7] Eribulin is a mechanistically-unique inhibitor of microtubule dynamics,[8][9] binding predominantly to a small number of high affinity sites at the plus ends of existing microtubules.[10] Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.[11][12]

A new synthetic route to E7389 was published in 2009.[13]


Eisai R&D Management Co., Ltd.


Halaven is a novel anticancer agent discovered and developed in-house by Eisai and is currently approved in more than 50 countries, including Japan, the United States and in Europe. In Russia, Halaven was approved in July 2012 for the treatment of locally advanced or metastatic breast cancer previously treated with at least two chemotherapy regimens including an anthracycline and a taxane. Approximately 50,000 women in Russia are newly diagnosed with breast cancer each year, with this type of cancer being the leading cause of death in women aged 45 to 55 years. read all at…………………….

Eribulin mesylate (Halaven; Eisai) — a synthetic analogue of the marine natural product halichondrin B that interferes with microtubule dynamics — was approved in November 2010 by the US Food and Drug Administration for the treatment of metastatic breast cancer.

Family members of the product patent, WO9965894, have SPC protection in the EU until 2024 and one of its Orange Book listed filings, US8097648, has US154 extension till January 2021.

The drug also has NCE exclusivity till November 2015.

HALAVEN (eribulin mesylate) Injection is a non-taxane microtubule dynamics inhibitor. Eribulin mesylate is a synthetic analogue of halichondrin B, a product isolated from the marine sponge Halichondria okadai. The chemical name for eribulin mesylate is 11,15:18,21:24,28-Triepoxy-7,9-ethano12,15-methano-9H,15H-furo[3,2-i]furo[2′,3′:5,6]pyrano[4,3-b][1,4]dioxacyclopentacosin-5(4H)-one, 2[(2S)-3-amino-2-hydroxypropyl]hexacosahydro-3-methoxy-26-methyl-20,27-bis(methylene)-, (2R,3R,3aS,7R,8aS,9S,10aR,11S,12R,13aR,13bS,15S,18S,21S,24S,26R,28R,29aS)-, methanesulfonate (salt).

It has a molecular weight of 826.0 (729.9 for free base). The empirical formula is C40H59NO11 •CH4O3S. Eribulin mesylate has the following structural formula:

HALAVEN® (eribulin mesylate) Structural Formula Illustration

HALAVEN is a clear, colorless, sterile solution for intravenous administration. Each vial contains 1 mg of eribulin mesylate as a 0.5 mg/mL solution in ethanol: water (5:95).

Full-size image (23 K)

Full-size image (15 K)

complete syn is available here

Nitrogen: dark blue, oxygen: red, hydrogen: light blue
graphics: Wurglics, Frankfurt am Main


Macrocyclization process for preparing a macrocyclic intermediate of halichondrin B analogs, in particular eribulin, from a non-macrocyclic compound, using a carbon-carbon bond-forming reaction.


WO 2015066729

Eisai has developed and launched eribulin mesylate for treating breast cancer.  Follows on from WO2014208774, claiming use of a combination comprising eribulin mesylate and lenvatinib mesylate, for treating cancer.

Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin B

By: Fang, Francis G.; Kim, Dae-Shik; Choi, Hyeong-Wook; Chase, Charles E.; Lee, Jaemoon

Assignee: Eisai R&D Management Co., Ltd., Japan

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy.  The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate.  The invention also provides compds. useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for prepg. the same.


In a recent discussion (Nicolau), about the suggested move of Prof. NicoIau from Scripps, the issue of the practicality of natural product total synthesis was raised. Here is a wonderful example of just that very usefulness, a wonderful piece of science extending over many years. It concerns the journey from Halichondrin B to Eribulin (E7389) a novel anti-cancer drug. The two compounds have the following structures:

I think you can see the relationship and as a development chemist I am glad they managed to simplify things (a bit).

Both compounds have an enormous number of possible isomers: Halichondrin B, with 32 stereocenters has 232possible isomers; Eribulin has 19 with 219 isomers (if I have counted correctly, it does not really matter, there are lots of isomers). Remarkable is the fact that only one of these isomers is active in the given area of anti-cancer agents.

An excellent review of the biology and chemistry of these compounds has been published by Phillips etal1. This review is an excellent read and is to be commended. Another one written by Kishi2, is also full of information about the discovery of E7389 and I hope you will all get a chance to read this chapter.

The history of Halichondrin B goes back to 1987 when Blunt2-5 isolated it with other similar compounds from extraction of 200Kg of a sponge. Independently Pettit isolated the same compound from a different species4. The appearance of this compound in different species of sponge may indicate that it is produced by a symbiote.

The biological activity of Halichondrin B is amazing. When evaluated against B-16 melanoma cells it was found to have an IC50 of 0.093ng/mL. Against various cancers, generated in mice, it was shown to be affective at a daily dose of 5ug/kg, which resulted in a doubling of the survival rate. It has also been demonstrated that Halichondrin acts as a microtubule destabiliser and mitoitic spindle poison. It was proven that it is has tremendous in vivo activity against a variety of drug resistant cancers, lung, colon, breast, ovarian to mention a few. Consequently the National Cancer Institute selected it for pre-clinical trials and it’s here that the problems began. According to reference 1 the entire clinical development would require some 10g, and if successful the annual production amount would be between 1-5 kg. Blunt and co-workers managed to isolate 310mg from 1000kg-harvested sponge therefore, the only way to obtain the amounts required is total chemical synthesis. But synthesising 1-5 kg of such a compound would indeed be a mammoth task.

Kishi synthesised this compound7 in 1992 starting from carbohydrate precursors employing the Nozaki-Hiyama-Kishi Ni/Cr reaction, several times, in the long synthetic sequence8, 9. Now as an aside I have used this reaction on scale several times and although it works well its success is very dependant upon the quality of the chromium source and also the presence of other trace transition metals.

In collaboration with Eisai work on the SAR of Halichondrin began. They had a good start: Thanks to the total syntheses of Kishi several advanced intermediates were available for biological screening and one popped out of the screen as being very active:

The first active lead compound

As one can see the complete left hand side of Halichondrin has gone! However, this compound was not active in vivo. Many derivatives and analogues of this compound were prepared: furans, diols, ketones and so on and a lead emerged from this complex SAR study, ER-076349. The vicinal diol was used as a handle for further refinement and lead ultimately to E7389, the clinical candidate.

It can be synthesised in around 35 steps from simple starting materials.

Going through all this work in a few sentences really belittles the tremendous amount of effort that went into discovery and development of this compound and the people involved are to be applauded for their dedication.

Kishi continues to optimise the synthesis of Eribulin as judged by a recent publication10. Where he describes an approach to the amino-alcohol-tetrahydrofuran part of Eribulin (top left fragment, compound 1 below). The retro-synthetic analysis is shown below. The numbering corresponds to that of Eribulin.

The first generation synthesis consisted of 20 steps and delivered compound 1 about 5% yield, the second-generation route was completed in 12 steps with a yield of 48%. One of the highlights includes a remarkable asymmetric hydrogenation11 with Crabtree’s catalyst12:

This selectivity was not just luck; it seems to quite general, at least in this system. I always wonder how long it took them to stumble across this catalyst, but then I suppose that Eisai like most of the large pharma. companies has a hydrogenation group that probably indulges in catalyst screening.

The C34-C35 diol was obtained by a Sharpless asymmetric hydroxylation, here the diastereoisomeric ratio was not very high, only about 3:1 in favour of the desired isomer. Fortunately the undesired isomer could be removedcompletely by crystallisation.

This is a remarkable story and references 1 and 2 are worth reading to obtain the complete picture and learn lots of new chemistry as well. Eisai filed a NDA and the FDA approved the compound in 2010 for the treatment of metastatic breast cancer.


EXAM PLE 23 : Preparation of Eribulin :

Figure imgf000049_0001

[00120] Compound E-12A (133 mg, 160 μηιοΙ, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL) and cooled to 0 °C. To this solution was sequentially added 2,6-lutidine (0.09 m L, 0.8 mmol, 5.0 eq), and trimethyl silyl triflate (TMSOTf) (0.12 m L, 0.64 mmol, 4.0 eq) and the cooling bath was removed . The reaction was stirred at room temperature for 1.5 hours and another portion of 2,6-lutidine (5.0 eq) and TMSOTf (4.0 eq) were added at room temperature. The reaction was further stirred for 1 hour and quenched with water (10 m L). The layers were separated and the organic phase was washed with additional water (2x 10 m L), brine (10 m L), dried over MgS04 and concentrated under reduced pressure. The residue was dissolved in MeOH (10 m L), a catalytic amount of K2C03 was added at room temperature and the resulting mixture was stirred for 2 hours. The reaction was diluted with dichloromethane and quenched with water (10 mL). The layers were separated and the aqueous phase was further extracted with dichloromethane (5 x 10 m L). The combined organic layers were washed with brine (20 m L), dried over MgS04, filtered and concentrated. The residue was dissolved in dichloromethane and purified by column chromatography on silica gel, using 1 : 9 MeOH : CH2CI2 to 1 : 9 : 90 N H4OH : MeOH : CH2CI2 as eluent. The product was afforded as a white amorphous solid (103 mg, 88%) . [00121] EXAMPLE 23 : Preparation of compound of formula 4a

Figure imgf000050_0001

D-Gulonolactone 4a

[00122] The compound of formula 4a was prepared from D-Gulonolactone according to the conditions described in PCT publication number WO 2005/118565. [00123] EXAMPLE 24: Preparation of Eribulin mesylate (3)

[00124] Eribulin mesylate (3) was prepared from Eribulin according to the conditions described in US patent application publication number US



Halichondrin B analogs, e.g., eribulin or pharmaceutically acceptable salts thereof, can be synthesized from the C14-C35 fragment as described in U.S. Patent No. 6,214,865 and International Publication No. WO 2005/118565. In one example described in these references, the C14-C35 portion, e.g., ER- 804028, of the molecule is coupled to the C1-C13 portion, e.g., ER-803896, to produce ER-804029, and additional reactions are carried out to produce eribulin (Scheme 1):

Figure imgf000022_0001

Scheme 1

eribulin, eribulin mesylate

Scheme 2


Figure imgf000042_0001

Compound AE (280 mg, 0.281 mmol, 1 eq) was dissolved in CH2C12 and cooled to 0 °C. Pyridine (0.045 ml, 0.56 mmol, 2.0 eq) was added followed by Ms20 (58.8 mg, 0.338 mmol, 1.20 eq). The reaction was allowed to warm to room temperature, and stirring was continued for an additional 1 h. The reaction mixture was cooled to 0 °C, diluted with MTBE (5.6 ml), washed with saturated NaHC03 (0.84 g), and concentrated to give crude product as colorless film. The crude was azeotropically dried with heptane (3 ml χ 2) and re-dissolved in THF (7.0 ml). The mixture was cooled to 0 °C and treated with 25 wt% NaOMe (0.13 ml). After 10 min, the reaction was allowed to warm to room temperature, and stirring was continued for an additional 30 min. The mixture was treated with additional 25 wt% NaOMe (0.045 ml), and stirring was continued for an additional 20 min. The reaction mixture was diluted with heptane (7.0 ml) and washed with water (1.4 ml). The organic layer was separated, sequentially washed with: 1) 20 wt% NH4C1 (0.84 g) and 2) 20 wt% NaCl (3 g), and concentrated to give crude product as brownish oil. The crude was purified by Biotage (Uppsala, Sweden) 12M (heptane-MTBE 2:3 v/v) to give ER-804028 (209 mg, 0.245 mmol, 87%) as pale yellow oil. 1H NMR (400 MHz, CDC13): δ 7.89 (2H, m), 7.64 (IH, m), 7.56 (2H, m), 4.85 (IH, d, J= 1.6 Hz), 4.80 (IH, s), 4.72 (IH, s), 4.61 (IH, d, J= 1.6 Hz), 4.23 (IH, br), 3.91 (IH, m), 3.79 (IH, m), 3.76 (2H, m), 3.63 (IH, m), 3.50-3.60 (4H, m), 3.43 (IH, dd, J= 5.6 Hz, 10.0 Hz), 3.38 (3H, s), 3.32 (IH, m), 2.98 (2H, m), 2.61 (IH, br), 2.56 (IH, m), 2.50 (IH, m), 2.08-2.22 (3H, m), 1.96 (IH, m), 1.84 (IH, m), 1.78 (IH, m), 1.70 (IH, m), 1.42-1.63 (6H, m), 1.28-1.42 (2H, m), 1.01 (3H, d, J= 6.8 Hz), 0.84 (18H, s), 0.05 (3H, s), 0.04 (3H, s), 0.00 (3H, s), -0.01 (3H, s); and 13C NMR (100 MHz, CDC13): δ 150.34, 150.75, 139.91, 134.18, 129.73 (2C), 128.14 (2C), 105.10, 85.97, 80.92, 79.72, 78.50, 77.45, 77.09, 75.53, 71.59, 68.04, 62.88, 58.27, 57.73, 43.51, 42.82, 39.16, 37.68, 35.69, 33.31, 32.41, 31.89, 31.48, 29.79, 26.21 (3C), 26.17 (3C), 18.58, 18.38, 18.13, -3.85, – 4.71, -5.12 (2C).


Eribulin mesylate (Halaven)
Eribulin is a highly potent cytotoxic agent approved in the US for the treatment of metastatic breast cancer for patients who have
received at least two previous chemotherapeutic regimens.30 Eribulin was discovered and developed by Eisai and it is currently
undergoing clinical evaluation for the treatment of sarcoma (PhIII) and non-small cell lung cancer which shows progression after platinum-based chemotherapy and for the treatment of prostate cancer (PhII). Early stage clinical trials are also underway to evaluate
eribulin’s efficacy against a number of additional cancers. Eribulin is a structural analog of the marine natural product halichondrin B.
Its mechanism of action involves the disruption of mitotic spindle formation and inhibition of tubulin polymerization which results
in the induction of cell cycle blockade in the G2/M phase and apoptosis.31 Several synthetic routes for the preparation of eribulin have
been disclosed,32–35 each of which utilizes the same strategy described by Kishi and co-workers for the total synthesis of halichondrin B.36 Although the scales of these routes were not disclosed in all cases, this review attempts to highlight what appears to be the production-scale route based on patent literature.37,38 Nonetheless, the synthesis of eribulin represents a significant accomplishment in the field of total synthesis and brings a novel chemotherapeutic option to cancer patients.
The strategy to prepare eribulin mesylate (V) employs a convergent synthesis featuring the following: the late stage coupling of
sulfone 22 and aldehyde 23 followed by macrocyclization under Nozaki–Hiyami–Kishi coupling conditions, formation of a challenging
cyclic ketal, and installation of the primary amine (Scheme 5).Sulfone 22 was further simplified to aldehyde 24 and vinyl triflate 25 which were coupled through a Nozaki–Hiyami–Kishi reaction.

The schemes that follow will describe the preparation of fragments 23, 24 and 25 along with how the entire molecule was assembled.
The synthesis of the C1–C13 aldehyde fragment 23 is described in Scheme 6. L-Mannonic acid-lactone 26 was reacted with cyclohexanone in p-toluene sulfonic acid (p-TSA) to give the biscyclohexylidene ketal 27 in 84% yield. Lactone 27 was reduced with
diisobutylaluminum hydride (DIBAL-H) to give lactol 28 followed by condensation with the ylide generated from the reaction of
methoxymethylene triphenylphosphorane with potassium tertbutoxide to give a mixture of E and Z vinyl ethers 29 in 81% yield.
Dihydroxylation of the vinyl ether of 29 using catalytic osmium teteroxide and N-methylmorpholine-N-oxide (NMO) with concomitant cyclization produced diol 30 in 52% yield. Bis-acetonide 30 was then reacted with acetic anhydride in acetic acid in the presence of ZnCl2 which resulted in selective removal of the pendant ketal protecting group. These conditions also affected peracylation, giving rise to tetraacetate 31 in 84% yield. Condensation of 31 with methyl 3-(trimethylsilyl)pent-4-enoate in the presence of boron trifluoride etherate in acetonitrile provided alkene 32. Saponification conditions using Triton B(OH) removed the acetate protecting groups within 32 and presumably induced isomerization of the alkene into conjugation with the terminal ester, triggering an intramolecular Michael attack of the 2-hydroxyl group, ultimately resulting in the bicylic-bispyranyl diol methyl ester 33 as a crystalline solid in 38% yield over two steps. Oxidative cleavage of the vicinal diol of 33 with sodium periodate gave aldehyde 34 which was coupled to (2-bromovinyl)trimethylsilane under Nozaki–Hiyami–Kishi conditions to give an 8.3:1 mixture of allyl alcohols 35 in 65% yield over two steps. Hydrolysis of the cyclohexylidine ketal 35 with aqueous acetic acid followed by recrystallization gave diastereomerically pure triol 36 which was reacted with tert-butyldimethylsilyl triflate (TBSOTf) to afford the tris-TBS ether 37 in good yield. Vinyl silane 37 was treated with NIS and catalytic tert-butyldimethylsilyl chloride (TBSCl) to give vinyl iodide 38 in 90% yield.
Reduction of the ester with DIBAL-H produced the key C1–C14 fragment 23 in 93% yield.
The preparation of the tetra-substituted tetrahydrofuran intermediate 24 is described in Scheme 7. D-Glucurono-6,3-lactone
39 was reacted with acetone and sulfuric acid to give the corresponding acetonide and the 5-hydroxyl group was then removed by converting it to its corresponding chloride through reaction with sulfuryl chloride (SO2Cl2) followed by hydrogenolysis
to give lactone 40 in good overall yield. Reduction of the lactone 40 with DIBAL-H gave the corresponding lactol which was condensed
with (trimethylsilyl)methylmagnesium chloride to afford silane 41. Elimination of the silyl alcohol of 41 was accomplished
under Peterson conditions with potassium hexamethyldisilazide (KHMDS) to afford the corresponding terminal alkene in 94% yield.
The secondary alcohol of this intermediate was alkylated with benzyl bromide to afford ether 42 in 95% yield. Asymmetric dihydroxylation of the alkene of 42 under modified Sharpless conditions using potassium osmate (VI) dehydrate (K2OsO4), potassium
ferricyanide (K3Fe(CN)6) and the (DHQ)2AQN ligand produced the vicinal diol which was then reacted with benzoyl chloride,
N-methylmorpholine, and DMAP to give di-benzoate 43 in excellent yield as a 3:1 mixture of diastereomeric alcohols. Allyl trimethylsilane was added to the acetal of 43 using TiCl3(OiPr) as the Lewis acid to give 44 in 83% yield. Re-crystallization of 44 from
isopropanol and n-heptane afforded 44 in >99.5% de in 71% yield.
Oxidation of the secondary alcohol of 44 under the modified Swern conditions generated the corresponding ketone which was condensed with the lithium anion of methyl phenyl sulfone to give a mixture of E and Z vinyl sulfones 45. Debenzylation of 45 using iodotrimethylsilane (TMSI) followed by chelation-controlled reduction of the vinyl sulfone through reaction with NaBH(OAc)3, and
then basic hydrolysis of the benzoate esters using K2CO3 in MeOH resulted in triol 46 as a white crystalline solid in 57% yield over the
five steps after re-crystallization. The vicinal diol of 46 was protected as the corresponding acetonide through reaction with 2,2-
dimethoxypropane and sulfuric acid and this was followed by methyl iodide-mediated methylation of the remaining hydroxyl
group to give methyl ether 47. The protecting groups within acetonide 47 were then converted to the corresponding bis-tert-butyldimethylsilyl ether by first acidic removal of the acetonide with aqueous HCl and reaction with TBSCl in the presence of imidazole to give bis-TBS ether 48. Then, ozonolysis of the olefin of 48 followed by hydrogenolysis in the presence of Lindlar catalyst afforded the key aldehyde intermediate 24 in 68% yield over the previous five steps after re-crystallization from heptane.
Two routes to the C14–C26 fragment 25 will be described as both are potentially used to prepare clinical supplies of eribulin.
The first route features a convergent and relatively efficient synthesis of 25, however it is limited by the need to separate enantiomers
and mixture of diastereomers via chromatographic methods throughout the synthesis.37 The second route to 25 is a
much lengthier synthesis from a step-counting perspective; however it takes full advantage of the chiral pool of starting materials
and requires no chromatographic separations and all of the products were carried on as crude oils until they could be isolated as
crystalline solids.38 The first route to fragment 25 is described in Scheme 8 and was initiated by the hydration of 2,3-dihydrofuran (49) using an aqueous suspension of Amberlyst 15 to generate the intermediate tetrahydro-2-furanol (50) which was then immediately reacted with 2,3-dibromopropene in the presence of tin and catalytic HBr to afford diol 51 in 45% for the two steps.

The primary alcohol of 51 was selectively protected as its tert-butyldiphenylsilyl ether using TBDPSCl and imidazole and the racemate was then separated using simulated moving bed (SMB) chromatography to give enantiopure 52 in 45% yield over the two steps. The secondary alcohol of 52 was reacted with p-toluenesulfonyl chloride and DMAP to give tosylate 53 in 78% yield which was used as a coupling partner later in the synthesis of this fragment. The synthesis of the appropriate coupling partner was initiated by condensing diethylmalonate with (R)-2-(3-butenyl)oxirane (54), followed by decarboxylation to give lactone 55 in 71% yield for the two step process. Methylation of the lactone with LHMDS and MeI provided 56 in 68% yield as a 6:1 mixture of diastereomers. The lactone 56 was reacted with the aluminum amide generated by the reaction of AlMe3 and N,O-dimethylhydroxylamine to give the corresponding Weinreb amide which was protected as its tert-butyldimethylsilyl ether upon reaction with TBSCl and imidazole to give 57 in 91% yield over the two steps. Dihydroxylation of the olefin of 57 by reaction with OsO4 and NMO followed by oxidative cleavage with NaIO4 gave the desired coupling partner aldehyde 58 in 93% yield. Aldehyde 58 was coupled with vinyl bromide 53 using an asymmetric Nozaki–Hiyami– Kishi reaction using CrCl2, NiCl2, Et3N and chiral ligand 66 (described in Scheme 9 below). The reaction mixture was treated with ethylene diamine to remove the heavy metals and give the secondary alcohol 59. This alcohol was stirred with silica gel in isopropanol to affect intramolecular cyclization to give the tetrahydrofuran 60 in 48% yield over the three step process. The Weinreb amide of 60 was reacted with methyl magnesium chloride to generate the corresponding methyl ketone which was converted to vinyl triflate 61 upon reaction with KHMDS and Tf2NPh. De-silylation of the primary and secondary silyl ethers with methanolic HCl gave the corresponding diol in 85% yield over two steps and the resulting mixture of diastereomers was separated using preparative HPLC to provide the desired diastereomer in 56% yield. The primary alcohol was protected as its pivalate ester with the use of pivaloyl chloride, DMAP and collidine; the secondary alcohol was converted     to a mesylate upon treatment with methanesulfonyl chloride (MsCl) and Et3N to give the C15–C27 fragment 25 in high yield.
The preparations of the chiral ligand 66 used in the coupling reaction in Scheme 8 along with the chiral ligand 67 utilized later
in the synthesis are described in Scheme 9. 2-Amino-3-methylbenzoic acid (62) was reacted with triphosgene to give benzoxazine
dione 63 in 97% yield, which then was reacted with either D- or L-valinol in DMF followed by aqueous LiOH to give alcohols 64
and 65, respectively in 65–75% yield for the two steps. Reaction of alcohol 64 or 65 with MsCl in the presence of DMAP effected formation of the dihydrooxazole ring and mesylation of the aniline to give the corresponding (R)-ligand 66 derived from D-valinol or the (S)-ligand 67 derived from L-valinol, respectively in high yield.
An alternative route to intermediate 25 is described in Scheme  10 and although much lengthier than the route described in
Scheme 8, it avoids chromatographic purifications as all of the products are carried on crude until a crystalline intermediate
was isolated and purified by re-crystallization. Quinic acid (68) was reacted with cyclohexanone in sulfuric acid to generate a protected
bicyclic lactone in 73% yield and the resulting tertiary alcohol was protected as its trimethylsilyl ether 69. Reduction of the
lactone 69 was accomplished with DIBAL-H and the resulting lactol  was treated with acetic acid to remove the TMS group and the resulting compound was reacted with acetic anhydride, DMAP and Et3N to give bis-acetate 70 in 65% yield for the three steps after re-crystallization. Methyl 3-(trimethylsilyl)pent-4-enoate was coupled to the acetylated lactol 70 in the presence of boron trifluoride etherate and trifluoroacetic anhydride to give adduct 71 in 62% yield. The acetate of 71 was removed upon reaction with sodium methoxide in methanol and the resulting tertiary alcohol cyclized on to the isomerized enone alkene to give the fused pyran ring. Reduction of the methyl ester with lithium aluminum hydride provided pyranyl alcohol 72. Mesylation of the primary alcohol was followed by displacement with cyanide anion to give nitrile 73.STR1 STR2

The nitrile was methylated upon reaction with KHMDS and MeI and the resulting product was purified by re-crystallization
to provide nitrile 74 in 66% over the previous five steps in a 34:1 diastereomeric ratio. Acid hydrolysis of the ketal of 74 liberated
the corresponding diol in 72% yield and this was reacted with 2-acetoxy-2-methylpropionyl bromide to give bromo acetate 75.
Elimination of the bromide was accomplished upon treatment with 1,8-diazabicycloundec-7-ene (DBU) to give alkene 76 in 63%
yield for two steps. Ozonolysis of the cyclohexene ring followed by reductive work-up with NaBH4 and basic hydrolysis of the acetate
produced a triol which upon reaction with NaIO4 underwent oxidative cleavage to give cyclic hemiacetal 77 in 75% yield over
the previous four steps. Wittig condensation with carbomethoxymethylene triphenylphosphorane gave the homologated unsaturated
ester 78. Catalytic hydrogenation of the alkene using PtO2 as the catalyst was followed by converting the primary alcohol to the
corresponding triflate prior to displacement with sodium iodide resulted in iodide 79 in 75% yield over four steps. The ester of 79
was reduced to the corresponding primary alcohol upon reaction with LiBH4 in 89% yield and the resulting iodoalcohol was treated
with Zn dust to affect reductive elimination of the iodide and decomposition of the pyran ring system to give the tetrahydrofuran
diol 80 in 90% yield. This diol was treated with methanolic HCl to affect an intramolecular Pinner reaction and this was followed
by protection of the primary alcohol as its tert-butyldiphenylsilyl ether to give lactone 81 The lactone was reacted with the
aluminum amide generated from AlMe3 and N,O-dimethylhydroxylamine and the resulting secondary alcohol was protected as
its tert-butyldimethylsilyl ether to give Weinreb amide 82 in 99% crude yield over four steps. Compound 82 is the diastereomerically
pure version of compound 60 and can be converted to compound 25 by the methods described in Scheme 8 absent the required
HPLC separation of diastereomers. With the three key fragments completed, the next step was to assemble them and complete the synthesis of eribulin. Aldehyde 24 was coupled to vinyl triflate 25 using an asymmetric Nozaki– Hiyami–Kishi reaction using CrCl2, NiCl2, Et3 N and chiral ligand 67 (Scheme 9) to give alcohol 83 (Scheme 11).


Formation of the THP ring was accomplished by reaction with KHMDS which allowed for displacement of the mesylate with the secondary alcohol and provided the THP containing product in 72% yield for the three steps. The pivalate ester group was removed with DIBAL-H to give the western fragment 22 in 92% yield.
The completion of the synthesis of eribulin is illustrated in Scheme 12. The lithium anion of sulfone 22 generated upon reaction
with nBuLi was coupled to aldehyde 23 to give diol 84 in 84% yield. Both of the alcohol functional groups of 84 were oxidized
using a Dess–Martin oxidation in 90% yield and the resulting sulfone was removed via a reductive cleavage upon reaction with
SmI2 to give keto-aldehyde 85 in 85% yield. Macrocyclization of 85 was accomplished via an asymmetric Nozaki–Hiyami–Kishi
reaction using CrCl2, NiCl2, Et3N and chiral ligand 67 to give alcohol 86 in 70% yield. Modified Swern oxidation of the alcohol provided the corresponding ketone in 91% yield and this was followed by removal of the five silyl ether protecting groups upon reaction with TBAF and subsequent cyclization to provide ketone 87. Compound 87 was treated with PPTS to provide the ‘caged’ cyclic ketal 88 in 79% over two steps. The vicinal diol of 88 was reacted with Ts2O in collidine to affect selective tosylation of the primary alcohol and this crude product was reacted with ammonium hydroxide to install the primary amine to give eribulin which was treated
with methanesulfonic acid in aqueous ammonium hydroxide to give eribulin mesylate (V) in 84% yield over the final three steps.


30. Zheng, W.; Seletsky, B. M.; Palme, M. H.; Lydon, P. J.; Singer, L. A.; Chase, C. E.;
Lemelin, C. A.; Shen, Y.; Davis, H.; Tremblay, L.; Towle, M. J.; Salvato, K. A.;
Wels, B. F.; Aalfs, K. K.; Kishi, Y.; Littlefield, B. A.; Yu, M. J. Bioorg. Med. Chem.
Lett. 2004, 14, 5551.
31. Wang, Y.; Serradell, N.; Bolós, J.; Rosa, E. Drugs Future 2007, 32, 681.
32. Chiba, H.; Tagami, K. J. Synth. Org. Chem. Jpn. 2011, 69, 600.
33. Choi, H.; Demeke, D.; Kang, F.-A.; Kishi, Y.; Nakajima, K.; Nowak, P.; Wan, Z.-
K.; Xie, C. Pure Appl. Chem. 2003, 75, 1.
34. Kishi, Y.; Fang, F.; Forsyth, C. J.; Scola, P. M.; Yoon, S. K. WO 9317690 A1, 1993.
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WO 9965894 A1, 1999.
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Eribulin (Halaven)

Halichondrin B is a wicked molecule. In tests in mice, it is an extremely potent cancer cell killer, active at around 80 picomolar concentration. It also possesses a fiendish macrocyclic polyketide structure, with 32 stereocentres meaning that it could adopt over four billion different isomers – with just one that fights cancer.

Eribulin and halichondrin BEribulin is a cut-down derivative of halichondrin B, which maintains most of its activity with significantly reduced complexity

Its power is therefore inherently hard to harness. Halichondrin B was found in various sea sponge species in the 1980s, but getting 400mg  of the compound from a tonne of sponge was doing well. Clinical development required at least 10g, and annual production takes kilograms.

Although developing a synthetic route to halichondrin B looked just as tough as trying to extract it from sponges, Yoshito Kishi’s group at Harvard University in the US accepted the challenge. Frank Fang, one of the team, recalls how the Nozaki–Hiyama–Kishi (NHK) coupling reaction would prove critical. ‘Another feature that was impressed upon me was the importance of crystalline intermediates,’ Fang adds. These allowed simple purification by recrystallisation, rather than expensive and time-consuming chromatography.

Published in 1992, their method used several NHK couplings, forming carbon–carbon bonds between multifunctional vinyl halides and aldehydes via a nickel-catalysed, chromium-mediated process.4 The sprawling convergent synthesis, whose longest linear sequence involved 47 steps, prompted Japanese pharmaceutical company Eisai to collaborate with Kishi in exploring halichondrin B’s structure–activity relationship. On screening the team’s intermediates, one featuring the macrocyclic half of halichondrin B proved especially active. A series of medicinal chemistry refinements led to what would eventually becomeeribulin (marketed by Eisai as Halaven), promising a slightly simpler synthesis. It has ‘just’ 19 stereocentres, which along with other structural restrictions cuts the possible number of isomers to a mere 16,384.

Fang joined Eisai in 1998 as it selected eribulin for further development, and worked to develop a production process for a route that produced it from three fragments. He again strove to exploit recrystallisation and use the NHK reaction, although making it reliable enough for manufacturing was challenging. ‘There was an appreciation for the somewhat sensitive nature of the reaction, particularly the asymmetric variant,’ he recalls.

The Eisai researchers therefore studied the NHK procedure as they applied it to redesigning the synthesis for part of the eribulin molecule they refer to as the C14–C26 fragment. Featuring just one ring, this fragment isn’t the most structurally complex of the three, but is still very difficult to make. That’s because it is a long chain with several stereocentres, whose stereochemistry is hard to link together.

Fang’s team initially broke this section down into two sub-fragments, C14–C19 and C20–C26, using asymmetric NHK reactions on each, learning about the reaction’s parameters as they did so.5 They then used what they’d found out to devise NHK reactions linking the two sub-fragments and attaching the two fragments on either side, which included closing the eribulin macrocycle. ‘We gained knowledge through our studies on the C19–C20 NHK coupling and were ultimately able to utilise that knowledge to try to execute an asymmetric NHK reaction in fixed equipment on multi-kilogram scale and construct the C19–C20, C26–C27, and C13–C14 bonds,’ Fang explains.

Synthesis of eribulin Synthesis of eribulin relies heavily on Nozaki–Hiyama–Kishi (NHK) coupling reactions to make key C–C bonds

Halaven was approved in the US in 2010 to treat breast cancer and earned ¥2.89 billion in sales (£159 million) in 2014. The commercial route initially took 62 steps across a convergent synthesis bringing together three fragments, with a longest linear sequence of 30 steps. Fang’s team has since added seven steps to the C14–C26 fragment route, which counterintuitively cuts costs and waste by 80% by eliminating chromatography.6 ‘I am hopeful that we can find the lessons applicable in future work,’ Fang says.

Cheaper synthesis would appear welcome, given that Halaven’s price tag has been criticised. In the UK it currently costs £2,000 per 21 day treatment cycle according to data from the British National Formularyand the country’s National Institute for Health and Clinical Excellence (Nice). As a result, Nice refused to cover the drug, and in January 2015 the remaining funding in England looked set to be closed off with Halaven being taken off the Cancer Drugs Fund (CDF)’s list. But Eisai was told in March that the drug would stay on the list, pending reconsideration, after an appeal against the decision.

In defence, Fang claims that Halaven is actually one of the most affordable breast cancer treatments on the CDF. ‘Eisai was given no opportunity to lower the price of Halaven before NHS England announced that the treatment would be removed from the fund, despite this being something we were, and still are, very willing to do,’ he adds.

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3 * ZHENG, W. ET AL.: “Macrocyclic ketone analogues of halichondrin B“, BIOORG. MED. CHEM. LETT., vol. 14, 2004, pages 5551 – 5554, XP004598592
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WO2015131286A1 * Mar 6, 2015 Sep 11, 2015 Alphora Research Inc. Crystalline derivatives of (s)-1-((2r,3r,4s,5s)-5-allyl-3-methoxy-4-(tosylmethyl)tetrahydrofuran-2-yl)-3-aminopropan-2-ol
CN103483352A * Oct 18, 2013 Jan 1, 2014 李友香 Medicinal bulk drug for resisting tumors
US9062020 Dec 24, 2012 Jun 23, 2015 Alphora Research Inc. 2-((2S,3S,4R,5R)-5-((S)-3-amino-2-hydroxyprop-1-yl)-4-methoxy-3-(phenylsulfonylmethyl)tetrahydrofuran-2-yl)acetaldehyde derivatives and process for their preparation
US9174956 Dec 14, 2012 Nov 3, 2015 Alphora Research Inc. Process for preparation of 3-((2S,5S)-4-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)propanol derivatives and intermediates useful thereof
US9181152 Nov 29, 2012 Nov 10, 2015 Alphora Research Inc. Process for preparation of (3R)-2,4-di-leaving group-3-methylbut-1-ene
WO2012129100A1 * Mar 16, 2012 Sep 27, 2012 Eisai R&D Management Co., Ltd. Methods and compositions for predicting response to eribulin
WO2012166899A2 * May 31, 2012 Dec 6, 2012 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
CA2828946A1 * Apr 16, 2012 Oct 26, 2012 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US7982060 * Jun 3, 2005 Jul 19, 2011 Eisai R&D Management Co., Ltd. Intermediates for the preparation of analogs of Halichondrin B
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.


  1. ^“FDA approves new treatment option for late-stage breast cancer” (Press release). USFDA. 2010-11-15. Retrieved November 15, 2010.
  2. ^Notice of Decision for HALAVEN
  3. ^
  4. ^ Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA (February 2001). “In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B”. Cancer Res.61 (3): 1013–21. PMID11221827.
  5. ^ Yu MJ, Kishi Y, Littlefield BA (2005). “Discovery of E7389, a fully synthetic macrocyclic ketone analogue of halichondrin B”. In Newman DJ, Kingston DGI, Cragg, GM. Anticancer agents from natural products. Washington, DC: Taylor & Francis. ISBN0-8493-1863-7.
  6. ^ Hirata Y, Uemura D (1986). “Halichondrins – antitumor polyether macrolides from a marine sponge”. Pure Appl. Chem.58 (5): 701–710. doi:10.1351/pac198658050701.
  7. ^ Bai RL, Paull KD, Herald CL, Malspeis L, Pettit GR, Hamel E (August 1991). “Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data”. J. Biol. Chem.266 (24): 15882–9. PMID1874739.
  8.  Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L (July 2005). “The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth”. Mol. Cancer Ther.4 (7): 1086–95. doi:10.1158/1535-7163.MCT-04-0345. PMID16020666.
  9.  Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA (July 2008). “Inhibition of Centromere Dynamics by Eribulin (E7389) during Mitotic Metaphase”. Mol. Cancer Ther.7 (7): 2003–11. doi:10.1158/1535-7163.MCT-08-0095. PMC2562299. PMID18645010.
  10.  Smith JA, Wilson L, Azarenko O, Zhu X, Lewis BM, Littlefield BA, Jordan MA (February 2010). “Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability”. Biochemistry49 (6): 1331–7. doi:10.1021/bi901810u. PMC2846717. PMID20030375.
  11. Kuznetsov G, Towle MJ, Cheng H, Kawamura T, TenDyke K, Liu D, Kishi Y, Yu MJ, Littlefield BA (August 2004). “Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389”. Cancer Res.64 (16): 5760–6. doi:10.1158/0008-5472.CAN-04-1169. PMID15313917.
  12. ^ Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis BM, Kishi Y, Yu MJ, Littlefield BA (January 2011). “Eribulin induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions”. Cancer Res.71 (2): 496–505. doi:10.1158/0008-5472.CAN-10-1874. PMID21127197.
  13. ^ Kim DS, Dong CG, Kim JT, Guo H, Huang J, Tiseni PS, Kishi Y (November 2009). “New syntheses of E7389 C14-C35 and halichondrin C14-C38 building blocks: double-inversion approach”. J. Am. Chem. Soc.131 (43): 15636–41. doi:10.1021/ja9058475. PMID19807076.


Systematic (IUPAC) name
2-(3-Amino-2-hydroxypropyl)hexacosahydro-3-methoxy- 26-methyl-20,27-bis(methylene)11,15-18,21-24,28-triepoxy- 7,9-ethano-12,15-methano-9H,15H-furo(3,2-i)furo(2′,3′-5,6) pyrano(4,3-b)(1,4)dioxacyclopentacosin-5-(4H)-one
Clinical data
Trade names Halaven
AHFS/ Consumer Drug Information
MedlinePlus a611007
License data
  • US: D (Evidence of risk)
Routes of
Legal status
Legal status
CAS Number 253128-41-5 
ATC code L01XX41 (WHO)
PubChem CID 17755248
ChemSpider 21396142 Yes
UNII LR24G6354G Yes
Chemical data
Formula C40H59NO11
Molar mass 729.90 g/mol

////////Halaven, ERIBULIN, anticancer drug ,  Eisai Co.  E7389,  ER-086526,  US NCI designation,  NSC-707389.   breast cancer,  liposarcoma, halichrondrin B analog, B1939, E7389, ER-086526, 441045-17-6, FDA 2010, 253128-41-5 , ERIBULIN MESYLATE, Antineoplastic, エリブリンメシル酸塩





253128-41-5  CAS




CAS : 21679-14-1
Additional Names: 9-b-D-arabinofuranosyl-2-fluoroadenine; 2-fluorovidarabine; 2-fluoro-9-b-D-arabinofuranosyladenine; 2-F-araA
Manufacturers’ Codes: NSC-118218; NSC-118218-H
Molecular Formula: C10H12FN5O4
Molecular Weight: 285.23
Percent Composition: C 42.11%, H 4.24%, F 6.66%, N 24.55%, O 22.44%
Properties: Crystals from ethanol + water, mp 260°. [a]D25 +17 ±2.5° (c = 0.1 in ethanol). uv max (pH 1, pH 7, pH 13): 262, 261, 262 nm (e ´ 10-3 13.2, 14.8, 15.0). Sparingly sol in water, organic solvents.
Melting point: mp 260°
Optical Rotation: [a]D25 +17 ±2.5° (c = 0.1 in ethanol)
Absorption maximum: uv max (pH 1, pH 7, pH 13): 262, 261, 262 nm (e ´ 10-3 13.2, 14.8, 15.0)
Fludarabine phosphate.svg
Derivative Type: 5¢-Monophosphate
CAS : 75607-67-9
Additional Names: 2-F-ara-AMP
Manufacturers’ Codes: NSC-328002; NSC-312887
Trademarks: Fludara (Schering AG)
Molecular Formula: C10H13FN5O7P
Molecular Weight: 365.21
Percent Composition: C 32.89%, H 3.59%, F 5.20%, N 19.18%, O 30.67%, P 8.48%
Properties: Sol in water.
Therap-Cat: Phosphate as antineoplastic.
Systematic (IUPAC) name
[(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid
Clinical data
Trade names Fludara
AHFS/ monograph
MedlinePlus a692003
  • D
Legal status
Routes Intravenous, oral
Pharmacokinetic data
Bioavailability 55%
Protein binding 19 to 29%
Half-life 20 hours
Excretion Renal
CAS number 75607-67-9 Yes
ATC code L01BB05
PubChem CID 657237
DrugBank DB01073
ChemSpider 571392 Yes
UNII P2K93U8740 Yes
KEGG D01907 Yes
ChEBI CHEBI:63599 
Chemical data
Formula C10H13FN5O7P 
Molecular mass 365.212 g/mol


Fludarabine or fludarabine phosphate (Fludara) is a chemotherapy drug used in the treatment of hematological malignancies(cancers of blood cells such as leukemias and lymphomas). It is a purine analog, which interferes with DNA synthesis.


Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone.[1] Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone,dexamethasone and rituximab in the treatment of indolent non-Hodgkins lymphomas. As part of the FLAG regimen, fludarabine is used together with cytarabine and granulocyte colony-stimulating factor in the treatment of acute myeloid leukaemia. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to allogeneic stem cell transplant.


Fludarabine is a purine analog, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering withribonucleotide reductase and DNA polymerase. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy.

Side effects

Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infectionssignificantly. Patients who have been treated with fludarabine will usually be asked to take co-trimoxazole or to use monthly nebulised pentamidine to prevent Pneumocystis jiroveci pneumonia. The profound lymphopenia caused by fludarabine renders patients susceptible to transfusion-associated graft versus host disease, an oftentimes fatal complication of blood transfusion. For this reason, all patients who have ever received fludarabine should only be given irradiated blood components.

Fludarabine causes anemia, thrombocytopenia and neutropenia, requiring regular blood count monitoring. Some patients require blood and platelet transfusion, or G-CSF injections to boost neutrophil counts.

Fludarabine is associated with the development of severe autoimmune hemolytic anemia in a proportion of patients.[2]

Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine.[3]


Fludarabine was produced by John Montgomery and Kathleen Hewson of the Southern Research Institute in 1968.[4] Their previous work involved 2-fluoroadenosine, which was unsafe for use in humans; the change to this arabinose analogue was inspired by the success of vidarabine.[4]

  • Fludarabine (9-β-D-arabinofuranosyl-2-fluoroadenine) (II) is a purine nucleoside antimetabolite resistant to adenosine deaminase, employed for the treatment of leukemia.

    Figure 00010002
  • Fludarabine is usually administered as a pro-drug, fludarabine phosphate, which is also the natural metabolite. Fludarabine was firstly synthesised by Montgomery (US 4,188,378 and US 4,210,745) starting from 2-aminoadenine. The method comprised acetylation of 2-aminoadenine, reaction with a benzyl-protected chlorosugar, deacetylation of the amino groups, diazotization and fluorination of the 2-amino group followed by deprotection of the sugar residue.
  • Fludarabine phosphate can be obtained according to conventional phosphorylation methods, typically by treatment with trimethylphosphate and phosphoryl chloride. Recently, a method for preparing highly pure fludarabine, fludarabine phosphate and salts thereof has been disclosed by Tilstam et al. (US 6,46,322).
  • Enzymatic synthesis has been regarded as a valid alternative to conventional methods for the synthesis of nucleosides and nucleotides derivatives. EP 0 867 516 discloses a method for the preparation of sugar nucleotides from sugar 1-phosphates and nucleosides monophosphates by use of yeast cells having nucleoside diphosphate-sugar pyrophosphorylase activity. EP 0721 511 B1 discloses the synthesis of vidarabine phosphate and fludarabine phosphate by reacting an arabinonucleotide with an arylphosphate in the presence of a microorganism able to catalyse the phosphorylation of nucleosides. This method is particularly convenient in that it does not require purified enzymes, but it does not allow to synthesise vidarabine and fludarabine.



Simple Modification To Obtain High Quality Fludarabine

API R & D Centre, Emcure Pharmaceuticals Ltd, I.TBT Park, Phase-II, M.IDC Hinjewadi, Pune-411057, India
Org. Process Res. Dev., 2012, 16 (5), pp 840–842
DOI: 10.1021/op3000509

Abstract Image

A simple and improved debenzylation process is described to obtain fludarabine in greater than 99.8% purity and 90–95% yield.



    • The present invention relates to a process for the preparation of fludarabine phosphate (I) illustrated in the scheme and comprising the following steps:
  • a) reaction of 2-fluoroadenine with 9-β-D-arabinofuranosyl-uracil in the presence of Enterobacter aerogenes to give crude fludarabine (II);
  • b) treatment of crude fludarabine with acetic anhydride to 2′,3′,5′-tri-O-acetyl-9-β-D-arabinofuranosyl-2-fluoroadenine (III);
  • c) hydrolysis and recrystallisation of intermediate (III) to give pure fludarabine;
  • d) phosphorylation of fludarabine to give fludarabine phosphate (I).
    Figure 00030001
  • Step a) is carried out in a 0.03 – 0.05 M KH2PO4 solution, heated to a temperature comprised between 50 and 70°C, preferably to 60°C, adjusted to pH 7 with KOH pellets and added with 2-fluoroadenine, Ara-U and EBA. The concentration of 2-fluoroadenine in the solution ranges from 0.02 to 0.03 M, while 9-β-D-arabinofuranosyl-uracil is used in a strong excess; preferably, the molar ratio between 9-β-D-arabinofuranosyl-uracil and 2-fluoroadenine ranges from 5:1 to 7:1, more preferably from 5.5:1 to 6.5:1. 2 – 2.5 1 of cell culture per 1 of KH2PO4 solution are used. The mixture is stirred at 60°C, adjusting the pH to 7 with a 25% KOH solution and the reaction is monitored by HPLC. Once the reaction is complete (about 24-26 hours), the cell material is separated by conventional dialysis and the permeated solutions are recovered and kept cool overnight. Crystallised fludarabine contains 10% 9-β-D-arabinofuranosyl adenine, which can be conveniently removed by means of steps b) and c).
  • In step b) crude fludarabine from step a) is dissolved in 9-11 volumes of acetic anhydride, preferably 10 volumes and reacted at 90 – 100°C under stirring, until completion of the reaction (about 10 – 12 h). Acetic anhydride is co-evaporated with acetone and the product is suspended in water.
  • The hydrolysis of step c) is carried out with methanol and ammonium hydroxide. Typically, compound (III) from step b) is suspended in 9-11 volumes of methanol and 2.5 – 3.5 volumes of 25% NH4OH and stirred at room temperature until complete hydrolysis (about 20 hours; the completion of the reaction can be promoted by mildly warming up the mixture to 30-32°C). Fludarabine precipitates by cooling the mixture to 10°C and is further hot-crystallised with water, preferably with 50 – 70 ml of water per gram of fludarabine or with a water/ethanol mixture (1/1 v/v) using 30 – 40 ml of mixture per gram of fludarabine. Fludarabine is recovered as the monohydrate and has a HPLC purity higher than 99%.
  • Even though the conversion of fludarabine into fludarabine phosphate (step d) can be carried out according to any conventional technique, for example as disclosed in US 4,357,324, we have found that an accurate control of the reaction and crystallisation temperature allows to minimise product decomposition and significantly improves the yield. According to a preferred embodiment of the invention, the reaction between phosphorus oxychloride, triethylphosphate and fludarabine is carried out at -10°C, and fludarabine phosphate is precipitated from water at 0°C.
  • In summary, the present invention allows to obtain the following advantages: fludarabine is prepared by enzymatic synthesis without the use of pure enzymes and is therefore particularly suitable for industrial scale; fludarabine is easily recovered and purified from 9-β-D-arabinofuranosyl adenine by acetylation without the need of chromatographic purification, since the triacetyl-derivative precipitates from water with high purity and yield; fludarabine phosphate can be obtained in high yield by controlling the reaction and crystallisation temperature in the phosphorylation step.
  • The following examples illustrate the invention in more detail.


Example 1 – Crude 9-β-D-arabinofuranosyl-2-fluoroadenine (II)

    • A solution of KH2PO4 (123 g, 0,9 moles) in water (13 l) was heated to 60°C under stirring and the pH adjusted to 7 with KOH pellets (130 g, 2.32 moles), then added with Ara-U (1451 g, 5.94 moles), 2-fluoroadenine (150 g, 0.98 moles) and EBA (ATCC® n° 13048) cell culture (30 l).
    • The mixture was stirred at 60°C for 24-26 hours, adjusting the pH to 7 with a 25% KOH solution and monitoring the reaction by HPLC.
    • After 24-26 hours the cell material was separated by dialysis at 50°-55°C, diluting the mixture with water. The permeated yellow clear solutions were collected, pooled (50 l) and left to stand at 0°-5°C overnight. The resulting crystalline precipitate was filtered and washed with cold water (2 l).
    • The product was dried at 45°C under vacuum for 16 hours to give 110 g of the crude compound (II) which was shown by HPLC to be a mixture of (I) (90%) and 9-β-D-arabinofuranosyl adenine (10%).

Example 2

Pure 9-β-D-arabinofuranosyl-2-fluoroadenine (II)

    • 9-β-D-arabinofuranosyl-2-fluoroadenine (II) (30 g, 0,095 moles) was suspended in acetic anhydride (300 ml) and heated to 95°C under stirring.
    • After 7 hours a clear solution was obtained and left to react at 95°C for further 2-3 hours until the acetylation was completed.
    • The resulting yellow solution was then concentrated under vacuum at 45°C and the residue was co-evaporated with acetone (2 x 50 ml) and suspended in water (600 ml). The water suspension was cooled to room temperature and left under stirring for 1 hour.
    • The product was collected by filtration and washed with water (2 x 100 ml) to give 34 g of wet 2′,3′,5′-tri-O-acetyl-9-β-D-arabinofuranosyl-2-fluoroadenine (III).
    • Wet compound (III) was suspended in methanol (300 ml) and added with 25% NH4OH (100 ml). The mixture was left to stand at room temperature overnight and after 19 hours was warmed to 30°-32°C for 3 hours, until no starting material was detected by HPLC.
    • The suspension was cooled to 10°C for 1 hour, then the product was collected by filtration and washed with a methanol-water mixture (2 x 25 ml, 3:1 v/v). The product was dried under vacuum at 45°C overnight to give 17.5 g of fludarabine (II) (98.4% HPLC purity).

Method A

    • Re-crystallisation of compound (II) (17.5 g, 0.061 moles) was also carried out by suspending the product in water (875 ml) and heating to 95°C until a clear solution was obtained. The solution was allowed to cool spontaneously to room temperature and the crystalline product was filtered, washed with cold water (2 x 50 ml) and dried under vacuum at 45°C overnight, to give 15.5 g of pure fludarabine (II) as the monohydrate (99.3% HPLC purity).
    • The monohydrate was further dried under vacuum at 90°C for 24 hours to give pure anhydrous fludarabine (II).

Method B

    • Fludarabine (II) (35 g, 0.123 moles) was also re-crystallized by suspending the product in a water/ethanol mixture (1/1, v/v) (1050 ml) and heating to 80°C until a clear solution was obtained. The solution was allowed to cool spontaneously to room temperature and the crystalline product was filtered, washed with a water/ethanol mixture (2 x 50 ml) and dried under vacuum at 45°C overnight, to give 32 g of pure fludarabine (II) as the monohydrate ( 99% HPLC purity ).
    • The monohydrate was further dried under vacuum at 90°C for 24 hours to give pure anhydrous fludarabine (II).

Example 3 – 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-phosphate (I)Method A

    • Phosphorous oxychloride (5 g, 3 ml, 0.033 moles) was added to cold (0°C, ice-bath) triethylphosphate (50 ml) and the solution was kept at 0°C for 1 hour, thereafter added with anhydrous fludarabine (II) (5 g, 0.018 moles) under stirring.
    • After about 3 hours, the reaction mixture became homogeneous and turned light-yellow and was kept at 0°C overnight. Once the phosphorylation was completed (about 23 hours) the mixture was added with water (10 ml) and the solution was stirred for 3 hours at 0°C. The mixture was then poured into cold (0°C) methylene chloride (400 ml) and kept at 0°C under stirring until a clear methylene chloride phase was obtained (at least 1 hours).
    • The methylene chloride phase was removed by decantation and the residual yellowish oil was dissolved in warm (50°C) water (30 ml). The solution was allowed to cool spontaneously to room temperature overnight and the resulting crystalline product was collected by filtration and washed with water (10 ml) and ethanol (2 x 10 ml).
    • The product was dried at room temperature under vacuum for 24 hours to give 4 g of compound (I).
    • Compound (I) was re-crystallised as follows: compound (I) (4 g) was dissolved in 60 ml of preheated deionized water (73°-75°C) and the solution was stirred and rapidly cooled to 50°C to minimize product decomposition. The solution was then allowed to cool spontaneously to room temperature: the precipitation started at 40°C. The resulting precipitate was collected by filtration and washed with water (10 ml) and ethanol (2 × 10 ml). The product was dried at room temperature under vacuum for 24 hours to give 2.5 g of compound (I).

Method B

  • Phosphorous oxychloride (5 g, 3 ml, 0.033 mol) was added to cold (-10°C) triethylphosphate (50 ml) and the solution was kept at -10°C for 1 hour, thereafter anhydrous fludarabine (II) (5 g, 0,018 mol) was added with stirring at -10°C.
  • After about 6 hours the reaction mixture turned light-yellow and became homogeneous. The mixture was kept at -10°C overnight and after 23 hours the phosphorylation was completed. After addition of 40 ml of cold water (2°C) the solution was stirred for 1 hour at 0°C and extracted with cold (0°C) methylene chloride (100 ml and two 50-ml portions).
  • The aqueous solution was kept under vacuum at room temperature for 1 hour and allowed to stand at 0°C for 24 hours. The resulting crystalline product (I) was collected by filtration and washed with ethanol (2 x 20 ml).
  • The product was dried at 40°C under vacuum for 24 hours (Yield: 5 g).
  • A final crystallization was carried out as follows. Compound (I) (5 g) was dissolved in 75 ml of preheated deionized water (73°-75°C) and the solution was stirred and rapidly cooled to 50°C to minimize decomposition. The solution was then allowed to cool spontaneously to room temperature (the precipitation started at 40°C). The resulting precipitate was collected by filtration and washed with water (10 ml ) and ethanol (2 x 10 ml). The product was dried at 40°C under vacuum for 24 hours (Yield: 4 g).



  1.  Rai KR et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-7. doi:10.1056/NEJM200012143432402 PMID 11114313
  2.  Gonzalez H et al. Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther. 1998;40:113-8. PMID 9698219
  3.  Tournilhac O et al. Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia. Blood 2004;103:363-5. PMID 12969985
  4.  Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 258. ISBN 0-471-89979-8.

Literature References:

Adenosine deaminase-resistant purine nucleoside antimetabolite. Prepn and in vitro cytotoxicity: J. A. Montgomery, K. Hewson, J. Med. Chem. 12, 498 (1969). Improved prepn: J. A. Montgomery et al., J. Heterocycl. Chem. 16, 157 (1979); J. A. Montgomery, US 4210745 (1980 to U.S. Dept. Health, Education and Welfare).

Inhibition of DNA synthesis and in vivo antileukemic activity: R. W. Brockman et al., Biochem. Pharmacol. 26, 2193 (1977). Metabolized to 5¢-monophosphate: R. W. Brockman et al., Cancer Res. 40, 3610 (1980).

HPLC determn in human leukemia cells: V. Gandhi et al., J. Chromatogr. 413,293 (1987). Prepn of 5¢-monophosphate: J. A. Montgomery, A. T. Shortnacy, US 4357324 (1982 to U.S. Dept. of Health and Human Services).

Pharmacokinetics in humans: M. R. Hersh et al., Cancer Chemother. Pharmacol. 17, 277 (1986).

Evaluation of therapeutic efficacy and CNS toxicity in acute refractory leukemia: R. P. Warrell, Jr., E. Berman, J. Clin. Oncol. 4, 74 (1986); H. G. Chun et al., Cancer Treat. Rep. 70, 1225 (1986). Series of articles on pharmacology and therapeutic use: Semin. Oncol. 17,Suppl. 8, 1-78 (1990).

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Location of Khajuraho Group of Monuments in India.

Location in Madhya PradeshLocation in Madhya Pradesh

  1. Khajuraho Group of Monuments – Wikipedia, the free …

    The Khajuraho Group of Monuments are a group of Hindu and Jain temples in Madhya Pradesh, India. About 620 kilometres (385 mi) southeast of New Delhi, …

Hotel Chandela – A Taj Leisure Hotel





CAS No:- [152459-95-5]

IUPAC Name:- 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide

M. P.:- 211-213 °C

MW: 493.604





Imatinib (INN), marketed by Novartis as Gleevec (Canada, South Africa and the USA) or Glivec (Australia, Europe and Latin America), and sometimes referred to by its investigational name STI-571, is a tyrosine-kinase inhibitor used in the treatment of multiple cancers, most notably Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML).[1]

Like all tyrosine-kinase inhibitors, imatinib works by preventing a tyrosine kinase enzyme, in this case BCR-Abl, fromphosphorylating subsequent proteins and initiating the signalling cascade necessary for cancer growth and survival, thus preventing the growth of cancer cells and leading to their death by apoptosis.[2] Because the BCR-Abl tyrosine kinase enzyme exists only in cancer cells and not in healthy cells, imatinib works as a form of targeted therapy—only cancer cells are killed through the drug’s action.[3] In this regard, imatinib was one of the first cancer therapies to show the potential for such targeted action, and is often cited as a paradigm for research in cancer therapeutics.[4]

Imatinib has been cited as the first of the exceptionally expensive cancer drugs, costing $92,000 a year. Doctors and patients complain that this is excessive, given that its development costs have been recovered many times over, and that the costs of synthesizing the drug are orders of magnitude lower. In the USA, the patent protecting the active principle will expire on 4 January 2015 while the patent protecting the beta crystal form of the active principal ingredient will expire on 23 May 2019.[5]

The developers of imatinib were awarded the Lasker Award in 2009 and the Japan Prize in 2012.[6][7]

bcr-abl kinase (green), which causes CML, inhibited by imatinib (red; small molecule).

Medical uses

Imatinib is used to treat chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of othermalignancies.

Chronic myelogenous leukemia

The U.S. Food and Drug Administration (FDA) has approved imatinib as first-line treatment for Philadelphia chromosome-positive CML, both in adults and children. The drug is approved in multiple Philadelphia chromosome-positive cases of CML, including after stem cell transplant, in blast crisis, and newly diagnosed.[8]

Gastrointestinal stromal tumors

The FDA first granted approval for advanced GIST patients in 2002. On 1 February 2012, imatinib was approved for use after the surgical removal of KIT-positive tumors to help prevent recurrence.[9] The drug is also approved in unresectable KIT-positive GISTs.[8]


The FDA has approved imatinib for use in adult patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), myelodysplastic/ myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements, aggressive systemic mastocytosis without or an unknown D816V c-KIT mutation, hypereosinophilic syndrome and/or chronic eosinophilic leukemia who have the FIP1L1-PDGFRα fusion kinase (CHIC2 allele deletion) or FIP1L1-PDGFRα fusion kinase negative or unknown, unresectable, recurrent and/or metastaticdermatofibrosarcoma protuberans.[8] On 25 January 2013, Gleevec was approved for use in children with Ph+ ALL.[10]

For treatment of progressive plexiform neurofibromas associated with neurofibromatosis type I, early research has shown potential for using the c-KIT tyrosine kinase blocking properties of imatinib.[11][12][13][14]

Legal challenge to generics

In 2007, imatinib became a test case through which Novartis challenged India’s patent laws. A win for Novartis would make it harder for Indian companies to produce generic versions of drugs still manufactured under patent elsewhere in the world. Doctors Without Borders argues a change in law would make it impossible for Indian companies to produce cheap generic antiretrovirals (anti-HIV medication), thus making it impossible for Third World countries to buy these essential medicines.[43] On 6 August 2007, the Madras High Court dismissed the writ petition filed by Novartis challenging the constitutionality of Section 3(d) of Indian Patent Act, and deferred to the World Trade Organization (WTO) forum to resolve the TRIPS compliance question. As of 2009 India has refused to grant patent exclusivity..

On April 01, 2013 Supreme Court of India dismissed the plea of Novartis for the grant of patent.

in germany

Mechanism of action

Mechanism of action of imatinib
Drug mechanism

Crystallographic structure of tyrosine-protein kinase ABL (rainbow colored, N-terminus = blue, C-terminus = red) complexed with imatinib (spheres, carbon = white, oxygen = red, nitrogen = blue).[31]
Therapeutic use chronic myelogenous leukemia
Biological target ABL, c-kit, PDGF-R
Mechanism of action Tyrosine-kinase inhibitor
External links
ATC code L01XE01
PDB ligand id STI: PDBe, RCSB PDB

Imatinib is a 2-phenyl amino pyrimidine derivative that functions as a specific inhibitor of a number of tyrosine kinase enzymes. It occupies the TK active site, leading to a decrease in activity.

There are a large number of TK enzymes in the body, including the insulin receptor. Imatinib is specific for the TK domain inabl(the Abelson proto-oncogene), c-kit and PDGF-R (platelet-derived growth factorreceptor).

In chronic myelogenous leukemia, the Philadelphia chromosome leads to a fusion protein of abl with bcr(breakpoint cluster region), termed bcr-abl. As this is now aconstitutively active tyrosine kinase, imatinib is used to decrease bcr-abl activity.

The active sites of tyrosine kinases each have a binding site for ATP. The enzymatic activity catalyzed by a tyrosine kinase is the transfer of the terminal phosphate from ATP to tyrosine residues on its substrates, a process known as protein tyrosinephosphorylation. Imatinib works by binding close to the ATP binding site of bcr-abl, locking it in a closed or self-inhibited conformation, and therefore inhibiting the enzyme activity of the protein semi-competitively.[32] This fact explains why many BCR-ABL mutations can cause resistance to imatinib by shifting its equilibrium toward the open or active conformation.[33]

Imatinib is quite selective for bcr-abl – it does also inhibit other targets mentioned above (c-kit and PDGF-R), but no other knowntyrosine kinases. Imatinib also inhibits the abl protein of non-cancer cells but cells normally have additional redundant tyrosine kinases which allow them to continue to function even if abl tyrosine kinase is inhibited. Some tumor cells, however, have a dependence on bcr-abl.[34] Inhibition of the bcr-abl tyrosine kinase also stimulates its entry in to the nucleus, where it is unable to perform any of its normal anti-apoptopic functions.[35]

The Bcr-Abl pathway has many downstream pathways including the Ras/MapK pathway, which leads to increased proliferation due to increased growth factor-independent cell growth. It also affects the Src/Pax/Fak/Rac pathway. This affects the cytoskeleton, which leads to increased cell motility and decreased adhesion. The PI/PI3K/AKT/BCL-2 pathway is also affected. BCL-2 is responsible for keeping the mitochondria stable; this suppresses cell death by apoptosis and increases survival. The last pathway that Bcr-Abl affects is the JAK/STAT pathway, which is responsible for proliferation.[36]



Imatinib is known as an inhibitor of protein-tyrosine kinase and is indicated for the treatment of chronic myeloid leukemia (CML). Imatinib also has potential for the treatment of various other cancers that express these kinase including acute lymphocyte leukemia and certain solid tumors. It can also be used for the treatment of atherosclerosis, thrombosis, restenosis, or fibrosis. Thus, imatinib can also be used for the treatment of non-malignant diseases. Imatinib is usually administered orally in the form of a suitable salt, e.g., in the form of imatinib mesylate.

The chemical name of Imatinib is 4-(4-methyl piperazine -1- methyl) -N-4-methyl-3-[4- (3- pyridyl) pyrimidine-2-amino] – benzamide and is represented by the following structural formula:

Figure imgf000003_0001


Imatinib Mesylate is an inhibitor of signal transduction (STI571) invented by Novartis AG after 7 years of hard work; it is the first inhibitor of cancer signal transduction ratified in the whole world. It is sold by Novartis as Gleevec capsules containing imatinib mesylate in amounts equivalent to 100 mg or 400 mg of imatinib free base.

Imatinib Mesylate is the rare drug in America, European Union and Japan. In May 10, 2001, it was ratified by American Food and Drug Administration (FDA) to treat the chronic myelogenous leukemia patients. EP0564409 (US5521 184) describes the process for the preparation of imatinib and the use thereof, especially as an anti tumour agent.

There are generally two synthetic routes for synthesis of Imatinib, suitable for the industrial production. One synthetic process as described in scheme-I comprises using 2-methyl-5-nitroaniline as the raw material which is reacted with cyanamide to obtain guanidine; cyclization reaction with 3-dimethylamino-l-(3-pyridyl)-2-propylene-l- ketone; reduction step of nitro to amine and condensation reaction with 4- (Chloromethyl)benzoyl chloride and N-methylpiperazidine to obtain Imatinib (WO 2004/108669). -I

Figure imgf000004_0001

Scheme-2 describes the successful process for the synthesis of Imatinib using 4-methyl-3- nitroanilines as the raw material, comprising reacting 4-methyl-3-nitroanilines with 4- (Chloromethyl)benzoyl chloride and N-methyl piperazidine in turns; followed by reduction of nitro group to amino group; then reaction with cyanamide to obtain guanidine; finally cyclization reaction with 3- dimethyl amino- 1 -(3- pyridyl)-2- propylene-1 -ketone to obtain Imatinib (WO 03/066613). The said PCT application discloses the use of 4-4-(methyl piperazin-l-ylmethyl)-benzoic acid methyl ester as one of the raw material but rest of the reactants are different from that of N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine in presence of trimethyl aluminium.


Figure imgf000005_0001

Common feature of the processes for preparing imatinib according to (WO 2004/108669) and (WO03/066613) lies in use of cyanamide as a reagent. The main difference between the two routes is that the reaction sequence of cyclization of pyrimidine chain is different. Example 10 of PCT International Publication no. WO 2003/066613 is less applicable to industrial purposes. These include the reaction between N-(3-bromo-4-methyl-phenyl)-4- (4-methyl-piperazin-l -ylmethyl)-benzamide and 4-(3-pyridyl)-2-pyrimidineamine which uses a mixture of rac-BINAP (a phosphine oxide catalyst) and Pd2 (dba)3*CHCl3. These catalysts are very expensive, therefore, their use is unfit for commercial production.

CN1630648A describes a process comprising reaction of 3- bromine-4- methyl aniline with 4-(4-methyl-piperazin- methyl) methyl benzoate in presence of trimethyl-Aluminum to obtain N-(4-methyl-3-bromobenzene)-4-(4-methyl-piperazin- 1 -methyl)-benzamide, which further reacts with 2-amino-4-(3-pyridyl)- pyrimidine in presence of palladium as catalyst to obtain Imatinib.

Figure imgf000006_0001
Figure imgf000006_0002

The drawback of the above process is the use of trimethyl-Aluminum, which is flammable and reacts severely when comes in contact with water.

CN101016293A describes another process using N-(4-methyl-3-3- aminophenyl)-4-(4- methyl-piperazin-1 -methyl)- benzamide as the raw material. The said raw material is reacted with 2-halogen-4-(3-pyridyl)- pyrimidine to obtain Imatinib.

Figure imgf000006_0003

The process disclosed in CN 101016293 A comprises use of halogenated agent, such as phosphorus oxychloride, which is used to synthesize 2-halogeno-4- methyl- (3-pyridyl) – pyridine is lachrymator and corrosive and has great influence to the surroundings. EP0564409 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4-(3- pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in the presence of high quantity of pyridine to starting reactant amine N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine. The ratio of the pyridine to the said reactant is 138 which is equivalent to about 40 parts v/w. Use of such a large quantity of pyridine is unsafe as it is a toxic solvent according to ICH guidelines. The workup of the reaction comprises evaporation of the remaining pyridine and further processing, which finally involves chromatography for purification, which is highly undesirable on industrial scale because it is expensive and time consuming.

Figure imgf000007_0001

US2006/0149061 and US20060223817 also discloses a similar synthetic approach comprising the use of similar pyridine /starting amine ratio (140 equivalents which is equals about 41 parts v/w). The product obtained is purified by slurring in ethyl acetate.

WO2004/074502 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride wherein solvent like dimethyl pharmamide , dimethyl acetamide, N-methyl pyrilidinone are used as solvents instead of pyridine. However the method described in this patent application lacks an advantage in that the coupling reaction produces the hydrohalide salt of imatinib, e.g. imatinib trihydrochloride monohydrate, which has to be treated with a base in order to afford the imatinib base, thus an extra step is required. Further, conventional methods for coupling N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2- pyrimidine amine require reaction with an acid halide, e.g. 4-(4-methyl piperazin-1- ylmethyl)-benzoyl chloride, which requires an additional production step that can involve harsh and/or toxic chlorinating agent.

Figure imgf000008_0001

WO2008/1 17298 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of a base selected from potassium carbonate, sodium carbonate, potassium or sodium hydroxide. Use of potassium carbonate as base results into the formation of Imatinib dihydrochloride which ultimately requires an additional operation of neutralization by using excessive base to get imatinib.

Figure imgf000008_0002

WO2008/136010 describes a coupling reaction between N-(5-amino -2-methylphenyl)-4- (3-pyridyl)-2-pyrimidine amine and 4-(4-methyl piperazin-l-ylmethyl)-benzoyl chloride in presence of base potassium hydroxide resulting into 78.6% yield of crude imatinib base. Preparation of crude requires imatinib hydrochloride preparation during the workup which is then basified to get base in crude form. This also describes maleate salt preparation as mode of purification which is again basified to give pure Imatinib base.

Figure imgf000009_0001

US patent application 2004/0248918 discloses a different approach using N-(5-amino -2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4-(2-chloromethyl)-benzoyl chloride as raw material. The reaction for the preparation of Imatinib is carried out in tetrahydrofuran as a reaction solvent and in the presence of pyridine as a base. However the method described in this patent application lacks an advantage as purification of the product requires column chromatography using chloroform: methanol (3: 1 v/v), which is not suitable purification method when performing the reaction on large scale, followed by crystallizati

Figure imgf000009_0002

US patent application 2008/0103305 discloses a process comprising reacting N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine or its alkyl derivative and an acid salt of 4-[(4-methyl-l-piperazinyl)-methyl] benzoyl derivative as given below in the scheme-3 using pyridine in an amount of about 2 to 10 volumes per gram of the said amine. However the drawback associated with this process is use of pyridine especially when reaction is performed on large scale. -3

Figure imgf000010_0001



Anticancer drug imatinib mesylate (Imatinib <wbr> Mesylate)

Inverse synthetic analysis will be divided into four imatinib into fragment A has 1,3 – parents electrical, fragment B are 1,3 – parent nuclear, fragments A and B constitute a pyrimidine ring.

Anticancer drug imatinib mesylate (Imatinib <wbr> Mesylate)

Compound 4 can be obtained in two ways, benzyl bromide 1 and secondary amines 2 by SN2 reaction, or the aldehyde 3 with a secondary amine 2 by reductive amination. Sodium cyanoborohydride electron withdrawing effect of the cyano group, thereby reducing the activity of the negative hydrogen, it may be present in acidic solution. Also in the acidic conditions of aldehydes and secondary amines imine positive ions, which is higher than the activity of aldehyde reduction.This is why the reductive amination reagent with inert negative and hydrogen under acidic conditions. 4 hydrolyzed ester with thionyl chloride into the acid chloride 5 . The reaction of aniline and cyanamide dinucleophile guanidine 7 . Compound 8 and DMF-DMA reaction electrophilic reagent parents 9 , 7 , and 9 ring closure under alkaline conditions to generate 10 . Finally, reduction, amidation, and a salt of imatinib mesylate generated.


Org. Process Res. Dev., 2012, 16 (11), pp 1794–1804
DOI: 10.1021/op300212u
Abstract Image

An efficient, economic process has been developed for the production of imatinib with 99.99% purity and 50% overall yield from four steps. Formation and control of all possible impurities is described. The synthesis comprises the condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine with 4-(4-methylpiperazinomethyl)benzoyl chloride in isopropyl alcohol solvent in the presence of potassium carbonate to yield imatinib base.


Org. Biomol. Chem., 2013,11, 1766-1800

DOI: 10.1039/C2OB27003J!divAbstract

Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API’s).

Graphical abstract: The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib


Organic Process Research & Development, 12(3), 490-495. DOI: 10.1021/op700270nAs an example of research aimed at industrial production one involving imatinib. This cancer drug was one of the first offspring of rational drug design and if you believe the Wikipedia page hugely expensive despite its simple appearance (no stereocenters!). A group of Northwest University researchers set out to improve the existing Novartis procedure DOI and here is how they did it.

2-acetylpyridine (1) was alkylated with the acetal of N,N-dimethylformamide 2 to enamine 3. A pyrimidine ring in 5was formed with base and reagent guanidine nitrate 4 and nitrotoluene fragment 6 was added in a Ullmann-type reaction with CuI generating secondary amine 7. The nitro group was reduced by hydrazine / FeCl3/C to the amine which was then converted to amide 8 with acid chloride 9. The final step is addition of piperazine 10 to form imatinib11.So is this procedure an improvement on the existing method and ready-made for industrial implementation? Surely they have eradicated the use of toxic cyanamide, cumbersome sodium metal and expensive palladium but they have also introduced equally toxic hydrazine and the harmful and explosive guanidine nitrate. As a further point of criticism the final step is demonstrated on a 0.5 gram scale. If the journal Organic Process Research & Development would live up to its standards the scale would at least be a kilogram.Liu, Y., Wang, C., Bai, Y., Han, N., Jiao, J., Qi, X. (2008). A Facile Total Synthesis of Imatinib Base and Its Analogues. Organic Process Research & Development, 12(3), 490-495. DOI: 10.1021/op700270n

Tetrahedron Lett. 2007, 48, 3455. DOI: 10.1016/j.tetlet.2007.03.033

Angelo Carotti and his group from University of Bari have developed a solid-phase synthesis of Imatinib which acts as a selective tyrosine kinase inhibitor (Tetrahedron Lett. 2007, 48, 3455. DOI: 10.1016/j.tetlet.2007.03.033). By applying microwave heating in five steps of the synthesis (preparation of linker 1, nucleophilic substitution, reduction of the nitro group, formation of guanidine and final cyclization) the total process could be accelerated. Key steps were the guanylation of aniline 2 where a higher yield and purity of product 3 could be obtained under microwave irradiation, and the final cyclization to resin bound Imatinib where the reaction time could be reduced from 20 h to 50 min. Addiotionally, resin stability was ensured due to the shorter reaction time.



process for the preparation of imatinib, which comprises the reaction of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)- benzene-l,3-diamine (II) also referred as N-(5-amino -2-methylphenyl)-4-(3-pyridyl)-2- pyrimidine amine with 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (III) in the presence of a base in a suitable solvent to yield substantially pure imatinib base in about 90% yield.

Figure imgf000012_0001

R is C1-C4 alkyl group The preparation of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (II) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid ester (III) may be carried out according to prior art methods.

Compound of formula (II) can be synthesized by the process disclosed in WO2004/ 108669 comprising

Figure imgf000012_0002

reacting 2-methyl-5-nitroaniline with 50% aqueous solution of cyanamide to obtain N-(2- Methyl-5-nitrophenyl)-guanidinium nitrate, which further reacted with 3-dimethylamino- l-pyridin-3-yI-propenone to yield (2-methyI-5-nitrophenyl)-(4-pyridin-3-yI-pyrimidin -2- yl)-amine, finally, reduction of nitro group to obtain compound of formula (Π).

Componds of formula (III) can be synthesized by the process disclosed in synthtic communications 2003, 3597

Figure imgf000013_0001

comprising reacting a-halogen-/?-toluinitrile or methanesulfonic acid 4-cyano-benzyl ester or toluene-4-sulfonic acid 4-cyano-benzyl ester with N-methylpiperazine, followed by hydrolysis of the cyano to acid which formed as dihydrochloride contain half crystalline hydrate, finally reaction with alcohol to obtain compound of formula (III).

The synthetic route for preparing imatinib according to the present invention is is given below

Figure imgf000013_0002


Example 1

To a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (27.7g) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (50g) in Tetrahydrofuran (250ml), a solution of sodium methylate (lOg) in methanol (10ml) was added. The reaction mixture was heated to reflux. After completion of the reaction solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (45g). Yield: 91%.

The spectral data is as follows:

Ή NMR ( 500M , DMSO ) δ : 10.2 (s, lH), 9.30 (s, 1H), 8.99 (s, 1H), 8.72 (d, J=4.0

Hz, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.58-7.51 (m, 4H), 7.44 (d, J=4.3 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 3.70 (s, 2H), 3.50-3.25 (m, 2H),

3.20-2.90 (m, 4H), 2.81 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H). 13C NMR (125M ,

DMSO ) δ : 164.9, 161.3, 161.1, 159.4, 150.8, 147.7, 137.7, 137.1, 134.9, 134.3, 132.3, 129.9, 129.1, 127.7, 127.6, 123.9, 117.2, 1 16.8, 107.5, 59.9, 52.1, 48.9, 42.2, 17.5.

MS (M++l): 494.3

Example 2

To a solution of 4-Methyl-N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (27.7g) and 4-(4-Methyl-piperazin-l-ylmethyl)-benzoic acid methyl ester (50g) in toluene (250ml), a solution of sodium ethoxide (20g) in methanol (10ml) was added. The reaction mixture was heated to reflux. After completion of the reaction, solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (44g). Yield: 91%.

Example 3

To a solution of potassium butoxide (250g) in methanol (1000ml), a solution of 4-Methyl- N-(4-pyridin-3-yl-pyrimidin-2-yl)-benzene-l,3-diamine (277g) and 4-(4-Methyl- piperazin-l-ylmethyl)-benzoic acid propyl ester (600g) in Tetrahydrofuran (2500ml) was added. The reaction mixture was stirred at room temperature. After completion of the reaction solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water and dried to obtain Imatinib base (450g). Yield: 91%. Example 4

To a solution of potassium butoxide (25kg) in ethanol (lOOLitre), a solution of 4-Methyl- N-(4-pyridin-3-yI-pyrimidin-2-yl)-benzene-l,3-diamine (27.7kg) and 4-(4-MethyI- piperazin-l-ylmethyl)-benzoic acid ethyl ester (50.0kg) in toluene (250Litre) was added. The reaction mixture was stirred at room temperature. After completion of reaction, solution was poured into ice-water and a large amount of solid precipitated, which was filtered and washed with water, and dried to obtain Imatinib base (40.0kg). Yield: 81%.




Synthesis of SKI696. (A) isopropanol/sodium hydroxide (a); iron/acetic acid/EtOH/water (b); triethyl amine/acetonitrile (c); 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/N,N-dimethylaminopyridine/dimethylformamide (d); trifluoroacetic acid/dichloromethane (e); potassium carbonate/acetonitrile (f). (B) 18F-KF/Kryptofix/1,2-dichlorobenzene (g); dimethylformamide/acetonitrile (h).


In order to prepare the core heterocyclic unit a direct condensation between a 1,3-dicarbonyl compound 3.39 and an amidine or guanidine 3.40 is frequently employed (Scheme 36a). Alternatively, an amidine can be condensed with a vinylogous amide 3.41 resulting in the direct formation of 2,4-disubstituted pyrimidines. These condensations often require relatively harsh reaction conditions despite this they are of great value as they involve cheap or easily accessible materials and typically only form water as the principle byproduct.

A modification of the above pyrimidine synthesis has been applied in the generation of imatinib (3.36, Gleevec) which is Novartis’ tyrosine kinase inhibitor used for the treatment of chronic myeloic leukaemia. In a patented route the aldol product 3.47 undergoes a condensation reaction with guanidine 3.48 in basic media to give the 2-aminopyrimidine 3.49 (Scheme 37) [93]. After generating the functional pyrimidine core a hydrazine-mediated reduction of the nitro group in the side chain was conducted with Raney-Nickel as the catalyst. Amide formation with 4-chloromethylbenzoyl chloride (3.50) and a direct displacement of the benzylic chloride with N-methylpiperazine (1.118) complete this synthesis of imatinib in excellent overall yields.

Scheme 37: Synthesis of imatinib.

One noteworthy feature of this imatinib synthesis is that it is specifically designed for facile isolation of intermediates by precipitation due to their limited solubility in non-polar solvents [94]. Whilst this process was efficient in enabling the isolation of pure material after each step, it does not encourage telescoping of steps, which would in principal increase the overall efficiency of the process. Recently, similar approaches have been utilised in the academic environment using enabling techniques in a route to imatinib. For instance, our group has employed continuous flow synthesis methods to imatinib [95,96]. The route not only afforded imatinib but led to many previously inaccessible derivatives in an automated fashion within a single working day (Scheme 38). In addition, this particular sequence showcases the uses of scavenger resins for in-line purification as the synthesis progresses and features the use of a Buchwald–Hartwig amination in a late stage fragment coupling. While it was sufficient to access only small amounts of these structures (around 50 mg), these techniques are currently being adopted by several major pharmaceutical companies in order to enhance drug development and even manufacturing sequences.

Scheme 38: Flow synthesis of imatinib.
pick up ref from


Imatinib is a tyrosine-kinase inhibitor used for the treatment of cancer.  A key steps in its synthesis is the enamine formation highlighted in green below.

1) Show a mechanism for this transformation?

2) This particular enamine is rather stable.  Comment on it relatively high stability?  (i.e. What make it so stable?)

Imatinib Synthesis


Org. Biomol. Chem., 2009,7, 5129-5136

DOI: 10.1039/B913333J!divAbstract

Protein kinases catalyze the phosphorylation of serine, threonine, tyrosine and histidine residues in proteins. Aberrant regulation of kinase activity has been implicated in many diseases including cancer. Thus development of new strategies for kinase inhibitor design remains an active area of research with direct relevance to drug development. Abelson (Abl)tyrosine kinase is one of the Src-family of tyrosine kinases and is directly implicated in Chronic Myelogenous Leukemia (CML). In this article, we have, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry. Subsequent biochemical screenings revealed a set of moderately potentinhibitors, a few of which have comparable potency to Imatinib (an FDA-approved drug for treatment of chronic myeloid leukemia) against Abl.

Graphical abstract: Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry


Medicine for Blood Cancer

‘Imitinef Mercilet’ is a medicine which cures blood cancer.
Its available free of cost at “Adyar Cancer Institute in Chennai”.
Create Awareness. It might help someone.Cancer Institute in Adyar, Chennai

‘Imitinef Mercilet’ is apparently an alternative spelling of the drug Imatinib mesylate which is used in the treatment of some forms of leukemia along with other types of cancer. Imatinib, often referred to a “Gleevec”, has proved to be an effective treatment for some forms of cancers. However, “blood cancer” is a generalized term for cancers that affect the blood, lymphatic system or bone marrow. The three types of blood cancer are listed as leukemia, lymphoma, and multiple myeloma. These three malignancies require quite different kinds of treatments. While drugs (including Imatinib), along with other treatments such as radiation can help to slow or even stop the progress of these cancers, there is currently no single drug treatment that can be said to actually cure all such cancers.

Category: Cancer
Address: East Canal Bank Road , Gandhi Nagar
Adyar, Chennai -600020
Landmark: Near Michael School
Phone: 044-24910754 044-24910754 ,
044-24911526 044-24911526 , 044-22350241

Imatinib is a small molecule selectively inhibiting specific tyrosine kinases that has emerged recently as a valuable treatment for patients with advanced GIST. The use of imatinib as monotherapy for the treatment of GIST has been described in PCT publication WO 02/34727, which is here incorporated by reference. However, it has been reported that primary resistance to imatinib is present in a population of patients, for example 13.7% of patients in one study. In addition, a number of patients acquire resistance to treatment with imatinib. More generally this resistance is partial with progression in some lesions, but continuing disease control in other lesions. Hence, these patients remain on imatinib treatment but with a clear need for additional or alternative therapy.

Imatinib is 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide having the formula I

The preparation of imatinib and the use thereof, especially as an anti-tumour agent, are described in Example 21 of European patent application EP-A-0 564 409, which was published on 6 Oct. 1993, and in equivalent applications and patents in numerous other countries, e.g. in U.S. Pat. No. 5,521,184 and in Japanese patent 2706682

flow synthesis

The flow-based route required minimal manual intervention and was achieved despite poor solubility of many reaction components

21 January 2013Michael Parkin

UK chemists have used a combination of flow chemistry methods with solid-supported scavengers and reagents to synthesise the active pharmaceutical ingredient, imatinib, of the anticancer drug Gleevec. The method avoids the need for any manual handling of intermediates and allows the drug to be synthesised in high purity in less than a day.

Gleevec, developed by Novartis, is a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia and gastrointestinal stromal tumours.




‘Wrapping’ Gleevec Fights Drug-Resistant Cancer, Study Shows

The anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area. This image shows the bandage (black box) on the modified version of the drug, WBZ-7. (Credit: Image courtesy of Rice University)

A new study in Cancer Research finds that the anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when the drug wraps the target with a molecular bandage that seals out water from a critical area.

FIG 23.8 Optimization of imatinib as a chemotherapeutic agent. The discovery that 2-phenylaminopyrimidine inhibitors of PKC also inhibit the unrelated v-Abl oncogene turned attention to its potential use in the treatment of chronic myelogenous leukaemia. Starting with the 2-phenylaminopyrimidine backbone, addition of the benzamidine group increased activity against tyrosine kinases, the methyl group reduced its activity against PKC (so-called ‘ target hopping ’ ). Addition of a 3’-pyridyl group improved the activity in cellular assays. Subsequent addition of N -methylpiperazine increased water solubility and oral bioavailability, enabling the drug to survive the stomach and to enter the bloodstream.


An automated flow-based synthesis of imatinib: the API of gleevec M.D. Hopkin, I.R. Baxendale, S.V. Ley, J.C.S. Chem. Commun.2010, 46, 2450-2452.


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External links


Title: Imatinib
CAS Registry Number: 152459-95-5
CAS Name: 4-[(4-Methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide
Additional Names: N-[5-[4-(4-methylpiperazinomethyl)benzoylamido]-2-methylphenyl]-4-(3-pyridyl)-2-pyrimidineamine
Molecular Formula: C29H31N7O
Molecular Weight: 493.60
Percent Composition: C 70.57%, H 6.33%, N 19.86%, O 3.24%
Literature References: Tyrosine kinase inhibitor; highly specific for BCR-ABL, the enzyme associated with chronic myelogenous leukemia (CML) and certain forms of acute lymphoblastic leukemia (ALL). Also shown to inhibit the transmembrane receptor KIT and platelet-derived growth factor (PDGF) receptors. Prepn: J. Zimmermann, EP 564409; idem, US 5521184 (1993, 1996 both to Ciba-Geigy); idem et al., Bioorg. Med. Chem. Lett. 7, 187 (1997). Structural mechanism of ABL specificity: T. Schindler et al., Science 289, 1938 (2000). Activity vs KIT and PDGF receptor kinases: E. Buchdunger et al., J. Pharmacol. Exp. Ther. 295, 139 (2000). Clinical trial in CML: H. Kantarjian et al., N. Engl. J. Med. 346, 645 (2002); in gastrointestinal stromal tumors related to KIT: G. D. Demetri et al., ibid. 347, 472 (2002). Review of clinical experience: D. G. Savage, K. H. Antman, ibid. 346, 683-693 (2002); and pharmacology: V. K. Pindolia et al., Pharmacotherapy 22, 1249-1265 (2002); and development of therapeutic target: B. J. Druker, Adv. Cancer Res. 91, 1-30 (2004).
Properties: mp 211-213°. pKa1 8.07; pKa2 3.73; pKa3 2.56; pKa4 1.52.
Melting point: mp 211-213°
pKa: pKa1 8.07; pKa2 3.73; pKa3 2.56; pKa4 1.52
Derivative Type: Methanesulfonate
CAS Registry Number: 220127-57-1
Manufacturers’ Codes: STI-571; CGP-57148B
Trademarks: Gleevec (Novartis); Glivec (Novartis)
Molecular Formula: C29H31N7O.CH3SO3H
Molecular Weight: 589.71
Percent Composition: C 61.10%, H 5.98%, N 16.63%, O 10.85%, S 5.44%
Literature References: Prepn of crystalline form: J. Zimmermann et al., WO 9903854 (1999 to Novartis).
Properties: Occurs in 2 crystalline modifications. a-form, begins to melt at 226°; b-form, mp 217°. Lipophilic at pH 7.4. Soly in water: >100 g/l (pH 4.2); 49 mg/l (pH 7.4).
Melting point: mp 217°
Therap-Cat: Antineoplastic.
Keywords: Antineoplastic, Tyrosine Kinase Inhibitors,  imatinib mesylate, GGP-57148B, STI-571, CGP-57148 (free base), Gleevec, Glivec, imatinib
Mp 206 – 207 °C (lit.:1   207 – 210 °C);
1=  1 Y.‐F. Liu, C.‐L. Wang, Y.‐J. Bai, N. Han, J.‐P. Jiao and X.‐L. Qi, Org. Process Res. Dev., 2008, 12, 490.
IR νmax/cm-1 3275.0(w), 2928.5(w),
2796.5(w), 1645.9(m), 1586.0(m), 1575.1(s), 1554.0(m), 1531.5(s), 1510.3(m), 1478.1(m),
1448.9(s), 1416.7(m), 1377.7(m), 1352.2(m), 1334.8(m), 1325.6(m), 1308.8(m), 1290.3(s),
1261.1(m), 1204.3(m), 1164.1(m), 1141.7(m), 1124.6(w), 1102.6(m), 1089.2(w), 1052.0(w),
1024.4(w), 1010.0(m), 992.5(w), 968.3(w), 924.5(w), 886.2(w), 857.9(w), 850.3(w),
807.8(m), 795.7(s), 748.1(m), 703.2(m), 690.1(m), 670.7(m);
δH (d6-DMSO, 600 MHz) =
10.14 (1 H, s, NH), 9.26 (1 H, d, J = 1.5 Hz, 2H-pyridin-3-yl), 8.95 (1 H, s, NH), 8.66 (1 H, dd,
J = 4.8 and 1.2 Hz, 6H-pyridin-3-yl), 8.49 (1 H, d, J = 5.1 Hz, 6H-pyridin-2-amine), 8.46 (1 H,
ddd, J = 7.9, 1.5 and 1.2 Hz, 4H-pyridin-3-yl), 8.06 (1 H, d, J = 1.5 Hz, 3H-2-aminotoluene),
7.89 (2 H, d, J = 8.1 Hz, 2H-benzamide), 7.50 (1 H, dd, J = 7.9 and 4.8 Hz, 5H-pyridin-3-yl),
7.46 (1 H, dd, J = 8.3 and 1.5 Hz, 5H-2-aminotoluene), 7.42 – 7.40 (3 H, m, 3H-benzamide
and 5H-pyridin-2-amine), 7.18 (1 H, d, J = 8.3 Hz, 6H-2-aminotoluene), 3.51 (2 H, s, CH2),
2.50 – 2.20 (8 H, m, piperazine CH2), 2.20 (3 H, s, CCH3), 2.13 (3 H, s, NCH3);
δC (CDCl3,
150 MHz) = 165.42(C), 162.72(C), 160.57(C), 158.99(CH), 151.44(CH), 148.48(CH),
142.52(C), 137.77(C), 136.60(C), 134.92(CH), 133.88(C), 132.66(C), 130.75(CH),
129.28(CH), 127.00(CH), 124.23(C), 123.71(CH), 115.35(CH), 113.19(CH), 108.32(CH),
62.49(CH2), 55.07(CH2), 53.10(CH2), 45.98(CH3), 17.65(CH3);
Rf (MeOH) = 0.09; Rt 3.48,
M+H m/z = 494.2; HRMS calculated for C29H31N7ONa [M + Na]+, 516.2488; found 516.2491.
Inline image 1
Inline image 3
13 C NMR
Inline image 4
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Pazopanib, パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид





Пазопаниба Гидрохлорид


Pazopanib is a small molecule inhibitor of multiple protein tyrosine kinases with potential antineoplastic activity. It is developed by GlaxoSmithKline and was FDA approved on October 19, 2009.

Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3,
PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food  and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline.

GW 786034

M.Wt: 437.53

Pazopanib CAS No.: 444731-52-6


ChemSpider 2D Image | Pazopanib Hydrochloride | C21H24ClN7O2S

Pazopanib Hydrochloride


  • MFC21H24ClN7O2S
  • MW473.979
GW786034;Votrient;Armala;GW 786034;GW-786034
GW786034GW786034, VOTRIENT
5-({4-[(2,3-Dimethyl-2H-indazol-6-yl)(methyl)amino]-2-pyrimidinyl}amino)-2-methylbenzenesulfonamide hydrochloride (1:1)
Antineoplastic; Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors; Renal Cell Carcinoma Therpay; Soft Tissue Sarcoma Therapy
Pazopanib Hydrochloride

C21H23N7O2S▪HCl : 473.98

Pazopanib (trade name Votrient) is a potent and selective multi-targeted receptor tyrosine kinase inhibitor that blocks tumour growth and inhibits angiogenesis. It has been approved for renal cell carcinoma and soft tissue sarcoma by numerous regulatory administrations worldwide.[2][3][4][5]

Pazopanib (Votrient®; GlaxoSmithKline, Brentford, U.K.)  is currently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of patients with metastatic renal cell carcinoma (mRCC)

Medical uses

It is approved by numerous regulatory administrations worldwide (including the FDA (19 October 2009), EMA (14 June 2010), MHRA(14 June 2010) and TGA (30 June 2010)) for use as a treatment for advanced/metastatic renal cell carcinoma and advanced soft tissue sarcomas.[1][2][3][4][5] In Australia and New Zealand, it is subsidised under the PBS and by Pharmac respectively, under a number of conditions, including:[6][7]

  • The medication is used to treat clear cell variant renal cell carcinoma.
  • The treatment phase is continuing treatment beyond 3-months.
  • The patient has been issued an authority prescription for pazopanib
  • The patient must have stable or responding disease according to the Response Evaluation Criteria In Solid Tumours (RECIST)
  • This treatment must be the sole tyrosine kinase inhibitor subsidised for this condition.

It has also demonstrated initial therapeutic properties in patients with ovarian and non-small cell lung cancer,[8] though plans to apply to the EMA for a variation to include advanced ovarian cancer have been withdrawn and a license will not be sought in any country.[9][10]



Pazopanib hydrochloride drug substance is manufactured by Glaxo Wellcome Manufacturing Pte. Limited, Jurong, Singapore

NDA 22-465 was submitted by GlaxoSmithKline (GSK) for VOTRIENT™ (pazopanib), an immediate release tablet for oral administration containing either 200 mg or 400 mg of pazopanib free base (GW786034X) as the hydrochloride salt (GW786034B). Pazopanib is a new molecular entity and is submitted for review pursuant to Section 505(b)(1) of the Food, Drug and Cosmetic Act. Reference is made to one active Investigational New Drug application, IND 65,747.

Quality by Design (QbD) approach and risk management to increase their understanding of the process and drug substance properties. A number of Critical Quality Attributes (CQAs) were identified. These are: Identity by IR, Chloride Identity, Crystalline Form, Content by HPLC, Drug-related Impurities (including named impurities and genotoxic (b) (4) (b) (4) (b) (4) (b) (4) Executive Summary Section CMC Review #1 Page 9 of 262 CMC REVIEW OF NDA 22-465 impurities content), Residue on Ignition, Particle Size, Residual Solvents, Water Content by Karl Fischer, Description, Pd Content, and Heavy Metals.

CQA are mainly controlled by controlling starting material attributes, intermediate attributes (e.g. specifications of GW786034 quality process parameters, and by following the manufacturing process. A risk based method (e.g. failure mode and effects analysis (FMEA)) was used to identify the Quality Critical Process Parameters (QCPPs), Quality Process Parameters (QPPs), CQAs and Quality Attributes (QAs) for the pazopanib hydrochloride manufacturing process. The inputs to the FMEA were knowledge gained through the work to develop the impurity fate map, spiking and purging studies, the Design of Experiments (DOE) work to establish potential QCPPs/QPPs, one factor at a time experiments to establish parameter proven acceptable ranges, and 6 years of plant experience preparing over batches of pazopanib hydrochloride in 3 plants throughout the GSK network. It was concluded from this risk assessment that there are no QCPP but a few QPP in the drug substance (DS) manufacturing process. Stages 1 and 2 had no QPP, the few were only present in stages 3 and 4. All the QPP were scale invariant. A combination of multivariate DOE and univariate experimentation was used to determine the Proven acceptable Ranges (PAR) for the variables. The risks for combining univariate and multivariate experimentation were found to be minimal, on the basis of outcome from the robustness study. For this study, all the process parameters were all set at the lower limit of the PARs to create a worst-case scenario for impurity purging. Neither new impurities nor elevated levels of known impurities were detected. This data demonstrated that multivariate interactions will not lead to elevated levels of impurities.

Drug Product Pazopanib Tablets, 200 mg and 400 mg are film-coated IR oral tablets. The two strengths contain 216.7 mg and 433.4 mg pazopanib hydrochloride, respectively, which are equivalent to 200 mg and 400 mg pazopanib (free base), respectively. Excipients in the tablet core are: microcrystalline cellulose, sodium starch glycolate, povidone, and magnesium stearate. Pazopanib Tablets, 200 mg are modified capsule-shaped, gray film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS JT’. Pazopanib Tablets, 400 mg are modified capsule-shaped, yellow film-coated tablets, one side plain and the opposite side debossed with an identifying code of ‘GS UHL’. The tablets are manufactured at Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom. Primary packaging of tablets will be performed by either Glaxo Operations UK Limited, Priory Street, Ware, Hertfordshire SG12 0DJ, United Kingdom or GlaxoSmithKline Inc, 1011 North Arendell Avenue, Zebulon, North Carolina 27597, USA.

Pazopanib hydrochloride is a new molecular entity of Biopharmaceutics Classification System (BCS) Class 2 (poor solubility, high permeability) and a crystalline solid. Its solubility in pH 1.1 is 0.65 mg/mL. The conjugate acids of the basic nitrogens have the following acidity constants: pKa – pK1 = 2.1 (indazole), pK2 = 6.4 (pyrimidine), pK3 = 10.2 (sulfonamide).


“Synthetic approaches to the 2009 new drugs”
Kevin K.-C. Liua, Subas M. Sakyab, Christopher J. O’Donnellb, Andrew C. Flickb, Jin Lic,
Bioorganic & Medicinal Chemistry, Volume 19, Issue 3, Pages 1136–1154

“An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals”., Beilstein J. Org. Chem., 2011, 7, 442–495.



Pazopanib is marketed as hydrochloride salt by Glaxoshiithkline under the trade name VOTRIENT® is tyrosine kinase inhibitor and indicated for the treatment of patients with advanced renal cell carcinoma (RCC) and treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

U.S. Patent No (s). US 7105530 (“the ‘530 patent”), US7262203 (“the ‘203 patent”) and US8114885 (“the ‘885 patent”) discloses a variety of pyrimidineamines and their derivatives such as Pazopanib, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof.

The process disclosed in the ‘530 patent is schematically represented as follows:


Patent publication No. WO 2011/050159 (“the Ί59 publication”) disclosed process for preparation of Pazopanib hydrochloride, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dicMoropyrimidine of Formula B in a solvent like industrial methylated sprit and specific reaction conditions like, in presence of a base, sodium bicarbonate having a particle size distribution of > 250μηι or 50 to 150μηι selected to ensure that the pH of the reaction mixture is less than 7 for the reaction time period not more than 300 min to obtain N-(2-c oropyrimidin-4-yl)- 2,3-dimethyl-2H-indazol-6-amine of Formula II. The compound of Formula Π was methylated in presence of a methylating agent in an organic solvent like dimethylformamide by using specific reaction conditions like, in presence of a base i.e. Potassium carbonate having a particle size distribution D99 of > 300μηι or D99 of < 200μηι selected to ensure that the reaction time needs to reduce the starting material to less than 2% in less than 8 his to obtain N-(2-cMoropyrimidin-4-yl)-N-2,3-trimemyl-2H-mdazol-6-amine of Formula III. The resultant methylated compound was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of 4M HC1 and methanol to yield Pazopanib hydrochloride.

WO Ί59 publication disclosed that use of sodium bicarbonate with specific particle size distribution of > 250μπι or 50 to 150μηι is key element in condensation of compound of Formula A and Formula B to niinimize the formation of Impurity of Formula 1 within

WO Ί59 publication also disclosed that use of potassium carbonate with specific particle size distribution D99 of > 300μπι or D99 of < 200μηι is key element in methylation of compound of Formula II to reduce the formation of Impurities of Formula 2, Formula 3 and Formula 4 within the range of about 0.05-3%.

Patent publication No. WO 2012/073254 (“the ‘254 publication”) disclosed a process for preparation of pazopanib hydrochloride, which involves condensation of 2,4-dicMoropyrimidine of Formula B with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of a base like sodium bicarbonate and a solvent like ethanol to yield 5-(4-chloropyrimidm-2-yl-ammo)-2-memylbenzenesulfonamide The resultant compound was condensed with N-2,3-1rimethyl-2H-indazole-6-amine of Formula D in an alcoholic solvent like ethanol. WO ‘254 publication also discloses process for purification of pazopanib hydrochloride from alcoholic solvent and water. The process disclosed in the ‘254 publication is schematically represented as follows:

Patent publication No. IN 2505/CHE/2011 disclosed a process for preparation of pazopanib, which involves condensation of 2,3-dimethyl-2H-indazol-6-amine of Formula A and 2,4-dichloropyrimidine of Formula B in presence of sodium bicarbonate and a phase transfer catalyst like tetrabutyl ammonium bromide in a solvent like methanol to obtain N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine of Formula II. The resultant compound was methylated in presence of methyl iodide, potassium carbonate in a solvent like dimethylformamide to obtain compound of Formula III. The obtained Formula III was condensed with 5-amino-2-methylbenzenesulfonamide of Formula C in presence of dimethylformamide and concentrated HC1 to yield pazopanib hydrochloride.

Patent publication No. CN 103373989 (“the ‘989 publication”) disclosed a process for preparation of Pazopanib intermediate of Formula III by condensation of N-2,3-trimethyl-2H-indazole-6-amine of Formula D with 2,4-dicWoropyrimidine of Formula B in

Patent publication No. WO 2014/97152 (“the Ί52 publication”) disclosed a process for preparation of Pazopanib hydrochloride starting from 2,3-dimethyl-6-nitro-2H-indazole.

The processes for preparation of pazopanib described in the above literature have certain drawbacks as it involves: a) use of specific predefined particles of bases like sodium bicarbonate and potassium carbonate, which involves additional process steps like milling, grinding etc, b) use of expensive phase transfer catalysts and c) multiple steps making the process quite expensive, particularly on large scale.

European Medicines Agency (EMA) public assessment report disclosed that pazopanib hydrochloride is a white to slightly yellow, non-hygroscopic, crystalline substance and the manufacturing process consistently produces pazopanib hydrochloride Form 1. However, the EMEA does not describe any particular characterization data for the disclosed polymorph Form 1.

PCT Publication No. WO 2011/058179 (“the Ί79 publication”) discloses pazopanib base crystalline Forms such as Form-I and Form-II and a process for its preparation; also disclosed characterization data of Form-I and Form-II by XRD, IR and melting point. –

PCT Publication No. WO 2011/069053 (“the ‘053 publication”) discloses crystalline pazopanib base and crystalline pazopanib hydrochloride Forms such as Form-II, Form-Ill, Form-TV, Form-V, Form- VI, Form- VIII, Form-IX, Form-X, Form-XI, Form-XII, Form-XIII, Form-A, Form-G and also discloses crystalline Pazopanib dihydrochloride Forms such as Form-I, Form-XIV, Form-XV. The crystalline Forms reported in the PCT publication characterized by its XRD pattern.

IN Publication No. 3023/CHE/2010 discloses crystalline pazopanib dihydrochloride Form-I and crystalline pazopanib mono hydrochloride, process for it preparation and characterization by XRD of the same.

IN Publication No. 1535/CHE/2012 discloses crystalline pazopanib hydrochloride Form-SP and a process for its preparation; also disclosed characterization data, of Form-SP by XRD, DSC and TR.

PCT Publication No (s): WO 2007/143483, WO 2007/064753, WO 2006/20564 and WO 2005/105094 as well as US Publication No. US 2008/0293691 disclose anhydrous and hydrated Forms of pazopanib hydrochloride and their process for preparation thereof. ‘

IP. Com journal disclosure Number IPCOM000207426D discloses crystalline Form of pazopanib hydrochloride Form-R, which is characterized by XRD pattern.

Further, IP.Com journal disclosure Number IPCOM000193076D discloses crystalline Forms of N-(2-cUoropyrirnidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine of

Formula III such as Form I and Form II along with characteristic data of XRD pattern



Example 1:

Preparation of 5-(4-chloropyrimidin-2ylamino)-2-methyIbenzenesulfonamide

To a mixture of 5-amino-2-methylbenzenesulfonamide (20 gm) in ethanol (208 ml) and tetrahydrofuran (52 ml) was added 2,4-dichloropryrimidine (44 gm) and sodium bicarbonate (36 gm) at room temperature. The contents were heated to 70 to 75°C and maintained for 13 hours. The reaction mass was then cooled to 10°C and maintained for 2 hours. The reaction mass was filtered and the solvent was distilled off under vacuum at below 50 to 55°C to obtain a residual mass. To the residual mass was added ethyl acetate (100 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 15.5 gm of 5-(4-chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide. Example 2:

Preparation of N,2,3-trimethyI-2H-indazol-6-amine

Sodium methoxide (19 gm) was dissolved in methanol (610 ml) and then added 2,3-dimethyl-2H-indazol-6-amine (13 gm). The reaction mixture was stirred for 15 minutes and then added paraformaldehyde (3.9 gm). The contents were heated to 60°C and stirred for 10 hours. The reaction mass was then cooled to room temperature and maintained for 4 hours 30 minutes. Sodium borohydride (2.8 gm) was added to the reaction mass slowly at room temperature and then heated to reflux. The reaction mass was maintained for 2 hours at reflux and then cooled to room temperature. The reaction mass was stirred for 14 hours at room temperature and then added sodium hydroxide solution (1M, 100 ml). The pH of the reaction mass was adjusted to 8.0 to 8.5 with hydrochloric acid solution (40 ml) and then added ethyl acetate (400 ml). Then the layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried with sodium sulfate and treated with carbon. The combined organic layers were washed with sodium chloride solution and dried with sodium sulfate. The organic layer was treated with carbon and filtered through hi-flow bed. The solvent was distilled off under vacuum at below 50°C to obtain a residual mass. To the residual mass was added diisopropyl ether (75 ml) and stirred for 1 hour, filtered. The solid obtained was dried to give 10 gm of N,2,3-trimethyl-2H-indazol-6-amine.

Example 3:

Preparation of pazopanib hydrochloride

5-(4-Chloropyrimidin-2ylamino)-2-methylbenzenesulfonamide (17 gm) as obtained in example 1, N,2,3-trimethyl-2H-indazol-6-amine (10 gm) as obtained in example 2 and ethanol (166 ml) were added at room temperature and then heated to reflux. The reaction mass was maintained for 3 hours at reflux and then added concentrated hydrochloric acid (1 ml). The reaction mass was maintained for 10 hours at reflux and then cooled to room temperature. The separated solid was filtered and dried to obtain 17 gm of pazopanib hydrochloride (HPLC Purity: 97.5%). Example 4:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (5 gm; HPLC Purity: 97.5%) as obtained in example 3 was dissolved in a mixture of methanol (100 ml) and water (10 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 30 minutes at reflux and filtered. The filtrate obtained was cooled to room temperature and maintained for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 3.5 gm of pazopanib hydrochloride (HPLC Purity: 99.9%). Example 5:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (22 gm; HPLC Purity: 98%), methanol (528 ml), water (55 ml) and concentrated hydrochloric acid (0.2 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. Take the filtrate and the solvent was distilled off under vacuum to obtain a residual mass. The residual mass was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents were further cooled to 0 to 5°C, stirred for 1 hour and filtered. The solid obtained was dried to give 19 gm of pazopanib hydrochloride (HPLC Purity: 99.85%).

Example 6:

Purification of pazopanib hydrochloride

Pazopanib hydrochloride (10 gm; HPLC Purity: 96%), methanol (250 ml), water (25 ml) and concentrated hydrochloric acid (0.1 ml) were added at room temperature. The contents were heated to reflux and maintained for 30 minutes, filtered. The filtrate obtained was then cooled to room temperature and stirred for 30 minutes at room temperature. The contents further cooled to 0 to 10°C and stirred for 1 hour. The separated solid was filtered and dried to obtain 6.6 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).

Example 7: Purification of pazopanib hydrochloride

Pazopanib hydrochloride (22 gm; HPLC Purity: 97%) was dissolved in a mixture of isopropanol (132 ml) and water (20 ml) at room temperature and then heated to reflux. The reaction mass was maintained for 1 hour at reflux and then cooled to room temperature. The reaction mass was stirred for 1 hour at room temperature and filtered. The solid obtained was dried to give 18 gm of pazopanib hydrochloride (HPLC Purity: 99.8%).


Assessment of Predictivity of Semiquantitative Risk Assessment Tool: Pazopanib Hydrochloride Genotoxic Impurities

GlaxoSmithKline, Park Road, Ware, Hertfordshire, United Kingdom SG12 0DP
GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States
Org. Process Res. Dev., 2013, 17 (8), pp 1036–1041
DOI: 10.1021/op400139z
Publication Date (Web): July 02, 2013
Copyright © 2013 American Chemical Society


Abstract Image

The recently developed semiquantitative assessment tool for the evaluation of carryover potential of mutagenic impurities (MIs) into the final API was applied to the five identified MIs within pazopanib hydrochloride (dimethyl sulfate (DMS) and compounds II, III, VI, and VIII). The theoretical and predicted purge factors were compared. The tool accurately predicted the purging capacity for the most reactive MI, DMS, giving a theoretical purge factor of 30000 versus an actual value of 29411 (for spiking at stage 1). For the other less reactive MIs, both measured and predicted values agreed reasonably well, and the high values for the purging factors were indicative of an effective process capability that could significantly reduce observed MI levels. The only exception was for compound VI, where although the measured and theoretical purge factors were in agreement, they were significantly lower (<200) than for the other MIs. In this case, a strategy was implemented including a requirement for control of this MI on API specification. The purge-factor assessment tool has the potential to play a key role in GRA (genotoxic risk assessment) processes and subsequent regulatory submissions. This tool could provide regulators with additional confidence to accept these purging arguments without resorting to testing. This could potentially significantly reduce the analytical testing burden for early clinical candidates.




WO 2011058179

The compound 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N-methylamino)pyrimidine-2- ylamino)-2-methylbenzenesulfonamide, also known as Pazopanib, is useful in the treatment of disorders associated with inappropriate or pathological angiogenesis, such as cancer, in mammals. Pazopanib has the following formula (I):


Figure imgf000002_0001


In WO 02/059110 the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride as well as the uses of this compound have been disclosed. In particular, this compound is an inhibitor of tyrosine kinase enzymes, namely vascular endothelial growth factor receptors, and can be used for the treatment and/or prevention of diseases which are associated with tyrosine kinase enzymes such as vascular endothelial growth factor receptors, such as cancer, particularly breast cancer and colon cancer.

Alternative methods for the preparation of 5-(4-(N-(2,3-dimethyl-2H-indazole-6-yl)-N- methylamino)pyrimidine-2-ylamino)-2-methylbenzenesulfonamide hydrochloride are disclosed in WO 03/106416.

In WO 2007/064752 the use of Pazopanib for the treatment of age related macula degeneration is disclosed. WO 2007/064753 further discloses Pazopanib for the treatment of various types of cancer, e.g. brain cancer, glioblastoma multiforme, neuroendocrine cancer, prostate cancer, myeloma, lung cancer, liver cancer, gallbladder cancer or skin cancer.

Typically Pazopanib is administered orally, as this route provides great comfort and convenience of dosing. Although the hydrochloride form of Pazopanib is known in the art, as described above, this form is not optimal in regard to bioavailability, inter-patient variability, and safety. Further, the known form of Pazopanib hydrochloride is not optimal with regard to mechanical and chemical stability, which is in particular necessary for manufacturing tablets, as well as not optimal in regard to flow properties, compressibility, dissolution rate. Additionally, it is at least to some extent hygroscopic and shows electrostatic charging. These properties constitute disadvantages in the preparation of pharmaceutical compositions


Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents


A series of novel pazopanib derivatives, 7am, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by 1H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC50 values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7mdemonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.

Chemical structure of pazopanib.

Figure 1.

Chemical structure of pazopanib.


Example 69

5-({4-[(2,3-dimethyl-2r/-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2- methylbenzenesulfonamide

Figure imgf000096_0002

To a solution of Intermediate Example 13 (200 mg, 0.695 mmol) and 5-amino-2- ethylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol (6 ml) was added 4 drops of cone. HCI. The mixture was heated to reflux overnight. The mixture was cooled to rt and diluted with ether (6 ml). Precipitate was collected via filtration and washed with ether. HCI salt of 5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2- yl}amino)-2-methylbenzenesulfonamide was isolated as an off-white solid. Y\ NMR (400 MHz, deDMSO+NaHCOa) δ 9.50 (br s, 1 H), 8.55 (br s, 1 H), 7.81 (d, J = 6.2 Hz, 1 H), 7.75 (d, J = 8.7 Hz, 1 H), 7.69 (m, 1 H), 7.43 (s, 1 H), 7.23 (s, 2H), 7.15 (d, J = 8.4 Hz, 1 H), 6.86 (m, 1 H), 5.74 (d, J = 6.1 Hz, 1 H), 4.04 (s, 3H), 3.48 (s, 3H), 2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

Example 13

Preparation of Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine

Figure imgf000061_0001

To a stirred solution of the Intermediate 12 (7.37 g) in DMF (50 ml) was added CS2CO3 (7.44 g, 2 eqv.) and Mel (1.84 ml, 1.1 eqv.) at room temperature. Mixture was stirred at rt for overnight The reaction mixture was poured into ice-water bath, and the precipitate was collected via filtration and washed with water. The precipitate was air- dried to afford Λ/-(2-chloropyrimidin-4-yl)-Λ/,2,3-trimethyl-2r/-indazol-6-amine as an off-white solid (6.43 g, 83%). ‘H NMR (400 MHz, dsDMSO) δ 7.94 (d, J = 6.0 Hz, 1 H), 7.80 (d, J = 7.0 Hz, 1 H), 7.50 (d, J = 1.0 Hz, 1 H), 6.88 (m, 1 H), 6.24 (d, J = 6.2 Hz, 1 H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 288 (M+H).

Intermediate Example 12 Preparation of Λ/-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine

Figure imgf000060_0001

to a stirred solution of Intermediate Example 11 (2.97 g, .015 mol) and NaHCOs (5.05 g, .06 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.70 g, .045 mol) at room temperature. After the reaction was stirred for four hours at 85 °C, the suspension was cooled to rt, filtered and washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting solid was triturated with ethyl acetate to yield 3.84 g (89 % yield) of Λ/-(2-chloropyrimidin-4-yl)- 2,3-dimethyl-2tf-indazol-6-amine. 1H NMR (400 MHz, deDMSO) δ 7.28 (d, J = 9.0 Hz, 1 H), 6.42 (d, J = 8.8 Hz, 1 H), 6.37 (s, 1 H), 5.18 (br s, 1 H), 3.84 (s, 3H), 2.43 (s, 3H). MS (ES+, m/z) 274 (M+H).

Intermediate Example 11

Preparation of 2,3-dimethyl-2r/-indazol-6-amine

Figure imgf000059_0002

To a stirred solution of 18.5 g (0.11 mol) of 3-methyl-6-nitro- 7W-indazole in 350 ml acetone, at room temperature, was added 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After the solution was allowed to stir under argon for 3 hours, the solvent was removed under reduced pressure. To the resulting solid was added saturated aqueous NaHC03 (600 ml) and a 4:1 mixture of chloroform-isopropanol (200 ml), and the mixture was agitated and the layers were separated. The aqueous phase was washed with additional chloroform: isopropanol (4 x 200 ml) and the combined organic phase was dried (Na2S04). Filtration and removal of solvent gave a tan solid. The solid was washed with ether (200 ml) to afford 2,3-dimethyl-6-nitro-2r/-indazole as a yellow solid (15.85 g, 73 o/o). 1H NMR (300 MHz, dβDMSO) δ 8.51 (s, I H), 7.94 (d, J = 9.1 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).

To a stirred solution of 2,3-dimethyl-6-nitro-2V-indazole (1.13 g) in 2- methoxyethyl ether (12 ml), at 0 °C, was added a solution of 4.48 g of tin(ll) chloride in 8.9 ml of concentrated HCI dropwise over 5 min. After the addition was complete, the ice bath was removed and the solution was allowed to stir for an additional 30 min. Approximately 40 ml of diethyl ether was added to reaction, resulting in precipitate formation. The resulting precipitate was isolated by filtration and washed with diethyl ether, and afforded a yellow solid (1.1 g, 95 %), the HCI salt 2,3-dimethyl-2/7-indazol-6- amine. 1H NMR (300 MHz, deDMSO) δ 7.77 (d, J = 8.9 Hz, 1 H), 7.18 (s, 1 H), 7.88 (m, 1 H), 4.04 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 162 (M+H).


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WO2003106416A2 (same appears in Drug Future 2006, 31, 7, 585-589)
Pazopanib synthesis: J Med Chem 2008, 51, 4632-4640 (same appears in Beilstein J Org Chem 2011, 7, 442–495)






A Novel Practical Synthesis of Pazopanib: An Anticancer Drug

Author(s): YiCheng Mei, BaoWei Yang, Wei Chen, DanDan Huang, Ying Li, Xin Deng, BaoMing Liu, JingJie Wang, Hai Qian and WenLong Huang

Affiliation: Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu 210009, P.R. China.


This paper reports a novel approach to synthesize pazopanib. In our synthetic route, the potently mutagenic alkylating agents such as dimethyl sulfate and methyl iodide are avoided. A novel regioselective methylation of the 2- position of 3-methyl-6-nitro-1H-indazole was reported. This novel route is one step shorter than the previously reported route.


Pazopanib is a tyrosine kinase inhibitor of Formula la.

Figure imgf000002_0001

Formula la

Pazopanib is marketed as the hydrochloride salt, with the chemical name 5-[[4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride, having the structure as depicted in Formula I:

Figure imgf000002_0002

Formula I

U.S. Patent No. 7,105,530 provides a process for the preparation of a hydrochloride salt of a compound of Formula II

Figure imgf000003_0001

Formula II involving the reduction of 2,3-dimethyl-6-nitro-2H-indazole with tin (II) chloride in concentrated hydrochloric acid in the presence of 2-methoxyethyl ether at 0°C. It also describes the preparation of a compound of Formula III

Figure imgf000003_0002

Formula III involving the reaction of a hydrochloride salt of compound of Formula II with 2,4- dichloropyrimidine in the presence of a base and solvent mixture of

tetrahydrofuran/ethanol followed by stirring for 4 hours at 85°C.

PCT Publication No. WO 2007/064752 provides a process for the preparation of a compound of Formula II comprising reducing 2,3-dimethyl-6-nitro-2H-indazole with 10% Palladium-carbon (50% wet) in the presence of methanol, followed by the addition of ammonium formate at a rate that ensures the reaction temperature is maintained at or between 25°C and 30°C. It also discloses the preparation of a compound of Formula III comprising heating the compound of Formula II with sodium bicarbonate in presence of tetrahydrofuran and ethanol at or between 75°C and 80°C followed by cooling to 20°C to


The present invention provides a process for the preparation of a compound of Formula II which offers recycling of the Raney nickel catalyst used in the process, and an easy filtration work-up procedure. Further, the present invention offers selective reduction under mild conditions that is economical to use at an industrial scale.

The present invention also provides a process for the preparation of compound of Formula III which avoids the use of two or more solvents, and additionally, also circumvents heating and cooling procedures during the reaction. The aforesaid advantages yield a compound of Formula III with a lesser amount of N-(4-chloropyrimidin-2-yl)-2,3- dimethyl-2H-indazol-6-amine (CPDMI) impurity.

The compounds of Formula II and Formula III prepared by the present invention yield a compound of Formula la or its salts in comparable yield and suitable purity required for medicinal preparations.


Step 1: Synthesis of 2,3-dimcthyl-6-nitro-2H-indazole

Example 1 :

Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals. The reaction mixture was stirred at 25 °C to 30°C for 16 hours. The solvent was recovered under reduced pressure. A saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4: 1 mixture of dichloromethane:isopropyl alcohol (1080 mL x 5). The solvent was recovered under reduced pressure. Methyl fert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45 °C to 50°C. The reaction mixture was cooled to 25 °C to 30°C and was stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tert- butyl ether (100 mL x 2), and dried in an air oven at 50°C for 12 hours to afford 2,3- dimethyl-6-nitro-2H-indazole as a yellow solid.

Yield: 82.4% w/w

Step 2: Synthesis of 2,3-dimethyl-2H-indazol-6-amine

Example 2a:

Raney nickel ( 12.50 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (50 g, 0.26 mol) in methanol (500 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm2 – 4.0 kg/cm2 at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (100 mL x 2). The filtrates were combined, and the solvent was recovered completely. «-Heptane (250 mL) and dichloromethane (50 mL) were added to the residue, and the reaction mixture was stirred for 1 hour at 25°C to 30°C. The solid was collected by filtration, washed with n-heptane (50 mL x 2), and dried under vacuum at 40°C to 45 °C to afford 2,3-dimethyl-2H-indazol-6-amine as a light brown solid.

Yield: 95% w/w

Example 2b:

Raney nickel (21.25 g) was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (85 g, 0.45 mol) in methanol (850 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm2 – 4.0 kg/cm2 at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (85 mL x 3). The filtrates were combined, and the solvent was recovered up to the volume of 850 mL. The 2,3-dimethyl-2H-indazol-6-amine in methanol was used as such in the next step. Step 3: Synthesis of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine

Example 3 :

Sodium bicarbonate ( 112 g, 1.34 mol) was added to a stirred solution of 2,3- dimethyl-2H-indazol-6-amine (as obtained from step 2; Examples 2a and 2b) in methanol. 2,4-Dichloropyrimidine (99.35 g, 0.67 mol) was added to the reaction mixture followed by stirring of the reaction mixture for 24 hours at 25°C to 30°C. De-ionized water (850 mL) was added to the reaction mixture followed by stirring of the reaction mixture at 25 °C to 30°C for 1 hour. The solid was filtered. The wet solid was washed with de-ionized water (170 mL x 2) to obtain a wet material. De-ionized water (850 mL) was added to the wet material to obtain a slurry, and the slurry was stirred at 25°C to 30°C for 30 minutes. The solid was filtered, then washed with de-ionized water (170 mL x 2). The wet material obtained was treated with ethyl acetate (340 mL) to obtain a slurry. The slurry was stirred at 35°C to 40°C for 30 minutes and then cooled to 0°C to 5°C. The slurry was further stirred at 0°C to 5°C for 30 minutes. The solid was collected by filtration, then washed with cold ethyl acetate (170 mL x 2). The solid was dried in an air oven at 50°C for 16 hours to afford N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine as an off- white solid.

Yield: 86.7% w/w

Step 4: Synthesis of pazopanib hydrochloride

Example 4a: Synthesis of N-(2-Chloropyrimidin-4-yl)-N.2.3-trimethyl-2H-indazol-6- amine

Cesium carbonate (238 g, 0.73 mol) and iodomethane (57 g, 0.40 mol) were added to a stirred suspension of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (lOOg, 0.37 mol) in N,N-dimethylformamide (300 mL) at 25°C to 30°C. The reaction mixture was further stirred at 25 °C to 30°C for 6 hours followed by cooling of the reaction mixture to 0°C to 5°C. De-ionized water (300 mL) was added drop-wise to the reaction mixture, then the reaction mixture was stirred at 5°C to 10°C for 30 minutes. The solid was collected by filtration, and washed with de-ionized water (100 mL x 2). The wet material so obtained was dried in an air oven at 50°C for 12 hours to obtain the title compound.

Yield: 90.4% w/w Example 4b: Synthesis of pazopanib hydrochloride

To a suspension of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6- amine (90 g, 0.312 mol) and 5-amino-2-methyl benzene sulfonamide (64.07 g, 0.344 mol) in isopropyl alcohol (900 mL) was added 4M hydrochloric acid solution in isopropyl alcohol (1.56 mL, 6.25 mol). The reaction mixture was heated to reflux temperature for 10 hours to 12 hours. The reaction mixture was cooled to 25°C. The reaction mixture was further stirred at 25°C to 30°C for 30 minutes, then the solid was filtered. The wet solid was washed with isopropyl alcohol (180 mL x 2), and then dried under vacuum at 45 °C to 50°C for 12 hours to afford the hydrochloride salt of 5-({4-[(2,3-dimethyl-21-I-indazol-6- yl)(methyl) amino] pyrimidin-2-yl} amino-Z-methylbenzene sulfonamide as a light brown solid.

Yield: 97% w/w


pazopanib hydrochloride monohydrate prepared:

(1) chemical reaction formula

Figure CN104557881AD00051

(2) Operation process

In the reaction flask pazopanib hydrochloride crude 100g, 700ml of acetonitrile was added under stirring and purified water 200ml, feeding is completed, begin heating to 75~80 ° C, until clear solvent filtration system, slowly dropped 10~20 ° C, keep stirring lh, filtered, and the filter cake washed with purified water and acetonitrile respectively, drained and the filter cake was dried at 60 ° C blast 5h, have pazopanib hydrochloride monohydrate solid 84g, yield 80.9%. For example, crystalline form pazopanib hydrochloride prepared the following examples.

pazopanib hydrochloride polymorph of preparation:

Example 1:

 In the reaction flask pazopanib hydrochloride monohydrate 8. 0g, ethanol 50ml and purified water 0.Iml (the volume of water accounted for a mixed solution of 2% of the total volume of the square, ethanol – water mixture total volume was 6.26 times pazopanib hydrochloride monohydrate quality), heated to 75 ° C, stirred at reflux for about 5h, after cooling to 10~20 ° C, keep stirring lh, the filter cake washed with ethanol, then blast drying at 105 ° C 5h, to obtain ultrafine powder solid 6. 8g, yield of 81. 9%, HPLC purity was 99.8%, as measured crystal X- ray powder diffraction pattern of FIG. 1 the basic consistent, as measured with a DSC thermogram consistent FIG. 2, the particle size distribution measurement is basically the same as Fig 3 (D90 <10ym).


Pazopanib is a highly bio-available, multi- tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-l, -2, -3, platelet-derived factor receptor (PDGFR) -α, -β, cytokine receptor (cKit), interleukin-2 receptor inducible T-cell kinase (Itk), leukocyte-specific protein tyrosine kinase (Lck), and transmembrane glycoprotein receptor tyrosine kinase (c-Fms). Pazopanib was recently approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced renal cell carcinoma; thus adding to the other FDA-approved VEGF pathway inhibitors, sunitinib, bevacizumab (in combination with interferon) and sorafinib for this same indication.

Processes by which pazopanib and its intermediates can be synthesized have been described in US Patent No. 7,105,530 as well as in the published PCT application WO03/106416.

U.S. patent no. 7,105,530 disclosed pyrimidineamines and their derivatives thereof. These compounds are antineoplastic agents, and are useful in the treatment of various cancers and renal cell carcinoma. Among them pazopanib hydrochloride, chemically 5-[4-[N-(2,3-Dimethyl-2H-indazol-6-yl)-N-methylamino]pyrimidin-2- ylamino]-2-methylbenzenesulfonamide hydrochloride. Pazopanib hydrochloride is represented by the following structure:
Pazopanib hydrochloride is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR (Vascular endothelial growth factor receptors)- 1, VEGFR-2, VEGFR-3, PDGFR (Platelet-derived growth factor receptors )-a/p, and c-kit that blocks tumor growth and inhibits angiogenesis. It has been approved for renal cell carcinoma by the U.S. Food and Drug Administration. Pazopanib hydrochloride may also be active in ovarian cancer and soft tissue sarcoma. Pazopanib hydrochloride also appears effective in the treatment of non-small cell lung carcinoma. Pazopanib hydrochloride is marketed under the brand name Votrient® by Glaxosmithkline in the form of tablet.

Processes for the preparation of pazopanib hydrochloride and related compounds were disclosed in U.S. patent no. 7,105,530 and U.S. patent no. 7,262,203.

According to U.S. patent no. 7,105,530, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine with 5- amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in isopropanol and ether.

U.S. patent application publication no. 2006/0252943 disclosed a process for the preparation of pazopanib hydrochloride. According to this patent, pazopanib hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N,2,3- trimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in ethanol or methanol or tetrahydrofuran or acetonitrile and dioxane.

Drugs of the Future, 2006, 31 (7): 585-589


Marcus BaumannEmail of corresponding author, Ian R. BaxendaleEmail of corresponding author, Steven V. LeyEmail of corresponding author and Nikzad NikbinEmail of corresponding author
Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK
Email of corresponding author Corresponding author email
Editor-in-Chief: J. Clayden
Beilstein J. Org. Chem. 2011, 7, 442–495.

Pazopanib (246, Votrient) is a new potent multi-target tyrosine kinase inhibitor for various human cancer cell lines. Pazopanib is considered a promising replacement treatment to imatinib and sunitinib and was approved for renal cell carcinoma by the FDA in late 2009. The indazole system is built up via diazotisation and spontaneous cyclisation of 2-ethyl-5-nitroaniline (247) using tert-butyl nitrite. The resulting indazole structure 249 can be methylated entirely regioselectively with either Meerwein’s salt, trimethyl orthoformate or dimethyl sulfate. A tin-mediated reduction of the nitro group unmasks the aniline which undergoes nucleophilic aromatic substitution to introduce the pyrimidine system with the formation of 253. Methylation of the secondary amine function with methyl iodide prior to a second SNAr reaction with a sulfonamide-derived aniline affords pazopanib .

Synthesis of pazopanib.
  1. Pandite, A. N.; Whitehead, B. F.; Ho, P. T. C.; Suttle, A. B. Cancer Treatment Method. WO Patent 2007/064753, June 7, 2007.
  2. Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N., III; Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. J. Med. Chem.2008,51,4632–4640. doi:10.1021/jm800566m



Pazopanib hydrochloride (Votrient)
Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-a/b, and c-kit that blocks tumor growth and inhibits angiogenesis. It was approved for renal cell carcinoma by the U.S. Food
and Drug Administration in 2009 and is marketed under the trade name Votrient by the drug’s manufacturer, GlaxoSmithKline. The
synthesis of pazopanib begins with methylation of 3-methyl-6-nitroindazole (82) with trimethyl orthoformate in the presence of BF3OEt to give indazole 83 in 65% yield (Scheme 14).65 Reduction of the nitro group was achieved via transfer hydrogenation to give 84 in 97% yield, and this was followed by coupling the aniline with 2,4-dichloropyrimidine in a THF-ethanol mixture at elevated
temperature to provide diarylamine 85 in 90% yield. The aniline nitrogen was then methylated using methyl iodide to give 86 in
83% yield prior to coupling with 5-amino-2-methylbenzenesulfonamide (87) and salt formation using an alcoholic solution of
HCl to furnish pazopanib hydrochloride (XIV) in 81% yield.


FDA Orange Book Patents

FDA Orange Book Patents: 1 of 3
Patent 7262203
Expiration Dec 19, 2021
Drug Application
  1. N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)
  2. N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)
FDA Orange Book Patents: 2 of 3
Patent 8114885
Expiration Dec 19, 2021
Drug Application
  1. N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)
  2. N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)
FDA Orange Book Patents: 3 of 3
Patent 7105530
Expiration Oct 19, 2023
Drug Application
  1. N022465 (Discontinued Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)
  2. N022465 (Prescription Drug: VOTRIENT. Ingredients: PAZOPANIB HYDROCHLORIDE)

VOTRIENT (pazopanib) is a tyrosine kinase inhibitor (TKI). Pazopanib is presented as the hydrochloride salt, with the chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide monohydrochloride. It has the molecular formula C21H23N7O2S•HCl and a molecular weight of 473.99. Pazopanib hydrochloride has the following chemical structure:

VOTRIENT (pazopanib) Structural Formula Illustration

Pazopanib hydrochloride is a white to slightly yellow solid. It is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media.

Tablets of VOTRIENT are for oral administration. Each 200 mg tablet of VOTRIENT contains 216.7 mg of pazopanib hydrochloride, equivalent to 200 mg of pazopanib free base. The inactive ingredients of VOTRIENT are:Tablet Core: Magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate. Coating: Gray film-coat: Hypromellose, iron oxide black, macrogol/polyethylene glycol 400 (PEG 400), polysorbate 80, titanium dioxide.

  1. FierceBiotech. 2008-09-15. Retrieved 2010-08-10.
Patent Number
Expires (estimated)
United States 7105530 2009-10-19 2023-10-19
United States 7262203 2009-10-19 2021-12-19
United States 8114885 2009-10-19 2021-12-19

JUNE 4 2013 old article cut paste

GlaxoSmithKline’s (GSK) Votrient (pazopanib) has met the primary objective of a statistically significant improvement in the time to disease progression or death that is the progression-free survival (PFS) against placebo in Phase III ovarian cancer..

Pazopanib shrinks lung cancers before surgery


Pazopanib is an angiogenesis inhibitor targeting vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, platelet-derived growth factor receptors (PDGFR)-α/-β, and c-Kit. The hydrochloride salt of pazopanib (5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonamide) is marketed by GlaxoSmithKline as Votrient®, which is approved in the United States and other countries for the treatment of renal cell carcinoma (RCC).

Votrient® is currently prescribed to adults in the form of 200 mg tablets for oral administration, with each 200 mg tablet containing an amount of pazopanib hydrochloride equivalent to 200 mg of pazopanib free base.

Though the current tablets are acceptable of use in adults, the tablets are not preferred for use in potential future use for administering pazopanib to children. In pediatric populations, it is often desired that drug be available as a powder for reconstitution to an oral suspension. Manufacture of such a powder requires dry blending of various excipients with the active substance to provide good flow properties and content uniformity of the powder blend.

Several additional challenges exist concerning the use of pazopanib in a pediatric formulation. For instance, the nature of the drug substance favors conversion from the hydrochloride salt to the free base and hydrate forms in an aqueous environment such that standard formulations fail to provide adequate suspension stability at long term storage conditions of 25° C./65% RH or room temperature. Further, the drug has been found to have a bitter taste and, therefore, taste masking is critical.It is desired to invent a pediatric formulation of pazopanib hydrochloride suitable for administration to a pediatric population


  1.  “Votrient (pazopanib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 27 January 2014.
  2.  “VOTRIENT (pazopanib hydrochloride) tablet, film coated [GlaxoSmithKline LLC]”(PDF). DailyMed. GlaxoSmithKline LLC. November 2013. Retrieved 27 January 2014.
  3.  “Votrient : EPAR – Product Information” (PDF). European Medicines Agency. Glaxo Group Ltd. 23 January 2014. Retrieved 27 January 2014.
  4.  “Votrient 200 mg and 400 mg film coated tablets – Summary of Product Characteristics (SPC)”. electronic Medicines Compendium. GlaxoSmithKline UK. 20 December 2013. Retrieved 27 January 2014.
  5.  “PRODUCT INFORMATION VOTRIENT® TABLETS” (PDF). TGA eBusiness Services. GlaxoSmithKline Australia Pty Ltd. 25 March 2013. Retrieved 27 January 2014.
  6.  “Pharmaceutical Benefits Scheme (PBS) – Pazopanib”. Pharmaceutical Benefits Scheme. Australian Government. Retrieved 27 January 2014.
  7.  “Pazopanib – Online Pharmaceutical Schedule”. Pharmaceutical Management Agency. Retrieved 9 June 2015.
  8. ^ “Pazopanib shows encouraging activity in several tumour types, including soft tissue sarcoma and ovarian cancer”. FierceBiotech. 2008-09-15. Retrieved 2010-08-10.
  9.  “GSK pulls bid to extend use of kidney drug to ovarian cancer”. Reuters. 31 March 2014. Retrieved 7 April 2014.
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  11. Zivi, A; Cerbone, L; Recine, F; Sternberg, CN (September 2012). “Safety and tolerability of pazopanib in the treatment of renal cell carcinoma”. Expert Opinion on Drug Safety. 11 (5): 851–859. doi:10.1517/14740338.2012.712108. PMID 22861374.
  12. Khurana V, Minocha M, Pal D, Mitra AK (March 2014). “Role of OATP-1B1 and/or OATP-1B3 in hepatic disposition of tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11. doi:10.1515/dmdi-2013-0062. PMID 24643910.
  13.  Khurana V, Minocha M, Pal D, Mitra AK (May 2014). “Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors.”. Drug Metabol Drug Interact. 0 (0): 1–11.doi:10.1515/dmdi-2014-0014. PMID 24807167.
  14.  Verweij, J; Sleijfer, S (May 2013). “Pazopanib, a new therapy for metastatic soft tissue sarcoma”. Expert Opinion on Pharmacotherapy. 14 (7): 929–935.doi:10.1517/14656566.2013.780030. PMID 23488774.
  15.  Schöffski, P (June 2012). “Pazopanib in the treatment of soft tissue sarcoma”. Expert Review of Anticancer Therapy. 12 (6): 711–723. doi:10.1586/era.12.41.PMID 22716487.
  16.  Pick, AM; Nystrom, KK (March 2012). “Pazopanib for the treatment of metastatic renal cell carcinoma”. Clinical Therapeutics. 34 (3): 511–520.doi:10.1016/j.clinthera.2012.01.014. PMID 22341567.
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Systematic (IUPAC) name
Clinical data
Trade names Votrient
AHFS/ Monograph
MedlinePlus a610013
License data
  • AU: D
  • US: D (Evidence of risk)
Routes of
Legal status
Legal status
Pharmacokinetic data
Protein binding >99%[1]
Metabolism Hepatic (CYP3A4, 1A2 and2C8-mediated)[1]
Biological half-life 31.9 hours[1]
Excretion Faeces (primary), urine (<4%)[1]
CAS Number 444731-52-6 
ATC code L01XE11 (WHO)
PubChem CID 11525740
ChemSpider 9700526 Yes
Chemical data
Formula C21H23N7O2S
Molar mass 437.517 g/mol

////////////PAZOPANIB, GW786034, Votrient, Armala, GW 786034, GW-786034, GW786034GW786034, VOTRIENT, Pazopanib hydrochloride, FDA 2009, Antineoplastic,  Tyrosine Kinase Inhibitors, Protein Kinase Inhibitors,  Renal Cell Carcinoma Therpay,  Soft Tissue Sarcoma Therapy, パゾパニブ塩酸塩 , Пазопаниба Гидрохлорид


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