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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 LIFE SCIENCES 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 PLUS year tenure till date June 2021, 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, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, 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 33 lakh plus views on New Drug Approvals Blog in 233 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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Ropeginterferon alfa-2b

(Disulfide bridge: 2-99, 30-139)

Ropeginterferon alfa-2b

  • AOP2014

CAS 1335098-50-4



PEPTIDE, Antineoplastic, Antiviral

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN), characterized by increased hematocrit and platelet/leukocyte counts, an increased risk for hemorrhage and thromboembolic events, and a long-term propensity for myelofibrosis and leukemia.1,2 Interferon alfa-2b has been used for decades to treat PV but requires frequent dosing and is not tolerated by all patients.2 Ropeginterferon alfa-2b is a next-generation mono-pegylated type I interferon produced from proline-IFN-α-2b in Escherichia coli that has high tolerability and a long half-life.4,6 Ropeginterferon alfa-2b has shown efficacy in PV in in vitro and in vivo models and clinical trials.3,4

Ropeginterferon alfa-2b was approved by the FDA on November 12, 2021, and is currently marketed under the trademark BESREMi by PharmaEssentia Corporation.6

Ropeginterferon alfa-2b, sold under the brand name Besremi, is a medication used to treat polycythemia vera.[1][2][3][4] It is an interferon.[1][3] It is given by injection.[1][3]

The most common side effects include low levels of white blood cells and platelets (blood components that help the blood to clot), muscle and joint pain, tiredness, flu-like symptoms and increased blood levels of gamma-glutamyl transferase (a sign of liver problems).[3] Ropeginterferon alfa-2b can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness.[2] Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).[2]

It was approved for medical use in the European Union in February 2019,[3] and in the United States in November 2021.[2][5] Ropeginterferon alfa-2b is the first medication approved by the U.S. Food and Drug Administration (FDA) to treat polycythemia vera that people can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.[2],FDA%20Approves%20Treatment%20for%20Rare%20Blood%20Disease,FDA%2DApproved%20Option%20Patients%20Can%20Take%20Regardless%20of%20Previous%20Therapies,-ShareFor Immediate Release:November 12, 2021

Today, the U.S. Food and Drug Administration approved Besremi (ropeginterferon alfa-2b-njft) injection to treat adults with polycythemia vera, a blood disease that causes the overproduction of red blood cells. The excess cells thicken the blood, slowing blood flow and increasing the chance of blood clots.

“Over 7,000 rare diseases affect more than 30 million people in the United States. Polycythemia vera affects approximately 6,200 Americans each year,” said Ann Farrell, M.D., director of the Division of Non-Malignant Hematology in the FDA’s Center for Drug Evaluation and Research. “This action highlights the FDA’s commitment to helping make new treatments available to patients with rare diseases.”

Besremi is the first FDA-approved medication for polycythemia vera that patients can take regardless of their treatment history, and the first interferon therapy specifically approved for polycythemia vera.

Treatment for polycythemia vera includes phlebotomies (a procedure that removes excess blood cells though a needle in a vein) as well as medicines to reduce the number of blood cells; Besremi is one of these medicines. Besremi is believed to work by attaching to certain receptors in the body, setting off a chain reaction that makes the bone marrow reduce blood cell production. Besremi is a long-acting drug that patients take by injection under the skin once every two weeks. If Besremi can reduce excess blood cells and maintain normal levels for at least one year, then dosing frequency may be reduced to once every four weeks.

The effectiveness and safety of Besremi were evaluated in a multicenter, single-arm trial that lasted 7.5 years. In this trial, 51 adults with polycythemia vera received Besremi for an average of about five years. Besremi’s effectiveness was assessed by looking at how many patients achieved complete hematological response, which meant that patients had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots. Overall, 61% of patients had a complete hematological response.

Besremi can cause liver enzyme elevations, low levels of white blood cells, low levels of platelets, joint pain, fatigue, itching, upper airway infection, muscle pain and flu-like illness. Side effects may also include urinary tract infection, depression and transient ischemic attacks (stroke-like attacks).

Interferon alfa products like Besremi may cause or worsen neuropsychiatric, autoimmune, ischemic (not enough blood flow to a part of the body) and infectious diseases, which could lead to life-threatening or fatal complications. Patients who must not take Besremi include those who are allergic to the drug, those with a severe psychiatric disorder or a history of a severe psychiatric disorder, immunosuppressed transplant recipients, certain patients with autoimmune disease or a history of autoimmune disease, and patients with liver disease.

People who could be pregnant should be tested for pregnancy before using Besremi due to the risk of fetal harm.

Besremi received orphan drug designation for this indication. Orphan drug designation provides incentives to assist and encourage drug development for rare diseases.

The FDA granted the approval of Besremi to PharmaEssentia Corporation.

Medical uses

In the European Union, ropeginterferon alfa-2b is indicated as monotherapy in adults for the treatment of polycythemia vera without symptomatic splenomegaly.[3] In the United States it is indicated for the treatment of polycythemia vera.[1][2][5]


The effectiveness and safety of ropeginterferon alfa-2b were evaluated in a multicenter, single-arm trial that lasted 7.5 years.[2] In this trial, 51 adults with polycythemia vera received ropeginterferon alfa-2b for an average of about five years.[2] The effectiveness of ropeginterferon alfa-2b was assessed by looking at how many participants achieved complete hematological response, which meant that participants had a red blood cell volume of less than 45% without a recent phlebotomy, normal white cell counts and platelet counts, a normal spleen size, and no blood clots.[2] Overall, 61% of participants had a complete hematological response.[2] The U.S. Food and Drug Administration (FDA) granted the application for Ropeginterferon_alfa-2b orphan drug designation and granted the approval of Besremi to PharmaEssentia Corporation[2]


  1. Bartalucci N, Guglielmelli P, Vannucchi AM: Polycythemia vera: the current status of preclinical models and therapeutic targets. Expert Opin Ther Targets. 2020 Jul;24(7):615-628. doi: 10.1080/14728222.2020.1762176. Epub 2020 May 18. [Article]
  2. How J, Hobbs G: Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature. Cancers (Basel). 2020 Jul 18;12(7). pii: cancers12071954. doi: 10.3390/cancers12071954. [Article]
  3. Verger E, Soret-Dulphy J, Maslah N, Roy L, Rey J, Ghrieb Z, Kralovics R, Gisslinger H, Grohmann-Izay B, Klade C, Chomienne C, Giraudier S, Cassinat B, Kiladjian JJ: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0. [Article]
  4. Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, Thaler J, Schloegl E, Gastl GA, Wolf D, Kralovics R, Gisslinger B, Strecker K, Egle A, Melchardt T, Burgstaller S, Willenbacher E, Schalling M, Them NC, Kadlecova P, Klade C, Greil R: Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015 Oct 8;126(15):1762-9. doi: 10.1182/blood-2015-04-637280. Epub 2015 Aug 10. [Article]
  5. EMA Approved Products: Besremi (ropeginterferon alfa-2b ) solution for injection [Link]
  6. FDA Approved Drug Products: BESREMi (ropeginterferon alfa-2b-njft) injection [Link]

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  1. Jump up to:a b c d e
  2. Jump up to:a b c d e f g h i j k l “FDA Approves Treatment for Rare Blood Disease”U.S. Food and Drug Administration (FDA) (Press release). 12 November 2021. Retrieved 12 November 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. Jump up to:a b c d e f g “Besremi EPAR”European Medicines Agency (EMA). Retrieved 14 November 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ^ Wagner SM, Melchardt T, Greil R (March 2020). “Ropeginterferon alfa-2b for the treatment of patients with polycythemia vera”. Drugs of Today. Barcelona, Spain. 56 (3): 195–202. doi:10.1358/dot.2020.56.3.3107706PMID 32282866S2CID 215758794.
  5. Jump up to:a b “U.S. FDA Approves Besremi (ropeginterferon alfa-2b-njft) as the Only Interferon for Adults With Polycythemia Vera” (Press release). PharmaEssentia. 12 November 2021. Retrieved 14 November 2021 – via Business Wire.
Clinical data
Trade namesBesremi
Other namesAOP2014, ropeginterferon alfa-2b-njft
License dataEU EMAby INNUS DailyMedRopeginterferon_alfa
Routes of
Drug classInterferon
ATC codeL03AB15 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]EU: Rx-only [3]
CAS Number1335098-50-4

/////////Ropeginterferon alfa-2b, FDA 2021, APPROVALS 2021,  BESREMI, PEPTIDE, Antineoplastic, Antiviral, AOP 2014, PharmaEssentia





Tisotumab vedotin

Pipeline – Tisotumab Vedotin – Seagen
A first-in-human antibody–drug conjugate: Hope for patients with advanced solid tumours? | Immunopaedia

Tisotumab vedotin

チソツマブベドチン (遺伝子組換え)Immunoglobulin G1, anti-(human blood-coagulation factor III) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide 

  • HuMax-TF-ADC
  • Immunoglobulin G1, anti-(human tissue factor) (human monoclonal HuMax-TF heavy chain), disulfide with human monoclonal HuMax-TF κ-chain, dimer, tetrakis(thioether) with N-[[[4-[[N-[6-(3-mercapto-2,5-dioxo-1-pyrrolidinyl)-1-oxohexyl]-L-valyl-N5-(aminocarbonyl)-L-ornithyl]amino]phenyl]methoxy]carbonyl]-N-methyl-L-valyl-N-[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenylethyl]amino]-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinyl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

Protein Sequence

Sequence Length: 1324, 448, 448, 214, 214multichain; modified (modifications unspecified)

  DiseaseCervical cancer
CommentAntibody-drug conjugateCAS:1418731-10-8
  • HuMax-TF-ADC
  • Tisotumab vedotin
  • Tisotumab vedotin [WHO-DD]
  • UNII-T41737F88A
  • WHO 10148


25 Great American USA Animated Flags Gifs

FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer………..

On September 20, 2021, the Food and Drug Administration granted accelerated approval to tisotumab vedotin-tftv (Tivdak, Seagen Inc.), a tissue factor-directed antibody and microtubule inhibitor conjugate, for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Approval was based on innovaTV 204, an open-label, multicenter, single-arm clinical trial (NCT03438396). Efficacy was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Sixty-nine percent of patients had received bevacizumab as part of prior systemic therapy. Patients received tisotumab vedotin-tftv 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity.

The main efficacy outcome measures were confirmed objective response rate (ORR) as assessed by an independent review committee (IRC) using RECIST v1.1 and duration of response (DOR). The ORR was 24% (95% CI: 15.9%, 33.3%) with a median response duration of 8.3 months (95% CI: 4.2, not reached).

The most common adverse reactions (≥25%), including laboratory abnormalities, were hemoglobin decreased, fatigue, lymphocytes decreased, nausea, peripheral neuropathy, alopecia, epistaxis, conjunctival adverse reactions, hemorrhage, leukocytes decreased, creatinine increased, dry eye, prothrombin international normalized ratio increased, activated partial thromboplastin time prolonged, diarrhea, and rash. Product labeling includes a boxed warning for ocular toxicity.

The recommended dose is 2 mg/kg (up to a maximum of 200 mg for patients ≥100 kg) given as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity.

View full prescribing information for Tivdak.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

A fully human monoclonal antibody specific for tissue factor conjugated to the microtubule-disrupting agent monomethyl auristatin E (MMAE) via a protease-cleavable valine-citrulline linker.

Tisotumab vedotin, sold under the brand name Tivdak is a human monoclonal antibody used to treat cervical cancer.[1]

Tisotumab vedotin was approved for medical use in the United States in September 2021.[1][2]

Tisotumab vedotin is the international nonproprietary name (INN).[3]


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  1. Jump up to:a b c d
  2. ^ “Seagen and Genmab Announce FDA Accelerated Approval for Tivdak (tisotumab vedotin-tftv) in Previously Treated Recurrent or Metastatic Cervical Cancer”. Seagen. 20 September 2021. Retrieved 20 September 2021 – via Business Wire.
  3. ^ World Health Organization (2016). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 75”. WHO Drug Information30 (1): 159–60. hdl:10665/331046.

External links

Monoclonal antibody
TypeWhole antibody
TargetTissue factor (TF)
Clinical data
Trade namesTivdak
Other namesTisotumab vedotin-tftv
License dataUS DailyMedTisotumab_vedotin
Routes of
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1]
CAS Number1418731-10-8

//////////Tisotumab vedotin, チソツマブベドチン (遺伝子組換え) , FDA 2021, APPROVALS 2021, Antineoplastic, CERVICAL CANCER, CANCER, MONOCLONAL ANTIBODY, UNII-T41737F88A, WHO 10148

Pepinemab, VX 15

(Heavy chain)
(Light chain)
(Disulfide bridge: H22-H96, H132-L218, H145-H201, H224-H’224, H227-H’227, H259-H319, H365-H423, H’22-H’96, H’132-L’218, H’145-H’201, H’259-H’319, H’365-H’423, L23-L92, L138-L198, L’23-L’92, L’138-L’198)



Antineoplastic, Anti-human semaphorin 4D antibody

Monoclonal antibody
Treatment of solid tumors, multiple sclerosis and Huntington’s disease

MOL WGT145481.0022
  • Moab VX15/2503
  • Pepinemab
  • VX-15
  • VX15
  • VX15/2503
Product namePepinemab Biosimilar – Anti-SEMA4D mAb – Research Grade
SourceCAS 2097151-87-4
Expression systemMammalian cells
  • OriginatorVaccinex
  • DeveloperBristol-Myers Squibb; Children’s Oncology Group; Emory University; Merck KGaA; National Cancer Institute (USA); Teva Pharmaceutical Industries; UCLAs Jonsson Comprehensive Cancer Center; Vaccinex
  • ClassAntibodies; Antidementias; Antineoplastics; Immunotherapies; Monoclonal antibodies
  • Mechanism of ActionCD100 antigen inhibitors
  • Orphan Drug StatusYes – Huntington’s disease
  • New Molecular EntityYes
  • Phase IIHuntington’s disease
  • Phase I/IIAlzheimer’s disease; Non-small cell lung cancer; Osteosarcoma; Solid tumours; Squamous cell cancer
  • Phase IColorectal cancer; Malignant melanoma; Pancreatic cancer
  • No development reportedMultiple sclerosis
  • 22 May 2021Pepinemab is still in phase I trials for Colorectal cancer and Pancreatic cancer in USA (NCT03373188)
  • 17 May 2021Phase-I/II clinical trials in Squamous cell cancer (Combination therapy, Late-stage disease, Metastatic disease, Recurrent, Second-line therapy or greater) in USA (IV) (NCT04815720)
  • 17 May 2021Vaccinex plans a phase I/II trial for Alzheimer’s disease (In volunteers), in H2 2021

Semaphorin 4D (SEMA4D) plays a role in multiple cellular processes that contribute to the pathophysiology of neuroinflammatory/neurodegenerative diseases. SEMA4D is, therefore, a uniquely promising target for therapeutic development.

Pepinemab is a novel monoclonal antibody that blocks the activity of SEMA4D, and preclinical testing has demonstrated the beneficial effects of anti-SEMA4D treatment in a variety of neurodegenerative disease models. Vaccinex is committed to the development of this potentially important antibody that has the potential to help people with different neurodegenerative disorders that share common mechanisms of pathology.

Note: Pepinemab (VX15/2503) is an investigational drug currently in clinical studies. It has not been demonstrated to be safe and effective for any disease indication. There is no guarantee that pepinemab (VX15/2503) will be approved for the treatment of any disease by the U.S. Food and Drug Administration or by any other health authority worldwide.

////////////////////Pepinemab, VX15/2503, vx 15, Antineoplastic, Anti-human semaphorin 4D antibody, Monoclonal antibody, solid tumors, multiple sclerosis,  Huntington’s disease, PEPTIDES








CAS 1672668-24-4

383.34 g·mol−1  C17H12F3NO4S





GTPL11251PT 2977 [WHO-DD]BDBM373040

FDA APPROVED 8/13/2021, Welireg

To treat von Hippel-Lindau disease under certain conditions

EMA Drug Information

Disease/ConditionTreatment of von Hippel-Lindau disease
Active Substance3-(((1S,2S,3R)-2,3-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile
Status of Orphan DesignationPositive
Decision Date2020-08-21

FDA approves belzutifan for cancers associated with von Hippel-Lindau disease

On August 13, 2021, the Food and Drug Administration approved belzutifan (Welireg, Merck), a hypoxia-inducible factor inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

Belzutifan was investigated in the ongoing Study 004 (NCT03401788), an open-label clinical trial in 61 patients with VHL-associated RCC (VHL-RCC) diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney. Enrolled patients had other VHL-associated tumors, including CNS hemangioblastomas and pNET. Patients received belzutifan 120 mg once daily until disease progression or unacceptable toxicity.

The primary efficacy endpoint was overall response rate (ORR) measured by radiology assessment, as assessed by an independent review committee using RECIST v1.1. Additional efficacy endpoints included duration of response (DoR), and time- to- response (TTR). An ORR of 49% (95% CI:36, 62) was reported in patients with VHL-associated RCC. All patients with VHL-RCC with a response were followed for a minimum of 18 months from the start of treatment. The median DoR was not reached; 56% of responders had DoR ≥ 12 months and a median TTR of 8 months. In patients with other VHL-associated non-RCC tumors, 24 patients with measurable CNS hemangioblastomas had an ORR of 63% and 12 patients with measurable pNET had an ORR of 83%. Median DoR was not reached, with 73% and 50% of patients having response durations ≥ 12 months for CNS hemangioblastomas and pNET, respectively.

The most common adverse reactions, including laboratory abnormalities, reported in ≥ 20% of patients who received belzutifan were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Anemia and hypoxia from belzutifan use can be severe. In Study 004, anemia occurred in 90% of patients and 7% had Grade 3 anemia. Patients should be transfused as clinically indicated. The use of erythropoiesis stimulating agents for treatment of anemia is not recommended in patients treated with belzutifan. In Study 004, hypoxia occurred in 1.6% of patients. Belzutifan can render some hormonal contraceptives ineffective, and belzutifan exposure during pregnancy can cause embryo-fetal harm.

The recommended belzutifan dosage is 120 mg administered orally once daily with or without food.
View full prescribing information for Welireg.

This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for concurrent submission and review of oncology drugs among international partners. For this review, FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, and the Medicines and Healthcare products Regulatory Agency (MHRA) of the United Kingdom. The application reviews are ongoing at the other regulatory agencies.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, as well as the Assessment Aid and the Product Quality Assessment Aid, voluntary submissions from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 1 month ahead of the FDA goal date.

This application was granted priority review for this indication. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Belzutifan, sold under the brand name Welireg, is a medication used for the treatment of von Hippel–Lindau disease-associated renal cell carcinoma.[1][2][3][4][5][6] It is taken by mouth.[1]

The most common side effects include decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea.[2]

Belzutifan is an hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.[1][2][7]

Belzutifan is the first drug to be awarded an “innovation passport” from the UK Medicines and Healthcare products Regulatory Agency (MHRA).[8][4] Belzutifan was approved for medical use in the United States in August 2021.[2][9] Belzutifan is the first hypoxia-inducible factor-2 alpha inhibitor therapy approved in the U.S.[9]

Medical uses

Belzutifan is indicated for treatment of adults with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.[2]


WO  2019191227


WO 2015035223 9

Figure imgf000075_0002
Figure imgf000301_0001

[01237] 3-r(15,25.3 ?)-2.3-difluoro-l-hvdroxy-7-methylsulfonyl-indan-4- νΠοχν-5-fluoro-benzonitrile (Compound 289)[01238] Step A: r(15.2/?V4- -cvano-5-fluoro-phenoxy)-2-fluoro-7- methylsulfonyl-indan-l -vH acetate: To a stirred solution of 3-fluoro-5-[(15,27?)-2-fluoro-l – hydroxy-7-methylsulfonyl-indan-4-yl]oxy-benzonitrile (2.00 g, 5.47 mmol) in DCM (27 mL) was added 4-(dimethylamino)pyridine (0.2 g, 1.64 mmol) and triethylamine (1.53 mL, 10.9 mmol). Acetic anhydride (1.00 mL, 10.9 mmol) was added dropwise at 0 °C under nitrogen. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHC03 and brine, dried andconcentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(lS,2/?)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl- indan-l-yl] acetate (1.95 g, 87%). LCMS ESI (+) m/z 408 (M+H).[01239] Step B: Γ( 1 .25.35)-3-bromo-4-(3-cvano-5-fluoro-Dhenoxy)-2-fluoro- 7-methylsulfonyl-indan-l-yll acetate and f(15.25,3/?)-3-bromo-4-(3-cyano-5-fluoro- phenoxy)-2-fluoro-7-methylsulfonyl-indan-l -yl1 acetate: To a stirred solution of [(15,2/?)-4- (3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-] -yl] acetate (1.95 g, 4.79 mmol) in 1 ,2-dichloroethane (24 mL) was added N-bromosuccinimide (0.94 g, 5.27 mmol) and 2,2′-azobisisobutyronitrile (8 mg, 0.05 mmol). The reaction mixture was heated at 80 °C for 3 hours. After cooling, the reaction mixture was diluted with DCM, washed with saturated aqueous NaHC03 and brine, dried and concentrated. The residue was purified by column chromatography on silica gel (20-30% EtOAc hexane) to give [(lS,2S,3S)-3-bromo- 4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-l-yl] acetate (1 .52 g, 65%). LCMS ESI (+) m/z 486, 488 (M+H). Further elution with 30-50% EtOAc/hexane gave the more polar product [(lS,2S,3/?)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7- methylsulfonyl-indan-l -yl] acetate (0.583 g, 25%). LCMS ESI (+) m/z 486, 488 (M+H). [01240] Step C: rd5.2^.3 V4-(3-cvano-5-fluoro-phenoxy)-2-fluoro-3- hvdroxy-7-methylsulfonyl-indan- 1 -yll acetate: To a combined mixture of [(1 ,25,35)-3- bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan-l -yl] acetate and [( 15,2S,3/?)-3-bromo-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-7-methylsulfonyl-indan- 1 -yl] acetate prepared in Step B (2.05 g, 4.22 mmol) were added 1 ,2-dimethoxyethane (28 mL) and water (0.050 mL) followed by silver perchlorate hydrate (1.42 g, 6.32 mmol). The reaction mixture was heated at 70 °C for 2 hours. After cooling, the reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-50%) to give [(15,2/?,35)-4-(3-cyano-5-fluoro-phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan- 1 -yl] acetate (0.416 g, 23%) as the less polar product. LCMS ESI (+) m/z 441 (M+NH4+). Further elution with 60% EtOAc/hexane gave [(15,2/?,3R)-4-(3-cyano-5-fluoro-phenoxy)-2- fluoro-3-hydroxy-7-methylsulfonyl-indan-l-yl] acetate (0.58 g, 32 %). LCMS ESI (+) m/z 441 (M+NH4+).[01241] Step D: r(15.25.3/? -4-(3-cvano-5-fluoro-phenoxyV2.3-difluoro-7- methylsulfonyl-indan-l-vH acetate: To a stirred solution of [(15,2/?,35)-4-(3-cyano-5-fluoro- phenoxy)-2-fluoro-3-hydroxy-7-methylsulfonyl-indan-l-yl] acetate (416 mg, 0.98 mmol) in DCM (10 mL) was added (diethylamino)sulfur trifluoride (DAST) (0.26 mL, 2.0 mmol) at – 78 °C under nitrogen. The reaction mixture was allowed to warm to 0 °C and stirred for 15 minutes. The reaction was quenched by saturated aqueous NaHC03. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (20-40% EtOAc/hexane) to give [(15,25,3/?)- 4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl-indan-l -yl] acetate (310 mg, 74%). LCMS ESI (+) m/z 426 (M+H).[01242] Step E: 3-r(15.25.3^)-2.3-difluoro-l-hvdroxy-7-methylsulfonyl-indan-4-vnoxy-5-fluoro-benzonitrile (Compound 289): Prepared as described in Example 288 Step F substituting [(l ?)-4-(3-cyano-5-fluoro-phenoxy)-3,3-difluoro-7-methylsulfonyl-indan- 1-yl] acetate with [(15,25,3/?)-4-(3-cyano-5-fluoro-phenoxy)-2,3-difluoro-7-methylsulfonyl- indan-l-yl] acetate. LCMS ESI (+) m/z 384 (M+H); Ή NMR (400 MHz, CDC13): δ 8.13 (d, 1H), 7.31-7.25 (m, 1 H), 7.23-7.19 (m, 1 H), 7.14-7.09 (m, 1H), 7.04 (d, 1H), 6.09-5.91 (m, 1 H), 5.87-5.80 (m, 1 H), 5.25-5.05 (m, 1H), 3.32 (s, 3H), 2.95 (d, 1H). 
PatentWO 2016145032 289

PATENTWO 2016145045WO 2016168510WO 2016057242WO 2019191227 

PMIDPublication DateTitleJournal
312821552019-08-083-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977), a Hypoxia-Inducible Factor 2α (HIF-2α) Inhibitor for the Treatment of Clear Cell Renal Cell CarcinomaJournal of medicinal chemistry
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WO-2020146758-A1Methods to treat mitochondrial-associated dysfunctions or diseases2019-01-10 
WO-2020092100-A1Solid dispersions and pharmaceutical compositions comprising a substituted indane and methods for the preparation and use thereof2018-10-30 
TW-202003430-AMethods of reducing inflammation of the digestive system with inhibitors of HIF-2-alpha2018-03-28 
WO-2019191227-A1Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha2018-03-28 
US-2019151347-A1Compositions and methods of modulating hif-2a; to improve muscle generation and repair2017-11-20
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US-2019048421-A1Biomarkers of response to hif-2-alpha inhibition in cancer and methods for the use thereof2015-09-21 
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US-10335388-B2Combination therapy of a HIF-2-alpha inhibitor and an immunotherapeutic agent and uses thereof2015-04-172019-07-02
US-2018140569-A1Combination therapy of a hif-2-alpha inhibitor and an immunotherapeutic agent and uses thereof2015-04-17 
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US-10278942-B2Compositions for use in treating pulmonary arterial hypertension2015-03-112019-05-07
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US-9969689-B2Aryl ethers and uses thereof2013-09-092018-05-15
WO-2015035223-A1Aryl ethers and uses thereof2013-09-09

Merck Team Wins 2021 Pete Dunn Award

‎05-17-2021 10:52 AM


The ACS Green Chemistry Institute (GCI) Pharmaceutical Roundtable honors the work of Stephen Dalby, François Lévesque, Cecilia Bottecchia and Jonathan McMullen at Merck with the 2021 Peter J. Dunn Award for Green Chemistry & Engineering Impact in the Pharmaceutical Industry. The team’s innovation is titled, “Greener Manufacturing of Belzutifan (MK-6482) Featuring a Photo-Flow Bromination.”

Belzutifan is an important new drug used in the treatment of cancer and other non-oncology diseases. Acquired by Merck in 2019 through the purchase of Peloton Therapeutics, a new, greener manufacturing process for its synthesis was needed. Over the next 18 months, the team developed a more direct route from commodity chemical to API, employed new reaction conditions, particularly in the oxidation sequence, and incorporated new technology, photo-flow.

Despite this accelerated timeline, the team achieved a five-fold improvement in overall yield with a commensurate 73% reduction in process mass intensity (PMI) compared to the original route. Notably, the Merck team also developed a visible light-initiated radical bromination performed in flow. According to the L.-C. Campeau, Executive Director and Head of Process Chemistry and Discovery Process Chemistry at Merck, this is the “first example of a photo-flow reaction run on manufacturing scale at Merck and represents the linchpin of the synthesis.”

The improved process for Belzutifan, which is expected to launch this year, will reduce the waste associated with its manufacture and is aligned with Merck’s corporate sustainability goals.

“The Merck team delivered an excellent example of the application of innovative technologies to develop a more sustainable synthesis of the pharmaceutically-active compound, Belzutifan,” comments Paul Richardson, Director of Oncology and Chemical Synthesis at Pfizer and Co-Chair of the ACS GCI Pharmaceutical Roundtable. “Using the guiding principles of green chemistry, for example, in the use of catalysis and a relatively benign reaction media, further illustrate the Merck team’s work as worthy of recognition for the 2021 Peter Dunn Award.”

The award will be presented at the June 11 GC&E Friday, part of the 25th Annual Green Chemistry & Engineering Conference. During this session from 10 a.m. – 1 p.m., Stephen Dalby & Jon MacMullen will be discussing the details of this innovative process.


  1. Jump up to:a b c d
  2. Jump up to:a b c d e f “FDA approves belzutifan for cancers associated with von Hippel-Lindau”U.S. Food and Drug Administration (FDA). 13 August 2021. Retrieved 13 August 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  3. ^ “Belzutifan”SPS – Specialist Pharmacy Service. 18 March 2021. Retrieved 25 April 2021.
  4. Jump up to:a b “MHRA awards first ‘innovation passport’ under new pathway”RAPS (Press release). Retrieved 25 April 2021.
  5. ^ “Merck Receives Priority Review From FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482)” (Press release). Merck. 16 March 2016. Retrieved 25 April 2021 – via Business Wire.
  6. ^ “FDA Grants Priority Review to Belzutifan for von Hippel-Lindau Disease–Associated RCC”Cancer Network. Retrieved 26 April 2021.
  7. ^ {{cite journal |vauthors=Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, Michaelson MD, Appleman LJ, Thamake S, Perini RF, Zojwalla NJ, Jonasch E | display-authors=6 |title=Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis |journal=Nat Med |volume= |issue= |pages= |date=April 2021 |pmid=33888901 |doi=10.1038/s41591-021-01324-7 }
  8. ^ “First Innovation Passport awarded to help support development and access to cutting-edge medicines”Medicines and Healthcare products Regulatory Agency (MHRA) (Press release). 26 February 2021. Retrieved 14 August 2021.
  9. Jump up to:a b “FDA Approves Merck’s Hypoxia-Inducible Factor-2 Alpha (HIF-2α) Inhibitor Welireg (belzutifan) for the Treatment of Patients With Certain Types of Von Hippel-Lindau (VHL) Disease-Associated Tumors” (Press release). Merck. 13 August 2021. Retrieved 13 August 2021 – via Business Wire.

External links

  • “Belzutifan”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT04195750 for “A Study of Belzutifan (MK-6482) Versus Everolimus in Participants With Advanced Renal Cell Carcinoma (MK-6482-005)” at
  • Clinical trial number NCT03401788 for “A Phase 2 Study of Belzutifan (PT2977, MK-6482) for the Treatment of Von Hippel Lindau (VHL) Disease-Associated Renal Cell Carcinoma (RCC) (MK-6482-004)” at
Clinical data
Trade namesWelireg
Other namesMK-6482, PT2977
License dataUS DailyMedBelzutifan
Routes of
By mouth
Drug classAntineoplastic
ATC codeNone
Legal status
Legal statusUS: ℞-only [1][2]
showIUPAC name
CAS Number1672668-24-4 [KEGG]
PubChem CID117947097
PDB ligand72Q (PDBeRCSB PDB)
Chemical and physical data
Molar mass383.34 g·mol−1
3D model (JSmol)Interactive image

/////////Belzutifan, Welireg, FDA 2021, APPROVALS 2021, MK 6482, PT 977, Antineoplastic






Tucidinostat, Chidamide

Tucidinostat (JAN/USAN/INN).png

Tucidinostat, Chidamide



Mol weight390.4103

Antineoplastic, Histone deacetylase inhibitor

Chidamide (Epidaza) is a histone deacetylase inhibitor (HDI) developed in China.[1] It was also known as HBI-8000.[2] It is a benzamide HDI and inhibits Class I HDAC1HDAC2HDAC3, as well as Class IIb HDAC10.[3]

Chidamide is approved by the Chinese FDA for relapsed or refractory peripheral T-cell lymphoma (PTCL), and has orphan drug status in Japan.[2][better source needed] As of April 2015 it is only approved in China.[1]

Chidamide is being researched as a treatment for pancreatic cancer.[4][5][6] However, it is not US FDA approved for the treatment of pancreatic cancer.

Chidamide (Epidaza®), a class I HDAC inhibitor, was discovered and developed by ChipScreen and approved by the CFDA in December 2014 for the treatment of recurrent of refractory peripheral T-cell lymphoma. Chidamide, also known as CS055 and HBI- 8000, is an orally bioavailable benzamide type inhibitor of HDAC isoenzymes class I 1–3, as well as class IIb 10, with potential antineoplastic activity. It selectively binds to and inhibits HDAC, leading to an increase in acetylation levels of histone protein H3.74 This agent also inhibits the expression of signaling kinases in the PI3K/ Akt and MAPK/Ras pathways and may result in cell cycle arrest and the induction of tumor cell apoptosis. Currently, phases I and II clinical trials are underway for the treatment of non-small cell lung cancer and for the treatment of breast cancer, respectively.

Chemical Synthesis

The scalable synthetic approach to chidamide very closely follows the discovery route. The sequence began with the condensation of commercial nicotinaldehyde (52) and malonic acid (53) in a mixture of pyridine and piperidine. Next, activation of acid 54 with N,N0-carbonyldiimidazole (CDI) and subsequent reaction with 4-aminomethyl benzoic acid (55) under basic conditions afforded amide 56 in 82% yield. Finally, activation of 56 with CDI prior to treatment with 4-fluorobenzene- 1,2-diamine (57) and subsequent treatment with TFA and THF yielded chidamide (VIII) in 38% overall yield from 52. However, no publication reported that mono-N-Boc-protected bis-aniline was used to approach Chidamide.


  1. Jump up to:a b Lowe D (April 2015). “China’s First Homegrown Pharma”Seeking Alpha.
  2. Jump up to:a b “Chipscreen Biosciences Announces CFDA Approval of Chidamide (Epidaza) for PTCLs in China”. PR Newswire Association LLC.
  3. ^ “HUYA Bioscience International Grants An Exclusive License For HBI-8000 In Japan And Other Asian Countries To Eisai”. PR Newswire Association LLC. February 2016.
  4. ^ Qiao Z, Ren S, Li W, Wang X, He M, Guo Y, et al. (April 2013). “Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells”. Biochemical and Biophysical Research Communications434 (1): 95–101. doi:10.1016/j.bbrc.2013.03.059PMID 23541946.
  5. ^ Guha M (April 2015). “HDAC inhibitors still need a home run, despite recent approval”. Nature Reviews. Drug Discovery14 (4): 225–6. doi:10.1038/nrd4583PMID 25829268S2CID 36758974.
  6. ^ Wang SS (2015-04-02). “A New Cancer Drug, Made in China”. The Wall Street Journal. Retrieved 13 April 2015.
Clinical data
Trade namesEpidaza
Other namesTucidinostat
showIUPAC name
CAS Number1616493-44-7 
PubChem CID9800555
Chemical and physical data
Molar mass390.418 g·mol−1
3D model (JSmol)Interactive image

/////Tucidinostat, Antineoplastic, Histone deacetylase inhibitor, ツシジノスタット , Epidaza, Chidamide, APPROVALS 2021, JAPAN 2021



one time



(Heavy chain)
(Light chain)
(Disulfide bridge: H22-H96, H130-L214, H143-H199, H222-H’222, H225-H’225, H257-H317, H363-H421, H’22-H’96, H’130-L’214, H’143-H’199, H’257-H’317, H’363-H’421, L23-L88, L134-L194, L’23-L’88, L’194-L’134)

>Heavy Chain
>Light Chain
  1. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]


Immunoglobulin G4, anti-​(programmed cell death protein 1 (PDCD1)​) (humanized clone ABT1 γ4-​chain)​, disulfide with humanized clone ABT1 κ-​chain, dimer

Protein Sequence

Sequence Length: 1314, 443, 443, 214, 214multichain; modified (modifications unspecified)

  • GSK-4057190
  • GSK4057190
  • TSR 042
  • TSR-042
  • WBP-285
  • ANB 011
Mol weight144183.6677

Jemperli FDA 2021/4/22 AND EMA 2021/4/21





Dostarlimab, sold under the brand name Jemperli, is a monoclonal antibody medication used for the treatment of endometrial cancer.[1][2][3][4]

The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation.[1][2] The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased.[1][2]

Dostarlimab is a programmed death receptor-1 (PD-1)–blocking antibody.[1][2]

Dostarlimab was approved for medical use in the United States in April 2021.[1][2][5]

JemperliInjection50 mg/1mLIntravenousGlaxoSmithKline LLC2021-04-22Not applicableUS flag 

Medical uses

Dostarlimab is indicated for the treatment of adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinum-containing regimen.[1][2]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior  platinum-containing regimen.

Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after  a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.

The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review (BICR) according to RECIST 1.1. Confirmed ORR was 42.3% (95% CI: 30.6%, 54.6%). The complete response rate was 12.7% and partial response rate was 29.6%. Median DOR was not reached, with 93.3% of patients having  durations  ≥6 months (range: 2.6 to 22.4 months, ongoing at last assessment).

Serious adverse reactions occurred in 34% of patients receiving dostarlimab-gxly. Serious adverse reactions in >2% of patients included sepsis , acute kidney injury , urinary tract infection , abdominal pain , and pyrexia . The most common adverse reactions (≥20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (≥2%) were anemia and transaminases increased. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.

View full prescribing information for Jemperli.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

FDA also approved the VENTANA MMR RxDx Panel as a companion diagnostic device for selecting endometrial cancer patients for treatment with dostarlimab-gxly.

This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

This application was granted priority review, and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Side effects

Serious adverse reactions in >2% of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia.[1][2]

Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.[1][2]


Like several other available and experimental monoclonal antibodies, it is a PD-1 inhibitor. As of 2020, it is undergoing Phase I/II and Phase III clinical trials.[6][7][8] The manufacturer, Tesaro, announced prelimary successful results from the Phase I/II GARNET study.[6][9][10]

In 2020, the GARNET study announced that Dostarlimab was demonstrating potential to treat a subset of women with recurrent or advanced endometrial cancer.[11]

April 2021, Dostarlimab is approved for the treatment of recurrent or advanced endometrial cancer with deficient mismatch repair (dMMR), which are genetic anomalies abnormalities that disrupt DNA repair.[12]

On April 22, 2021, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC).[1] Efficacy was evaluated based on cohort (A1) in GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors.[1]

Society and culture

Legal status

On 25 February 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[13] The applicant for this medicinal product is GlaxoSmithKline (Ireland) Limited.[13]


  1. Jump up to:a b c d e f g h i j k “FDA grants accelerated approval to dostarlimab-gxly for dMMR endometri”U.S. Food and Drug Administration(FDA) (Press release). 22 April 2021. Retrieved 22 April 2021. This article incorporates text from this source, which is in the public domain.
  2. Jump up to:a b c d e f g h i “Jemperli- dostarlimab injection”DailyMed. Retrieved 28 April 2021.
  3. ^ Statement On A Nonproprietary Name Adopted By The USAN Council – DostarlimabAmerican Medical Association.
  4. ^ World Health Organization (2018). “International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 119” (PDF). WHO Drug Information32 (2).
  5. ^ “FDA grants accelerated approval for GSK’s Jemperli (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer” (Press release). GlaxoSmithKline. 22 April 2021. Retrieved 22 April 2021 – via PR Newswire.
  6. Jump up to:a b Clinical trial number NCT02715284 for “A Phase 1 Dose Escalation and Cohort Expansion Study of TSR-042, an Anti-PD-1 Monoclonal Antibody, in Patients With Advanced Solid Tumors (GARNET)” at
  7. ^ Clinical trial number NCT03981796 for “A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY)” at
  8. ^ Clinical trial number NCT03602859 for “A Phase 3 Comparison of Platinum-Based Therapy With TSR-042 and Niraparib Versus Standard of Care Platinum-Based Therapy as First-Line Treatment of Stage III or IV Nonmucinous Epithelial Ovarian Cancer (FIRST)” at
  9. ^ “Data from GARNET study indicates robust activity of dostarlimab in patients with advanced or recurrent endometrial cancer”Tesaro (Press release). Retrieved 1 January 2020.
  10. ^ Scalea B (28 May 2019). “Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status”Targeted Oncology. Retrieved 1 January 2020.
  11. ^ “GSK Presents New Data from the GARNET Study Demonstrating Potential of Dostarlimab to Treat a Subset of Women with Recurrent or Advanced Endometrial Cancer – MedNews” Retrieved 29 April 2020.
  12. ^ “FDA Approves New Immunotherapy for Endometrial Cancer”Medscape. Retrieved 23 April 2021.
  13. Jump up to:a b “Jemperli: Pending EC decision”European Medicines Agency (EMA) (Press release). 25 February 2021. Retrieved 22 April 2021.

External links

  • “Dostarlimab”Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT02715284 for “Study of TSR-042, an Anti-programmed Cell Death-1 Receptor (PD-1) Monoclonal Antibody, in Participants With Advanced Solid Tumors (GARNET)” at
  1. Kaplon H, Muralidharan M, Schneider Z, Reichert JM: Antibodies to watch in 2020. MAbs. 2020 Jan-Dec;12(1):1703531. doi: 10.1080/19420862.2019.1703531. [Article]
  2. Temrikar ZH, Suryawanshi S, Meibohm B: Pharmacokinetics and Clinical Pharmacology of Monoclonal Antibodies in Pediatric Patients. Paediatr Drugs. 2020 Apr;22(2):199-216. doi: 10.1007/s40272-020-00382-7. [Article]
  3. Green AK, Feinberg J, Makker V: A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503. [Article]
  4. Deshpande M, Romanski PA, Rosenwaks Z, Gerhardt J: Gynecological Cancers Caused by Deficient Mismatch Repair and Microsatellite Instability. Cancers (Basel). 2020 Nov 10;12(11). pii: cancers12113319. doi: 10.3390/cancers12113319. [Article]
  5. FDA Approved Drug Products: Jemperli (dostarlimab-gxly) for intravenous injection [Link]
  6. FDA News Release: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Link]
  7. Statement on a Nonproprietary Name Adopted by the USAN Council: Dostarlimab [Link]
Monoclonal antibody
TypeWhole antibody
Clinical data
Trade namesJemperli
Other namesTSR-042, WBP-285, dostarlimab-gxly
License dataUS DailyMedDostarlimab
Routes of
Drug classAntineoplastic
ATC codeL01XC40 (WHO)
Legal status
Legal statusUS: ℞-only [1][2]
CAS Number2022215-59-2
PubChem SID384585344
Chemical and physical data
Molar mass144325.73 g·mol−1

/////////Dostarlimab,  PEPTIDE, ANTINEOPLASTIC, CANCER, ドスタルリマブ , GSK 4057190, GSK4057190, TSR 042, TSR-042, WBP-285, FDA 2021, EU 2021


File:Sitravatinib.svg - Wikipedia





1,1-Cyclopropanedicarboxamide, N-[3-fluoro-4-[[2-[5-[[(2-methoxyethyl)amino]methyl]-2-pyridinyl]thieno[3,2-b]pyridin-7-yl]oxy]phenyl]-N’-(4- fluorophenyl)-


シトラバチニブ; ситраватиниб , سيترافاتينيب , 司曲替尼 , 
Mol weight629.6763


Sitravatinib (MGCD516)





Antineoplastic, Receptor tyrosine kinase inhibitor

Sitravatinib (MGCD516) is an experimental drug for the treatment of cancer. It is a small molecule inhibitor of multiple tyrosine kinases.

Sitravatinib is being developed by Mirati Therapeutics.[1]

Ongoing phase II trials include a trial for liposcarcoma,[2] a combination trial for non-small cell lung cancer,[3] and a combination trial with nivolumab for renal cell carcinoma.[4]

Mirati Therapeutics and licensee BeiGene are developing sitravatinib, an oral multitargeted kinase inhibitor which inhibits Eph, Ret, c-Met and VEGF-1, -2 and -3, DDR, Trk, Axl kinases, CHR4q12, TYRO3 and Casitas B-lineage, in combination with immune checkpoint inhibitors, for treating advanced solid tumors.

In March 2021, sitravatinib was reported to be in phase 3 clinical development.


WO2009026717 , in which sitravatinib was first disclosed, claiming heterocyclic compounds as multi kinase inhibitors.

Scheme 10

Example 52
N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1 , 1 -dicarboxamide

Step 1 : tert-Butyl (6-(7-(2-Fluoro-4-(1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxamido)phenoxy)thieno [3 ,2-b]pyridin-2-yl)pyridin-3 -y l)methyl(2-methoxyethyl)carbamate (146)
To aniline 126 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol) in dry DMF

(20 mL) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarbpxylic acid (0.35 g, 1.5 mmol) and HATU (0.72 g, 1.9 mmol) and the mixture was stirred at r.t. for 18 h. It was then partitioned between ethyl acetate and water, the organic phase was washed with water, IM NaOH, brine, dried (MgSO4), filtered, and concentrated. Silica gel chromatography (ethyl acetate) afforded title compound Ϊ46 (0.60 g, 74 % yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J = 8.2, 2.1 Hz, 1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J = 8.8 Hz, 2H), 6.65 (d, J = 5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H), 1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).
Step 2. N-(3-Fluoro-4-(2-(5-((2-methoxyethylamino)methyl)pyridin-2-yl)thieno[3,2-blpyridin-7-yloxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (147)
To the compound 146 (0.59 g, 0.81 mmol) in dichloromethane (50 mL) was added TFA (3 mL). The solution was stirred for 18 h then concentrated. The residue was partitioned between dichloromethane and 1 M NaOH, and filtered to remove insolubles. The organic phase was collected, washed with IM NaOH, brine, dried (MgSO4), filtered, and concentrated to afford title compound 147 (0.35 g, 69 % yield).

1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.55 (d, J = 1.6 Hz, 1H), 8.51 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.92-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.52-7.43 (m, 2H), 7.17-7.12 (m, 2H), 6.64 (d, J = 5.5 Hz, 1H), 3.77 (s, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.23 (s, 3H), 2.64 (t, J = 5.7 Hz, 2H), 1.46 (br s, 4H). MS (m/z): 630.1 (M+H).


WO 2009026720



Novel, stable crystalline polymorphic forms (form D) of sitravatinib , useful for treating a multi tyrosine kinase-associated cancer eg sarcoma, glioma, non-small cell lung, bladder, kidney, ovarian, gastric, breast or liver cancer. 

 International publication No. W02009/026717A disclosed compounds with the inhibition activities of multiple protein tyrosine kinases, for example, the inhibition activities of VEGF receptor kinase and HGF receptor kinase. In particular, disclosed N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1) is a multi-tyrosine kinase inhibitor with demonstrated potent inhibition of a closely related spectrum of tyrosine kinases, including RET, CBL, CHR4ql2, DDR and Trk, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression.


Compound 1

[004] Compound 1 shows tumor regression in multiple human xenograft tumor models in mice, and is presently in human clinical trials as a monotherapy as well as in combination for

treating a wide range of solid tumors. Compound 1 is presently in Phase 1 clinical trial for patients with advanced cancer, in Phase 2 studies for patients with advanced liposarcoma and non-small cell lung cancer (NSCLC).

[005] The small scale chemical synthesis of the amorphous Compound 1 had been disclosed in the Example 52 (compound 147) of W02009/026717A, however, in order to prepare the API of Compound 1 with high quality and in large quantity, crystalline forms of Compound 1 would be normally needed so the process impurities could be purged out by recrystallization.

Practically, it is difficult to predict with confidence which crystalline form of a particular compound will be stable, reproducible, and suitable for phamaceutical processing. It is even more difficult to predict whether or not a particular crystalline solid state form will be produced with the desired physical properties for pharmaceutical formulations.

[006] For all the foregoing reasons, there is a great need to produce crystalline forms of Compound 1 that provide manufacturing improvements of the pharmaceutical composition.

The present invention advantageously addresses one or more of these needs.


Preparation of N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2- yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-l,l- dicarboxamide (Compound 1)

[0085] This Example illustrates the preparation ofN-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane- 1,1 -di carboxamide (Compound 1).

[0086] Step 1: N-(Y6-bromopyridin-3-vDmethvD-2-methoxyethan-l-amine (Compound 1A)

Compound 1A

[0087] To a stirred solution of 2-Methoxyethylamine (3.0 eq) in dichloromethane (DCM) (12 vol) was added Molecular sieves (0.3 w/w) and stirred for 2 hours at 25±5°C under nitrogen atmosphere. The reaction mass water content was monitored by Karl Fischer analysis until the water content limit reached 0.5 % w/w. Once the water content limit was reached, the reaction mass cooled to 5±5°C and 6-bromonicotinaldehyde (1.0 eq) was added lot wise over period of 30 minutes to the above reaction mass at 5±5°C. The reaction mass was stirred for 30±5 minutes at 5±5°C and acetic acid (1.05 eq) was added drop wise at 5±5°C. After completion of the addition, the mass was slowly warmed to 25±5°C and stirred for 8 h to afford Compound 1 A. The imine formation was monitored by HPLC.

[0088] Step 2: tert-butyl (Y6-brom opyri din-3 -vQmethvO(2-m ethoxy ethvDcarbamate (Compound


Compound 1B

[0089] Charged Compoud 1A (1.0 eq) in THF (5.0 vol) was added and the reaction mass was stirred for 30 minutes at 25±5°C under nitrogen atmosphere. The reaction mass was cooled to temperature of about 10±5°C. Di-tert- butyl dicarbonate (1.2 eq) was added to the reaction mass at 10±5°C under nitrogen atmosphere and the reaction mass temperature was raised to 25±5°C and the reaction mass for about 2 hours. The progress of the reaction was monitored by HPLC. After IPC completion, a prepared solution of Taurine (1.5 eq) in 2M aq NaOH (3.1 vol) was charged and stirred at 10±5°C for 16 h to 18 h. The reaction mass was further diluted with 1M aq.NaOH solution (3.7 vol) and the layers were separated. The aqueous layer was extracted with DCM (2 x 4.7vol) and the extract combined with the organic layer. The combined organic layers were washed with 1M aq.NaOH solution (3.94 vol), followed by water (2×4.4 vol), and dried over sodium sulfate (2.0 w/w) . The filtrate was concentrated under reduced pressure below 40° C until no distillate was observed. Tetrahydrofuran (THF) was sequentially added (1×4 vol and lx 6vol) and concentrated under reduced pressure below 40°C until no distillate was observed to obtained Compound IB as light yellow colored syrup liquid.

[0090] Step 3: tert-butyl 7-chlorothieno[3.2-b1pyridin-2-yl)pyridin-3-yl )methyl)(2- 

methoxyethvDcarbamate (Compound 1C)

Compound 1C

[0091] To a stirred solution of 7-chlorothieno[3,2-b]pyridine (1.05 eq) in tetrahydrofuran (7 vol) was added n-butyl lithium (2.5 M in hexane) drop wise at -15±10°C and stirred for 90 minutes at same temperature under nitrogen atmosphere. Zinc chloride (1.05 eq) was added to the reaction mass at -15±10°C. The reaction mass was slowly warmed to 25±5°C and stirred for 45 minutes under nitrogen atmosphere to afford Compound 1C. The progress of the reaction was monitored by HPLC.

[0092] Step 4: tert-butyl (Y6-(7-(4-amino-2-fluorophenoxy)thieno[3.2-b1pyridin-2-v0pyridin-3-vDmethvD(2-methoxyethvDcarbamate (Compound ID)

Compound 1D

[0093] 3-fluoro-4-hydroxybenzenaminium chloride (1.2 eq) in DMSO (3.9 vol) at 25±5°C was charged under nitrogen atmosphere and the reaction mass was stirred until observance of a clear solution at 25±5°C. t-BuOK was added lot wise under nitrogen atmosphere at 25±10°C. The reaction mass temperature was raised to 45±5°C and maintained for 30 minutes under nitrogen atmosphere. Compound 1C was charged lot-wise under nitrogen atmosphere at 45±5°C and stirred for 10 minutes at 45± 5°C.The reaction mixture was heated to 100± 5°C and stirred for 2 hrs. The reaction mass is monitored by HPLC.

[0094] After reaction completion, the reaction mass was cooled to 10± 5°C and quenched with chilled water (20 vol) at 10±5°C. The mass temperature was raised to 25± 5°C and stirred for 7-8 h. The resulting Compound ID crude was collected by filtration and washed with 2 vol of water. Crude Compound ID material taken in water (10 vol) and stirred for up to 20 minutes at 25±5°C. The reaction mass was heated to 45±5°C and stirred for 2-3 h at 45±5°C, filtered and vacuum-dried.

[0095] Crude Compound ID was taken in MTBE (5 vol) at 25±5°C and stirred for about 20 minutes at 25±5°C. The reaction mass temperature was raised to 45±5°C, stirred for 3-4 h at 45±5°C and then cooled to 20±5°C. The reaction mass was stirred for about 20 minutes at 20±5°C, filtered, followed by bed wash with water (0. 5 vol) and vacuum-dried.

[0096] The crude material was dissolved in acetone (10 vol) at 25±5°C and stirred for about 2h at 25±5°C. The reaction mass was filtered through a celite bed and washed with acetone (2.5 vol). The filtrate was slowly diluted with water (15 vol) at 25±5°C. The reaction mass was stirred for 2-3 h at 25±5°C, filtered and bed washed with water (2 vol) & vacuum-dried to afford Compound ID as brown solid.

[0097] Step 5 : 1 -((4-((2-(5-(((tert-butoxycarbonv0(2-methoxy ethvOaminolmethvOpyri din-2 -yl )thieno[3.2-b]pyridin-7-yl )oxy)-3 -fluorophenyl icarbamoyl level opropane-1 -carboxylic acid (Compound IE)

Compound 1E

[0098] To a solution of Compound ID (1.0 eq.) in tetrahydrofuran (7 vol.), aqueous potassium carbonate (1.0 eq.) in water (8 vol.) was added. The solution was cooled to 5±5°C, and stirred for about 60 min. While stirring, separately triethylamine (2.0 eq.) was added to a solution of 1,1-cyclopropanedicarboxylic acid (2.0 eq.) in tetrahydrofuran (8 vol.), at 5±5°C, followed by thionyl chloride (2.0 eq.) and stirred for about 60 min. The acid chloride mass was slowly added to the Compound ID solution at 5±5°C. The temperature was raised to 25±5°C and stirred for 3.0 h. The reaction was monitored by HPLC analysis.

[0099] After reaction completion, the mass was diluted with ethyl acetate (5.8 vol.), water (5.1 vol.), 10% (w/w) aqueous hydrochloric acid solution (0.8 vol.) and 25% (w/w) aqueous sodium chloride solution (2 vol.). The aqueous layer was separated and extracted with ethyl acetate (2 x 5 vol.). The combined organic layers were washed with a 0.5M aqueous sodium bicarbonate solution (7.5 vol.). The organic layer was treated with Darco activated charcoal (0.5 w/w) and sodium sulfate (0.3 w/w) at 25±5°C for 1.0 h. The organic layer was filtered through celite and washed with tetrahydofuran (5.0 vol.). The filtrate was concentrated under vacuum below 50°C to about 3 vol and co-distilled with ethyl acetate (2 x 5 vol.) under vacuum below 50°C up to ~ 3.0 vol. The organic layer was cooled to 15±5°C, stirred for about 60 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). The material was dried under vacuum at 40±5°C until water content was less than 1% to afford Compound IE as brown solid.

[00100] Step 6: tert-butyl (Y6-(7-(2-fluoro-4-(T-(Y4-fluorophenvDcarbamovDcvclopropane-l-carboxamido)phenoxy)thieno[3.2-b]pyridin-2-v0pyri din-3 – (2- 
methoxyethvDcarbamate (Compound IF)

[00101] Pyridine (1.1 eq.) was added to a suspension of Compound IE (1.0 eq.) in tetrahydrofuran (10 vol.) and cooled to 5±5°C. Thionyl chloride (2.0 eq.) was added and stirred for about 60 min. The resulting acid chloride formation was confirmed by HPLC analysis after quenching the sample in methanol. Separately, aqueous potassium carbonate (2.5 eq.) solution (7.0 vol. of water) was added to a solution of 4-fluoroaniline (3.5 eq.) in tetrahydrofuran (10 vol.), cooled to 5±5°C, and stirred for about 60 min. The temperature of the acid chloride mass at 5±5°C was raised to a temperature of about 25±5°C and stirred for 3 h. The reaction monitored by HPLC analysis.

[00102] After completion of the reaction, the solution was diluted with ethyl acetate (25 vol.), the organic layer was separated and washed with a 1M aqueous sodium hydroxide solution (7.5 vol.), a 1M aqueous hydrochloric acid solution (7.5 vol.), and a 25% (w/w) aqueous sodium chloride solution (7.5 vol.). The organic layer was dried and and filtered with sodium sulfate (1.0 w/w). The filtrate was concentrated ~ 3 vol under vacuum below 50°C and co-distilled with ethyl acetate (3 x 5 vol.) under vacuum below 50°C to ~ 3.0 vol. Ethyl acetate (5 vol.) and MTBE (10 vol.) were charged, heated up to 50±5°C and stirred for 30-60 min. The mixture was cooled to 15±5°C, stirred for about 30 min., filtered, and the solid was washed with ethyl acetate (2.0 vol.). MGB3 content was analyzed by HPLC analysis. The material was dried under vacuum at 40±5°C until the water content reached about 3.0% to afford Compound IF as brown solid.

[00103] Step 7 : N-(3-fluoro-4-((2-(5-(((2-methoxyethv0amino)methv0pyridin-2-yl )thieno[3.2-b]pyridin-7-yl )oxy)phenyl)-N-(4-fluorophenyl level opropane-1. 1 -dicarboxamide (Compound 1)

Compound 1

[0100] To a mixture of Compound IF in glacial acetic acid (3.5 vol.) concentrated hydrochloric acid (0.5 vol.) was added and stirred at 25±5°C for 1.0 h. The reaction was monitored by HPLC analysis.

[0101] After reaction completion, the mass was added to water (11 vol.) and stirred for 20±5°C for 30 min. The pH was adjusted to 3.0 ± 0.5 using 10% (w/w) aqueous sodium bicarbonate solution and stirred for 20±5°C for approximately 3.0 h.. The mass was filtered, washed with water (4 x 5.0 vol.) and the pH of filtrate was checked after every wash. The material was dried under vacuum at 50±5°C until water content was about 10%.

[0102] Crude Compound 1 was taken in ethyl acetate (30 vol.), heated to 70±10°C, stirred for 1.0 h., cooled to 25±5°C, filtered, and washed with ethyl acetate (2 vol.). The material was dries under vacuum at 45±5°C for 6.0 h.

[0103] Crude Compound 1 was taken in polish filtered tetrahydrofuran (30 vol.) and pre washed Amberlyst A-21 Ion exchange resin and stirred at 25±5°C until the solution became clear. After getting the clear solution, the resin was filtered and washed with polish filtered tetrahydrofuran (15 vol.). The filtrate was concentrated by -50% under vacuum below 50°C and co-distilled with polish filtered IPA (3 x 15.0 vol.) and concentrated up to -50% under vacuum below 50°C. Charged polish filtered IPA (15 vol.) was added and the solution concentrated under vacuum below 50°C to – 20 vol. The reaction mass was heated to 80±5°C, stirred for 60 min. and cooled to 25±5°C. The resultant reaction mass was stirred for about 20 hours at 25±5°C. The reaction mass was cooled to 0±5°C, stirred for 4-5 hours, filtered, and washed with polish filtered IPA (2 vol.). The material was dried under vacuum at 45±5°C, until the water content was about 2%, to obtain the desired product Compound 1. ¾-NMR (400 MHz, DMSO- d): 510.40 (s, 1H), 10.01 (s, 1H), 8.59 – 8.55 (m, 1H), 8.53 (d, J= 5.6 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J= 8.0 Hz, 1H), 7.96 – 7.86 (m, 2H), 7.70 – 7.60 (m, 2H), 7.56 – 7.43 (m, 2H), 7.20 – 7.11 (m, 2H), 6.66 (d, J= 5.6 Hz, 1H), 3.78 (s, 2H), 3.41 (t, J= 5.6 Hz, 2H), 3.25 (s, 3H), 2.66 (t, J= 5.6 Hz, 2H), 1.48 (s, 4H)ppm. MS: M/e 630 (M+l)+.


Preparation of Crystalline Form D of N-(3-fluoro-4-((2-(5-(((2- methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4- fluorophenyl)cyclopropane-l, 1-dicarboxamide

EXAMPLE 2A: Preparation of Compound 1 Crystalline Form D

[0104] To a 50 L reactor, 7.15 Kg of Compound 1, 40 g of Form D as crystal seed and 21 L acetone (>99%) were added. The mixture was heated to reflux ( ~56 °C) for 1~2 h. The mixture was agitated with an internal temperature of 20±5 °C for at least 24 h. Then, the suspension was filtered and washed the filter cake with 7 L acetone. The wet cake was dried under vacuum at <45 °C, to obtain 5.33 kg of Compound 1 of desired Form D

[0105] X-Ray Powder Diffraction (XRPD)

The XRPD patterns were collected with a PAN alytical X’ Pert PRO MPD diffractometer using auincident beam of Cu radiation produced using au Optix long, fine-focus source. An elliptically graded multilayer mirror was used to focus Cu Ka X -rays through the specimens and onto the detector. Prior to the analysis, a silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si Ill peak is consistent with the NIST-certified position. A specimen of each sample was sandwiched between 3 -pm -thick films and analyzed in transmission geometly. A beam-stop, short autiscatter extension, and an autiscatter knife edge were used to minimize the background generated by air. Sober slits for the incident aud diffracted beauls were used to minimize broadening from axial divergence. The diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimens and Data Collector software v. 2.2b. Pattern Match v2.3.6 was used to create XRPD patterns.

[0106] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D), see Figure 1A. The XRPD pattern yielded is substantially the same as that shown in Figure 3C.

[0107] Differential Scanning Calorimetry (DSC)

[0108] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Temperature calibration was performed using octane, phenyl salicylate, indium, tin, and zinc. The TAWN sensitivity was 11.9. The samples were placed into aluminum DSC pans, covered with lids, and the weights were accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The pan lids were pierced prior to sample analyses. The method name on the thermograms is an abbreviation for the start and end temperature as well as the heating rate; e.g., -30-250-10 means “from ambient to 250°C, at 10°C/min.” The nitrogen flow rate was 50.0 mL/min. This instrument does not provide gas pressure value as required by USP because it is the same as atmospheric pressure.

[0109] A broad small endotherm with a peak maximum at approximately 57°C to 62°C (onset ~20°C to 22°C) followed by a sharp endotherm with a peak maximum at approximately 180°C (onset ~178°C) were observed. These events could be due to the loss of volatiles and a melt, respectively (see Figure IB).

[0110] In an alternative embodiment Form D was prepared as follows. Designated Material O was suspended in 600 pL of acetone. Initial dissolution was observed followed by re precipitation. The amount of suspended solids was not measured because the target of the experiment was to get a suspension with enough solids to slurry isolate and collect XRPD data. Based on the solubility of Form D in acetone a very rough estimate for the scale of the experiment is about 80-100mg. The suspension was stirred at ambient temperature for approximately 2 5 weeks after which the solids were isolated by centrifugation with filtration. XRPD data appeared to be consistent with Form D The sample was then dried in vacuum oven at ~40 °C for ~2 5 hours. The XRPD pattern of the final solids was consistent with Form D EXAMPLE 2B: Preparation of Compound 1 Form D

[0111] 427.0 mg of Compound 1 was dissolved in 5 mL of THF to obtain a clear brown solution. The resulting solution was filtered, and the filtrate evaporated under flow of nitrogen. A sticky solid was obtained, which was dried under vacuum in room temperature for ~5 min, still a sticky brown solid obtained. It was dissolved in 0.2 mL of EtOAc and sonicated to dissolve. The solution obtained was stirred at room temperature for 15 min and a solid precipitated. The resulting solid was added 0.4 mL of EtOAc and stirred in room temperature for 21 h 40 min to ontian a suspension. The solid was spparated from mother liquor by centrifugation, then the resulting solid was resuspended the in 0.6 mL of EtOAc and stirred in room temperature for 2 days. The solid was isolated by centrifugation, to obtain Compound 1 of desired Form D.

[0112] The X-ray powder diffraction (XRPD) pattern was used to characterize the Compound 1 obtained, which showed that the Compound 1 was in Crystalline Form D of Compound 1 (Compound 1 Form D).

EXAMPLE 2C: Preparation of Compound 1 Form D

[0113] Single crystal X-ray diffraction data of Compound 1 was collected at 180 K on a Rigaku XtaLAB PRO 007HF(Mo) diffractometer, with Mo Ka radiation (l = 0.71073 A). Data reduction and empirical absorption correction were performed using the CrysAlisPro program. The structure was solved by a dual-space algorithm using SHELXT program. All non-hydrogen atoms could be located directly from the difference Fourier maps. Framework hydrogen atoms were placed geometrically and constrained using the riding model to the parent atoms. Final structure refinement was done using the SHELXL program by minimizing the sum of squared deviations of F2 using a full-matrix technique.

Preparation of Compound 1 Form D ( a Single Crystal )

[0114] Compound 1 Form D was dissolved in a mixture of acetone/ ACN (1/2) with the concentration of Compound 1 at ~7 mg/mL. A block single crystal was obtained, which was a single crystal.

[0115] The XRPD pattern was used to characterize the single crystal of Compound 1 Form D obtained, see Figure 2A. The crystal structural data are summarized in Table IB. The refined single crystal structure were shown in Figure 2B. The single crystal structure of Compound 1 Form D is in the P-1 space group and the triclinic crystal system. The terminal long alkyl chain is found to have large ellipsoids, indicating high mobility with disordered atoms.

[0116] The theoretical XRPD calculated from the single crystal structure and experimental XRPD are essentially similar (Figure 2A). A few small peaks are absent or shift because of orientation preference, disorder and tested temperature (180 K for single crystal data and 293 K for experimental one).

[0117] Table IB. Crystal Data and Structure Refinement for Compound 1 Form D (a Single Crystal)


  1. ^
  2. ^ “MGCD516 in Advanced Liposarcoma and Other Soft Tissue Sarcomas – Full Text View –”.
  3. ^ “Phase 2 Study of Glesatinib, Sitravatinib or Mocetinostat in Combination With Nivolumab in Non-Small Cell Lung Cancer – Full Text View –”.
  4. ^ “MGCD516 Combined With Nivolumab in Renal Cell Cancer (RCC) – Full Text View –”.
showIUPAC name
CAS Number1123837-84-2
Chemical and physical data
Molar mass629.68 g·mol−1
3D model (JSmol)Interactive image

///////////// sitravatinib, phase 3, シトラバチニブ , MGCD516, MG-516Sitravatinib (MGCD516)UNII-CWG62Q1VTBCWG62Q1VTBMGCD-516ситраватиниб , سيترافاتينيب , 司曲替尼 , Antineoplastic, MGCD 516

#sitravatinib, #phase 3, #シトラバチニブ , #MGCD516, #MG-516#Sitravatinib (MGCD516), #UNII-#CWG62Q1VTB, #CWG62Q1VTB, #MGCD-516ситраватиниб , سيترافاتينيب , 司曲替尼 , #Antineoplastic, #MGCD516


Tagraxofusp タグラクソフスプ

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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.;
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Lett. 2004, 14, 5551.
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K.; Xie, C. Pure Appl. Chem. 2003, 75, 1.
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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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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.


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  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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