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DR ANTHONY MELVIN CRASTO Ph.D

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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 38 lakh plus views on New Drug Approvals Blog in 227 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc He has total of 32 International and Indian awards

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This Little Weed is one of the Most Useful Medicines on the Planet

June 27, 2014 1:48 am / Leave a comment

plantain

http://www.thefutureofhealthnow.com/little-weed-one-useful-medicines-planet/

There are two major types of plantain in BC, Canada: Lance and Broadleaf. Generally, all 200-plus varieties of plantain yield the same results. It grows especially well in poor, rocky soil (such as driveways) and is often seen alongside dandelion. More often than not, you will see plantain growing in gravel pits and construction sites as nature seeks to regenerate the soil. Introduced to North America in the 1600s, it was once called “White Man’s Foot” by the Native Americans who witnessed that where the Europeans tread and disrupted the soil, plantain sprung up.

How To Treat Migraines With Red Raspberry Leaf

June 27, 2014 1:41 am / 1 Comment on How To Treat Migraines With Red Raspberry Leaf

How To Treat Migraines With Red Raspberry Leaf

http://www.selfsufficiencymagazine.com/how-to-treat-migraines-with-red-raspberry-leaf/

If you, or someone close to you, suffers from migraines then you’ll know just how frustrating it can be. You can try all sorts of approaches and conventional medications, but often they don’t work!

Why not try some red raspberry leaf tea? It’s packed full of essential vitamins and minerals and is widely used for helping to cure those painful headaches.

Allergy Test Could Spot Unexpected Milk Allergens Medical Diagnostics: Test can identify both common and unfamiliar milk allergens for a patient

June 27, 2014 1:38 am / Leave a comment

Milk Allergen Tracker

Researchers run an allergic patient’s blood serum (top row) past a column of magnetic beads (orange circles) dotted with antibodies (black Y-shapes) that bind human immunoglobulin E (IgE) antibodies. The scientists next chemically crosslink any bound IgE antibodies (red Y-shapes) to the beads, then expose the now-personalized IgE-bound column to milk (bottom row). Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) identifies the mass and helps predict the structure of both familiar and unfamiliar bound milk allergens.

Credit: Natalia Gasilova

http://cen.acs.org/articles/92/web/2014/06/Allergy-Test-Spot-Unexpected-Milk.html?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+analytical_scene+%28Chemical+%26+Engineering+News%3A+Analytical+SCENE%29

Mast Therapeutics’ MST-188 Would Fit Well In Merck’s Drug Development Pipeline

June 26, 2014 5:37 am / 3 Comments on Mast Therapeutics’ MST-188 Would Fit Well In Merck’s Drug Development Pipeline

http://seekingalpha.com/article/2283763-mast-therapeutics-mstminus-188-would-fit-well-in-mercks-drug-development-pipeline

MST-188 (purified poloxamer 188)

MST-188 is an investigational agent, formulated using a purified form of poloxamer 188. Substantial research has demonstrated that poloxamer 188 has cytoprotective and hemorrheologic properties and inhibits inflammatory processes and thrombosis. We believe the pharmacologic effects of poloxamer 188 support the development of MST-188 in multiple clinical indications for diseases and conditions characterized by microcirculatory insufficiency (endothelial dysfunction and/or impaired blood flow). We are enrolling patients in EPIC, a pivotal phase 3 study of MST-188 in sickle cell disease. In addition, our MST-188 pipeline includes development programs in adjunctive thrombolytic therapy (e.g., acute limb ischemia, stroke), heart failure, and resuscitation (i.e., restoration of circulating blood volume and pressure) following major trauma.

What is MST-188 and How Does it Work?

POTENTIAL APPLICATIONS OF MST-188

We believe the pharmacodynamic properties of MST-188 (cytoprotective, hemorheologic, anti-inflammatory, antithrombotic/pro-fibrinolytic) enable it simultaneously to address, or prevent activation of, multiple biochemical pathways that can result in microcirculatory insufficiency, a multifaceted condition principally characterized by endothelial dysfunction and impaired blood flow. The microcirculation is responsible for the delivery of blood through the smallest blood vessels (arterioles and capillaries) embedded within tissues. A healthy endothelium is critical to a functional microcirculation. Without the regular delivery of blood and transfer of oxygen to tissue from the microcirculation, individual cells (in both the endothelium and tissue) are unable to maintain aerobic metabolism and, through a series of complex and interrelated events, eventually die. If microcirculatory insufficiency continues, the patient will suffer tissue necrosis, organ damage and, eventually, death.

Microcirculatory Insuffiency

Sickle Cell Disease (SCD)

MST-188 for Sickle Cell Disease

Sickle cell disease is an inherited genetic disorder that affects millions of people worldwide. It is the most common inherited blood disorder in the U.S., where it is estimated to affect approximately 90,000 to 100,000 people, including approximately 1 in 500 African American births. The estimated annual cost of medical care for patients with sickle cell disease in the U.S. exceeds $1.0 billion.

Sickle cell disease is characterized by the “sickling” of red blood cells, which normally are disc-shaped, deformable and move easily through the microvasculature carrying oxygen from the lungs to the rest of the body. Sickled, or crescent-shaped, red blood cells, on the other hand, are rigid and sticky and tend to adhere to each other and the walls of blood vessels. The hallmark of the disease is recurring episodes of severe pain commonly known as crisis or vaso-occlusive crisis. Vaso-occlusive crisis occurs when the proportion of sickled cells rises, leading to obstruction of small blood vessels and reduced blood flow to organs and bone marrow. This obstruction results in intense pain and tissue damage, including tissue death. Over a lifetime, the accumulated burden of damaged tissue frequently results in the loss of vital organ function and a greatly reduced lifespan. In fact, organ failure is the leading cause of death in adults with sickle cell disease¹ and the average life expectancy is around 45 years.²

We estimate that, in the U.S., sickle cell disease results in approximately 100,000 hospitalizations and, in addition, approximately 69,000 emergency department treat-and-release encounters each year. Further, although the number is difficult to measure, we estimate that the number of untreated vaso-occlusive crisis events is substantial and in the hundreds of thousands in the U.S. each year.

1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376.
2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.

Complications of Arterial Disease

MST-188 for Complications of Arterial Disease

Data from experimental models demonstrate the potential for MST-188, when used alone or in combination with thrombolytics, to improve outcomes in patients experiencing complications of arterial disease resulting from atherosclerotic and thromboembolic processes. We believe that, based on the similar pathophysiology of atherosclerotic arterial disease, an agent that is effective in one form of occlusive arterial disease also may be effective in its other manifestations. We plan to first demonstrate the potential of MST-188 in patients with acute limb ischemia, a complication of peripheral arterial disease.

Arterial disease resulting from atherosclerotic and thromboembolic processes is associated with significant morbidity and mortality. It is a common circulatory problem in which plaque-obstructed arteries reduce the flow of blood to tissues. Atherosclerosis occurs with advanced age, smoking, hypertension, diabetes and dyslipidemia. Peripheral arterial disease, or PAD, refers to disease affecting arteries outside the brain and heart and often refers to blockage of arteries in the lower extremities. Progression of PAD is associated with ongoing obstruction, or occlusion, of the peripheral arteries, which can occur slowly over time or may lead to a sudden, acute occlusion. Acute limb ischemia, or ALI, is a sudden decrease in perfusion of a limb, typically in the legs, that often threatens viability of the limb. The condition is considered acute if clinical presentation occurs within approximately two weeks after symptom onset. ALI rapidly threatens limb viability because there is insufficient time for new blood-vessel growth to compensate for loss of perfusion.

A Brief History of MST-188

Definitions

RheothRx – A first-generation product with unpurified, excipient-grade poloxamer 188 as the active ingredient. Associated with elevated serum creatinine.

MST-188 (formerly known as ANX-188, FLOCOR and CRL-5861) – A second-generation product with purified poloxamer 188 as the active ingredient. Certain low molecular weight substances present in excipient-grade poloxamer 188 that are associated with elevated serum creatinine are not present in MST-188. No clinically significant elevations in creatinine have been observed in clinical studies conducted with the purified material (>300 administrations).

Early Development: The CytRx Corporation/Burroughs Wellcome Alliance

Poloxamer 188 is a well studied compound. It was originally used as an emulsifying agent in topical wound cleansers and parenteral nutrition products. However, the therapeutic use of poloxamer 188 was largely conceived by Dr. Robert Hunter, MD, PhD (Distinguished Professor and Chairman, Department of Pathology and Laboratory Medicine, University of Texas Medical School at Houston). Dr. Hunter (then at Emory University) identified the compound’s rheologic, cytoprotective and antithrombotic activities through an extensive series of laboratory studies. His work led to the formation of CytRx Corporation, a start-up company that licensed Dr. Hunter’s inventions from Emory. CytRx conducted a wide range of pre-clinical and clinical studies with first-generation poloxamer 188, then known as RheothRx. These studies led to a major alliance with Burroughs Wellcome (today, GSK). Burroughs also performed an extensive series of nonclinical studies and 8 clinical trials, primarily focused on acute myocardial infarction (AMI). Early studies investigating RheothRx were promising. The largest AMI trial planned to enroll approximately 20,000 patients. However, during the 3,000-patient lead-in phase of this study, elevations in serum creatinine were observed, particularly in those patients aged 65 years and older and in subjects with elevated creatinine at baseline. This phenomenon was referred to as “acute renal dysfunction” and resulted in the discontinuation of the program by Glaxo, which had recently merged with Burroughs Wellcome.

Addressing Renal Toxicity and Pursuing Sickle Cell Disease

After Glaxo returned the RheothRx program, CytRx investigated the source of the renal dysfunction and determined the elevation in serum creatinine was attributable to preferential absorption of certain low molecular weight substances by the proximal tubule epithelial cells in the kidney. CytRx developed a proprietary method of manufacture based on supercritical fluid chromatography that reduced the level of these low molecular weight substances present in poloxamer 188, creating what is now known as purified poloxamer 188. Nonclinical testing of purified poloxamer 188 (now known as MST-188), demonstrated less accumulation in kidney tissue, less pronounced vacuolization of proximal tubular epithelium, more rapid recovery from vacuolar lesions, and less effect on serum creatinine. A full report of the differential effects of commercial-grade and purified poloxamer 188 on renal function has been published.¹

Subsequently, CytRx sought to re-introduce MST-188 into the clinic. However, CytRx lacked the resources to conduct a 20,000-patient heart attack study. Instead, they focused the development of MST-188 in sickle cell disease (SCD), a rare disease with a huge unmet need and in which RheothRx had demonstrated positive results in a pilot Phase 2 study conducted by Burroughs Wellcome. In that Phase 2 study (n=50), RheothRx significantly reduced the duration of crisis, pain intensity, and total analgesic use and showed trends to shorter days of hospitalization in the subgroup of patients who received the full dose of study drug (n=31). These data were reported more fully by Adams-Graves et al.² Notably, CytRx conducted safety studies in both adult and pediatric sickle cell patients and, even at significantly higher levels of exposure than anticipated therapeutic doses, there were no clinically significant changes in serum creatinine observed and no acute kidney failure reported. Based on these promising Phase 1 and 2 results, CytRx subsequently launched a randomized, double-blind, placebo-controlled Phase 3 study of MST-188 in 350 patients with sickle cell disease. The primary endpoint was a reduction in the duration of a painful crisis. However, CytRx concluded the study at 255 patients, in part due to capital constraints. Nonetheless, the study demonstrated treatment benefits in favor of MST-188. However, it did not achieve statistical significance in the primary study endpoint (p=0.07). Mast believes that enrolling fewer than the originally-planned number of patients and key features of the study’s design negatively affected the outcome of the primary endpoint. In particular, the study assumed that most patients would resolve their crisis within one week (168 hours). However, a substantial number of patients did not achieve crisis resolution within 168 hours and were assigned a “default” value of 168 hours, which had a potentially significant effect on the primary endpoint. Notably, in a post hoc “responder’s analysis” of the intent-to-treat population (n=249), which analyzed the proportion of patients who achieved crisis resolution at 168 hours (excluding those who had been assigned the default of 168 hours), over 50% of subjects receiving MST-188 achieved crisis resolution within 168 hours, compared to 37% in the control group (p=0.02). Data from the Phase 3 study are reported more fully by Orringer et al.³ Following conclusion of the Phase 3 study, CytRx merged with a private company and modified its business strategy by discontinuing development of all of its existing programs (including MST-188) to focus on assets held by the private company with which it merged.

SynthRx

After the corporate reorganization at CytRx, a group of individuals, including Dr. Hunter, formed a private entity, which they named SynthRx, Inc., to acquire rights to the data, know-how, and extensive clinical and pre-clinical and manufacturing information necessary to continue development of MST-188. SynthRx developed new intellectual property and conducted additional analyses of the existing data. However, they were unable to raise capital to fund development of MST-188 during the “great recession.”

Mast Therapeutics

In 2010, Mast Therapeutics met with Dr. Hunter and his colleagues to negotiate the acquisition of SynthRx and continue the development of MST-188. The merger was finalized in April 2011.

Since April 2011, Mast Therapeutics has re-established the unique manufacturing process through a partnership with Pierre Fabre (FRA) and met with the FDA multiple times to discuss a pivotal study protocol for MST-188 in sickle cell disease. In 2013, Mast initiated the EPIC study, a 388-patient pivotal Phase 3 trial of MST-188 in sickle cell disease, and, in 2014, Mast initiated its second MST-188 clinical program with a Phase 2, proof-of-concept study of MST-188 in combination with rt-PA in patients with acute limb ischemia. In addition, based on recent nonclinical study data showing improvements in cardiac ejection fraction and key biomarkers and prior studies showing MST-188 improved cardiac function without increasing cardiac energy requirements, Mast has announced its intent to pursue clinical development of MST-188 in heart failure.

1. Emanuele, M. and Balasubramaniam, B. Differential Effects of Commercial-Grade and Purified Poloxamer 188 on Renal Function. Drugs in R&D April 2014. Available at http://link.springer.com/article/10.1007/s40268-014-0041-0
2. Adams-Graves P, Kedar A, Koshy M, et al. RheothRx (Poloxamer 188) Injection for the Acute Painful Episode of Sickle Cell Disease: A Pilot Study. Blood 1997;90:2041-6
3. Orringer EP, Casella JF, Ataga KI, et al. Purified poloxamer 188 for treatment of acute vaso-occlusive crisis of sickle cell disease: A randomized controlled trial. JAMA 2001;286(17):2099-106

EPIC’s study drug, MST-188, is a new class of drug that acts by attaching to the damaged surfaces of the cell membranes, potentially improving blood flow and oxygen delivery.

Improving blood flow and oxygen delivery may reduce the duration and severity of pain crises faced by sickle cell patients.

Minisci reactions: Versatile CH-functionalizations for medicinal chemists

June 26, 2014 4:46 am / 1 Comment on Minisci reactions: Versatile CH-functionalizations for medicinal chemists

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DOI: 10.1039/C1MD00134E (Review Article) Med. Chem. Commun.,2011, 2, 1135-1161

Show Compounds Show Chemical Terms Show Biomedical Terms

Minisci reactions: Versatile CH-functionalizations for medicinal chemists

Matthew A. J. Duncton† *
Renovis, Inc. (a wholly-owned subsidiary of Evotec AG), Two Corporate Drive, South San Francisco, CA 94080, United States. E-mail: mattduncton@yahoo.com; Tel: +1 917-345-3183

Received 24th May 2011 , Accepted 3rd July 2011

First published on the web 22nd August 2011

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

The addition of a radical to a heteroaromatic base is commonly referred to as a Minsici reaction. Such reactions constitute a broad-set of selective CH-functionalization processes. This review describes some of the major applications of Minisci reactions and related processes to medicinal or biological chemistry, and highlights some potential developments within this area.

Introduction

The aim of this review is to summarize the use of Minisci reactions within medicinal chemistry, and to highlight some future opportunities to continue progression of this chemistry. As such, it is not an aim that detailed mechanistic information, or a comprehensive list of examples be described. For this, the reader is directed to excellent articles from Minisci, Harrowven and Bowman.^1–3 Rather, the review is written to show that Minisci reactions are extremely valuable CH-functionalization processes within medicinal chemistry. However, their use has been somewhat under-utilized when compared with other well-known selective transformations (e.g. palladium-catalysed cross-couplings). Therefore, it is hoped that in the future, Minisci chemistry will continue to develop, such that the reactions become a staple-set of methods for medicinal and biological chemists alike.

To aid discussion, the review is divided in to several sections. First, some historical perspective is given. This is followed by a discussion of scope and limitations. The main-body of the review describes some specific examples of Minisci reactions and related processes, with a focus on their use within medicinal, or biological chemistry. Finally, brief mention is given to potential future applications, some of which may be beneficial in providing ‘high-content’ diverse libraries for screening.

http://pubs.rsc.org/en/content/articlehtml/2011/md/c1md00134e

…………………….

WIKI

The Minisci reaction is a named reaction in organic chemistry. It is a radical substitution to an aromatic compound, in particular to a heteroaromatic base, that introduces an alkyl group. The reaction was published about in 1971 by F. Minisci.^[1] The aromatic compound is generally electron-deficient and with N-aromatic compounds the nitrogen atom is protonated.^[2] A typical reaction is that between pyridine and pivalic acid to 2-tert-butylpyridine with silver nitrate, sulfuric acid and ammonium persulfate. The reaction resembles Friedel-Crafts alkylation but with opposite reactivity and selectivity.^[3]

The Minisci reaction proceeds regioselectively and enables the introduction of a wide range of alkyl groups.^[4] A side-reaction is acylation.^[5] The ratio between alkylation and acylation depends on the substrate and the reaction conditions. Due to the simple raw materials and the simple reaction conditions the reaction has many applications in heterocyclic chemistry.^[6]^[7]

Mechanism

A free radical is formed from the carboxylic acid in an oxidative decarboxylation with silver salts and an oxidizing agent. The oxidizing agent reoxidizes the silver salt. The radical then reacts with the aromatic compound. The ultimate product is formed by rearomatisation. The acylated product is formed from the acyl radical.^[4]^[5]

References

F. Minisci, R. Bernardi, F. Bertini, R. Galli, M. Perchinummo: Nucleophilic character of alkyl radicals—VI : A new convenient selective alkylation of heteroaromatic bases, in: Tetrahedron 1971, 27, 3575–3579.
Minisci reaction Jie Jack Li in Name Reactions 2009, 361-362, doi:10.1007/978-3-642-01053-8_163
Strategic applications of named reactions in organic synthesis: background and detailed mechanisms László Kürti, Barbara Czakó 2005
F. Fontana, F. Minisci, M. C. N. Barbosa, E. Vismara: Homolytic acylation of protonated pyridines and pyrazines with α-keto acids: the problem of monoacylation, in: J. Org. Chem. 1991, 56, 2866–2869; doi:10.1021/jo00008a050.
M.-L. Bennasar, T. Roca, R. Griera, J. Bosch: Generation and Intermolecular Reactions of 2-Indolylacyl Radicals, in: Org. Lett. 2001, 3, 1697–1700; doi:10.1021/ol0100576.
P. B. Palde, B. R. McNaughton, N. T. Ross, P. C. Gareiss, C. R. Mace, R. C. Spitale, B. L. Miller: Single-Step Synthesis of Functional Organic Receptors via a Tridirectional Minisci Reaction, in: Synthesis 2007, 15, 2287–2290; doi:10.1055/s-2007-983792.
J. A. Joules, K. Mills: Heterocyclic Chemistry, 5. Auflage, S. 125–141, Blackwell Publishing, Chichester, 2010, ISBN 978-1-4051-9365-8.

Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

June 26, 2014 4:14 am / 1 Comment on Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

Sorafenib

(4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide)

BAY 43-9006

Bayer HealthCare has obtained approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for its Nexavar (sorafenib) for treatment of patients with unresectable differentiated thyroid carcinoma.

http://www.pharmaceutical-technology.com/news/newsbayers-nexavar-receives-japanese-approval-4300422?WT.mc_id=DN_News

Nexavar’s approval in Japan is supported by data from the multicentre, placebo-controlled Phase III DECISION (‘stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer’) study.

The international Phase III DECISION study, which randomised a total of 417 patients, met its primary endpoint of extended progression-free survival. Safety and tolerability profile of sorafenib was generally consistent with the known profile of sorafenib.

The most common treatment-emergent adverse events in the sorafenib arm were hand-foot skin reaction, diarrhea, alopecia, weight loss, fatigue, hypertension and rash.

Nexavar was awarded orphan drug status by the MHLW for thyroid carcinoma in September 2013.

Sorafenib (co-developed and co-marketed by Bayer and Onyx Pharmaceuticals as Nexavar),^[1] is a drug approved for the treatment of primary kidney cancer (advanced renal cell carcinoma), advanced primary liver cancer (hepatocellular carcinoma), and radioactive iodine resistant advanced thyroid carcinoma.

Medical uses

At the current time sorafenib is indicated as a treatment for advanced renal cell carcinoma (RCC), unresectable hepatocellular carcinomas (HCC) and thyroid cancer.^[2]^[3]^[4]^[5]

Kidney cancer

An article in The New England Journal of Medicine, published January 2007, showed compared with placebo, treatment with sorafenib prolongs progression-free survival in patients with advanced clear cell renal cell carcinoma in whom previous therapy has failed. The median progression-free survival was 5.5 months in the sorafenib group and 2.8 months in the placebo group (hazard ratio for disease progression in the sorafenib group, 0.44; 95% confidence interval [CI], 0.35 to 0.55; P<0.01).^[6] A few reports described patients with stage IV renal cell carcinomas that were successfully treated with a multimodal approach including neurosurgical, radiation, and sorafenib.^[7] This is one of two TGA-labelled indications for sorafenib, although it is not listed on the Pharmaceutical Benefits Scheme for this indication.^[5]^[8]

Liver cancer

At ASCO 2007, results from the SHARP trial^[9] were presented, which showed efficacy of sorafenib in hepatocellular carcinoma. The primary endpoint was median overall survival, which showed a 44% improvement in patients who received sorafenib compared to placebo (hazard ratio 0.69; 95% CI, 0.55 to 0.87; p=0.0001). Both median survival and time to progression showed 3-month improvements. There was no difference in quality of life measures, possibly attributable to toxicity of sorafenib or symptoms related to underlying progression of liver disease. Of note, this trial only included patients with Child-Pugh Class A (i.e. mildest) cirrhosis. The results of the study appear in the July 24, 2008, edition of The New England Journal of Medicine. Because of this trial Sorafenib obtained FDA approval for the treatment of advanced hepatocellular carcinoma in November 2007.^[10]

In a randomized, double-blind, phase II trial combining sorafenib with doxorubicin, the median time to progression was not significantly delayed compared with doxorubicin alone in patients with advanced hepatocellular carcinoma. Median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone.^[10] A prospective single-centre phase II study which included the patients with unresectable hepatocellular carcinoma (HCC)concluding that the combination of sorafenib and DEB-TACE in patients with unresectable HCC is well tolerated and safe, with most toxicities related to sorafenib.^[11] This is the only indication for which sorafenib is listed on the PBS and hence the only Government-subsidised indication for sorafenib in Australia.^[8] Along with renal cell carcinoma, hepatocellular carcinoma is one of the TGA-labelled indications for sorafenib.^[5]

Thyroid cancer

A phase 3 clinical trial has started recruiting (November 2009) to use sorafenib for non-responsive thyroid cancer.^[12] The results were presented at the ASCO 13th Annual Meeting and are the base for FDA approval. The Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The Phase 3 DECISION trial showed significant improvement in progression-free survival but not in overall survival. However, as is known, the side effects were very frequent, specially hand and foot skin reaction.^[13]

Adverse effects

Adverse effects by frequency
Note: Potentially serious side effects are in bold.
Very common (>10% frequency)

Lymphopenia
Hypophosphataemia^{[Note 1]}
Haemorrhage^{[Note 2]}
Hypertension^{[Note 3]}
Diarrhea
Rash
Alopecia (hair loss; occurs in roughly 30% of patients receiving sorafenib)
Hand-foot syndrome
Pruritus (itchiness)
Erythema
Increased amylase
Increased lipase
Fatigue
Pain^{[Note 4]}
Nausea
Vomiting^{[Note 5]}^[14]

Common (1-10% frequency)

Leucopoenia^{[Note 6]}
Neutropoenia^{[Note 7]}
Anaemia^{[Note 8]}
Thrombocytopenia^{[Note 9]}
Anorexia (weight loss)
Hypocalcaemia^{[Note 10]}
Hypokalaemia^{[Note 11]}
Depression
Peripheral sensory neuropathy
Tinnitus^{[Note 12]}
Congestive heart failure
Myocardial infarction^{[Note 13]}
Myocardial ischaemia^{[Note 14]}
Hoarseness
Constipation
Stomatitis^{[Note 15]}
Dyspepsia^{[Note 16]}
Dysphagia^{[Note 17]}
Dry skin
Exfoliative dermatitis
Acne
Skin desquamation
Arthralgia^{[Note 18]}
Myalgia^{[Note 19]}
Renal failure^{[Note 20]}
Proteinuria^{[Note 21]}
Erectile dysfunction
Asthenia (weakness)
Fever
Influenza-like illness

Transient increase in transaminase

Uncommon (0.1-1% frequency)

Folliculitis
Infection
Hypersensitivity reactions^{[Note 22]}
Hypothyroidism^{[Note 23]}
Hyperthyroidism^{[Note 24]}
Hyponatraemia^{[Note 25]}
Dehydration
Reversible posterior leukoencephalopathy
Hypertensive crisis
Rhinorrhoea^{[Note 26]}
Interstitial lung disease-like events^{[Note 27]}
Gastro-oesophageal reflux disease (GORD)
Pancreatitis^{[Note 28]}
Gastritis^{[Note 29]}
Gastrointestinal perforations^{[Note 30]}
Increase in bilirubin leading, potentially, to jaundice^{[Note 31]}
Cholecystitis^{[Note 32]}
Cholangitis^{[Note 33]}
Eczema
Erythema multiforme^{[Note 34]}
Keratoacanthoma^{[Note 35]}
Squamous cell carcinoma
Gynaecomastia (swelling of the breast tissue in men)
Transient increase in blood alkaline phosphatase
INR abnormal
Prothrombin level abnormal
bulbous skin reaction^[15]

Rare (0.01-0.1% frequency)

QT interval prolongation^{[Note 36]}
Angiooedema^{[Note 37]}
Anaphylactic reaction^{[Note 38]}
Hepatitis^{[Note 39]}
Radiation recall dermatitis
Stevens-Johnson syndrome^{[Note 40]}
Leucocytoclastic vasculitis
Toxic epidermal necrolysis^{[Note 41]}
Nephrotic syndrome
Rhabdomyolysis^{[Note 42]}

Mechanism of action

Sorafenib is a small molecular inhibitor of several tyrosine protein kinases (VEGFR and PDGFR) and Raf kinases (more avidly C-Raf than B-Raf).^[16]^[17] Sorafenib also inhibits some intracellular serine/threonine kinases (e.g. C-Raf, wild-type B-Raf and mutant B-Raf).^[10] Sorafenib treatment induces autophagy,^[18] which may suppress tumor growth. However, autophagy can also cause drug resistance.^[19]

History

Renal cancer

Sorafenib was approved by the U.S. Food and Drug Administration (FDA) in December 2005,^[20] and received European Commission marketing authorization in July 2006,^[21] both for use in the treatment of advanced renal cancer.

Liver cancer

The European Commission granted marketing authorization to the drug for the treatment of patients with hepatocellular carcinoma(HCC), the most common form of liver cancer, in October 2007,^[22] and FDA approval for this indication followed in November 2007.^[23]

In November 2009, the UK’s National Institute of Clinical Excellence declined to approve the drug for use within the NHS in England, Wales and Northern Ireland, stating that its effectiveness (increasing survival in primary liver cancer by 6 months) did not justify its high price, at up to £3000 per patient per month.^[24] In Scotland the drug had already been refused authorization by the Scottish Medicines Consortium for use within NHS Scotland, for the same reason.^[24]

In March 2012, the Indian Patent Office granted a domestic company, Natco Pharma, a license to manufacture generic Sorafenib, bringing its price down by 97%. Bayer sells a month’s supply, 120 tablets, of Nexavar for280000 (US$4,700). Natco Pharma will sell 120 tablets for 8800 (US$150), while still paying a 6% royalty to Bayer.^[25]^[26] Under Indian Patents Act, 2005 and the World Trade Organisation TRIPS Agreement, the government can issue a compulsory license when a drug is not available at an affordable price.^[27]

Thyroid Cancer

As of November 22, 2013, sorafenib has been approved by the FDA for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.^[28]

Research

Lung

In some kinds of lung cancer (with squamous-cell histology) sorafenib administered in addition to paclitaxel and carboplatin may be detrimental to patients.^[29]

Brain (Recurrent Glioblastoma)

There is a phase I/II study at the Mayo Clinic^[30] of sorafenib and CCI-779 (temsirolimus) for recurrent glioblastoma.

Desmoid Tumor (Aggressive Fibromatosis)

A study performed in 2011 showed that Sorafenib is active against Aggressive fibromatosis. This study is being used as justification for using Sorafenib as an initial course of treatment in some patients with Aggressive fibromatosis.^[31]

Nexavar Controversy

In January 2014, Bayer’s CEO stated that Nexavar was developed for “western patients who [could] afford it”. At the prevailing prices, a kidney cancer patient would pay $96,000 (£58,000) for a year’s course of the Bayer-made drug. However, the cost of the Indian version of the generic drug would be around $2,800 (£1,700).^[32]

Notes

Low blood phosphate levels
Bleeding; including serious bleeds such as intracranial and intrapulmonary bleeds
High blood pressure
Including abdominal pain, headache, tumour pain, etc.
Considered a low (~10-30%) risk chemotherapeutic agent for causing emesis)
Low level of white blood cells in the blood
Low level of neutrophils in the blood
Low level of red blood cells in the blood
Low level of plasma cells in the blood
Low blood calcium
Low blood potassium
Hearing ringing in the ears
Heart attack
Lack of blood supply for the heart muscle
Mouth swelling, also dry mouth and glossodynia
Indigestion
Not being able to swallow
Sore joints
Muscle aches
Kidney failure
Excreting protein [usually plasma proteins] in the urine. Not dangerous in itself but it is indicative kidney damage
Including skin reactions and urticaria (hives)
Underactive thyroid
Overactive thyroid
Low blood sodium
Runny nose
Pneumonitis, radiation pneumonitis, acute respiratory distress, etc.
Swelling of the pancreas
Swelling of the stomach
Formation of a hole in the gastrointestinal tract, leading to potentially fatal bleeds
Yellowing of the skin and eyes due to a failure of the liver to adequately cope with the amount of bilirubin produced by the day-to-day actions of the body
Swelling of the gallbladder
Swelling of the bile duct
A potentially fatal skin reaction
A fairly benign form of skin cancer
A potentially fatal abnormality in the electrical activity of the heart
Swelling of the skin and mucous membranes
A potentially fatal allergic reaction
Swelling of the liver
A potentially fatal skin reaction
A potentially fatal skin reaction
The rapid breakdown of muscle tissue leading to the build-up of myoglobin in the blood and resulting in damage to the kidneys

Sorafenib
Systematic (IUPAC) name


4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino] phenoxy]-N-methyl-pyridine-2-carboxamide
Clinical data
Trade names	Nexavar
AHFS/Drugs.com	monograph
MedlinePlus	a607051
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	D (AU) D (US)
Legal status	Prescription Only (S4) (AU) ℞-only (CA) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	38–49%
Protein binding	99.5%
Metabolism	Hepatic oxidation and glucuronidation (CYP3A4 & UGT1A9-mediated)
Half-life	25–48 hours
Excretion	Faeces (77%) and urine (19%)
Identifiers
CAS number	284461-73-0
ATC code	L01XE05
PubChem	CID 216239
DrugBank	DB00398
ChemSpider	187440
UNII	9ZOQ3TZI87
KEGG	D08524
ChEBI	CHEBI:50924
ChEMBL	CHEMBL1336
Synonyms	Nexavar Sorafenib tosylate
PDB ligand ID	BAX (PDBe, RCSB PDB)
Chemical data
Formula	C₂₁H₁₆Cl F₃N₄O₃
Mol. mass	464.825 g/mol

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-Λ/²-methylpyridine-2- carboxamide is commonly known as sorafenib (I). Sorafenib is prepared as its tosylate salt. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.

Sorafenib, marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer). It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor.

Sorafenib and pharmaceutically acceptable salts thereof is disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patents disclose processes for the preparation of sorafenib.

WO0042012 and WO0041698 describe the process as given in scheme I which comprises reacting picolinic acid (II) with thionyl chloride in dimethyl formamide (DMF) to form acid chloride salt (III). This salt is then reacted with methylamine dissolved in tetrahydrofuran (THF) to give carboxamide (IV). This carboxamide when further reacted with 4- aminophenol in anhydrous DMF and potassium tert-butoxide 4-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline (V) is formed. Subsequent reaction of this aniline with 4-chloro-3- (trifluoromethyl) phenyl isocyanate (Vl) in methylene chloride yields sorafenib (I). The reaction is represented by Scheme I as given below.

Scheme I

Picolini

Sorafenib (I)

WO2006034796 also discloses a process for the preparation of sorafenib and its tosylate salt. The process comprises reacting 2-picolinic acid (II) with thionyl chloride in a solvent inert toward thionyl chloride without using dimethyl formamide to form acid chloride salt (III). This acid salt on further reaction with aqueous solution methylamine or gaseous methylamine gives compound (IV). Compound (IV) is then reacted with 4-aminophenol with addition of a carbonate salt in the presence of a base to yield compound (V).

Compound (V) can also be obtained by reacting compound (IV) with 4-aminophenol in the presence of water with addition of a phase transfer catalyst. Compound (V) when reacted with 4-chloro-3-(trifluoromethyl) phenyl isocyanate (Vl) in a non-chlorinated organic solvent, inert towards isocyanate gives sorafenib (I). Sorafenib by admixing with p- toluenesulfonic acid in a polar solvent gives sorafenib tosylate (VII). The reaction is represented by Scheme Il as given below.

Scheme Il

A key step in the synthesis of sorafenib is the formation of the urea bond. The processes disclosed in the prior art involve reactions of an isocyanate with an amine. These isocyanate compounds though commercially available are very expensive. Further synthesis of isocyanate is very difficult which requires careful and skillful handling of reagents.

Isocyanate is prepared by reaction of an amine with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) or trichloromethyl chloroformate (diphosgene). Isocyanate can also be prepared by using a hazardous reagent such as an azide. Also, the process for preparation of an isocyanate requires harsh reaction conditions such as strong acid, higher temperature etc. Further, this isocyanate is reacted with an amine to give urea.

Reactions of isocyanates suffer from one or more disadvantages. For example phosgene or phosgene equivalents are hazardous and dangerous to use and handle on a large scale. These reagents are also not environment friendly. Isocyanates themselves are thermally unstable compounds and undergo decomposition on storage and they are incompatible with a number of organic compounds. Thus, the use of isocyanate is not well suited for industrial scale application.

Sorafenib and its pharmaceutically acceptable salts and solvates are reported for the first time in WO0041698 (corresponding US 03139605) by Bayer. In the literature only one route is disclosed for the preparation of sorafenib. According to this route (Scheme-I), picolinic acid of formula III is reacted with thionyl chloride to give the 4-chloro derivative which on treatment

VII

Scheme-I with methanol gave the methyl ester of formula V. Compound of formula V is reacted with methylamine to get the corresponding amide of formula VL Compound of formula VI is reacted with 4-aminophenol to get the ether derivative of formula VII. Compound of formula VII is reacted with 4-chloro-3-trifluoromethylphenylisocyante to get sorafenib base of formula I. Overall yield of sorafenib in this process is 10% from commercially available 2-picolinic acid of formula II. Main drawback in this process is chromatographic purification of the intermediates involved in the process and low yield at every step.

Donald Bankston’s (Org. Proc. Res. Dev., 2002, 6, 777-781) development of an improved synthesis of the above basic route afforded sorafenib in an overall yield of 63% without involving any chromatographic purification. Process improvements like reduction of time in thionyl chloride reaction; avoid the isolation of intermediates of formulae IV and V₅ reduction of base quantity in p-aminophenol reaction, etc lead to the simplification of process and improvement in yield of final compound of formula I.

Above mentioned improvements could not reduce the number of steps in making sorafenib of formula-I. In the first step all the raw materials are charged and heated to target temperature (72°C). Such a process on commercial scale will lead to sudden evolution of gas emissions such as sulfur dioxide and hydrogen chloride. Also, in the aminophenol reaction two bases (potassium carbonate and potassium t-butoxide) were used in large excess to accomplish the required transformation.

A scalable process for the preparation of sorafenib is disclosed in WO2006034796. In this process also above mentioned chemistry is used in making sorafenib of formula I. In the first step, catalytic quantity. of DMF used in the prior art process is replaced with reagents like hydrogen bromide, thionyl bromide and sodium bromide. Yield of required product remained same without any advantages from newly introduced corrosive reagents. Process improvements like change of solvents, reagents, etc were applied in subsequent steps making the process scalable. Overall yield of sorafenib is increased to 74% from the prior art 63% yield. Purity of sorafenib is only 95% and was obtained as light brown colored solid.

Main drawbacks in this process are production of low quality sorafenib and requirement of corrosive and difficult to handle reagents such as thionyl bromide and hydrogen bromide. Also, there is no major improvement in the yield of sorafenib.

Sorafenib tosylate ( Brand name: Nexavar ®, BAY 43-9006 other name, Chinese name: Nexavar, sorafenib, Leisha Wa) was Approved by U.S. FDA for the treatment of advanced kidney cancer in 2005 and liver cancer in 2007 .

Sorafenib, co-Developed and co-marketed by Germany-based Bayer AG and South San Francisco-based Onyx Pharmaceuticals , is an Oral Multi-kinase inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRbeta, Kit, RET and Raf-1.

In March 2012 Indian drugmaker Natco Pharma received the first compulsory license ever from Indian Patent Office to make a generic Version of Bayer’s Nexavar despite the FACT that Nexavar is still on Patent. This Decision was based on the Bayer Drug being too expensive to most patients. The Nexavar price is expected to drop from $ 5,500 per person each month to $ 175, a 97 percent decline. The drug generated $ 934 million in global sales in 2010, according to India’s Patent Office.

Sorafenib tosylate

Chemical Name: 4-Methyl-3-((4 – (3-pyridinyl)-2-pyrimidinyl) amino)-N-(5 – (4-methyl-1H-imidazol-1-yl) -3 – (trifluoromethyl) phenyl) benzamide monomethanesulfonate, Sorafenib tosylate

CAS Number 475207-59-1 (Sorafenib tosylate ) , 284461-73-0 (Sorafenib)

References for the Preparation of Sorafenib References

1) Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl Substituted diphenyl Ureas as RAF kinase inhibitors ; U.S. Patent numberUS7235576
2) Rossetto, Pierluigi; Macdonald, Peter, Lindsay; Canavesi, Augusto; Process for preparation of sorafenib and Intermediates thereof , PCT Int. Appl., WO2009111061
3) Lögers, Michael; gehring, Reinhold; Kuhn, Oliver; Matthäus, Mike; Mohrs, Klaus; müller-gliemann, Matthias; Stiehl, jürgen; berwe, Mathias; Lenz, Jana; Heilmann, Werner; Process for the preparation of 4 – {4 – [( {[4-chloro-3-(TRIFLUOROMETHYL) phenyl] amino} carbonyl) amino] phenoxy}-N-methylpyridine-2-carboxamide , PCT Int. Appl., WO2006034796
4) Shikai Xiang, Liu Qingwei, Xieyou Rong, sorafenib preparation methods, invention patent application Publication No. CN102311384 , Application No. CN201010212039
5) Zhao multiply there, Chenlin Jie, Xu Xu, MASS MEDIA Ji Yafei; sorafenib tosylate synthesis ,Chinese Journal of Pharmaceuticals , 2007 (9): 614 -616

Preparation of Sorafenib Tosylate (Nexavar) Nexavar, sorafenib Preparation of methyl sulfonate

Sorafenib (Sorafenib) chemical name 4 – {4 – [({[4 – chloro -3 – (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl-pyridine -2 – formamide by Bayer (Bayer) research and development, in 2005 the U.S. Food and Drug Administration (FDA) approval. Trade name Nexavar (Nexavar). This product is an oral multi-kinase inhibitor, for the treatment of liver cancer and kidney cancer.

Indian Patent Office in March this year for Bayer’s Nexavar in liver and kidney cancer drugs (Nexavar) has released a landmark “compulsory licensing” (compulsory license). Indian Patent Office that due to the high price Nexavar in India, the vast majority of patients can not afford the drug locally, thus requiring local Indian pharmaceutical company Natco cheap Nexavar sales. Nexavar in 2017 before patent expiry, Natco pay only Bayer’s pharmaceutical sales to 6% royalties. The move to make Nexavar patent drug prices, the supply price from $ 5,500 per month dropped to $ 175, the price reduction of 97%. Compulsory licensing in India for other life-saving drugs and patent medicines overpriced open a road, the Indian Patent Office through this decision made it clear that the patent monopoly does not guarantee that the price is too high. Nexavar is a fight against advanced renal cell carcinoma, liver cancer cure. In China, a box of 60 capsules of Nexavar price of more than 25,000 yuan. In accordance with the recommended dose, which barely enough to eat half of patients with advanced cancer. In September this year India a patent court rejected Bayer Group in India cheap drugmaker emergency appeal. Indian government to refuse patent medicine overpriced undo “compulsory licensing rules,” allowing the production of generic drugs Nexavar.

Sorafenat by Natco – Sorafenib – Nexavar – India natco Nexavar

Chemical Synthesis of Sorafenib Tosylate (Nexavar)

Sorafenib tosylate (brand name :Nexavar®, other name BAY 43-9006, was approved by US FDA for the treatment of kidney cancer in 2005 and advanced liver cancer in 2007.

US Patent US7235576, WO2006034796, WO2009111061 and Faming Zhuanli Shenqing(CN102311384) disclosed processes for preparation of sorafenib base and its salt sorafenib tosylate.

References

1)Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors; US patent numberUS7235576
2)Rossetto, pierluigi; Macdonald, peter, lindsay; Canavesi, augusto; Process for preparation of sorafenib and intermediates thereof, PCT Int. Appl., WO2009111061
3)Lögers, michael; gehring, reinhold; kuhn, oliver; matthäus, mike; mohrs, klaus; müller-gliemann, matthias; stiehl, jürgen; berwe, mathias; lenz, jana; heilmann, werner; Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide, PCT Int. Appl., WO2006034796CN102311384, CN201010212039

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar)

Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro- N -methyl-2-pyridinecarboxamide (15.0 g, 87.9mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80°C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35°C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%):. 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA’BB’ quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz; 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+).

Synthesis of 4-{4-[({[4-Chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide (sorafenib)

4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals. m.p. 206-208° C. 1H-NMR (DMSO-d6, 500 MHz): δ =2.79 (d, J=4.4 Hz, 3H, NCH3); 7.16 (dd, J=2.5, 5.6 Hz, 1H, 5-H); 7.18 (d, J=8.8 Hz, 2H, 3′-H, 5′-H); 7.38 (d, J=2.4 Hz, 1H, 3-H); 7.60-7.68 (m, 4H, 2′-H, 6′-H, 5″-H, 6″-H); 8.13 (d, J=1.9 Hz, 1H, 2″-H); 8.51 (d, J=5.6 Hz, 1H, 6-H); 8.81 (d, J=4.5 Hz, 1H, NHCH3); 9.05 (br. s, 1H, NHCO); 9.25 (br. s, 1H, NHCO) MS (ESI, CH3CN/H2O): m/e=465 [M+H]+.

Synthesis of Sorafenib Tosylate (Nexavar)

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (50g, 0.1076 mol) is suspended in ethyl acetate (500 g) and water (10g). The mixture is heated to 69°C within 0.5 h, and a filtered solution of p-toluenesulfonic acid monohydrate (3.26 g, 0.017 mol) in a mixture of water (0.65 g) and ethyl acetate (7.2 g) is added. After filtration a filtered solution of p-toluenesulfonic acid monohydrate (22g, 0.11 mol) in a mixture of ethyl acetate (48 g) and water (4.34 g) is added. The mixture is cooled to 23°C within 2 h. The product is filtered off, washed twice with ethyl acetate (92.5 g each time) and dried under reduced pressure. The sorafenib tosylate (65.5 g, 96% of theory) is obtained as colorless to slightly brownish crystals.

…………………..

http://www.google.com/patents/EP2195286A2?cl=en

Example 22: Synthesis of Sorafenib

Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4- aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N₁N- dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was agitated at 40-45⁰C for 2-3 hours, cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCI (250ml) and finally with brine (250 ml). The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).

Example 23: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)urea (Compound 4)

Sodium cyanate (1.7 g, 0.02mol) was dissolved in water (17ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3- trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40°C-45°C within 1- 2 hours. The reaction mass was agitated for whole day and cooled gradually to room temperature. The obtained solid was filtered washed with water and vacuum dried at 50⁰C to afford the desired product (5.8 g) i.e. 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.

Example 24: Synthesis of Sorafenib

1-(4-chloro-3-(trifluoromethyl) phenyl)urea (15 g, 0.0628 mol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N- methylpicolinamide (15.27 g, 0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and the reaction mass was then heated to 110-120⁰C for 12-18 hours. The reaction mass was cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).

………………………..

http://www.google.com/patents/WO2009054004A2?cl=en

http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009054004A2&KC=A2&FT=D&date=20090430&DB=EPODOC&locale=en_gb

Figure imgf000006_0002

EXAMPLES

Example 1

Preparation of l-(4-chloro-3-(trifluoromethyl)phenyI)-3-(4-hydroxyphenyl)urea Into a 250 ml, four-necked RB flask was charged 1O g of 4-aminophenol and 100 ml of toluene. A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyante (20.4 g) in toluene (50 ml) was added to the reaction mass at 25-30⁰C. The reaction mass was stirred at room temperature for 16 h. The reaction mass was filtered and washed the. solid with 50 ml of toluene. The wet material was dried in the oven at 50-60°C to get 29.8 g of title compound as white solid. M.P. is 218-222°C. IR (KBr): 3306, 1673, 1625, 1590, 1560, 1517, 1482, 1435, 1404, 1328, 1261, 1182, 1160, 1146, 1125, 1095, 1032, 884, 849, 832, 812, 766, 746, 724, 683, 539 and 434 cm^“1.

Example 2 Preparation of sorafenib tosylate

Into a 100 ml, three-necked RB flask was charged 2.0 g of l-(4-chloro-3- (trifluoromethyl)-phenyl)-3-(4-hydroxyphenyl)urea and 10 ml of DMF. Potassium tert- butoxide (2.3 g) was added to the reaction mass and stirred for 45 min at RT. 4-Chlro-N- methylpicolinamide (1.14 g) and potassium carbonate (0.42 g) were added to the reaction mass and heated to 80°C. The reaction mass was maintained at 80-85°C for 8 h and cooled to 30°C. The reaction mass was poured into water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine and dried over sodium sulphate. Solvent was distilled of under reduced pressure.

The crude compound (4.7 g) was dissolved in 10 ml of IPA and added 1.9 g of p- toluenesulfonic acid. The reaction mass was stirred at RT for 15 h and filtered. The wet solid was washed with 10 ml of IPA and dried at 50-60°C to get 3.4 g of title compound as off-white crystalline solid.

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A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

Donald Bankston,*Jacques Dumas,Reina Natero,Bernd Riedl,Mary-Katherine Monahan, andRobert Sibley

Bayer Research Center, Pharmaceutical Division, 400 Morgan Lane, West Haven, Connecticut 06516, U.S.A.

Org. Proc. Res. Dev., 2002, 6 (6), pp 777–781

DOI: 10.1021/op020205n

http://pubs.acs.org/doi/abs/10.1021/op020205n

Urea 3 (BAY 43–9006), a potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases >50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43–9006).

A suspension of 9 (67.00 g, 275.43 mmol) in methylene chloride ———————-DELETE………………………………The solids were washed with methylene chloride (2 × 50 mL) and dried under vacuum for 4 h at 35 °C to afford 3 (118.19 g, 254.27 mmol, 92%) as an off-white solid.

Mp = 210−212 °C.

¹H NMR (DMSO-d₆, 300 MHz):

δ 2.77 (d, J = 4.8 Hz, 3H, −NHCH₃);

7.16 (m, 3H, aromatic);

7.37 (d, J = 2.5 Hz, 1H, aromatic);

7.62 (m, 4H, aromatic);

8.11 (d, J = 2.5 Hz, 1H, aromatic);

8.49 (d, J = 5.5 Hz, 1H, aromatic);

8.77 (br d, 1H, −NHCH₃);

8.99 (s, 1H, −NHCO−); 9.21 (s, 1H, −NHCO−).

Mass spectrum (HPLC/ES): m/e = 465 (M + 1).

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃: C, 54.26; H, 3.47; N, 12.05. Found: C, 54.11; H, 3.49; N, 12.03.

HPLC (ELS) purity >98%: t_R = 3.5 min.

Synthesis of N-[4-Chloro-3-(trifluoromethyl)phenyl]({4-[2-(N-methyl-carbamoyl)(4-pyridyloxy)]phenyl}amino)carboxamide (3, BAY 43–9006): Use of CDI.

A solution of 11 (1.25 g, 6.39 mmol) in methylene chloride———————-DELETED……………………. high vacuum at 35 °C for 2 h to afford 3 (2.55 g, 5.49 mmol, 91%) as a white solid. Proton NMR and mass-spectral data were consistent with structure.

Anal. Calcd for C₂₁H₁₆N₄ClF₃O₃: C, 54.26; H, 3.47; N, 12.05; Cl, 7.63. Found: C, 54.24; H, 3.31; N, 12.30; Cl, 7.84.

Mp (differential scanning calorimetry, 10 °C/min): 205.6 °C;

no polymorphs observed.

References

“FDA Approves Nexavar for Patients with Inoperable Liver Cancer” (Press release). FDA. November 19, 2007. Retrieved November 10, 2012.
“Nexavar (sorafenib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 26 December 2013.
“NEXAVAR (sorafenib) tablet, film coated [Bayer HealthCare Pharmaceuticals Inc.]”. DailyMed. Bayer HealthCare Pharmaceuticals Inc. November 2013. Retrieved 26 December 2013.
“Nexavar 200mg film-coated tablets – Summary of Product Characteristics (SPC) – (eMC)”. electronic Medicines Compendium. Bayer plc. 27 March 2013. Retrieved 26 December 2013.
“PRODUCT INFORMATION NEXAVAR® (sorafenib tosylate)” (PDF). TGA eBusiness Services. Bayer Australia Ltd. 12 December 2012. Retrieved 26 December 2013.
Escudier, B; Eisen, T; Stadler, WM; Szczylik, C; Oudard, S; Siebels, M; Negrier, S; Chevreau, C; Solska, E; Desai, AA; Rolland, F; Demkow, T; Hutson, TE; Gore, M; Freeman, S; Schwartz, B; Shan, M; Simantov, R; Bukowski, RM (January 2007). “Sorafenib in advanced clear-cell renal-cell carcinoma”. New England Journal of Medicine 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530.
Walid, MS; Johnston, KW (October 2009). “Successful treatment of a brain-metastasized renal cell carcinoma”. German Medical Science 7: Doc28. doi:10.3205/000087. PMC 2775194. PMID 19911072.
“Pharmaceutical Benefits Scheme (PBS) -SORAFENIB”. Pharmaceutical Benefits Scheme. Australian Government Department of Health. Retrieved 27 December 2013.
Llovet, et al. (2008). “Sorafenib in Advanced Hepatocellular Carcinoma” (PDF). New England Journal of Medicine 359 (4): 378–90.
Keating GM, Santoro A (2009). “Sorafenib: a review of its use in advanced hepatocellular carcinoma”. Drugs 69 (2): 223–40. doi:10.2165/00003495-200969020-00006. PMID 19228077.
Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N, Geschwind JF (October 2011). “Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma”. J. Clin. Oncol. 29 (30): 3960–7. doi:10.1200/JCO.2011.37.1021. PMID 21911714.
“Phase 3 Trial of Nexavar in Patients With Non-Responsive Thyroid Cancer”^{[dead link]}
[1]
“Chemotherapy-Induced Nausea and Vomiting Treatment & Management”. Medscape Reference. WebMD. 3 July 2012. Retrieved 26 December 2013.
Hagopian, Benjamin (August 2010). “Unusually Severe Bullous Skin Reaction to Sorafenib: A Case Report”. Journal of Medical Cases 1 (1): 1–3. doi:10.4021/jmc112e. Retrieved 11 February 2014.
Smalley KS, Xiao M, Villanueva J, Nguyen TK, Flaherty KT, Letrero R, Van Belle P, Elder DE, Wang Y, Nathanson KL, Herlyn M (January 2009). “CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations”. Oncogene 28 (1): 85–94. doi:10.1038/onc.2008.362. PMC 2898184. PMID 18794803.
Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M (October 2008). “Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling”. Mol. Cancer Ther. 7 (10): 3129–40. doi:10.1158/1535-7163.MCT-08-0013. PMID 18852116.
Zhang Y (Jan 2014). “Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways.”. J Mol Med Rep 9 (1): 83–90. PMID 24213221.
Gauthier A (Feb 2013). “Role of sorafenib in the treatment of advanced hepatocellular carcinoma: An update..”. Hepatol Res 43 (2): 147–154. doi:10.1111/j.1872-034x.2012.01113.x. PMID 23145926.
FDA Approval letter for use of sorafenib in advanced renal cancer
European Commission – Enterprise and industry. Nexavar. Retrieved April 24, 2007.
“Nexavar® (Sorafenib) Approved for Hepatocellular Carcinoma in Europe” (Press release). Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. October 30, 2007. Retrieved November 10, 2012.
FDA Approval letter for use of sorafenib in inoperable hepatocellular carcinoma
“Liver drug ‘too expensive‘“. BBC News. November 19, 2009. Retrieved November 10, 2012.
http://www.ipindia.nic.in/ipoNew/compulsory_License_12032012.pdf
“Seven days: 9–15 March 2012”. Nature 483 (7389): 250–1. 2012. doi:10.1038/483250a.
“India Patents (Amendment) Act, 2005”. WIPO. Retrieved 16 January 2013.
[2]
“Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients”
ClinicalTrials.gov NCT00329719 Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma
“Activity of sorafenib against desmoid tumor/deep fibromatosis”
“‘We didn’t make this medicine for Indians… we made it for western patients who can afford it‘“. Daily Mail Reporter. 24 Jan 2014.

External links

Nexavar.com – Manufacturer’s website
Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau gene)
Patient Information from FDA
Sorafenib in Treating Patients With Soft Tissue Sarcomas
Sorafenib Sunitinib differences – diagram
ClinicalTrials.gov NCT00217399 – Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
Cipla launches Nexavar generic at 1/10 of Bayer’s price

Reference
1	*	D. BANKSTON ET AL.: “A Scalable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer” ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 6, no. 6, 2002, pages 777-781, XP002523918 cited in the application
2	*	PAN W ET AL: “Pyrimido-oxazepine as a versatile template for the development of inhibitors of specific kinases” BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 15, no. 24, 15 December 2005 (2005-12-15), pages 5474-5477, XP025314229 ISSN: 0960-894X [retrieved on 2005-12-15]

Citing Patent	Filing date	Publication date	Applicant	Title
WO2011036647A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
WO2011036648A1	Sep 24, 2010	Mar 31, 2011	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
WO2011058522A1	Nov 12, 2010	May 19, 2011	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
WO2011092663A2	Jan 28, 2011	Aug 4, 2011	Ranbaxy Laboratories Limited	4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-n2-methylpyridine-2-carboxamide dimethyl sulphoxide solvate
WO2011113367A1 *	Mar 17, 2011	Sep 22, 2011	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated ω-diphenylurea
US8552197	Nov 12, 2010	Oct 8, 2013	Ranbaxy Laboratories Limited	Sorafenib ethylsulfonate salt, process for preparation and use
US8604208	Sep 24, 2010	Dec 10, 2013	Ranbaxy Laboratories Limited	Polymorphs of sorafenib acid addition salts
US8609854	Sep 24, 2010	Dec 17, 2013	Ranbaxy Laboratories Limited	Process for the preparation of sorafenib tosylate
US8618305	Jan 28, 2011	Dec 31, 2013	Ranbaxy Laboratories Limited	Sorafenib dimethyl sulphoxide solvate
US8669369	Mar 17, 2011	Mar 11, 2014	Suzhou Zelgen Biopharmaceutical Co., Ltd.	Method and process for preparation and production of deuterated Ω-diphenylurea

Plant flavonoid luteolin blocks cell signaling pathways in colon cancer cells

June 26, 2014 4:02 am / Leave a comment

CLINICALNEWS.ORG

30 Jan 2012

Luteolin is a flavonoid commonly found in fruit and vegetables. This compound has been shown in laboratory conditions to have anti-inflammatory, anti-oxidant and anti-cancer properties but results from epidemiological studies have been less certain. New research published in BioMed Central’s open access journal BMC Gastroenterology shows that luteolin is able to inhibit the activity of cell signaling pathways (IGF and PI3K) important for the growth of cancer in colon cancer cells.

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What GMP Changes can we still expect for 2014?

June 26, 2014 4:01 am / 1 Comment on What GMP Changes can we still expect for 2014?

What GMP Changes can we still expect for 2014?

http://www.gmp-compliance.org/enews_4349_What%20GMP%20Changes%20can%20we%20still%20expect%20for%202014%3F_n.html

Heraclitus once said: “There is nothing permanent except change”. This statement is even true for the rather conservative GMP environment. What can we still expect for 2014? The answer to that question can be found in a work plan of EMA’s GMP/GDP Inspectors Working Group.

What are the coming plans?

Finalising the changes planned for the Chapters 3 and 5 of the EU GMP Guide
Finalising the revision of Chapter 8 of the EU GMP guide (with regard to product shortage notifications and specific risk management concepts)
Agreeing, in consultation with PIC/S, whether guidance is needed on biofilms concerning Annex 1 of the EU GMP Guide
Finalising the revision of Annex 15 of the EU GMP Guide (comparison with the new EMA process validation guideline and inclusion of necessary changes in the light of ICH Q 8-10)
Finalising the revision of Annex 16 of the EU GMP Guide
Finalising the revision of Annex 17 of the EU GMP Guide
Further measures regarding the EudraGMDP database

The finalisation of the revision of Chapter 6 (Quality Control) of the EU GMP Guide is already completed (April 2014). The revised chapter will apply as of October 2014.

The following topics are also addressed in the work paper:

Inspections under the centralised system
Mutual Recognition Agreements (MRAs)
Harmonisation topics
Collaboration with the EU Commission (the collaboration should enable by the end of 2014 the publication of the GDP guidelines for APIs and the risk assessment guidelines to establish GMP for excipients)
Collaboration with other groups (i.e. Reverse Osmosis for the production of WFI and biological indicators for monitoring and the control of sterilisation are topics addressed together with the EDQM in Strasburg)

Please also see the complete “Work plan for GMP/GDP Inspectors Working Group for 2014“.

Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity

June 26, 2014 3:43 am / 2 Comments on Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity

Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
The applicant for an ANDA in the USA has to submit data of several stability tests. The FDA guidance on this topic coming into force last year left open some issues, however, that now are clarified with a questions and answers document published lately.

Epilogue: Envisioning New Insights in Cancer Translational Biology

June 26, 2014 3:36 am / Leave a comment

larryhdotme

Epilogue: Envisioning New Insights in Cancer Translational Biology.

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MST-188 (purified poloxamer 188)

POTENTIAL APPLICATIONS OF MST-188

1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376. 2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.

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Minisci reactions: Versatile CH-functionalizations for medicinal chemists

Introduction

Mechanism

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BAY 43-9006

Medical uses

Kidney cancer

Liver cancer

Thyroid cancer

Adverse effects

Mechanism of action

History

Renal cancer

Liver cancer

Thyroid Cancer

Research

Lung

Brain (Recurrent Glioblastoma)

Desmoid Tumor (Aggressive Fibromatosis)

Nexavar Controversy

Notes

Chemical Synthesis of Sorafenib Tosylate (Nexavar)

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar)

…………………..

A Scaleable Synthesis of BAY 43-9006: A Potent Raf Kinase Inhibitor for the Treatment of Cancer

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1. Powars, D .R. et al. November 2005. Outcome of Sickle Cell Anemia: A 4-Decade Observational Study of 1056 Patients. Medicine. Vol 84 No. 6: pp 363-376.
2. Platt et al., June 1994. Mortality in Sickle Cell Disease: Life Expectancy and Risk Factors for Early Death. NEJM. Vol 330; No. 2: 1639-1644.