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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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DR ANTHONY MELVIN CRASTO Ph.D

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 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 amcrasto@gmail.com, 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......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

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EMA Accepts AstraZeneca’s Naloxegol Application


naloxegol

http://www.ama-assn.org/resources/doc/usan/naloxegol.pdf

Morphinan-3,14-diol, 4,5-epoxy-6-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-17-(2-
propen-1-yl)-, (5α,6α)-

4,5α-epoxy-6α-[(3,6,9,12,15,18,21-heptaoxadocosan-1-yl)oxy]-17-(prop-2-en-1-
yl)morphinan-3,14-diol

MOLECULAR FORMULA C34H53NO11
MOLECULAR WEIGHT 651.8

SPONSOR AstraZeneca
CODE DESIGNATION NKTR-118
CAS REGISTRY NUMBER 854601-70-0
WHO NUMBER 9434

Marketing Authorisation Application for naloxegol accepted by European Medicines Agency

Friday, 27 September 2013

AstraZeneca today announced that the European Medicines Agency (EMA) has accepted the Marketing Authorisation Application (MAA) for naloxegol, an investigational peripherally-acting mu-opioid receptor antagonist, which has been specifically designed for the treatment of opioid-induced constipation (OIC) for adult patients 18 years and older, including patients with inadequate response to laxatives.

read more

http://www.pharmalive.com/ema-accepts-astrazeneca-s-naloxegol-application

Naloxegol (INNNKTR-118), or PEGylated naloxol,[1] is a peripherallyselective opioid antagonist under development byAstraZeneca, licensed from Nektar, for the treatment of opioid-induced constipation.[2]

Opioids are commonly prescribed to patients experiencing chronic pain, which can provide relief from serious medical conditions including osteoarthritis, cancer, and chronic back pain.  There are about 250 million opioid prescriptions written annually in the US alone to treat these conditions.  Patients taking opioids to treat chronic pain commonly experience a side effect known as opioid-induced constipation, which may include infrequent bowel movements and difficulty passing stools or emptying bowels. Clinically, OIC is the most prevalent side effect of opioid therapy.  For those patients who take opiates for long term pain management, approximately 40-50 percent commonly experience OIC.5 Only about 40-50 percent of those patients experience effective relief from current treatment options

  1. ^ Roland Seifert; Thomas Wieland; Raimund Mannhold; Hugo Kubinyi, Gerd Folkers (17 July 2006). G Protein-Coupled Receptors as Drug Targets: Analysis of Activation and Constitutive Activity. John Wiley & Sons. p. 227. ISBN 978-3-527-60695-5. Retrieved 14 May 2012.
  2. ^ “Nektar | R&D Pipeline | Products in Development | CNS/Pain | Oral Naloxegol (NKTR-118) and Oral NKTR-119”. Retrieved 2012-05-14.

Naloxegol (NKTR-118) is an investigational drug candidate in Phase 3 studies being developed as a once-daily oral tablet for the treatment of opioid-induced constipation. Naloxegol (NKTR-118) was designed using Nektar’s proprietary small molecule polymer conjugate technology. Results of the Phase 2 study of naloxegol (NKTR-118) were presented in October 2009 at the American College of Gastroenterology Annual Clinical Meeting and the American Academy of Pain Management. NKTR-119 is an early stage drug development program that is intended to combine oral naloxegol (NKTR-118) with selected opioids, with the goal of treating pain without the side effect of constipation traditionally associated with opioid therapy.

Nektar and AstraZeneca have a global agreement for both naloxegol (NKTR-118) and NKTR-119. Under the agreement, AstraZeneca has responsibility for the development, global manufacturing and marketing of both naloxegol (NKTR-118) and NKTR-119. For naloxegol (NKTR-118), Nektar is eligible to receive up to $235 million in aggregate payments upon the achievement of certain regulatory milestones, as well as additional tiered sales milestone payments of up to $375 million if the product achieves considerable levels of commercial success. Nektar will also be eligible to receive significant double-digit royalty payments on net sales of naloxegol (NKTR-118) worldwide. For NKTR-119, Nektar would receive development milestone payments as well as tiered sales milestone payments. Nektar will also receive significant double-digit royalty payments on NKTR-119 net sales worldwide.

oxalate derivative

http://www.ama-assn.org/resources/doc/usan/naloxegol-oxalate.pdf

Morphinan-3,14-diol, 4,5-epoxy-6-(3,6,9,12,15,18,21-heptaoxadocos-1-yloxy)-
17-(2-propen-1-yl)-, (5α,6α)-, ethanedioate (1:1)
4,5α-epoxy-6α-[(3,6,7,12,15,18,21-heptaoxadocosyl)oxy]-17-(prop-2-
enyl)morphinan-3,14-diol hydrogen ethanedioate

MOLECULAR FORMULA C34H53NO11 . C2H2O4
MOLECULAR WEIGHT 741.8
TRADEMARK None as yet
SPONSOR AstraZeneca
CODE DESIGNATIONS NKTR-118 oxalate, AZ13337019 oxalate
CAS REGISTRY NUMBER 1354744-91-4

Glaxo Gets EU OK for New Revolade Indication


 

GSK receives marketing authorisation from the European Commission for additional Revolade™ (eltrombopag) indication as the first approved treatment for chronic hepatitis C-associated thrombocytopenia

GlaxoSmithKline plc announced today that the European Commission has granted an additional indication for Revolade™ (eltrombopag) as a treatment for low platelet counts (thrombocytopenia) in adult patients with chronic hepatitis C infection, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon (IFN)-based therapy

read all at

http://www.pharmalive.com/glaxo-gets-eu-ok-for-new-revolade-indication

Xofigo Injection Recommended for Approval in EU


Cl 223Ra Cl

is the structure

http://www.ama-assn.org/resources/doc/usan/radium-ra-223-dichloride.pdf  check out yourself

Xofigo® (radium Ra 223 dichloride) Injection Recommended for Approval in the European Union

Oslo, Norway, 20 September 2013 – Algeta ASA (OSE: ALGETA), announced today that Bayer has received a positive opinion from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommending approval of Xofigo® (radium Ra 223 dichloride) in Europe. The proposed indication is for the treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. The decision of the European Commission (EC) on the approval is expected in the fourth quarter of 2013.

Xofigo® (radium Ra 223 dichloride) injection was approved by the US Food and Drug Administration (FDA) in May 2013 for the treatment of patients with CRPC, symptomatic bone metastases and no known visceral metastatic disease and is now available in the United States at licensed facilities. read all at

http://www.pharmalive.com/xofigo-injection-recommended-for-approval-in-eu

 

old article

FDA Approves Xofigo for Advanced Prostate Cancer

May 15, 2013 — The U.S. Food and Drug Administration today approved Xofigo (radium Ra 223 dichloride) to treat men with symptomatic late-stage (metastatic) castration-resistant prostate cancer that has spread to bones but not to other organs. It is intended for men whose cancer has spread after receiving medical or surgical therapy to lower testosterone.

Prostate cancer forms in a gland in the male reproductive system found below the bladder and in front of the rectum. The male sex hormone testosterone stimulates the prostate tumors to grow. According to the National Cancer Institute, an estimated 238,590 men will be diagnosed with prostate cancer and 29,720 will die from the disease in 2013.

Xofigo is being approved more than three months ahead of the product’s prescription drug user fee goal date of Aug. 14, 2013, the date the agency was scheduled to complete review of the drug application. The FDA reviewed Xofigo under the agency’s priority review program, which provides for an expedited review of drugs that appear to provide safe and effective therapy when no satisfactory alternative therapy exists, or offer significant improvement compared to marketed products.

“Xofigo binds with minerals in the bone to deliver radiation directly to bone tumors, limiting the damage to the surrounding normal tissues,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Xofigo is the second prostate cancer drug approved by the FDA in the past year that demonstrates an ability to extend the survival of men with metastatic prostate cancer.”

In August 2012, the FDA approved Xtandi to treat men with metastatic castration-resistant prostate cancer that has spread or recurred, even with medical or surgical therapy to minimize testosterone. Xtandi is approved for patients who have previously been treated the chemotherapy drug docetaxel.

Xofigo’s safety and effectiveness were evaluated in a single clinical trial of 809 men with symptomatic castration-resistant prostate cancer that spread to bones but not to other organs. Patients were randomly assigned to receive Xofigo or a placebo plus best standard of care.

The study was designed to measure overall survival. Results from a pre-planned interim analysis showed men receiving Xofigo lived a median of 14 months compared to a median of 11.2 months for men receiving placebo. An exploratory updated analysis conducted later in the trial confirmed Xofigo’s ability to extend overall survival.

The most common side effects reported during clinical trials in men receiving Xofigo were nausea, diarrhea, vomiting and swelling of the leg, ankle or foot. The most common abnormalities detected during blood testing included low levels of red blood cells (anemia), lymphocytes (lymphocytopenia), white blood cells (leukopenia), platelets (thrombocytopenia) and infection-fighting white blood cells (neutropenia).

Xofigo is marketed by Wayne, N.J.-based Bayer Pharmaceuticals. Xtandi is co-marketed by Astellas Pharma U.S., Inc. of Northbrook, Ill., and Medivation, Inc. of San Francisco, Calif.

EC Approves Second Sanofi MS Drug


Source: Genzyme

Wed, 09/18/2013 – 9:50am

Source: Genzyme
http://www.dddmag.com/news/2013/09/ec-approves-second-sanofi-ms-drug
Sanofi and its subsidiary Genzyme announced that the European Commission has granted marketing authorization for Lemtrada. This follows the Aug. 30 approval of Aubagio. The company intends to begin launching both products in the EU soon.

Alemtuzumab (marketed as CampathMabCampath or Campath-1H and currently under further development as Lemtrada) is a monoclonal antibody used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma. It is also used in some conditioning regimens for bone marrow transplantationkidney transplantation and Islet cell transplantation.

Alemtuzumab binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction.

Alemtuzumab is used as second-line therapy for CLL. It was approved by the US Food and Drug Administration for CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. It has been approved by Health Canadafor the same indication, and additionally for CLL patients who have not had any previous therapies.

It is also used under clinical trial protocols for treatment of some autoimmune diseases, such as multiple sclerosis, in which it shows promise. Alemtuzumab was withdrawn from the markets in the US and Europe in 2012 to prepare for a higher-priced relaunch aimed at multiple sclerosis.

A complication of therapy with alemtuzumab is that it significantly increases the risk for opportunistic infections, in particular, reactivation of cytomegalovirus.

Genzyme’s multiple sclerosis treatment approved by European Commission


Alemtuzumab
Sanofi and its subsidiary Genzyme have been given marketing approval by the European Commission for Lemtrada (alemtuzumab), a treatment for multiple sclerosis.  read all at

click on title below

Genzyme’s multiple sclerosis treatment approved by European Commission

http://www.pharmaceutical-technology.com/news/newsgenzymes-multiple-sclerosis-treatment-approved-by-european-commission?WT.mc_id=DN_News

Bayer seeks EMA approval for marketing of regorafenib to treat GIST


 

Bayer seeks EMA approval for marketing of regorafenib to treat GIST
Bayer HealthCare has submitted an application to the European Medicines Agency (EMA) for marketing authorisation regarding the oral multi-kinase inhibitor, regorafenib.

read all at

http://www.pharmaceutical-technology.com/news/newsbayer-seeks-ema-approval-for-marketing-of-regorafenib-to-treat-gist?WT.mc_id=DN_News

Novartis Ilaris Approved for SJIA in Europe


Novartis Ilaris Approved for SJIA in Europe
Zacks.com
The EC cleared Ilaris for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and above in the EU, who did not respond adequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and http://www.zacks.com/stock/news/108513/novartis-ilaris-approved-for-sjia-in-europe

Canakinumab (INN, trade name Ilaris, previously ACZ885)[1] is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.[2]

Canakinumab was approved for the treatment of cryopyrin-associated periodic syndromes (CAPS) by the U.S. Food and Drug Administration (FDA) on June 2009[3] and by the European Medicines Agency in October 2009.[4] CAPS is a spectrum of autoinflammatory syndromes including familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and neonatal-onset multisystem inflammatory disease.

Canakinumab was being developed by Novartis for the treatment of rheumatoid arthritis but this trial has been discontinued.[5] Canakinumab is also in phase I clinical trials as a possible treatment for chronic obstructive pulmonary disease,[6] gout and coronary artery disease.

Ilaris neutralises IL-1 beta for a sustained period of time, and reduces inflammation. Image courtesy of Novartis.

  1.  Dhimolea, Eugen (2010). “Canakinumab”. MAbs 2 (1): 3–13. doi:10.4161/mabs.2.1.10328. PMC 2828573. PMID 20065636.
  2.  Lachmann, HJ; Kone-Paut I, Kuemmerle-Deschner JB et al. (4 June 2009). “Use of canakinumab in the cryopyrin-associated periodic syndrome”. New Engl J Med 360 (23): 2416–25. doi:10.1056/NEJMoa0810787. PMID 19494217.
  3.  “New biological therapy Ilaris approved in US to treat children and adults with CAPS, a serious life-long auto-inflammatory disease” (Press release). Novartis. 18 June 2009. Retrieved 28 July 2009.
  4.  Wan, Yuet (29 October 2009). “Canakinumab (Ilaris) and rilonacept (Arcalyst) approved in EU for treatment of cryopyrin-associated periodic syndrome”. National electronic Library for Medicines. Retrieved 14 April 2010.
  5.  “clinicaltrials.gov, Identifier NCT00784628: Safety, Tolerability and Efficacy of ACZ885 (Canakinumab) in Patients With Active Rheumatoid Arthritis”. Retrieved 2010-08-21.
  6.  Yasothan U, Kar S (2008). “Therapies for COPD”. Nat Rev Drug Discov 7 (4): 285. doi:10.1038/nrd2533.

DETAILS OF FDA APPROVAL

Ilaris Approved by FDA to Treat Active Systemic Juvenile Idiopathic Arthritis

20130516-023249.jpg

Basel, May 10, 2013 – Novartis announced today that the US Food and Drug Administration (FDA) has approved Ilaris (canakinumab) for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older. Ilaris is the first interleukin-1 beta (IL-1 beta) inhibitor approved for SJIA and the only treatment approved specifically for SJIA that is given as a once-monthly subcutaneous injection[1]. SJIA is a rare and disabling form of childhood arthritis characterized by spiking fever, rash and arthritis that can affect children as young as 2 years old and can continue into adulthood[2],[3].

This approval was based on two Phase III trials in SJIA patients, aged 2-19, showing significant improvement in the majority of Ilaris-treated patients[1]. Study 1 showed that 84% of patients treated with one subcutaneous dose of Ilaris achieved the primary endpoint of the adapted pediatric American College of Rheumatology 30 (ACR30), compared to 10% achievement of ACR30 for placebo at Day 15[1]. In the open-label part of Study 2, 92 of 128 patients attempted “corticosteroid tapering”. Of those 92 patients, 62% were able to substantially reduce their use of corticosteroids, and 46% completely discontinued corticosteroids[1]. In the controlled portion of Study 2, there was a 64% relative reduction in the risk of flare for patients in the Ilaris group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75).

 

About Ilaris

Ilaris is a selective, fully human, monoclonal antibody that inhibits IL-1 beta, which is an important part of the body’s immune system defenses[1]. Excessive production of IL-1 beta plays a prominent role in certain inflammatory diseases[8]. Ilaris works by neutralizing IL-1 beta for a sustained period of time, therefore inhibiting inflammation[1].

In addition to its approval for SJIA in the US, Ilaris is approved in the EU for the treatment of refractory gouty arthritis, and in more than 60 countries, including in the EU, US, Switzerland and Japan for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), a rare, lifelong, genetic disorder with debilitating symptoms[1]. The approved indication may vary depending upon the individual country

1 Ilaris [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2013.
2. Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol 2006; 2(1):28-34.
3. Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology (Oxford) 2005; 44(11):1350-3.

Animasi Kimia

European Approval for Glaxos Tafinlar


 

European Approval for Glaxos Tafinlar

 


Zacks.com

GlaxoSmithKline (GSKAnalyst Report) recently announced that its melanoma drug, Tafinlar, has been cleared by the European Commission (EC). Tafinlar is indicated as a monotherapy for treating adults suffering from unresectable or metastatic melanoma with a BRAF V600 mutation


The approval came on the basis of encouraging data from several multi-center global trials including the phase III BREAK-3 study. We remind investors that Currently approved melanoma drugs include Zelboraf and Yervoy. Glaxo carries a Zacks Rank #3 http://www.zacks.com/stock/news/108341/european-approval-for-glaxos-tafinlar

European Commission Approves Genzyme’s Once-Daily, Oral Multiple Sclerosis Treatment Aubagio® (teriflunomide)


Teriflunomide,

Teriflunomide, HMR-1726, 1726, A-771726, RS-61980, SU-0020,
(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
108605-62-5, 282716-73-8 (monosodium salt)
C12-H9-F3-N2-O2
270.2091
Aventis Pharma (Originator), Sanofi-Aventis U.S. Llc
Sugen (Licensee)
Antiarthritic Drugs, Disease-Modifying Drugs, Immunologic Neuromuscular Disorders, Treatment of, IMMUNOMODULATING AGENTS, Immunosuppressants, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Dihydroorotate Dehydrogenase Inhibitors

CAMBRIDGE, Mass.–Aug. 30, 2013–(BUSINESS WIRE)–Genzyme, a Sanofi company (EURONEXT: SAN and NYSE: SNY), announced today that the European Commission has granted marketing authorization for Aubagio® (teriflunomide) 14 mg, a once-daily, oral therapy indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).

read all at

http://www.pharmalive.com/ec-approves-genzyme-s-aubagio-for-ms

Teriflunomide (trade name Aubagio, marketed by Sanofi, also known as A77 1726) is the active metabolite of leflunomide.[1]Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[2] 2-year results were positive.[3] However, the subsequent TENERE head-to-head superiority trial reported that “although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide.”[4] The drug was approved by the FDA on September 13, 2012.[5]

Mechanisms of action

Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions.[6]

Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system.[7]

It has been found that teriflunomide blocks the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.[8]

Activation of leflunomide to teriflunomide

Leflunomide.svgE-Teriflunomide structure.svgTeriflunomide structure.svg

The structure which results from ring opening can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z enol being the most stable and therefore most predominant form.

Space filling model of the E isomer of teriflunomide


  1. ^
     Magne D, Mézin F, Palmer G, Guerne PA (2006). “The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha”. Inflamm. Res. 55 (11): 469–75. doi:10.1007/s00011-006-5196-xPMID 17122964.
  2. ^ ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  3.  “Sanofi-Aventis’ Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial”. 15 Oct 2010.
  4.  Gever, John (June 4, 2012). “Teriflunomide Modest Help but Safe for MS”medpage. Retrieved June 04, 2012. Unknown parameter |source= ignored (help)
  5. ^ “FDA approves new multiple sclerosis treatment Aubagio” (Press release). US FDA. Retrieved 2012-09-14.
  6. ^ H. Spreitzer (March 13, 2006). “Neue Wirkstoffe – Teriflunomid”. Österreichische Apothekerzeitung (in German) (6/2006).
  7.  Dr. Timothy Vollmer (May 28, 2009). “MS Therapies in the Pipeline: Teriflunomide”. EMS News (in English) (May 28, 2009).
  8. ^ Breedveld, FC; Dayer, J-M (November 2000). “Leflunomide: mode of action in the treatment of rheumatoid arthritis”Ann Rheum Dis 59 (11): 841–849. doi:10.1136/ard.59.11.841.PMC 1753034PMID 11053058.

SYNTHESIS

………………………

http://www.google.com/patents/WO2014177978A3?cl=en

Formula i

Teriflunomide is an immunosuppressant, acting as a tyrosine kinase inhibitor. It is also evaluated in the treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis. An oral film coated tablet containing teriflunomide as the active ingredient is marked in the United States by Sanofi Aventis US using brand AUBAGIO™. AUBAGIO is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

U.S. Patent No. 5,679,709 appears to claim teriflunomide and its pharmaceutically acceptable salts, the same patent also further covers pharmaceutical composition and method of administering top a patients suffering from autoimmune disease.

U.S. Patent No. 5,494,91 I disclosesthe process for the preparation of teriflunomide by reacting 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline in the presence of acetonitrile to yield Leflunomide with on further hydrolysis with aqueous sodium hydroxide solution in methanol gives teriflunomide of formula I.

U.S. Patent No. 5,990,141 discloses the process for the preparation of teriflunomide by reacting 4-trifluoromethyl aniline with cyano acetic acid ethyl ester to yield cyanoaceto-(4-trifluromethyl)-aniline, with on further reacted with acetyl chloride in the presence of sodium hydride base and THF and acetonitrile solvent to give teriflunomide of formula I.

U.S. patent No. 6,365,626 discloses the process for the preparation of teriflunomide by reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetyl chloride in the presence of sodium hydride to give teriflunomide of formula I.

U.S. Patent No. 6,894,184 discloses the process for the preparation of teriflunomide involves reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetic anhydride in the presence of base to give teriflunomide of formula I.

International PCT application No. WO 2009/147624 discloses the process for the preparation of teriflunomide involves condensation of ethyl-2-cyano-3-hydroxybut-2-enoate and 4-(trifluoromethyl) aniline in presence of xylene solvent at reflux temperatures for 16 hours to give teriflunomide of formula I.

preparation of teriflunomide (I) comprises steps of;

1 ) condensation of cyanoacetic acid of formula (II) with 4-trifluoromethyl aniline of formula (III) in the presence of chlorinating agent to give 2-cyano-N-[4-(trifluromethyl)phenyl]acetamide of formula (IV);

(II I) (IV)

2) acetylation of 2-cyano-N-[4-(trifluromethyl)phenyl] acetamide of

formula (IV) with an acetylating agent in the presence of base and suitable solvents to yield teriflunomide of formula (I).

EXAMPLE 1 : Preparation of 2-cvano-N-f4-(trifluoromethyl> phenyl! acetamide (IV)

A round bottom flask is charged with cyanoacetic acid (100 g) and phosphorous pentachloride and tetrahydrofuran (300 ml) and the reaction mixture is stirred at room temperature for 4 hours. 4-trifluoromethyl aniline (161 g) dissolved in tetrahydrofuran (100 ml) is slowly added to the reaction mixture and stirred for completion of reaction. The resultant reaction mass is cooled and separated solid is filtered and washed with slurry of Isoproapnol and cyclohexane and dried under reduced pressure to afford the title compound. Weight: 196 gm.

Purity by HPLC: 98%

EXAMPLE 2: preparation of 2-cyano-3-hvdroxy-N-f4-( trifluoromethyl) phenyl] but-2-enamide (Teriflunomide crude)

A round bottom flask is charged with 2-cyano-N-[4-{trifluromethyl} phenyl] acetamide (100g), sodium hydroxide (70 gm) and dimethyl formamide is added and the reaction mixture is stirred for 30 minutes. Isopropenyl acetate (60 ml) is added slowly and the resultant mixture is stirred for about 4-5 hours at room temperature. After completion of the reaction, the resulting reaction mixture is diluted with water and acidified with Cone. HCI solution and stirred for solid separation. The separated solid is filtered and washed with water and dried under reduced pressure to afford Teriflunomide.

The obtained teriflunomide is charged in round bottom flask and aqueous solution of sodium hydroxide solution (29.6 g in 300 ml water) is added slowly at 25-35°C and stirred for 1 to 2 hours. The mixture is brought to 5 to 10°C and dichloromethane is added, the mixture is stirred for 15 minutes. The organic and the aqueous layer are separated, and the resultant aqueous layer is acidified with aq. Hcl and stirred. The separated solid is filtered and washed with water and dried under vacuum at 65-70°C for 10-12 hours to afford teriflunomide.

Weight: 101 gm

Purity by HPLC: 95%

EXAMPLE 3; Purification of Teriflunomide:

Teriflunomide (5 g) is charged into a flask followed by addition of acetonitrile (125 ml) and heated to reflux and stirred for 2 hours. The resultant reaction solution is filtered through highflow bed to obtain a clear solution and cooled to room temperature and stirred for solid separation. The separated solid is filtered, washed with Isopropanol (50 ml) and dried under vacuum to afford pure teriflunomide.

Weight: 3.8 gm

Purity by HPLC: 99.7%

…………………………………………………………………………………………………………

EP 0527736; JP 1993506425; JP 1999322700; JP 1999343285; US 5494911; US 5532259; WO 9117748

5-Methylisoxazole-4-carboxylic acid (I) was converted to the corresponding acid chloride (II) upon refluxing with SOCl2. Coupling of acid chloride (II) with 4-(trifluoromethyl)aniline (III) produced anilide (IV). Finally, isoxazole ring opening in the presence of NaOH gave rise to the title cyano amide.

Teriflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, is the active metabolite of leflunomide a synthetic, low-molecular-weight drug currently used in the treatment of rheumatoid arthritis. The mechanisms by which teriflunomide exerts its antiinflammatory, antiproliferative and immunosuppressive effects are not yet completely understood, although inhibition of pyrimidine biosynthesis (via suppression of DHODH) and interference with tyrosine kinase activity both appear to be involved. Based on its efficacy shown in animal models of experimental allergic encephalomyelitis, teriflunomide was tested in a phase II study in patients with multiple sclerosis with relapses. Recruitment is ongoing for a phase III study to determine the efficacy of teriflunomide in reducing the frequency of relapses and accumulation of disability in multiple sclerosis patients.

The chemical name of Teriflunomide is 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is C12H9F3N2O2 and molecular weight is 270.207.

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in U.S. Pat. No. 5,679,709 but this patent does not mention any process of preparation for salt formation.

U.S. Pat. No. 5,494,911, U.S. Pat. No. 5,990,141 disclose various processes for preparing Teriflunomide. These patents do not disclose process for preparation Teriflunomide salts or mention any its polymorphic form.

EP 2280938 A2

HISTORY OF SYNTHESIS

The chemical name of Teriflunomide is

2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is Ci2H9 F3N2O2 and molecular weight is 270.207.

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.

US patent no. 5,494,911 discloses a process for preparation of Teriflunomide as shown in given below

Figure imgf000002_0002

4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below

Figure imgf000003_0001

Teriflunomide (I)

The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).

US patent no. 6,365,626 discloses a process for preparation of Teriflunomide  which is as given in below

Figure imgf000003_0002

Teriflunomide

ONE MORE

Graphical abstract: Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery

http://pubs.rsc.org/en/content/articlelanding/2012/cc/c2cc36352f GET ABOVE DETAILS HERE

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.

[H] US patent no. 5,494,911 discloses a process for preparation of Teriflunomide in Example-4 as shown in given below scheme-I

(V) (IV) (VI) (D

Scheme-I

The proces; 5 involves re acting 5-metlr

4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below scheme-II.

Teriflunomide (I)

Scheme-II  The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).

US patent no. 6,365,626 discloses a process for preparation of Teriflunomide in Fig. 19 which is as given in below scheme-Ill.

Teriflunomide

(I)

Scheme-Ill  The process involves reacting 4-trifluoromethyl aniline (IV) with cyanoacetic acid (Ha) to give compound of formula (VII). This compound is further reacted first with sodium hydride and then with acetylchloride to give Teriflunomide (I)

………………………….

Example-1  Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).

Yield: 84.6%Example-2 ] Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.

Yield: 71.0%

Purity: 99.4%

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.

13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3, 122.2, 126.5, 126.9, 142.1, 167.4,

187.8 ppm.

MS(FD) : m/e 269(M”, 100). [88] IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,

842, 684 cm-1.

…………………

see

http://pubs.rsc.org/en/Content/ArticleLanding/2004/OB/b312682j#!divAbstract

………………………………

http://www.google.com/patents/CN103848756A?cl=en

Currently, for the preparation of teriflunomide mainly in the following three categories:

The first synthetic methods: mainly 5-methyl-isoxazole-4-carboxylic acid starting materials or by Synthesis of 5-methyl-isoxazole-4-carboxylic acid intermediate, then reacted with 4- trifluoromethyl base – aniline was synthesized teriflunomide, specific synthetic route is as follows:

[0007]

Figure CN103848756AD00042

The general reaction step above normal class methods, not easy to intermediate purification, total yield is low, and the synthesis process using a large number of chloride corrosion of equipment can easily produce large amounts of acid mist and acidic water, thus polluting the environment .

  The second class of methods: 2-cyano-acetic acid derivatives and 4-trifluoromethyl aniline. Such methods will be first prepared as a 2-cyano acetic acid chloride, and then 4-trifluoromethyl-aniline to give the corresponding amide, and then acetyl chloride for

With, the condensation reaction between the molecules to give the desired product, the synthesis route is as follows:

Figure CN103848756AD00051

This class methods used in the reaction process large amounts of chloride reagent for large equipment and environmental damage.

The third method: This method is quite similar to the second type of method, mainly in the 2-cyano-acetic acid derivatives and 4-trifluoromethyl-aniline; The method of the second type is different, In the last step with 1-methyl-2-chloro-propylene oxide as raw materials to build α, β-unsaturated nitrile of the enol structure, i.e., to give the desired product, the synthesis route is as follows:

Figure CN103848756AD00052

Teriflunomide Preparation Example 18 [0185] Implementation

Example 17 was obtained as a pale yellow solid of 61.2g crude compound was used directly in the synthesis of teriflunomide. In a 2L round bottom flask was added compound 27.2g (0.32mol) having the structure shown in formula IV, dry dioxane (620mL), sodium hydride 4g (0.16mol, in g / mL count, mass volume ratio 60% saving in kerosene), calcium hydride

6.7g (0.16mol), 15 ° C was stirred for I h, then slowly added dropwise in Example 17 was obtained as a pale yellow solid compound 61.2g (0.32mol) embodiment of dioxane 200mL, approximately I hour addition was complete, After the addition was complete the reaction was heated to reflux, the reaction at 80 ° C for 24 hours, the reaction process using a nitrogen blanket. After completion of the reaction was added 500mL of ice water to quench the reaction, with 2mol / L of HCl (aq.) And the reaction solution was adjusted to neutral pH, and extracted with EtOAc three times each in an amount of 500mL, and the combined organic phase was washed with saturated aqueous NaCl solution 800mL, dried over anhydrous Na2SO4, concentrated under reduced pressure, the mixed solution was twice recrystallized from methanol i_PrOH, the volume ratio of 1-PrOH and methanol is 2: 1, by volume of each recrystallized with a mixed solution of methanol with i_PrOH for 600mL, the crystallization temperature of 10 ° C, to give 58.8g of white solid compound in a yield of 66%, the total yield of 54% ο

Figure CN103848756AD00221

using mass spectrometry, nuclear magnetic resonance spectroscopy and NMR spectra of the resulting white solid carbon compound structures were identified. MS data [M-H +] = 269.1, H NMR data = 1H-NMR (DMSO-Cie) δ the white solid compound: 10.88 (s, 1Η), 10.07 (br, s, 1H), 7.79 ( d, 2H), 7.66 (d, 2H), 2.26 (s, 3H), carbon NMR spectral data for: 13C-NMR (DMS0-d6) δ: 23.5,80.2,119.1,119.9,120.3,122.4,122.0, 123.5,125.3,126.2,141.8,166.2,186.0. Structural analysis by a white solid compound obtained in the present embodiment example for teriflunomide. Cases detected by HPLC obtained teriflunomide the embodiment of purity, calculated based on the peak area normalization method available, the present embodiment obtained teriflunomide a purity of 99.9%.

………………………

http://www.google.com/patents/WO2015029063A2?cl=en

front page image

Scheme-A

Scheme-A

Pure Teriflunomide ………………………………………….Crude Teriflunomide

xamples

Example- 1: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (Formula-2)

Methylene chloride (125 ml) and dimethyl formamide (2.87 gms) were added to 5-methylisoxazole-4-carboxylic acid (25 gms) at 25-30°C. Heated the reaction mixture to 35-40°C and thionyl chloride (47.59 gms) was slowly added and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. To the obtained compound, dichloromethane was added at 25-30°C. Distilled off the solvent completely from the reaction mixture. Acetonitrile (50 ml) was added to the obtained compound at 25-30°C and slowly added to a mixture of acetonitrile (300 ml) and 4-(trifluoromethyl)aniline (64.45 gms) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (225 ml), followed by activated carbon (2.5 gms) were added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (250 ml) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 39.8 gms; Melting point: 165-168°C. Purity by HPLC: 99.63%.

Example-2: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazoIe-4-carboxamide (FormuIa-2)

Methylene chloride (15 Its) and dimethyl formamide (40 ml) were added to 5-methylisoxazole-4-carboxylic acid (3 kgs) at 25-30°C. Thionyl chloride (5.70 kgs) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dichloromethane was added at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dissolved the obtained compound in acetonitrile (6.0 Its) at the same temperature. Slowly added to a mixture of acetonitrile (36 Its) and 4-(trifluoromethyl)aniline (7.70 kgs) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. After completion of the reaction, filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (27 Its), followed by activated carbon (30 gms) was added to obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (30 Its) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water. To the obtained wet compound, toluene (9 Its) was added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 4.7 kg.

Example-3: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-l)

Methanol (150 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (50 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 2 hours at 0-5°C. Water was added to the reaction mixture. Adjust the pH of the reaction mixture to 7.5 by using dilute hydrochloric acid at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 46.0 gms;

Example-4: Preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-1)

Dimethylformamide (300 ml) was added to (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide (50 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with dimethyl formamide. To the obtained filtrate, methanol (350 ml) was added at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the title compound. Yield: 41 gms;

Melting point: 228-231°C; Water content: 0.06% w/w; Phenyl isoxazole impurity: 0.004%; Purity by HPLC: 99.97%.

Particle size distribution before micronisation: D10: 6.71 μιτι; D50: 34.4 μπι; D90: 109.8 μηι; Particle size distribution after micronisation: DIO: 1.35 μητ, D50: 4.52 μητ, D90: 10.26 μιη.

The P-XRD of the obtained compound is shown in figure- 1.

The DSC thermogram of the obtained compound is shown in figure-2.

Reference Example- 1: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethylphenyl)-amide according to US5494911 (Formula-1)

Methanol (74 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (20 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution {prepared by dissolving sodium hydroxide (3.26 gms) in water (74 ml)} was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 1 hour at 0-5°C. After completion of the reaction, 20% aqueous hydrochloric acid solution was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 8.7 gms.

The P-XRD pattern of the obtained compound is shown in figure-3.

The DSC thermogram of the obtained compound is shown in figure-4.

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Displaying image018.png

Displaying image019.png

TERIFLUNOMIDE SPECTRAL DATA


Teriflunomide,
HMR-1726, 1726, A-771726, RS-61980, SU-0020,
(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
108605-62-5, 282716-73-8 (monosodium salt)
C12-H9-F3-N2-O2 270.2091

17= US2011/0105795A1

NMR DASTA

1H NMR AND 13C NMR

1H NMR 13C NMR

above 13C NMR

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.
 
13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3, 122.2, 126.5, 126.9, 142.1, 167.4,
187.8 ppm.
MS(FD) : m/e 269(M”, 100).
 IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,
842, 684 cm-1.

REF EP 2280938 A2

Example-1  Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).

Yield: 84.6% Example-2 Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.

Yield: 71.0%

Purity: 99.4%

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.

13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3,

122.2, 126.5,

126.9, 142.1, 167.4,

187.8 ppm.

MS(FD) : m/e 269(M”, 100).

IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,

842, 684 cm-1.

1H NMR PREDICT

2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide NMR spectra analysis, Chemical CAS NO. 108605-62-5 NMR spectral analysis, 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide H-NMR spectrum

2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide NMR spectra analysis, Chemical CAS NO. 108605-62-5 NMR spectral analysis, 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide C-NMR spectrum

COSY

COSY

HPLC

HPLC method of analysis:

N-(4′-trifluoromethylphenyI)-5-methylisoxazole-4-carboxamide of formula-2:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Cosmicsil APT CI 8, 100 x 4.6 mm, 3 μιη (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 20 μί; Run time: 40 min; Diluent: Mobile phase; Needle wash: Tetrahydrofuran; Elution: Isocratic; Mobile phase: 5 ml of triethyl amine into a 650 ml of water. Adjusted the pH to 3.4 with dil. Orthophosphoric acid and filter this solution through 0.22 μπι nylon membrane filter paper and sonicate to degas it. (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethyl phenyl)-amide compound of formula- 1:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Kromasil 100 C18, 250 x 4.6 mm, 5 μηι (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 250 nm; Column Temperature: 35°C; Injection volume: 5 μί; Run time: 37 min; Diluent: 0.01 M dipotassium hydrogen orthophosphate in 1000 ml of water; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Buffer (70:30 v/v); Buffer: 1 ml of ortho phosphoric acid into a 1000 ml of water and 3.0 grams of 1 -octane sulfonic acid sodium salt anhydrous. Adjust pH to 6.0 with potassium hydroxide solution and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it……..http://www.google.com/patents/WO2015029063A2?cl=en

WO2009147624A2 * 3 Jun 2009 10 Dec 2009 Alembic Limited A process for preparing teriflunomide
WO2011004282A2 * 22 Jun 2010 13 Jan 2011 Alembic Limited Novel polymorphic form of teriflunomide salts
US5494911 24 Oct 1990 27 Feb 1996 Hoechst Aktiengesellschaft Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use
US5679709 7 Jun 1995 21 Oct 1997 Hoechst Aktiengesellschaft N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide or salts, used for reduction of b-cell produced self-antibodies
US5990141 6 Jan 1995 23 Nov 1999 Sugen Inc. Administering 5-methyl-isoxazole-4-carboxylic acid-n-(4-trifluoromethyl)anilide or 2-cyano-3-hydroxy-n-(4-trifluoro-methyl)phenyl-2-butenamide; antitumor,-carcinogenic and proliferative agents; kinase inhibitors

Bayer’s Stivarga® (regorafenib) Tablets Approved in Europe


WHIPPANY, N.J. and SOUTH SAN FRANCISCO, Calif., Aug. 30, 2013 /PRNewswire/ — Bayer HealthCare and Onyx Pharmaceuticals, Inc. (NASDAQ: ONXX) announced today that the European Commission has approved Stivarga® (regorafenib) tablets for the treatment of adult patients with metastatic colorectal cancer (mCRC).

In September 2012, Stivarga was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.

READ ALL AT http://www.pharmalive.com/ec-approves-bayer-s-stivarga

OLD ARTICLE PASTED

File:Regorafenib.svg

Regorafenib

cas 755037-03-7

4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide hydrate

February 25, 2013 — The U.S. Food and Drug Administration today expanded the approved use of Stivarga (regorafenib) to treat patients with advanced gastrointestinal stromal tumors (GIST) that cannot be surgically removed and no longer respond to other FDA-approved treatments for this disease.

GIST is a tumor in which cancerous cells form in the tissues of the gastrointestinal tract, part of the body’s digestive system. According to the National Cancer Institute, an estimated 3,300 to 6,000 new cases of GIST occur yearly in the United States, most often in older adults.

Stivarga, a multi-kinase inhibitor, blocks several enzymes that promote cancer growth. With this new approval, Stivarga is intended to be used in patients whose GIST cancer cannot be removed by surgery or has spread to other parts of the body (metastatic) and is no longer responding to Gleevec (imatinib) and Sutent (sunitinib), two other FDA-approved drugs to treat GIST.

“Stivarga is the third drug approved by the FDA to treat gastrointestinal stromal tumors,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “It provides an important new treatment option for patients with GIST in which other approved drugs are no longer effective.”

Stivarga was approved in September 2012 to treat colorectal cancer. It is marketed by Bayer HealthCare Pharmaceuticals, based in Wayne, N.J. Gleevec is marketed by East Hanover, N.J.-based Novartis, and Sutent is marketed by New York City-based Pfizer.

Regorafenib (BAY 73-4506, commercial name Stivarga) is an oral multi-kinase inhibitor developed by Bayer which targets angiogenic, stromal and oncogenic receptor tyrosine kinase (RTK). Regorafenib shows anti-angiogenic activity due to its dual targetedVEGFR2-TIE2 tyrosine kinase inhibition. It is currently being studied as a potential treatment option in multiple tumor types.[1]

Metastatic colorectal cancer

Regorafenib demonstrated to increase the overall survival of patients with metastaticcolorectal cancer[2] and has been approved by the US FDA on September 27, 2012.[3]Stivarga is being approved with a Boxed Warning alerting patients and health care professionals that severe and fatal liver toxicity occurred in patients treated with Stivarga during clinical studies. The most common side effects reported in patients treated with Stivarga include weakness or fatigue, loss of appetite, hand-foot syndrome (also called palmar-plantar erythrodysesthesia), diarrhea, mouth sores (mucositis), weight loss, infection, high blood pressure, and changes in voice volume or quality (dysphonia).[4]

  1.  “Bayer Announces New Data on Oncology Portfolio To Be Presented at the ECCO-ESMO Congress 2009″. Retrieved 2009-09-19.
  2. “Phase III Trial of Regorafenib in Metastatic Colorectal Cancer Meets Primary Endpoint of Improving Overall Survival”. Retrieved 2011-10-26.
  3. “FDA approves new treatment for advanced colorectal cancer”. 27 Sep 2012.
  4. “FDA Prescribing Information”. 27 Sept 2012.

Regorafenib from the structure consists of three simple aromatic ring structure, which fragments can be connected from urea by the corresponding two aniline with phosgene or triphosgene prepared by oxygen fragments can be connected SNAr from the corresponding phenol by reaction of. Carboxylic acid 1 by esterification of Thionyl Chloride 2 , methyl amine solution to 2 the ester group is converted to an amide to obtain 3 , 3 , and 4 in alkaline conditions by SNAr reaction of 5 , 5 , and then the isocyanate 6 ( from the corresponding aniline with phosgene or triphosgene was obtained) to obtain the Regorafenib.

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