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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

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


Mukund K Gurjar

Chief Scientific Officer, Director of Research & Development and Executive Director, Emcure Pharmaceuticals
Emcure Pharmaceuticals Limited
ITBT Park Phase II
Hinjwadi, PUNE, INDIA

Among the vast ocean of literature on organic chemistry , you will find a pearl in the form of Emcure

we are treated to excellent reading material and important communications in our field

hats off to this team

Dr. Mukund K. Gurjar serves as the Chief Scientific Officer of Emcure Pharmaceuticals Limited and serves as its Director of Research & Development.

Dr. Gurjar has been closely associated with Drugs and Pharmaceutical Sciences since 1975 and is a distinguished Researcher in the country. He has carried out extensive work in the field of new chemical entities (NCEs). Dr. Gurjar has been an Executive Director of Emcure Pharmaceuticals Ltd. since 2001.

He serves as Deputy Director at National Chemical Laboratory, Pune. Dr. Gurjar served as Non-Executive Director of Cipla Limited since January 19, 2002 until August 27, 2007.

Dr. Gurjar has the distinction of being one of the 43 scientists from India who have been mentioned in the Institute of Scientific Information of Chemists and has more than 500 citations. Dr. Gurjar has obtained Master of Science degree in Organic Chemistry and Ph.D. in chemistry from the Nagpur University. He also obtained the second Ph.D. degree from the London University, UK.

He is a leading Fellow at various National and International Academies

Board Members Memberships

2001-Present
Chief Scientific Officer, Director of Research & Development and Executive Director
2002-2007
Former Non Executive Director

Education

PhD
University Of London
MS
Rashtrasant Tukadoji Maharaj Nagpur University
PhD
Rashtrasant Tukadoji Maharaj Nagpur University

Other Affiliations

DOB-28-08-1952

LINKS

http://www.emcure.co.in/bod.asp

http://www.ias.ac.in/php/fell_detail.php3?name=Gurjar&intials=Mukund&year=28-08-1952

http://www.researchgate.net/profile/Mukund_Gurjar/

About EMCURE : Company Profile as quoted by COMPANY WEBSITE
The Company was incorporated as Emcure Pharmaceuticals Private Limited on April 16, 1981 as a private limited company under the Companies Act, 1956.Emcure Pharmaceuticals is a fast growing Indian pharmaceutical company engaged in developing, manufacturing and marketing a broad range of pharmaceutical products globally. Our core strength lies in developing and manufacturing differentiated pharmaceutical products in-house, which we commercialize through our marketing infrastructure across geographies and relationships with multi-national pharmaceutical companies.Emcure Pharmaceuticals is ranked as the 14th largest pharmaceutical company (Source: IMS Health India, Secondary Stockist Audit (“SSA”), March 2013) in India in terms of market share based on the domestic sales of pharmaceutical products. We believe that our competitive advantage in the domestic market lies in our established presence in all major therapeutic areas including blood related, cardiology, pain and analgesics, HIV, gynecology, nephrology, anti-infective, and vitamins, minerals and nutrients products. We have also recently entered the oncology and diabetes therapeutic areas.Emcure Pharmaceuticals have a well-diversified income base thanks to our business in the international markets. We have our own sales and marketing infrastructure in the United States through our subsidiary, Heritage. We sell our portfolio of branded generic products to the Rest of World. Our products are currently shipped to over 65 countries, where we have established our presence by focusing on important alliances with local and multi-national companies that enjoy a leadership position in the therapeutic areas on which we focus. We have subsidiaries in Dubai, Brazil, South Africa, Singapore and Nigeria and branch offices in Russia and Morocco.Emcure Pharmaceuticals…….quote………. are focus our research and development efforts on developing a portfolio of differentiated products across several platforms, including chiral molecules and biosimilars, and novel drug delivery systems. We have a portfolio of 11 chiral molecules, eight of which we launched for the first time in India. We also have capabilities to develop complex products, including difficult iron preparations, oncology drugs and controlled release products. Our portfolio of in-house manufactured five commercialized biosimilars including TNK-tPA, which we launched for the first time in India, and our brand Vintor is ranked no. 1 in erythropoietin market (Epoetin Alfa Recombinant) (Source: IMS Health India, SSA, March 2013).

..

 

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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

Purdue Pharma L.P. Receives FDA Approval For 15 mcg/hour Dosage Strength Of Butrans (buprenorphine) Transdermal System CIII


buprenorphine

STAMFORD, Conn., Sept. 24, 2013 /PRNewswire/ — Purdue Pharma L.P. announced that the U.S. Food and Drug Administration (FDA) approved a new 15 mcg/hour dosage strength of Butrans® (buprenorphine) Transdermal System CIII, which will provide an additional titration option for healthcare professionals. Four strengths of Butrans will now be available: 5, 10, 15 and 20 mcg/hour. Purdue expects to launch Butrans 15 mcg/hour commercially in the U.S. in October 2013.

read all at

http://www.drugs.com/newdrugs/purdue-pharma-l-p-receives-fda-approval-15-mcg-hour-butrans-buprenorphine-transdermal-ciii-3909.html

Buprenorphine is a semi-synthetic opioid that is used to treat opioid addiction in higher dosages (>2 mg), to control moderate acute pain in non-opioid-tolerant individuals in lower dosages (~200 µg), and to control moderate chronic pain in dosages ranging from 20–70 µg/hour. It is available in a variety of formulations: Subutex, Suboxone, Zubsolv (buprenorphine HCl and naloxone HCl; typically used for opioid addiction), Temgesic (sublingual tablets for moderate to severe pain), Buprenex (solutions for injection often used for acute pain in primary-care settings), Norspan and Butrans (transdermal preparations used for chronic pain).

  • The treatment of opiate abuse and dependence by substitution of the abused opiate with a safer, longer-acting opioid is often a successful pharmacotherapeutic intervention strategy. Heroin, a widely abused opiate, acts as an agonist for the mu-opioid receptor (MOR). Heroin is often abused using intravenous injection, often resulting in needle-sharing among addicts, which is often responsible for the spread of life-threatening infections such as hepatitis C and HIV/AIDS. Methadone has been used as a substitute MOR agonist. Methadone is orally active, and has sufficient duration of action to enable it to be given as a single daily dose. More recently, buprenorphine 1, 21-(cyclopropyl-7α-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6,14-endo-ethano-6,7,8,14-tetrahydro-oripavine, a MOR partial agonist, has been used as a pharmacotherapy (see, e.g., U.S. Pat. No. 4,935,428 ). As a partial MOR agonist, it has a lower ceiling to its MOR-mediated effects than a full MOR agonist (e.g., methadone). As a result, buprenorphine has a greater margin of safety than full MOR agonists. In addition, buprenorphine also has a long duration of action. Buprenorphine’s enhanced safety, coupled with its extended duration, enables a relatively long dosing interval, typically every 24 hours, but this can be extended to every 72 hours or more.

    Buprenorphine’s favorable safety profile compared to methadone has allowed it to be prescribed by office-based physicians, which has substantially decreased the cost of treatment, and increased the number of addicts in pharmacotherapy treatment.

  • For the treatment of opiate abuse and dependence, buprenorphine is available as tablets formulated for sublingual administration, and is sold under the trademark Subutex®. The daily maintenance dose for Subutex® is in the range 4-16 mg. Subutex®is readily soluble in aqueous media, making it possible for addicts to misuse the formulation by dissolving the tablets in water, and then injecting the resulting solution. To counter this misuse, buprenorphine has been formulated as a mixture with the MOR antagonist naloxone in a 4:1 ratio (Suboxone®).
  • Sublingual administration of buprenorphine has several drawbacks, notably the need to avoid swallowing the tablet because of buprenorphine’s low bioavailability (∼5%) when taken orally. In comparison, buprenorphine’s bioavailability is approximately fifty percent when absorbed sublingually (see, e.g., Jasinski and Preston, Buprenorphine, Ed. A Cowan, JW Lewis, Wiley-Lis, NY pp. 189-211).
  • Several buprenorphine ester derivatives are described by Stinchcomb et al. in Pharm. Res (1995), 12, 1526-1529. The physiochemical properties of the esters are described, and compared with those of buprenorphine hydrochloride and its free base. Stinchcomb et al. also describe transdermal absorption of these esters in Biol. Pharm. Bull. (1996), 19, 263-267 and Pharm. Res. (1996), 13, 1519-1523. Wang, Published U.S. Patent Application No. 2005/0075361 , also describes some buprenorphine derivatives, which are apparently useful for pain relief when delivered intramuscularly or subcutaneously. EP 1 422 230 discloses buprenorphine monocarboxylic ester derivatives and dibuprenorphine dicarboxylic ester derivatives which exert a longer analgesic effect as compared to buprenorphine hydrochloride.

Buprenorphine hydrochloride was first marketed in the 1980s by Reckitt & Colman (now Reckitt Benckiser) as an analgesic, generally available as Temgesic 0.2 mg sublingual tablets, and as Buprenex in a 0.3 mg/mL injectable formulation. In October 2002, the Food and Drug Administration (FDA) of the United States also approved Suboxone and Subutex, buprenorphine’s high-dose sublingual tablet preparations indicated for detoxification and long-term replacement therapy in opioid dependency, and the drug is now used predominantly for this purpose.

In the European Union, Suboxone and Subutex, buprenorphine’s high-dose sublingual tablet preparations, were approved for opioid addiction treatment in September 2006.[3] In the Netherlands, buprenorphine is a List II drug of the Opium Law, though special rules and guidelines apply to its prescription and dispensation. In the United States, it was rescheduled to Schedule III drug from Schedule V just before FDA approval of Suboxone and Subutex.[4] In recent years, buprenorphine has been introduced in most European countries as a transdermal formulation for the treatment of chronic pain.

Commercial preparations

British firm Reckitt & Colman (now Reckitt Benckiser) first marketed buprenorphine under the trade names Temgesic (sublingual/parenteral preparations) and Buprenex (parenteral). Subsequently, two more formulations were released: Subutex (white, oval-shaped, bitter, no active additives) and Suboxone (white color [orange in the U.S.], hexagonal tablet, lemon-lime-flavored, one part naloxone for every four parts buprenorphine). The orange film strips form of Suboxone are lemon flavor. More than 71% of patients gave Suboxone film a favorable taste rating.[5]

8mg Suboxone film strip

Subutex and Suboxone are available in 2 mg and 8 mg sublingual dosages. (Suboxone Film is also available in doses of 4 mg/1 mg & 12 mg/3 mg buprenorphine/naloxone respectively). On October 8, 2009, Roxane Laboratories of Columbus, Ohio, United States won FDA approval for a generic preparation of Subutex[6] and as of October 23, 2009, announced that it is ready for distribution nationwide in 2 mg and 8 mg sublingual dosages. The demand for this generic was so high that Roxane did not produce enough to meet market demand, resulting in pharmacies running out and being unable to order more.[7] Teva Pharmaceutical Laboratories of Tel Aviv, Israel also received approval (as of April 1, 2010) for a generic formulation of Subutex sublingual tablets in 2 mg and 8 mg dosages that are currently available in limited distribution in America as of June 20, 2010. In 2013, Reckitt Benckiser voluntarily discontinued the sale of Suboxone tablets in the United States based on data from Poison control centers that consistently found significantly higher rates (7.8–8.5 times greater) of accidental pediatric exposure with Suboxone tablets as compared with Suboxone Film.[8]

Since 2001, buprenorphine is also available transdermally as 35, 52.5, and 70 µg/h transdermal patches that deliver the dose over 96 hours. This dosage form is marketed as Transtec in most European countries by Grunenthal (Napp Pharmaceuticals in the UK,[9][10] Norpharma in Denmark) for the treatment of moderate to severe cancer pain and severe non-cancer pain not responding to non-opioids.

Other available buprenorphine formulations include a 5, 10, and 20 µg/h, 7-day patch, marketed as Butrans in the U.S. by Purdue Pharma (and by Napp Pharmaceuticals in the UK) indicated for the management of moderate to severe chronic pain in patients requiring a continuous, around-the-clock opioid analgesic for an extended period of time.[11] A similar transdermal system is marketed by a collaboration between Mundipharma and Grunenthal in Australia under the name Norspan, with indications for moderate chronic pain not responding to non-opioids, dosed in 5, 10, or 20 µg/h patches.[12]

In India: Addnok 0.4, 2 & 8 Mg Sublingual Tablets by Rusan Pharma Ltd.,[13] Tidigesic 0.2 mg (slow release) or 0.3 mg/mL injectable by Sun Pharmaceuticals;[14] Buprigesic (0.3 mg/mL) by Neon Laboratories;[15] Morgesic (0.3 mg/mL) by Samarth Pharma; Norphin (0.3 mg/mL) Unichem Laboratories.

A novel implantable formulation of buprenorphine (Probuphine), using a polymer matrix sustained-release technology, has been developed to offer treatment for opioid dependence while minimizing risks of patient noncompliance and illicit diversion. FDA requested additional information about Probuphine on April 30, 2013, in a complete response letter to Titan Pharmaceuticals pending NDA.[16]

In addition to the sublingual tablet, Suboxone is now marketed in the form of a sublingual film, available in the 2 mg/0.5 mg, 4 mg/1 mg, 8 mg/2 mg, and recently 12 mg/3 mg dosages; the film is not available in Canada or the United Kingdom (where it was discovered). The makers of Suboxone, Reckitt Benckiser, claim that the film has some advantages over the traditional tablet in that it dissolves faster and, unlike the tablet, adheres to the oral mucosa under the tongue, preventing it from being swallowed or falling out; that patients favor its taste over the tablet, stating that “more than 71% of patients scored the taste as neutral or better”; that each film strip is individually wrapped in a compact unit-dose pouch that is child-resistant and easy to carry; and that it is clinically interchangeable with the Suboxone tablet and can also be dosed once daily.[17] Reckitt Benckiser also states that the film discourages misuse and abuse, as the paper-thin film is more difficult to crush and snort. Also, a ten-digit code is printed on each pouch, which helps facilitate medication counts and, therefore, serves to deter diversion into the illegal drug market. Although Suboxone film may deter snorting the drug it makes injecting the drug much easier as the films are extremely easy to dissolve in water making for easy injection and the fact that the naloxone in suboxone is ineffective at blocking the effects of buprenorphine when injected by addicts not dependent on another opioid.

Physicochemical properties

Buprenorphine is a semi-synthetic derivative of thebaine, one of the most chemically reactive opium alkaloids. Buprenorphine has a molecular weight of 467 and its structure is typically opioid with the inclusion of a C-7 side-chain containing a t-butyl group. This group confers overall lipophilicity on the molecule which has an important influence on its pharmacology.

Opioids exert their pharmacological effects by binding to opioid receptors. The pharmacological effects are determined by the nature of opioid-receptor interaction. Some of these effects such as analgesia, mediated by an agonistic action at the μ-opioid receptor are desirable, whereas others such as nausea, sedation, or constipation can be considered as unwanted adverse effects. Buprenorphine is a μ-opioid receptor agonist with high affinity, but low intrinsic activity. Compared with morphine (a full μ-opioid agonist) buprenorphine is considered a partial μ-opioid agonist displaying high affinity for and slow dissociation from the μ-opioid receptor. A full dose-dependent effect on analgesia has been seen within the clinically relevant dose range (up to 10 mg), but no respiratory depression which levels off at higher doses (Dahan et al. 2005). Clinically, there is also a less marked effect of buprenorphine-binding to μ-opioid receptors on gastrointestinal transit times, and indeed constipation seen in the clinic is remarkably low (Griessinger et al. 2005). Buprenorphine also shows partial agonistic activity at the opioid receptor-like receptor 1 (ORL1)-receptors which are (at least at supraspinal receptors) postulated to induce a pronociceptive effect. A study by Lutfy et al. (2003) reported that co-activation of ORL1-receptors compromises the antinociception induced by activation of the μ-opioid receptor. ORL1-activation has also an effect on hyperalgesia. It might be that buprenorphine’s partial agonism reduces this effect compared with full ORL1-agonists such as morphine or fentanyl. Buprenorphine’s antagonistic action at the δ-receptors which have a marked anti-opioid action and seem to negatively modulate central analgesia seems further to contribute to its clinically seen analgesic effect. Its likewise antagonistic activity at the κ-opioid receptors might explain the fact that it induces much less sedation and psychotomimetic effects than morphine or fentanyl (Lewis 1985; Leander 1988). Animal studies have shown that buprenorphine has a 20–40 times higher potency than morphine (Martin et al. 1976).

The strong binding of buprenorphine to the μ-opioid receptor has several consequences. Initial binding is relatively slow compared with other opioids such as fentanyl (Boas and Villiger 1985). However, the onset of analgesia is not dissimilar, since buprenorphine achieves effective analgesia at relatively low receptor occupancy (5%–10%) (Tyers 1980) and thus relatively low plasma concentrations of buprenorphine are sufficient to provide effective pain relief. The slow dissociation of buprenorphine from the receptor results in a long duration of effect and also confers another advantage in that when the drug is withdrawn an abstinence syndrome is rarely seen because of the long time taken for the drug to come off the receptor (Bickel et al. 1988).

1 Weinberg, D. S.; Inturrisi, C. E.; Reidenberg, B.; Moulin, D. E.; Nip, T. J.; Wallenstein, S.; Houde, R. W.; Foley, K. M. (1988). “Sublingual absorption of selected opioid analgesics”. Clinical pharmacology and therapeutics 44 (3): 335–342. PMID 2458208.
2. Eriksen, J.; Jensen, N. H.; Kamp-Jensen, M.; Bjarnø, H.; Friis, P.; Brewster, D. (1989). “The systemic availability of buprenorphine administered by nasal spray”. The Journal of pharmacy and pharmacology 41 (11): 803–805. PMID 2576057.
3. Suboxone EU Approval
4.DEA Rescheduling
5.What flavor do suboxone come in?. Kgbanswers.com (2012-09-06). Retrieved on 2013-05-19.
6.FDA Approval Letter to Roxane
7.Generic buprenorphine shortage
8.Reckitt Benckiser Announcement of Suboxone tablets withdrawal
9.Napp Pharmaceuticals
10.electronic Medicines Compendium (eMC) of UK medicines, Transtec product characteristics. Medicines.org.uk (2010-10-21). Retrieved on 2013-05-19.
11. “Butrans”, accessed January 23, 2011.
12. “Norspan Buprenorphine Drug/Medicine information”. news-medical.net
13.Addnok information
14. Tidigesic in India
15. Buprigesic in India
16.Probuphine complete response letter
17. Suboxone film patient information
18 Likar, R. (2006). “Transdermal buprenorphine in the management of persistent pain – safety aspects”. Therapeutics and clinical risk management 2 (1): 115–125. PMC 1661652. PMID 18360586.

    • Buprenorphine acts as a mixed agonist / antagonist and it is an important treatment option for opiate addiction and analgesia.
      • Opiate compounds such as (-)-naltrexone, (-)-naloxone, (-)-nalbuphene, (-)-nalmefene, and (-)-buprenorphine have been used for addiction therapy. (-)-Buprenorphine, in particular, is increasingly being used for the treatment of heroin addiction. Recently, the (+)-opiate enantiomers have been shown to have important bioactivities that differ from their (-) counter parts. Because of the exceptional opiate medicinal activity of (-)-buprenorphine, there is great interest in the therapeutic efficacy of (+)-buprenorphine. In order to explore the possible benefits of this compound, there is a need in the art for synthetic routes to produce (+)-buprenorphine or its derivatives in an efficient and cost effective manner that generates a high yield of product having a high degree of purity.
      • The following documents disclose processes for the preparation of buprenorphine:

    • [0002]
      The conventional synthetic route used world-wide to prepare buprenorphine utilizes thebaine as the starting material.

    • [0003]
      Through a series of chemical reactions, thebaine is converted into nor-buprenorphine, the immediate precursor to buprenorphine. The final step adds a cyclopropyl methyl group to the nitrogen to form buprenorphine from nor-buprenorphine.
    • [0004]
      An outline of the conventional series of reactions from thebaine to buprenorphine follows:

      1. 1. Reaction of thebaine with methyl vinyl ketone to form the 4 + 2 reaction product.
      2. 2. Hydrogenation of the carbon-carbon double bond.
      3. 3. Addition of a tertiary butyl group via a Grignard Reaction.
      4. 4. An N-demethylation, via a two step reaction sequence.
      5. 5. An O-demethylation reaction and an N-cyano hydrolysis.
      6. 6. Addition of the cyclopropyl methyl group to form buprenorphine.
    • [0005]
      A drawback of this conventional production scheme is that the O-demethylation step is considered a low to moderate yield transformation. There is therefore a need for a norbuprenorphine/buprenorphine production scheme that does not include an O-demethylation step.
    • [0006]
      Processes for preparing Bupremorphine or Bupremorphine derivatives are disclosed in EP1439179 , US5849915 and Chem. Commun., 16, 2002, 1762-1763

 

    • [0007]
      An aspect of the present invention is to provide a method for producing norbuprenorphine utilizing oripavine as the starting material. The method comprises:

      • reacting oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II;
      • hydrogenating the compound according to Formula II to form a compound according to Formula III;
      • adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X; and
      • demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.
    • [0008]
      Another aspect of the present invention is to provide a method of making buprenorphine utilizing oripavine as the starting material.

 

    • [0009]
      There is provided a method utilizing oripavine as the preferred starting material for the synthesis of nor-buprenorphine and optionally buprenorphine. Oripavine is a naturally occurring alkaloid of Papaver somniferum. The key difference between the conventional technology and the present use of oripavine as a starting material is that the O-demethylation step, typically a low to moderate yield transformation, is not needed since the oripavine molecule lacks an O-3 methyl group. In a synthesis involving several steps, it is advantageous to have only high yield reactions, in order for the overall transformation to be economical. Since the present oripavine based synthesis does not require the O-3 demethylation step, the overall yield from oripavine provides an improved yield over that traditionally achieved when thebaine is used as the starting material. The conversion route from oripavine to produce buprenorphine is convenient and more straightforward as compared to other synthetic routes.
    • [0010]
      An illustrative embodiment of the steps for converting oripavine into norbuprenorphine, and optionally buprenorphine, is as follows:

    • [0011]
      The sequence outlined above is an illustrative embodiment presented to show the transformations required, but is not limited as to the order in which the transformations may be employed. In an alternative embodiment, the hydrogenation of the Diels-Alder double bond can also be accomplished as part of step 7 when the removal of the Y protecting group is through catalytic hydrogenation.

Step 1:

    • [0012]
      The first step involves reaction of the oripavine with methyl vinyl ketone. This addition reaction may be accomplished by any conventional method known in the art. An illustrative embodiment is a Diels-Alder reaction in which the oripavine and methyl vinyl ketone are dissolved in a solvent and refluxed until the reaction is substantially complete. Illustrative suitable solvents include isopropyl alcohol, methanol, ethanol, toluene and mixtures thereof. The reaction mixture is then filtered to isolate the Diels-Alder adduct solids. Typical reactions result in at least about an 85% yield of at least about 98% purity.

Step 2:

    • [0013]
      The second step involves the hydrogenation of the C-C double bond. In an illustrative embodiment, the Diels-Alder adduct formed in step 1 was charged to a reaction vessel with Pd/ Carbon catalyst, then dissolved in a solvent. A presently preferred solvent is methanol, but any suitable solvent may be used, including methanol, ethanol, isopropyl alcohol, acetic acid and mixtures thereof. The hydrogenation takes place under nitrogen at an elevated pressure and temperature. The temperature and pressure are selected to insure substantial completion of the reaction, as is well known in the art. An illustrative temperature range typical of this reaction is about 50-90°C, with about 60°C being preferred and an illustrative pressure range typical of this reaction is about 20-60 psi, with about 35 psi being preferred. The reaction mixture is filtered to remove the catalyst and the resulting filtrate reduced under vacuum to yield the product according to Formula III.

Step 3:

    • [0014]
      Optional step 3 discloses the addition of a protecting group Y to form a compound according to Formula IV. The preferred method using oripavine as the starting material for norbuprenorphine and then buprenorphine utilizes an O-3 protecting group. However, the reaction can be accomplished without the use of the protection group, although the overall yield may be compromised. Further, the protecting group may be removed simultaneously with another step thereby eliminating one chemical step. Addition of an O-3 protecting group may minimize unwanted chemical reactions involving the unprotected phenol function at the 3-position. Illustrative suitable protecting groups include benzyl, O-t-butyl and silyl groups.
    • [0015]
      In an illustrative embodiment, the reduced Diels-Alder adduct according to Formula III and ground K2CO3 are added (K2CO3 not soluble) in chloroform and benzyl bromide, heated and refluxed. After cooling to room temperature, the reaction mixture is filtered to remove the K2CO3. The filtrate is then reduced under vacuum and azeo dried in toluene.

Step 4:

    • [0016]
      The fourth step utilizes the crude material according to Formula IV, formed in step 3. in a Grignard reaction. Under moisture free conditions and further under an inert atmosphere, t-BuMgCl is added, followed by anhydrous toluene. The solution is distilled until a pot temperature of about 100 °C is achieved, and the compound according the Formula IV is added. The reaction is quenched, and the temperature of the reaction mixture lowered. The organic and aqueous layers are separated, and the organic layer is concentrated under vacuum yielding an oily residue. The oily residue is then purified resulting in a compound according to Formula V, of up to about 93% purity.
    • [0017]
      In an alternate embodiment, the t-butyl group is added using a t-butyl lithium reagent, as is well known in the art.
    • [0018]
      The N-demethylation reaction may be accomplished by any suitable method known in the art. In the illustrative embodiment shown in steps 5 and 6, the methyl group is first converted into a nitrite in step 5, followed by reduction of the nitrile group in step 6.

Step 5:

    • [0019]
      In an illustrative embodiment of step 5, the tertiary alcohol starting material according to Formula V is dissolved in a solvent, flushed with an inert atmosphere, and then K2CO3 and cyanogen bromide are added. This reaction mixture is then refluxed until the reaction is substantially complete, cooled to room temperature and filtered to remove the K2CO3. The reaction mixture is then extracted and the organic layers reduced and dried under vacuum. The resulting solid is purified yielding up to about 93% clean material after drying.

Step 6:

    • [0020]
      In an illustrative embodiment, potassium hydroxide is dissolved in diethylene glycol and heated. The N-CN compound according to Formula VII is added and the reaction mixture heated until the reaction is substantially complete. After cooling to room temperature, distilled water is added and the resulting solid collected and dried, with up to about 100% yield.
    • [0021]
      The N-demethylation may be accomplished by any method know to those skilled in the art without departing from the instant method.

Step 7:

    • [0022]
      The seventh step involves the removal of the optional protecting group. In the illustrative embodiment, the Y protecting group added in step 3 is removed. In this embodiment, the secondary amine starting material may be catalytically removed by Pd/Carbon in a suitable , solvent. Suitable solvents include methanol, ethanol, isopropyl acetate and mixtures thereof. The resulting filtrate is dried under vacuum to yield norbuprenorphine. In another embodiment, the Y protecting group may be removed with an acid, such as HCl, HOAc, HF or an F anion.

Step 8:

  • [0023]
    Finally the norbuprenorphine is optionally converted to buprenorphine as illustrated in step 8. In an illustrative embodiment, the norbuprenorphine is converted to buprenorphine.
  • [0024]
    In an illustrative embodiment, a mixture of norbuprenorphine, a mild base, and cyclopropylmethyl bromide are heated in an oilbath at about 80-100°C until the reaction is substantially complete. The reaction mixture is then added over 5 minutes to 160ml of water, with mechanical stirring, yielding a gum. The mixture is stirred and filtered, and the filter cake is washed with water. The HPLC will show about 90% by area of desired product, and 0.2-0.5% of an N-butenyl substituted impurity. The resulting product is dried, and then boiled in alcohol, cooled, and filtered to yield buprenorphine.
  • [0025]
    In the alternative, norbuprenorphine can be converted to buprenorphine by reductive amination, or by acylation followed by reduction of the amide.
  • [0026]
    In an alternative embodiment, the hydrogenation step 2 is performed on the crude reaction mixture formed in step 1, thereby providing a one-pot reaction scheme for forming a compound according to Formula III.

  • [0027]
    The oripavine, methyl vinyl ketone and isopropyl alcohol are heated under pressure. Upon cooling, a Pd-C catalyst is added, and the reaction mixture is heated under pressure until the reaction is substantially complete. The product is then solubilized and the catalyst removed by filtration. The filtrate is then concentrated under vacuum.
  • [0028]
    In another alternative embodiment, illustrated below, a method for producing norbuprenorphine, and optionally buprenorphine, from oripavine, without the use of a protecting group on O-3. The individual reactions are as discussed in more detail above.
  • [0029]
    The method comprises:

    1. a) reacting the oripavine according to Formula I with methyl vinyl ketone to form a compound according to Formula II;
    2. b) hydrogenating the compound according to Formula II to form a compound according to Formula III;
    3. c) adding a t-butyl group to the compound according to Formula III to form a compound according to Formula X; and
    4. d) demethylating the nitrogen of the compound according to Formula X to form norbuprenorphine, Formula VIII.
      Figure imgb0012

    ………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….

    WO 2009078986 A1

    Th invention provides processes and intermediate compounds for producing buprenorphine. In particular, the process encompasses synthetic routes for the production of buprenorphine or derivatives of buprenorphine from norhydromorphone or derivatives of norhydromorphone. While it is envisioned that the synthetic routes described herein may be utilized to produce (+/-)-buprenorphine, in an exemplary aspect of the invention, the process encompasses the production of (+)-buprenorphine or derivatives of (+)-buprenorphine.

    For purposes of illustration, Reaction Scheme 1 depicts the production of compound 8 from compound 1 in accordance with one aspect of the present invention:

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

Kadcyla, breast cancer treatment from Roche, approved by the EMA


September 24,2013 | By Márcio Barra

Kadcyla (ado-trastuzumab emtansine, or T-DM1), from Roche/Genentech, was approved on the September 2013 meeting of the EMA’s Committee for Medicinal Products for Human Use. This is the drug’s third approval in a major territory, following the US FDA’s approval back in February and in Japan for the treatment of HER2+ positive inoperable or recurrent breast cancer.

Kadcyla is a therapy for patients with HER2-positive, late-stage (metastatic) breast cancer, consisting of the antibody trastuzumab, connected to a drug called DM1, from ImmunoGen. The medicine, which comes in two dosage forms, 100 mg and 160 mg, was approved for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and chemotherapy, separately or in combination.

HER2 is a protein encoded by ERBB2, a proto-oncogene located in chromosome 17. Over-expression of this proto-oncogene occurs in roughly 30% of breast cancers, and…

View original post 203 more words

Discovery could help develop new treatments for blood diseases


VALSARTAN


File:Valsartan.svg

VALSARTAN

CAS 137862-53-4

Molecular FormulaC24H29N5O3, Average mass435.519 Da

(2S)-3-methyl-2-[N-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)pentanamido]butanoic acid

PAPER

Greening the Valsartan Synthesis: Scale-up of Key Suzuki–Miyaura Coupling over SiliaCat DPP-Pd

 SiliCycle Inc., 2500 Parc-Technologique Blvd, Quebec City, Quebec, Canada G1P 4S6
 Istituto per lo Studio dei Materiali Nanostrutturati, CNR, via U. La Malfa 153, 90146 Palermo, Italy
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op400118f
Publication Date (Web): June 17, 2013
Abstract Image

The study of the scale-up of the heterogeneous Suzuki-Miyaura coupling reaction in batch conditions between 2-chlorobenzonitrile and 4-tolylboronic acid, a key step in valsartansynthesis, to produce 4′-methyl-2-biphenylcarbonitrile over the SiliaCat DPP-Pd catalyst in ethanol under reflux allows to identify the optimal reaction conditions.

The catalyst, regardless of limited Pd leaching, is not reusable, and the method can be effectively applied to the high yield synthesis of several coupling products, opening the route to efficient continuous coupling syntheses.

http://pubs.acs.org/doi/full/10.1021/op400118f

ABOUT VALSARTAN

Valsartan (Angiotan or Diovan) is an angiotensin II receptor antagonist (more commonly called an “ARB”, or angiotensin receptor blocker), with particularly high affinity for the type I (AT1) angiotensin receptor. By blocking the action of angiotensin, valsartan dilates blood vessels and reduces blood pressure.[1] In the U.S., valsartan is indicated for treatment ofhigh blood pressurecongestive heart failure (CHF), or post-myocardial infarction (MI).[2] In 2005, Valsartan was prescribed more than 12 million times in the United States[citation needed] and global sales were approximately $6.1 billion in 2010.[3] The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012.[4][5]

A study released in 2010, based on 819,491 cases in U.S. Department of Veterans Affairs database from 2002 to 2006, demonstrated a significant reduction in the incidence and progression of Alzheimer’s disease and dementia.[6] An earlier study released by theJournal of Clinical Investigation in 2007 found some efficacy in the use of valsartan in the treatment and prevention of Alzheimer’s disease (in a mouse model).[7]

Valsartan, also known as (S)—N-(1-Carboxy-2-methyl-prop-1-yl)-N-pentanoyl-N-[2′-(1H-tetrazol-5-yl)bi phenyl-4-ylmethyl]-amine, has the following structure:

Figure US07199144-20070403-C00001

and is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.

Valsartan and/or its intermediates are disclosed in various references, including: U.S. Pat. Nos. 5,399,578, 5,965,592, 5,260,325, 6,271,375, WO 02/006253, WO 01/082858, WO 99/67231, WO 97/30036, Peter Bühlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29–34 (1994), Th. Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245–1252 (2000), and Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385–387 (2001).

Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is prescribed for the treatment of hypertension. U.S. Pat. No. 6,395,728 is directed to use of valsartan for treatment of diabetes related hypertension. U.S. Pat. Nos. 6,465,502 and 6,485,745 are directed to treatment of lung cancer with valsartan. U.S. Pat. No. 6,294,197 is directed to solid oral dosage forms of valsartan.

The synthesis of valsartan is discussed, inter alia, in U.S. Pat. No. 5,399,578. In the synthesis disclosed therein, the final synthetic step (exclusive of work-up and purification) involves the reaction of a cyano group on the biphenyl ring with an azide, for example, tributyl tin azide. The reaction scheme of the ‘578 patent is as follows:

Figure US07199144-20070403-C00002

Peter Bühlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29–34 (1994)

In Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245–1252 (2000), various schemes for synthesis of valsartan are provided, with one being:

Figure US07199144-20070403-C00003

Another paper, Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385–387 (2001), discloses a synthesis scheme for valsartan as follows:

Figure US07199144-20070403-C00004

There is a need in the art for an improved synthetic process for the preparation of valsartan and precursors of valsartan.

DOSE
Oral tablets, containing 40 mg (scored), 80 mg, 160 mg, or 320 mg of valsartan. Usual dosage ranges from 40–320 mg daily.

In some markets available as a hard gelatin capsule, containing 40 mg, 80 mg, or 160 mg of valsartan.

Diovan HCT contains a combination of valsartan and hydrochlorothiazide but, unlike Diovan, is only indicated for hypertension, not for CHF or post-MI. Diovan HCT is available in oral tablets, containing (valsartan/HCTZ mg) 80/12.5, 160/12.5, 160/25, 320/12.5, and 320/25.

Whether angiotensin receptor blockers may or may not increase the risk of myocardial infarction (heart attack) was announced in BMJ[8] and was debated in 2006 in the medical journal of the American Heart Association.[9][10] To date[when?], there is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI.

In the VALUE trial, the angiotensin II receptor blocker valsartan produced a statistically significant 19% (p=0.02) relative increase in the prespecified secondary end point of myocardial infarction (fatal and non-fatal) compared with amlodipine.[11]

The CHARM-alternative trial showed a significant +52% (p=0.025) increase in myocardial infarction with candesartan (versus placebo) despite a reduction in blood pressure.[12]

Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.[13][14][15]

In patients with impaired glucose tolerance, valsartan may decrease the incidence of developing diabetes mellitus type 2.[16] However, the absolute risk reduction is small (less than 1 percent per year) and diet, exercise or other drugs, may be more protective. In the same study, no reduction in the rate of cardiovascular events (including death) was shown.

There is a case report of a stillbirth in which valsartan is implicated.[18]In the US, UK and Australia, valsartan is marketed by Novartis under the trade name Diovan. In Pakistan, it is marketed by Efroze under the trade name Angiotan. In India, it is marketed by Cipla under the trade name Valtan and by Torrent Pharmaceuticals under the trade name Valzaar. In Egypt and in France, it is marketed by Novartis under the name of Tareg. In Ukraine, it is marketed by Фарма Старт under the trade name Диокор, Диокор Соло

  1. Marks JW (2007-02-15). “Valsartan, Diovan”. MedicineNet. Retrieved 2010-03-04.
  2.  “Diovan prescribing information”. Novartis.
  3. J “Novartis Annual Report”. Novartis. 2010. Retrieved June 15, 2011.
  4.  Philip Moeller (April 29, 2011). “Blockbuster Drugs That Will Go Generic Soon”U.S.News & World Report.
  5.  Eva Von Schaper (August 5, 2011). “Novartis’s Jimenez Has Blockbuster Plans For Diovan After Patent Expires”. Bloomberg.
  6.  Li NC, Lee A, Whitmer RA, et al. (January 2010). “Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis”BMJ 340: b5465. doi:10.1136/bmj.b5465.PMC 2806632PMID 20068258.
  7.  Wang J, Ho L, Chen L, et al. (November 2007). “Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease” (PDF). J. Clin. Invest. 117 (11): 3393–402. doi:10.1172/JCI31547.PMC 2040315PMID 17965777. Retrieved 2009-11-11.
  8.  Verma S, Strauss M (November 2004). “Angiotensin receptor blockers and myocardial infarction: These drugs may increase myocardial infarction—and patients may need to be told”. BMJ329 (7477): 1248–9. doi:10.1136/bmj.329.7477.1248.PMC 534428PMID 15564232.
  9.  Strauss MH, Hall AS (August 2006). “Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox”Circulation 114 (8): 838–54.doi:10.1161/CIRCULATIONAHA.105.594986.PMID 16923768.
  10.  Tsuyuki RT, McDonald MA (August 2006). “Angiotensin receptor blockers do not increase risk of myocardial infarction”Circulation 114 (8): 855–60.doi:10.1161/CIRCULATIONAHA.105.594978.PMID 16923769.
  11.  Julius S, Kjeldsen SE, Weber M, et al. (June 2004). “Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial”. The Lancet 363 (9426): 2022–31.doi:10.1016/S0140-6736(04)16451-9PMID 15207952.
  12.  Granger CB, McMurray JJ, Yusuf S, et al. (September 2003). “Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial”. The Lancet 362 (9386): 772–6.doi:10.1016/S0140-6736(03)14284-5PMID 13678870.
  13.  Levy BI (September 2005). “How to explain the differences between renin angiotensin system modulators”. Am. J. Hypertens. 18 (9 Pt 2): 134S–141S.doi:10.1016/j.amjhyper.2005.05.005PMID 16125050.
  14.  Levy BI (January 2004). “Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system”Circulation 109 (1): 8–13.doi:10.1161/01.CIR.0000096609.73772.C5.PMID 14707017.
  15.  Reudelhuber TL (December 2005). “The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous”Hypertension 46 (6): 1261–2.doi:10.1161/01.HYP.0000193498.07087.83.PMID 16286568.
  16.  McMurray JJ, Holman RR, Haffner SM, et al. (April 2010).“Effect of valsartan on the incidence of diabetes and cardiovascular events” (PDF). The New England Journal of Medicine 362 (16): 1477–90. doi:10.1056/NEJMoa1001121.PMID 20228403.
  17.  Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag.ISBN 3-85200-196-X.
  18.  Briggs GG, Nageotte MP (2001). “Fatal fetal outcome with the combined use of valsartan and atenolol”. The Annals of Pharmacotherapy 35 (7–8): 859–61. doi:10.1345/aph.1A013.PMID 11485133.

 

UPDATE……

 

VALSARTAN


mp 114–118 °C; 


1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 7.72 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.94 (m, 1H), 4.58 (m, 1H), 4.40 (m, 1H), 3.33 (m, 1H), 2.25 (m, 1H), 1.52 (m, 6H), 0.9 (m, 3H), 0.84 (m, 3H), 0.74 (m, 3H); 



13C NMR (100 MHz, DMSO-d6): δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 131.0, 129.3,128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05, 27.3, 22.2, 20.6, 14.2; 


ESIMS: m/z calcd [M]+: 435; found: 436 [M+H]+; HRMS (ESI): m/z calcd [M]+: 435.5187; found: 435.5125 [M]+

US 7439261 B2

1H-NMR (CDCl3) (0.80-1.15 (m, 9H); 1.20-1.50 (m, 2H); 1.60-1.80 (m, 2H); 2.60 (t, 2H); 2.65-2.80 (m, 2H), 3.70 (d, 1H), 4.10 (d, 0.3 H), 4.30 (d, 0.7 H), 4.90 (d, 0.7H), 5.2 (d, 0.3H); 7.00 (d, 0.3H); 7.10-7.20 (m, 4H), 7.40-7.60 (m, 3H), 7.85 (d, 0.7 H).

SHORT DESCRIPTION

Valsartan, N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine, is a known anti-hypertensive agent having the following formula (I):

Figure US07439261-20081021-C00001

Valsartan and its preparation are disclosed in U.S. Pat. No. 5,399,578, in particular in Example 16. One of the synthetic routes according to U.S. Pat. No. 5,399,578 can be schematically represented as follows:

Figure US07439261-20081021-C00002

Figure US07439261-20081021-C00003

The synthetic pathway comprises various steps, among which:

    • coupling of compound (3) with 2-chlorobenzonitrile to obtain compound (4),
    • radicalic bromination of compound (4) to give compound (5),
    • transformation of the brominated derivative (5) into the respective aldehyde derivative (6),
    • reductive alkylation of compound (6) to obtain intermediate (8),
    • acylation of compound (8) to obtain intermediate (9),
    • conversion of the cyano group to the tetrazole group to afford intermediate (10),
    • deprotection of the carboxylic group by hydrogenolysis to obtain valsartan.
  • It is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg ofvalsartan.

  • [0004]

    Valsartan and/or its intermediates are disclosed in various references, including: U.S. Pat. Nos. 5,399,578 ,5,965,592 5,260,325 6,271,375 , WO 02/006253 , WO 01/082858 , WO 99/67231 , WO 97/30036 , Peter Bühlmayer, et. al., Bioorgan. & Med. Chem. Let., 4(1) 29-34 (1994), Th. Moenius, et. al., J. Labelled Cpd. Radiopharm., 43(13) 1245 – 1252 (2000), and Qingzhong Jia, et. al., Zhongguo Yiyao Gongye Zazhi, 32(9) 385-387 (2001), all of which are incorporated herein by reference.

  • [0005]

    Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is prescribed for the treatment of hypertension. U.S. Pat. No. 6,395,728 is directed to use of valsartan for treatment of diabetes related hypertension. U.S. Pat. Nos. 6,465,502 and 6,485,745 are directed to treatment of lung cancer with valsartan. U.S. Pat. No. 6,294,197 is directed to solid oral dosage forms of valsartan

GOOD ARTICLES

http://users.uoa.gr/~tmavrom/2009/valsartan2009.pdf

http://www.acgpubs.org/JCM/2009/Volume%203/Issue%201/JCM-0908-14.pdf

https://www.beilstein-journals.org/bjoc/single/printArticle.htm?publicId=1860-5397-6-27 REPORTS

 mp 114–118 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 7.72 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.94 (m, 1H), 4.58 (m, 1H), 4.40 (m, 1H), 3.33 (m, 1H), 2.25 (m, 1H), 1.52 (m, 6H), 0.9 (m, 3H), 0.84 (m, 3H), 0.74 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 131.0, 129.3,128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05, 27.3, 22.2, 20.6, 14.2; ESIMS: m/z calcd [M]+: 435; found: 436 [M+H]+; HRMS (ESI): m/z calcd [M]+: 435.5187; found: 435.5125 [M]+

Valsartan 

Structural formula

UV – Spectrum

Conditions : Concentration – 1 mg / 100 ml
The solvent designation schedule methanol
water
0.1М HCl
0.1M NaOH
maximum absorption 249 nm 250 nm 248 nm 251 nm
309 302 289 311
e 13400 13100 12600 13500

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

References

  • UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV
  • NIST/EPA/NIH Mass Spectral Library 2008
  • Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.
  • Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Image result for VALSARTAN SYNTHESIS

CLIP

Image result for VALSARTAN SYNTHESIS

Scheme 2: (a) Et3N, CH2Cl2, 0 °C, 95%; (b) NaH, THF, 70%; (c) n-BuLi, 25 °C, THF, anhyd ZnCl2, −20 °C, Q-phos, Pd(OAc)2, 75 °C, 2 h, 80%; (d) 3 N NaOH, MeOH, reflux, 90%.

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-6-27

valsartan 8; mp 114–118 °C; 1H NMR (400 MHz, DMSO-d6): δ 12.6 (brs, 1H), 7.72 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.94 (m, 1H), 4.58 (m, 1H), 4.40 (m, 1H), 3.33 (m, 1H), 2.25 (m, 1H), 1.52 (m, 6H), 0.9 (m, 3H), 0.84 (m, 3H), 0.74 (m, 3H); 13C NMR (100 MHz, DMSO-d6): δ 174.0, 172.4, 171.8, 141.7, 138.2, 131.54, 131.1, 131.0, 129.3,128.8, 128.2, 127.4, 126.7, 70.3, 63.4, 49.9, 32.9, 28.05, 27.3, 22.2, 20.6, 14.2; ESIMS: m/z calcd [M]+: 435; found: 436 [M+H]+; HRMS (ESI): m/z calcd [M]+: 435.5187; found: 435.5125 [M]+

PAPER

An Improved Synthesis of Valsartan

Department of Chemical Engineering, Anyang Institute of Technology, Anyang 455000, China
Org. Process Res. Dev., 2011, 15 (5), pp 986–988
DOI: 10.1021/op200032b
Publication Date (Web): July 5, 2011
Copyright © 2011 American Chemical Society

Abstract

Abstract Image

Biphenyltetrazole group, an important component of sartans, is usually formed in excellent yield by the reaction of 4′-alkylbiphenyl-2-carbonitrile with excessive organotin azide. However, it is restricted in industrial scale because of the difficult post-treatment. In this article, an improved synthetic method for valsartan and the quantitative recovery of tri-n-butyltin chloride are reported. During this process, the tetrazole–Sn complex and excessive organotin azide were decomposed by HCl to furnish tri–n-butyltin chloride, and then reacted with NaF to lead to filterable polymer tributyltin fluoride which was converted again to tributyltin chloride by HCl in ethyl acetate. This approach is facile for the efficient manufacture of sartans using organotin azide to form the tetrazole group and is valuable for industry readers.

http://pubs.acs.org/doi/suppl/10.1021/op200032b

valsartan (1) (6.5 g, HPLC, 99.7%) as a white crystalline powder with a yield of 72.5% calculated on valstartan benzyl ester (2), mp 113117 C (lit.:14 mp 105115 C, from ethyl acetate). ESI-MS (-p): 434.32. HPLC purity 99.62%, ee =100% (OD-H, mobile phase: n-hexane and isopropyl alcohol in the ratio of 850:150). [R] 20 D = () 67.2 (1% w/v in methanol).

1 H NMR (DMSO-d6) δ: 0.690.94 (m, 9H), 1.101.20 (m, 1H), 1.281.58 (m, 3H), 1.982.10 (m, 1H), 2.172.50 (m, 2H), 4.074.63 (m, 3H), 6.967.21(m, 4H), 7.517.71 (m, 4H), 12.69 (br, 1H), 16.29 (br, 1H).

IR (KBr) νmax/cm1 : 3446(br, w), 3060(w), 2963(s), 2932(m), 2873(m), 2744(w), 2612(w), 1732(s), 1604(s), 1471(s), 1410(m), 1390(w), 1354(w), 1273(w), 1204(m), 1166(m), 1129(w), 1105(w), 1065(w), 1052(w), 1025(w), 996(w), 939(w), 901(w), 852(w), 822(w), 777(w), 760(m), 682(w), 670(w), 624(w), 559(w).

str0str1str2str3

HPLC Conditions for Enantiomer Purity of Valsartan are listed below. Instrument: Water, Breeze 2 Column: Chiralcel OD-H Detection: UV, 220 nm Flow: 0.8 mL/min Injection volume: 10 µL Run time: 30 min Mobile phase: the ratio of n-hexane and isopropyl alcohol is 850:150 Retention time of valsartan: ∼12 min The enantiomeric purity of the crystallized Valsartan prepared in our experiments is nearly 100%. The peak occurred in 4 min can be attributed to the solvent peak in dead time.

str0

Diovan (valsartan) is a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype.

Valsartan is chemically described as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl) [1,1′-biphenyl]-4- yl]methyl]-L-valine. Its empirical formula is C24H29N5O3, its molecular weight is 435.5, and its structural formula is:

DIOVAN (valsartan) Structural Formula Illustration

Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water.

Diovan is available as tablets for oral administration, containing 40 mg, 80 mg, 160 mg or 320 mg of valsartan. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides (yellow, black and/or red), magnesium stearate, microcrystalline cellulose, polyethylene glycol 8000, and titanium dioxide.

 137862-53-4.png
Valsartan
Valsartan skeletal.svg
Valsartan ball-and-stick.png
Systematic (IUPAC) name
(S)-3-methyl-2-(N-{[2′-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid
Clinical data
Trade names Diovan
AHFS/Drugs.com Monograph
MedlinePlus a697015
License data
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability 25%
Protein binding 95%
Biological half-life 6 hours
Excretion Renal 30%, biliary 70%
Identifiers
CAS Number 137862-53-4 Yes
ATC code C09CA03 (WHO)
PubChem CID 60846
IUPHAR/BPS 3937
tritiated: 593
DrugBank DB00177 Yes
ChemSpider 54833 Yes
UNII 80M03YXJ7I Yes
KEGG D00400 Yes
ChEBI CHEBI:9927 Yes
ChEMBL CHEMBL1069 Yes
Chemical data
Formula C24H29N5O3
Molar mass 435.519 g/mol
3D model (Jmol) Interactive image
Valsartan
CAS Registry Number: 137862-53-4
CAS Name: N-(1-Oxopentyl)-N-[[2¢-(1H-tetrazol-5-yl)[1,1¢-biphenyl]-4-yl]methyl]-L-valine
Additional Names: N-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine; (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2¢-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]amine
Manufacturers’ Codes: CGP-48933
Trademarks: Diovan (Novartis); Tareg (Novartis)
Molecular Formula: C24H29N5O3
Molecular Weight: 435.52
Percent Composition: C 66.19%, H 6.71%, N 16.08%, O 11.02%
Literature References: Nonpeptide angiotensin II AT1-receptor antagonist. Prepn: P. Bühlmayer et al., EP 443983; eidem, US5399578 (1991, 1995 both to Ciba Geigy); idem et al., Bioorg. Med. Chem. Lett. 4, 29 (1994). Pharmacological profile: L. Criscione et al., Br. J. Pharmacol. 110, 761 (1993). HPLC determn in human plasma: A. Sioufi et al., J. Liq. Chromatogr. 17, 2179 (1994). Clinical pharmacology: P. Müller et al., Eur. J. Clin. Pharmacol. 47, 231 (1994). Clinical comparison with captopril, q.v., in high risk patients following myocardial infarction: M. A. Pfeffer et al., N. Engl. J. Med. 349, 1893 (2003). Review of pharmacology and clinical experience in heart failure: R. Latini et al., Expert Opin. Pharmacother. 5, 181-193 (2004).
Properties: Crystals from diisopropyl ether, mp 116-117°. Partition coefficient (n-octanol/aq phosphate buffer): 0.033. Sol in water at 25°.
Melting point: mp 116-117°
Log P: Partition coefficient (n-octanol/aq phosphate buffer): 0.033
Therap-Cat: Antihypertensive.
Keywords: Angiotensin II Receptor Antagonist; Antihypertensive; Biphenyltetrazole Derivatives.

 

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CCCCC(=O)N(CC1=CC=C(C=C1)C1=CC=CC=C1C1=NNN=N1)[C@@H](C(C)C)C(O)=O

Glenmark receives final ANDA approval for Desoximetasone Ointment USP, 0.25%


            Desoximetasone                      382-67-2 cas   

         

September 23, 2013: Glenmark Generics Inc., USA the subsidiary of Glenmark Generics Limited has been granted final abbreviated new drug approval (ANDA) from the United States Food

and Drug Administration (U.S. FDA) for Desoximetasone Ointment USP, 0.25% their generic version of Topicort® by Taro Pharmaceuticals USA Inc and shipping will commence immediately.

Desoximetasone Ointment is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. According to IMS Health sales data for the

12 month period ending June 2013, Desoximetasone Ointment garnered annual sales of approximately USD 40 million.

more info

Desoximetasone is a medication belonging to the family of medications known as topical corticosteroids. It is used for the relief of various skin conditions, including rashes. It helps to reduce redness, itching, and irritation. Desoximetasone is a synthetic corticosteroid, a class of primarily synthetic steroids used as anti-inflammatory and anti-pruritic agents.

There are two brand name products:

  • Topicort Emollient Cream (0.25% desoximetasone)
  • Topicort LP Emollient Cream (0.05% desoximetasone)

When using desoximetasone, some of the medication may be absorbed through the skin and into the bloodstream. Too much absorption can lead to unwanted side effects elsewhere in the body. To keep this problem to a minimum, avoid using large amounts of desoximetasone over large areas, do not use it for extended periods of time, and do not cover it with airtight dressings such as plastic wrap or adhesive bandages unless specifically told to by your doctor. Children may absorb more medication than adults do. Desoximetasone is for use only on the skin and should be kept out of the eyes.

Desoximetasone can also be used to treat some types of psoriasis.

Stelara (ustekinumab) Receives FDA Approval to Treat Active Psoriatic Arthritis


Ustekinumab

CAS No: 815610-63-0
Molecular Weight: 145.64 g/mol
Chemical Formula: C9H18N2O2
IUPAC Name: Immunoglobulin G1, anti-(human interleukin 12 p40 subunit) (human monoclonal CNTO 1275 gamma1-chain), disulfide with human monoclonal CNTO 1275 kappa-chain, dimer

HORSHAM, Pa., Sept. 23, 2013 /PRNewswire/ — Janssen Biotech, Inc., announced today that the U.S. Food and Drug Administration (FDA) has approved Stelara (ustekinumab) alone or in combination with methotrexate for the treatment of adult patients (18 years or older) with active psoriatic arthritis. It is estimated that more than two million people in the U.S. are living with psoriatic arthritis, a chronic autoimmune disease characterized by both joint inflammation and psoriasis skin lesions

read all at

http://www.drugs.com/newdrugs/stelara-ustekinumab-receives-fda-approval-active-psoriatic-arthritis-3903.html

Ustekinumab  (INN, experimental name CNTO 1275, proprietary commercial name StelaraCentocor) is a human monoclonal antibody. It is directed against interleukin 12 and interleukin 23, naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders.

Ustekinumab is a fully human monoclonal antibody (mAb) targeting the interleukin (IL)-12/23p40 subunit.

Interleukins are  small soluble proteins that communicate between white blood cells (leukocytes), such as T cells. Interleukins mediate the differentiation, proliferation and many other processes of these cells. IL-12 and IL-23 are involved in the differentiation of naive T cells into T helper (Th) 1 and Th17 cells respectively.

Th1 and Th17 cells have been implicated in several autoimmune disorders, such as psoriasis. Ustekinumab targets the common p40 subunit of IL-12 and IL-23 to stop these cytokines from binding to their receptors and consequently preventing the development of Th1 and Th17 cells in an immune response.

In two Phase III trials for moderate to severe psoriasis, the longest >76 weeks, ustekinumab was safe and effective.

A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with etanercept in the treatment of moderate to severe plaque psoriasis. This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept. It also demonstrated the clinical benefit of ustekinumab among patients who failed to respond to etanercept.

Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.

As of November 2009, the drug is being investigated for the treatment of psoriatic arthritis. It has also been tested in Phase II studies for multiple sclerosis and sarcoidosis, the latter versus golimumab (Simponi).

The US Food and Drug Administration (FDA) and European Union (EU) have approved the interleukin (IL) 12/23 inhibitor ustekinumab (Stelara, Janssen Biotech) for adults with active psoriatic arthritis who have not responded adequately to previous nonbiological disease-modifying antirheumatic drug therapy, the company announced today.

Approval of ustekinumab for psoriatic arthritis is “significant for patients and physicians as it marks the first treatment approved for this devastating and complex disease since the introduction of anti-TNF biologic medicines more than a decade ago,” Jerome A. Boscia, MD, vice president and head of immunology development, Janssen Research & Development, LLC, said in a statement.

The European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended approval of ustekinumab for active psoriatic arthritis in June, as reported by Medscape Medical News.

Ustekinumab is already approved in the US and EU for treatment of moderate to severe psoriatic plaques in adults. The drug, which can be used alone or in combination with methotrexate, is novel in that it targets both IL-12 and IL-23.

Image source: Crystal structure of human IL-12, Wikipedia, public domain

Ustekinumab binding to IL-12/23p40

Toward an early diagnostic tool for Alzheimer’s disease


EFAVIRENZ – Huahai Pharma China-Approved to Produce AIDS Treatment


File:Efavirenz skeletal.svg

Efavirenz

DMP 266

Efavirenz, L-743725((+)-enantiomer), DMP-266, L-741211(racemate), L-743726, Stocrin, Sustiva
(S)-(-)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
154598-52-4

Generic brands India:

Zhejiang Huahai Pharma received CFDA approval to produce efavirenz, an oral non-nucleoside reverse transcriptase inhibitor (NNRTI) used to control the symptoms of AIDS. Huahai is the first China drugmaker approved to make the drug. Huahai produced efavirenz API for Merck, which marketed the drug under the name Stocrin

read at

http://www.sinocast.com/readbeatarticle.do?id=99634

Efavirenz (EFV), sold under the brand names Sustiva among others, is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1. For HIV infection that has not previously been treated, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines currently recommends the use of efavirenz in combination with tenofovir/emtricitabine (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents.[1] Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex etc.).

It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.

Efavirenz was combined with the HIV medications tenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications under the brand name Atripla, provides HAART in a single tablet taken once a day.

Efavirenz was discovered at Merck Research Laboratories. It is on the WHO Model List of Essential Medicines, the most important medication needed in a basic health system.[2] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[3]

 

Efavirenz (EFV, brand names SustivaStocrinEfavir etc.) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy(HAART) for the treatment of a human immunodeficiency virus (HIV) type 1.

For HIV infection that has not previously been treated, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines currently recommends the use of efavirenz in combination with tenofovir/emtricitabine (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents.

Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex etc.).

The usual adult dose is 600 mg once a day. It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.

Efavirenz was combined with the popular HIV medication Truvada, which consists oftenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications approved by the U.S. Food and Drug Administration(FDA) in July 2006 under the brand name Atripla, provides HAART in a single tablet taken once a day. It results in a simplified drug regimen for many patients.

 

doi:10.1016/0040-4039(95)01955-H

Merck synthesis of Efavirenz

 

 

History

Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.

  •  Efavirenz is a non-nucleoside reverse trancriptase inhibitor being studied clinically for use in the treatment of HIV infections and AIDS.
  • Efavirenz chemically known as (-) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1 , 4- dihydro-2H-3, 1-benzoxa zin-2-one, is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI).A number of compounds are effective in the treatment of the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system. Effective treatment through inhibition of HIV reverse transcriptase is known for non- nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase.(-) β-chloro^-cyclopropylethynyM-trifluoromethyl-l ,4-dihydro-2H-3,l -ben zoxazin-2-one (Efavirenz) is efficacious against HIV reverse transcriptase resistance. Due to the importance of (-)6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-l,4-dihydro-2H-3,l-ben zoxazin-2- one, economical and efficient synthetic processes for its production needs to be developed.The product patent US5519021. discloses the preparation of Efavirenz, in Example-6, column-29, involving cyclisation of racemic mixture of 2-(2-amino-5-chlorophenyl)-4- cyclopropyl-l,l,l-trifluoro-3-butyn-2-ol using l ,l ‘-carbonyldiimidazole as carbonyl delivering agent to give racemic Efavirenz. Further, resolution of the racemic Efavirenz is carried out using (-) camphanic acid chloride to yield optically pure Efavirenz. However, research article published in the Drugs of the future, 1998, 23(2), 133-141 discloses process for manufacture of optically pure Efavirenz. The process involves cyclisation of racemic 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-l, 1, l-trifluoro-3-butyn-2- ol using 1, 1-carbonyldiimidazole as carbonyl delivering agent to give racemic Efavirenz and further resolution by (-) camphanic acid chloride.Similarly research article published in Synthesis 2000, No. 4, 479-495 discloses stereoselective synthesis of Efavirenz (95%yield, 99.5%ee), as shown below
    Figure imgf000003_0001

    Even though many prior art processes report method for the preparation of Efavirenz, each process has some limitations with respect to yield, purity, plant feasibility etc. Hence in view of the commercial importance of Efavirenz there remains need for an improved process.

  • US 6 028 237 discloses a process for the manufacture of optically pure Efavirenz.
  • The synthesis of efavirenz and structurally similar reverse transcriptase inhibitors are disclosed in US Patents 5,519,021, 5,663,169, 5,665,720 and the corresponding PCT International Patent Application WO 95/20389, which published on August 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on November 28, 1996.
  • Additionally, several applications have been filed which disclose various aspects of the synthesis of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one including: 1) a process for making the chiral alcohol, U.S.S.N. 60/035,462, filed 14 January 1997; 2) the chiral additive, U.S.S.N. 60/034,926, filed 10 January 1997; 3) the cyclization reaction, U.S.S.N. 60/037,059, filed 12 February 1997; and the anti-solvent crystallization procedure, U.S.S.N. 60/037,385 filed 5 February 1997 and U.S.S.N. 60/042,807 filed 8 April 1997.

Efavirenz has been obtained by two related ways: 1) The acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by means of Na2CO3 in toluene gives the expected anilide (III), which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2′-amino-5′-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords the protected acetophenone (VI), which is regioselectively condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium in cyclohexane] by means of butyllithium in THF in the presence of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the (S)-isomer of the tertiary alcohol (X) exclusively. The cyclization of (X) with phosgene and triethylamine or K2CO3 in toluene/THF yields the benzoxazinone (XI), which is finally deprotected with ceric ammonium nitrate in acetonitrile/water. 2) The condensation of 2′-amino-5′-chloro-2,2,2-trifluoroacetophenone (IV) with cyclopropylacetylene (VIII) by means of butyllithium or ethylmagnesium bromide in THF gives (?-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (XII). The cyclization of (XII) with carbonyldiimidazole (XIII) in hot THF yields the racemic benzoxazinone (XIV). Compound (XIV) is submitted to optical resolution by condensation with (S)-(-)-camphanoyl chloride by means of dimethylaminopyridine (DMAP) in dichloromethane to give the acyl derivative (XVI) as a diastereomeric mixture that is resolved by crystallization and finally decomposed with HCl in ethanol or butanol.
Corley, E.G.; Thompson, A.S.; Huntington, M.F.; Grabowski, E.J.J.; Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: Asymmetric synthesis of the reverse transcriptase inhibitor L-743,726.
Tetrahedron Lett1995,36,(49):8937-40
EP 1332757 A1
Clips
When a commercial market already exists for the RMs used in synthesizing an API, their cost can be rather modest. When RMs used in synthesizing an API have no other commercial use, however, they can contribute very substantially to API cost. With a continued growth of volume demand, improved chemistry and competition from multiple suppliers, however, the cost of API RMs can greatly decrease over time. The inhibitor of HIV-1 RT, EFV, provides an illustration of this situation. Cyclopropylacetylene (CPA) is an RM for the synthesis of EFV (Figure 4). During clinical trials, when the demand for CPA was only a few metric tons, this material was produced at a price of USD800–1,350/kg. When the drug was first approved in 1998, and demand for CPA was about 50 metric tons per year, the price of CPA had fallen to USD350/kg. Today, with global demand for EFV at greater than 1,000 metric tons/year, CPA can be purchased for about USD50–60/kg. In the earliest stages of production, nearly 1 kg of CPA was needed to produce a kilogram of EFV. Current production processes are more efficient; roughly 3 kg of EFV is now produced for each 1 kg of CPA used. From this it can be roughly estimated that the contribution of CPA to the cost of EFV API production has fallen from as high as USD425/kg to about USD17–20/kg today.
https://i1.wp.com/www.intmedpress.com/journals/avt/iframePopup_fig.cfm
The most recent chemistry for asymmetric alkynylation of manufacturing EFV uses inexpensive, safe reagents and processing at ambient temperature to reach EFV pricing that would have been thought impossible when the drug was launched by Dupont Pharmaceuticals in 1998
Biao J, Yugui S. inventors; Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, assignee. Amino alcohol ligand and its use in preparation of chiral propargylic tertiary alcohols and tertiary amines via enantioselective addition reaction. US Patent 7,439,400. 2008 October 21.
Bollu RB, Ketavarapu NR, Indukuri VSK, Gorantla SR, Chava S. inventors; Laurus Labs Private Limited, assignee. Efficient process to induce enantioselectivity in procarbonyl compounds. US Patent Application 2012/0264933 A1. 2012 October 18.
FPPs for adult ART are usually capsules or tablets. A general rule-of-thumb is that an FPP as a conventional, solid oral dosage formulation costs about 33–40% more than the corresponding API in a competitive market. It has been widely quoted, conversely, that APIs contribute about 60–80% of the cost of an FPP. The API contribution to FPP cost increases with the complexity of synthesis and API cost per kilogram. Although marketing is a substantial incremental cost for originator pharmaceutical companies, generic producers do not incur high marketing costs for ART.

Syntheses of EFV API; different routes of manufacturingAPI, active pharmaceutical ingredient; EFV efavirenz. BELOW

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Related substances and degradants (partial listing) in EFVAPI, active pharmaceutical ingredient; CPA, cyclopropylacetylene; EFV, efavirenz

Syntheses of EFV API; different routes of manufacturingAPI, active pharmaceutical ingredient; EFV efavirenz.

illustrates the great effect of new routes of synthesis on API costs. The manufacturing cost of route 1 for the launch of EFV in 1998 was about USD1,800/kg [31,41]. EFV API was priced at about USD1,100/kg for the first generic launch in 2005. At this time the price of CPA was about USD250/kg. The best prices for EFV API in 2012–2013 are USD120–130/kg prepared under GMP. This drastic 89% reduction in generic API pricing is due in part to volume demand – the LMIC use of generic EFV in 2012 exceeded 750 metric tons and was estimated to exceed 900 metric tons in 2013. Reductions in the cost of RMs have also had a significant effect. More efficient processes for producing the final intermediate SD 573, have contributed the largest part to price reductions [42]. The route 1 synthesis requires five steps while routes 2 through 4 require only two steps from the same starting materials for the commercial production of EFV.

Chemical properties

Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14H9ClF3NO2. Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68 g/mol. It is practically insoluble in water (<10 µg/mL).

History

Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.

Society and culture

Pricing information

A one-month supply of 600 mg tablets cost approximately $550 in April 2008.[16] Merck provides efavirenz in certain developing countries at cost, currently about $0.65 per day.[17] Some emerging countries have opted to purchase Indian generics[18] such as Efavir by Cipla Ltd.[19] In Thailand, one month supply of efavirenz + truvada, as of June 2012, costs THB 2900 ($90), there’s also a social program for poorer patients who can’t afford even this price. In South Africa, a license has been granted to generics giant Aspen Pharmacare to manufacture, and distribute to Sub-Saharan Africa, a cost-effective antiretroviral drug.[20]

 PATENT

http://www.google.com/patents/WO1999061026A1?cl=en

EXAMPLE 1

Cl

1a

To a solution of trifluoroethanol and (IR, 2S)-N-pyrrolidinyl norephedrine in THF (9 L) under nitrogen is added a solution of diethylzinc in hexane at 0 °C slowly enough to keep the temperature below 30 °C. The mixture is stirred at room temperature for 0.5 ~ 1 h. In another dry flask a solution of chloromagnesium cyclopropyl acetylide is prepared as follows: To neat cyclopropyl acetylene at 0 °C is added a solution of rc-butylmagnesium chloride slowly enough to keep the internal temperature < 30 °C. The solution is stirred at 0 °C for ~ 40 min and transfered to the zinc reagent via cannula with 0.36 L of THF as a wash. The mixture is cooled to -10 °C and ketoaniline la is added. The mixture is stirred at -2 to -8 °C for 35 h, warmed to room temperature, stirred for 3 h, and quenched with 30% potassium carbonate over 1.5 h. The mixture is stirred for 4 h and the solid is removed by filtration and washed with THF (2 cake volume). The wet solid still contains -18 wt% of pyrrolidinyl norephedrine and is saved for further study. The filtrate and wash are combined and treated with 30% citric acid. The two layers are separated. The organic layer is washed with water (1.5 L). The combined aqueous layers are extracted with 2.5 L of toluene and saved for norephedrine recovery. The toluene extract is combined with the organic solution and is concentrated to ~ 2.5 L. Toluene is continuously feeded and distilled till THF is not detectable by GC. The final volume is controlled at 3.9 L. Heptane (5.2 L) is added over 1 h. The slurry is cooled to 0 °C, aged for 1 h, and filtered. The solid is washed with heptane (2 cake volume) and dried to give 1.234 Kg (95.2% yield) of amino alcohol 3 as a white crystalline. The material is 99.8 A% pure and 99.3% ee.

EXAMPLE 2

To a three necked round bottom flask, equipped with a mechanical stirrer, nitrogen line, and thermocouple, was charged the solid amino alcohol 3, MTBE (500 L), and aqueous KHCO3 (45 g in 654 mL H2O). Solid 4-nitrophenyl chloroformate was added, in 4 batches, at 25°C. During the addition the solution pH was monitored. The pH was maintained between 8.5 and 4 during the reaction and ended up at 8.0. The mixture was stirred at 20-25°C for two hours. Aqueous KOH (2N) was added over 20 minutes, until the pH of the aqueous layer reached 11.0.

The layers were separated and 500 mL brine was added to the MTBE layer. 0.1 N Acetic acid was added until the pH was 6-7. The layers were separated and the organic phase was washed with brine (500 mL). At this point the mixture was solvent switched to EtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 3

To a three necked round bottom flask, equipped with a mechanical stirrer, nitrogen line, and thermocouple, was charged the solid amino alcohol 3a, toulene (500 mL), and aqueous KHCO3 (86.5 g in 500 L H2O). Phosgene solution in toulene was added at 25°C, and the mixture was stirred at 20-25°C for two hours.

The layers were separated and the organic phase was washed with brine (500 mL). At this point the mixture was solvent switched to EtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 4

To a three necked round bottom flask, equipped with a mechanical stirrer, nitrogen line, and thermocouple, was charged the solid amino alcohol 3a, MTBE (500 mL), and aqueous KHCO3 (86.5 g in 500 mL H2O). Phosgene gas was slowly passed into the solution at 25°C, until the reaction was complete.

The layers were separated and the organic phase was washed with brine (500 mL). At this point the mixture was solvent switched to EtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 5

Crystallization of efavirenz from 30% 2-Propanol in Water using a ratio of 15 ml solvent per gram efavirenz Using Controlled Anti-Solvent Addition on a 400 g Scale.

400 g. of efavirenz starting material is dissolved in 1.8 L of 2- propanol. The solution is filtered to remove extraneous matter. 1.95 L of deionized (DI) water is added to the solution over 30 to 60 minutes. 10 g. to 20 g. of efavirenz seed (Form II wetcake) is added to the solution. The seed bed is aged for 1 hour. The use of Intermig agitators is preferred to mix the slurry. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet-milled for 15 – 60 seconds. 2.25 L of DI water is added to the slurry over 4 to 6 hours. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet- milled for 15 – 60 seconds during the addition. The slurry is aged for 2 to 16 hours until the product concentration in the supernatant remains constant. The slurry is filtered to isolate a crystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of 30 % 2-propanol in water and then twice with 1 bed volume of DI water each. The washed wet cake is dried under vacuum at 50°C.

EXAMPLE 6

Crystallization of efavirenz from 30% 2-Propanol in Water using a ratio of 15 ml solvent per gram efavirenz Using a Semi-Continuous Process on a 400 g Scale.

400 g. of efavirenz starting material is dissolved in 1.8 L of 2- propanol. A heel slurry is produced by mixing 20 g. of Form II efavirenz in 0.3 L of 30 % (v/v) 2-propanol in water or retaining part of a slurry froma previous crystallization in the crystallizer. The dissolved batch and 4.2 L of DI water are simultaneously charged to the heel slurry at constant rates over 6 hours to maintain a constant solvent composition in the crystallizer. Use of Intermig agitators during the crystallization is preferred. During this addition the slurry is wet-milled when the crystal lengths become excessively long or the slurry becomes too thick. The slurry is aged for 2 to 16 hours until the product concentration in the supernatant remains constant. The slurry is filtered to isolate a crystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of 30 % 2-propanol in water and then twice with 1 bed volume of DI water each. The washed wet cake is dried under vacuum at 50°C.

EXAMPLE 7 Preparation of Amino Alcohol 3 and ee Upgrading— Through Process

1a

A solution of diethyl zinc in hexane was added to a solution of trifluoroethanol (429.5 g, 4.29’mol) and (IR, 2S)-N-pyrrolidinyl norephedrine (1.35 kg, 6.58 mol) in THF (9 L), under nitrogen, at 0 °C. The resulting mixture was stirred at room temperature for approx. 30 min. In another dry flask a solution of chloromagnesium- cyclopropylacetylide was prepared as follows. To a solution of n- butylmagnesium chloride in THF (2 M, 2.68 L, 5.37 mol) was added neat cyclopropylacetylene at 0 °C keeping the temperature < 25 °C. The solution was stirred at 0 °C for 1 ~ 2 h. The solution of chloromagnesiumcyclopropylacetylide was then warmed to room temperature and was transferred into the zinc reagent via cannula over 5 min followed by vessel rinse with 0.36 L of THF. The resulting mixture was aged at ~ 30 °C for 0.5 h and was then cooled to 20 °C. The ketoaniline 1 (1.00 kg, 4.47 mol) was added in one portion as a solid, and the resulting mixture was stirred at 20-28 °C for 3 h.

The reaction was quenched with 30% aq. potassium carbonate (1.2 L) and aged for 1 h. The solid waste was filtered and the cake was washed with THF (3 cake volumes). The filtrate and wash were combined and solvent switched to IP Ac.

The IPAc solution of product 3 and pyrrolidinyl norephedrine was washed with citric acid (3.5 L) and with water (1.5 L). The combined aqueous layers were extracted with IPAc (2 L) and saved for norephedrine recovery. To the combined organic layers was added

12N HC1 (405 mL, 4.88 mol), to form a thin slurry of the amino alcohol-

HC1 salt. The mixture was aged for 30 min at 25 °C and was then dried azeotropically. The slurry was aged at 25 °C for 30 min and filtered. The cake was washed with 2.5 L of IPAc and dried at 25 °C under vacuum/nitrogen for 24 h to give 1.76 kg of the wet HC1 salt.

The salt was dissolved in a mixture of MTBE (6 L) and aq Na2Cθ3 (1.18 kg in 6.25 L water). The layers were separated and the organic layer was washed with 1.25 L of water. The organic layer was then solvent switched into toluene.

Heptane (5 L) was added over 1 h at 25 °C. The slurry was cooled to 0 °C, aged for 1 h, and filtered. The solid was washed with heptane (2 cake volumes) and was dried to give 1.166 kg (90% overall yield) of amino alcohol 3 as a white crystalline solid. Norephedrine recovery

The aqueous solution was basified to pH13 using 50% aq NaOH, and extracted with heptane (2 L). The heptane solution was washed with water (1 L) and concentrated to remove residual IPAc and water. The final volume was adjusted to about 3 L. The heptane solution was cooled to -20 °C, aged for 2 h, and filtered. The solid was washed with cold heptane (1 cake volume) and dried to give 1.269 kg solid (94% recovery)

 

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CLIPS

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References

  1. Gatch, M. B.; Kozlenkov, A.; Huang, R. Q.; Yang, W.; Nguyen, J. D.; González-Maeso, J.; Rice, K. C.; France, C. P.; Dillon, G. H.; Forster, M. J.; Schetz, J. A. (2013). “The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties”. Neuropsychopharmacology 38 (12): 2373–84. doi:10.1038/npp.2013.135. PMC 3799056. PMID 23702798.
  • Sütterlin, S.; Vögele, C.; Gauggel, S. (2010). “Neuropsychiatric complications of Efavirenz therapy: suggestions for a new research paradigm”. The Journal of Neuropsychiatry and Clinical Neurosciences 22 (4): 361–369. doi:10.1176/jnp.2010.22.4.361.

External links

Efavirenz
Efavirenz.svg

 

 

Efavirenz.svg

Efavirenz ball-and-stick model.png
Systematic (IUPAC) name
(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
Clinical data
Trade names Sustiva, Stocrin, others
AHFS/Drugs.com monograph
MedlinePlus a699004
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
By mouth (capsules, tablets)
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 40–45% (under fasting conditions)
Protein binding 99.5–99.75%
Metabolism Hepatic (CYP2A6 and CYP2B6-mediated)
Onset of action 3–5 hours
Biological half-life 40–55 hours
Excretion Urine (14–34%) and feces (16–61%)
Identifiers
CAS Number 154598-52-4 Yes
ATC code J05AG03 (WHO)
PubChem CID 64139
DrugBank DB00625 Yes
ChemSpider 57715 Yes
UNII JE6H2O27P8 Yes
KEGG D00896 Yes
ChEBI CHEBI:119486 Yes
ChEMBL CHEMBL223228 Yes
NIAID ChemDB 032934
PDB ligand ID EFZ (PDBe, RCSB PDB)
Chemical data
Formula C14H9ClF3NO2
Molar mass 315.675 g/mol
1H NMR spectrum of C14ClF3H9NO2 in CDCL3 at 400 MHz
//////////////
FC([C@@]1(C#CC2CC2)OC(=O)Nc2c1cc(Cl)cc2)(F)F
Figure 1
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