Home » Posts tagged 'PROCESS' (Page 5)

Tag Archives: PROCESS

VINCRISTINE……..Chemistry, Isolation

September 28, 2013 12:27 pm / 1 Comment on VINCRISTINE……..Chemistry, Isolation

VINCRISTINE

(3aR,3a1R,4R,5S,5aR,10bR)-methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-3,7-methano[1]azacycloundecino[5,4-b]indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1H-indolizino[8,1-cd]carbazole-5-carboxylate

…………………………………………………………..

Advanced study of natural sources of anti-cancer from harmoini

………………………………………………………………….

Vincristine (brand name, Oncovin), formally known as leurocristine, sometimes abbreviated “VCR”, is a vinca alkaloid from the Catharanthus roseus (Madagascar periwinkle), formerly Vinca rosea and hence its name. It is amitotic inhibitor, and is used in cancer chemotherapy. Vincristine is created by the coupling of indole alkaloids vindoline and catharanthine in the vinca plant.^[1]

Mechanism

Tubulin is a structural protein that polymerizes to microtubules. The cell cytoskeleton and mitotic spindle, among other things, are made of microtubules. Vincristine binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. Therefore, the vinca alkaloids affect all rapidly dividing cell types including cancer cells, but also those of intestinal epithelium and bone marrow.

Uses

Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens. Its main uses are in non-Hodgkin’s lymphoma as part of the chemotherapy regimen CHOP, Hodgkin’s lymphoma as part of MOPP, COPP, BEACOPP, or the less popular Stanford V chemotherapy regimen, in acute lymphoblastic leukemia, and in treatment for nephroblastoma (Wilms tumor, a kidney tumor most common in young children). It is also used to induce remission in ALL with Dexamethasone and L-Asparaginase. Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP). It is used in combination with prednisone to treat childhood leukemia.

The main side-effects of vincristine are peripheral neuropathy, hyponatremia, constipation, and hair loss.

Peripheral neuropathy can be severe, and hence a reason to avoid, reduce, or stop the use of vincristine. One of the first symptoms of peripheral neuropathy is foot drop: A person with a family history of foot drop and/or Charcot-Marie-Tooth disease (CMT) should avoid the taking of vincristine.^[2]

Accidental injection of vinca alkaloids into the spinal canal (intrathecal administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending paralysis due to massive encephalopathy and spinal nerve demyelination, accompanied by intractable pain, almost uniformly leading to death; a handful of survivors were left with devastating neurological damage with no hope of recovery. Rescue treatments consist of washout of the cerebrospinal fluid and administration of protective medications.^[3] A significant series of inadvertent intrathecal vincristine administration occurred in China in 2007 when batches of cytarabine andmethotrexate (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine.^[4]

Having been used as a folk remedy for centuries, studies in the 1950s revealed that C. roseus contained 70 alkaloids, many of which are biologically active. While initial studies for its use in diabetes mellitus were disappointing, the discovery that it caused myelosuppression (decreased activity of the bone marrow) led to its study in mice withleukemia, whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with Skelly-B defatting agent and an acid benzene extract led to a fraction termed “fraction A”. This fraction was further treated withaluminium oxide, chromatography, trichloromethane, benz-dichloromethane, and separation by pH to yield vincristine.^[5]

Vincristine was approved by the United States Food and Drug Administration (FDA) in July 1963 as Oncovin. The drug was initially discovered by a team led by Dr. J.G. Armstrong, then marketed by Eli Lilly and Company.

Like LSD, the microtubule toxin vincristine allegedly causes not-unpleasant visual hallucinations in humans. Other side-effects of vincristine include depression, agitation, and insomnia. Very small doses are needed for the effects of LSD or vincristine, for example, these drugs are active at concentrations of 4.3E-7 M-1 vincristine and 1.0E-8 M-1 LSD.

Many researchers have favored the drug-receptor theory to explain drug-induced hallucinations, usually at the 5-HT2A receptor. In the drug-receptor theory, signal amplification takes place when one molecule of drug binds to a receptor, which activates G-proteins, which affects more proteins, thus signaling cascades explain how a small amount of LSD can lead to widespread changes in the cell.

Van Woerkom suggests instead that LSD binds an element of the cytoskeleton, in a fashion similar to colchicine or vinblastine, which directly bind tubulin. The amount of LSD needed to produce hallucinations is so vanishly small, that it seems hard to believe that a submicromolar dosage of LSD could act on a substrate as vast as the cytoskeleton. However, some microtubule inhibitors such as vincristine are effective at very low dosages. The potency of vincristine may partly explain the success of this drug as a chemotherapeutic drug.

Three generic drug makers supply vincristine in the United States – APP, Mayne, and Sicor (Teva).

^ “Pharmacognosy of Vinca Alkaloids”.
Graf, W. D.; Chance, P. F.; Lensch, M. W.; Eng, L. J.; Lipe, H. P.; Bird, T. D. (1996). “Severe Vincristine Neuropathy in Charcot-Marie-Tooth Disease Type 1A”. Cancer 77 (7): 1356–1362. doi:10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-#. PMID 8608515.
Qweider, M.; Gilsbach, J. M.; Rohde, V. (2007). “Inadvertent Intrathecal Vincristine Administration: A Neurosurgical Emergency. Case Report”. Journal of Neurosurgery: Spine 6 (3): 280–283. doi:10.3171/spi.2007.6.3.280. PMID 17355029.
Jake Hooker and Walt Bogdanich (January 31, 2008). “Tainted Drugs Tied to Maker of Abortion Pill”. New York Times.
Johnson, I. S.; Armstrong, J. G.; Gorman, M.; Burnett, J. P. (1963). “The Vinca Alkaloids: A New Class of Oncolytic Agents” (pdf). Cancer Research 23 (8 Part 1): 1390–1427.PMID 14070392.

External links

Cytostatic Vinca alkaloids rosea L. Catharanthus roseus G.Don) are now well known anticancer and particularly useful. Given the small amount of vincristine in Catharanthus present, quite a number of ways of preparation have been proposed by chemists. Thus FR-A-2296418 describes the synthesis of vincristine by coupling Catha-ranthine and vindoline. Other laboratories have achieved the transformation of vinblastine vincristine oxidation under controlled conditions, very strict.
FR-A-2210393 and US-A-3899493 perform the oxidation by chromic acid at -30, -90 ° C in a mixture of acetic acid-acetone or chloroform-acetic acid at -55 ° C.
In U.S. 4,375,432, chromic compound is also used in acid medium at -65 ° C, -50 ° C in a medium based solvent THF. In addition, EP-A-37289 boasts an oxidation mixture ferrous salt, hydrogen peroxide, perchlorate in acetonitrile. ZA-A-82 08939 discloses a method with chromic acid and an ether-chloroform.
HU-A-23638 offers diterbutylchromate in pelargonic acid, and finally EP-A-117861 gets vinblastinel transformation vincristine oxidant potassium permanganate in acetic acid medium. It is clear that these dimeric alkaloids are a valuable material because of their low levels in vegetable raw materials, and therefore the processes of synthesis or semi-synthesis performance are of extreme interest.

Vincristine is used in cancer chemotherapy, particularly for the treatment of certain acute leukemias.
This alkaloid is obtained mainly by extraction from leaves of Catharanthus Ro-seus (U.S. Patent No. 3,205,220) where it is accompanied by other alkaloids bis-Indo-holic, especially vinblastine.Vinblastine (I, R = CH _3), however, is present at a concentration much higher than that of vincristine and is therefore a precursor of choice for the semisynthesis of the latter.
Several processes of vincristine from vinblastine were disclosed. We note in particular patents or patent applications include:
- a) Belgian Patent 739,337 (Gedeon Richter) which describes a method for the oxidation of vinblastine vincristine in a mixture chromic acid, acetic acid and acetone.
- b) Belgian Patent 823560 (Gedeon Richter) the oxidation is performed with oxygen in the presence of formic acid and of a catalyst based on platinum at room temperature.
- c) European Patent Application 18231 (Gedeon Richter): is carried out by oxidation with chromic acid or an alkali metal dichromate in the presence of acetic anhydride and, optionally, of ethanol and an organic solvent immis target with water.
- d) European Patent Application 37289 (Eli Lil-ly): the oxidation is effected by the perchlorate of iron (II) in the presence of hydrogen peroxide and acetonitrile.
In addition, the European patent application 37. 290 discloses a process for the oxidation of vinblastine base with Na ₂ Cr ₂ O ₇ in the presence of sulfuric acid in tetrahydrofuran. This reaction led to -50 ° C, is achieved with a yield of 80-92% calculated for each estimation.
Observed yields or purity of the products obtained characterizing the processes described above are, however, significant disadvantages.
Frequently a secondary product formed is N-demethyl vinblastine need then reformulate for vincristine.

Thus Potier and Kutney obtained products with the C18’S-C2’R absolute configuration, which is critical for anti-tumor activity, by a coupling reaction of the N.sup.b -oxide of catharanthine, or its derivatives, with vindoline, in the presence of trifluoroacetic anhydride, followed by a reduction reaction. [See Potier et. al. J. Am. Chem. Soc. 98. 7017 (1976) and Kutney et. al. Helv. Chim. Acta, 59, 2858 (1976)].

The Potier and Kutney coupling process has disadvantages. The yields are not satisfactory except for the coupling of catharanthine N-oxide with vindoline and even there the preparative yield is low. While vindoline is the most abundant alkaloid of Vinca rosea and is thus readily available, the other possible components of the Potier-Kutney coupling process (catharanthine, allocatharanthine, voacangine,) are relatively inaccessible, costly, and they do not allow a wide range of structural variation of that component of the coupling process.

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

EP 0117861 B1
clips
The process of the present invention produces a simple vincristine, in quantity and purity requiring little or no additional purification by recrystallization or chromatography.
[0009]

The reagent used is oxidation permanganate ion dissolved in toluene or dichloromethane as solvent. An alternative consists in immobilizing the resin on a permanganate anion, for example a polymer such as polystyrene comprising ammonium groups. Solubilization can be achieved by the action of a complexing agent crown ether (“crown-ether”) of potassium permanganate.
[0010]

The permanganate anion can also be solubilized by preparing an ammonium salt or quaternary phosphonium corresponding which is soluble in methylene chloride or toluene. For this purpose, it is preferable to use potassium permanganate benzyltriethylammonium.
[0011]

Obtaining from vincristine vinblastine using a permanganate salt is unexpected since the potassium permanganate used in some acetone oxide derivatives of vinblastine at the portion of the molecule velbanamine (Kutney, Balsevich and Worth, Heterocycles, 11, 69, 1978). The N-methyl group of the vindoline part intact.
[0012]

The formation of N-CHO indoline skeleton on a bis-indole group vinblastine using a permanganate salt has never been reported.
[0013]

According to one embodiment of the method of the present invention, vinblastine, preferably in the form of sulphate, is treated in the presence of an organic acid such as acetic acid, with an excess of potassium permanganate dissolved in dichloromethane or toluene in the presence of “18-crown-6” or ether derivatives dibenzo-or di-cyclohexylcorrespondants. The reaction is conducted at a temperature between -40 ° C and -75 ° C and is preferably followed by thin layer chromatography. The reaction time generally ranges from 5 minutes to 3 hours.
[0014]

Potassium permanganate is preferably dissolved in dichloromethane and the oxidation reaction is then carried out at -70 ° C.
[0015]

The solubility of potassium permanganate is indeed substantially increased in the presence of a macrocyclic polyether as the “18-crown-6” ether (1, 4, 7, 10, 13, 16-hexaoxacy-clooctadécane) or derivative dibenzo – or corresponding dicyclohexyl-hexyl.
[0016]

The reaction mixture is then treated simultaneously by a mild reducing and alkaline. For this purpose, use is preferably an aqueous solution of bisulfite, disulfite or sodium metabisulfite and ammonia.
[0017]

The organic phase was separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases were concentrated in vacuo to give a residue containing 80-85% of base vincristine, a 90-95% yield.
[0018]

Alternatively, you can proceed with the extraction of the reaction mixture after reduction without conducting a simultaneous alkalinization. The acidic aqueous solution was then extracted with dichloromethane. This route is a novel process for purification of vincristine formed in the reaction medium.
[0019]

According to another embodiment of the present invention, vincristine is obtained by oxidation of vinblastine by reacting a quaternary ammonium permanganate. The ammonium cation is preferably benzyltriethylammonium group or benzyl trimethyl ammonium (see eg Angew. Chem., Intern. Ed. 13, 170, 1974). The reaction is carried out in 2 to 6 hours at -60 ° C in an inert solvent wherein the ammonium salt is soluble, and an acid, preferably an organic acid of low molecular weight. A mixture of dichloromethane and glacial acetic acid can be used. After treatment with a mild reducing agent in aqueous medium, the resulting acidic solution is extracted with dichloromethane, and the organic phase is made alkaline by washing with a basic aqueous solution and concentrated. Vincristine solvate is isolated with a yield higher than 90%.
[0020]

The latest variant of the method of the invention is particularly advantageous in terms of economic and technical.
[0021]

Purification or separation may be effected by crystallization and chromatography using techniques well known this from the crude product of the reaction. The product can also be lyophilized.
[0022]

In most cases, vincristine thus obtained can be converted directly into an addition salt with an organic or inorganic acid, preferably pharmaceutically acceptable. This salt is preferably a sulfate that may arise in a more or less solvated or hydrated.
[0023]

We can also prepare vincristine dissolved in a physiologically acceptable solvent and ready to be injected.
[0024]

In particular, vincristine sulfate is obtained by addition of H ₂ S0 ₄ to a solution of vincristine gross or recrystallized from ethanol, dissolved in a mixture of methylene chloride and anhydrous ethanol, partial removal in vacuo chloride methylene and crystallization.
[0025]

Vincristine sulfate thus obtained has a purity sufficient for use as a medicament, particularly in the form of injectable solutions.

Madagascar Periwinkle: Public Domain Illustration by Sydenham Edwards

The Madagascar periwinkle, an attractive flowering plant, contains the powerful anti-cancer chemicals vinblastine and vincristine. Velvet beans, which are named from the covering of soft hairs on the young plant, contain L-dopa, a very helpful chemical in the treatment of Parkinson’s disease. The Madagascar periwinkle and the velvet bean are just two of the large number of plants that have been found to contain medicinal chemicals. There are almost certainly many more plants that have undiscovered health benefits.

The Madagascar Periwinkle

The Madagascar periwinkle is native to Madagascar and India, but is now grown in many countries as a garden plant. It has also escaped from gardens and grows as a weed. The red, purple, pink or white flowers often have a center which is a different color from the rest of the flower. Madagascar periwinkles may grow up to one meter tall and have glossy green leaves.

The sap of the Madagascar periwinkle, which has a milky appearance and is poisonous, contains vinblastine, vincristine and many other alkaloids. Researchers are discovering that many of these alkaloids are biologically active inside the human body.

Vinblastine and Vincristine

Vinblastine and vincristine have very similar chemical structures, but their effects on the body are not the same. Vinblastine is used to treat specific types of cancer, such as Hodgkin’s disease, breast cancer, testicular cancer and non-small cell lung cancer. Vincristine is used in the treatment of acute lymphoblastic leukemia (ALL) and has provided a great breakthrough in successful treatment of this disease in children. When vincristine is added to the treatment regimen for children suffering from ALL, the survival rate reaches eighty percent. Vincristine is not so impressive in the treatment of ALL in adults.

Cells contain a supporting network of protein tubules, which are known as microtubules. Microtubules also play a vital role in the process of cell division. Before a cell divides, each chromosome in the cell is replicated. The replicated chromosomes are separated from their partners and pulled to opposite ends of the cell by microtubules during a process called mitosis. The cell then divides down the middle.

Vinblastine and vincristine stop microtubule formation during mitosis and therefore prevent cells from reproducing. This effect is strongest in cells that have a high rate of division, such as cancer cells. However, vinblastine and vincristine also affect cells lining the intestine, the cells in the bone marrow that produce blood cells, and the cells in the hair follicles, since these too have a high rate of cell division.

Possible vinblastine or vincristine side effects include constipation, hair loss, a low platelet count, which can cause increased bleeding, a low white blood cell count, which can lead to increased infections, or a low red blood cell count, resulting in anemia. There may occasionally be nerve damage, possibly due to the effect of the medicines on the microctubules in the nerve cells. Vincristine is more likely to cause nerve damage than vinblastine.

,,,,,,,,,,,,,

vol. 101 no. 33
> Takeshi Kuboyama, 11966–11970

Total synthesis of (+)-vincristine (2). TFA, trifluoroacetic acid or trifluoroacetyl; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene.

Stereocontrolled total synthesis of (+)-vincristine

vol. 101 no. 33
> Takeshi Kuboyama, 11966–11970

………………….

see docstoc presentation

click below
Vincristine

var docstoc_docid=”51697405″;var docstoc_title=”Vincristine”;var docstoc_urltitle=”Vincristine”;

…………………….

isolation

Kumar A, Patil D, Rajamohanan PR, Ahmad A (2013)

Isolation, Purification and Characterization of Vinblastine and Vincristine from Endophytic Fungus Fusarium oxysporumIsolated from Catharanthus roseus. PLoS ONE 8(9): e71805. doi:10.1371/journal.pone.0071805

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

Isolation, purification and characterization of vinblastine and vincristine from the endophytic fungus Fusarium oxysporum

A two stage fermentation procedure was employed for the isolation of vinblastine and vincristine by Fusarium oxysporum. In the first stage, 500 ml Erlenmeyer flasks containing 100 ml medium (MGYP, (0.3%) malt extract, (1.0%) glucose, (0.3%) yeast extract and (0.5%) peptone) were inoculated with 7 days old culture and incubated at 28°C on a rotary shaker (240 rpm) for 4–5 days, which was used as seed culture (I stage). Later, 10 ml seed culture was transferred to 500 ml Erlenmeyer flask containing 100 ml production medium called as vinca medium-1 (Glucose: 3%, Succinic acid: 1%, Sodium benzoate: 100 mg, Peptone: 1%, Magnesium sulphate: 3.6 mg, Biotin: 1 mg, Thiamine: 1 mg, Pyridoxal: 1 mg, Calcium pentothenate: 1 mg, Phosphate buffer: 1 ml (pH 6.8), L-Tryptophan: 0.1%, Geranium oil: 0.05%.) which were incubated at 28°C for 20 days as shake culture (II stage), after which it was harvested and used for further study. Culture filtrates and mycelia were separated with the help of muslin cloth and then lyophilized. Lyophilized culture filtrate was extracted using ethyl acetate as a solvent system. The organic layer was separated from the aqueous layer using separating funnel. The extraction was repeated thrice and the solvent was dried using anhydrous sodium sulphate and concentrated under vacuum using rotavapour at 40°C in order to get crude extract. A small amount of crude extract was dissolved in ethyl acetate and subjected to thin layer chromatography (TLC) on silica gel-G (0.5 mm thickness) using chloroform:methanol (8:2) as a solvent system. The TLC plates were sprayed with ceric ammonium sulphate reagent. Vinca alkaloids spots produced brilliant violet color as well as purple color with above spraying reagent. Purification of fungal vinblastine and vincristine were done by silica gel column chromatography. The crude extract was loaded on silica gel column (60–120 mesh size, 40 cm×2 cm length width) pre-equilibrated with chloroform and eluted with a gradient of chloroform:methanol (100% chloroform, 9:1, 8:2, 7:3, 1:1 and 3:7 and 100% methanol). Fractions containing compounds with Rf values similar to that of the standard vinblastine and vincristine were pooled and subjected to preparative TLC on a 0.5 mm thick (20 cm×20 cm) silica plate and developed in chloroform:methanol (8:2) solvent system. The putative bands of fungal vinblastine and vincristine were scraped and eluted out with methanol. Purity of the isolated compounds was checked on TLC in the solvent systems such as (a) chloroform:methanol (8:2) (b) chloroform:methanol (9:1) and (c) ethyl acetate: acetonitrile (8:2).

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0071805

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

September 25, 2013 3:36 am / 1 Comment on 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:
  - D1: WO 2007/081506 A (MALLINCKRODT INC [US]) 19 July 2007 (2007-07-19)
  - D2: J. MARTON ET AL: “Herstellung von 6,14-Ethenomorphinan-Derivaten” LIEBIGS ANNALEN DER CHEMIE, 1993, pages 915-919, XP002519987
  - D1 discloses a process for the preparation of buprenorphine from oripavine.
  - D2 discloses a process
[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.
………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………….

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:

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

VALSARTAN

September 24, 2013 8:00 am / Leave a comment

VALSARTAN

CAS 137862-53-4

Molecular FormulaC₂₄H₂₉N₅O_{3, A}verage 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

Valerica Pandarus †, Delphine Desplantier-Giscard†, Geneviève Gingras , François Béland †*, Rosaria Ciriminna ‡, and Mario Pagliaro ‡*

^† 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

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

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 pressure, congestive 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:

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:

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:

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

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.

Most commonly, headache and dizziness.
Sometimes fatigue^[17]

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

Marks JW (2007-02-15). “Valsartan, Diovan”. MedicineNet. Retrieved 2010-03-04.
“Diovan prescribing information”. Novartis.
J “Novartis Annual Report”. Novartis. 2010. Retrieved June 15, 2011.
Philip Moeller (April 29, 2011). “Blockbuster Drugs That Will Go Generic Soon”. U.S.News & World Report.
Eva Von Schaper (August 5, 2011). “Novartis’s Jimenez Has Blockbuster Plans For Diovan After Patent Expires”. Bloomberg.
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 2806632. PMID 20068258.
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 2040315. PMID 17965777. Retrieved 2009-11-11.
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 534428. PMID 15564232.
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.
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.
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)16451-9. PMID 15207952.
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)14284-5. PMID 13678870.
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.2005.05.005. PMID 16125050.
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.
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.
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.
Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag.ISBN 3-85200-196-X.
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):

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:

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

The solvent designation schedule	methanol	water	0.1М HCl	0.1M NaOH

Conditions : Concentration – 1 mg / 100 ml
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.

^CLIP

^{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

Guo-xi Wang*, Bao-ping Sun, and Cong-hu Peng

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

njuwgx@yahoo.com.cn.

Abstract

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).

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.

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.

Valsartan
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	US FDA: Valsartan
Pregnancy category	US: D (Evidence of risk)
Routes of administration	oral
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	25%
Protein binding	95%
Biological half-life	6 hours
Excretion	Renal 30%, biliary 70%
Identifiers
CAS Number	137862-53-4
ATC code	C09CA03 (WHO)
PubChem	CID 60846
IUPHAR/BPS	3937 tritiated: 593
DrugBank	DB00177
ChemSpider	54833
UNII	80M03YXJ7I
KEGG	D00400
ChEBI	CHEBI:9927
ChEMBL	CHEMBL1069
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.

^////////

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

EFAVIRENZ – Huahai Pharma China-Approved to Produce AIDS Treatment

September 23, 2013 3:27 am / 42 Comments on EFAVIRENZ – Huahai Pharma China-Approved to Produce AIDS Treatment

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

Sustiva (USA, Bristol-Myers Squibb)
Stocrin (EU, MSD)
Aspen Efavirenz (Sub-Saharan Africa, Aspen Pharmacare)

Generic brands India:

E.F (McNeil & Argus)
Efavir (Cipla)
Efcure (Emcure Pharmaceuticals)
Efferven (Ranbaxy Laboratories)
Estiva (Hetero)
Evirenz (Alkem Laboratories)
Viranz (Aurobindo Pharma)

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 Sustiva, Stocrin, Efavir 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

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.

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

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

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

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)

CLIPS

http://www.mdpi.com/1420-3049/21/2/221/htm

WO2007013047A2 *	Jul 31, 2006	Feb 1, 2007	Ranbaxy Lab Ltd	Water-dispersible anti-retroviral pharmaceutical compositions
WO2007013047A3 *	Jul 31, 2006	May 31, 2007	Ranbaxy Lab Ltd	Water-dispersible anti-retroviral pharmaceutical compositions
WO2007052289A2 *	Jul 24, 2006	May 10, 2007	Rubicon Res Pvt Ltd	Novel dispersible tablet composition
WO2007052289A3 *	Jul 24, 2006	Dec 27, 2007	Rubicon Res Pvt Ltd	Novel dispersible tablet composition
WO2011131943A2	Apr 20, 2011	Oct 27, 2011	Cipla Limited	Pharmaceutical compositions
WO2012048884A1	Oct 14, 2011	Apr 19, 2012	Lonza Ltd	Process for the synthesis of cyclic carbamates
WO2012048886A1	Oct 14, 2011	Apr 19, 2012	Lonza Ltd	Process for the synthesis of cyclic carbamates
WO2015059466A1	Oct 22, 2014	Apr 30, 2015	Cipla Limited	Pharmaceutical compositions comprising efavirenz
EP1448170A2 *	Nov 26, 2002	Aug 25, 2004	Bristol-Myers Squibb Company	Efavirenz tablet formulation having unique biopharmaceutical characteristics
EP2441759A1	Oct 14, 2010	Apr 18, 2012	Lonza Ltd.	Process for the synthesis of cyclic carbamates
EP2447255A1	Oct 14, 2010	May 2, 2012	Lonza Ltd.	Process for the synthesis of cyclic carbamates
US6238695	Apr 6, 1999	May 29, 2001	Dupont Pharmaceuticals Company	Formulation of fast-dissolving efavirenz capsules or tablets using super-disintegrants
US6555133	Apr 2, 2001	Apr 29, 2003	Bristol-Myers Squibb Company	Formulation of fast-dissolving efavirenz capsules or tablets using super-disintegrants
US8871271	Jul 29, 2013	Oct 28, 2014	Gilead Sciences, Inc.	Method and composition for pharmaceutical product
US8957204	Oct 14, 2011	Feb 17, 2015	Lonza Ltd.	Process for the synthesis of cyclic carbamates
US8969550	Oct 14, 2011	Mar 3, 2015	Lonza Ltd.	Process for the synthesis of cyclic carbamates
US9018192	Oct 10, 2013	Apr 28, 2015	Bristol-Myers Squibb & Gilead Sciences, Inc.	Unitary pharmaceutical dosage form
US9198862	Jul 24, 2006	Dec 1, 2015	Rubicon Research Private Limited	Dispersible tablet composition

WO1995020389A1 *	Jan 24, 1995	Aug 3, 1995	Merck & Co Inc	Benzoxazinones as inhibitors of hiv reverse transcriptase
WO1996037457A1 *	May 21, 1996	Nov 28, 1996	Merck & Co Inc	Asymmetric synthesis of (-) 6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2h-3,1-benzoxazin-2-one
WO1998052570A1 *	May 14, 1998	Nov 26, 1998	David Walter Barry	Antiviral combinations containing the carbocyclic nucleoside 1592u89

References

1 “Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents”. Retrieved 10 May 2013.
2
“WHO Model List of EssentialMedicines” (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
3
Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 62. ISBN 9781284057560.
4
Cespedes, MS; Aberg, JA (2006). “Neuropsychiatric complications of antiretroviral therapy.”. Drug safety : an international journal of medical toxicology and drug experience 29 (10): 865–74. doi:10.2165/00002018-200629100-00004. PMID 16970510.
5
“www.accessdata.fda.gov” (PDF).
6
DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (October 10, 2006). (Available for download from AIDSInfo)
7
Ford, N.; Mofenson, L.; Kranzer, K.; Medu, L.; Frigati, L.; Mills, E. J.; Calmy, A. (2010). “Safety of efavirenz in first-trimester of pregnancy: A systematic review and meta-analysis of outcomes from observational cohorts”. AIDS 24 (10): 1461–1470. doi:10.1097/QAD.0b013e32833a2a14. PMID 20479637.
8
Rossi, S; Yaksh, T; Bentley, H; Van Den Brande, G; Grant, I; Ellis, R (2006). “Characterization of interference with 6 commercial delta9-tetrahydrocannabinol immunoassays by efavirenz (glucuronide) in urine”. Clinical Chemistry 52 (5): 896–7. doi:10.1373/clinchem.2006.067058. PMID 16638958.
9
Röder, CS; Heinrich, T; Gehrig, AK; Mikus, G (2007). “Misleading results of screening for illicit drugs during efavirenz treatment”. AIDS (London, England) 21 (10): 1390–1. doi:10.1097/QAD.0b013e32814e6b3e. PMID 17545727.
10
Ren J, Bird LE, Chamberlain PP; et al. (2002). “Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors”. Proc Natl Acad Sci USA 99 (22): 14410–15. doi:10.1073/pnas.222366699. PMC 137897. PMID 12386343.
11
Sustiva (efavirenz) capsules and tablets. Product information (April 2005)
12
Simen AA, Ma J, Svetnik V, Mayleben D, Maynard J, Roth A, Mixson L, Mogg R, Shera D, George L, Mast TC, Beals C, Stoch A, Struyk A, Shire N, Fraser I (2014). “Efavirenz modulation of sleep spindles and sleep spectral profile”. J Sleep Res 24: 66–73. doi:10.1111/jsr.12196. PMID 25113527.
13
Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA (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.
14
Dabaghzadeh F, Ghaeli P, Khalili H, Alimadadi A, Jafari S, Akhondzadeh S, Khazaeipour Z (2013). “Cyproheptadine for prevention of neuropsychiatric adverse effects of efavirenz: a randomized clinical trial”. AIDS Patient Care STDS 27 (3): 146–54. doi:10.1089/apc.2012.0410. PMID 23442031.
15
Dabaghzadeh F, Khalili H, Ghaeli P, Dashti-Khavidaki S (2012). “Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz”. Expert Opin Pharmacother 13 (18): 2613–24. doi:10.1517/14656566.2012.742887. PMID 23140169.
16
Price listed on http://drugstore.com website, 4/20/2008
17
“Merck & Co., Inc., Again Reduces Price of Stocrin (efavirenz) for Patients in Least Developed Countries and Countries Hardest Hit by Epidemic – Drugs.com MedNews”.
18
IndiaDaily – A new trend in emerging nations – Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz
19
http://www.cipla.com
20
Patrick Lumumba Osewe; Yvonne Korkoi Nkrumah; Emmanuel K. Sackey (15 June 2008). Improving Access to HIV/AIDS Medicines in Africa: Trade-Related Aspects of Intellectual Property Rights (TRIPS) Flexibilities Utilization. World Bank Publications. pp. 35–39. ISBN 978-0-8213-7544-0. Retrieved 30 June 2012.
21
http://www.sustiva.com/
22
http://www.medsafe.govt.nz/consumers/cmi/s/stocrin.pdf
23
Drugsupdate.com generic brands list: http://www.drugsupdate.com/brand/generic/Efavirenz/87
24
http://mcneilargusindia.com/
25
http://www.alkemlabs.com/
26
“Regast® (efavirenz) film-coated tablets.”. http://www.pharmasyntez.com (in Russian). Pharmasyntez, 2011. Retrieved 28 June 2015. External link in |website= (help)
27
IOL: Thugs get high on stolen Aids drugs IOL News May 12, 2007
28
Getting high on HIV drugs in S Africa. BBC News, 8 December 2008.
29
‘No Turning Back’: Teens Abuse HIV Drugs. ABC News, April 6, 2009.
30
Getting High On HIV Medication Vice 7.04.2014.
31

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
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
ATC code	J05AG03 (WHO)
PubChem	CID 64139
DrugBank	DB00625
ChemSpider	57715
UNII	JE6H2O27P8
KEGG	D00896
ChEBI	CHEBI:119486
ChEMBL	CHEMBL223228
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

SEE………..http://www.ijppsjournal.com/Vol6Issue1/8170.pdf IR MASS HPLC ETC

//////////////

FC([C@@]1(C#CC2CC2)OC(=O)Nc2c1cc(Cl)cc2)(F)F

The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast,

September 17, 2013 4:04 am / Leave a comment

capecitabine

154361-50-9

R-340, Ro-09-1978, Xeloda

pentyl [1-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo-1H-pyrimidin-4-yl]carbamate

MONDAY Sept. 16, 2013 — The first generic version of the oral chemotherapy drug Xeloda (capecitabine) has been approved by the U.S. Food and Drug Administration to treat cancers of the colon/rectum or breast, the agency said Monday in a news release.

This year, an estimated 142,820 people will be diagnosed with cancer of the colon/rectum, and 50,830 are predicted to die from the disease, the FDA said, citing the U.S. National Cancer Institute. An estimated 232,340 women will be diagnosed with cancer of the breast this year, and some 39,620 will die from it.

The most common side effects of the drug are diarrhea, vomiting; pain, redness, swelling or sores in the mouth; fever and infection, the FDA said.

The agency stressed that approved generics have the same high quality and strength as their brand-name counterparts.

License to produce the generic drug was given to Israel-based Teva Pharmaceuticals. The brand name drug is produced by the Swiss pharma firm Roche.

Capecitabine (INN) /k eɪ p ˈ s aɪ t ə b iː n / (Xeloda, Roche) is an orally-administered chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCR) and 5′-deoxy-5-fluorouridine (5′-DFUR), to form 5-fluorouracil

Indications

Capecitabine is FDA-approved for:

Adjuvant in colorectal cancer Stage III Dukes’ C – used as first-line monotherapy.
Metastatic colorectal cancer – used as first-line monotherapy, if appropriate.
Metastatic breast cancer – used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons (i.e., the patient has already received the maximum lifetime dose of an anthracycline).

In the UK, capecitabine is approved by the National Institute for Health and Clinical Excellence (NICE) for colon and colorectal cancer, and locally advanced or metastatic breast cancer.^[1] On March 29, 2007, the European Commission approved Capecitabine, in combination with platinum-based therapy (with or without epirubicin), for the first-line treatment of advanced stomach cancer.

Capecitabine is a cancer chemotherapeutic agent that interferes with the growth of cancer cells and slows their distribution in the body. Capecitabine is used to treat breast cancer and colon or rectum cancer that has spread to other parts of the body.

Formulation

Capecitabine (as brand-name Xeloda) is available in light peach 150 mg tablets and peach 500 mg tablets.

Lacy, Charles F; Armstrong, Lora L; Goldman, Morton P; Lance, Leonard L (2004). Lexi-Comp’s Drug Information Handbook (12th Edition). Lexi-Comp Inc. ISBN 1-59195-083-X
Fischer, David S; Knobf, M Tish; Durivage, Henry J; Beaulieu, Nancy J (2003). The Cancer Chemotherapy Handbook (6th Edition). Mosby. ISBN 0-323-01890-4
Thomson Centerwatch: Drugs Approved by the FDA (Xeloda) Retrieved 6/05
Mercier C, Ciccolini J (2007). “Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit?”. Trends in pharmacological sciences 28 (12): 597–598. doi:10.1016/j.tips.2007.09.009. PMID 18001850.

“Subtopics”. Nice.org.uk. Retrieved 2012-08-15.
Fingerprints May Vanish With Cancer Drug – US News and World Report
Cancer Drug Erases Man’s Fingerprints – CNN
“Stritch School of Medicine”. Stritch.luc.edu. Retrieved 2012-08-15.

Xeloda.com (patient information, tools, and resources)
OralChemo Advisor (patient information)

WO2009066892A1

Capecitabine is an orally-administered anticancer agent widely used in the treatment of metastatic breast and colorectal cancers. Capecitabine is a ribofuranose-based nucleoside, and has the sterochemical structure of a ribofuranose having an β-oriented 5-fluorocytosine moiety at C-I position.

US Patent Nos. 5,472,949 and 5,453,497 disclose a method for preparing capecitabine by glycosylating tri-O-acetyl-5-deoxy-β-D-ribofuranose of formula I using 5-fluorocytosine to obtain cytidine of formula II; and carbamoylating and hydrolyzing the resulting compound, as shown in Reaction Scheme 1 :

Reaction Scheme 1

The compound of formula I employed as an intermediate in Reaction

Scheme 1 is the isomer having a β-oriented acetyl group at the 1 -position, for the reason that 5-fluorocytosine is more reactive toward the β-isomer than the α-isomer in the glycosylation reaction due to the occurrence of a significant neighboring group participation effect which takes place when the protecting group of the 2-hydroxy group is acyl.

Accordingly, β-oriented tri-O-acetyl-5-deoxy-β-D-ribofuranose (formula

I) has been regarded in the conventional art to the essential intermediate for the preparation of capecitabine. However, such a reaction gives a mixture of β- and α-isomers from which cytidine (formula II) must be isolated by an uneconomical step.

Meanwhile, US Patent No. 4,340,729 teaches a method for obtaining capecitabine by the procedure shown in Reaction Scheme 2, which comprises hydrolyzing 1-methyl-acetonide of formula III to obtain a triol of formula IV; acetylating the compound of formula IV using anhydrous acetic anhydride in pyridine to obtain a β-/α-anomeric mixture of tri-O-acetyl-5-deoxy-D-ribofuranose of formula V; conducting vacuum distillation to purify the β-/α-anomeric mixture; and isolating the β-anomer of formula I therefrom:

Reaction Scheme 2

III IV

However, the above method is also hampered by the requirement to perform an uneconomical and complicated recrystallization steps for isolating the β-anomer from the mixture of β-/α-anomers of formula V, which leads to a low yield of only about 35% to 40% (Guangyi Wang et al., J. Med. Chem., 2000, vol. 43, 2566-2574; Pothukuchi Sairam et al., Carbohydrate Research, 2003, vol. 338, 303-306; Xiangshu Fei et al., Nuclear Medicine and Biology, 2004, vol. 31, 1033-1041; and Henry M. Kissman et al., J. Am. Chem. Soc, 1957, vol. 79, 5534-5540).

Further, US Patent No. 5,476,932 discloses a method for preparing capecitabine by subjecting 5′-deoxy-5-fluorocytidine of formula VI to a reaction with pentylchloroformate to obtain the compound of formula VII having the amino group and the 2-,3-hydroxy groups protected with C₅Hi₁CO₂ groups; and removing the hydroxy-protecting groups from the resulting compound, as shown in Reaction Scheme 3 :

Reaction Scheme 3

Vl VII 1

However, this method suffers from a high manufacturing cost and also requires several complicated steps for preparing the 5′-deoxy-5-fluorocytidine of formula VI: protecting the 2-,3-hydroxy groups; conducting a reaction thereof with 5-fluorocytosine; and deprotecting the 2-,3-hydroxy groups.

Accordingly, the present inventors have endeavored to develop an efficient method for preparing capecitabine, and have unexpectedly found an efficient, novel method for preparing highly pure capecitabine using a trialkyl carbonate intermediate, which does not require the uneconomical β-anomer isolation steps.

synthesis

WO2010065586A2

more info and description

Aspects of the present invention relate to capecitabine and processes for the preparation thereof.

The drug compound having the adopted name “capecitabine” has a chemical name 5′-deoxy-5-fluoro-N-[(pentyloxy) carbonyl] cytidine and has structural formula I.

OH OH I

This compound is a fluoropyrimidine carbamate with antineoplastic activity. The commercial product XELODA™ tablets from Roche Pharmaceuticals contains either 150 or 500 mg of capecitabine as the active ingredient.

U.S. Patent No. 4,966,891 describes capecitabine generically and a process for the preparation thereof. It also describes pharmaceutical compositions, and methods of treating of sarcoma and fibrosarcoma. This patent also discloses the use of ethyl acetate for recrystallization of capecitabine. The overall process is summarized in Scheme I.

Scheme I

U.S. Patent No. 5,453,497 discloses a process for producing capecitabine that comprises: coupling of th-O-acetyl-5-deoxy-β-D-hbofuranose with 5- fluorocytosine to obtain 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine; acylating a 2′, 3′- di-O-acetyl-5′-deoxy-5-fluorocytidine with n-pentyl chloroformate to form 5′-deoxy- 2′,3′-di-O-alkylcarbonyl-5-fluoro-N-alkyloxycarbonyl cytidine, and deacylating the 2′ and 3′ positions of the carbohydrate moiety to form capecitabine. The overall process is summarized in Scheme II.

Capecitabine

Scheme Il

The preparation of capecitabine is also disclosed by N. Shimma et al., “The Design and Synthesis of a New Tumor-Selective Fluoropyrimidine Carbamate, Capecitabine,” Bioorganic & Medicinal Chemistry, Vol. 8, pp. 1697-1706 (2000). U.S. Patent No. 7,365,188 discloses a process for the production of capecitabine, comprising reacting 5-fluorocytosine with a first silylating agent in the presence of an acid catalyst under conditions sufficient to produce a first silylated compound; reacting the first silylated compound with 2,3-diprotected-5- deoxy-furanoside to produce a coupled product; reacting the coupled product with a second silylating agent to produce a second silylated product; acylating the second silylated product to produce an acylated product; and selectively removing the silyl moiety and hydroxyl protecting groups to produce capecitabine. The overall process is summarized in Scheme III. te

R: hydrocarbyl

Scheme III

Further, this patent discloses crystallization of capecitabine, using a solvent mixture of ethyl acetate and n-heptane. International Application Publication No. WO 2005/080351 A1 describes a process for the preparation of capecitabine that involves the refluxing N₄– pentyloxycarbonyl-5-fluorocytosine with trimethylsiloxane, hexamethyl disilazanyl, or sodium iodide with trimethyl chlorosilane in anhydrous acetonitrile, dichloromethane, or toluene, and 5-deoxy-1 ,2,3-tri-O-acetyl-D-ribofuranose, followed by hydrolysis using ammonia/methanol to give capecitabine. The overall process is summarized in Scheme IV.

Scheme IV

International Application Publication No. WO 2007/009303 A1 discloses a method of synthesis for capecitabine, comprising reacting 5′-deoxy-5- fluorocytidine using double (trichloromethyl) carbonate in an inert organic solvent and organic alkali to introduce a protective lactone ring to the hydroxyl of the saccharide moiety; reacting the obtained compound with chloroformate in organic alkali; followed by selective hydrolysis of the sugar component hydrolytic group using an inorganic base to give capecitabine. The overall process is summarized in Scheme V.

Scheme V

Even though all the above documents collectively disclose various processes for the preparation of capecitabine, removal of process-related impurities in the final product has not been adequately addressed. Impurities in any active pharmaceutical ingredient (API) are undesirable, and, in extreme cases, might even be harmful to a patient. Furthermore, the existence of undesired as well as unknown impurities reduces the bioavailability of the API in pharmaceutical products and often decreases the stability and shelf life of a pharmaceutical dosage form.

nmr

¹H NMR(CD₃OD) δ 0.91(3H₅ t), 1.36~1.40(4H, m), 1.41(3H, d), 1.68~1.73(2H, m), 3.72(1H, dd), 4.08(1H, dd), 4.13~4.21(3H, m), 5.7O(1H, s), 7.96(1H, d)

The acetylation of 5′-deoxy-5-fluorocytidine (I) with acetic anhydride in dry pyridine gives 2′,3′-di-O-acetyl-5′-deoxy-5-fluorocytidine (II), which is condensed with pentyl chloroformate (III) by means of pyridine in dichromethane yielding 2′,3′-di-O-acetyl-5′-deoxy-5-fluoro-N4-(pentyloxycarbonyl)cytidine (IV). Finally, this compound is deacetylated with NaOH in dichloromethane/water. The diacetylated cytidine (II) can also be obtained by condensation of 5-fluorocytosine (V) with 1,2,3-tri-O-acetyl-5-deoxy-beta-D-ribofuranose (VI) by means of trimethylchlorosilane in acetonitrile or HMDS and SnCl4 in dichloromethane..
- EP 602454, JP 94211891, US 5472949.
  - Capecitabine. Drugs Fut 1996, 21, 4, 358,
    - Bioorg Med Chem Lett2000,8,(7):1697,

BENAZEPRIL HYDROCHLORIDE SYNTHESIS AND REVIEW

September 14, 2013 4:00 am / 5 Comments on BENAZEPRIL HYDROCHLORIDE SYNTHESIS AND REVIEW

BENAZEPRIL HYDROCHLORIDE, CAS NO 86541-74-4

Benazepril, brand name Lotensin (Novartis), is a medication used to treat high blood pressure (hypertension), congestive heart failure, and chronic renal failure. Upon cleavage of its ester group by the liver, benazepril is converted into its active form benazeprilat, a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor.

Dosage forms

Benazepril is available as oral tablets, in 5-, 10-, 20-, and 40-mg doses.

Benazepril is also available in combination with hydrochlorothiazide, under the trade name Lotensin HCT, and with amlodipine(trade name Lotrel).

Side effects

Most commonly, headaches and cough can occur with its use. Anaphylaxis, angioedema and hyperkalemia, the elevation of potassium levels, can also occur.

Benazepril may cause harm to the fetus during pregnancy.

According to coverage of the study on WebMD:

“

ACE inhibitors can pose a potential threat to kidneys as well. The key question was whether damaged kidneys would worsen if patients took ACE inhibitors. In a nutshell, concerns centered on blood levels of potassium andcreatinine, waste products that are excreted by the kidneys. Testing creatinine levels in the blood is used as a way to monitor kidney function (…) kidney problems worsened more slowly in those taking Lotensin. Overall, there were no major differences in side effects between patients taking Lotensin or the placebo.^[2]

”

This study marks the first indication that benazepril, and perhaps other ACE inhibitors, may actually be beneficial in the treatment of hypertension in patients with kidney disease.

The Benazepril hydrochloride, with the CAS registry number 86541-74-4, is also known as (3S)-3-(((1S)-1-Carboxy-3-phenylpropyl)amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid, 3-ethyl ester, monohydrochloride; Benazepril HCl; Cibacen; Cibacen CHF; Labopol. It belongs to the product categories of Intermediates & Fine Chemicals; Pharmaceuticals; Amines; Aromatics; Heterocycles. This chemical’s molecular formula is C₂₄H₂₉ClN₂O₅ and molecular weight is 460.96. What’s more, its IUPAC name 2-[(3S)-3-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-dihydro-3H-1-benzazepin-1-yl]acetic acid hydrochloride. In addition, Benazepril hydrochloride (CAS 86541-74-4) is crystalline solid which is soluble in DMSO. It is used in high blood pressure and congestive heart failure. When you are using this chemical, you should not breathe dust and avoid contact with skin and eyes.

Veterinary use

Under the brand names Fortekor (Novartis) and VetACE (Jurox Animal Health), benazepril hydrochloride is used to treat congestive heart failure in dogs and chronic renal failure in dogs and cats.

^ Hou F, Zhang X, Zhang G, Xie D, Chen P, Zhang W, Jiang J, Liang M, Wang G, Liu Z, Geng R (2006). “Efficacy and safety of benazepril for advanced chronic renal insufficiency”. N Engl J Med 354 (2): 131–40. doi:10.1056/NEJMoa053107. PMID 16407508.
^ ^a ^b Hitti, Miranda; Chang, Louise (January 11, 2006). “Drug May Treat Advanced Kidney Disease”. WebMD. Retrieved 2006-09-07.

Prescribing Information for Lotensin

	Benazepril hydrochloride, TWT-8154, CGS-14824A, Cibacene, Briem, Cibacen, Lotensin
	1-Carboxymethyl-3(S)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one monohydrochloride; 3(S)-[1(S)-Ethoxycarbonyl-3-phenylpropylamino]-2-oxo-2,3,4,5-tetrahydro-1-benzazepine-1-acetic acid monohydrochloride
【CAS】	86541-74-4, 86541-75-5 (free base)
MF	C24-H28-N2-O5.Cl-H
MW	460.9551rot–[Alpha] 20 D -141.0 °. (C = 0.9, ethanol)
	Cardiovascular Drugs, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors
	Launched-1990
	Novartis (Originator), Pierre Fabre (Licensee), Andrx (Generic), Eon Labs (Generic), KV Pharmaceutical (Generic), Mylan (Generic)

Above Preparation of Benazepril hydrochloride (CAS 86541-74-4): The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.

ABOVE SCHEME-EP 1891014 B1

BACKGROUND

Benazepril (CAS REGISTRY No. 86541-75-5) first disclosed inUS 4,410,520 is one of the well-known ACE inhibitors and is used for the treatment of hypertension.
Chemically, Benazepril, is (3S)-1-(carboxymethyl-[[(1(S)-1-(ethoxycarbonyl)-3-phenylpropyl]amino]-2,3,4,5-tetrahydro-1H-[1]benzazepine-2-one.
Benazepril is administered orally in the form of hydrochloride salt (CAS REGISTRY No. 86541-74-4) represented by formula (I).
The preparation of benazepril disclosed in US 4,410,520 , J. Med. Chem. 1985, 28, 1511-1516, and Helvetica Chimica Acta (1988) 71, 337-342, as given in scheme 1, involves reductive amination of ethyl 2-oxo-4-phenyl butyrate (IV) with sodium salt of (3S)-3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1 H-benzazepin-2-one (III).
In example 12 of US 4,410,520 , the crude benazepril (II) obtained in a diastereomeric ratio of SS: SR=70:30 was dissolved in dichloromethane and treated with HCl gas to obtain benazepril hydrochloride. The benazepril hydrochloride of formula (I) obtained as a foam was crystallized from methyl ethyl ketone to obtain in a SS: SR=95:5 diastereomeric ratio. Benazepril hydrochloride was further purified by recrystallization from a mixture of 3-pentanone/methanol (10:1), melting point: 188-190 °C.
Alternatively, in example 27 of US 4,410,520 , benazepril hydrochloride was purified by refluxing in chloroform, filtering, and washing first with chloroform and then with diethyl ether. The melting point of benazepril hydrochloride obtained as per this example is 184-186 °C.
An alternative process disclosed in US 4,785,089 involves nucleophilic substitution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepine-2-one (V), using the chiral substrate ethyl (2R)-2-(4-nitrobenzenesulfonyl)-4-phenyl butyrate (VI) in presence of N-methylmorpholine (scheme 2). The benazepril t-butyl ester (IIa) obtained in a diastereomeric ratio of SS: SR=96:4 was hydrolyzed to benazepril (II) and converted to hydrochloride salt by treating with HCl gas in ethyl acetate. The crystalline suspension of benazepril hydrochloride in ethyl acetate was diluted with acetone and filtered to obtain in a diastereomeric ratio of SS: SR=99.1:0.9. Further purification by refluxing in ethyl acetate afforded benazepril hydrochloride in a diastereomeric ratio of SS: SR=99.7:0.3, melting point of 181 °C.
The above documents do not disclose the crystalline form of benazepril hydrochloride obtained by following the purification processes disclosed in the examples.
The Merck Index., 12^th edition reports benazepril hydrochloride crystals obtained from 3-pentanone+methanol (10:1), melting point 188-190 °C
The crystallization methods taught in the prior art does not consistently produce a constant diastereomeric composition of SS:SR diastereomer. This is evident from the variation in the melting points of the benazepril hydrochloride reported in three different working examples, which varies between 181 to 190°C.
The variation in diastereomeric composition of a pharmaceutical substance is not desirable as it would affect its efficacy. Hence there is a need for a crystallization process that consistently produce a constant diastereomeric composition of SS diastereomer in greater than 99.8%.
Coming to the crystalline form, it is well known in the art that the solid form of a pharmaceutical substance affect the dissolution rate, solubility and bioavailability. The solid form may be controlled by process employed for the manufacture of the pharmaceutical substance. In particular the process of purification of the solid substance by crystallization is used to control the solid form (Organic Process Research & Development, 2003, 7, 958-1027).
It has been found that the crystalline form of benazepril hydrochloride obtained from processes of prior art documents is designated as crystalline Form A as evident from the following documents.
In a monograph published by Al-badar et al in Profiles of Drug Substances, Excipients, and Related Methodology, Vol. 31, 2004, p117-161; benazepril hydrochloride prepared by the process disclosed in US 4,410,520 , and J. Med. Chem. 1985, 28, 1511-1516, has been characterized by powder X-ray diffraction pattern having 2θ peaks at 6.6, 9.9, 11.9, 13.7, 14.0, 14.9, 15.3, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 22.2, 25.2, 25.5, 26.4, 26.6, 27.1, 27.9, 29.8, 30.4, 31.0, 32.6, 33.3, 33.8, 34.4, 35.5, 38.2, 39.9, 43.9, 48.9.
The major peaks are at 6.6, 9.9, 11.9, 13.7, 14.9, 16.4, 17.3, 18.9, 19.6, 20.2, 20.9, 21.5, 25.2, 25.5, 26.4, 26.6, 27.9, 31.0, and 32.6.
WO 2004/013105 A1 also discloses that by following the processes of the prior art mentioned above, crystalline benazepril hydrochloride is isolated in a form designated as Form A having a powder X-ray diffraction pattern with 2θ values at 6.7, 10.1, 12.0, 13.8, 15.1, 16.4, 17.4, 19.0, 19.6, 20.2, 20.9, 21.0, 25.3, 25.5, 26.4, 26.6, 27.6, 28.0, 31.0, 32.7.
WO 2004/013105 A1 discloses that benazepril hydrochloride Form A may be prepared from a concentrated solution of the benazepril hydrochloride in a solvent selected from C₁-C₁₀ alcohol, N,N-dimethylformamide, N-methylpyrrolidone by adding an anti-solvent selected from C₄-C₁₂ alkane or C₁-C₁₀ acetate, preferably, hexane or ethyl acetate.
WO 2004/013105 A1 in Example 5 describes a process of making crystalline form A of benazepril hydrochloride by passing HCl gas into a solution of benazepril free base in diethyl ether and filtering the resulting suspension.
Similarly, in Example 6, the benazepril hydrochloride was dissolved in water free ethanol and the resulting solution was added to heptane at 20° C to obtain the crystalline Form A.
Further, WO 2004/013105 A1 , mentions a list of solvents and anti-solvents that can be used to make benazepril hydrochloride crystalline Form A. However, there is no enabling disclosure and the document is silent on the diastereomeric purity of the crystalline form A obtainable by the process disclosed.
The processes of crystallization and/or recrystallization disclosed in the prior art do not consistently produce benazepril hydrochloride with constant diasteromeric content as evident from the variation in the melting point of the crystalline benazepril hydrochloride obtained from crystallization from various solvents.

SYNTHETIC SCHEMES

	Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use
	Watthey, J.W.H. (Novartis AG)
	EP 0072352; GB 2103614; JP 8338260

The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.


	Process for the preparation of benazepril
	Kumar, Y.; De, S.; Thaper, R.K.; Kumar, D.S.M. (Ranbaxy Laboratories Ltd.)
	WO 0276375

The reaction of 2(R)-hydroxy-4-phenyl butyric acid ethyl ester (I) with trifluoromethanesulfonic anhydride in dichloromethane gives the corresponding triflate (II), which is then condensed with the amino benzazepinone (III) by means of NMM in the same solvent to provide the target benazepril.


	CGS-14824 A
	Casta馿r, J.; Serradell, M.N.
	Drugs Fut 1984,9(5),317

The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.


	Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A)
	Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.
	J Label Compd Radiopharm 1987,24(10),1177-84

A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.

US 6548665 B2– above

see translated vesrsion————-First, 2,3,4,5 – tetrahydro-1H-[1] azepin-2 phenyl – one (2) Preparation of
the dry reaction flask, add α- tetralone 20g (0.137mol), stacked acid 7.36g (0.171mol) and chloroform 140ml, was stirred at 40 ℃ in 1h concentrated sulfuric acid was slowly added dropwise 36ml, acid layer was separated and poured into 900ml water to give a creamy solid. Recrystallization with hot water to give white crystals (2) 15.5g (70%), mp141 ℃. (Acidic filtrate and after a small amount of product can be obtained.)
Second, 3,3 – dichloro-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (3) of the prepared
in a dry reaction flask, (2) 48.3g (0.3mol) and xylene solution of 1300ml, phosphorus pentachloride 188g (0.9mol), stirred and gradually heated to at 0.5h 90 ℃, (Caution! When phosphorus pentachloride dissolved hydrogen chloride gas had severe.) 90 ℃ the reaction was continued for 0.5h, filtered to remove a small amount of suspended solids, solvent recovery under reduced pressure, to the residue was added saturated sodium bicarbonate solution, 100ml, stirred until a solid precipitate complete, filtered and the cake washed with ethanol (100ml × 2), diethyl ether (50ml) and dried to give (3) 69.0g (90%), mp185 ~ 187 ℃.
III.3 – chloro-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (4) Preparation of
the reaction flask (3) 10g (0.087mol), Sodium acetate 77g (0.11mol), acetic acid 460ml and 5% Pd-C 0.86g, under atmospheric pressure at room temperature to a hydrogen-absorbing up total of 950ml (about 0.5h). Filtration, recycling the catalyst recovered solvent, the residue was dried under reduced pressure, and then added 900ml of 10% sodium bicarbonate solution and dichloromethane 300ml, stirring, standing, the organic layer was separated and the aqueous layer extracted with dichloromethane (300ml × 3) extracted organic layers were combined, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure. Diethyl ether was added to the cured 350ml, and mashed, filtered and dried to give (4) 8.19g (95%), mp163 ~ 167 ℃.
4 (3) – azido-2, 3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one (5) Preparation of
the dry reaction flask (4) 15.9g ( 0.08mol), sodium azide 6.4g (0.10mol) and 320ml solution of dimethyl sulfate, the reaction was stirred at 80 ℃ 3h, cooled to room temperature, poured into ice-water (1L) to precipitate a pale yellow solid , filtered and dried under reduced pressure at 75 ℃ to give (5) 14.7g (90%), mp142 ~ 145 ℃.
V.3 – azido-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (6) Preparation of
the dry reaction flask, (5) 3.0g (0.015mol), tetrabutylammonium bromide, 0.5g (0.0015 mol), powdered potassium hydroxide 1.1g (0.016mol) and 30ml of tetrahydrofuran solution of ethyl bromoacetate was added 1.9ml ( 0.016mol), stirred rapidly at room temperature for 1.5h (nitrogen). Water was added: dichloromethane (50:100 ml), stirred, allowed to stand, the organic layer separated. Washed with water, dried over anhydrous sodium sulfate, the solvent recovered under reduced pressure to give a pale yellow oil (6) 4.1g (96%) (can be used directly in the next step).
VI.3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (7) Preparation of
the dry reaction flask, (6 ) 20.0g (0.070mol), ethanol 100ml, 10% Pd-C 1.0g stirring, at room temperature, 303.9kPa hydrogenated under a hydrogen pressure 1.5h, intermittent deflated to remove the generated nitrogen gas, after the reaction was collected by filtration Pd / C, recovery of solvents under reduced pressure to give a yellow oil, add ether l00ml, mashed, filtered and dried to give a white solid (7) 17.0g (93%) mp101 ~ 102 ℃.
Seven, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (8) Preparation of
the reaction flask, adding (7) 25.1g (0.096mol), L – tartaric acid 14.4g (0.096mol) and hot ethanol 200ml, stirring to dissolve, cooled at room temperature overnight, filtered and dried under reduced pressure to give a white powder 30.7g, with ethanol Recrystallization twice (each 200ml), to give (8) tartaric acid salt of 13.6g (34%), mp168 ~ 169 ℃, with 10% ammonium hydroxide, to give a white solid (8) 8.0g (95%) mp104 ~ 106 ℃.
Eight, (3S) -3 – amino-2 ,3,4,5 – tetrahydro-1H-[1] benzene azepin-2 – one-1 – acetate (9) Preparation of
the reaction flask, (8) 4.0g (0.056mol) and 150ml of methanol solution of sodium hydroxide 2.1g (0.056moI) and a solution of 5ml of water, stirred at room temperature for 2h, the solvent recovered under reduced pressure, the residue was dried and diethyl ether was added 100ml, trace broken, filtered, and dried to give (9) 12.9g (89%) (used directly in the next step).
IX benazepril (1) Synthesis of
the reaction flask (9) 12.9g (0.050mol), 2 – oxo-4 – phenylbutyrate 31.0g (0.15mol), acetic acid and 100ml methanol 75ml, the reaction was stirred at room temperature for 1h (nitrogen). Of sodium borohydride cyanide was slowly added dropwise 3.8g (0.062mol) and 30ml of methanol solution of (4h was completed within), stirred overnight, heat. Concentrated hydrochloric acid 10ml, 1h stirring at room temperature, the solvent was recovered under reduced pressure, water was added to the residue and diethyl ether 400ml l00ml, dissolved with concentrated ammonium hydroxide and the pH adjusted to 9.3, the organic layer was separated and the aqueous layer acidified with concentrated hydrochloric to pH 4.3, extracted with ethyl acetate (100ml × 3) extracted organic layers were combined, dried over anhydrous magnesium sulfate, the solvent recovered under reduced pressure, to the residue was added methylene chloride (150ml) to dissolve. And pass into dry hydrogen chloride after 5min recovered solvent under reduced pressure, to the residue was added hot ethyl ketone 100ml, stirring to dissolve, cooled and precipitated solid was filtered to give crude product (1). A 3 – amyl ketone / methanol (volume ratio 10:1) (110ml) was recrystallized (1) 5.8 g, mp 188 ~ 190 ℃, [alpha] _D²⁰ -141.0 (C = 0.9, C ₂ H ₅ OH )
[Spectral Data] (free base) ^[2]
MS: m / Z (%) 424 (M ⁺ , 2), 351 (100), 190 (22), 91 (65)
] [other synthetic routes
described in the reference literature.

[References]
[1] Briggs LH et al. J Chem Soc, 1937, 456
[2] Watthey WH et al. J Med Clmm, 1985, 28:1511
[3] EP 1986, 206933 (CA, 1987, 107: 77434e)
[4] EP 1983, 72352 (CA, 1983, 99:53621 d)
[5] package insert: Lotensin
[6] property protection case I: Lotensin
[7] property protection case II: Lotensin
[8] Drug Monograph information: BENAZEPRIL

more info

Benazepril M.p. 148.5°.

Proprietary names. Briem; Cibace; Cibacen; Cibacene; Labopal; Lotensin; Tensanil; Zinandril.

C₂₄H₂₈N₂O₅,HCl=461.0

CAS—86541–74–4

A white to off–white crystalline powder. It is soluble in water, ethanol and methanol.

Partition Coefficient.

Log P(octanol/water), 3.50.

Gas Chromatography.

System GP—RI 3030 (benazepril-ME); RI 2985 (M (benazeprilate)-ME3).

Column: 3% OV-101 on Gaschrom Q, 80–100 mesh (Ciba-Geigy), pyrex glass (1.5 m × 2 mm i.d.). Column and injector port temperature: 275°. Carrier gas: helium, flow rate 30 mL/min. MS detection (EI, SIM). Retention times: benazepril (methyl ester derivative) 2.55 min; benazeprilat (derivative) 2.3 min. [G. Kaiser et al.,J. Chromatogr.,1987, 419, 123–133].

High Performance Liquid Chromatography.

System HAA—retention time 17.0 min.

Column: C₁₈ (RP-BDS, 5 μm packing, 250 × 3 mm i.d.). Mobile phase: sodium dihydrogen phosphate (0.025 M, pH 4.8):acetonitrile (55:45). 0.4 mL/min flow rate. UV detection (λ=250 nm). Retention time: benazepril hydrochloride, 4.95 min. [I. E. Panderi and M. Parissi-Polou,J. Pharm. Biomed. Anal.,1999, 21, 1017–1024].

Column: Hypersil ODS (5 μm, 250 × 4.5 mm). Mobile phase: sodium heptanesulfonate (20 mM, pH 2.5):acetonitrile (5% THF) (52:48 v/v), 1.0 mL/min flow rate. UV detection (λ=215 nm). Retention time: 15 min. [D. Bonazzi et al.,J. Pharm. Biomed. Anal.,1997, 16, 431–438].

Ultraviolet Spectrum.

Aqueous acid (0.2 M NH₂SO₄)—237 nm; basic—241 nm; aqueous acid (0.1 M hydrochloric acid)—237.2 nm (hydrochloride salt).

Reference(s):
Clarke’s Analysis of Drugs and Poisons
Watthey, J.W.H. et al.: J. Med. Chem. (JMCMAR) 28, 1511 (1985).
US 4 410 520 (Ciba-Geigy; 18.10.1983; prior. 11.8.1981, 9.11.1981, 19.7.1982).
EP 72 352 (Ciba-Geigy; appl. 5.8.1982; USA-prior. 11.8.1981, 9.11.1981).

Welcome to Bioinfomedical.com

September 5, 2013 4:31 am / 2 Comments on Welcome to Bioinfomedical.com

http://www.bioinfomedical.com/index.php

Prof. Dr. Rafael Boritzer

P.O.Box 88355, Honolulu, Hawaii 96830 U.S.A.

boritzer@bioinfomedical.com

http://www.bioinfomedical.com/index.php

we are marketers of non-branded recombinant proteins with a primary mission of high quality, low priced material for encouraging biopharma research and development outside of North America. We try to integrate our supply services with education of our clients’ with industry videos and information.

Welcome to Bioinfomedical.com

BioInfoMedical was established in 1989 by a team of experienced medical specialists, world-known scientists and marketing professionals. The company has two operating divisions:

InfoMedical Biotechnology and InfoMedical Consulting.

InfoMedical Biotechnology provides products and services used in gene, protein and cell research, drug discovery and development, as well as in biopharmaceutical manufacturing.

InfoMedical Consulting assists companies in strategic market expansion, industry research, environmental analysis, and developing successful market plans for worldwide business-winners.

We are proud to serve our customers around the globe. Our clients are: academic research institutions, biotechnology and pharmaceutical companies, medical research centers, hospitals, reference laboratories, agricultural and chemical companies, as well as leading private and governmental business organizations.

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

see a video of DR RAFI

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

Cytokines

Growth Factors

Chemokines

CD Antigens

CD Antigens

Neurotrophins

Hormones

Enzymes

Viral Antigens

Recombinant Proteins

Natural Proteins

Monoclonal Antibodies

Polyclonal Antibodies

Test Category New

http://www.bioinfomedical.com/index.php

The Cost Of Creating A New Drug Now $5 Billion, Pushing Big Pharma To Change

September 1, 2013 10:27 am / 2 Comments on The Cost Of Creating A New Drug Now $5 Billion, Pushing Big Pharma To Change

Susan Desmond-Hellmann

There’s one factor that, as much as anything else, determines how many medicines are invented, what diseases they treat, and, to an extent, what price patients must pay for them: the cost of inventing and developing a new drug, a cost driven by the uncomfortable fact than 95% of the experimental medicines that are studied in humans fail to be both effective and safe.

A new analysis conducted at Forbes puts grim numbers on these costs. A company hoping to get a single drug to market can expect to have spent $350 million before the medicine is available for sale. In part because so many drugs fail, large pharmaceutical companies that are working on dozens of drug projects at once spend $5 billion per new medicine.

read all at

http://www.forbes.com/sites/matthewherper/2013/08/11/how-the-staggering-cost-of-inventing-new-drugs-is-shaping-the-future-of-medicine/

How Much They Cost: R&D Spending Per New Drug

	Company	Number of new drugs	10 year R&D spending ($MIL)	R&D per drug ($MIL)
1	Abbott	1	13183	13183
2	Sanofi	6	60768	10128
3	AstraZeneca	4	38245	9561
4	Hoffmann-La Roche	8	70928	8866
5	Pfizer	10	77786	7779
6	Wyeth	3	22702	7567
7	Eli Lilly	4	26710	6678
8	Bayer	5	33118	6624
9	Schering-Plough	3	18845	6282
10	Novartis	10	60727	6073
11	Takeda	4	24132	6033
12	Merck&Co	9	49133	5459
13	GlaxoSmithKline	11	57595	5236
14	J&J	13	67624	5202
15	Novo Nordisk	2	9251	4625
16	UCB	1	4325	4325
17	Yamanouchi	1	4321	4321
18	Fujisawa	1	4286	4286
19	Amgen	5	21350	4270
20	Astellas	3	12582	4194
21	Shionogi	1	3854	3854
22	Celgene	2	7193	3596
23	Bristol-Myers Squibb	9	30352	3372
24	Eisai	4	11534	2883
25	Teva	2	5763	2881
26	Biogen Idec	4	9470	2368
27	Vertex	2	4140	2070
28	Sunovion	1	1967	1967
29	Human Genome Sciences	1	1954	1954
30	Elan	1	1903	1903
31	Gilead	3	5527	1842
32	Exelixis	1	1789	1789
33	Lundbeck	2	3527	1763
34	Millennium	1	1593	1593
35	Genentech	4	6277	1569
36	Allergan	1	1559	1559
37	Baxter	3	4627	1542
38	Ipsen	1	1459	1459
39	Forest	4	5184	1296
40	Cephalon	1	1221	1221
41	Onyx	1	1219	1219
42	Sepracor	1	1170	1170
43	Alcon	1	1133	1133
44	Theravance	1	1010	1010
45	Genzyme	5	4814	963
46	Shire	4	3827	957
47	Arena	1	934	934
48	Watson	1	930	930
49	Adolor	1	877	877
50	Valeant	1	844	844
51	Schwarz	2	1545	772
52	NPS	1	756	756
53	Regeneron	3	2149	716
54	Affymax	1	660	660
55	Seattle Genetics	1	610	610
56	CV Therapeutics	1	599	599
57	ImClone	1	517	517
58	Dendreon	1	509	509
59	Alexion	1	490	490
60	The Medicines Company	1	455	455
61	Ariad	1	444	444
62	OSI	1	402	402
63	Talecris	1	396	396
64	Progenics	1	356	356
65	Actelion	1	346	346
66	Savient	1	339	339
67	Praecis	1	311	311
68	Vivus	1	309	309
69	MGI	1	294	294
70	Vicuron	1	286	286
71	Salix	2	560	280
72	Idenix	1	280	280
73	Mylan	3	762	254
74	Discovery Laboratories	1	228	228
75	Indevus	1	222	222
76	Cubist	1	220	220
77	Acorda	1	185	185
78	Ista	1	171	171
79	Optimer	1	171	171
80	Theratechnologies	1	164	164
81	MediGene	1	155	155
82	Vanda	1	150	150
83	Eyetech	1	144	144
84	ThromboGenics	1	137	137
85	BioMarin	3	403	134
86	Protalix	1	125	125
87	Amarin	1	122	122
88	Insmed	1	118	118
89	NeurogesX	1	89	89
90	Hyperion	1	87	87
91	Cypress Bioscience	1	82	82
92	New River	1	79	79
93	Aegerion	1	74	74
94	Sucampo	1	62	62
95	Fibrocell	1	62	62
96	Tercica	1	49	49
97	Pharmion	1	47	47
98	Kamada	1	37	37
99	Lev	1	26	26
100	OMRIX	1	15	15

ATORVASTATIN SYNTHESIS

August 23, 2013 7:17 am / 15 Comments on ATORVASTATIN SYNTHESIS

atorvastatin

Atorvastatin (INN) /ə ˌ t ɔr v ə ˈ s t æ t ən /, marketed by Pfizer as a calcium salt under the trade name Lipitor,^[1] is a member of the drug class known as statins, used for lowering blood cholesterol. It also stabilizes plaque and prevents strokes through anti-inflammatory and other mechanisms. Like all statins, atorvastatin works by inhibitingHMG-CoA reductase, an enzyme found in liver tissue that plays a key role in production of cholesterol in the body.

Atorvastatin was first synthesized in 1985 by Bruce Roth of Parke-Davis Warner-Lambert Company (since acquired by Pfizer). The best selling drug in pharmaceutical history, sales of Lipitor since it was approved in 1996 exceed US$125 billion, and the drug has topped the list of best-selling branded pharmaceuticals in the world for nearly a decade.^[2] When Pfizer’s patent on Lipitor expired on November 30, 2011,^[3] generic atorvastatin became available in the United States, initially manufactured only by generic drugmakers Watson Pharmaceuticals and India’s Ranbaxy Laboratories. Prices for the generic version did not drop to the level of other generics—$10 or less for a month’s supply—until other manufacturers were able to supply the drug in May 2012.^[4]

	Atorvastatin calcium, YM-548, CI-981, Prevencor, Tahor, Lipibec, Torvast, Sortis, Lipitor
	(3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrol-1-yl]-3,5-dihydroxyheptanoic acid calcium salt (2:1)
	134523-03-8, 134523-00-5 (free acid), 110862-48-1 (free acid (R,R)-isomer)
	2-C33-H34-F-N2-O5.Ca
	1155.35
	Alzheimer’s Dementia, Treatment of , Cardiovascular Drugs, Cognition Disorders, Treatment of, Immunologic Neuromuscular Disorders, Treatment of, Lipoprotein Disorders, Treatment of , Metabolic Drugs, Multiple Sclerosis, Agents for, Neurologic Drugs, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors, TNFSF6 Expression Inhibitors
	Launched-1997
	Jouveinal (Originator), Pfizer (Originator), Almirall Prodesfarma (Licensee), Syncro (Licensee), Yamanouchi (Licensee), Stanford University (Codevelopment)

	SYNTHESISTrans-6-[2-(3- or 4-carboxamido-substd. pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis
	Roth, B.D. (Pfizer Inc.)
	EP 0247633; US 4681893

1) The condensation of 2-(1,3-dixolan-2-yl)ethylamine (I) with ethyl 2-bromo-2-(4-fluorophenyl)acetate (II) by means of triethylamine in acetonitrile gives ethyl 2-[2-(1,3-dioxolan-2-yl)ethylamino]-2-(4-fluorophenyl)acetate (III), which is acylated with isobutyryl chloride (IV) and triethylamine in dichloromethane yielding the corresponding amide (V). Saponification of the ester (V) with NaOH in methanol/water affords the free acid (VI), which is cyclized with N,3-diphenylpropynamide (VII) [obtained in the reaction of 3-phenylpropynoic acid (VIII) with aniline (IX) by means of dicyclohexylcarbodiimide (DCC)] by heating at 90 C in acetic anhydride giving 1-[2-(1,3-dioxolan-2-yl)ethyl]-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenylpyrrole-3-carboxamide (X). The hydrolysis of the dioxolane group of (X) with HCl yields the corresponding aldehyde (XI), which is condensed with methyl acetoacetate (XII) by means of NaH in THF affording 7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(N-phenylcarbamoyl)pyrrol-1-yl]-5-hydroxy-3-oxoheptanoic acid methyl ester (XIII). The reduction of the carbonyl group of (XIII) with tributylborane and NaBH4 in THF gives the (3R,5R)-dihydroxy ester (XIV), which is saponified with NaOH in water yielding the corresponding free acid (XV). The lactonization of (XV) by heating in refluxing toluene affords the (R,R)-lactone (XVI), which is submitted to optical resolution by reaction with (R)-1-phenylethylamine (XVII) followed by fractional crystallization thus obtaining the amide (XVII) as the pure (R,R,R)-enantiomer. The hydrolysis of the amide (XVIII) with NaOH, followed by heating in refluxing toluene gives the (R,R)-lactone (XIX), which is finally treated first with NaOH in methanol/water, and then with CaCl2 or calcium acetate.

“Pfizer product promotion page (Liptor)”. Retrieved 2011-12-05.
“Lipitor becomes world’s top-selling drug”. Crain’s New York Business. 2011-12-28.
CNN Wire Staff (November 30, 2011). “Lipitor loses patent, goes generic”. CNN. Retrieved November 18, 2012.
NeLM, June 2012: Price to UK National Health Service for 28 tablets from £3.25 (10mg) to £10.00 (80mg).
“Atorvastatin Calcium”. Drugs.com. Retrieved 3 April 2011.

External links

Atorvastatin bound to proteins in the PDB
Lipitor.com – manufacturer’s site
MedlinePlus Drug information: Atorvastatin (Systemic) – information from USP DI Advice for the Patient
U.S. National Library of Medicine: Drug Information Portal – Atorvastatin

	An improved synthesis of 1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, a key intermediate for atorvastatin synthesis
	Radl, S.; et al.
	Tetrahedron Lett 2002,43(11),2087

The 6-cyanohexanoic ester (VII), intermediate in the synthesis of 180072 (see intermediate (XLI) in scheme no. 18007204a) has been obtained as follows: the reaction of 1,6-heptadien-4-ol (I) with BuLi, CO2, and I2 in THF gives the cyclic carbonate (II), which is treated with Ts-OH in acetone to yield the acetonide (III). The reaction of the iodine atom of (III) with KCN in hot DMSO affords the nitrile (IV), which is oxidized at the terminal double bond with OsO4 and NaIO4, or O3 and Me2S, to provide the carbaldehyde (V). The oxidation of (V) with CrO3/H2SO4 in acetone gives the carboxylic acid (VI), which is finally esterified with tert-butanol by means of DCC and DMAP in dichloromethane, yielding the target ester intermediate (VII).

Lipitor industrial production shown below (TL, 1985, 2951; TL, 1992, 2279; 2283)

Divided into two fragments. Primary amine fragment iso-ascorbic acid as a starting material (stereoisomer of vitamin C) in the system. 1,4 – dione as a starting material isobutyrylacetanilide fragment, obtained by the Stetter reaction, the reaction of benzoin conjugated version Michael addition. Diketone related primary amine with a substituted pyrrole ring obtained five, after deprotection and salt formation Lipitor.

Atorvastatin of IC50-0.025μM, its RR configuration is as high IC50-0.007μM (SS configuration IC50-0.44μM).

Initially synthesized as shown above (JMC, 1991, 357).
Which polysubstituted pyrrole ring by the Munchnone of 1,3-dipolar [3 +2] cycloaddition get.

(atorvastatin), a part of statin (statins) a class of drugs.

Big boost for Incyte as Jakafi shines in PhII

August 23, 2013 3:30 am / Leave a comment

ruxolitinib

Top-line results from a Phase II trial showed that its JAK inhibitor Jakafi (ruxolitinib), in combination with Roche’s Xeloda (capecitabine), improved survival in some patients with recurrent or treatment refractory advanced pancreatic cancer

http://www.pharmatimes.com/Article/13-08-

22/Big_boost_for_Incyte_as_Jakafi_shines_in_PhII.aspx

Ruxolitinib (trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of bone marrow cancer.It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer), for polycythemia vera, and for plaque psoriasis.
The phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size, relieving debilitating symptoms, and improving overall survival.

Mechanism of action

Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.
Side effects

Immunologic side effects have included herpes zoster (1.9%) and case reports of opportunistic infections.[10] Metabolic side effects have included weight gain (7.1%). Laboratory abnormalities have included alanine transaminase (ALT) abnormalities (25.2%), aspartate transaminase (AST) abnormalities (17.4%), and elevated cholesterol levels (16.8%).
Legal status

In November 2011, ruxolitinib was approved by the USFDA for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials.

Some analysts believe this to be a potential blockbuster drug.[3] As of the end of March 2012, and according to an Incyte spokesman, approximately 1000 physicians had prescribed the drug in the United States, out of a total 6500 hematologists and oncologists nationwide.

The US Food and Drug Administration had approved Incyte’s Jakafi (ruxolitinib) to treat patients with the bone marrow disease myelofibrosis (MF). Jakafi is the first and only drug granted license specifically for the treatment of the rare blood cancer.

Jakafi approved by FDA to treat rare bone marrow disease

Posted By Edward Su On November 17th, 2011

MF is a rare, potentially life-threatening blood cancer with limited treatment methods. Patients with the bone marrow disoder, characterized by bone marrow failure, enlarged spleen (splenomegaly), suffer from the symptoms of fatigue, night sweats and pruritus, poor quality of life, weight loss and shortened survival. The US drug firm Incyte estimates the disease affects about 16,000-18,500 people in the USA. Currently, the disease is treated with chemotherapy or bone marrow transplant.

Incyte’s Jakafi, the first drug to reach market from the Wilmington-based drug company, was approved by the FDA as a twice-a-day pill for the treatment of patients with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF. The US regulators reviewed Jakafi under its priority review program for important new therapies.

The approval of Jakafi was based on the results from two clinical studies involved 528 patients with the disease. Patients in the Jakafi treatment arm experienced a significant reduction in the size of their spleen as well as a 50 percent decrease in symptoms, including pain, discomfort and night sweats.

Jakafi, generically known as ruxolitinib, works by blocking JAK1 and JAK2 enzymes associated with the disease. The company has co-developed the drug with Novartis as part of their collaboration signed in 2009. The Swiss drug firm has the rights to market Jakafi in other countries.

“The availability of Jakafi is a significant medical advancement for people living with myelofibrosis, a debilitating disease,” said Paul A. Friedman, M.D., President and Chief Executive Officer of Incyte. “This milestone marks a tremendous achievement for Incyte because a scientific discovery from our research laboratories has become the first JAK inhibitor to reach the market and provide a clinical benefit to patients.”

Richard Pazdur, director of the Office of Hematology and Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research, said that Jakafi “represents another example of an increasing trend in oncology where a detailed scientific understanding of the mechanisms of a disease allows a drug to be directed toward specific molecular pathways”.

Incyte says Jakafi will be available next week, and the drug will cost $7,000 per month, or $84,000 for a year’s supply for insured patients. The company plans to provide Jakafi free to uninsured patients and will offer co-pay assistance to patients with financial need.

(JAK1, JAK2) inhibitor, developed by the Incyte Corporation, trade name Jakafi.
Ruxolitinib synthetic route as shown below. 4 – bromo-pyrazole ( 1 ) with ethyl vinyl ether ( 2 ) to protect, and then with a Grignard reagent to a halogen – exchanged with isopropyl magnesiumpinacol ester ( 3 ) quenching to obtain 4 . Compound 5 is obtained consisting of hydrogen is protected 6 , and then with a boronic acid ester 4 Suzuki coupling occurs under acidic conditions after removal of the protecting group pyrazolyl 7 , 7 and α, β-unsaturated aldehyde 8 chiral catalyst 9 of under the catalysis of asymmetric Michael addition to give ( R ) -10 (90% EE). ( R) -10 , after reaction with ammonia to obtain an imine oxidation with iodine nitrile 11 , respectively, with different conditions for the final removal of the protecting group to afford Ruxolitinib.

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Tag Archives: PROCESS

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Mechanism

Uses

External links

The Madagascar Periwinkle

Vinblastine and Vincristine

Stereocontrolled total synthesis of (+)-vincristine

Isolation, purification and characterization of vinblastine and vincristine from the endophytic fungus Fusarium oxysporum

Share this:

Commercial preparations

Physicochemical properties

Share this:

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.

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

Valsartan

Structural formula

UV – Spectrum

IR – spectrum

References

An Improved Synthesis of Valsartan

Abstract

Share this:

Merck synthesis of Efavirenz

History

Chemical properties

History

Society and culture

Pricing information

PATENT

References

External links

Share this:

Indications

Formulation

Share this:

Dosage forms

Side effects

According to coverage of the study on WebMD:

Veterinary use

Partition Coefficient.

Gas Chromatography.

High Performance Liquid Chromatography.

Ultraviolet Spectrum.

Share this:

Share this:

Share this:

Further reading

External links

Share this:

Jakafi approved by FDA to treat rare bone marrow disease

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email

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