Jul 242014
 

Dedicated to all moms

C=O group is dad

 

O atom is mom

 

 

Carbonyl is dad and oxygen mom hence c labelled methyl has higher chemical shift  and gets a little more attention

SEE BELOW

NMR IS EASY

A chemical has Formula: C5H10O2

C5H10O2
Rule 2, omit O, gives C5H10
5 – 10/2 + 1 = 1 degree of unsaturation.
Look for 1 pi bond or aliphatic ring.

IR

IR spectrum

 

 

The band at 1740 indicates a carbonyl, probably a saturated aliphatic ester. The bands at 3000-2850 indicate C-H alkane stretches. The bands in the region 1320-1000 could be due to C-O stretch, consistent with an ester.

 

 

NMR spectrum

 Structure answer

Structure answerThis is the structure. See if you can assign the peaks on your own.

NMR answer

NMR answerC has a higher chemical shift than D because it’s closer to a more electron-withdrawing functional group.

Carbonyl is dad and oxygen mom,  hence c has higher chemical shift  and gets a little more attention in proton nmr

13 C NMR

Mass spectrum

 

RAMAN

 

 

 

WHAT HAPPENS WHEN A CHLORO IS INTRODUCED

 

 

 

WHEN THERE IS ONE METHYL

 

 

 

WHEN THERE ONE CH2 SHORT 

 

WHEN MOM HAS ONE MORE CH2

PROPYL PROPIONATE, try this on your own

Propyl propanoate.png

1H NMR

image of Propyl proprionate

 

 

image of Propyl proprionate

 

13C NMR

image of Propyl proprionate

 

APT

image of Propyl proprionate

 

COSY

image of Propyl proprionate

WILL PASTE INTERPRETATION AFTER ONE WEEK……………….

 

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Jul 242014
 

Dantrolene Tanaka et al.svg

Dantrolene sodium

1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione

 

FDA Approves Ryanodex for the Treatment of Malignant Hyperthermia

WOODCLIFF LAKE, N.J.(BUSINESS WIRE) July 23, 2014 — Eagle Pharmaceuticals, Inc. (“Eagle” or “the Company”) (Nasdaq:EGRX) today announced that the U. S. Food and Drug Administration (FDA) has approved Ryanodex (dantrolene sodium) for injectable suspension indicated for the treatment of malignant hyperthermia (MH), along with the appropriate supportive measures. MH is an inherited and potentially fatal disorder triggered by certain anesthesia agents in genetically susceptible individuals. FDA had designated Ryanodex as an Orphan Drug in August 2013. Eagle has been informed by the FDA that it will learn over the next four to six weeks if it has been granted the seven year Orphan Drug market exclusivity.

read at

http://www.drugs.com/newdrugs/fda-approves-ryanodex-malignant-hyperthermia-4058.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+July+23%2C+2014

 

Dantrium Intravenous is a sterile, non-pyrogenic, lyophilized formulation of dantrolene sodium for injection.

Dantrium Intravenous is supplied in 70 mL vials containing 20 mg dantrolene sodium, 3000 mg mannitol,

and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 mL sterile water for injection USP (without a bacteriostatic agent).

Dantrium is classified as a direct-acting skeletal muscle relaxant. Chemically, Dantrium is hydrated 1-[[[5-(4-nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione sodium salt. The structural formula for the hydrated salt is:

Dantrium<br /><br /><br /><br /><br /><br />
  (dantrolene sodium) Structural Formula Illustration

The hydrated salt contains approximately 15% water (3-1/2 moles) and has a molecular weight of 399. The anhydrous salt (dantrolene) has a molecular weight of 336.

 

 

Dantrolene
Dantrolene Tanaka et al.svg
Systematic (IUPAC) name
1-{[5-(4-nitrophenyl)-2-furyl]methylideneamino}
imidazolidine-2,4-dione
Clinical data
Trade names Dantrium
AHFS/Drugs.com monograph
Pregnancy cat. (US)
Legal status ?
Routes Oral, intravenous
Pharmacokinetic data
Bioavailability 70%
Metabolism Liver
Excretion Biliary, renal
Identifiers
CAS number 7261-97-4 Yes
ATC code M03CA01
PubChem CID 2952
IUPHAR ligand 4172
DrugBank DB01219
ChemSpider 2847 Yes
UNII F64QU97QCR Yes
KEGG D02347 
ChEBI CHEBI:4317 Yes
ChEMBL CHEMBL1201288 
Chemical data
Formula C14H10N4O5 
Mol. mass 314.253 g/mol

Dantrolene sodium is a muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells, probably by action on the ryanodine receptor. It is the only specific and effective treatment for malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia. It is also used in the management of neuroleptic malignant syndrome, muscle spasticity (e.g. afterstrokes, in paraplegiacerebral palsy, or patients with multiple sclerosis), 3,4-methylenedioxymethamphetamine (“ecstasy”)intoxication, serotonin syndrome, and 2,4-dinitrophenol poisoning.[1] It is marketed by JHP Pharmaceuticals LLC as Dantrium (in North America) and by Norgine BV as Dantrium, Dantamacrin, or Dantrolen (in Europe).

History

Dantrolene was first described in the scientific literature in 1967, as one of several hydantoin derivatives proposed as a new class of muscle relaxant.[2] Dantrolene underwent extensive further development, and its action on skeletal muscle was described in detail in 1973.[3]

Dantrolene was widely used in the management of spasticity before its efficacy in treating malignant hyperthermia was discovered by South African anesthesiologist Gaisford Harrison and reported in a landmark 1975 article published in the British Journal of Anaesthesia.[4] Harrison experimentally induced malignant hyperthermia with halothane anesthesia in genetically susceptible pigs, and obtained an 87.5% survival rate, where seven of his eight experiments survived after intravenous administration of dantrolene. The efficacy of dantrolene in humans was later confirmed in a large, multicenter study published in 1982,[5] and confirmed epidemiologically in 1993.[6] Before dantrolene, the only available treatment for malignant hyperthermia was procaine, which was associated with a 60% mortality rate in animal models.[4]

JULY 2014

The US Food and Drug Administration (FDA) has approved an injectable form of dantrolene sodium (Ryanodex, Eagle Pharmaceuticals) for rapid treatment of malignant hyperthermia (MH), along with the appropriate supportive measures, the company announced in a news release today.

MH is a potentially fatal inherited disorder triggered by exposure to certain drugs used for general anesthesia, including the neuromuscular blocking agent succinylcholine.

Ryanodex — which can be administered much more quickly than current formulations of dantrolene — is the first significant enhancement to MH treatment options in more than 3 decades, according to the company.

Ryanodex will be available in single-use vials containing 250 mg of dantrolene sodium in lyophilized powder form. It is formulated for rapid reconstitution and administration in less than 1 minute to patients in MH crisis. “Ryanodex should be administered by continuous rapid intravenous push beginning with a loading dose of 2.5 mg/kg, and continuing until symptoms subside,” the company says.

Ryanodex allows anesthesiologists to deliver a therapeutic dose of dantrolene sodium in a much more expedient manner than currently possible with existing IV formulations of dantrolene sodium, “potentially saving lives and reducing MH-related morbidity,” according to the company.

Other dantrolene sodium formulations require multiple 20-mg vials reconstituted in large volumes of sterile water, a process that can take 15 to 20 minutes to mix reconstitute and administer, the company notes.

MH during surgery is a “life-threatening emergency requiring immediate treatment including the administration of the ‘antidote’ drug dantrolene sodium,” Henry Rosenberg, MD, CPE, a founder and president of the Malignant Hyperthermia Association of the United States, said in the release.

“The ability for healthcare professionals in hospitals and surgery centers to more quickly prepare and administer this new formulation of the antidote dantrolene sodium is expected to bring the crisis under control more rapidly and prevent severe complications from MH,” he said.

The FDA granted Ryanodex orphan drug status in August 2013 and priority review status in March 2014.Ryanodex will be available to order through national and regional drug wholesalers in August with product shipping shortly after. More information is available at http://www.ryanodex.com/.

 

Contraindications

Oral dantrolene cannot be used by:

  • people with a pre-existing liver disease
  • people with compromised lung function
  • people with severe cardiovascular impairment
  • people with a known hypersensitivity to dantrolene
  • pediatric patients under five years of age
  • people who need good muscular balance or strength to maintain an upright position, motoric function, or proper neuromuscular balance

If the indication is a medical emergency, such as malignant hyperthermia, the only significant contraindication is hypersensitivity.

Pregnancy and breastfeeding

If needed in pregnancy, adequate human studies are lacking, therefore the drug should be given in pregnant women only if clearly indicated. It may cause hypotonia in the newborn if given closely before delivery.[1]

Dantrolene should not be given to breastfeeding mothers. If a treatment is necessary, breastfeeding should be terminated.

Adverse effects

Central nervous system side effects are quite frequently noted and encompass speech and visual disturbances, mental depression and confusion, hallucinations, headache, insomnia and exacerbation or precipitation of seizures, and increased nervousness. Infrequent cases of respiratory depression or a feeling of suffocation have been observed. Dantrolene often causes sedation severe enough to incapacitate the patient to drive or operate machinery.

Gastrointestinal effects include bad taste, anorexia, nausea, vomiting, abdominal cramps, and diarrhea.

Hepatic side effects may be seen either as asymptomatic elevation of liver enzymes and/or bilirubin or, most severe, as fatal and nonfatal hepatitis. The risk of hepatitis is associated with the duration of treatment and the daily dose. In patients treated for hyperthermia, no liver toxicity has been observed so far.

Pleural effusion with pericarditis (oral treatment only), rare cases of bone marrow damage, diffuse myalgias, backache, dermatologic reactions, transient cardiovascular reactions, and crystalluria have additionally been seen. Muscle weakness may persist for several days following treatment.

Mutagenicity and carcinogenity

Dantrolene gave positive results in animal high dose studies (with and without enzymatic activation) regarding mutagenicity and carcinogenity. No evidence for human mutagenicity and carcinogenity has been found during the long years of clinical experience.

Mechanism of action

Dantrolene depresses excitation-contraction coupling in skeletal muscle by binding to the ryanodine receptor, and decreasing free intracellular calcium concentration.[1]

Chemistry

Skeletal formula of azumolene. The bromine atom replacing the nitro group found in dantrolene may be seen at left.

Chemically it is a hydantoin derivative, but does not exhibit antiepileptic activity like other hydantoin derivates such as phenytoin.[1]

The poor water solubility of dantrolene leads to certain difficulties in its use.[1][7] A more water-soluble analog of dantrolene, azumolene, is under development for similar indications.[7] Azumolene has a bromine residue instead of the nitro group found in dantrolene, and is 30 times more water-soluble.[1]

…………………………………………….

Bioorganic and medicinal chemistry letters, 2002 ,  vol. 12,   22  p. 3263 – 3265

http://www.google.co.in/patents/US4543359

 

…………………………………………………………………………………………………

US4543359

http://www.google.co.in/patents/US4543359

 

 

Dantrolene sodium (1-[[5-(p-nitrophenyl) furfurylidene]-amino]hydantoin sodium salt) is described in U.S. Pat. No. 3,415,821. It is used as a skeletal muscle relaxant particularly in controlling the manifestations of clinical spasticity resulting from upper neuron disorders (Physicians’ Desk Reference, 36th Edition, 1982). It is also used in the prevention and treatment of malignant hyperthermia in humans (Friesen et al., Can. Anaesth. Soc. J. 26:319-321, 1979). In connection with the use of dantrolene sodium in hyperthermic crisis it was observed that there was an elimination of the arrhythmias accompanying such crisis [Salata et al., Effects of Dantrolene Sodium on the Electrophysiological Properties of Canine Cardiac Purkinje Fibers, J. Pharmacol. Exp. Ther. 220(1):157-166 (Jan.) 1982] incorporated herein by reference.

………………………………………….

 

 

 

Drug interactions

Dantrolene may interact with the following drugs:[8]

References

  1.  Krause T, Gerbershagen MU, Fiege M, Weisshorn R, Wappler F (2004). “Dantrolene – a review of its pharmacology, therapeutic use and new developments”Anaesthesia 59(4): 364–73. doi:10.1111/j.1365-2044.2004.03658.xPMID 15023108.
  2.  Snyder HR, Davis CS, Bickerton RK, Halliday RP (September 1967). “1-[(5-arylfurfurylidene)amino]hydantoins. A new class of muscle relaxants”. J Med Chem 10 (5): 807–10.doi:10.1021/jm00317a011PMID 6048486.
  3.  Ellis KO, Castellion AW, Honkomp LJ, Wessels FL, Carpenter JE, Halliday RP (June 1973). “Dantrolene, a direct acting skeletal muscle relaxant”. J Pharm Sci 62 (6): 948–51.doi:10.1002/jps.2600620619PMID 4712630.
  4.  Harrison GG (January 1975). “Control of the malignant hyperpyrexic syndrome in MHS swine by dantrolene sodium”. Br J Anaesth 47 (1): 62–5. doi:10.1093/bja/47.1.62.PMID 1148076. A reprint of the article, which became a “Citation Classic”, is available in Br J Anaesth 81 (4): 626–9. PMID 9924249 (free full text).
  5.  Kolb ME, Horne ML, Martz R (April 1982). “Dantrolene in human malignant hyperthermia”. Anesthesiology 56 (4): 254–62. doi:10.1097/00000542-198204000-00005PMID 7039419.
  6.  Strazis KP, Fox AW (March 1993). “Malignant hyperthermia: review of published cases”. Anesth Analg 77 (3): 297–304. doi:10.1213/00000539-199377020-00014.
  7.  Sudo RT, Carmo PL, Trachez MM, Zapata-Sudo G (March 2008). “Effects of azumolene on normal and malignant hyperthermia-susceptible skeletal muscle”. Basic Clin Pharmacol Toxicol 102 (3): 308–16. doi:10.1111/j.1742-7843.2007.00156.xPMID 18047479.
  8.  “Dantrolene Drug Interactions”Epocrates Online. Epocrates. 2008. Retrieved on December 31, 2008.

External links

 

Reference
1 * Dissertation Abstracts International, 42(4), 1337 B, (1981), Malloy, K., PH.D. Thesis, 1981 .
2 Dissertation Abstracts International, 42(4), 1337-B, (1981), [Malloy, K., PH.D. Thesis, 1981].
3 * Dissertation Abstracts International, 42(8), 3222 B, (1982), Salata, J., Ph.D. Thesis, 1981 .
4 Dissertation Abstracts International, 42(8), 3222-B, (1982), [Salata, J., Ph.D. Thesis, 1981].
5 * Malloy, K., Ph.D. Thesis, Univ. of Rochester, 1981.
6 * Salata, J. et al., J. Pharmacol. Exp. Ther., 220(1), 157 166, (1982).
7 Salata, J. et al., J. Pharmacol. Exp. Ther., 220(1), 157-166, (1982).
Citing Patent Filing date Publication date Applicant Title
US4822629 * 12 Dec 1986 18 Apr 1989 Norwich Eaton Pharmaceuticals, Inc. Azumolene dosage form
US4837163 * 2 Oct 1987 6 Jun 1989 Tsuyoshi Ohnishi Simple blood test for diagnosing malignant hyperthermia
US4861790 * 28 Oct 1987 29 Aug 1989 Norwich Eaton Pharmaceuticals, Inc. Use of azumolene for the treatment of malignant hyperthermia
US5462940 * 3 Jun 1994 31 Oct 1995 Norwich Eaton Pharmaceuticals, Inc. 4-oxocyclic ureas useful as antiarrhythmic and antifibrillatory agents
US5691369 * 7 Jun 1995 25 Nov 1997 The Proctor & Gamble Company Cardiovascular disorders
US5994354 * 7 Jun 1995 30 Nov 1999 The Procter & Gamble Company Cyclic urethanes useful as antiarrhythmic and antifibrillatory agents
US7758890 1 Mar 2004 20 Jul 2010 Lyotropic Therapeutics, Inc. Treatment using dantrolene
US8110225 4 Mar 2010 7 Feb 2012 Lyotropic Therapeutics, Inc. Treatment using dantrolene
US8604072 19 Jan 2012 10 Dec 2013 Lyotropic Therapeutics, Inc. Treatment using dantrolene
US8685460 19 Jan 2012 1 Apr 2014 Lyotropic Therapeutics, Inc Treatment using dantrolene
EP2583670A1 5 Sep 2008 24 Apr 2013 US Worldmeds LLC Co-solvent compositions and methods for improved delivery of dantrolene therapeutic agents
WO2005013919A2 * 1 Mar 2004 17 Feb 2005 Lyotropic Therapeutics Inc Treatment using dantrolene

 

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Jul 232014
 

Granulation is the act or process of forming or crystallizing into grains.[1] Granules typically have a size range between 0.2 to 4.0 mm depending on their subsequent use.

Synonym “Agglomeration”: Agglomeration processes or in a more general term particle size enlargement technologies are great tools to modify product properties. Agglomeration of powders is widely used to improve physical properties like: wettability, flowability, bulk density and product appearance.

 

 

Chemical industry

Granulation

In the chemical industry, granulation refers to the act or process in which large objects are cut or shredded and remelted into granules or pellets.

Pharmaceutical industry

In the pharmaceutical industry, granulation refers to the act or process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. It is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation is extensively used in the manufacturing of tablets and pellets (or spheroids).

The granulation process combines one or more powder particles and forms a granule that will allow tableting or spheronization process to be within required limits. This way predictable and repeatable process is possible and quality tablets or pellets can be produced using tabletting or spheronization equipment.

Purpose

Granulation is carried out for various reasons, one of those is to prevent the segregation of the constituents of powder mix. Segregation is due to differences in the size or density of the component of the mix. Normally, the smaller and/or denser particles tend to concentrate at the base of the container with the larger and/or less dense ones on the top. An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule and segregation of granules will not occur.

Many powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well. Granules produced from such a cohesive system will be larger and more isodiametric, both factors contributing to improved flow properties.

Some powders are difficult to compact even if a readily compactable adhesive is included in the mix, but granules of the same powders are often more easily compacted. This is associated with the distribution of the adhesive within the granule and is a function of the method employed to produce the granule.

For example, if one were to make tablets from granulated sugar versus powdered sugar, powdered sugar would be difficult to compress into a tablet and granulated sugar would be easy to compress. Powdered sugar’s small particles have poor flow and compression characteristics. These small particles would have to be compressed very slowly for a long period of time to make a worthwhile tablet. Unless the powdered sugar is granulated, it could not efficiently be made into a tablet that has good tablet characteristics such as uniform content or consistent hardness.

Granulation techniques

In pharmaceutical industry, two types of granulation technologies are employed, namely, wet granulation and dry granulation.

Wet granulation

In wet granulation, granules are formed by the addition of a granulation liquid onto a powder bed which is under the influence of an impeller (in a High shear granulator, screws (in a twin screw granulator) [2] or air (in a fluidized bed granulator). The agitation resulting in the system along with the wetting of the components within the formulation results in the aggregation of the primary powder particles to produce wet granules.[2] The granulation liquid (fluid) contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include waterethanol and isopropanol either alone or in combination. The liquid solution can be either aqueous based or solvent based. Aqueous solutions have the advantage of being safer to deal with than solvents.

Water mixed into the powders can form bonds between powder particles that are strong enough to lock them together. However, once the water dries, the powders may fall apart. Therefore, water may not be strong enough to create and hold a bond. In such instances, a liquid solution that includes a binder (pharmaceutical glue) is required. Povidone, which is a polyvinyl pyrrolidone (PVP), is one of the most commonly used pharmaceutical binders. PVP is dissolved in water or solvent and added to the process. When PVP and a solvent/water are mixed with powders, PVP forms a bond with the powders during the process, and the solvent/water evaporates (dries). Once the solvent/water has been dried and the powders have formed a more densely held mass, then the granulation is milled. This process results in the formation of granules.

The process can be very simple or very complex depending on the characteristics of the powders, the final objective of tablet making, and the equipment that is available. In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which is subsequently dried.

Dry granulation

The dry granulation process is used to form granules without using a liquid solution because the product granulated may be sensitive to moisture and heat. Forming granules without moisture requires compacting and densifying the powders. In this process the primary powder particles are aggregated under high pressure. Sweying granulator or high shear mixer-granulator can be used for the dry granulation.

Dry granulation can be conducted under two processes; either a large tablet (slug) is produced in a heavy duty tabletting press or the powder is squeezed between two counter-rotating rollers to produce a continuous sheet or ribbon of materials (roller compactor, commonly referred to as a chilsonator).

When a tablet press is used for dry granulation, the powders may not possess enough natural flow to feed the product uniformly into the die cavity, resulting in varying degrees of densification. The roller compactor (granulator-compactor) uses an auger-feed system that will consistently deliver powder uniformly between two pressure rollers. The powders are compacted into a ribbon or small pellets between these rollers and milled through a low-shear mill. When the product is compacted properly, then it can be passed through a mill and final blend before tablet compression.

See also

[3]

References

  1.  Granulation definition
  2. Jump up to:a b Dhenge, Ranjit M.; Washino, Kimiaki; Cartwright, James J.; Hounslow, Michael J.; Salman, Agba D. (2012). “Twin screw granulation using conveying screws: Effects of viscosity of granulation liquids and flow of powders”. Powder Technologydoi:10.1016/j.powtec.2012.05.045.
  3.  Osborne, James; T. Althaus; L. Forny; G.Neideiretter; S.Palzer; M.Hounslow; A.D. Salman (2013). “Bonding Mechanisms Involved in the Roller Compaction of an Amorphous Material”.Chemical Engineering Science 86 (5th International Granulation Workshop): 61–69. doi:10.1016/j.ces.2012.05.012.
  • Pharmaceutics – The science of dosage form design – M. E. Aulton 2nd EDT
  • Pharmaceutical dosage forms and drug delivery system – Loyd V. Allen, Nicholas G. Popovich & Howard C. Ansel 8th EDT
  • Lachman leon, Industrial pharmacy, special indian edition, CBS publishers

External links

READ

March 2014, Volume 9, Issue 1, pp 16-37

Closed-Loop Feedback Control of a Continuous Pharmaceutical Tablet Manufacturing Process via Wet Granulation

http://link.springer.com/article/10.1007/s12247-014-9170-9

Abstract

The wet granulation route of tablet manufacturing in a pharmaceutical manufacturing process is very common due to its numerous processing advantages such as enhanced powder flow and decreased segregation. However, this route is still operated in batch mode with little (if any) usage of an automatic control system. Tablet manufacturing via wet granulation, integrated with online/inline real time sensors and coupled with an automatic feedback control system, is highly desired for the transition of the pharmaceutical industry toward quality by design as opposed to quality by testing. In this manuscript, an efficient, plant-wide control strategy for an integrated continuous pharmaceutical tablet manufacturing process via wet granulation has been designed in silico. An effective controller parameter tuning strategy involving an integral of time absolute error method coupled with an optimization strategy has been used. The designed control system has been implemented in a flowsheet model that was simulated in gPROMS (Process System Enterprise) to evaluate its performance. The ability of the control system to reject the unknown disturbances and track the set point has been analyzed. Advanced techniques such as anti-windup and scale-up factor have been used to improve controller performance. Results demonstrate enhanced achievement of critical quality attributes under closed-loop operation, thus illustrating the potential of closed-loop feedback control in improving pharmaceutical tablet manufacturing operations.

……. CASE STUDY

http://www.madehow.com/Volume-4/Birth-Control-Pill.html

Oral contraceptives, or birth control pills, have been used by more than 60 million women worldwide, and are considered by many to be the most socially significant medical advance of the twentieth century. The birth control pill is a tablet taken daily by a woman to prevent pregnancy. The birth control pill does this by inhibiting the development of the egg in the woman’s ovary during her monthly menstrual cycle. During a woman’s menstrual cycle, a low estrogen level normally triggers the pituitary gland to send out a hormone that initiates development of an egg. The birth control pill releases enough synthetic estrogen to keep that hormone from being released during the monthly cycle.
Using a process known as the wet granulation method, the active ingredients are mixed together with a dilutant and a disintegrant in a large mixer. Once mixed, the powder mass is forced through a mesh screen.

Using a process known as the wet granulation method, the active ingredients are mixed together with a dilutant and a disintegrant in a large mixer. Once mixed, the powder mass is forced through a mesh screen.

A part is pasted.  article talks of manufacturing process

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Jul 232014
 

 

Place your arrow on above structure of Ethyl acetate………………It will flash

see label A,B,C

Integration in NMR

The intensity of the signal is proportional to the number of hydrogens that make the signal. Sometimes, NMR machines display signal intensity as an automatic display above the regular spectrum. (The exact number of hydrogens giving rise to each signal is sometimes also explicitly written above each peak, making our job a lot easier.) The intensity of the signal allows us to conclude that the more hydrogens there are in the same chemical environment, the more intense the signal will be.

Introduction

We can get the following information from a 1H Nuclear Magnetic Resonance (NMR) structure:

  1. The number of signals gives the number of non-equivalent hydrogens
  2. Chemical shifts show differences in the hydrogens’ chemical environments
  3. Splitting presents the number of neighboring hydrogens (N+1 rule)
  4. Integration gives the relative number of hydrogens present at each signal

The integrated intensity of a signal in a 1H NMR spectrum (does not apply to 13C NMR) gives a ratio for the number of hydrogens that give rise to the signal, thereby helping calculate the total number of hydrogens present in a sample.NMR machines can be used to measure signal intensity, a plot of which is sometimes automatically displayed above the regular spectrum. To show these integrations, a recorder pen marks a vertical line with a length that is proportional to the integrated area under a signal (sometimes referred to as a peak)– a value that is proportional to the number of hydrogens that are accountable for the signal. The pen then moves horizontally until another signal is reached, at which point, another vertical marking is made. We can manually measure the lengths by which the horizontal line is displaced at each peak to attain a ratio of hydrogens from the various signals. We can use this technique to figure out the hydrogen ratio when the number of hydrogens responsible for each signal is not written directly above the peak (look in the links section for an animation on how to manually find the ratio of hydrogens as described here).

 

 

 

 

 

 

Now that we’ve seen how the signal intensity is directly proportionate to the number of hydrogens that give rise to that signal, it makes sense to conclude that the more hydrogens of one kind there are in a molecule (equivalent hydrogens, so in the same chemical environment), the more intense the corresponding NMR signal will be. Here’s above  a model that may help clear up some of the uncertainties. 

Problems

1.) True or False? The number of hydrogens determines the intensity of a signal.

 

ans…………False. The relative number of hydrogens determines the intensity of a signal. The signal given by the three hydrogens in CH3CH2CHCl2 will not have the same intensity as the three hydrogens in ClCH2OCH3.

2.) Give the number of signals, the chemical shift value for each signal, and the number of integrating hydrogens for   CH3OCH2CH2OCH3

answer There are 2 signals. One is at 3.3 ppm (6 hydrogens); the other at 3.5 ppm (4 hydrogens).

3

 

 

 

4.) scan0002.jpganswer is a and d

 scan0004.jpg

answer is c

Answers

  1. False. The relative number of hydrogens determines the intensity of a signal. The signal given by the three hydrogens in CH3CH2CHCl2 will not have the same intensity as the three hydrogens in ClCH2OCH3.
  2. There are 2 signals. One is at 3.3 ppm (6 hydrogens); the other at 3.5 ppm (4 hydrogens).
  3. a and d
  4. c

Number of Different Hydrogens

 

Ethyl acetate contains 8 hydrogens and some of them are different from each other. 

For example, those labeled A are attached to a carbon bonded to a carbonyl group and are different from the hydrogens labeled which are bonded to a carbon attached to an oxygen atom.

 

You can check whether certain hydrogens are the same or equivalent by replacing each hydrogen with some group X and seeing if you generate the same compound. You should convince yourself that replacing each hydrogen labeled A by X gives you identical compounds which are all equivalent by a C-C bond rotation. If this is difficult to “see” look at this molecular model of ethyl acetate to see if you can convince yourself that all the hydrogens labeled A are the same.

Integration

The area under the NMR resonance is proportional to the number of hydrogens which that resonance represents. In this way, by measuring or integrating the different NMR resonances, information regarding the relative numbers of chemically distinct hydrogens can be found. Experimentally, the integrals will appear as a line over the NMR spectrum.Integration only gives information on the relative number of different hydrogens, not the absolute number. 

 

 


 

 Review Questions

For ethyl acetate,
What ratio would you expect to see for the integrals for the hydrogens labeled A:B:C?

3-2-3
For ethyl ether,
What ratio would you expect to see for the integrals for the hydrogens labeled A:B?3-2
For t-butyl acetate,
What ratio would you expect to see for the integrals for the hydrogens labeled A:B:C?

6-2-3

ratio

2 3 3

or

4 6 6

Outside Links

References

  1. Schore, Neil E. and Vollhardt, K. Peter C. Organic Chemistry: Structure and Function. New York: Bleyer, Brennan, 2007. (405-407)
  2. UC Davis 118A Supplementary Booklet for the Laboratory/Discussion (Fall quarter 2008)_ Page 39

 

 

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Jul 222014
 

 

 

Formula: C5H10O

C5H10O
Rule 2, omit O, gives C5H10
5 – 10/2 + 1 = 1 degree of unsaturation.
Look for 1 pi bond or aliphatic ring.

IR spectrum

The band at 1727 indicates a carbonyl, probably an aldehyde; an aldehyde is also suggested by the band at 2719 which is likely the C-H stretch of the H-C=O group. The bands at 3000-2850 indicate C-H alkane stretches.

 

 

 

NMR spectrum

 

Structure answern

 

NMR answer

 

Proton NMR Spectrum

Since the IR spectrum indicates an aldehyde, look for this functionality in the NMR spectrum. The aldehydic proton appears in the NMR from 9-10, usually as a small singlet.

The spectrum above shows a small singlet corresponding to one proton at 9.2 ppm, confirming that the compound is an aldehyde. Protons on the carbon adjacent to the aldehyde carbonyl will show up at 2-2.7 ppm; this is the triplet peak of 2 protons at 2.4 ppm on the above spectrum. Thus, so far we know that there is an aldehyde group next to a methylene group which is next to a carbon that has two hydrogens:

This accounts for 3 of the 5 carbons in the molecule. The un-colored hydrogens in the above structure could correspond to the peak of 2 hydrogens centered at 1.6 ppm; this peak is a pentet indicating that these protons are adjacent to carbons with a total of 4 hydrogens. The peak centered at 1.35 ppm has two hydrogens and is a sextet, indicating it is next to carbons that have a total of 5 hydrogens. Finally, the peak at 0.9 ppm has 3 hydrogens and is a triplet, indicating it is a methyl group adjacent to a carbon that has 2 hydrogens. Therefore, it looks like the molecule is a straight-chain of 5 carbons with the aldehyde group at one end:

Note that the closer a group is to the carbonyl function, the further downfield it is shifted. Here is how the NMR correlates to the structure:

MASS SPECTRUM

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Jul 222014
 

Structure of simian virus very similar to human. / SUPERSTOCK / AGE FOTOSTOCK

Three days is what it takes for the virus simian immunodeficiency (SIV), the most similar to HIV, to reach reservoirs (cells in which it is to siemrpe) microorganism. The measurement, which made ​​scientific accuracy of Beth Israel Deaconess Medical Center in Boston, is key to preventing the affected macaque becomes a carrier for life VIS. The study sheds light on what happens in humans with HIV, and explains some of the latest achievements and disappointments that research has this infectious agent in recent years. The work is published in the latest edition ofNature.

READ AT

http://sociedad.elpais.com/sociedad/2014/07/20/actualidad/1405875909_623856.html

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Jul 212014
 
09229-notw8-strucs

An enantioselective oxidative reaction produces optically active chromanols, which can then be made into tocopherols and related compounds.

read at

http://cen.acs.org/articles/92/i29/GreenRoute-Chromanols.html

‘Green’ Route To Chromanols

Organic Chemistry: Organocatalysis creates tocopherol’s chiral core.

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Jul 202014
 

- the reduction of carbonyl compounds is one of the most important synthetic reactions

- the catalytic enantioselective reduction of C=O has been achieved using:

* chiral oxazaborolidines and other related boronates (H3B as a source of hydrogen)

here is an example

* transition metal catalysts (H2 as a source of hydrogen)

here is an example

 

- first described by Itsuno et al. who observed that valinol reacts with 1 mol eq. of borane by producing 1 ml eq. of hydrogen gas and giving rise to the alkoxyborane derivative shown below:

here is an example

- the aminoalkoxyborane derivatives (A and B) shown below are a result of the reaction of valinol with 2 eq. of borane (producing 2 mol eq. of hydrogen gas)

here is an example

- the resulting aminoalkoxyborane (A or B) was found to catalyze the enantioselective reduction of PhCOMe

- the optical yield of the reduction was found to depend on the relative amounts of valinol and borane

here is an example

- maximum optical yeild is reached with a borane-valinol ratio of 2.0

- the optical yeild remains almost constant within the borane-valinol ratio range of 2.0-3.0

- Itsuno et al. observed significantly higher optical yeilds when the hydrogens attached to the carbon atom of the terminal hydroxyl group were replaced by bulky groups, such as phenyls

here is an example

- in the case of ketones other than aromatic ones optical yeilds were lower

here is an example

here is an example

- the optical yeild increases with the increasing difference in the volume of the substituents of the ketone

- an unusual relation between the optical yeild and reaction temperature was observed (studied by Itsuno et al. using methyl-tert-butyl ketone as a test system)

here is an example

- the catalyst was found to work with more efficiency near 0 °C than at -78 °C

- reductions of functionalized ketones were studied

here is an example

Other related reductions: (by Itsuno et al.)

here is an example

- best optical yeilds were observed in the case of halohydrin formation

- the halohydrins were converted to form optically active epoxides without rasemization

here is an example

- the reduction works best with chlorinated acetophenones

- two years latter Corey et al. developed the ideas of Itsuno et al. further and described a new and better catalyst (an oxazaborolidine derived from diphenylprolinol)

here is an example

here is an example

- the oxazaborolidine derived from diphenylprolinol gave better enantioselectivities for arylalkyl ketones than diphenylvalinol based derivatives

- Corey et al. proposed a mechanism for the catalytic reduction

here is an example

  

- proline based oxazaborolidines are also known as CBS (Corey,Bakshi,Shibata) catalysts

- the better performance of CBS catalysts, relative to the performance of valinol-based catalysts, was related (by Corey et al.) to the higher angle strain on the partial B=N double bond at the 5,5-ring fusion

here is an example

- the angle strain disturbs PI-resonance (A) and exposes the lone pair of the nitrogen atom (B) for borane to coordinate

here is an example

- in THF (needed to stabilize highly polar reactive intermediates) the borane atom is not totally coordinated to the catalyst:

here is an example

- the bicyclic (CBS) catalyst is capable of binding the borane more tightly than the related monocyclic system

- the more strained the B-N bond, the higher the proportion of catalyst present as a borane complex (ready to operate as a chiral catalyst)

- computational studies on the CBS catalyst indicate that not all atoms adjacent to the borane and nitrogen atoms of the partial B=N bond lie in the same plane (for the related torsion angles at 0 °C/180 °C +/- 22 °C see THA 3,1563(1992))

- similar distortions were not observed with monocyclic oxazaborolidines

- the rigidity of the structure of CBS catalysts would also orient the borane to coordinate selectively on one of the faces of the oxazaborolidine ring

- coordination on the faces would involve:

* an attack on the less hindered side of the ring system (kinetic control)

here is an example

* the formation of a 5,5,-cis-fused ring system is favoured over that of the highly strained 5,5-trans-fused system (thermodynamic control)

here is an example

 

- in the formation of borane adducts of CBS catalysts only one adduct (lowering angle strain) is formed selectively

- other isomers of borane-oxazaborolidine adducts have also been considered, e.g.

here is an example

- the system containing a hydride-bridged 6-ring was found to be more stable than the other diborane adducts

- the formation of hydride-bridged adducts indicates that the hydrogens of borons “scramble” in a mixture of borane and oxazaborolidine(s)

- this hydrogen – deuterium exchange “scrambling” has been observed experimentally [Tlahuext and Contreras, THA 5, 395 (1994)]

here is an example

- an X-ray study on a borane adduct of a CBS catalyst (a B-methylated derivative) proves that the borane atom coordinates to the nitrogen atom

- the X-ray structure of the N-adduct proves that the formation of N-adducts is possible and probably even favoured over the other adducts; nevertheless, the involvement of borane O-adducts of oxazaborolidines (as reactive intermediates) cannot completely be ruled out

- the mechanism of catalysis in the case of monocyclic systems has been proposed to be controlled by factors partially different from those controlling CBS catalysis

- the selectivity of the formation of borane cis/trans-adducts of monocyclic oxazaborolidines (e.g. those derived from valinols) has been calculated to be too low to fit the experimentally observed enantioselectivities, e.g. in the case of the simple model shown below:

here is an example

- computational studies on simple models imply that the next step in the mechanistic cycle of catalysis should show significant selectivity

here is an example

…………

 

 

- one of the most significant consequences of the N-coordination of borane to an oxazaborolidine is the substantially enhanced acidity of the ring boron [intramolecular stabilization through the partial PI-bond between the boron and adjacent nitrogen atom is not possible in the N-adduct]

- computational studies on the formation of N-O- and N,O-(di)adducts (related to LUMO energies) imply that the parent oxazaborolidine is the weakest Lewis acid (highest LUMO energy), the borane N,O-diadduct being the strongest (lowest LUMO energy)

here is an example

- the more the borane coordinates to the N- and O- atoms of an oxazaborolidine ring the less the ring boron is stabilized by partial PI-bonding

here is an example

- not only are there differences in the Lewis acidities of the borane N- and O-adducts, but there are also many possible orientations from which a Lewis base (in this case a ketone) can best approach the ring boron

here is an example

- in the case of borane N-adducts the orientation of the dipole moment favours the coordination of ketones

- in the case of borane O-adducts the orientation of the dipole moment is not particularly favourable; the incoming Lewis base has to approach the ring boron in the plane of the ring (this inhibits binding)!

- the orientation of the dipole moment of the borane N-adduct of the parent oxazaborolidine implies that the ketone (or any Lewis base) could react to form a borane-ketone cis-adduct

- the 5,5-diphenyl substituents direct the ketone to favour the anti-conformation over the syn-conformation (see the figure below)

here is an example

- the structures of both the syn- and anti-adducts a borane-formaldehyde complex coordinating to the parent oxazaborolidine have been generated and assessed using computational methods

- these simple models, extended with two phenyl groups on C-5 of the oxazaborolidine ring (the orientations of the phenyls were set on the basis of the orientations of the corresponding hydrogens), show how hindered the syn-conformation is in the case of oxazaborolidines bearing bulky substituents on C-5

here is an example

- plausible conformations of both the anti- and syn-adducts and the related transition states of the hydride transfer have been studied computationally

here is an example

- the hydride transfer taking place in the borane-ketone adducts of oxazaborolidines has been proposed to lead to the formation of an intramolecular adduct of an alkoxyborane, which in turn results in the formation of an aminoborane (A)

- the aminoborane can react further to form an oxazadiboretane (structure B)

here is an example

- the oxazaboretane system (B) may undergo a number of reactions, one of which leads to the regeneration of the catalyst, whereas another leads to the formation of an alkoxyborane adduct analogous to the original borane adduct of oxazaborolidine

here is an example

- NMR studies performed on the products of the related stoichiometric reduction carried out in the presence of Et3N gave the alkoxyborane

here is an example

- a few other examples:

here is an example

- further NMR studies on the products formed in the reduction of acetaldehyde with the same catalyst led to the structural interpretations shown below:

here is an example

- on the basis of data obtained with 13C-NMR studies, it is not clear whether the species the signals originate from are oxazadiboretanes or their related openchain isomers (of which the latter ones are shown in the figure above)

- the results indicate that the first (of the two) hydride transfer(s) occurs with higher enantioselectivity than the second

here is an example

- in addition to the mechanism of the regeneration of the catalyst discussed above, another plausible pathway has been proposed on the basis of computational studies carried out on hydride-bridged adducts of borane coordinated to oxazadiboretanes

- the regeneration of oxazaborolidine catalysts used in the enantioselective reduction of ketones was proposed to involve the hydride-bridged adduct shown below (two conformers; H2C=O as a model of the ketone and the parent oxazaborolidine as a model of the catalyst)

here is an example

- the energies of the insertion of borane into oxazadiboretanes are rather low relative to those involved with most energy requiring/liberating steps in the reduction

…………

 

- the latest mechanistic proposal (on the basis of a computational AM1 study) is shown below:

here is an example

- in contrast to the results of NMR studies on the model reaction of CBS reduction (H3C-CHO as a model of ketones), an alkoxyborane adduct (structurally analogous to that of the related borane adduct) is not included in the mechanism

- although the mechanism of the CBS reduction is not completely clear at this time, the stereochemical outcome of the reduction can easily be predicted

- boranes other than BH3 can also be used as a source of hydrogen in CBS reductions; e.g. catecholborane shown below

 

here is an example

 


here is an example

- in addition to the enantioselective synthesis of epoxides (Itsuno et al.), the products of these enantioselective reductions have been converted to many valuable compounds

a) The enantioselective synthesis of ALPHA-amino-acids (including unnatural ones)

here is an example

b) The enantioselective synthesis of ALPHA-hydroxy-acids

here is an example

c) The enantioselective synthesis of 1-deuterio primary alcohols

here is an example

d) The enantioselective synthesis of benzylic thiols

here is an example

e) The enantioselective synthesis of oxiranes

here is an example


here is an example

- in the case of CBS reductions, the coordination site of the ketone is usually determined by the difference in bulkiness of the substituents (RL and RS), but other selection mechanisms also exist

- any effect making one of the two lone pairs on the carbonyl oxygen atom of a ketone more basic than the other should work, e.g. CBS reduction of benzophenones

here is an example

- the lone pair “a” (trans to the donating group) should be more basic

- two transition states:

here is an example

- the formation of A (stabililzed by PI-electron donation from the p-OR group) should be favoured over B

- the stereochemical outcome of the reduction corresponds to the transition state A

- high selectivities are observed (although both substituents of the ketone being reduced are almost equally bulky)

here is an example


here is an example

- polymer-bound chiral oxazaborolidines have also been shown to work with enantioselectivities similar to those of their free monomeric analogs, e.g.

here is an example


here is an example

- the reduction of acetophenone using this polymeric catalyst gave 95% ee (the corresponding monomeric catalyst gave 97% ee)

- it has been shown that oxazaborolidines of which the basicity of the ring nitrogen has been reduced can also be utilized in the enantioselective reduction performed using oxazaborolidines

- in these catalysts:

* the basicity of the ring nitrogen has been reduced by an electron withdrawing substituent (e.g. Me-SO2)

* one of the bulky 5,5-substituents has been removed (one face of the ring has been made more accessible than the other)

* the bulky 5-substituent of the H3O-adduct affords an axial conformation in which it:

a) is almost orientated against the plane of the sp2-hybridized oxygen of the ring, e.g.

here is an example

b) substituents 4 and 5 are trans about the ring (otherwise repulsive interactions between the substituents will exist)

the substituents of the ring:

c) will block one face of the borane-oxazaborolidine O-adduct (the incoming ketone can approach the Lewis acidic boron with greater ease than from the face opposite the 5-substituent)

d) will direct the coordination of the incoming ketone towards an equatorial conforamation [the substituent of the boron (e.g. H) being cis to the bulky 5-substituent]

e) orient the coordinated H3B optimally (if the 5-substituent is in an equatorial conformation, the borane bound to the ring oxygen will reside far from the carbonyl carbon of the coordinated ketone)

 

here is an example

(a complex in which the ketone is in an equatorial conformation would have even more problems)

here is an example


here is an example


here is an example
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Jul 202014
 

1= methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate+methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate

2=

http://www.google.com/patents/US20130189222?cl=en

an unsaturated hydroxy ester pheromone collected from the headspace and feces of male Diaprepes abbreviatus was isolated, identified and synthesized. The pheromone, methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate, was discovered by gas chromatography-coupled electroantennogram detection (GC-EAD) and identified by gas chromatography-mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). The synthetic protocol yielded a 86:14 mixture of methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate and an inactive methyl (Z)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate along with a lactone decomposition product. The activity of the synthetic E isomer was confirmed by GC-EAD, GC-MS, NMR and behavioral assays. No antennal response was observed to the Z isomer or the lactone. In a two-choice olfactometer bioassay, female D. abbreviatus moved upwind towards the synthetic pheromone or a source of natural pheromone more often as compared to clean air. Males showed no clear preference for the synthetic pheromone.

 

 

 

The root weevil Diaprepes abbreviatus (L.), is a major pest of citrus in the Caribbean and Florida. Prior to the 1960′s, D. abbreviatus was reported only in the Caribbean. Because multiple phenotypic populations occur on Puerto Rico it is suggested that D. abbreviatus originated in Puerto Rico (Lapointe 2004). Since its discovery near Apopka, Fla. in 1964, it has spread to Louisiana, Texas and California. There is no geographic or climatic barrier to prevent the southern movement of this insect to Mexico, Mesoamerica and South America (Lapointe et al. 2007).

This migration is of concern because this insect is destructive. Adult beetles of D. abbreviatus oviposit and feed on leaves of a wide range of hosts including more than 270 species of plants in 59 plant families. Feeding by adults on leaves causes a characteristic notching pattern; however, the larval stage causes the most serious damage. Neonate larvae fall to the ground and burrow into the soil where they feed on progressively larger roots over a period of months as they grow. Larval feeding on citrus tree roots can eventually girdle the crown area of the root system, killing the host plant. When larval development is completed, adults emerge from the soil to feed upon foliage where aggregation, mating and oviposition take place. In certain citrus growing areas, root damage by larval D. abbreviatus creates favorable conditions for species ofPhytophthora, a very serious and often lethal plant pathogen, to invade roots and further hasten the decline of trees.

In Florida, citrus growers spend up to $400/acre for combined control of D. abbreviatus and Phytophthora. In 2009, it was estimated that the total increase in costs per ton due to the establishment and spread of Diaprepes root weevil in California would be $53.60 for orange, $45.20 for grapefruit, $42.50 for lemon and $200.00 for avocado. In view of the negative economic impact caused by the feeding of this insect and in view of the fact that there appear to be no natural barriers to important agricultural citrus growing areas, attractants that will allow for the monitoring, tracking, trapping and destroying of this insect have been sought.

Diaprepes abbreviatus has been placed in the subfamily Entiminae of the Curculionidae (Marvaldi et al. 2002) Within the superfamily Cu rculionoidea (weevils) the majority of attractants or pheromones identified to date are long-range, male-produced aggregation pheromones (Seybold and Vanderwel 2003, Ambrogi et al. 2009). Aggregation of D. abbreviatus adults and the occurrence of so-called “party trees” have been observed (Wolcott 1936). Schroeder (1981) suggested a male-produced pheromone attracted females and a female-produced pheromone attracted males. Beavers et al. (1982) showed in laboratory tests that male and female D. abbreviatus were significantly attracted to the frass of the opposite sex. Jones and Schroeder (1984) demonstrated a male-produced pheromone in the feces that attracted both sexes. A pheromone responsible for arrestment behavior was suggested by Lapointe and Hall (2009). U.S. Pat. No. 8,066,979 to Dickens et al. showed for the first time that D. abbreviatus adults have olfactory receptors for secondary plant metabolites that belong to diverse chemical groups: (a) alcohol and aldehyde monoterpenes (e.g., linalool, citronellal, nerol, and trans-geraniol), (b) green leaf volatiles (e.g., cis-3-hexen-1-ol and trans-2-hexen-1-ol), and (c) an aromatic monoterpenoid (e.g., carvacrol). Otálora-Luna et al. (2009) identified by gas-chromatograph electroantennograph detection (GC-EAD) a number of plant volatiles from citrus leaves that elicited antennal response in D. abbreviatus. Such kairomones may act in concert with a pheromone to attract conspecifics to a suitable food source (Dickens 1990). Only one pheromone, that of Sitona lineatus (4-methyl-3,5-heptanedione), an aggregation pheromone, has been isolated from the Entiminae (broad-nosed weevils) (Blight et al. 1984). Blight and Wadhams (1987) suggested that S. lineatus produces its aggregation pheromone in the spring and that the pheromone activity is synergized by host plant volatiles including (Z)-3-hexen-1-ol and linalool.

chromatographed again with hexanes/ethyl acetate/MeOH, 16:6:1 to furnish 1 (E/Z 86:14, approximately 90 mg, approximately 58%) in the less polar fraction.

1H NMR (600 MHz, C6D6, 6): 0.79 (d, J=6.6 Hz, (CH3)2, a 0.91 (d, J=6.6 Hz, (CH3)2, Z), 2.01-2.08 (m, H-4 E, CH2C═C, Z), 2.46 (t, J=5.4 Hz, OH, E), 2.76 (t, J=6.6 Hz, CH2C═C, E), 3.34 (s, OCH3, E), 3.36-3.38 (m, CH2OH, Z), 3.41 (s, OCH3, Z), 3.70 (q, J=5.4 Hz, CH2OH, E), 4.32 (septet, H-4, Z), 5.71 (br. s, H-2, Z), 5.80 (br. s, H-2, E).

13C NMR (151 MHz, C6D6, E isomer): 21.7 (two carbons), 35.6, 36.7, 51.1, 62.5, 115.6, 167.7, 168.7; Z isomer: 20.9 (two carbons), 29.8, 35.1, 50.8, 61.6, 116.0, 165.7, 166.8.

Lactone 2 (approximately 10 mg) was recovered from the more polar (second) fraction. GC-MS (m/z, relative intensity): 140 (M+, 16), 125 (7), 110 (15), 97 (19), 96 (59), 95 (96), 82 (24), 81 (100), 67 (73), 55 (17), 41 (40). 1H NMR (400 MHz, C6D6, 6): 0.57 (d, J=6.6 Hz, (CH3)2), 1.37 (br. t, J=6.5 Hz, CH2C═), 1.70 (septet, J=6.6 Hz, CH(CH3)2), 3.61 (t, J=6.5 Hz, CH2O), 5.67 (d, J=1.0 Hz, CHC═). NMR data are in agreement with ones obtained for this compound in CDCl(D’Annibale et al. 2007).

 

 

 

TABLE 1
HMBC and NOESY NMR spectroscopic data for the putative
pheromone of Diaprepes abbreviatus in CDCl3
Figure US20130189222A1-20130725-C00001
J coupling
δ 13C δ 1H constants HMBC
Position [ppm] [ppm] [Hz] correlations NOESY
1 169.0*
2 115.5 5.83 s 1.10
3 166.9*
4 36.35* 2.43 m J = 6.7
5 and 6 21.7 1.10 d, J = 6.8 C4, C3 5.83
and
2.84
7 35.2 2.84 t, J = 6.4 C2, C3, C4, 1.10
C8
8 62.5 3.8 br t J = 6.3
9 51.7 3.7 s Cl
1H (600 MHz), 13C (151 MHz),.
Chemical shifts referenced to δ(CHCl3) = 7.26 ppm for 1H and δ(CHCl3) = 77.36 ppm for 13C.
Coupling constants are given in Herzt [Hz].
*The 13C chemical shifts are deduced from HMBC; others are deduced from HSQC.
1H chemical shifts are deduced from 1D 1H NMR

lactone 2

TABLE 2
1H (600 MHz) and 13C (151 MHz) spectroscopic data for
the lactoneinactive degradation product of the putative
pheromone of Diaprepes abbreviatus found in
headspace collections
Figure US20130189222A1-20130725-C00002
δ 1H
.Position δ 13C [ppm] [ppm]
2 114.08 5.80
4 34.8 2.47
5 and 6 20.2 1.12
7 26.4 2.39
8 66.3 4.36
Only HSQC data are reported for the lactone.
Chemical shifts referenced to δ(CHCl3) = 7.26 ppm for 1H and δ(CHCl3) = 77.36 ppm for 13C.
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Jul 192014
 

Kalydeco is truly a wonder drug.

Developed by Vertex Pharmaceuticals, it is the first drug that attacks not just the symptoms but the underlying cause of cystic fibrosis, a genetic lung disease that usually kills victims by the time they reach their 40s. It doesn’t work for every sufferer of the disease, but rather for a small subset — probably around 2,000 people — who have a specific genetic mutation that the drug targets. But for those it helps, it is life changing.  text clipped read at

http://www.nytimes.com/2014/07/19/opinion/joe-nocera-cystic-fibrosis-drug-price.html?_r=0

Ivacaftor.svg

ivacaftor..kalydeco

read all at

http://www.nytimes.com/2014/07/19/opinion/joe-nocera-cystic-fibrosis-drug-price.html?_r=0

A drug called Sovaldi, marketed by Gilead Sciences, takes aim at hepatitis C. It is described as a “breakthrough” drug. But each pill costs $1,000

 

sovaldi.sofosbuvir

 

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