Dec 192014
 

 

 

 

(S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone

bp 85–87°C at 3.7 mm, [α]21D + 23.0° (CHCl3, c 2.0)

The spectral properties of (S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone are as follows:

 

IR vmax (film) cm−1: 3470 (s), 1705 (s), 1120 (m), 1055 (s), 985 (s), 965 (m);

 

1H NMR (250 MHz, CDCl3) δ: 1.11 (s, 3 H), 1.15 (s, 3 H), 1.60–1.71 (m, 1 H), 1.76–1.86 (m, 1 H), 1.96–2.05 (m, 2 H), 2.16 (br s, 1 H), 2.35–2.45 (m, 2 H), 3.69 (dd, 1 H, J = 7.6, 2.9);

 

13C NMR (76 MHz, CDCl3) δ: 19.7, 20.7, 22.9, 29.0, 37.3, 51.3, 77.8, 215.3.

The optical purity of (S)-(+)-3-hydroxy-2,2-dimethylcyclohexanone can be determined by HPLC analysis.
The (S)-α-methoxy-α-trifluoromethylphenylacetate (MTPA ester) is prepared according to the reported procedure:3 HPLC analysis (Column, Nucleosil® 50-5, 25 cm × 4.6 mm; eluant, hexane : THF = 30 : 1, 1.03 mL/min; detected at UV 256 nm) retention time 35.6 min (98.0–99.4%) and 29.6 min (0.6–(2.0%). Therefore, the optical purity is determined to be 96.0–98.8% ee.
Analysis of the MTPA ester of this product by 250 MHz 1H NMR and capillary GLC (12.5 m, 5% methyl silicone column) failed to detect any more of the minor diastereomer than would have been expected from the purity (98% ee) of the MTPA-Cl employed.

 

NOTE….Intermediate is

2,2-dimethylcyclohexane-1,3-dione bp 92–97°C (4 mm)

37–38°C.

The spectra are as follows: 1H NMR (250 MHz, CDCl3) δ: 1.29 (s, 6 H), 1.93 (5 lines, 2 H, J = 6.5), 2.67 (t, 4 H, J = 6.9); 13C NMR (76 MHz, CDCl3) δ: 18.1, 22.3, 37.4, 61.8, 210.6.

 

Natural products synthesized from (S)-3-hydroxy-2,2-dimethylcyclohexanone
Figure 1. Natural products synthesized from (S)-3-hydroxy-2,2-dimethylcyclohexanone

 


References and Notes
  1. Department of Agricultural Chemistry, The University of Tokyo, Yayoi 1-1-1, Bunkyo-Ku, Tokyo 113, Japan.
  2. Mekler, A. B.; Ramachandran, S.; Swaminathan, S.; Newman, M. S. Org. Synth., Coll. Vol. V 1973, 743, 3.
  3. Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
  4. Kieslich, K. “Microbial Transformations of Non-Steroid Cyclic Compounds;” Georg Thieme; Stuttgart, 1976, pp. 28–31.
  5. Lu, Y.; Barth, G.; Kieslich, K.; Strong, P. D.; Duax, W. L.; Djerassi, C. J. Org. Chem. 1983, 48, 4549.
  6. Mori, K.; Mori, H. Tetrahedron 1985, 41, 5487.
  7. Yanai, M.; Sugai, T.; Mori, K. Agric. Biol. Chem. 1985, 49, 2373.
  8. Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 273.
  9. Mori, K.; Nakazono, Y. Tetrahedron 1986, 42, 283.
  10. Mori, K.; Mori, H.; Yanai, M. Tetrahedron 1986, 42, 291.
  11. Mori, K.; Tamura, H. Tetrahedron 1986, 42, 2643.
  12. Sugai, T.; Tojo, H.; Mori, K. Agric. Biol. Chem. 1986, 50, 3127.
  13. Mori, K.; Mori, H. Tetrahedron 1986, 42, 5531.
  14. Mori, K.; Mori, H. Tetrahedron 1987, 43, 4097.
  15. Mori, K.; Komatsu, M. Liebigs Ann. Chem. 1988, 107.
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Dec 182014
 

Arterolane.png
Arterolane
cas 664338-39-0, UNII-3N1TN351VB, OZ277, RBX-11160, NCGC00274173-01
Molecular Formula: C22H36N2O4
 Molecular Weight: 392.53224
Ranbaxy Lab Ltd innovator
 cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane
cis-adamantane-2-spiro-3′-8′-[[[(2′- amino-2′-methylpropyl)amino]carbonyl]-methyl]- 1 ‘,2′,4′-trioxaspiro[4.5]decane
Arterolane maleate is a synthetic trioxolane compound. The chemical name of arterolane maleate is cis-adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpropyl) amino] carbonyl] methyl] 1’,2’,4’-trioxaspiro [4.5] decane hydrogen maleate. The molecular formula is C26H40N2O8 and molecular weight is 508.61. The structural formula is as follows:
PATENT
Example 6: Preparation of c/s-adamantane-2-spiro-3′ -8 ‘-πT(2′-amino-2′ -methyl propyl) amino! carbonyl] methyli-l ‘, 2\ 4′-U-JoXaSpJrQ [4.51 decane maleate To a solution of c/s-adamantane-2-spiro-3′-8′-[[[(2′-amino-2′-methyl propyl) amino] carbonyl] methyl]-! ‘, 2′, 4′-trioxaspiro [4.5] decane (example 5) (60 g, 0.153 moles) in ethanol (150 mL) was added a solution of maleic acid (17.3 g, 0.15 moles, 0.98 equiv. in ethanol 90 mL) and the reaction mixture was stirred for about 1 h. To this clear solution, n- heptane (720 mL) was added at room temperature in 1 h and the reaction mixture was stirred for 3 h. It was then cooled to 0 to 100C and filtered. The cake was washed with n-heptane (60 mL) and dried under vacuum at 40-450C.
Yield: 67 g, 77.4%,
 mp: 1490C (decomp),
(M++l) 393.5,  
1HNMR (300 MHz, DMSO-^ ): δ 1.05-1.11 (2H,m), 1.18 (6H,s), 1.64-1.89 (21H,m), 2.07(2H,d), 3.21 (2H,d), 6.06 (2H,d), 7.797 (2H, bs), 8.07 (IH, t).
 
SEE FULL ARTICLE WITH SYNTHESIS AT
 http://newdrugapprovals.org/2014/12/18/ranbaxy-to-introduce-malarial-treatment-synriam-in-african-nations/

ANTHONY MELVIN CRASTO

 amcrasto@gmail.com

http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO

 amcrasto@gmail.com

http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Dec 162014
 

 

Lexipafant

 

Lexipafant
CAS : 139133-26-9
 N-Methyl-N-[[4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]phenyl]sulfonyl]-L-leucine ethyl ester
 N-methyl-N-[[a-(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)-p-tolyl]sulfonyl]-L-leucine ethyl ester
N-Methyl-N-[4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-ylmethyl)phenylsulfonyl]-L-leucine ethyl ester
Manufacturers’ Codes: BB-882
DO6
GR-167089
ISV-611
UNII-H14917M9YW
Trademarks: Zacutex (Brit. Biotech)
MF: C23H30N4O4S
M Wt: 458.57
Percent Composition: C 60.24%, H 6.59%, N 12.22%, O 13.96%, S 6.99%
Properties: White crystalline solid from ethyl acetate, mp 105°. [a]D20 -6.7° (c = 2.0 in CDCl3).
Melting point: mp 105°
Optical Rotation: [a]D20 -6.7° (c = 2.0 in CDCl3)
Therap-Cat: Anti-inflammatory. (Nonsteroidal); Platelet Activating Factor Antagonist.
Lexipafant is a platelet-activating factor (PAF) antagonist that was in early clinical development at DevCo for the oral treatment of dementia and motor function disorders in HIV patients, intravenous treatment of acute pancreatitis, as well as for the prevention of certain serious renal and neurological complications experienced by patients undergoing cardiac surgery, including stroke. However, no recent developments of the drug candidate have been reported by the company.
Lexipafant was also being studied at British Biotech (now Vernalis) for the intravenous treatment of pancreatitis, but development for this indication was discontinued. In 2002, DevCo obtained from British Biotech exclusive rights to develop, manufacture and sell lexipafant for the treatment of human disease, excluding the fields of oncology and ophthalmology.
……………………………
 
……………………………………………
WO 1993016075

 ………………………………

WO 1995013064
Chemical structure for LEXIPAFANT
Literature References:
Platelet activating factor (PAF) antagonist. Prepn: M. Whittaker, A. Miller, WO 9203422eidem, US5200412 (1992, 1993 both to British Bio-Technology).
Structure-activity report: M. Whittaker et al., J. Lipid Mediators Cell Signalling 10, 151 (1994).
Pharmacology: F. M. Abu-Zidan et al., Pharmacol. Toxicol. 78, 23 (1996).
Clinical evaluation in acute pancreatitis: A. N. Kingsnorth et al., Br. J. Surg. 82, 1414 (1995).
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Dec 162014
 

Figure

Dithiocarbamates: Reagents for the Removal of Transition Metals from Organic Reaction Media

http://pubs.acs.org/doi/abs/10.1021/op500336h

Chemical Development, Bristol-Myers Squibb Co., 1 Squibb Drive, New Brunswick, New Jersey 08903,United States
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/op500336h
Dithiocarbamates (DTCs) are ligands known to chelate with Cu and other transition metals to form insoluble complexes. Wastewater treatment protocols have utilized DTCs to remove trace (ppb) metals from waste streams. We have extended the applicability of DTCs to a protocol that readily enables control of the residual Cu in isolated material in a quick and cost-effective manner. Formation of the chelate complex typically results in purging of Cu and a variety of other metals in an array of reaction media to ≤10 ppm. Furthermore, the simplicity of the method makes it very attractive for large-scale applications late in a synthetic sequence because of the low toxicity and efficient removal of the metal complex by filtration.
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Dec 092014
 

 

 

 

 

 

 

 

 

 

1H NMR RABEPRAZOLE

RAB standard: (DMSOd6 400 MHz) δ 8.28 (d, 1H, J=5.56 Hz), 7.46 (m, 2H), 6.93 (d, 1H, J=5.68 Hz), 6.88 (m, 2H), 4.57 (AB, 2H, J=12.88 Hz), 4.10 (t, 2H, J=6.19 Hz), 3.49 (t, 2H, J=6.32 Hz), 3.25 (S, 3H), 2.17 (S, 3H), 1.98 (quin., 2H, J=6.19 Hz) 13C NMR (DMSOd6, 101 MHz) δ 162.61, 152.41, 147.95, 146.62, 121.74, 118.20, 117.32, 105.92, 68.30, 64.92, 59.64, 57.96, 28.67, 10.83.

 

 

The 1H spectrum for the RAB starting material is shown with peaks labelled and integrated. Data were collected on a 400 MHz NMR in DMSOd6, corrected to TMS by residual non-deuterated solvent.


 

 

 

 

 

 

 

 

 

 

 

 

Figure S13 COSY NMR spectrum of RAB

 

The COSY spectrum for the RAB starting material is shown. This was used to assign the methoxypropoxy carbon chain δ 1.98, 3.49 and 4.10. Data were collected on a 400 MHz NMR in DMSOd6, corrected to TMS by residual non-deuterated solvent.


 

 

 

 

 

 

 

 

 

 

 

Figure S14 HMBC spectrum of RAB

 

The spectrum shows the long range coupling of 1H to 13C nuclei. Coupling is observed between the 3-methyl group and the AB system, and between the various hydrogens on the alkyl chain.

 

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Dec 092014
 

 

Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process

Rachana Kamble, Sadhana Sathaye, DP Shah
University Institute of Chemical Technology, N. Parekh Marg, Matunga, Mumbai-400 019, India

According to ayurvedic texts shodhan vidhi is an important process which enhances the biological activity of a compound and reduces the toxicity at the same time. Before incorporating into formulations, guggul is processed using Shodhan vidhi involving different shodhan dravyas like gulvel, gomutra, triphala, dashmul. We have evaluated the antispasmodic activity of guggul on ileum of guinea pig and Wistar rats. The animals were sacrificed and ileum tissue of guinea pig and rat was isolated and tested for antispasmodic activity using different spasmogens like acetylcholine, histamine and barium chloride. It was observed that the different shodhit guggul (shudha guggul) i.e. processed using different shodhan vidhi, showed good antispasmodic activity as compared to Ashudha guggul. When acetylcholine was used as spasmogen, gulvel and triphala shodhit guggul showed good antispasmodic activity than other shodhit guggul. Thus shodhan vidhi enhances the therapeutic properties of guggul.
Kamble R, Sathaye S, Shah D P. Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process. Indian J Pharm Sci 2008;70:368-72
URL:
Kamble R, Sathaye S, Shah D P. Evaluation of antispasmodic activity of different Shodhit guggul using different shodhan process. Indian J Pharm Sci [serial online] 2008 [cited 2014 Dec 9];70:368-72. Available from: http://www.ijpsonline.com/text.asp?2008/70/3/368/43005

Sadhana Sathaye

Sadhana Sathaye

Associate professor of Pharmacy(Pharmacology) at Institute Of Chemical Technology

in.linkedin.com/pub/sadhana-sathaye/14/290/84a

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Dec 082014
 

Basel University Chemists developed new novel method to twist molecule

The new helical molecule (right) was due to the different length strands (blue and gray) a spatial arrangement of a (schematized in the middle), similar to the railing of a spiral staircase (left).

BASEL, SWITZERLAND: Chemists at the University of Basel have managed to twist a molecule in a novel way by different combined long molecular strands together. In this case, the longer strand winds like a stair railing around a central axis, and there is a mirror-image structure, which has special physical properties.

http://www.worldofchemicals.com/media/academy/new-novel-method-to-twist-molecule/7778.html

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Dec 042014
 

Which Pharmas Spend the Most on R&D?

Pharmas and biotechs have spent $1 trillon on R&D over the last decade.

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Dec 032014
 

The source of spin-spin coupling

The 1H-NMR spectra that we have seen so far (of methyl acetate and para-xylene) are somewhat unusual in the sense that in both of these molecules, each set of protons generates a single NMR signal.  In fact, the 1H-NMR spectra of most organic  molecules contain proton signals that are ‘split’ into two or more sub-peaks.  Rather than being a complication, however, this splitting behavior actually provides us with more information about our sample molecule.

Consider the spectrum for 1,1,2-trichloroethane.  In this and in many spectra to follow, we show enlargements of individual signals so that the signal splitting patterns are recognizable.

image058.png

The signal at 3.96 ppm, corresponding to the two Ha protons, is split into two subpeaks of equal height (and area) – this is referred to as adoublet.  The Hb signal at 5.76 ppm, on the other hand, is split into three sub-peaks, with the middle peak higher than the two outside peaks – if we were to integrate each subpeak, we would see that the area under the middle peak is twice that of each of the outside peaks.  This is called a triplet.

The source of signal splitting is a phenomenon called spin-spin coupling, a term that describes the magnetic interactions between neighboring, non-equivalent NMR-active nuclei. In our 1,1,2 trichloromethane example, the Ha and Hb protons are spin-coupled to each other. Here’s how it works, looking first at the Ha signal: in addition to being shielded by nearby valence electrons, each of the Ha protons is also influenced by the small magnetic field generated by Hb next door (remember, each spinning proton is like a tiny magnet). The magnetic moment of Hb will be aligned with B0 in (slightly more than) half of the molecules in the sample, while in the remaining half of the molecules it will be opposed to B0.  The Beff ‘felt’ by Ha is a slightly weaker if Hb is aligned against B0, or slightly stronger if Hb is aligned with B0.  In other words, in half of the molecules Ha is shielded by Hb (thus the NMR signal is shifted slightly upfield) and in the other half Ha isdeshielded by Hb(and the NMR signal shifted slightly downfield).  What would otherwise be a single Ha peak has been split into two sub-peaks (a doublet), one upfield and one downfield of the original signal.  These ideas an be illustrated by a splitting diagram, as shown below.

 

image060.png

 

Now, let’s think about the Hbsignal.  The magnetic environment experienced by Hb is influenced by the fields of both neighboring Haprotons, which we will call Ha1 and Ha2.  There are four possibilities here, each of which is equally probable.  First, the magnetic fields of both Ha1 and Ha2 could be aligned with B0, which would deshield Hb, shifting its NMR signal slightly downfield.  Second, both the Ha1 and Ha2 magnetic fields could be aligned opposed to B0, which would shield Hb, shifting its resonance signal slightly upfield.  Third and fourth, Ha1 could be with B0 and Ha2 opposed, or Ha1opposed to B0 and Ha2 with B0.  In each of the last two cases, the shielding effect of one Haproton would cancel the deshielding effect of the other, and the chemical shift of Hb would be unchanged.

image062.png

So in the end, the signal for Hb is a triplet, with the middle peak twice as large as the two outer peaks because there are two ways that Ha1and Ha2 can cancel each other out.

Now, consider the spectrum for ethyl acetate:

image064.png

We see an unsplit ‘singlet’ peak at 1.833 ppm that corresponds to the acetyl (Ha) hydrogens – this is similar to the signal for the acetate hydrogens in methyl acetate that we considered earlier.  This signal is unsplit because there are no adjacent hydrogens on the molecule.  The signal at 1.055 ppm for the Hc hydrogens is split into a triplet by the two Hb hydrogens next door.  The explanation here is the same as the explanation for the triplet peak we saw previously for 1,1,2-trichloroethane.

The Hbhydrogens give rise to a quartet signal at 3.915 ppm – notice that the two middle peaks are taller then the two outside peaks.  This splitting pattern results from the spin-coupling effect of the three Hc hydrogens next door, and can be explained by an analysis similar to that which we used to explain the doublet and triplet patterns.

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By now, you probably have recognized the pattern which is usually referred to as the n + 1 rule: if a set of hydrogens has n neighboring, non-equivalent hydrogens, it will be split into n + 1 subpeaks. Thus the two Hb hydrogens in ethyl acetate split the Hc signal into a triplet, and the three Hc hydrogens split the Hb signal into a quartet.  This is very useful information if we are trying to determine the structure of an unknown molecule: if we see a triplet signal, we know that the corresponding hydrogen or set of hydrogens has two `neighbors`.  When we begin to determine structures of unknown compounds using 1H-NMR spectral data, it will become more apparent how this kind of information can be used.

Three important points need to be emphasized here.  First, signal splitting only occurs between non-equivalent hydrogens – in other words, Ha1 in 1,1,2-trichloroethane is not split by Ha2, and vice-versa.

image066.png

 

Second, splitting occurs primarily between hydrogens that are separated by three bonds.  This is why the Ha hydrogens in ethyl acetate form a singlet– the nearest hydrogen neighbors are five bonds away, too far for coupling to occur.

image068.png

Occasionally we will see four-bond and even 5-bond splitting, but in these cases the magnetic influence of one set of hydrogens on the other set is much more subtle than what we typically see in three-bond splitting (more details about how we quantify coupling interactions is provided in section 5.5B). Finally, splitting is most noticeable with hydrogens bonded to carbon.  Hydrogens that are bonded to heteroatoms (alcohol or amino hydrogens, for example) are coupled weakly – or not at all – to their neighbors.  This has to do with the fact that these protons exchange rapidly with solvent or other sample molecules.

Below are a few more examples of chemical shift and splitting pattern information for some relatively simple organic molecules.

image070.png

image072.png

 

image074.png

 

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Coupling constants

Chemists quantify the spin-spin coupling effect using something called the coupling constant, which is abbreviated with the capital letterJ.  The coupling constant is simply the difference, expressed in Hz, between two adjacent sub-peaks in a split signal.  For our doublet in the 1,1,2-trichloroethane spectrum, for example, the two subpeaks are separated by 6.1 Hz, and thus we write 3Ja-b = 6.1 Hz.

image078.png

The superscript 3 tells us that this is a three-bond coupling interaction, and the a-b subscript tells us that we are talking about coupling between Ha and Hb. Unlike the chemical shift value, the coupling constant, expressed in Hz, is the same regardless of the applied field strength of the NMR magnet.  This is because the strength of the magnetic moment of a neighboring proton, which is the source of the spin-spin coupling phenomenon, does not depend on the applied field strength.

When we look closely at the triplet signal in 1,1,2-trichloroethane, we see that the coupling constant – the `gap` between subpeaks – is 6.1 Hz, the same as for the doublet. This is an important concept!  The coupling constant 3Ja-b quantifies the magnetic interaction between the Ha and Hb hydrogen sets, and this interaction is of the same magnitude in either direction. In other words, Ha influences Hb to the same extent that Hb influences Ha. When looking at more complex NMR spectra, this idea of reciprocal coupling constants can be very helpful in identifying the coupling relationships between proton sets.

Coupling constants between proton sets on neighboring sp3-hybridized carbons is typically in the region of 6-8 Hz.  With protons bound to sp2-hybridized carbons, coupling constants can range from 0 Hz (no coupling at all) to 18 Hz, depending on the bonding arrangement.

image080.png

 

For vinylic hydrogens in a trans configuration, we see coupling constants in the range of 3J = 11-18 Hz, while cis hydrogens couple in the 3J= 6-15 Hz range. The 2-bond coupling between hydrogens bound to the same alkene carbon (referred to as geminal hydrogens) is very fine, generally 5 Hz or lower.  Ortho hydrogens on a benzene ring couple at 6-10 Hz, while 4-bond coupling of up to 4 Hz is sometimes seen between meta hydrogens.

image082.png

Fine (2-3 Hz) coupling is often seen between an aldehyde proton and a three-bond neighbor. Table 4 lists typical constant values.

Complex coupling

In all of the examples of spin-spin coupling that we have seen so far, the observed splitting has resulted from the coupling of one set of hydrogens to just one neighboring set of hydrogens. When a set of hydrogens is coupled to two or more sets of nonequivalent neighbors, the result is a phenomenon called complex coupling. A good illustration is provided by the 1H-NMR spectrum of methyl acrylate:

image084.png

 

First, let’s first consider the Hc signal, which is centered at 6.21 ppm.  Here is a closer look:

image086.png

With this enlargement, it becomes evident that the Hc signal is actually composed of four sub-peaks. Why is this? Hc is coupled to both Haand Hb , but with two different coupling constants.  Once again, a splitting diagram can help us to understand what we are seeing.  Ha istrans to Hc across the double bond, and splits the Hc signal into a doublet with a coupling constant of 3Jac = 17.4 Hz. In addition, each of these Hc doublet sub-peaks is split again by Hb (geminal coupling) into two more doublets, each with a much smaller coupling constant of2Jbc = 1.5 Hz.

image088.png

The result of this `double splitting` is a pattern referred to as a doublet of doublets, abbreviated `dd`.

The signal for Ha at 5.95 ppm is also a doublet of doublets, with coupling constants 3Jac= 17.4 Hz and 3Jab = 10.5 Hz.

image090.png

The signal for Hb at 5.64 ppm is split into a doublet by Ha, a cis coupling with 3Jab = 10.4 Hz. Each of the resulting sub-peaks is split again by Hc, with the same geminal coupling constant 2Jbc = 1.5 Hz that we saw previously when we looked at the Hc signal.  The overall result is again a doublet of doublets, this time with the two `sub-doublets` spaced slightly closer due to the smaller coupling constant for the cisinteraction.  Here is a blow-up of the actual Hbsignal:

image092.png

 

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When constructing a splitting diagram to analyze complex coupling patterns, it is usually easier to show the larger splitting first, followed by the finer splitting (although the reverse would give the same end result).

When a proton is coupled to two different neighboring proton sets with identical or very close coupling constants, the splitting pattern that emerges often appears to follow the simple `n + 1 rule` of non-complex splitting.  In the spectrum of 1,1,3-trichloropropane, for example, we would expect the signal for Hb to be split into a triplet by Ha, and again into doublets by Hc, resulting in a ‘triplet of doublets’.

image094.png

 

Ha and Hc are not equivalent (their chemical shifts are different), but it turns out that 3Jab is very close to 3Jbc.   If we perform a splitting diagram analysis for Hb, we see that, due to the overlap of sub-peaks, the signal appears to be a quartet, and for all intents and purposes follows the n + 1 rule.

image096.png

For similar reasons, the Hc peak in the spectrum of 2-pentanone appears as a sextet, split by the five combined Hb and Hd protons. Technically, this ‘sextet’ could be considered to be a ‘triplet of quartets’ with overlapping sub-peaks.

image098.png

 

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In many cases, it is difficult to fully analyze a complex splitting pattern.  In the spectrum of toluene, for example, if we consider only 3-bond coupling we would expect the signal for Hb to be a doublet, Hd a triplet, and Hc a triplet.

image102.png

In practice, however, all three aromatic proton groups have very similar chemical shifts and their signals overlap substantially, making such detailed analysis difficult.  In this case, we would refer to the aromatic part of the spectrum as a multiplet.

When we start trying to analyze complex splitting patterns in larger molecules, we gain an appreciation for why scientists are willing to pay large sums of money (hundreds of thousands of dollars) for higher-field NMR instruments.  Quite simply, the stronger our magnet is, the more resolution we get in our spectrum.  In a 100 MHz instrument (with a magnet of approximately 2.4 Tesla field strength), the 12 ppm frequency ‘window’ in which we can observe proton signals is 1200 Hz wide.   In a 500 MHz (~12 Tesla) instrument, however, the window is 6000 Hz – five times wider.  In this sense, NMR instruments are like digital cameras and HDTVs: better resolution means more information and clearer pictures

 

 

 

 

 

 

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Dec 022014
 

Pimobendan

Pimobendan

 

Pimobendan
CAS: 74150-27-9
3-[2-(4-methoxyphenyl)-3H-benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one
 4,5-Dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazinone
 UD-CG 115; UD-CG 115 BS; 2-(4-methoxyphenyl)-5(6)-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)benzimidazole
  1. 4,5-dihydro-6-(2-(4-methoxyphenyl)-1H-benzimidazole-5-yl)-5-methyl-3(2H)-pyridazinone
  2. pimobendan
  3. pimobendane
  4. UD CG 115
  5. UD-CG 115
  6. UD-CG115
MF: C19H18N4O2
MW: 334.37
Percent Composition: C 68.25%, H 5.43%, N 16.76%, O 9.57%
Boehringer Ingelheim (Originator)
Derivative Type: Hydrochloride
CAS : 77469-98-8
MF: C19H18N4O2.HCl
MW: 370.83
Percent Composition: C 61.54%, H 5.16%, N 15.11%, O 8.63%, Cl 9.56%
Prop: Crystals from methanol and ethereal HCl, mp 311°(dec). LD50 orally in mice: ~600 mg/kg (Austel, 1982).
MP: mp 311°(dec)
Toxicity data: LD50 orally in mice: ~600 mg/kg (Austel, 1982)
Therap-Cat: Cardiotonic.
pimobendan.png

Pimobendan (INN is a veterinary medication manufactured by Boehringer Ingelheim under the trade names Vetmedin and Acardi) or pimobendane. It is a calcium sensitizer with positive inotropic and vasodilator effects. It is also a selective inhibitor ofphosphodiesterase III (PDE3).

Pimobendan is used in the management of heart failure in dogs, most commonly caused by myxomatous mitral valve disease (also known as endocardiosis), or dilated cardiomyopathy.[1] Research has shown that pimobendan increases survival time and improves quality of life in patients with congestive heart failure secondary to mitral valve disease when compared with benazepril, anangiotensin-converting-enzyme (ACE) inhibitor.[2] Under the trade name Acardi, it is available for human use in Japan.[3]

Mechanism of action

Pimobendan is a positive inotrope. It sensitizes and increases the binding efficiency of cardiac myofibril to the calcium ions that are already present without increasing the consumption of oxygen and energy. Pimobendan also causes peripheral vasodilation by inhibiting the function of phosphodiesterase III. This results in decreased pressure, translating into smaller cardiac preload andafterload (decreases the failing heart’s workload).

Pharmacokinetics

Pimobendan is absorbed rapidly when given via the oral route and has a bioavailability of 60-65%. It is metabolized into its active form by the liver. The half-life of pimobendan in the blood is 0.4 hours and the half-life of its metabolite is 2 hours. Elimination is by excretion in the bile and then feces. Pimobendan is 90–95% bound to plasma proteins in circulation. This has implications in patients suffering from low blood protein levels (hypoproteinemia/hypoalbuminemia) and with patients that are on concurrent therapies that are also highly protein bound.

Combinations

Pimobendan is often used in combination with three other drugs to palliate dogs with heart disease and reduce clinical signs of disease. These are:

Other drugs may also be used as required to manage certain arrhythmias that are often associated with heart disease.

Synthesis

Pimobendan can be synthesized beginning with anisoyl chloride.

Pimobendan synthesis:[4]

The cyclization of methyl 3- [4- (4-methoxybenzoylamino) -3-nitrobenzoyl] butyrate (I) with hydrazine hydrate in refluxing acetic acid gives 4,5-dihydro-6- [4- (4-methoxybenzoylamino) -3- nitrobenzoyl] -5-methylpyridazin-3 (2H) -one (II), which is reduced with H2 over Pd / C in ethanol yielding the corresponding amino derivative (III). Finally, this compound is cyclized in refluxing acetic acid.

References

  1.  Gordon SG, Miller MW, Saunders AB (2006). “Pimobendan in heart failure therapy—a silver bullet?”J Am Anim Hosp Assoc 42 (2): 90–3. PMID 16527909.
  2.  Häggström J, Boswood A, O’Grady M, et al. (July 2008). “Effect of Pimobendan or Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease: The QUEST Study”. J. Vet. Intern. Med. 22 (5): 1124–35. doi:10.1111/j.1939-1676.2008.0150.xPMID 18638016.
  3.  “Kusuri-no-Shiori Drug Information Sheet”. RAD-AR Council, Japan. April 2005. Retrieved 2008-08-06.
  4.  Nicolas, C.; Verny, M.; Maurizis, J. C.; Payard, M.; Faurie, M. (1986). “Synthesis of 14C-bucromarone succinate and hydrochloride”. Journal of Labelled Compounds and Radiopharmaceuticals 23 (8): 837. doi:10.1002/jlcr.2580230806edit

Further reading

External links

Pimobendan
Pimobendan skeletal.svg
Systematic (IUPAC) name
(RS)-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-4,5-dihydropyridazin-3(2H)-one
Clinical data
AHFS/Drugs.com International Drug Names
Legal status
  • ℞ Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 60 to 65%
Half-life 0.4 hours
Excretion In feces
Identifiers
CAS number 74150-27-9 Yes
ATCvet code QC01CE90
PubChem CID 4823
ChemSpider 4657 
UNII 34AP3BBP9T 
KEGG D01133 Yes
ChEMBL CHEMBL24646 
Chemical data
Formula C19H18N4O2 
Mol. mass 334.37 g/mol
References: Positive inotropic agent. Prepn: V. Austel et al., DE 2837161eidem, US 4361563 (1980, 1982 both to Thomae).
Cardiovascular effects: J. C. A. von Meel, Arzneim.-Forsch. 35, 284 (1985); P. D. Verdouw et al., Eur. J. Pharmacol.126, 21 (1986). Comparison of enantiomer activity: K. Fujino et al., J. Pharmacol. Exp. Ther. 247, 519 (1988).
Clinical trial in congestive heart failure: F. Hagemeijer, Am. Heart J. 122, 517 (1991); S. D. Katz et al., ibid. 123, 95 (1992).
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