The Claimed Intermediate database by Tcipatent Ltd « New Drug Approvals

The Claimed Intermediate database by Tcipatent Ltd « New Drug Approvals:

'via Blog this'

Eddie Kehoe

Principal & Technical Director at Tcipatent Ltd

Hove, Brighton and Hove, United KingdomPharmaceuticalsThe Claimed Intermediate – a Structure Searchable Process Patent Database for Marketed Pharmaceutical Drugs (INNs).
Patent examining, searching, analysis and abstracting especially in the Chemical subject area.

http://www.tcipatent.com/

          

The Claimed Intermediate is an online database
which covers Process Patents for Named Marketed Pharmaceutical Drugs – whether intermediates are claimed or not – for a low-cost subscription.

• Structure Searchable
• Includes INNs in at least one major Market
• Includes Drug Synthesis often buried in a Plethora of Patents
• Informs Pipeline decisions
• Provides targeted Patent data in a Visual form
• Informs Commercial Synthesis profitability

http://www.tcipatent.com/

http://www.tcipatent.com/images/tcipatent_sample_report.pdf

shared message from Eddie Kehoe

If anybody would like a trial of the database they could contact either myself eddie.kehoe@tcipatent.com, or my wife and fellow director, Pat Kehoe (pat.kehoe@tcipatent.com).

Here are temporary logons , please request trial

(deactivated automatically in five working days):
Link: Link: www.tcipatent.com/tcidb/
Structure Searchable Patent Database for Processes covering Named Marketed Pharmaceutical Drugs (INNs). The database is an ongoing Watching Service combined with a Backward Drug Service.

Eddie Kehoe
Principal & Technical Director
Tcipatent Ltd
www.tcipatent.com

eddie.kehoe@tcipatent.com

info@tcipatent.om

tcipatent.com
Office: +44 (0)1273 736080
43 Farm Road, Hove, BN3 1FD, United Kingdom

Eddie Kehoe:
eddie.kehoe@tcipatent.com
Mobile – 07425629637
Skype – eddieskihoe

TWITTER-TCIPATENT

Pat Kehoe:
pat.kehoe@tcipatent.com
Mobile – 07585295531
Skype – patkehoe170348

Database Updates:
Recently Added Records

Aliskiren	Ambrisentan
Asenapine	Atorvastatin
Bosentan	Cabazitaxel
Cefamandole	Dasatinib
Desogestrel	Dexmedetomidine
Docetaxel	Doripenem
Doxapram	Duloxetine
Etonogestrel	Etoricoxib
Etravirine	Fluvastatin
Gefitinib	Iodixanol
Iohexol	Iopamidol
Linagliptin	Mitiglinide
Montelukast	Moxonidine
Oseltamivir	Paclitaxel
Perampanel	Pitavastatin
Pravastatin	Praziquantel
Ritodrine	Rosuvastatin
Silodosin	Sitagliptin
Ticagrelor	Ulipristal
Zidovudine

………..

photo

Coopers Cask - Pub in Hove BN3 1FB

Eddie is closeby\\\




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PÖRK CHìLLY FRY. CÜT Ñ CLÉÄÑ PÖRK ìÑ TO MÉDìMìÜM ÖR SMÄLL PìÉCÉS, WÄSH Ñ MÄRìÑÄTÉ WìJH SÄLT ÖR VìÑÉGÄR FÖR MÄX 1 .HÖÜR THÉÑ ìÑ Ä PÅÑ ÖR KÄDÄìL ADD WÅTèR Ñ MÄRìÑATÉD MÉÄT Ñ
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Making HSQC look nicer « Naturalproductman’s Blog

Malleobactin Structure Elucidated

A team of scientists based in Germany have elucidated the structure and absolute configuration of malleobactin, which is the siderophore of the pathogenic Burkholderia mallei. Siderophores are strong iron-binding agents, and act as virulence factors for pathogenic bacteria.

The virulence factor malleobactin has been shown to contain an unprecedented nitro-bearing amino acid
Read more



http://www.chemistryviews.org/details/ezine/4997511/Malleobactin_Structure_Elucidated.html





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Computed NMR spectra predicts the structure of Nobilisitine A

Nobilisitine A was isolated by Evidente and coworkers, who proposed the structure 1.¹ Banwell and co-workers then synthesized the enantiomer of 1, but its NMR did not correspond to that of reported for Nobilisitine A.; the largest differences are 4.7 ppm for the ¹³C NMR and 0.79 ppm for the ¹H NMR.²

1

Lodewyk and Tantillo³ examined seven diastereomers of 1, all of which have a cis fusion between the saturated 5 and six-member rings (rings C and D). Low energy conformations were computed for each of these diasteromers at B3LYP/6-31+G(d,p). NMR shielding constants were then computed in solvent (using a continuum approach) at mPW1PW91/6-311+G(2d,p). A Boltzmann weighting of the shielding contants was then computed, and these shifts were then scaled as described by Jain, Bally and Rablen⁴ (discussed in this post). The computed NMR shifts for 1 were compared with the experimental values, and the mean deviations for the ¹³C and ¹H svalues is 1.2 and 0.13 ppm, respectively. (The largest outlier is 3.4 ppm for ¹³C and 0.31 for ¹H shifts.) Comparison was then made between the computed shifts of the seven diasteomers and the reported spectrum of Nobilisitine A, and the lowest mean deviations (1.4 ppm for ¹³C and 0.21 ppm for ¹H) is for structure 2. However, the agreement is not substantially better than for a couple of the other diasteomers.

2

They next employed the DP4 analysis developed by Smith and Goodman⁵ for just such a situation – where you have an experimental spectrum and a number of potential diastereomeric structures. (See this post for a discussion of the DP4 method.)The DP4 analysis suggests that 2 is the correct structure with a probability of 99.8%.

Banwell has now synthesized the compound with structure 2 and its NMR matches that of the original natural product.⁶ Thus Nobilisitine A has the structure 2.

References

(1) Evidente, A.; Abou-Donia, A. H.; Darwish, F. A.; Amer, M. E.; Kassem, F. F.; Hammoda, H. A. m.; Motta, A., "Nobilisitine A and B, two masanane-type alkaloids from Clivia nobilis,"Phytochemistry, 1999, 51, 1151-1155, DOI: 10.1016/S0031-9422(98)00714-6.

(2) Schwartz, B. D.; Jones, M. T.; Banwell, M. G.; Cade, I. A., "Synthesis of the Enantiomer of the Structure Assigned to the Natural Product Nobilisitine A," Org. Lett., 2010, 12, 5210-5213, DOI:10.1021/ol102249q

(3) Lodewyk, M. W.; Tantillo, D. J., "Prediction of the Structure of Nobilisitine A Using Computed NMR Chemical Shifts," J. Nat. Prod., 2011, 74, 1339-1343, DOI: 10.1021/np2000446

(4) Jain, R.; Bally, T.; Rablen, P. R., "Calculating Accurate Proton Chemical Shifts of Organic Molecules with Density Functional Methods and Modest Basis Sets," J. Org. Chem., 2009, DOI:10.1021/jo900482q.

(5) Smith, S. G.; Goodman, J. M., "Assigning Stereochemistry to Single Diastereoisomers by GIAO NMR Calculation: The DP4 Probability," J. Am. Chem. Soc., 2010, 132, 12946-12959, DOI:10.1021/ja105035r

(6) Schwartz, B. D.; White, L. V.; Banwell, M. G.; Willis, A. C., "Structure of the Lycorinine Alkaloid Nobilisitine A," J. Org. Chem., 2011, ASAP, DOI: 10.1021/jo2016899

Absolute Configuration of (+)-Erythro-Mefloquine

 

The absolute configuration of (+)-erythro-mefloquine has been confirmed by X-ray crystallography, CD spectroscopy, and molecular modeling
Read more
http://www.chemistryviews.org/details/ezine/4948391/Absolute_Configuration_of_-Erythro-Mefloquine.html

Absolute Configuration and Antimalarial Activity of erythro-Mefloquine Enantiomers,
Alexandra Dassonville-Klimpt, Christine Cézard, Catherine Mullié, Patrice Agnamey, Alexia Jonet, Sophie Da Nascimento, Mathieu Marchivie, Jean Guillon, Pascal Sonnet,
ChemPlusChem 2013.
DOI: 10.1002/cplu.201300074

The Absolute Configuration of (+)- and (−)-erythro-Mefloquine,
Michael Müller, Claudia M. Orben, Nina Schützenmeister, Manuel Schmidt, Andrei Leonov, Uwe M. Reinscheid, Birger Dittrich, Christian Griesinger,
Angew. Chem. Int. Ed. 2013.
DOI: 10.1002/anie.201300258

1-Adamantyl cation – Predicting its NMR spectra

1-Adamantyl cation – Predicting its NMR spectra

What is required in order to compute very accurate NMR chemical shifts? Harding, Gauss and Schleyer take on the interesting spectrum of 1-adamantyl cation to try to discern the important factors in computing its ¹³C and ¹H chemical shifts.¹

1

To start, the chemical shifts of 1-adamtyl cation were computed at B3LYP/def2-QZVPP and
MP2/qz2p//MP2/cc-pVTZ. The root means square error (compared to experiment) for the carbon chemical shifts is large: 12.76 for B3LYP and 6.69 for MP2. The proton shifts are predicted much more accurately with an RMS error of 0.27 and 0.19 ppm, respectively.

The authors speculate that the underlying cause of the poor prediction is the geometry of the molecule. The structure of 1 was optimized at HF/cc-pVTZ, MP2/cc-pVTZ and CCSD(T)/pVTZ and then the chemical shifts were computed using MP2/tzp with each optimized geometry. The RMS error of the ¹²C chemical shifts are HF/cc-pVTZ: 9.55, MP2/cc-pVTZ: 5.62, and CCSD(T)/pVTZ: 5.06. Similar relationship is seen in the proton chemical shifts. Thus, a better geometry does seem to matter. The CCSD(T)/pVTZ optimized structure of 1 is shown in Figure 1.

1

Figure 1. CCSD(T)/pVTZ optimized structure of 1.

Unfortunately, the computed chemical shifts at CCSD(T)/qz2p//CCSD(T)/cc-pVTZ are still in error; the RMS is 4.78ppm for the carbon shifts and 0.26ppm for the proton shifts. Including a correction for the zero-point vibrational effects and adjusting to a temperature of 193 K to match the experiment does reduce the error; now the RMS for the carbon shifts is 3.85 ppm, with the maximum error of 6 ppm for C3. The RMS for the proton chemical shifts is 0.21ppm.

The remaining error they attribute to basis set incompleteness in the NMR computation, a low level treatment of the zero-point vibrational effects (which were computed at HF/tz2p), neglect of the solvent, and use of a reference in the experiment that was not dissolved in the same media as the adamantyl cation.

So, to answer our opening question – it appears that a very good geometry and treatment of vibrational effects is critical to accurate NMR shift computation of this intriguing molecule. Let the
computational chemist beware!

References

(1) Harding, M. E.; Gauss, J.; Schleyer, P. v. R., "Why Benchmark-Quality Computations Are Needed To Reproduce 1-Adamantyl Cation NMR Chemical Shifts Accurately," J. Phys. Chem. A, 2011, 115, 2340-2344, DOI: 10.1021/jp1103356

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