Inductive electrospray ionization (iESI) is an ambient ionization method that is particularly well-suited to online reaction monitoring. It allows the potential of electrospray mass spectrometry (MS) to be realized as a routine process analytical technology (PAT) tool to monitor practical synthetic reactions in real time. In this study, a synthetic route to Anagliptin (target API) was successfully monitored using online iESI-MS. Starting materials not seen by traditional reaction monitoring tools (HPLC-UV/Vis and GC-FID) were observed, as well as water-sensitive reagents and intermediates which cannot easily be followed by other methods. Online tandem mass spectrometry (MS/MS) was used to characterize chemical species in the reaction mixture. Impurities and byproducts were identified, and information on the progress of byproduct formation enabled implementation of strategies to eliminate these byproducts in the course of the reaction. This work demonstrates how iESI-MS can be employed to obtain comprehensive information and solutions to some practical problems that occur in small-molecule synthetic reaction monitoring.

Online Inductive Electrospray Ionization Mass Spectrometry as a Process Analytical Technology Tool To Monitor the Synthetic Route to Anagliptin

Xin Yan†, Ryan M. Bain†, Yafeng Li†, Ran Qiu†, Tawnya G. Flick*‡, and R. Graham Cooks*†

† Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States

‡ Department of Analytical Research & Development, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, California 91320, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00039

Publication Date (Web): April 12, 2016

Copyright © 2016 American Chemical Society

*E-mail for T.G.F.: tflick@amgen.com., *E-mail for R.G.C.: cooks@purdue.edu.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00039

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Yazd, Iran

Yazd
City in Iran
Yazd is the capital of Yazd Province, Iran. The city is located 270 km southeast of Esfahan. At the 2011 census, the population was 1,074,428 in 270٬575 families. Wikipedia
Weather: 26°C, Wind N at 8 km

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PIPERONAL

PIPERONAL

HNMR peaks  Piperonal.

As I assigned number 1-5, i have identified 5 different types of hydrogens that are going to show the five different peaks on the HNMR spectrum. Hydrogens labeled as number are equivalent so there are no coupling and are going to show a singlet but with the height of 2H. (S,2H). 

Hydrogen labelled as 2 is going to show a doublet (d,1H) because of spin-spin splitting with Hydrogen 3 on the same aromatic ring. Hydrogen 2 and 3 are adjacent to each other which makes them have the spin-spin splitting. the J constant for this Hydrogen is about 8Hz which we can calculate by the difference of the ranges in PPM an multiplying by 300 . 

and after the calculation i have found it to be about 7.2 which is close to 8 is valid for out argument. Hydrogen 3 show two spin-spin splitting because it it adjacent to Hydrogen 2 and meta relation to Hydrogen 5 on the aromatic ring. so Hydrogen 3 has (d,d,1H) two doublets next to each other. Hydrogen 4 is an aldehyde and had no coupling effect from the aromatic ring and therefore shows only a singlet (S,1H). also we know it is going to lie between the ranges of 9-10 because it's an aldehyde.

 As i mentioned before Hydrogen 5 is experiencing meta coupling effect because of Hydrogen 3 on the aromatic ring so it is going to show a doublet (d,1H). Hydrogens 2,3,and 5 all lie between the ranges of about 7-8. Also Hydrogen 5 is going to have a J constant of about 2Hz. After the integration we see that our assumptions are correct and the length of the integration lines correlates to the numbers of hydrogen.


IR




Piperonal (1,3-benzenodioxole-5-carbaldehyde)




The C=O double bond can be found in the range from 165 to 210 ppm. The C=O bond in this molecule shows up at about 190 ppm. A C-O single bond lies between 55 and 90 ppm and can be found for piperonal at about 78 ppm. The remaining carbons in the piperonal molecule are part of a benzene ring.

Aromatic carbons have a chemical shift of 115 to 150 ppm. As can be seen below, there are numerous peaks that fall in this range. It can be expected that the carbons bonded to the oxygen atoms have a stronger chemical shift due to the electronegativity of the oxygen. 

The peaks for these two carbons could fall in the 145 to 160 ppm range. The carbon attached to the carbonyl group would also have a greater chemical shift, and could be estimated to be in a range from 120 to 135 ppm.


MASS

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Yazd, Iran

Yazd
City in Iran
Yazd is the capital of Yazd Province, Iran. The city is located 270 km southeast of Esfahan. At the 2011 census, the population was 1,074,428 in 270٬575 families. Wikipedia
Weather: 26°C, Wind N at 8 km

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