5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one

          

 COSY PREDICT

                      

1H NMR PREDICT

                      

¹H NMR (DMSO-d₆, 400 MHz): δ_H 0.95 (3H, d, H4), 3.09–3.23 (2H, m, H2), 3.29–3.49 (5H, m, H14, H11, H3), 3.94–4.04 (2H, m, H5), 8.14 (1H, s, H8), 8.02 (1H, s, H9).

                      

13C NMR PREDICT

 

                      

¹³C NMR (DMSO-d₆, 100 MHz): δ_C 50.54 (C2), 54.33 (C3), 11.28 (C4), 52.31 (C5), 166.81 (C6), 147.15 (C7), 128.95 (C8), 135.96 (C9), 147.07 (C10), 51.93 (C11, C14), 172.41 (C12, C13);

 

 

                      

Houben-Weyl methods of organic chemistry, 4th ed.; Vol. E 9c Hetarenes III part 3; p 279.

5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one (Impurity A)

M.p.: 252.09 °C.

 

¹H NMR (DMSO-d₆, 400 MHz): δ_H 0.95 (3H, d, H4), 3.09–3.23 (2H, m, H2), 3.29–3.49 (5H, m, H14, H11, H3), 3.94–4.04 (2H, m, H5), 8.14 (1H, s, H8), 8.02 (1H, s, H9).

 

¹³C NMR (DMSO-d₆, 100 MHz): δ_C 50.54 (C2), 54.33 (C3), 11.28 (C4), 52.31 (C5), 166.81 (C6), 147.15 (C7), 128.95 (C8), 135.96 (C9), 147.07 (C10), 51.93 (C11, C14), 172.41 (C12, C13);

                       

 

 

 

HRMS (ESI) calcd for C₁₃H₁₇O₃N₆: 305. 13338 ([M + H]⁺), found; 305.13566([M + H]⁺).

 

IR (KBr, cm^–1): 3248.13 (NH), 2970.38 and 2931.80 (CH), 1705.07 and 1689.64 (C═O), 1564.27 (NH bending), 1512.19 (C═N).

                       

Study on the Isolation and Chemical Investigation of Potential Impurities in Dexrazoxane Using 2D-NMR and LC-PDA-MS

Vinodh Guvvala^§†, Venkatesan Chidambaram Subramanian^*†, Jayashree Anireddy^§, and Mahesh Konda^*† 

^§ Centre for Chemical Science & Technology, Institute of Science & Technology, Jawaharlal Nehru Technological University, Hyderabad 500085, Telangana, India

^†Gland Pharma Ltd, Research and Development, D.P.Pally, Hyderabad 500043, Telangana, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00219

Publication Date (Web): December 7, 2016

Copyright © 2016 American Chemical Society

*E-mail: venkatesan@glandpharma.com. Phone: 040-30510999 Ext: 280. Fax: 30510800., *E-mail: maheshk@glandpharma.com. Phone: 040-30510999 Ext: 280. Fax: 30510800.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00219

 

Vinodh Guvvala

 

 

 

A chemical investigation of process related impurities associated with the synthesis of dexrazoxane was performed. The degradation product of dexrazoxane is known in the literature; however, the information related to process impurities is not available. For the first time, two process related impurities were isolated, characterized, and confirmed by their individual chemical synthesis. The present study describes the isolation methods of the impurities and their structural elucidation using IR, ¹H, ¹³C, 2D NMR, and mass spectrometry. The identification of these impurities would be highly valuable for the quality control during the production of the dexrazoxane drug substance

The U.S. Food and Drug Administration (FDA)(5) and the European Medicine Agency (EMA)(6) require analytical characterization not only for the active pharmaceutical ingredient (API), but also for its key starting materials and advanced intermediates. The determination of a drug substance impurity profile, including especially known pharmacopeial impurities, as well as other unknown impurities, could have a significant impact on the quality and the safety of the drug products. The health implications of the impurities could be significant because of their potential mutagenic or carcinogenic effects. Therefore, the International Conference on Harmonization (ICH) has set a high standard for the purity of drug substances.(7) If the dose is less than 2 g/day, then impurities over 0.10% are expected to be identified, qualified, and controlled. If the dose exceeds 2 g/day, then the qualification threshold is lowered to 0.05%. It is therefore essential to monitor and control the impurities in both the drug substance (API) and the drug products.

1. 5 Guidance for Industry on Abbreviated New Drug Applications: Impurities in Drug Substances; Availability;Fed. Regist. 2009, 74, 34359– 34360.
   

    
2. 6.The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline: Impurities in New Drug Substances Q3A (R2); IGH: Geneva, Switzerland, 2006.
   

    
3. 7.International Conference on Harmonization; revised guidance on Q3A impurities in new drug Substances; Availability; Fed. Regist. 2003, 68, 6924– 6925.
   

    

//////////5-(2-(3-Oxopiperazin-1-yl) propyl)-5,6-dihydropteridin-7(8H)-one

O=C1Nc3ncncc3N(C1)[C@@H](C)CN2CC(=O)NC(=O)C2

 

2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

1-Piperazineacetic acid, 4-(4-chlorophenyl)-α,α-dimethyl-, ethyl ester

2-[4-(4-Chlorophényl)-1-pipérazinyl]-2-méthylpropanoate d'éthyle

Ethyl 2-[4-(4-chlorophenyl)-1-piperazinyl]-2-methylpropanoate

Ethyl-2-[4-(4-chlorphenyl)-1-piperazinyl]-2-methylpropanoat

1206769-44-9

2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester (en)

AGN-PC-0JIRMK

AKOS016034964

ethyl 2-[4-(4-chlorophenyl)piperazin-1-yl]-2-methylpropanoate

MWt310.819

MFC16H23ClN2O2

 

 

NMR IS EASY

 

 

1H NMR PREDICT

 

ACTUAL VALUES........¹H NMR (400 MHz, CDCl₃): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH₂-CH₃), 1.35 (s, 6H, 2 x CH₃), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 4.20 (q, 2H, J = 7.2 Hz, -CH₂-CH₃), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).

13C NMR PREDICT

 

ACTUAL VALUES........¹³C NMR (100 MHz, CDCl₃): δ ppm 14.3 (CH₃), 22.7 ((CH₃)₂), 46.6 (-CH₂-N-CH₂-), 49.7 (-CH₂-N-CH₂-), 60.5 (O-CH₂), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).

 

 

Paper

To a solution of 4-(4-chlorophenyl)piperazine dihydrochloride 1 (5.0 g, 0.0185 mol) in DMSO (30 ml), anhydrous cesium carbonate (30.0 g, 0.0925 mol), sodium iodide (1.39 g, 0.0093 mol) and ethyl 2-bromo-2-methylpropanoate 2 (3.97 g, 0.02 mol) were added. The resulting mixture was stirred at 25-30^oC for 12 hours. The reaction mass was diluted with water (200 ml) and extracted with ethyl acetate (2 x 200 ml). The ethyl acetate layer was washed with water (2 x 100 ml), dried over anhydrous sodium sulfate (10.0 g) and concentrated under vacuum. The crude product thus obtained was purified by column chromatography (stationary phase silica gel 60-120 mesh; mobile phase 10% ethyl acetate in hexane). The title compound 3 was obtained as a white solid (4.73 g, 82 %).

 

Melting Point: 56^oC.

 

EI-MS m/z (rel. int. %): 311 (100) [M+1]⁺, 236(40), 197(60), 154(45).

 

IR ν _max (KBr) cm^-1: 2839-2996 (C-H aliphatic); 1728 (C=O), 1595, 1505 (C=C aromatic), 1205 (C-O bending), 758 (C-Cl bending).

 

¹H NMR (400 MHz, CDCl₃): δ ppm 1.27 (t, 3H, J = 7.2 Hz, -CH₂-CH₃), 1.35 (s, 6H, 2 x CH₃), 2.74-2.76 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 3.14-3.17 (m, 4H, J = 4.8 Hz, -CH₂-N-CH₂-), 4.20 (q, 2H, J = 7.2 Hz, -CH₂-CH₃), 6.81-6.83 (d, 2H, J = 6.8 Hz, phenyl protons), 7.17-7.20 (d, 2H, J = 6.8 Hz, phenyl protons).

 

¹³C NMR (100 MHz, CDCl₃): δ ppm 14.3 (CH₃), 22.7 ((CH₃)₂), 46.6 (-CH₂-N-CH₂-), 49.7 (-CH₂-N-CH₂-), 60.5 (O-CH₂), 62.4 (N-C-), 117.0, 124.3, 128.8, 149.8 (aromatic carbons), 174.3 (C=O).

 

Elemental analysis: Calculated for C₁₆H₂₃ClN₂O₂: C, 61.83%, H, 7.46%, N, 9.01%; Found: C, 61.90%, H, 7.44%, N, 8.98%.

 

Molbank 2009, 2009(3), M607; doi:10.3390/M607

http://www.mdpi.com/1422-8599/2009/3/M607

Synthesis of 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropanoic Acid Ethyl Ester

Hari N. Pati ^1,* ,Bijay K. Mishra ¹ andVijay S. Satam ²

 

¹Department of Chemistry, Sambalpur University, JyotiVihar-768019, Orissa, India

²Institute of Chemical Technology (ICT), Matunga, Mumbai-400019, Maharashtra, India

 

^*Author to whom correspondence should be addressed.

Received: 17 May 2009 / Accepted: 30 June 2009 / Published: 27 July 2009

 

Bijay K Mishra

Professor at Sambalpur University, Chemistry Department

Abstract

The title compound was synthesized by N-alkylation of 4-(4-chlorophenyl)piperazine with ethyl 2-bromo-2-methylpropanoate and its IR, ¹H NMR, ¹³C NMR and Mass spectroscopic data are reported.

 

Keywords: 2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-methylpropionic acid; N-alkylation; 4-(4-Chlorophenyl)piperazine

/////////

CCOC(=O)C(N1CCN(CC1)c1ccc(cc1)Cl)(C)C