Green Chemical Route for Process Development of Atenolol Intermediate

 

Dr. Nandini R. Pai * and Swapnali Suhas Patil 

Department of Chemistry, D.G. Ruparel College, Mahim, Mumbai 400016, Maharashtra, INDIA

 

ABSTRACT:

There is increasing pressure from both society and governments for chemistry-based industries to become more sustainable through development of eco-friendly products and processes that both reduce waste and prevent toxic substances from entering the environment. The Pharmaceutical industry is vitally important to the Indian economy; however the success of the industry has led to some environmental damage and a low public perception of the industry.  In order to prevent further environmental damage and to encourage people by adoption of greener and cleaner manufacturing processes.

 

 

INTRODUCTION:

Atenolol Like metoprolol competes with sympathomimetic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart and vascular smooth muscle, inhibiting sympathetic stimulation. This results in a reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension. Higher doses of Atenolol also competitively block beta(2)-adrenergic responses in the bronchial and vascular smooth muscles^.[8][9]

 

Manufacturing process of Atenolol is of four stages, the most important and critical stage is to convert PHAP (Para hydroxyl acetophenone) to PHPA (Para hydroxyl phenyl acetamide) which is generally done with sulphur and ammonia which is a pressure reaction. Gases like H₂S is generated as byproducts of this reaction. Keeping in mind the need for avoiding hazardous chemicals which harm our environment and human beings.^[10][11]

 

MATERIAL AND METHOD:

Purity of the compound was monitored on silica gel 60 F₂₅₄ purchased from Merck and solvent from Aldrich chemical Co Ltd. Anhydrous silica gel 60 was used as solid support after dehydration in oven at 100°C for 5 minutes. Mobile phase used was Benzene: Ethyl acetate (7:3) as an eluent. TLC spots were detected in UV chamber. Melting point of synthesized compound was determined on open capillary in liquid paraffin.

 

Structural interpretation was done by performing Mass spectra, IR and HPLC which were compared with reference standard.[Ref Fig 1 and 2]

 

Novel Process to synthesis PHPA by green chemistry

3.0 gm of Parahydroxy phenyl acetic acid was dissolved in 40.0 ml of Methanol at RT and 1.8gm of Ammonium Carbonate was added to above solution under stirring reaction mass was stirred for 30 min at RT, checked for complete dissolution and then slowly heated to reflux for 4-5 hrs. Reaction was monitored till completion on TLC. As soon as reaction completed 60.0 ml of di isopropyl ether was added to it under stirring reaction mass was cool to room temperature and then chilled to 10- 15°C and maintained for 30 mins and  filtered, solid obtained was washed with chilled water. Solid was dried at 55-60°C under vacuum to get para Hydroxy phenyl acetamide. Purity of the compound was matched with standard PHPA and found to be 99.89% on HPLC^[3][4] but yield was almost 28 to 30% of the current process^[5][6][7].

 

Reaction Mechanism:

            

2-(4 –hydroxyphenyl)acetic acid            4-Hydroxyphenylacetamide

 

Synthesized 4- hydroxyl phenyl acetamide intermediate of Atenolol was matched with standard 4-hydroxy phenyl acetamide by HPLC and by Mass Spectra.[1][2]

 

Fig 1 Mass Spectra of 4-hydroxy phenyl acetamide

 

Fig 2 IR spectra

 

Fig 3: Blank Chromatogram (HPLC)

 

Fig 4: WS  4-hydroxy phenyl acetamide intermediate

 

Fig 5: Sample  of 4-hydroxy phenyl acetamide   intermediate

 

CONCLUSION:

Generally reaction is carried out by Sulphur which leads to the formation and release of hazardous gases like H₂S^[7]. However by synthesizing 4-hydroxy phenyl acetamide Atenolol intermediate using above reaction, leads to green chemistry route by achieving  eliminating release of hazardous gases and also minimizing the  time required for completion of reaction. Purity of this compound is 99.89% of Standard. [Ref Fig 3, 4 and5]

 

ACKNOWLEDGEMENTS:

I am thankful to Ultratech India Ltd. and D. G. Ruparel College for providing all the necessary analytical details of the compound, required support and co-operation for executing this project. I am also thankful to Mr. Deepak U. Shanbhag, Mr. Manoj Thakur, Mr. Devi Prasad, Mr. Arun and Mr. Mahesh Afzalpurkar for their help and cooperation.

 

REFERENCES:

1.       International Conference on Harmonisation tripartite guideline (ICH), Impurities In New Drug Substances Q3A (R2), Current Step 4 version dated 25 October 2006.

2.       Arun Bahal, B. S. Bahl, A Textbook of Organic Chemistry

3.      Indian Journal of chemistry Vol 48B may 2009, pp741-745

4.       J. Chem. Pharm. Res., 2010, 2(5):7-9 Isolation of Lansoprazole intermediate impurity resulting in yield improvement

5.       Der Chemica Sinica, 2013, 4(2):122-126  Green chemical route for process development of lansoprazole intermediate  Nandini R. Pai

6.       BP, British Pharmacopoeia (2009).

7.       Name reaction by Li Jie Jack

8.       http://www.organic-chemistry.org

9.       www.rxlist

10.     http://www.wipo.int/pctdb/en/

11.     http://www.daviddarling.info/encyclopedia/alphindexv.html

12.     http://www.ias.ac.in/resonance/November2008/p1041-1048.pdf

 

 

 

Received on 24.08.2013       Modified on 15.09.2013

Accepted on 24.11.2013      © RJPT All right reserved