Optimization of the yields in the synthesis of midazolam

The benzodiazepines most frequently used in the perioperative period is midazolam (VERSED) followed distantly by diazepam (VALIUM) and lorazepam (ATIVAN)³.

Chemically Midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo [1,5-α] [1,4] benzodiazepine. It is white or yellowish crystalline powder, practically insoluble in water, freely soluble in acetone and in ethanol (96%), and soluble in methanol⁴.

Condensation of 1,4-benzodiazepines having a N-nitrosomethylamino group in the 2 position with a primary nitroalkane led to the nitroalkylidene derivatives. These nitro compounds were converted to imidazo[1,5-α][1,4]benzodiazepines by a sequence of steps involving catalytic reduction, condensation with triethylorthoacetate, and oxidation with activated manganese dioxide⁵.

• 
  Various derivatives of benzodiazepines, lorazepam, midazolam etc have been
  

• 
  British pharmacopoeia has given structure, molecular formulae, preparations, identification test, and tests for related compounds, storage condition, impurities and assay of midazolam⁴.
  
• 
  Foye WO et al., given about GABA or benzodiazepine receptors complex which is receptor for major inhibitory neurotransmitters².
  
• 
  International conference on harmonization harmonized tripartite guideline 2006 given guidelines for reporting impurity profile of new drug substances⁶.
  
• 
  Karlos DP et al., reported the synthesis of midazolam from 1,4-benzodiazepinic N-Nitrosoamidine with tosyl methyl isocyanide⁷.
  
• 
  Kamal A et al., have reported synthesis of 4(3H)-quinazolinones and pyrrolo [2,1-c][1,4]Benzodiazepines by microwave enhanced reduction of nitro and azido arenes to N-arylformamides employing Zn-HCOONH₄⁸.
  
• 
  Midazolam is 8-chloro-6-(2-flurophenyl)-1-methyl-4H-imidazo[1,5-α][1,4] benzodiazepine and it has been reported that due to the bridging of N-1nitrogen and 2-keto of the azepine ring which form a third fused ring like in the case of midazolam shows more potent sedative hypnotic activity when compared with the corresponding 1-methyl compounds⁹.
  
• 
  Anwar B et al., reported synthesis of imine containing 1,2,5-benzodiazepines-1,1-dioxides and 1,4-benzodiazepin-5-ones using iminophosphoranyl thiazine-s-oxides as precursors¹⁰.
  
• 
  Kamal A et al., described solid phase synthesis of pyrrolo[2,1-c][1,4-]benzodiazepines, a methodology based on reductive cleavage followed by cyclization employing DIBAL-H¹¹.
  
• 
  Herrero S et al., reported stereo controlled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines¹².
  
• 
  Srinivas U et al., described polyaniline-sulfate as an efficient catalyst for the preparation of benzodiazepines and 2-phenyl benzimidazoles in excellent yields¹³.
  
• 
  Gorog S et al., described the role of HPLC/diode-array UV spectroscopy in the identification of minor impurities ion drug substances¹⁴.
  
• 
  Argentine MD et al., described strategies for the investigation and control of process related impurities in the drug substances, they discussed quality assessment of starting materials from sources and the impact of starting material impurities on the impurity profile of drug substances¹⁵.
  
• 
  Rao RN et al., reviewed impurity profile data of analgesic, antibiotics, antiviral, antihypertensive, antidepressant, gastrointestinal and antineoplastic agents by HPLC¹⁶.
  
• 
  Laviand L et al., have developed a rapid, sensitive and selective HPLC method coupled with UV detection for the determination of midazolam and its synthesis precursors¹⁷.
  
• 
  Lepper ER et al., developed a novel method of HPLC with mass spectroscopy for the quantitative determination of the cytochrome P4503A phenotyping probe midazolam in human plasma¹⁸.
  

The present work is an attempt to:

1. 
   Synthesis: To synthesize Midazolam using standard route of synthesis.
   
2. 
   Isolation: To design an effective isolation procedure for crude
   

3. 
   Purification: To increase/optimize the yield of pure Midazolam by
   

Data will be obtained from Internet facilities, Literature and related articles from libraries of Krupanidhi College of Pharmacy, Indian Institute of Sciences, Bangalore &

Publications and Journals of Medicinal chemistry.

Data from observations and inference will be collected on the basis of experiments to be carried out during the course of research in laboratories of Krupanidhi College of Pharmacy and Lake Chemicals Pvt.Ltd., Bangalore.

This study aims to improve/optimize the yield of Midazolam with decreased impurity using various purification procedures and to study the impurity profile of the product at various stages of purification by HPLC.

Characterization of synthesized compounds will be performed by using modern analytical techniques like Melting point, IR, NMR and Mass spectroscopy, TLC.

Not Applicable.

Not Applicable.

1. 
   Burger A. Abraham DJ, editor. Burger’s Medicinal Chemistry And Drug Discovery. 6^th ed. Hoboken (New Jersey): A John Wiley and Sons, Inc., Publication; 2003. p. 553 (Nervous System Agents;vol 6).
   
2. 
   Foye WO, Lemke TL, Williams DA. Foye’s principles of Medicinal Chemistry. 5^th ed. Philadelphia: Lippincott Williams and Wilkins; 2002. p. 374,488.
   
3. 
   Goodman & Gilman. Brunton LL, Lazo JS, Parker KL editors. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11^th ed. New York: McGraw-Hill Medical Publishing Division, International ed; 2006. p. 361.
   
4. 
   British Pharmacopoeia, 2009. p. 1377-79 (vol 2).
   
5. 
   Walser A, Benjamin LE, Flynn ST, Mason C, Schwartz R, Fryer RI. Quinazolines and 1,4-Benzodiazepines. 84.¹ Synthesis and Reactions of Imidazo[1,5-α][1,4]benzodiazepines. J Org Chem Aug 15;43(5):936-44.
   
6. 
   Impurities in new drug substances, International conference on harmonization, ICH Harmonized Tripartite Guideline Oct 2006.
   
7. 
   http://www.thiemeconnect.com (access on 11 Nov.)
   
8. 
   Kamal A, Reddy KS, Prasad BR, Babu AH, Ramana AV. Microwave enhanced reduction of nitro and azido arenes to N-aryl formamaides employing Zn-HCOONH₄. Synthesis of 4(3H)-quinazolinones and pyrrolo [2,1-c][1,4] benzodiazepines. Tetrahedron Lett 2004 July 20;45:6517-21.
   
9. 
   Gringauz A. Introduction to Medicinal chemistry. How drugs act and why. New York: Wiley-VCH Inc. p. 578-82.
   
10. 
    Anwar B, Grimsey P, Hemming K, Krajniewski M Loukou C. A thiazine-s-oxide, Staudinger aza-wittig based synthesis of benzodiazepines and benzothiadiazepines. Tetrahedron Lett 2000 Oct 11;41:10107-10.
    
11. 
    Kamal A, Reddy L, Devaiah V, Shankaraiah N, Reddy YN. A new approach for the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines involving reductive cleavage. Tetrahedron Lett 2004 Aug 17;45:7667-69.
    
12. 
    Herrero S, Garcia-Lopez T, Cenarruzabeitia E, Rio JD, Herranz R. Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building. Tetrahedron 2003 Apr 30;59:4491-99.
    
13. 
    Srinivas U, Srinivas CH, Narender P, Rao VJ, Palaniappan S. Polyaniline-sulfate salt as an efficient and reusable catalyst for the synthesis of 1,5-benzodiazepines and 2-phenyl benzimidazoles. Catal Commun 2006 May 25;8:107-10.
    
14. 
    Gorog S, Bihari M, Csizer E, Dravetz F, Gazdag M, Herenyi B. Estimation of impurity profiles of drugs and related materials Part 14: The role of HPLC/diode-array UV spectroscopy in the identification of minor components (impurities, degradation products, metabolites) in various matrices. J Pharm Biomed Anal 1995 Apr 24;14:85-92.
    
15. 
    Argentine MD, Owens PK, Olsen BA. Strategies for the investigation and control of process-related impurities in drug substances. Adv Drug Deliv Rev 2007;59:12-28.
    
16. 
    Rao RN, Nagaraju V. An overview of the recent trends in development of HPLC methods for determination of impurities in drugs. J Pharm Biomed Anal 2003 Jan 5;33:335-77.
    
17. 
    Laviand L, Llohente I, Bayod M, Blanco D. In process control of Midazolam synthesis by HPLC. J Pharm Biomed Anal 2003 Jan 27;32:167-74.
    
18. 
    Lepper ER, Hicks JK, Verweij J, Zhai S, Figg WD, Sparreboom A.