Title of Invention

PROCESS FOR SYNTHESIS OF QUINAZOLINONES AS ANTI MYCOBACTERIAL AGENTS

Abstract

A process for the synthesis of 4-(2-methyl-4-oxo-4h-quinazolin-3yl)-benzoyl pyrrolidine-2-carboxylic acid of the formula: Wherein X=H, C1, Br, H, etc., and X1=H, C1, Br, I, etc., from the starting material of anthranilic acid by using among other reagents acetic anhydride, sodium acetate, phosphorus pentoxide, pentoxide, glacial acetic acid in presencde of typically 1,4-dioxan as solvent of the kind such as herein described". the claimed compounds are active against Mycobacterium tuberculosis as per the concentrations in the preferred embodiment.  1. Niementowski, j p prakt Chem., 51, (1895) 564.

Full Text

Wherein X- H, CI, Br, H, etc., and X1 = H, CI, Br, I, etc., which can be prepared by the following references4,5,6. 4. Alvin S.Wheeler and W.M. Oates, J.Am.chem.soc, 32, 770, (1910). 5. Organic Synthesis Collective Volume 4, A revised edn of annual volumes 30-39, John wiley and Sons, Inc, Newyork, 872 (1960). 6. J.Am.Chem.Soc, 39, 441, (1917). The conversion of the formula I compounds into the compounds of formula II Wherein X= H, CI, Br, H, etc., and X, = H, CI, Br, I, etc., which can be prepared by acetylating the formula I compounds with acetic anhydride and sodium acetate. The conversion of the formula II compounds into the compounds of formula III Wherein X= H, CI, Br, H, etc., and X1 = H, CI, Br, I, etc., which can be prepared by reacting the formula II compounds with phosphorus pentoxide and para amino benzoic acid by reflux under anhydrous condition and using glacial acetic acid as solvent. The conversion of the formula III compounds into the compounds of formula IV Wherein X= H, CI, Br, H, etc., and Xi = H, CI, Br, I, etc., which can be prepared by reacting the formula III compounds with thionyl chloride by reflux under anhydrous condition and using 1,4 - dioxan as solvent. The conversion of the formula IV compounds into the compounds of formula V Wherein X= H, CI, Br, H, etc., and X1 = H, CI, Br, I, etc., which can be prepared by reacting the formula IV compounds with L-Proline by reflux under anhydrous condition and using dilute sodium hydroxide as solvent. As mentioned earlier, quinazolinone derivatives got by the present process of this invention are useful as inhibitors of pathological mycobacteria. Evaluation of the antimycobacterial activity of title compounds was determined against mycobacterium tuberculosis using isoniazid as a standard drug. Theses compounds are superior to the Isoniazid in the concentrations of 100, 10, 1,0.1 |Jg/ml. The following examples are given for the purpose of illustrating the present invention: Example 1: The method of preparation of N-acetyl anthranilic acid as in formula II will be described in this example. 5 g of Anthranilic acid was mixed with 2.9 g of sodium acetate and acetic anhydride (in slight excess) and refluxed on suitable bath under anhydrous condition for one hour. The reaction mixture was then poured into water and the product was filtered and dried. Percentage Yield: 72.2%, Melting Point: 185°C Example 2: The method of preparation of 2-Acetyl amino- 3,5, dichloro benzoic acid as in formula II will be described in this example. 8 g of 3,5- dichloro anthranilic acid was mixed with 2.2 g of sodium acetate and acetic anhydride (in slight excess) and refluxed on suitable bath under anhydrous condition for two hours. The reaction mixture was then poured into water and the product was filtered and dried. Percentage Yield: 72.68%, Melting Point: 175°C Example 3: The method of preparation of 2-Acetyl amino 3,5, dibromo benzoic acid as in formula II will be described in this example. 8 g of 3,5- dibromo anthranilic acid was mixed with 2.2g of sodium acetate and acetic anhydride (in slight excess) and refluxed on suitable bath under anhydrous condition for three hours. The reaction mixture was then poured into water and the product was filtered and dried. Percentage Yield: 87.62%, Melting Point: 210°C Example 4: The method of preparation of 2-acetyl amino- 5- bromo benzoic acid as in formula II will be described in this example. 10 g of 5-bromo anthranilic acid was mixed with 2.78g of sodium acetate and acetic anhydride (in slight excess) and refluxed on suitable bath under anhydrous condition for five hours. The reaction mixture was then poured into water and the product was filtered and dried. Percentage Yield: 75.63%, Melting Point: 120°C Example 5: The method of preparation of 2-acetyl amino- 5- iodo benzoic acid as in formula II will be described in this example. 15 g of 5-iodo anthranilic acid was mixed with 4.1g of sodium acetate and acetic anhydride (in slight excess) and refluxed on suitable bath under anhydrous condition for two hours and thirty minutes. The reaction mixture was then poured into water and the product was filtered and dried. Percentage Yield: 63.58%, Melting Point: 160°C Example 6: The method of preparation of 4-[2-methyl-4-oxo-4H-quinazolin-3-yl]-benzoic acid as in formula III will be described in this example. 4 g of N-acetyl anthranilic acid was mixed with 3.52 g of para amino benzoic acid, 3.64 g of phosphorous pentoxide and glacial acetic acid (in slight excess) and refluxed under anhydrous condition for six hours. The reaction mixture was then poured into 10 % sodium bi carbonate and the product was filtered and dried. Percentage Yield: 93.47%, Melting Point: 210°C Example 7: The method of preparation of 4-(6,8 - dichloro-2-methyl-4-oxo-4H-quinazolin-3yl)- benzoic acid as in formula III will be described in this example. 4 g of 2-Acetyl amino- 3,5- dichloro benzoic acid was mixed with 3,07 g of para amino benzoic acid, 3.18 g of phosphorous pentoxide and glacial acetic acid (in slight excess) and refluxed under anhydrous condition for eight hours and thirty minutes. The reaction mixture was then poured into 10 % sodium bi carbonate and the product was filtered and dried. Percentage Yield: 88.8%, Melting Point: 170°C Example 8: The method of preparation of 4-(6,8 - dibromo-2-methyl-4-oxo-4H-quinazolin-3yl)- benzoic acid as in formula III will be described in this example. 5 g of 2-Acetyl amino- 3,5- dibromo benzoic acid was mixed with 3.8 g of para amino benzoic acid, 3.9 g of phosphorous pentoxide and glacial acetic acid (in slight excess) and refluxed under anhydrous condition for five hours and thirty minutes. The reaction mixture was then poured into 10 % sodium bi carbonate and the product was filtered and dried. Percentage Yield: 119.4%, Melting Point: 160°C Example 9: The method of preparation of 4-(8 - bromo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoic acid as in formula III will be described in this example. 6 g of 2-Acetyl amino- 5- bromo benzoic acid was mixed with 4.6 g of para amino benzoic acid, 4.7 g of phosphorous pentoxide and glacial acetic acid (in slight excess) and refluxed under anhydrous condition for twelve hours. The reaction mixture was then poured into 10 % sodium bi carbonate and the product was filtered and dried. Percentage Yield: 93.02%, Melting Point: 155°C Example 10: The method of preparation of 4-(8 - iodo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoic acid as in formula III will be described in this example. 8 g of 2-Acetyl amino- 5- iodo benzoic acid was mixed with 6.1 g of para amino benzoic acid, 6.3 g of phosphorous pentoxide and glacial acetic acid (in slight excess) and refluxed under anhydrous condition for three hours. The reaction mixture was then poured into 10 % sodium bi carbonate and the product was filtered and dried. Percentage Yield: 109%, Melting Point: 175°C Example 11: The method of preparation of 4-[2-methyl-4-oxo-4H-quinazolin-3-yl]-benzoyl chloride as in formula IV will be described in this example. 5 g of 4-[2-methyl-4-oxa—4H-quinazolin-3-yl]-benzoic acid in 1,4 dioxan was mixed with thionyl chloride (in slight excess) and refluxed under anhydrous condition for four hours. Excess thionyl chloride was removed by distillation. The reaction mixture was then poured into ice-cold water and the product was filtered and dried. Percentage Yield: 84.66%, Melting Point: 93°C Example 12: The method of preparation of 4-(6,8 - dichloro-2-methyl-4-oxo-4H-quinazolin-3yl)- benzoyl chloride as in formula IV will be described in this example. 3.5 g of 4-(6,8 - dichloro-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoic acid in 1,4 dioxan was mixed with thionyl chloride (in slight excess) and refluxed under anhydrous condition for six hours. Excess thionyl chloride was removed by distillation. The reaction mixture was then poured into ice-cold water and the product was filtered and dried. Percentage Yield: 81.52%, Melting Point: 120°C Example 13: The method of preparation of 4-(6,8 - dibromo-2-methyl-4-oxo-4H-quinazolin-3yl)- benzoyl chloride as in formula IV will be described in this example. 5 g of 4-(6,8 - dibromo- 2-methyl-4-oxo-4H-quinazolin-3yl)-benzoic acid in 1,4 dioxan was mixed with thionyl chloride (in slight excess) and refluxed under anhydrous condition for six hours and fifteen minutes. Excess thionyl chloride was removed by distillation. The reaction mixture was then poured into ice-cold water and the product was filtered and dried. Percentage Yield: 77.07%, Melting Point: 130°C Example 14: The method of preparation of 4-(8 - bromo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl chloride as in formula IV will be described in this example. 6 g of 4-(8 - bromo- 2-methyl-4-oxo-4H-quinazolin-3yl)-benzoic acid in 1,4 dioxan was mixed with thionyl chloride (in slight excess) and refluxed under anhydrous condition for ten hours. Excess thionyl chloride was removed by distillation. The reaction mixture was then poured into ice-cold water and the product was filtered and dried. Percentage Yield: 96.77%, Melting Point: 175°C Example 15: The method of preparation of 4-(8 - iodo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl chloride as in formula IV will be described in this example. 8 g of 4-(8 - iodo- 2-methyl-4-oxo-4H-quinazolin-3yl)-benzoic acid in 1,4 dioxan was mixed with thionyl chloride (in slight excess) and refluxed under anhydrous condition for seven hours and thirty minutes. Excess thionyl chloride was removed by distillation. The reaction mixture was then poured into ice-cold water and the product was filtered and dried. Percentage Yield: 60.24%, Melting Point: 165°C Example 16: The method of preparation of l-[4-(2-methyl-4-oxo-4H-quinazolin-3-yl)-benzoyl]-pyrrolidine-2-carboxylic acid as in formula V will be described in this example. 3 g of 4-(2-methyi-4-oxo-4H-quinazolin-3-yl)- benzoyl chloride in 1,4 dioxan was mixed with 1.33 g of L-Proline in 0.1N sodium hydroxide and refluxed under anhydrous condition for six hours. The reaction mixture was then poured into 1 N hydrochloric acid and the product was filtered and dried. Percentage Yield: 66.4%, Melting Point: 83°C Example 17: The method of preparation of 1 - [4-(6,8 - dichloro-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl] - pyrrolidine -2- carboxyhc acid as in formula V will be described in this example. 2 g of 4-(6,8 - dichloro-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl chloride in 1,4 dioxan was mixed with 0.6 g of L-Proline in 0.1N sodium hydroxide and refluxed under anhydrous condition for ten hours and fifteen minutes. The reaction mixture was then poured into 1 N hydrochloric acid and the product was filtered and dried. Percentage Yield: 62.5%, Melting Point: 210°C Example 18: The method of preparation of 1 - [4-(6,8-dibromo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl] - pyrrolidine -2- carboxyhc acid as in formula V will be described in this example. 3 g of 4-(6,8-dibromo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl chloride in 1,4 dioxan was mixed with 0.9 g of L-Proline in 0.1N sodium hydroxide and refluxed under anhydrous condition for eight hours. The reaction mixture was then poured into 1 N hydrochloric acid and the product was filtered and dried. Percentage Yield: 88.23%, Melting Point: 220°C Example 19: The method of preparation of 1 - [4-(8-bromo-2-methyl-4-oxo-4H-quinazolin-3yl)- benzoyl] - pyrrolidine -2- carboxylic acid as in formula V will be described in this example. 3 g of 4-(8-bromo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl chloride in 1,4 dioxan was mixed with 0.9 g of L-Proline in 0.1N sodium hydroxide and refluxed under anhydrous condition for eleven hours and fifteen minutes. The reaction mixture was then poured into 1 N hydrochloric acid and the product was filtered and dried. Percentage Yield: 85.71%, Melting Point: 235°C Example 20: The method of preparation of 1 - [4-(8 - iodo-2-methyl-4-oxo-4H-quinazolin-3yl)- benzoyl] - pyrrolidine -2- carboxylic acid as in formula V will be described in this example. 3 g of 4-(8 - iodo-2-methyl-4-oxo-4H-quinazolin-3yl)-benzoyl chloride in 1,4 dioxan was mixed with 0.9 g of L-Proline in 0.1N sodium hydroxide and refluxed under anhydrous condition for ten hours and forty five minutes. The reaction mixture was then poured into 1 N hydrochloric acid and the product was filtered and dried. Percentage Yield: 57.14%, Melting Point: 230°C We claim 1. A novel feature of the present invention relates to the synthesis of a new quinazolinones, which contains proline amino acid instead of amino compounds. 2. A process for the preparation of formula II compounds in which the anthranilic acid and its halogenated derivatives were refluxed on sand bath to get the formula II compounds. 3. All the title compounds (A, B, C, D and E) are superior to the standard isoniazid drug. 4. Compounds derived from dibromo and mono iodo anthranilic acids (C and E) are generally superior to the other title compounds (A, B and D). 5. A process for the synthesis of quinazolinones as antimycobacterial agents substantially as herein described and illustrated. All the five title compounds synthesised were screened for in vitro anti tubercular activity against Mycobacterium tuberculosis by using Alamar Blue assay method. The standard drug, Isoniazid and the title compounds are compared for antimycobacterial activity. The activity of the title compounds against mycobacterium tuberculosis was checked at the concentrations of 100, 10, 1, 0.1 and 0.05 |Jg / ml and for the standard drug, Isoniazid respectively. All the title compounds are sensitive to organism in the concentrations of 100, 10, 1 and 0.1 µg / ml and two compounds derived from dibromo and mono iodo anthranilic acids (C and E) are sensitive at 0.05 |µg / ml. Standard drug Isoniazid is sensitive to organism only in the concentrations of 100, 10, 1 (Jg / ml.

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