Reaction of 1-Carboxymethyluracil with Amino acid alkyl ester hydrochloride

Introduction

Heterocyclic compounds [1, 2] have received considerable attention due to their wide range of pharmacological activities. Pyrimidine is most important heterocyclic compound with two nitrogen atoms. Different Pyrimidine derivatives [3] comprises of interesting medicinal properties. Uracil is among the five nucleobases like adenine, guanine, cytosine, and thymine but is only found in RNA. 5-Fluorouracil [4] is found to be antimetabolite of uracil and is one of most widely used antineoplastic agents. Antimicrobial properties of various nitro uracil derivatives have been studied. Peter G. Schultz et al [5] have reported the preparation of 1-carboxymethyluracil methyl glycinate amide and 1-carboxymethyluracil glycine amide by the photocleavage reaction of uracil dimer.

By considering the above facts we have started our work on the synthesis of uracil derivatives and therefore reporting here a method for the synthesis of uracil derivative 3.

Chemistry

The first step involves the preparation of 1-carboxymethyluracil by the usual reported method [5-7]. The synthesis of the 1-carboxymethyluracil  alkyl glycinate amide  derivatives 3 was carried out by the reaction of 1-carboxymethyluracil 1 and amino acid alkyl ester hydrochloride 2 at 0°C in the presence of Et₃N_, DCC/HOBt  as the coupling reagent [8-10] .The desired compounds 3 was isolated as the sole product in good yield. Scheme 1 represents the sequence of reaction for the synthesis of the desired compounds 3.The structure of all the synthesized compounds were characterized by means of IR, ¹H NMR and mass spectra.

Result and Discussion

The present work describes the synthesis of 1-carboxymethyluracil alkyl glycinate amide derivatives 3 synthesized from 1-carboxymethyluracil 1 and amino acid alkyl ester hydrochloride 2 in the presence of Et₃N_, DCC/HOBt. The structure of the synthesized compounds 3 was characterized by means of IR, ¹H NMR, mass spectra and all data are in accordance with the assigned structure 3.

Experimental

Spectral data were recorded as follows: IR Spectra was run on a Perkin Elmer and Schimadzu 8201 PC, FT Infrared spectrophotometer (ν in cm^-1). Mass spectra were recorded on Jeol SX-102 (FAB). ¹H NMR has been recorded on Bruker Avance-300 (300 MHz) and chemical shifts (δ in ppm) were reported relative to the solvent peak (CDCl₃+DMSO-d₆) or TMS as internal standard. Signals were designated as follows: s, singlet; bs, broad signal; d, doublet; t, triplet; m, multiplet. Melting points were determined by open capillary method and were uncorrected. All reagents used were of commercial grade and used as received without further purification unless otherwise specified. Dry DMF was used wherever required. Reagent grade solvents were used in all other cases unless otherwise specified. Organic solutions were dried over anhydrous Na₂SO₄ and concentrated at reduced pressure.

General Procedure for Synthesis of 1-Carboxymethyluracil Alkyl Glycinate Amide 3 A-B

To a well stirred solution of amino acid alkyl ester hydrochloride 2 (12 mmol) suspended in anhydrous DMF (12 mL) neutralized with triethylamine in portions (12 mmol) at 0^oC, 1-caboxy methyluracil 1 (12 mmol) and 1-hydroxy benzotriazole (12 mmol), dissolved in dry DMF (8 mL) were added consequently in the reaction flask in the small portions. The mixture was stirred at the same temperature for few min and dicyclohexyl carbodiimide (DCC, 12 mmol) dissolved in dry DMF (16 mL) was added drop wise in 30 min under the same condition. Stirring was continued in ice-cold condition for 4 h and left for overnight at the room temperature. The precipitated dicyclohexylurea (DCU) was filtered off and washed with DMF and combined filtrates were evaporated to dryness under reduced pressure. The solid residue was triturated with ethyl acetate and the resulting organic layer was washed with H₂O (2×60 mL), ice-cold 1N HCl (3×60 mL), water (2×60 mL), saturated NaHCO₃ (3×60 mL) and finally with H₂O (3×80 mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to get the desired product.

Scheme 1  Click here to View scheme

 

Spectral characterization of synthesized compounds 3a and 3b are given below

Carboxymethyluracil Methyl Glycinate Amide (3a)

Yield: 90%; mp: 190 ⁰C; elemental analysis: Anal. Calcd. for C₉H₁₁N₃O₅: C,44.82, H,4.60, and N,17.42, Found: C,44.70, H,4.81, and N,17.11; IR (KBr, cm^-1 ): 301, 3015, 2825, 1740, 1680, 1550, 1450, 1225, 1080, 740, 625 cm^-1; ¹H-NMR (300 MHz,CDCl₃+DMSO-d₆) δ(ppm): 3.52 (s, 3H, -OCH₃), 3.84(d, 2H, -CH₂-), 4.40 (s, 2H, -CH₂-), 5.50 (d, 1H, Ar-H) , 7.50 (d, 1H, Ar-H),8.60 (bs, ,1H ,NH) ,11.10 (s, 1H, NH); MS m/z 241 (M⁺).

Carboxymethyluracil Ethyl Glycinate Amide (3b)

Yield: 85%; mp: 210 ⁰C; elemental analysis: Anal. Calcd. for C₁₀H₁₃N₃O₅:C,47.06, H,5.13, N,16.46; found: C,47.45, H,5.51, N,16.23; IR (KBr, cm^-1):3425, 3300, 3125, 2805, 1700, 1665, 1566, 1430, 1228, 1005, 752, 650; ¹H-NMR (300 MHz, CDCl₃+DMSO-d₆) δ(ppm): 1.20(t,3H, -CH₂CH₃),  3.70(d,2H,-CH₂),4.15 (q, 2H, -OCH₂CH₃), 4.40 (s, 2H, -CH₂-), 5.40 (d, 1H, Ar-H) ,7.30 (d, 1H, Ar-H), 8.33 (bs, 1H, NH), 10.50(s, 1H, NH); MS m/z 255 (M⁺).

Acknowledgements

This work was financially supported by the University Grant Commission, New Delhi (Grant no 31-128/2005 SR). We thank to Sophisticated Analytical Instrument Facility (SAIF), Central Drug Research Institute, Lucknow-226001(India) for providing spectral data on payment basis.

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