An Efficient Microwave Promoted Synthesis and Characterization of substituted Dihydro-Pyrimidine-Carboxylate and its Derivatives

 

Bindiya Sharma*, Anamika Jain,  Navneeta Upadhyay

Department of Chemistry, Acropolis Technical Campus, Indore- 425020,  (M.P.) India.

 

ABSTRACT:

Green protocol for the synthesis of series of substituted dihydro-pyrimidine-carboxylate using solid support has been designed with the assistance of microwave irradiation technique. Purpose of green synthesis via microwave irradiation is to proceed with all the synthetic procedures which are eco friendly and economic in terms of better yields, shorter reaction time as compared to conventional methods. The success of reaction was observed by physical methods like melting point, TLC, molecular weight and formula. On completion of reaction, reaction products were characterized in details using physical and chemical and spectral techniques such as melting point, IR, NMR, FTIR, Mass spectra etc. Not only is direct microwave irradiation technique able to reduce reaction times from hours to minutes, but it is also known to reduce side reactions, increase yields and improve reproducibility. The obtained products were of moderate to good yields.

 

 

 

INTRODUCTION:

The use of microwave irradiation technique and solvent free reactions in organic synthesis has received a great amount of attention especially within the pharmaceutical and academic arenas. It is a new enabling environmentally benign technology for drug discovery and development because of its rapid reaction rates, cleaner reaction conditions and ease of manipulation¹. From the literature review it is evident that dihydro-pyrimidines systems exhibit many biological properties particularly antimicrobial activity. Polyfunctionalized dihydropyrimidines represent a heterocyclic system of remarkable pharmacological properties such as antiviral, antitumor, antibacterial, and anti-inflammatory properties. These have recently emerged as important target molecules due to their therapeutic and pharmacological properties² such as antiviral³, antimitotic⁴ ,anticarcinogenic⁵.

 

 

One of the most potent drug synthesized was 4‐subsituted‐1,2,3,4‐ tetrahydropyrimidine derivative, which has been found to be potent anti‐hypertensive, calcium channel antagonist that is comparable with standard drug Nifedipine^6,7.

 

In 1893, the synthesis of functionalize 3,4-dihydropyrmidine 2-(one H) ones (DHPMs) by a three compound condensation reaction of an aromatic aldehyde, urea and ethyl aceto acetate, was reported for first time by P. Biginelli. In post decade, such Biginelli type dihydropyrimidines have received a considerable amount of attention, due to interesting pharmacological property associated with calcium channel blocker activity, antihypertensive activity, antibacterial and antimicrobial activity. Several improvised reaction protocols for the synthesis of Biginelli compounds have been reported in past several decades, either by modification of the classical one-pot Biginelli reaction, novel multi-step methods, use of combinatorial approaches, by using different catalysts and many more. These methods suffer from disadvantages like use of high boiling and use of hazardous solvents, strong acidic conditions, high temperature, long reaction times, formation of regioisomeric products and low yields. Therefore, there was a need for designing and improving the synthetic methodologies towards this class of compounds. As compared to traditional methods the use of green protocols like employing microwave irradiated technique has become increasingly popular within the pharmaceutical, drug discovery and academic arenas, because of its high-yielding and clean approaches⁸.

 

Over the past few years several lead-compounds were developed having wide range of biological and pharmacological activities having superior in potency and duration of antihypertensive activity to classical DHP drugs. Dihydropyrimidines and their derivatives have attracted considerable attention in natural and synthetic organic chemistry because of their biological and medicinal properties. Cyclocondensation of aldehyde, β-ketoester, and urea or thiourea, using several catalysts acidic in nature like Amberlyst-70, Nafion-NR-50, KSF clay and dry acetic acid using microwave irradiation in moderate to high yields is one of the most useful multi-component reactions⁹.

 

DHPM derivatives which have proved as very effective calcium channel modulators are extensively studied for their structure-activity relationships and also to get further details into molecular interactions at the receptor level^10-16.

 

MATERIAL AND METHODS:

Chemicals and reagents:

In consideration to sustainable chemistry, in the current procedure, the mild and efficient synthetic protocols for the synthesis of compounds is described through eco-friendly green chemistry approach with the help of microwave irradiation technique by using solid support. The microwave assisted synthesis were carried out using locally modified domestic microwave synthesizer  monitored manually and temperature maintained at a constant value 140°C within the power modulation of 980 W. All reagents were obtained from Merk Chemicals Limited. Solvents used were of analytical grade and whenever required, were purified and dried by standard methods.

 

Instrumentation:

The designed compounds were successfully synthesized and characterized. Open capillary tube method was used to determine the melting points and were uncorrected. Each step for the formation of the compounds was continuously monitored on silica gel-G plates of 0.4 mm thickness using TLC technique and spot location was done by iodine. Infrared spectra was recorded in Shimadzu 8201 FT IR spectrophotometer. Ultraviolet spectra was recorded by making use of Shimadzu 1601 UV-visible spectrophotometer. Final compounds were characterized by Mass spectrum were determined using Shimadzu GC-MS-QP-2000 mass spectrometer using Direct Inlet Probe technique. H NMR (δ, ppm)  spectra was recorded in CDCl₃ or DMSO with TMS as internal standard using on Bruker Advance III NMR spectrophotometer at 500 MHz. Elemental analysis was performed on a Vario EL III Elemental Analyzer using sulfanilamide as standard.

 

Experimental Procedure:

Scheme of Reaction:

The desired compounds abbreviated as code PTC: 01 – 15 were synthesized through microwave synthesis irradiation technique by using solid support resulting in the formation of new improved synthesized compounds with comparatively higher yields in lesser time. Fuller’s earth was prior coated with ZnCl₂, which fulfills the requirement of the Biginelli condensation.

 

Scheme I: Preparation of n-butyl acetoacetate:

In order to obtain the target compound we first need to synthesize butyl acetoacetate. Initially the mixture of ethyl acetoacetate and butyl alcohol along with toluene and sodium ethoxide as catalyst was taken in a round bottomed flask. The mixture was made alcohol free by using a distillation condenser. The mixture was refluxed for approximately 5-6 hours at about 110-120 °C. Later on the catalyst was filtered and the filtrate was concentrated to obtain the product in the crude form. Butyl acetoacetate was distilled and collected for further reaction.

 

 

 

Scheme II: Preparation of n-butyl-6-methyl-4(substituted)phenyl-2-thio-oxo-1,3-N,N-dimethyl-2,4-dihydropyrimidine-5-carboxylate:

Thus a mixture of n-butyl acetoacetate was obtained from Scheme No. I along with appropriate aldehyde and thiourea were taken in Microwave flask containing solid support in the form of Fuller’s earth. The mixture was mixed by stirring for 5-10 minutes and a homogeneous mixture was obtained.  The mixture was then irradiated in the domestic type microwave oven 980 W with a frequency 2450 MHz. for 7 - 10 minutes. After the completion of reaction (reaction monitoring by TLC), the reaction-mixture was then allowed to cooled at room temperature. After cooling at room temperature water (50 ml) was added to it and extracted with 25 ml CHCl₃. The product formed was filtered off, washed with ethanol, dried and recrystallized from suitable solvent. The product was dried over anhydrous Na₂SO₄ and the solvent was removed by vacuum under reduced pressure. The solid thus obtained was further purified by recrystallization from ethanol to give a pure compound as pale yellow crystals as shown in (Scheme No. II).

 

 

 

RESULT AND DISCUSSION:

A series of synthesized compounds of substituted n-butyl-6-methyl-phenyl-2-thio-oxo-1,3-N,N-dimethyl-2,4-dihydropyrimidine-5-carboxylate (PTC : 01 – 15) were obtained using microwave irradiation technique with a mixture of butyl acetoacetate, suitable aldehyde, and thiourea  as per the Scheme No. I and II. After each cycle of microwave exposure the TLC was done to check conversion of reaction in good to better yields (Table 1).

 

Table 1: Results of synthesized compounds:

Comp. Code	Substitution (R)	MF	MW	MP (°C)	Yield %
PTC-01	H	C18H24N2O2S	332	206-208	60
PTC-02	2-OCH3	C19H26N2O3S	362	187-188	60
PTC-03	2,4-(OCH3)2	C20H24N2O4S	388	203-204	62
PTC-04	2,4-(OC2H5)2	C22H30N2O5S	434	196-198	62
PTC-05	2-Cl	C18H23ClN2O2S	366.5	210-212	52
PTC-06	3-Cl	C18H23ClN2O2S	366.5	204-206	56
PTC-07	4-Cl	C18H23ClN2O2S	366.5	214-216	55
PTC-08	2-NO2	C18H23N3O4S	377	190-192	61
PTC-09	4-NO2	C18H23N3O4S	377	202-204	59
PTC-10	2-OH	C18H24N2O3S	348	208-210	57
PTC-11	4-OH	C18H24N2O3S	348	216-218	55
PTC-12	4-F	C18H23FN2O2S	350	195-197	50
PTC-13	4-CH3	C19H26N2O2S	346	187-189	53
PTC-14	4-OCH3	C18H25N3O2S	347	234-236	61
PTC-15	[2,3] Dimethyl	C20H28N2O2S	360	228-230	58

 

Spectral Analysis of synthesized compounds:

The desired compounds were synthesized as per Scheme No. I and II and the structures were elucidated by physicochemical and spectroscopic data. Infrared spectra was recorded using Shimadzu 8201 FT-IR spectrophotometer. IR spectral study for newly synthesized dihydropyrimidine derivatives shows the stretching vibration around 3100-3200 cm^-1 for secondary amine (>NH). The symmetric and asymmetric C-H stretching vibration of methyl and methylene group was observed between 2850-2990 cm^-1). Methyl and methylene C-H bending vibration was shown around 1380 and 1450 cm^-1 respectively as per IR spectra. The stretching vibration for carbonyl (>C=O) was observed near 1700 cm^-1. The ring skeleton vibration was shown between 1500-1600 cm^-1. Infrared spectral data analysis is shown in Table 2.

 

Table 2: Results of Spectral Analysis (IR) of synthesized compounds:

Comp. Code	Substitution (R)	λmax.  (nm)	IR (KBr) (cm-1)
PTC-01	H	240	3165.3 (-NH, 2°amide); 3018 (=C-H, aromatic); 1733.6 (-C=O).
PTC-02	2-OCH3	246	3127.3 (-NH, 2°amide); 3014 (=C-H, aromatic); 2929.9 (-CH2-); 1684.9 (-C=O).
PTC-03	2,4-(OCH3)2	248	3127.3 (-NH, 2°amide); 3019 (=C-H, aromatic); 2935.6 (-CH2-); 1683.2 (-C=O).
PTC-04	2,4-(OC2H5)2	245	3091 (-NH, 2°amide); 3019.6 (=C-H, aromatic); 2963.6 (-CH2-); 1684.8 (-C=O).
PTC-05	2-Cl	234	3200 (-NH, 2°amide); 3081.2 (=C-H, aromatic); 2924.4 (-CH2-); 1684.5 (-C=O).
PTC-06	3-Cl	237	3333.3, 3204.5 (-NH2);3076 (=C-H, aromatic); 1655.9 (-C=N); 1591.6 (-NH, defor.).
PTC-07	4-Cl	240	3342.9, 3204.5 (-NH2); 3025 (=C-H, aromatic); 2925. (-CH2-); 1638.8 (-C=N); 1590.9 (-NH, defor.).
PTC-08	2-NO2	241	3345, 3204.5 (-NH2); 3075.6 (=C-H, aromatic); 2924.4 (-CH2-); 1655.94 (-C=N); 1591.6 (-NH, defor.).
PTC-09	4-NO2	236	3479, 3164.5 (-NH2); 3081.2 (=C-H, aromatic); 2962.2 (-CH2-); 1684 (-C=N); 1590.7 (-NH, defor.).
PTC-10	2-OH	245	3355.7, 3201 (-NH2); 3054.5 (=C-H, aromatic); 1664.3 (-C=N); 1559.5 (-NH, defor.).
PTC-11	4-OH	240	3333.3, 3204.5 (-NH2);3076 (=C-H, aromatic); 1655.9 (-C=N); 1591.6 (-NH, defor.).
PTC-12	4-F	239	3342.9, 3204.5 (-NH2); 3025 (=C-H, aromatic); 2925. (-CH2-); 1638.8 (-C=N); 1590.9 (-NH, defor.).
PTC-13	4-CH3	234	3345, 3204.5 (-NH2); 3075.6 (=C-H, aromatic); 2924.4 (-CH2-); 1655.94 (-C=N); 1591.6 (-NH, defor.).
PTC-14	4-OCH3	232	3479, 3164.5 (-NH2); 3081.2 (=C-H, aromatic); 2962.2 (-CH2-); 1684 (-C=N); 1590.7 (-NH, defor.).
PTC-15	[2,3] Dimethyl	250	3355.7, 3201 (-NH2); 3054.5 (=C-H, aromatic); 1664.3 (-C=N); 1559.5 (-NH, defor.).

 

CONCLUSION:

In conclusion, we have successfully developed an easy and efficient method to prepare a variety of novel, facile, microwave assisted eco-friendly convenient route, for the synthesis of a series of biologically active compounds n-butyl-6-methyl-phenyl-2-thio-oxo-1,3-N,N-dimethyl-2,4-dihydropyrimidine-5-carboxylate TC : 01 – 15) were obtained as per Scheme No. I and II taking a mixture of n-butyl acetoacetate, appropriate aldehyde, and thiourea using solid support has been developed. Physical and spectral data of synthesized compounds are in agreement with those reported in the literature. Microwave heating enhances organic reaction by energy efficient heating thereby leading to reduction in reaction time from hours to minutes. Rapid heating inhibits the formation of byproducts leading to greater purity, increasing yields and higher reproducibility.

 

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Accepted on 14.10.2018        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(12): 5541-5544.