TECHNICAL FIELD
The present disclosure relates to a one-pot synthesis of substituted hydantoins having formula (I).
(I)
BACKGROUND AND PRIOR ART
Hydantoin, also known as, glycolylurea is an important class of hyeterocycles with a wide range of biological activities [B. R. Sudani et al Asian J. Pharm. Tech., 2015, 5, 153-157]. The derivatives of hydantoin (imidazolidine-2,4-dione) have been found to exert various effects on nervous systems, most of which are compatible with an anticonvulsant action. Hydantoin derivatives are also reported as oldest non-sedative antiepileptic drugs.
Beside the traditional use as antiepileptic, hydantoins also constitutes the core structure of various valuable pharmaceuticals such as azimilide (an antiarrhythmic), nitrofurantoin (antibacterial), dantrium (sceletal muscle relaxant), nilutamide (nonsteroidal, orally active antiandrogen) [M. Meusel et al Org. Prep. Proc. Int., 2004, 36, 391-443].
Hydantoins and some of their derivatives are also structural units in many naturally occurring substances, mostly obtained from marine organisms, but also from bacteria. [M. Meusel et al Org. Prep. Proc. Int., 2004, 36, 391-443]
Hydantoins with a wide range of biological activities have emerged as an important class of therapeutically important molecules and there have been shortcomings associated with earlier synthetic processes to synthesize these molecules. Therefore, an efficient and facile process for the synthesis of substituted hydantoins deemed highly desirable. A number of synthesis has been reported for preparing substituted hydantoins but most of the processes require multistep synthesis and/or use toxic and expensive reagents and also suffer from other difficulties such as regioselectivity related issues. Some of the literature methodologies have been discussed below.
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M. Beller et al. [Angew. Chem. Int. Ed., 1999, 38, 1454-1457] discloses a reaction of different aldehydes with various ureas and carbon monoxide in presence of palladium catalysis to yield mono, di and tri-substituted hydantoins. This process involves use of high cost and moisture sensitive metal catalyst. Further, this is not a suitable process for the preparation of hydantoins which are un-substituted at 5 position.
L. Konnert et al. [RSC Adv., 2016, 6, 36978–36986] discloses the mechanochemical preparation of 3,5-disubstituted hydantoins from α-amino methyl esters using either 1,1’-carbonyldiimidazole (CDI) or alkyl isocyanates. This process involves the use of highly costly and moisture sensitive 1,1’-carbonyldiimidazole (CDI) in one case and toxic and hazardous alkyl isocyanates in the other. Further, specific instrument i.e. ball mill is required for this purpose rendering this process difficult for scale-up.
H. Liu et al. [Org. Lett., 2014, 16, 5902-5905] discloses a process that involves the synthesis of highly substituted chiral hydantoins by Tf2O-mediated dual activation of Boc-protected dipeptidyl compounds. This process uses Boc-protected dipeptidyl compounds as a starting material, and preparation of Boc-protected dipeptide itself is a difficult and costly affair. Also, this method is expected to have low atom economy because use of a bulky protecting group and protection-deprotection reaction are required.
J. Matthews et al. [J. Org. Chem., 1997, 62, 6090-6092] discloses a solid-phase synthesis of hydantoins that proceeds via formation of isocyanate with the use of phosgene, then formation of urea derivative, and finally cyclative cleavage from the resin with simultaneous formation of the hydantoin ring. The main drawback of this process is the use of highly toxic and hazardous gas phosgene for the generation of isocyanate. This is also a multistep procedure which makes it a costly affair.
G. Baccolini et al. [Tetrahedron Lett., 2011, 52, 1713-1717] discloses a preparation of hydantoins in the aqueous media. This process involves a reaction between N-methylurea and aldehydes (glyoxal and its simple derivatives) in the presence of phosphoric anhydride. This process is limited only to N-methylurea and glyoxal and its simple derivatives and also suffers from low regioselectivity i.e. a mixture of 3 and 5 substituted hydantoins are produced.
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Z. Rajic et al. [Molecules 2006, 11, 837-848] discloses a method of hydantoin preparation that involves a base induced cyclization of the corresponding N-(1-benzotriazolecarbonyl)-L-and D-amino acid amides. The synthesis reported by Z. Rajic et al. is overall a lengthy process with four steps and does involve the use of expensive reagents such as BtcCl. It also involves the use of corrosive thionyl chloride for the activation of acid.
The synthetic processes disclosed above as prior art suffer from the various drawbacks, like; (a) multi-step process for synthesis (b) use of chemicals like isocyantes/ phosgene/ thionyl chloride which are highly toxic and costly reagents (c) use of protection-deprotection chemistry, and (d) non regioselective substitution of hydantoin itself that requires tedious purification to obtain pure compounds.
Thus, in the view of the aforementioned drawbacks of the processes disclosed in the prior art, there is an existing need of an improved process for the synthesis of substituted hydantoins. Also, an efficient process with high yields, high purity and high atom economy is highly desirable. Keeping in mind the existing problems associated with the synthesis of the substituted hydantoins, the present applicant discloses a simple, efficient and facile one-pot process for the synthesis of substituted hydantoins with high yield, high atom economy, high purity, environmental benign and the process without any use of toxic reagents mentioned in the earlier processes.
OBJECTIVES
The main objective of the present disclosure is to develop a simple, safe, efficient, cost effective and environmentally friendly process for the synthesis of substituted hydantoins.
SUMMARY
The present disclosure relates to a process for the synthesis of substituted hydantoins having formula (I) in an efficient, safe and simple manner, which is free from the problems encountered in the methods described in the prior art. The synthesis reported in this disclosure is a single step one-pot process for the preparation of substituted hydantoins. Accordingly, the present disclosure involves reaction of various α-amino methyl ester or salts thereof with different carbamates in the presence of base.
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DETAILED DESCRIPTION
Accordingly, the present disclosure provides a one-pot process for the synthesis of substituted hydantoins having formula (I) in an efficient and simple manner.
(I)
Wherein,
R1 and R2 are independently selected from hydrogen, a straight or branched C1-C8 alkyl, C1-C8 alkoxy, C3-C8 substituted or unsubstituted cycloalkyl, alkyl-aryl, substituted or unsubstituted aryl; substituted or unsubstituted alkylaryl;
R1 and R2 is also be selected independently from a group comprising of C2-C8 alkenyl, C2-C8 alkynyl, C4-C8 (alkyl-cycloalkyl) wherein the alkyl is C1-C2 alkyl and cycloalkyl is C3-C6 cycloalkyl, an aryl, a substituted aryl, a phenyl, a substituted phenyl group, substituted aryl or phenyl group are substituted by X on various positions in various combinations, wherein each X is defined herein below;
X is each and independently selected from any of hydrogen, CH3, CF3; halogen; C1-C3 alkoxy; hydroxyl; acetoxy; -NH2; -NO2; -OCF3; -CONRaRb; -COORa; -CORa; (CH2)p4SORaRb; Ra and Rb is each and independently selected from hydrogen, a branched or straight C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 (alkyl-cycloalkyl)
wherein the process comprising steps of:
(i) reacting α-amino methyl ester or salt thereof with a substituted carbamate and an organic base in a first solvent at a temperature ranging from 80°-100°C and obtaining a reaction mixture;
(ii) adding an inorganic base to the reaction mixture of the step (i) and refluxing for 7-12 hours and obtaining a crude product;
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(iii) extracting the crude product of the step (ii) by a second solvent and obtaining a substituted hydantoins of formula (I).
The term “C1-C8 alkyl” refers to structural isomers or homologues of alkyl groups having 1 to 8 carbon atoms.
The term “cycloalkyl” means cycloalkanes having from 3 to 8 carbon atoms i.e. from cyclopropane to cyclooctane. The term substituted cycloalkyl means but is not restricted to a cycloalkyl substituted independently by an alkyl, alkoxy, halogen, hydroxyl, acetoxy, nitro, alkenyl, alkyl, trifluromethyl groups.
The term “aryl” means groups having the Huckel 4n+2 pi electron arrangements and includes for example phenyl, benzyl, napthyl etc. The term substituted aryl means but is not restricted to an aryl substituted independently by an alkyl, alkoxy, halogen, hydroxyl, acetoxy, nitro, alkenyl, alkyl, trifluromethyl groups.
In another embodiment of the present disclosure, the α-amino methyl ester or salt thereof is selected from glycine methyl ester, L-phenylalanine methyl ester, L-Valine methyl ester, phenylglycine methyl ester, D-(-)-2-phenylglycine methyl ester, DL-phenylalanine methyl ester, alanine methyl ester, isoleucine methylester, leucine methyl ester.
In another embodiment of the present disclosure, the salt of α-amino methyl ester is hydrochloric salt.
In another embodiment of the present disclosure, the substituted carbamate is selected from phenyl carabamte, phenyl benzylcarbamate, phenyl phenethylcarbamate, phenyl methylcarbamate, phenyl ethylcarbamate, phenyl propylcarbamate, pheny isopropyl carbamate, phenyl butylcarbamate, phenyl pentylcarbamate, phenyl (1-phenylethyl) carbamate, phenyl cyclopropylcarbamate, phenyl cyclohexylcarbamate, phenyl octylcarbamate
In another embodiment of the present disclosure, the substituted carbamate is used in slight excess to the α-amino methyl ester i.e. 1-1.2 equivalents of α-amino methyl ester.
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In yet another embodiment of the present invention, the first solvent is selected from acetonitrile, benzene and toluene or a combination thereof.
In yet another embodiment of the present disclosure, the organic base is selected from triethylamine, N-ethyl diisopropylamine, pyridine or combination thereof.
In another embodiment of the present disclosure, organic base is used in excess i.e. one third of total volume of the solvent used.
In yet another embodiment of the present invention, the inorganic base is selected from K2CO3, NaOH, Na2CO3, KOH or a combination thereof.
In yet another embodiment of the present disclosure, inorganic base is used in slight excess from 2 to 3 equivalents. In yet another embodiment of the present disclosure, the second solvent is selected from ethylacetate, dichloromethane, diethyl ether or a combination thereof.
In yet another embodiment of the present disclosure, the compound of formula (I) is optionally crystalized with an organic solvent selected from hexane, ethyl acetate, diethyl ether, methanol, ethyl alcohol, acetone or a combination thereof, or by column chromatography.
In another embodiment of the present disclosure, the compound of the formula (I) is optionally recrystallized by the conventional organic solvents.
In yet another embodiment the present disclosure relates to a single step, one-pot process for the synthesis of the substituted hydantoins having formula (I), via scheme 1, comprising the reaction of α-amino methyl ester or salt thereof hydrochloride salts with the substituted carbamates.
Scheme 1
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In order to have a better understanding, the present disclosure is explained by the following experimental work. The experimental work is given by way of illustrations of the present disclosure and therefore should not be construed to limit the scope of the present disclosure.
EXAMPLE 1
3-benzylimidazolidine-2,4-dione
Glycine methyl ester hydrochloride (1 equivalent) and phenyl benzylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine: acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then K2CO3 (3 equivalent) was added and refluxing was continued for another 12 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 3-benzylimidazolidine-2,4-dione in an isolated yield of 67%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.12 (br. s, 1H), 7.35-7.26 (m, 5H), 4.53 (s, 2H), 3.98 (s, 2H). 13C-NMR (100 MHz, DMSO-d6): 172.4, 157.8, 137.2, 128.9, 127.9, 127.8, 46.4, 41.4. HRMS (ESI): calcd. for C10H10N2NaO2 [M+Na]+, 213.0640, found: 213.0625.
EXAMPLE 2
3-phenethylimidazolidine-2,4-dione
Glycine methyl ester hydrochloride (1 equivalent) and phenyl phenethylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 7 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The
9
organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 3-phenethylimidazolidine-2,4-dione in an isolated yield of 74%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.01 (br. s, 1H), 7.30-7.17 (m, 5H), 3.85 (s, 2H), 3.56 (t, J=7.6 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H). 13C-NMR (100 MHz, CDCl3): 177.1, 162.6, 143.4, 133.8, 133.6, 131.6, 50.9, 44.0, 38.5. HRMS (ESI): calcd. for C11H12N2NaO2 [M+Na]+, 227.0796, found: 227.0789.
EXAMPLE 3
3-benzyl-5-methylimidazolidine-2,4-dione
L-Alanine methyl ester hydrochloride (1 equivalent) and phenyl benzylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 7 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 3-benzyl-5-methylimidazolidine-2,4-dione in an isolated yield of 71%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.32 (br. s, 1H), 7.36-7.23 (m, 5H), 4.53 (s, 2H), 4.17 (quartet, J=6.8 Hz, 1H), 1.27 (d, J=6.9 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 175.5, 156.8, 137.1, 129.0, 127.8, 127.6, 52.6, 41.3, 17.6. HRMS (ESI): calcd.for C11H12N2NaO2 [M+Na]+, 227.0796, found: 227.0780.
EXAMPLE 4
5-methyl-3-phenethylimidazolidine-2,4-dione
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L-Alanine methyl ester hydrochloride (1 equivalent) and phenyl phenethylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 7 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by column chromatography (hexane:ethylacetate, 23%) to afford the pure 5-methyl-3-phenethylimidazolidine-2,4-dione in an isolated yield of 72%.
1H-NMR (400 MHz, CDCl3): δ (ppm) 7.30-7.20 (m, 5H), 5.96 (br. s, 1H), 4.01 (dq, J=6.9, 1.1, Hz, 1H), 3.80-3.68 (m, 2H), 2.94 (t, J=7.6 Hz, 2H), 1.36 (d, J=6.9 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 175.7, 157.0, 138.4, 129.1, 128.8, 126.8, 52.4, 39.2, 33.3, 17.4. HRMS (ESI): calcd.for C12H14N2NaO2 [M+Na]+, 241.0953, found: 241.0949.
EXAMPLE 5
3-benzyl-5-isopropylimidazolidine-2,4-dione
L-Valine methyl ester hydrochloride (1 equivalent) and phenyl benzylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then KOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between dichloromethane and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 3-benzyl-5-isopropylimidazolidine-2,4-dione in an isolated yield of 73%.
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1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.34 (br. s, 1H), 7.34-7.23 (m, 5H), 4.51 (d, J=4.9 Hz, 2H), 4.03 (dd, J=3.4, 1.3 Hz, 1H), 2.08-2.00 (m, 1H), 0.92 (d, J=6.9 Hz, 3H), 0.73 (d, J=6.8 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 174.1, 157.5, 137.2, 128.9, 127.9, 127.8, 61.9, 41.3, 30.1, 18.9, 16.2. HRMS (ESI): calcd. for C13H16N2NaO2 [M+Na]+, 255.1109, found: 255.1113.
EXAMPLE 6
Synthesis of 5-isopropyl-3-phenethylimidazolidine-2,4-dione
L-Valine methyl ester hydrochloride (1 equivalent) and phenyl phenethylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then KOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between diethyl ether and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by column chromatography (hexane:ethylacetate, 20%) to afford the pure 5-isopropyl-3-phenethylimidazolidine-2,4-dione in an isolated yield of 70%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.15 (br. s, 1H), 7.25-7.12 (m, 5H), 3.84 (d, J=2.5 Hz, 1H), 3.64-3.48 (m, 2H), 2.79 (t, J=7.2 Hz, 2H), 1.95-1.87 (m, 1H), 0.82 (d, J=6.9 Hz, 3H), 0.59 (d, J=6.7 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 174.4, 157.8, 138.3, 129.1, 128.8, 126.8, 61.8, 39.1, 33.4, 29.8, 18.7, 16.0. HRMS (ESI): calcd. for C14H18N2NaO2 [M+Na]+, 269.1266, found: 269.1271.
EXAMPLE 7
5-phenylimidazolidine-2,4-dione
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D-(-)-2-Phenylglycine methyl ester hydrochloride (1 equivalent) and phenyl carbamate (1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 7 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by column chromatography (hexane:ethylacetate, 35%) to afford the pure 5-phenylimidazolidine-2,4-dione in an isolated yield of 73%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 10.80 (br. s, 1H), 8.41 (br. s, 1H), 7.41-7.32 (m, 5H), 5.16 (s, 1H). 13C-NMR (100 MHz, DMSO-d6): 174.7, 158.0, 136.4, 129.1, 128.7, 127.1, 61.6. HRMS (ESI): calcd. for C9H8N2NaO2 [M+Na]+, 199.0483, found: 199.0477.
EXAMPLE 8
3-methyl-5-phenylimidazolidine-2,4-dione
D-(-)-2-Phenylglycine methyl ester hydrochloride (1 equivalent) and phenyl methylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by column chromatography (hexane:ethylacetate, 30%) to afford the pure 3-methyl-5-phenylimidazolidine-2,4-dione in an isolated yield of 72%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.71 (br. s, 1H), 7.40-7.33 (m, 5H), 5.20 (s, 1H), 2.86 (s, 3H). 13C-NMR (100 MHz, DMSO-d6): 173.1, 157.5, 136.1, 129.1, 128.8, 127.3, 60.4, 24.7. HRMS (ESI): calcd. for C10H10N2NaO2 [M+Na]+, 213.0640, found: 213.0637.
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EXAMPLE 9
3-ethyl-5-phenylimidazolidine-2,4-dione (Ethotoin)
D-(-)-2-Phenylglycine methyl ester hydrochloride (1 equivalent) and phenyl ethylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by column chromatography (hexane:ethylacetate, 28%) to afford the pure 3-ethyl-5-phenylimidazolidine-2,4-dione (Ethotoin) in an isolated yield of 75%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.70 (br. s, 1H), 7.43-7.31 (m, 5H), 5.20 (s, 1H), 3.43(quartet, J=3.7 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 172.8, 157.2, 136.2, 129.1, 128.8, 127.2, 60.2, 33.2, 13.7. HRMS (ESI): calcd. for C11H12N2NaO2 [M+Na]+, 227.0796, found: 227.0782.
EXAMPLE 10
3-benzyl-5-phenylimidazolidine-2,4-dione
D-(-)-2-Phenylglycine methyl ester hydrochloride (1 equivalent) and phenyl benzylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The
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organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by column chromatography (hexane:ethylacetate, 22%) to afford the pure 3-benzyl-5-phenylimidazolidine-2,4-dione in an isolated yield of 72%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.83 (br. s, 1H), 7.41-7.25 (m, 10H), 5.32 (s, 1H), 4.57 (d, J=2.5 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): 172.9, 157.1, 137.1, 136.0, 129.2, 129.0, 128.9, 127.8, 127.7, 127.2, 60.4, 41.7. HRMS (ESI): calcd. for C16H14N2NaO2 [M+Na]+, 289.0953, found: 289.0943.
EXAMPLE 11
3-phenethyl-5-phenylimidazolidine-2,4-dione
D-(-)-2-Phenylglycine methyl ester hydrochloride (1 equivalent) and phenyl phenethylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by column chromatography (hexane:ethylacetate, 20%) to afford the pure 3-phenethyl-5-phenylimidazolidine-2,4-dione in an isolated yield of 73%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.64 (br. s, 1H), 7.37-7.15 (m, 10H), 5.13 (s, 1H), 3.70-3.57 (m, 2H), 2.87 (t, J=7.0 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): 173.3, 157.8, 137.7, 135.0, 128.6, 128.4, 128.3, 128.1, 126.5, 126.2, 60.4, 39.2, 33.1. HRMS (ESI): calcd. for C17H16N2NaO2 [M+Na]+, 303.1109, found: 303.1095.
EXAMPLE 12
5-benzylimidazolidine-2,4-dione
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DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl carbamate (1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 7 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzylimidazolidine-2,4-dionein an isolated yield of 73%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 10.44 (br. s, 1H), 7.92 (br. s, 1H), 7.29-7.17 (m, 5H), 4.33 (t, J=4.8 Hz, 1H), 2.97-2.88 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): 175.7, 157.6, 136.0, 130.2, 128.5, 127.1, 58.8, 36.8. HRMS (ESI): calcd. for C10H10N2NaO2 [M+Na]+, 213.0640, found: 213.0637.
EXAMPLE 13
5-benzyl-3-methylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and methyl phenyl carbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The
16
concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-methylimidazolidine-2,4-dione in an isolated yield of 76%.
1H-NMR (400 MHz, MeOD): δ (ppm) 7.30-7.19 (m, 5H), 4.36 (t, J=5.1 Hz, 1H), 3.12 (dd, J=13.9, 4.5 Hz, 1H), 3.02 (dd, J=13.9, 5.7 Hz, 1H), 2.77 (s, 3H). 13C-NMR (100 MHz, MeOD): 174.4, 157.8, 135.0, 129.3, 127.9, 126.7, 58.0, 36.6, 22.9. HRMS (ESI): calcd. for C11H12N2NaO2 [M+Na]+, 227.0796, found: 227.0794.
EXAMPLE 14
5-benzyl-3-ethylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl ethylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-ethylimidazolidine-2,4-dione in an isolated yield of 74%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.19 (br. s, 1H), 7.27-7.15 (m, 5H), 4.34 (t, J=4.4 Hz, 1H), 3.25-3.09 (m, 2H), 2.95 (d, J=4.7 Hz, 2H), 0.73 (t, J=7.1 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 173.6, 156.8, 135.5, 130.2, 128.4, 127.1, 57.3, 36.8, 32.6, 13.2. HRMS (ESI): calcd. for C12H14N2NaO2 [M+Na]+, 241.0953, found: 241.0942.
EXAMPLE 15
5-benzyl-3-propylimidazolidine-2,4-dione
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DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl propylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-propylimidazolidine-2,4-dione in an isolated yield of 75%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.21 (br. s, 1H), 7.25-7.13 (m, 5H), 4.35 (t, J=4.4 Hz, 1H), 3.17-3.00 (m, 2H), 2.96 (d, J=4.5 Hz, 2H), 1.24-1.10 (m, 2H), 0.50 (t, J=7.4 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 174.0, 157.1, 135.3, 130.2, 128.4, 127.2, 57.3, 39.4, 36.5, 21.0, 11.1. HRMS (ESI): calcd. for C13H16N2NaO2 [M+Na]+, 255.1109, found: 255.1102.
EXAMPLE 16
5-benzyl-3-cyclopropylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl cyclopropylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The
18
concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-cyclopropylimidazolidine-2,4-dione in an isolated yield of 68%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.13 (br. s, 1H), 7.25-7.10 (m, 5H), 4.25 (t, J=4.1 Hz, 1H), 2.91 (d, J=4.2 Hz, 2H), 2.27-2.22 (m, 1H), 0.65-0.20 (m, 4H). 13C-NMR (100 MHz, DMSO-d6): 174.3, 157.1, 135.3, 130.1, 128.3, 127.2, 56.6, 36.9, 20.8, 5.3, 4.8. HRMS (ESI): calcd.for C13H14N2NaO2 [M+Na]+, 253.0953, found: 253.0949.
EXAMPLE 17
5-benzyl-3-butylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl butylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-butylimidazolidine-2,4-dione in an isolated yield of 73%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.27 (br. s, 1H), 7.25-7.13 (m, 5H), 4.35 (t, J=4.3 Hz, 1H), 3.19-3.04 (m, 2H), 2.95 (d, J=4.3 Hz, 2H), 1.17-1.04 (m, 2H), 0.92-0.78 (m, 2H), 0.70 (t, J=7.0 Hz, 3H). 13C-NMR (100 MHz, DMSO-d6): 173.9, 157.0, 135.3, 130.2, 128.4, 127.1, 57.3, 37.4, 36.5, 29.7, 19.4, 13.9. HRMS (ESI): calcd. for C14H18N2NaO2 [M+Na]+, 269.1266, found: 269.1257.
EXAMPLE 18
5-benzyl-3-pentylimidazolidine-2,4-dione
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DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl pentylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-pentylimidazolidine-2,4-dione in an isolated yield of 74%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.21 (br. s, 1H), 7.26-7.14 (m, 5H), 4.35 (t, J=4.1 Hz, 1H), 3.20-3.04 (m, 2H), 2.95 (d, J=4.0 Hz, 2H), 1.19-1.08 (m, 4H), 0.91-0.74 (m, 5H). 13C-NMR (100 MHz, DMSO-d6): 173.8, 157.0, 135.4, 130.2, 128.4, 127.1, 57.2, 37.7, 36.6, 28.3, 27.3, 22.1, 14.1. HRMS (ESI): calcd. for C15H20N2NaO2 [M+Na]+, 283.1422, found: 283.1414.
EXAMPLE 19
5-benzyl-3-hexylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl hexylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The
20
concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-pentylimidazolidine-2,4-dione in an isolated yield of 77%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.20 (br. s, 1H), 7.25-7.13 (m, 5H), 4.34 (t, J=4.1 Hz, 1H), 3.19-3.04 (m, 2H), 2.95 (d, J=4.6 Hz, 2H), 1.21-1.04 (m, 6H), 0.96-0.77 (m, 5H). 13C-NMR (100 MHz, DMSO-d6): 173.3, 156.5, 134.9, 129.7, 127.8, 126.6, 56.7, 37.2, 36.1, 30.7, 27.1, 25.4, 21.8, 13.8. HRMS (ESI): calcd. for C16H22N2NaO2 [M+Na]+, 297.1579, found: 297.1579.
EXAMPLE 20
5-benzyl-3-cyclohexylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl cyclohexylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-cyclohexylimidazolidine-2,4-dione in an isolated yield of 65%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.16 (br. s, 1H), 7.26-7.13 (m, 5H), 4.28 (t, J=4.0 Hz, 1H), 3.50-3.45 (m, 1H), 2.98-2.89 (m, 2H), 1.85-1.49 (m, 5H), 1.23-0.94 (m, 5H). 13C-NMR (100 MHz, DMSO-d6): 173.7, 156.7, 135.2, 130.3, 128.3, 127.1, 56.5, 50.2, 36.8, 29.1, 28.9, 25.73, 25.71, 25.2. HRMS (ESI): calcd. for C16H20N2NaO2 [M+Na]+, 295.1422, found: 295.1417.
EXAMPLE 21
5-benzyl-3-octylimidazolidine-2,4-dione
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DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl octylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-octylimidazolidine-2,4-dione in an isolated yield of 71%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.20 (br. s, 1H), 7.26-7.13 (m, 5H), 4.35 (t, J=4.0 Hz, 1H), 3.19-3.04 (m, 2H), 2.95 (d, J=4.2 Hz, 2H), 1.28-1.08 (m, 10H), 0.94-0.80 (m, 5H). 13C-NMR (100 MHz, DMSO-d6): 173.8, 157.0, 135.4, 130.2, 128.3, 127.1, 57.2, 37.7, 36.6, 31.6, 28.97, 28.91, 27.7, 26.2, 22.5, 14.3. HRMS (ESI): calcd. for C18H26N2NaO2 [M+Na]+, 325.1892, found: 325.1901.
EXAMPLE 22
3,5-dibenzylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl benzylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was
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continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 3,5-dibenzylimidazolidine-2,4-dione in an isolated yield of 73%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.37 (br. s, 1H), 7.26-7.15 (m, 8H), 6.78-6.70 (m, 2H), 4.50 (t, J=4.6 Hz, 1H), 4.42 (d, J=15.6 Hz, 1H), 4.31 (d, J=15.6 Hz, 1H), 3.01 (d, J=4.7 Hz, 2H). 13C-NMR (100 MHz, DMSO-d6): 173.7, 156.7, 136.7, 135.4, 130.3, 128.7, 128.6, 127.3, 127.2, 127.0, 57.6, 41.1, 36.5. HRMS (ESI): calcd. for C17H16N2NaO2 [M+Na]+, 303.1109, found: 303.1100.
EXAMPLE 23
5-benzyl-3-phenethylimidazolidine-2,4-dione
DL-Phenylalanine methyl ester hydrochloride (1 equivalent) and phenyl phenethylcarbamate (1.1 equivalent) were dissolved in a mixture of triethylamine:acetonitrile (1:2) and the reaction mixture was refluxed for 10 h. Then NaOH (2.5 equivalent) was added and refluxing was continued for another 8 hours. After the completion of the reaction, solvents were distilled off, and the residue was partitioned between ethyl acetate and 1N aqueous HCl and extracted. The organic layer was washed with brine followed by drying over anhydrous sodium sulphate. The concentration of the organic layer gave the crude product which was purified by recrystallization from ethyl acetate-hexane mixture to afford the pure 5-benzyl-3-phenethylimidazolidine-2,4-dione in an isolated yield of 74%.
1H-NMR (400 MHz, DMSO-d6): δ (ppm) 8.22 (br. s, 1H), 7.28-7.15 (m, 8H), 7.05 (d, J=7.1 Hz, 2H), 4.32 (t, J=4.8 Hz, 1H), 3.44-3.31 (m, 2H), 2.97-2.86 (m, 2H), 2.53-2.40 (m, 2H). 13C-NMR (100 MHz, DMSO-d6): 173.3, 156.2, 138.0, 135.1, 129.7, 128.4, 128.3, 128.0, 126.7, 126.3,
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56.9, 38.5, 36.4, 33.0. HRMS (ESI): calcd. for C18H18N2NaO2 [M+Na]+, 317.1266, found: 317.1257.
Advantages
 A single step, one-pot synthesis of substituted hydantoins;
 High yield and purity of the synthesized compounds;
 Environmentally benign process with non-toxic reagents;
 Cost effective process with easy availability of reactants;
 Ambient reaction conditions;
 Economical process with high atom economy.

We Claim:
1. A one-pot process for preparing substituted hydantoins of formula I:
(I)
wherein
R1 and R2 are independently selected from hydrogen, a straight or branched C1-C8 alkyl, C1-C8 alkoxy, C3-C8 substituted or unsubstituted cycloalkyl, alkyl-aryl, substituted or unsubstituted aryl; substituted or unsubstituted alkyl aryl;
wherein the process comprising steps of:
(iv) reacting α-amino methyl ester or salt thereof with a substituted carbamate and an organic base in a first solvent at a temperature ranging from 80°-100°C and obtaining a reaction mixture;
(v) adding an inorganic base to the reaction mixture of the step (i) and refluxing for 7-12 hours and obtaining a crude product;
(vi) extracting the crude product of step (ii) with a second solvent and obtaining a substituted hydantoins of formula (I).
2. The process as claimed in claim 1, wherein the α-amino methyl ester or salt thereof is selected from glycine methyl ester, L-phenylalanine methyl ester, L-Valine methyl ester, phenylglycine methyl ester, D-(-)-2-phenylglycine methyl ester, DL-phenylalanine methyl ester, alanine methyl ester, isoleucine methyl ester, leucine methyl ester.
3. The process as claimed in claim 2, wherein the salt of α-amino methyl ester is a hydrochloride salt.
4. The process as claimed in claim 1, wherein the substituted carbamate is selected from phenyl carabamte, phenyl benzylcarbamate, phenyl phenethylcarbamate, phenyl
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methylcarbamate, phenyl ethylcarbamate, phenyl propylcarbamate, phenyl isopropylcarbamate, phenyl butylcarbamate, phenyl pentylcarbamate, phenyl (1-phenylethyl) carbamate, phenyl cyclopropylcarbamate, phenyl cyclohexylcarbamate, phenyl octylcarbamate.
5. The process as claimed in claim 1, wherein the substituted carbamate is used 1-1.2 equivalents to the α-amino methyl ester.
6. The process as claimed in claim 1, wherein the first solvent is selected from acetonitrile, benzene, toulene or a combination thereof.
7. The process as claimed in claim 1, wherein the organic base is selected from triethylamine, N-ethyl diisopropylamine, pyridine or combination thereof.
8. The process as claimed in claim 1, wherein the inorganic base is selected from K2CO3, NaOH, Na2CO3, KOH or a combination thereof.
9. The process as claimed in claim 1, wherein the inorganic base is used 2-3 equivalents to α-amino methyl ester.
10. The process as claimed in claim 1, wherein the second solvent is selected from ethylacetate, dichloromethane, diethyl ether or a combination thereof.
11. The process as claimed in claim 1, wherein the compound of formula (I) is optionally crystalized with organic solvents selected from hexane, ethyl acetate, diethyl ether, methanol, ethyl alcohol, acetone or a combination thereof, or by column chromatography.