Title of Invention

"A PROCESS FOR THE PRODUCTION OF 3,4-DIHYDROPYRIMIDIN-2 (1H)-ONES USING STANNOUS CHLORIDE CATALYST"

Abstract This invention relates to a process for the production of 3,4-dihydropyrimidin-2(lH)-ones using stannous chloride catalyst. The new process is for the preparation of various substituted 3,4-dihydropyrimidin-2(lH)-ones of the general formula (1), by the century old Biginelli condensation catalyzed by stannous chloride. The process s very simple, solvent less and can be carried out at one-pot in solid state under microwave irradiation. The reaction time is reduced dramatically from 18 h to 1.5-2 minute in a solvent free conditions. Stannous chloride dihydrate catalyzes the Biginelli condensation without effecting any substituents in the aromatic ring and without any side product formation as observed by earlier workers. The product obtained from the reaction mixture is pure and the yield is 95-99%.
Full Text This invention relates to a process for the production of 3,4-dihydropyrimidin-2(1H)-ones using stannous chloride catalyst. The new process is for the preparation of various substituted 3,4-dihydropyrimidin-2(lH)-ones of the general formula (1), by the century old Biginelli condensation catalyzed by stannous chloride.
(Formula Removed)
In 1893 Pietro Biginelli reported the first synthesis of 3,4-dihydropyrimidin-2(1H)-ones of type (1) by a very simple and one pot condensation reaction an aromatic aldehyde, urea and ethylacetoacetate in ethanolic solution. This efficient approach to reduced pyridines was largely ignored in the following years. In recent years however, interest in these compounds has increased rapidly and the scope of the original cyclocondensation reaction has been widely extended. Currently the number of publications and patents dealing with the synthesis has reached approximately 200. The present popularity of these dihydropyrimidines is mainly due to their close structural relationship to the clinically important dihydropyridine calcium channel blockers of the nifedipine-type and also due to the strong antihypertensive activity exhibited by certain of its derivatives. Dihydropyrimidines have found wide spread use in cardiovancular medicine and have served as important tools for the study of calcium channel structure and function, references on this may be made to T. Godfriaind, O. R. Miller, M. Wibo, Pharmaco. Rev., 1986, 38, 321; M. Kurono, M. Hayashi, K. Hivras, Y. Isosawa, K. Sawai (Sanwa Kasaku Kenkyusho Co.) Jpn. Kokai Tokyo Koho JP 1987, 62 267, 272 (Chem. Abstr., 1988. 109. 378320) K. S. Atwal, G C. Rovnyak. J. Schwartz, S. Moreland, A. Hedbers. J. Z. Goueoutas, N. F. Malley, D. M. Floyd, J. Med. Chem.. 1990, 33, 1570.
References may also be made to K. Kumsars, A. Velena, G. Duburs, J. Uldrikis, A. Zidermane, Biokhimiya, 1971, 36 1201; Chem. Abstr., 1971, 75, 47266e; Y. S. Sadanandam, M. M. Shetty, P. V. Diwan, Eur. J. Med. Chem., 1992, 27, 87, wherein dihydropyrimidine (1) and some of its analogs were screened as antitumor agents and found to be active against e.g. Walker carcinosarcoma in rats and mice and also as anti inflammatory analgesics.
Although the classical Biginelli reaction has been used widely in the past decades it is not always reliable and often gives only moderate yields, in particular when aliphatic or ortho substituted aromatic aldehydes are employed. A reference may be made to K. S. Atwal, G C. Revnvak, B. C. O'Reilly, J. Schwartz, J. Ors. Chem., 1989, 54, 5898, wherein, a reliable approach to Biginelli compounds 4 was reported. In the first step an unsaturated ketoester 1 is condensed with a suitable protected urea 2 in the presence of sodium bicarbonate. The reaction presumably proceeds through a Michael addition product and affords dihydro pyrimidinones 3. Deprotection with HC1 leads to the desired Biginelli compounds 4 in good yields. But this method requires prior synthesis of the unsaturated ketoesters 1 (Scheme 1).
(Scheme Removed)
In another reference H. Bohme, E. Mundlos, Chem. Ber., 1953, 86, 1414, wherein, substituted acetoacetate can react with urea with elimination of MeSH to furnish dihydropyrimidinones 2 is described. The same compound 2 is also obtained upon hydrogenation of pyrimidine 3 with H2/Pt, a reference on this may be made to W. Bergmann, T. B. Johnson, Ber. Dtsch. Chem. Ges., 1933, 66, 1492. (Scheme-2)


(Scheme Removed)
A reference may be made to B. C. O'Reilly and K. S. Atwal, Heterocycles, 1987, 26, 1185, wherein the biologically important l,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidine carboxylic acid esters 1 was synthesised via the reaction of methoxy pyrimidine 2, which might provide an effective alternative to the Biginelli condensation. In order to prepare 2, authors explored the reaction of o-methylisourea hydrogen sulphate 3 with the unsaturated keto esters 4. The report resulted in a general synthesis of substituted pyrimidines 1 via a multistep process (Scheme-3).
(Scheme Removed)
References may be made to K. Folkers, T.B. Johnson, J. Am. Chem. Soc, 1933, 55, 2886; K. Folkers, T. B. Johnson, J. Am. Chem. Soc, 1933, 55, 3784, wherein H2SO4EtOH reflux condition was used in the Biginelli condensation and dihydropyrimidines were obtained in 10-68% yield within 18 h of time. The reaction utilized a 1:1:1.5 ratio of p-keto ester, aryl aldehyde and urea in a one-pot condensation.
Another reference may be made to B. C. Ranu, A. Hajra and U. Jana, J. Org. Chem., 2000, 65, 6270 , wherein expensive indium trichloride was used as a catalyst for
the one-pot condensation of 1,3-dicarbonyl compound, aldehyde and urea to afford dihydropyrimidin-2( 1 H)-ones (Scheme-4).
(Scheme Removed)
Still another reference may be made to D. S. Bose, L. Fatima, H. B. Mereyala, J. Org. Chem., 2003, 68, 587, wherein a general route for the Biginelli condensation using expensive cerium(III) chloride heptahydrate as the catalyst is described. Here the catalyst employed is 25 mol% against the substrate. Authors have synthesized various dihydropyrimidine-2(lH)-ones using reflux, aqueous and solvent free conditions (Scheme-5).
(Scheme Removed)
Yet another reference may be made to J. C. Bussolari and P. A. McDonnell, J. Ore. Chem., 2000, 65, 6777, wherein the expedient synthesis of 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones using oxalacetic acid as an unprecedented substrate for the Biginelli reaction is described. Cyclization and in-situ decarboxylation yielded 5-unsubstituted 3,4-dihydropyrimidin-2(1H)-ones in good to poor yields. A more effective method using trifluoroacetic acid as the acid catalyst and dichloroethane as the solvent are advantageous for N-acyliminium ion formation, a key intermediate in the reaction pathway. The loss of carbondioxide may be occurring on the acyclic and/or cyclic adduct in the reaction pathway. The resultant product can be further transformed by activation of the free acid with EDC and esterification with a carbinol such as ethanol (Scheme-6).

(Scheme Removed)
The present process appears to be superior as well as novel for the preparation of 3,4-dihydropyrimidin-2(1H)-one derivatives.
Accordingly, the present invention provides a process for the production of 3,4-dihydropyrimidin-2(lH)-ones using stannous chloride catalyst which comprises: characterized in i) reacting 1,3-dicarbonyl compound of formula 1 wherein R1 is methyl or ethoxy groups, aldehyde of formula 2 wherein R2 is phenyl, p-nitrophenyl, p-chlorophenyl, p-tolyl or furyl groups and urea of formula 3 wherein X is O or S groups in the presence of stannous chloride in Microwave oven for a period of 1.5 to 2 minutes , ii) cooling the reaction mixture to room temperature followed by adding ice cold water and separating the precipitated products by filtration, iii) purifying the crude product by recrystallisation from ethanol to afford the corresponding pure 3,4-dihydropyrimidin-2(1H)-one derivatives of formula 4.

(Scheme Removed)
In an embodiment to the present invention, the products can be prepared in 95-99% yields.
In another embodiment to the present invention, the process avoids the need for isolation of any intermediates, thereby avoiding any losses during such isolation.
Still in another embodiment of the process catalytic stannous chloride dihydrate greatly enhances the efficiency of the Biginelli condensation.
In another embodiment to the present invention, the reaction time can be reduced dramatically from 18 h to 1.5-2 min.
Still in another embodiment if the process, the catalyst selectively produces various dihydropyrimidin-2(lH)-ones without affecting the nitro, chloro, methyl and furyl groups present in the substrates.
In yet another embodiment of the invention, the process avoids the use of any organic solvents as the reaction proceed successfully in the solid phase under microwave irradiation. Moreover, the catalyst is very cheap, less hazardous and the method is eco-friendly.
The details of the method disclosed in this invention have been described in the following specific examples which are provided to illustrate the invention only and therefore, these should not be construct to limit the scope of the present invention.
Example 1
5-(Ethoxycarbonyl)-4-phenyl-6-methyl-3,4-dihydropyrimidine-2-one (1a, R1= EtO, R2 =
C6H5, X = O)
A mixture of ethylacetoacetate (1.30 g, 10 mmol) urea (0.90 g, 15 mmol) benzaldehyde (1.06 g, 10 mmol) and stannous chloride dihydrate (0.225 g, 1 mmol) were placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave Microwave reactor at power 60%. The automatic made stirred helps in mixing and uniform heating of the reactants. After 1.5 min. the reacion vessel was cooled to room temperature and ice-cold water (20 ml) was added to it. The solid separated was filtered and recrystallised from ethanol to afford the title compound la in 96% yield, mp. 201-202 °C in 96% yield.
Example 2
5-(Ethoxycarboyl)-4-(p-nitrophenyl)-6-methyl-3,4-dihydropyrimidine-2-one (lb, R1 =
EtO, R2 = 4-NO2C6H4-, X = O).
A mixture of ethylacetoacetate (1.30 g, 10 mmol) urea (0.90 g, 15 mmol) 4-nitrobenzaldehyde (150 g, 10 mmol) and stannous chloride dihydrate (0.225g, 1 mmol) were placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave Microwave reactor at power 60%. The automatic made stirred helps in mixing and uniform heating of the reactants. After 1.5 min. the reacion vessel was cooled to room temperature and ice-cold water (20 ml) was added to it. The solid separated was filtered and recrystallized from ethanol to afford the title dihydropyrimidinone lb in 97% yield, mp 206-208 °C.
Example 3
5-(Ethoxycarboyl)-4-(p-tolyl)-6-methyl~3,4-dihydropyrimidine-2-one (1c, R1 = EtO, R2
= 4-MeC6H4-, X = O).
A mixture of ethylacetoacetate (1.30 g, 10 mmol) urea (0.90 g, 15 mmol) p-tolualdehyde (1.20 g, 10 mmol) and stannous chloride dihydrate (0.225 g, 1 mmol) were placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave Microwave reactor at power 60%. The automatic made stirred helps in mixing and uniform heating of the reactants. After 1.5 min. the reacion vessel was cooled to room temperature and ice-cold water (20 ml) was added to it. The solid separated was filtered and recrystallized from ethanol to afford the title dihydropyrimidine lc in 96% yield, mp. 215-216 °C.
Example 4
5-(Ethoxycarboyl)-4-(p-chlorophenyl)-6-methyl-3,4-dihydropyrimidine-2-one (1d, R1 =
EtO, R2 = 4-ClC6H4-, X = O).
A mixture of ethylacetoacetate (1.30g, 10 mmol) urea (0.90g, 15 mmol) p-chlorobenzaldehyde (1.40 g, 10 mmol) and stannous chloride dihydrate (0.225 g, 1 mmol) were placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave Microwave reactor at power 60%. The automatic made stirred helps in mixing and uniform heating of the reactants. After 2 minute the reacion vessel was cooled to room temperature and ice-cold water (20 ml) was
added to it. The solid separated was filtered and recrystallized from ethanol to afford the title compound 1d in 98% yield, mp 215-216 °C.
Example 5
5-(Ethoxycarboyl)-4-(2-furyl)-6-methyl-3,4-dihydropyrimidine-2-one(le, R = EtO, R =
2-furyl, X = O).
A mixture of ethylacetoacetate (1.30 g, 10 mmol) urea (0.90 g, 15 mmol)
furfuraldehyde (1.0 g, 10 mmol) and stannous chloride dihydrate (0.225 g, 1 mmol) were
placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave
Microwave reactor at power 60%). The automatic made stirred helps in mixing and
uniform heating of the reactants. After 2 minute the reacion vessel was cooled to room
temperature and ice-cold water (20 ml) was added to it. The solid separated was filtered
and recrystallized from ethanol to afford the title compound 1e in 95% yield, mp 208-209
°C.
Example 6
5-Acetyl-4-phenyl-6-methyl-3,4-dihydropyrimidine-2-one (1f, R1 = Me, R2 = C6H5-, X =
O).
A mixture of acetylacetone (1.0 g, 10 mmol) urea (0.90 g, 10 mmol) benzaldehyde (1.06 g, 10 mmol) and stannous chloride dihydrate (0.225 g, 1 mmol) were placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave Microwave reactor at power 60%. The automatic made stirred helps in mixing and uniform heating of the reactants. After 2 minute the reacion vessel was cooled to room temperature and ice-cold water (20 ml) was added to it. The solid separated was filtered and recrystallized from ethanol to afford the title dihydropyrimidine If in 98% yield, mp 207-209 °C.
Example 7
5-(Ethoxycarboyl)-4-phenyl-6-methyl—3,4-dihydropyrimidin-2(lH)-thione (1g, R1 =
EtO, R2 = C6H5-, X = S).
A mixture of ethylacetoacetate (1.30 g, 10 mmol) urea (0.90 g, 15 mmol) p-tolualdehyde (1.20 g, 10 mmol) and stannous chloride dihydrate (0.225 g, 1 mmol) were placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave Microwave reactor at power 60%. The automatic made stirred
helps in mixing and uniform heating of the reactants. After 1.5 min. the reacion vessel was cooled to room temperature and ice-cold water (20 ml) was added to it. The solid separated was filtered and recrystallized from ethanol to afford the title compound 1g in 96% yield, mp. 208-209 °C.
Example 8
5-(Ethoxycarboyl)-4-(p-chlorophenyl)-6-methyl—3,4-dihydropyrimidin-2(lH)-thione
(1h, R1 = EtO, R2 = 4-ClC6H4-, X = C1).
A mixture of ethylacetoacetate (1.30 g, 10 mmol) urea (0.90 g, 15 mmol) p-chlorobenzaldehyde (1.20 g, 10 mmol) and stannous chloride dihydrate (0.225 g, 1 mmol) were placed in reaction vessel and heated under microwave irradiation in a Prolabo Synthwave Microwave reactor at power 60%. The automatic made stirred helps in mixing and uniform heating of the reactants. After 2 minute the reacion vessel was cooled to room temperature and ice-cold water (20 ml) was added to it. The solid separated was filtered and recrystallized from ethanol to afford the title compound lh in 99% yield, mp 191-192 °C.
The main advantages of the present invention are
1 The method is very simple and can be carried out at one-pot in solid state under microwave irradiation.
2 The reaction time is reduced dramatically from 18 h to 1.5-2 minute in a solvent free conditions.
3 The work-up procedure is very simple and stannous chloride dihydrate catalyzes the Biginelli condensation without effecting any substituents in the aromatic ring and without any side product formation as observed by earlier workers.
4 1 mol% of the catalyst is found to be optimal to perform this reaction. More or less than 1 mol% catalyst is not effective, rather the reaction results side product formation and incompletion
5 The product obtained from the reaction mixture is pure and the yield is 95-99%.
6 In this process no organic solvent is used.
7 Also, the process is efficient, mild and selective over the existing methods and the catalyst is less hazardous and inexpensive.











WE CLAIM:
1. A process for the production of 3,4-dihydropyrimidin-2(1H)-ones using stannous chloride catalyst which comprises: characterized in i) reacting 1,3-dicarbonyl compound of formula 1 wherein R1 is methyl or ethoxy groups, aldehyde of formula 2 wherein R2 is phenyl, p-nitrophenyl, p-chlorophenyl, p-tolyl or furyl groups and urea of formula 3 wherein X is O or S groups in the presence of stannous chloride in Microwave oven for a period of 1.5 to 2 minutes , ii) cooling the reaction mixture to room temperature followed by adding ice cold water and separating the precipitated products by filtration, iii) purifying the crude product by recrystallisation from ethanol to afford the corresponding pure 3,4-dihydropyrimidin-2(1H)-one derivatives of formula 4.
(Formula Removed)
A process as claimed in claim 1 wherein the catalyst stannous chloride is used in 1 mol%.
2. A process as claimed in claims 1 to 2, wherein the product yield is 95-99%.
3. A process as claimed in claims 1 to 2, wherein the product yield is 95-99%
4. A process for the production of 3,4-dihydropyrimidin-2(1H)-ones using stannous chloride catalyst substantially as herein described with reference to the examples.

Documents:

1794-DEL-2004-Abstract-(26-10-2010).pdf

1794-del-2004-abstract.pdf

1794-DEL-2004-Claims-(26-10-2010).pdf

1794-del-2004-claims.pdf

1794-DEL-2004-Correspondence-Others-(26-10-2010).pdf

1794-del-2004-correspondence-others.pdf

1794-DEL-2004-Description (Complete)-(26-10-2010).pdf

1794-del-2004-description (complete).pdf

1794-del-2004-form-1.pdf

1794-del-2004-form-18.pdf

1794-DEL-2004-Form-2-(26-10-2010).pdf

1794-del-2004-form-2.pdf

1794-DEL-2004-Form-3-(26-10-2010).pdf

1794-del-2004-form-3.pdf

1794-del-2004-form-5.pdf


Patent Number 244392
Indian Patent Application Number 1794/DEL/2004
PG Journal Number 50/2010
Publication Date 10-Dec-2010
Grant Date 06-Dec-2010
Date of Filing 22-Sep-2004
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 MUKUT GOHAIN REGIONAL RESEARCH LABORATORY, JORHAT-785006, ASSAM, INDIA.
2 DIPAK PRAJAPATI REGIONAL RESEARCH LABORATORY, JORHAT-785006, ASSAM, INDIA.
PCT International Classification Number C07D 01/12
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA