FORM – 2
THE PATENT ACT 1970 (39 of 1970)
&
The Patents Rules, 2003 COMPLETE SPECIFICATION (Section 10 and Rule 13)
1. TITLE OF THE INVENTION: - A process for the preparation of 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylates.
2. ADDRESS OF THE APPLICANT:-
(a)NAME: -Dr. M. M. V. Ramana
(b)NATIONAUTY: INDIAN
(c) ADDRESS: Department of Chemistry, University of Mumbai. Vidyanagari,Santacruz (East), Mumbai- 400 098. India.
3. PREAMBLE TO THE DESCRIPTION: - COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

4) DESCRIPTION
Title of Invention
A process for the preparation of 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylates.
Abstract of Invention
This process involves the synthesis of 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylate derivatives by the reaction of aromatic aldehyde, malononitrile and (3-dicarbonyl compound using CsOH-Al2O3 as heterogeneous basic catalyst in alcohol solvent.
Background of Invention and Prior Art
The 4H-pyran nucleus is a fertile source of biologically important molecules possessing a wide spectrum of biological and pharmacological activities, such as antimicrobial, mutagenicity, antiproliferative, sex hormones, antitumour, cancer therapy and central nervous system activity. (Khadafy M.M, F.A.EID, E.I.Agrody, Farmaco 2002, 57,715; HiramotoK, Nasuhara A, Mutat.Res 1997, 47,395; Bell C.P, Smith C.W, EP 537,949; Bianchi G, Tava A,Agric.BioI.Chem 1987, 51, 2001: Mohr S.J, Chirigos M.A, Cancer Res. 1975,35,3750; Skommer TWlodkowik D, Matto M,Eray M, Pelkonen J, Leukemia Res 2006,30,322; Eiden F, Denk F. Arch. Pharma.Weinhein Ger(Arch.Pharma.), 1991,324,353). Some of 4H-pyran derivatives are widely used as cosmetics, pigments and potential biodegradable agrochemicals. (Hefez E.A.A, Elnagdi M.H, Elagamer A.G.A, heterocycles, 1987, 26, 903).The 4H-pyran derivatives are potent agents for the control of fungi and bacteria. (U.S. 3,284,287; U.S. 3,799,945; U.S. 3, 852,444). They show muscle relaxant effect as described (U.S. 3,968.236). They are useful for the treatment and prevention of atherosclerosis, thrombotic, degenerative disorders, depressions, psychoses and molybdenum cofactor deficiency (U.S. 5,252,735; U.S. 5,874,462; U.S.2013/0310390A1).
This invention involves the preparation of 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylate derivatives. Several methods for preparation of 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxylate derivatives are described (E.P. 06193 14A1; U.S. 3,968,236, U.S. 4,214,963; U.S. 4,599,327; U.S. 5,252,735; U.S. 5,254,581; U.S. 5,723,633: U.S. 5.874,462: U.S. 8,183,398B2; Vijay Kumar M. Joshi, Rupali L.Magar Chinese Chemical Letters. 2014,25.455-458; Giriwar Singh, Gajendra S'ingh,Ind J. of Chem, 2002, 41B,430-432; Subhash Banejee,Alissa Horn, Hari Khatri, Grigority Seveda, Tetrahedron Letters,201 1,52,3 878-1881; Sheng-Li Zhao. Chang-Wu Zeng, Gang Zhao, Tetrahedron: Assymmetry, 2009,20,1046-1051).
Most of the above methods for the synthesis of 4H-pyrans involve high temperature, long reaction time, toxic bases and solvents. The typical procedure to synthesize 4H-pyran derivatives is usually a two-step reaction carried out between Michael acceptor (arylidenemalononitrile) and (3-dicarbonyl compound in the presence of a base as the catalyst in solvents. Moreover, the most suitable protocol for the synthesis of functionalized organic compounds could be multicomponent reaction because the synthesis could be performed without isolation of intermediates and within short reaction time.
The present invention describes a simple, mild and highly efficient protocol for the synthesis of 6-amino-5-cyano-2-methyl-4-aryMH-pyran-3-carboxylate derivatives by the reaction of aromatic aldehyde, malononitrile and (3-dicarbonyl compound using CsOH-AI203 as a heterogeneous basic catalyst at room temperature in good yield.
Description of Invention
The main objectives of the present invention is to synthesize compounds 1-X by the reaction of aromatic aldehydes, malononitrile and [3-dicarbonyl compounds using CsOH-AI2O3 as a heterogeneous basic catalyst at room temperature in alcohol solvent.

Synthesis of compounds I-X
Compounds I-X were synthesized as per the Scheme
Scheme

COMPOUNDS R1 R2 R3 R4 R5
I H CF, H CF3 C2H5
II H H H H CH(CH3)2
III H H F H CH(CH3)2
IV H F H H CH(CH3)2
V H F F H CH(CH3)2
VI H CF 3 H CF3 CH(CH3)2
VII CI H H H CH(CH3)2
VIII H CI H H CH(CH3)2
IX H H CN H CH(CH3)2
X OH H OCH3 H C2H5

Procedure for the preparation of CsOH-Al2O3
CsOH (t.Og) and Al2O3 (2.0g) were suspended in 20 ml methanol and stirred for 2h at room temperature. Methanol was removed under reduced pressure and the residue was dried.
Example 1:Ethyl 6-amino-4-(3, 5-bis (trifluoromethyl) phenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (I)
CSOH-AI2O3 (0.2g) was added to the mixture of 3,5-bis(trifluoromethyl)benzaldehyde (lmmol), malononitrile(lmmol) and ethyl acetoacetate (lmmol) in 50 ml ethanol and kept for stirring at room
temperature for 30 min. Completion of reaction was monitored by TLC. After completion of reaction, mixture was poured into cold water, filtered off the precipitate, recrystallized from ethanol and dried to afford pure product.Yield: 85%.
UV (λmax): 294; IR (cm-1): 3407.06, 3340.94, 2973.30, 2195.08, 1679.18, 1645,18, 1605, 1455.8, 1370.99, 1275.04, 1168.77, 1 125.99, 898.27, 680.97; 1H-NMR (DMSO): 0.79-0.77(d,J=6Hz,3H), 2.3 (s,3H), 4.64(s,lH), 4.80-4.72(m.2H), 7.11(s,2H), 7.18(s,2H,NH2), 8.01(s,lH): 13C-NMR(DMSO): 18.20, 38.37, 55.91, 67.67, 105.56. 119.14, 121.42, 125.04, 130.11, 130.54, 148.73, 158.14, 158.44, 164.35; HRMS(m/z): 420.11: Elem.Anal.Calculated tor C18H14F6N203:C.5 1.44; H,3.36; F,27.12; N,6.67.Found: C, 51.45; H, 3.40; F, 27.0; N, 6.60.
Example 2: Isopropyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (II)
Compound (II) was synthesized by the procedure as described in Example 1 using benzaidehyde, malononitrile and isopropyl acetoacetate. Yield: 90%.
UV (JO: 290; IR (cm-1): 3458.63, 3403.25, 3324.0, 3264.18, 3224.38, 3200.69, 2981.19, 2937.10, 2197.06, 1677.91, 1641.76, 1608.55, 1578.89. 1469.61, 1362.82, 1264.31, 1175.04, 1069.17,750.29; 1H-NMR (DMSO): 0.90-0.88(d..J=6Hz,3H), 1.13-1.1 l(d../=6Hz,3H), 2.315(s,3H), 4.02-3.9l(m,l H), 4.30(s,lH), 7.33-7.13(m,5H), 6.89(s,2H,NH3); l3C-NMR(DMSO): 18.0. 20.8, 20.9, 38.1, 57.7, 60.1, 107.2, 119.6, 126.7, 127.1. 128.3, 144.8, 156.5, 158.4, 165.41; HRMS(m/z): 298.00; Elem.Anal.Calculated for C17HISN203:C,68.44: H.6.08; N,9.39. Found: C, 68.40; H, 6.10; N, 9.40.
Example 3: Isopropyl 6-amino-5-cyano-4-(4-fluorophenyl)-2-methy|-4H-pyran-3-carboxylate (III)
Compound (III) was synthesized by the procedure as described in Example 1 using 4-fluorobenzaldehyde, malononitrile and isopropyl acetoacetate. Yield: 87%.
UV (λmax): 285; IR (cm-1): 3399.54, 3330.94. 3267.60, 3221.57, 3200.36, 2980.21, 2925.63, 2186.63. 1680.75, 1651.34, 1453.30. 1362.74, 1264,96, 1178.83, 1056.08,747.76: 1 H-NMR (DMSO):0.90-0.88(d, J=6Hz, 3H), 1.13-1.1 l(d.J=6Hz,3H),. 2.30(s,3H), 4.29(s,IH), 4.82-4.73(m.lH), 6.90(S,2H,NH2), 7.17-7.13(dd,J=12Hz,2H), 7.20-7.17(dd,/=9Hz,2H); (13C-NMR(DMSO): 18.0. 20.8, 20.9, 38.1, 57.0, 67.5, 107.1, 115.1, 119.5, 129.2. 141.1. 156.4, 158.3, 159.3, 164.7; HRMS(m/z): 3 16.1 i; Elem.Anal.Calculated for C17H17FN2O3:C,64.55;H,5.42;F,6.01;N,8.86. Found: C, 64.50, H, 5.45; F, 6.05; N, 8.90.
Example 4: Isopropyl 6-amino-5-cyano-4-(3-fluorophenyl)-2-methy|-4//-pyran-3-carboxylate(IV)
Compound (IV) was synthesized by the procedure as described in Example 1 using 3-fluorobenzaldehyde, malononitrile and isopropyl acetoacetate. Yield: 85%.
UV (λmax): 287; IR (cm-1): 3400.54, 3350.94, 3267.60, 3210.57, 3100.36, 2970.21, 2925.63, 2190.63, 1690.75, 1655.34, 1453.30, 1362.74, 1264.96. 1178.83, 1056.08, 747.76; 1H-MMR (DMSO): 0.82-0.80(d^/=Hz,3H), 1.13-l.l0(d,./=Hz,3H), 2.32{s.3H), 4.61(s,lH). 4.80-4.71(m,lH), 6.92(s,2H;NH2), 7.09(s,lH), 7.28-7.!2(m,3H): l3C-NMR(DMSO): 18.00, 20.78, 21.34, 32.30, 55.82, 67.44, 105.73,

115.05, 115.34, 119.41. 124.56, 131.71, 157.55. 158.05, 158.59.. 161.31, 164.55; HRMS(m/z): 316.12; Elem.Anal.Calculated for C17H1,FN2O3: C,64.55; H,5.42; F,6.01; N,8.86. Found: C, 64.50, H, 5.45; F, 6.05; N, 8.90.
Example 5: Isopropyl 6-amino-5-cyano-4-(3, 4-difluorophenyl)-2-methyl-4//-pyran-3-carboxylate(V)
Compound (V) was synthesized by the procedure as described in Example 1 using 3, 4-fluorobenzaldehyde. malononitrile and isopropyl acetoacetate. Yield: 80%.
UV (λmax): 292; IR (cm-1): 3401,54, 3355.94, 3270.60, 3200.57, 3102.36. 2975.21, 2925.63, 2200.63,
1695.75, 1656.34, 1463.30. 1372.74, 1254.96. 1170.83, 1060.08, 750.76: IH-NMR (DMSO): 0.81-
0.79(d,J=6Hz,3H), 1.14-1,12(d,.J=6Hz,3H), 2.23(s,3H). 4.50(s,lH), 4.8S(m,lH), 6.70(s,lH), 6.90-
6.93(d,J=9Hz, lH),6.95(S,2H,NH2) 7.15-7.12(d.J= 1 OHz,1H); l3C-NMR(DMSO): 18.25, 20.0, 20.5, 38.9,
58.2, 68.0, 107.90, 118.00, 118.60, 119.70, 117.56, 117.13, 127.10, 138.40, 145.20, 150.76, 157.89,
159.12, 164.15; HRMS(nVz): 334.10; Elem.Anal.Calculated for Ci7Hl6F2N203: C,61.07, H,4.82, F,11.37,
N, 8.38. Found: C, 60.87. H. 4.70, F, 11.50. N, 8.40.
Example 6: Isopropyl 6-amino-4-(3, 5-bis (irifluoromethy!) phenyl)-5-cyano-2-methyl-4//-pyran-3-carboxylate (VI)
Compound (VI) was synthesized by the procedure as described in Example 1 using 3, 5-bis (trifluoromethyl) benzaldehyde. malononitrile and isopropyl acetoacetate. Yield: 83%.
UV(lmax):295:IR(cnrl): 3407.06,3330.94,2983.30,2195.08, 1679.18, 1645.18, 1605, 1455.8, 1370.99, 1275.04, 1168.77, 1125.99, 898.27, 680.97; 1H-NMR (DMSO): 0.79-0.77(d,J=6Hz,3H), 1.10-1.08(d^/=6Hz,3H), 2.3 (sJH), 4.64(s,lH). 4.80-4.72(m. 1H), 7.1 l(s,2H), 7.l8(s,2H,NH2), 8.01(s,lH); ,3C-NMR(DMSO): 18.20,20.67.21.24,38.37, 55.91,67.67, 105.56, 119.14, 121.42, 125.04, 130.11, 130.54, 148.73, 158.14, 158.44. 164.35; HRMS(m/z): 434; : Elem.Anal.Calculated for C19H|6F6N203: C,52.54; H,3.71; F,26.24; N,6.45. Found: C. 52.50; H. 3.65; F. 6.20: N, 6.50.
Example 7: Isopropyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-methyl-4//-pyran-3-carboxylate (VII)
Compound (VII) was synthesized by the procedure as described in Example 1 using 2-chlorobenzaldehyde. malononitrile and isopropyl acetoacetate. Yield: 91%.
UV (λmx): 291; IR (cm-1): 3463.38. 3302.62, 3221.62, 3186.66, 2982.04, 2925.35, 2207.18, 1683.45, 1603.00, 1469.66, 1378.67, 1223.45. 1174.37, 1060.16, 748.23; IH-NMR (DMSO): 0.74-0.72(d,J=6Hz,3H), J. 12-1.10(d../=6Hz!3H), 2.34(s,3H), 4.78-4.70(m,l H). 4.86(s,lH), 6.90(s,2H,NH2), 7.40-7.17(m,4H); l3C-NMR(DMSO): 17.95, 20.66, 21.32, 35.15, 55.98, 67.33, 106.06, 119.09, 127.66, 128.30, 129.14, 129.68, 132.00, 142.19, 157.65, 158.34, 164.51; HRMS(m/z): 332.01; Elem.Anal.Calculated for C17H17ClN2O3: C,61.36: H,5.15; C1,10.65; N,8.42.Found: C, 61.40; H, 5.10; Cl, 11.00; N, 8.60.
Example 8: Isopropyl 6-amino-4-(3-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (VIII)
Compound (VIII) was synthesized by the procedure as described in Example 1 using 3-chlorobenzaldehyde. malononitrile and isopropyl acetoacetate. Yield: 90%.
UV (λ,nax): 290; IR (cm-1): 3403.25, 3324.00, 3264.18, 3224.38, 2981.19, 2937.10, 2200.00, 1677.91,
1641.76, 1608.55, 1578.89, 1469.61. 1374.85. 1264.31, 1175.04, 1120.56, 1060.17. 750.29: IH-NMR
(DMSO): 0.90-0.88(d.,/=6Hz,3 H), 1.14-1.12(d..J=6Hz.3H), 2.3 l(s,3H), 4.31 (s, IH), 4.82(m, 1H),
6.97(s,2H,NH2), 7.35(M.3H), 7.38(s,IH): L;C-NMR(DM$0): 18.06, 20.94, 21.42, 38.56, 56.58, 67.64,
106.64, 119.46, 126.06. 126.74, 127.20. 130.31. 132.84, 147.44, 156.94, 158.41, 164.64; HRMS(m/z):
332.01; Elem.Anal.Calculaied for Cl7H,7CIN,0^ C.6I.36; H,5.15: CI.10.65; N,8.42.Found: C, 61.40; H,
5.10; Cl, 11.00; N, 8.60.

Example 9: Isopropyl 6-amino-5-cyano-4-(4-cyanophenyl)-2-methyl-4W-pyran-3-carboxyIate(IX)
Compound (IX) was synthesized by the procedure as described in Example 1 using 4-cyanobenzaldehyde, malononitrile and isopropyl acetoacetate. Yield: 85%.
UV (λmax): 296; 1R (cm-1): 3403.25, 3334.00, 3261.18, 3227.38. 2970.19. 2947.10, 2200.00, 2195.67, 1680.91, 1648.76, 1608.46, 1578.79, 1459.62, 1374.88, 1254.21, 1185.34, 11500.56, 1070.27, 850.79; IH-NMR(DMSO): 0.87-0.85(d,.J=6Hz,3H), l.I7-1.15(d,J=6Hz,3H); 2.34(s,3H), 4.25(s,lH), 4.90(m,lH), 6.90(s,2H,NH2), 7.5 l-7.50(dd,J=3Hz.2H), 7.63-7.6 l(dd,/=6Hz,2H); 13C-NMR(DMSO): 17.90, 20.78, 21.45, 38.14, 59.01, 67.34, 107.77. ! 10.66, 118,67, 119.78, 129.11, 130.80, 147,11, 158,78, 159,99, 164,5,5; HRMS(m/z): 323.00; Elem.Anal.Calculated for C18H17N3O3 C,66.86: H.5.30: N,13.00.found: C; 66.90; H, 5.45; N, 12.87.
Example 10: Ethyl 6-amino-5-cyano-4-(2-hydroxy-4-methoxyphenyl)-2-methyl-4/-/-pyran-3-carboxylate (X)
Compound (X) was synthesized by the procedure as described in Example I using 2-hydroxy-4-methoxybenzaldehyde. malononitrile and ethyl acetoacetate. Yield: 89%.
UV (λmax): 322; 1R (cm-1):3402, 3336.16, 3229.79, 2975.16, 2206.44, 1697.68, 1655.38, 1609.45, 1584.56, 1465.70, 1321.40, 1224.32, 1185.81, 1017.53, 865.68; 1H-NMR (DMSO): 1.61-1.20(t,J=Hz,3H), 2.49(s;3H). 3.77(s,3H); 4.09(m,2H), 5.71(s,lH), 6.83(s,lH), 6.91-6.90(d,J=3Hz,lH), 6.94-6.93(d,y-3HzJH), 8.53(s.2H,NH2), 9.32(s,lH,OH); L1C-NMR(DMSO): 14.11, 21.7, 42.9, 55.69, 59.31, 80.12, 107.54. 111.46, 112.00, 113.09, 115.17, 126.37, 147.35, 147.44, 147.84, 151.20, 165.5; HRMS(m/z): 330.10: f lem.Anal.Calculated for C17Hl8N205: C,61 81; H,5.49: N,8.48.Found: C, 61.85; H, 5.60: N, 8.30.

5) CLAIMS
We claim
1) Synthesis of ethyl 6-amino-4-(3. 5-bis (trifluoromethyl) phenyl)-5-cyano-2-methyl-4//-pyran-3-carboxylate (I) by the reaction of 3,5-bis(Trifluoromethyl)benzaldehyde, malononitrile and ethyl acetate using CsOH-AI203 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 1.
2) Synthesis of isopropyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate (II) by the reaction of benzaldehyde, malononitrile and isopropyl acetoacetate using CsOH-Al2O3 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 2.

3) Synthesis of isopropyl 6-amino-5-cyano-4-(4-fluorophenyl)-2-methyI-4H-pyran-3-carboxylate (III) by the reaction of 4-fluorobenzaldehyde, malononitrile and isopropyl acetoacetate using CsOH-AI2O3 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 3.
4) Synthesis of isopropyl 6-amino-5-cyano-4-(3-fluorophenyl)-2-methyl-4H-pyran-3-carboxylate (IV) by the reaction of 3-fluorobenzaldehyde, malononitrile and isopropyl acetoacetate using CsOH-Al2O3 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 4.
5) Synthesis of isopropyl 6-amino-5-eyano-4-(3; 4-difluorophenyl)-2-melhyl-4H-pyran-3-carboxylate (V) by the reaction of 3, 4-fluorobenzaldehyde, malononitrile and isopropyl acetoacetate using CsOH-Al2O3 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 5.
6) Synthesis of isopropyl 6-amino-4-(3, 5-bis (trifluoromethyl) phenyl)-5-cyano-2-methyl-4//-pyran-3-carboxylate (VI) by the reaction of 3, 5-bis (trifluoromethyl) benzaldehyde, malononitrile and isopropyl acetoacetate using CsOH-Al2O3 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 6.
7) ) Synthesis of isopropyl 6-amino-4-(2-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (VII) by the reaction of 2-chlorobenzaldehyde, malononitrile and isopropyl acetoacetate using CsOH-AI203 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 7.
8) Synthesis of isopropyl 6-amino-4-(3-chlorophenyl)-5-cyano-2-methyl-4H-pyran-3-carboxylate (VIII) by the reaction of 3-chlorobenzaldehyde. malononitrile and isopropyl acetoacetate using CsOH-AI2O3 as a heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 8.

9) Synthesis of isopropyl 6-amino-5-cyano-4-(4-cyanophenyl)-2-methyl-4H-pyran-3-carboxy]ate(lX) by
the reaction of 4-cyanobenzaldehyde, malononitrile and isopropyl acetoacetate using CsOH-AI2O3 as a
heterogeneous basic catalyst in alcohol solvent at room temperature as described in Example 9.
10) Synthesis of ethyl 6-amino-5-cyano-4-(2-hydroxy-4-rnethoxyphenyl)-2-methyl-4H-pyran-3-
carboxylate (X) by the reaction of 2-hydroxy-4-methoxybenzaldehyde. malononitrile and ethyl
acetoacetate using CSOH-AUO3 as a heterogeneous basic catalyst in alcohol solvent at room temperature
as described in Example 10.