Scientific paper
Transformations of Dialkyl Acetone-1,3-dicarboxylates via Their Dimethylaminomethylidene Derivatives Into 1-substituted 4-ethoxycarbonyl-5-(ethoxycarbonylmethyl)pyrazoles, 7-amino-2-ethoxycarbonyl-1fl^, 2.^-pyrazolo[2,3-c]pyrimidin-5-one, 4-hydroxypyridin-2(1fl^)-ones and 6-substituted 3-benzoylamino-2,5-dioxo-5,6-dihydro-2^-pyrano[3,2-c]pyridine-8-carboxylates.
Silvo Zupan~i~, Jurij Svete and Branko Stanovnik*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P. O. box 537,
1000 Ljubljana, Slovenia
* Corresponding author: E-mail: branko.stanovnik@fkkt.uni-lj.si
Received: 04-06-2008
Dedicated to the memory of Professor Ljubo Golic
Abstract
Diethyl 1-dimethylamino-3-oxobut-1-ene-2,4-dicarboxylate (2a), prepared from diethyl acetone-1,3-dicarboxylate and W,W-dimethylformamide dimethylacetal (DMFDMA), was transformed with hydrazines 3a-g into 1-susbtituted 4-et-hoxycarbonyl-5-(ethoxycarbonylmethyl)pyrazoles 5a-g, with aminoguanidine (6) into 7-amino-2-ethoxycarbonyl-1ff,2ff-pyrazolo[2,3-c]pyrimidin-5-one (9), and with amines 10a-k into 4-hydroxypyridin-2(1H)-ones 11a-k. Compounds 11 were treated with methyl (Z)-2-benzoylamino-3-dimethylaminopropenoate (12) to give 6-substituted 3-ben-zoylamino-2,5-dioxo-5,6-dihydro-2H-pyrano[3,2-c]pyridine-8-carboxylates 14, while in the reaction with methyl 3-di-methylamino-2-(methoxycarbonyl)propenoate (15) decarboxylation of one of the ester groups took place producing alkyl (E)-1-alkyl-4-hydroxy-5-(3-methoxy-3-oxoprop-1-enyl)-6-oxo-1,6-dihydropyridine-3-carboxylates 17.
Keywords: 1-substituted 4-ethoxycarbonyl-5-(ethoxycarbonylmethyl)pyrazoles, 1H,2H-pyrazolo[2,3-c]pyrimidin-5-one, 4-hydroxypyridin-2(1fl)-ones, 6-substituted 2H-pyrano[3,2-c]pyridine-8-carboxylates.
1. Introduction
There are many methods for the synthesis of pyrazo-les,1 pyrazolopyrimidines,2 and pyranopyridines3 described in the literature.
In connection with our interest in enaminones and related compounds, as building blocks for the preparation of various heterocyclic systems4 including also some natural products,5'6 dialkyl acetone-1,3-dicarboxylates have
been recently employed for the synthesis of heteroaryl substituted pyrimidines,7 dialkyl 1-substituted 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates,8 pyrazolo[4,3-d] pyridine-7-carboxylates,9 pyrazolyl substituted pyridop-yrimidines, pyranopyranediones, and chromenediones,10 and pyrazolo[4,3-d][1,2]diazepines.11'12
In this paper the following transformations were studied:
1. 1. Transformations of Diethyl 1-dimethyla-mino-3-oxobut-1-ene-2,4-dicarboxylate (2) with Hydrazines Into 1-substituted 4-ethoxycarbonyl-5-(ethoxycarbonyl-methyl)-pyrazoles (5) Diethyl acetone-1,3-dicarboxylate (1a) reacts with ^,^-dimethylformamide dimethylacetal (DMFDMA) in ethanol at room temperature to give diethyl 1-dimethyla-mino-3-oxobut-1-ene-2,4-dicarboxylate (2a), which was used without isolation and purification for further reac-
tion. To this reaction mixture an equivalent amount of mo-nosubstituted hydrazine was added and the reaction mixture was stirred at room temperature or heated at reflux for several hours to form the intermediate 4, which was without isolation cyclised into 1-substituted 4-ethoxycar-bonyl-5-(ethoxycarbonylmethyl)pyrazoles 5. (Scheme 1). Structures of compounds 5 were determined on the basis of elemental analyses for C, H, and N, and 1H NMR spectra. The chemical shift for H3 appears in the range 5H3 = 7.80-8.30 ppm, while CH2 group appears at 5CH2 = 4.15-4.68 ppm.
5	Reaction conditions	R1	Yield (%)	Mp (°C) solvent
a	Reflux, 2 h	Me	66.1	59-66 (MTBE)
b	Reflux, 1 h	benzyl	23.7	67-69 (Hex)
c	RT, 1h	2-pyridyl	47.0	60-61 (EtOH)
d	RT, 1h	2-pyrimidinyl	49.3	56-65 (Hex)
e	RT, 1h	6-chloro-3-pyridazinyl	61.2	91-93 (EtOH)
f	RT, 1.5 h	6-phenyl-3-pyridazinyl	57.4	111-114 (EtOH)
g	RT, 1h	imidazo[1,2-b]pyridazin-6-yl	71.1	138-139 (EtOH)
Scheme 1. Preparation of 1-substituted 4-ethoxycarbonyl-5-(ethoxycarbonylmethyl)-pyrazoles (5).
Scheme 2. The synthesis of 7-amino-2-ethoxycarbonyl-1ff,2ff-pyrazolo[2,3-c]pyrimidin-5-one (9).
1. 2. The Synthesis of 7-amino-2-ethoxycar-bonyl-1H,2H-pyrazolo[2,3-c]pyrimidin-5-one (9).
In the reaction of diethyl 1-dimethylamino-3-oxo-but-1-ene-2,4-dicarboxylate (2a) with aminoguanidine (6) first a substitution intermediate 7 is formed, which cycli-ses into pyrazole derivative 8, followed by cyclisation into the bicyclic 7-amino-2-ethoxycarbonyl-1H,2H-pyrazo-lo[2,3-c]pyrimidin-5-one (9). The intermediates 7 and 8 were not isolated. (Scheme 2).
1. 3. The Synthesis of 4-hydroxypyridin-2 (1H)-ones (11) and 6-substituted 3-benzoylamino-2,5-dioxo-5,6-dihydro-2H -pyrano[3,2-c]pyridine-8-carboxylates (14).
The dimethylamino group in diethyl (2a) and dimethyl 1-dimethylamino-3-oxobut-1-ene-2,4-dicarboxylates (2b) can be exchanged very easily with nitrogen nucleophiles. In the reaction with primary amines in methanol or ethanol un-
der reflux for several hours first the substitution of the di-methylamino group by an amine is taking place followed by intramolecular nucleophilic attack of the amino group to the ester group to afford the corresponding 1-substituted 5-alkoxycarbonyl-4-hydroxypyridin-2(1H)-ones (11) in 16-93% yields. (Scheme 3). In the reaction of 11a,b,e,f with methyl (Z)-2-benzoylamino-3-dimethyla-minopropenoate (12) first the intermediate 13 was formed, which cyclised into 6-substituted 3-benzoylamino8-ethoxycarbonyl-2H,5H-pyrido[4,3-b]pyran-2,5-diones (14). On the other hand, reaction with 3-dimethylamino-2-(methoxycarbonyl)propenoate (15) first the intermediate 16 is formed, which did not produce the corresponding pyranopyridine derivative, instead hydrolysis and decar-boxylation of one of the ester groups took place to give 4-hydroxy-5-methoxycarbonyl-1-methyl-3-(2-methoxycar-bonyl)ethenylpyridin-2(1H)-one (17).
2. Experimental
Melting points were determined on a Kofler micro hot stage. 1H and 13C NMR spectra were obtained on a
Scheme 3. The synthesis of 4-hydroxypyridin-2(1H)-ones (11) and 6-substituted 3-benzoylamino-2'5-dioxo-5'6-dihydro-2H-pyrano[3'2-c]pyridi-ne-8-carboxylates (14).
11	Reaction condition	R1	R2	Yield (%)	Mp (oC) solvent
a	Reflux, MeOH , 13.5h	Me	H	51.7	247-253 (MeOH)
b	RT, EtOH , 20 h	Et	H	52.3	(19-((1(EtOH)
c	Reflux, MeOH , 1.5 h	Me	Me	93.0	148-151(MeOH)
d	Reflux, EtOH , 1 h	Et	Me	62.9	109-113 (MTBE)
e	Reflux, EtOH , 24 h	Et	CH(CH(OH	21.9	157-161(toluene)
f	Reflux, EtOH , 3.5 h	Et	i-Pr	56.0	130-156 (MTBE)
g	Reflux, EtOH , 2.5 h	Et	Bn	16.4	105-11( (nBuCl)
h	Reflux, EtOH , 2.0 h	Et	N(Me)(	17.7	95-105 (MTBE)
i	Reflux, EtOH , 24 h	Et	Ph	((.8	95-97(n-BuCl)
.i	Reflux, EtOH , 2.5 h	Et	A	32.2	264-268(DMF)
k	RT, EtOH , 1 h	Et	B	28.8	268-270(DMF)
A)	R2 = (phthalazin-1-yl)amino				
B)	R2 = (4-chlorophthalazin-1-yl)amino				
14	Reaction condition	R1	R2	Yield (%)	Mp (oC) solvent
a	Reflux, 16 h	Me	Me	18.9	277-290
b	Reflux, 1 h	Et	Me	47.5	267-270(AcOH)
c	Reflux, 9 h	Et	i-Pr	38.8	19(-194 (Ether)
d	Reflux, 9 h	Et	CH(CH(OCOCH3	81.8	(18-((4 (AcOH)
					
17	Reaction condition	R1	R2	Yield (%)	Mp (oC) solvent
a	Reflux, 16 h	Me	Me	22.6	(10-(14 (toluene)
b	Reflux, 1 h	Et	i-Pr	55.8	140-147 (MeOH)
Bruker Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C nucleus, using DMSO-d6 and CDCl3 with TMS as the internal standard. Mass spectra were recorded on an AutoSpecQ spectrometer, IR spectra on a Perkin-El-mer Spectruim BX FTIR spectrophotometer. Microanalyses were performed on a Perkin-Elmer CHN Analyser 2400.
Diethyl 2-((dimethylamino)methylene)-3-oxopen-tanedioate (2a)
To a solution of diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5 mmol) in ethanol (10 ml) DMFDMA (0.72 ml, 5 mmol) was added and the mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated and the residue was chromatographed on a column of Al2O3. Elution with hexane / aceton (2 : 1, v:v) gave 750 mg (58%) of the title product as a yellow oil. 1H NMR (300 MHz, DMSO-d6/TMS) 5: 1.28 (m, 6H: 2 x OCH2CH3), 2.91 (bs, 3H: NfCH3), 3.29 (bs, 3H: NCH3), 3.79 (s, 2H: CH2), 4.18 (m, 4H: 2 x OCH2CH3), 7.83 (s, 1H: H2); 13C NMR (75.5 MHz, DMSO-d6/TMS), 5: 14.11 (OCH2CH3), 14.38 (OCH2CH3), 42.60, 47.89, 48.59, 59.94 (OCH2CH3), 60.68 (OCH2CH3), 101.05, 159.34, 167.35 (COC(Et), 169.23 (COOEt), 189.60 (CO); IR (Na-Cl) V (cm-1): 2981, 1735, 1686, 1641, 1580; MS (MH+) m
/z: 258. HRMS for C12H19NO5: calcd: 257.126323, found: 257.126650. 12 19 5
This compound was prepared in situ and was used without isolation and purification in further experiments,
Dimethyl 2-((dimethylamino)methylidene)-3-oxo-pentanedioate (2b)
To a solution of dimethyl acetone-1,3-dicarboxylate (1b; 0.72 ml, 5 mmol) in methanol (10 ml) DMFDMA (0.72 ml, 5 mmol) was added and the mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated in reduced pressure. The residue was chromatograp-hed on a column of Al2O3. Elution with hexane / aceton (2 :
1,	v:v) gave 412 mg (36%) of the title product as a yellow oil. 1H NMR (300 MHz, DMSO-d6/TMS) 5: 2.92 (bs, 3H: NCH3), 3.30 (bs, 3H: NCH3), 3.71 (s, 3H: CH3), 3.72 (s, 3H: CH3), 3,80 (s, 2H: COCH2COOMe), 7.85 (s, 1H: H1); IR (NaCl) V (cm-1): 2982, 1733, 1680, 1647, 1586; HRMS for C1oH15NO5: calcd: 229.095023, found: 229.095560. This compound was prepared in situ and was used without isolation and purification in further experiments,
2.	1. General Procedure for the Synthesis
of Pyrazoles 5
To a solution of diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol) in ethanol (4 ml) DMFDMA (0.29 ml, 2.0 mmol) was added and the mixture was stirred at room temperature for 45 min. Then hydrazine (3; 2 mmol) was added and the reaction mixture was stirred to complete the reaction. The mixture was then cooled to 0oC and the product was separated by filtration. The crude products were purified by recrystallisation form an appropriate solvent.
Ethyl 5-(2-ethoxy-2-oxoethyl)-1-methyl-1H-pyra-zole-4-carboxylate (5a)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol), ethanol (4 ml), DMFDMA (0.29 ml, 2.0 mmol) and methylhydrazine (3a; 0.11 ml, 2.0 mmol), 2 hours of reflux in 66% yield, mp = 59-61 °C (from TBME). 1H NMR (300 MHz, DMSO-d6/TMS) 5: 1.19 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.25 (t, 3H: 0CH2CH3, J = 7.2 Hz), 3.80 (s, 3H: NCH3), 4.11 (q, 2H: 0CH2CH3, J = 7.2 Hz), 4.15 (s, 2H: CH2COOEt), 4.18 (q, 2H: OCH2CH3, J = 7.2 Hz), 7.80 (s, 1H: H3); 13C NMR (75.5 MHz, DMSO-d6/TMS), 5: 13.99 (OCH2CH3), 14.12 (0CH2CH3), 30.13 (CH2COOEt), 36.62 (NfCH3), 59.52 (0CH2CH3), 60.82 (OCH2CH3), 111.92 (C4), 139.56 (C5), 13^.60 (C3), 162.60 (COOEt), 168.38 (CH2COOE;t); IR (KBr) v (cm-1): 3432, 2994, 1723, 1703, 156^, 1248; MS (MH+) m/z: 241; elemental analysis: cal-cd (%) for C11H1gN2O4 (240.3): C 54.99, H 6.71, N 11.66; found: C 54.93, H (5.75, N 11.43.
Ethyl 1-benzyl-5-(2-ethoxy-2-oxoethyl)-1H-pyra-zole-4-carboxylate (5b)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol), ethanol (4 ml), DMFDMA (0.29 ml, 2.0 mmol) and benzylhydrazine dihydrochloride (3; 390 mg, 2.0 mmol), 1 hour of reflux in 24% yield, mp = 67- 69 °C (from hexane). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.11 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.24 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.00 (q, 2H: 0CH2CH3, J = 7.2 Hz), 4.14 (s3 2H: CH2COOEt), 4.18 (q, 2H: 0CH2CH3, J = 7.2 Hz), 5.42 (s, 2H: CH2Ph), 7.167.19 (m, 2H: Ph), 7.27-7.32 (m, 3H: Ph), 7.90 (s, 1H: H3)); 13C NMR (300 MHz, DMSO-d./TMS, 5: 13.89 (0CH2CH3), 14.12 (0CH2CH3), 30.38 (CH2COOEt), 52.32 (CH2Ph), 59.57 (OCH2CH3), 60.68 (OCH2CH3), 112.40 (C4), 127.33, 127.58, 128.42, 136.40, 139.88, 140.32, 162.52(COOEt), 168.13 (COOEt); IR (KBr) v (cm-1): 3456, 2980, 1734, 1703, 1563, 1242; elemental analysis: calcd (%) for C17H20N2O4 (316.4): C 64.54, H 6.37, N 8.86; found: C 64.:56, ^ 65.41, N 8.83.
Ethyl 5-(2-ethoxy-2-oxoethyl)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate (5c)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol), ethanol (4 ml), DMFDMA (0.29 ml, 2.0 mmol) and 2-hydrazinopyridine (3c; 218 mg, 2.0 mmol), 1 hour of reflux in 47% yield, mp = 60-61 °C (from ethanol). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.10 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.30 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.03 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.27 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.58 (s, 2H: CH2COOEt), 7.44 (ddd, 1H: H^ (Het), J = 7.2 Hz, J = 4.8 Hz, J = 0.9 Hz), 7.94 (bd, 1H: H3 (Het), J = 8.4Hz), 8.06 (ddd, 1H: H4 (Het) J = 8.4 Hz, J = 7.2 Hz, J = 1.8 Hz), 8.16 (s, 1H: H3), 8.45 (ddd, 1H: H, (Het), J = 4.8 Hz, J = 1.8 Hz, J = 0,9 Hz); 13C NMR (75.5 MHz, DMSO-d./TMS),
5: 13.96 (OCH2CH3), 14.13 (OCH2CH3), 32.26 (CH2COOEt), 60.07 (OCH2CH3), 60.43 (OCH2CH3), 114.75, 115.95, 122.93, 139.70, 140.60, 141.76, 147.50, 152.04, 162.52 (COOEt), 168.48 (COOEt); IR (KBr) v (cm-1): 3411, 2984, 1728, 1707, 1405, 1243; elemental analysis: calcd (%) for C15H17N3O4 (303.3): C 59.40, H 5.65, N 13.85; found: C 59.45, H 5.76, N 13.77.
Ethyl 5-(2-ethoxy-2-oxoethyl)-1-(pyrimidin-2-yl)-1H-pyrazole-4-carboxylate (5d)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol), ethanol (4 ml), DMFDMA (0.29 ml, 2.0 mmol) and 2-hydrazinopyrimi-dine (3d; 220 mg, 2.0 mmol), 1 hour of reflux in 49% yield, mp = 63-65 °C (from hexane). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.10 (t, 3H: OCH5CH3, J = 7.2Hz), 1.30 (t, 3H: OCH5CH3, J = 7.2Hz), 4.03 (q, 2H: OCH5CH3, J = 7.2 15z), 4.27 (q, 2H: OCH5CH3, J = 7.2 Hz), 4.55 (s, 2H: CH5COOEt), 7.59 (dd, 1H: H5 (Het), J = 5.1 Hz, J = 5.1 Hz), 8.17 (s, 1H: H3), 8.92 (d, ^H: H4, Hg (Het) J = 5.1 Hz); 13C NMR (75.5 MHz, DMSO-d./TlVIS), 5:13.96 (OCH5CH3), 14.09 (OCH5CH3), 32.20 (CH5COOEt), 60.16 (OCH5CH3), 60.51 (OCH5CH3), 114.98, 120.56, 141.79, 142.03, 156.09, 158.34, 159.13, 162.42 (COOEt), 168.40 (COOEt); IR (KBr) v (cm-1): 3443, 2982, 1732, 1716, 1567, 1428, 1266; elemental analysis: calcd (%) for C14H15N4O4 (304.3): C 55.26, H 5.30, N 18.41; found: C 54t.85, H 5.26, N 18.79.
Ethyl 1-(6-chloropyridazin-3-yl)-5-(2-ethoxy-2-ox-oethyl)-1H-pyrazole-4-carboxylate (5e)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol), ethanol (4 ml), DMFDMA (0.29 ml, 2.0 mmol) and 6-chloro-3-hydrazi-nopyridazine (3e; 288 mg, 2.0 mmol), 1 hour of reflux in 61% yield, mp = 91-93 °C (from ethanol). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.13 (t, 3H: OCH5CH3, J = 7.2 Hz), 1.30 (t, 311: OCH5CH3, J = 7.2 Hz), 4.07 (q, 2H: OCH5CH3, J = 7.2 Hz), 4.29 (q, 2H: OCH5CH3, J = 7.2 Hz), 44.58 (s, 2H: CH5COOEt), 8.17 (d, 1H: (Het), J = 9.3 Hz), 8.30 (d, 1H: (Hejt), J = 9.3 Hz), 8.31 (s, 1H: H3); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: 13.97 (OCH5CH3), 14.08 (OCH5CH3), 32.23 (CH5COOEt), 60.34 (OCH5CH3), 60.66 (OCH5CH3), 115.79, 124.44, 132.05, 141.52, 143.10, 155.06, 155.40, 162.18 (COOEt), 168.17 (COOEt); IR (KBr) v (cm-1): 3418, 2981, 1736, 1710, 1582, 1546, 1271; elemental analysis: calcd (%) for C14H15ClN4O4 (338.8): C 49.64, H 4.46, N 16.54; found: C 449.990, H 4.60, N 16.52.
Ethyl 5-(2-ethoxy-2-oxoethyl)-1-(6-phenylpyrida-zin-3-yl)-1H-pyrazole-4-carboxylate (5f)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol), ethanol (4 ml), DMFDMA (0.29 ml, 2.0 mmol) and 3-hydrazino-6-phenylpyridazine (3f; 372 mg, 2.0 mmol), 1.5 hours of
reflux in 57% yield, mp = 111-114 °C (from ethanol). 1H NMR (300 MHz, DMSO-d6/TMS) 5: 1.12 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.32 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.07 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.29 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.68 (s, 2H: CH2COOEt), 7.50-7.65 (m, 3H: Ph), 8.15-8.25 (m, 2H: Ph), 8.29 (d, 1H: (Het), J = 9.3 Hz), 8.30 (s, 1H: H3), 8.51 (d, 1H: (Het), J = 9.3 Hz); 13C NMR (75.5 MHz, DMSO-d6/TMS), 5: 13.95 (OCH2CH3), 14.09 (OCH2CH3), 32.30 (CH2COOEt), 60.25 (OCH2CH3), 60.60 (OCH2CH3), 115.49, 121.60, 126.88, 127.51, 129.11, 130.41, 134.95, 141.18, 142.78, 155.04, 157.86, 162.30 (COOEt), 168.30 (COOEt); IR (KBr) v (cm-1): 3422, 2984, 1731, 1709, 1549, 1180; elemental analysis: calcd (%) for C20H20N4O4 (380.4): C 63.15, H 5.30, N 14.73; found: C 63.04, H 5.35, N 14.66.
Ethyl 5-(2-ethoxy-2-oxoethyl)-1-(imidazo[1,2-b]pyridazin-6-yl)-1H-pyrazole-4-carboxylate (5g)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2.0 mmol), ethanol (4 ml), DMFDMA (0.29 ml, 2.0 mmol) and 6-hydrazinoimida-zo[1,2-&]pyridazine (3g; 298 mg, 2.0 mmol), 1 hour of reflux in 71% yield, mp = 138-139 °C (from ethanol). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.09 (t, 3H: OCH2CH3, J = 7.2 Hz), 1.31 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.08 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.29 (q, 2H: OCH2CH3, J = 7.2 Hz), 42.55 (s, 2H: CH2COOEt), 7.76 (d, 1H: II5 (Het), J = 9.8 Hz ), 7.89 (d, 1H: H2 (Het), J = 1.1 Hz), 8.15 (dd, 1H: H1 (Het), J = 1.1Hz, J ^ 0.7 Hz), 8.27 (s, 1H: H3), 8.37 (dd, 1H: Hg (Het), J = 9.8 Hz, J = 0.7 Hz); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: 13.93 (OCH2CH3), 14.09 (OCH2CH3), 31.96 (CH2COOEt), 60.29 (OCH2CH3), 60.78 (OC112CH3), 113.1,^, 115.32, 117.39, 128.10, 134.98, 137.43, 141.27, 142.57, 147.99, 162.23 (COOEt), 168.31 (COOEt); IR (KBr) v (cm-1): 2990, 1740, 1716, 1537, 1270; elemental analysis: calcd (%) for C1gH17N5O4 (343.3): C 55.97, H 4.99, N 20.40; found: C 5^.01, H 4.91, N 20.29.
11.00 (bs, 1H: NH); 13C NMR (75.5 MHz, CDCl3/TMS), 5: 14.42 (OCH2CH3), 59.05 (OCH2CH3), 80.28, 100.06, 145.62, 146.53, 1427.55, 162.15, 162.67; IR (KBr) v (cm-1): 3364, 3166, 1693, 1597, 1514, 1317, 1036; MS (M+) m /z: 222; elemental analysis: calcd (%) for C5H10N4O3 (222.2): C 48.65, H 4.54, N 25.21; found: C 48.45, H 4.37, N 24.67.
2. 2. General Procedure for the Synthesis
of Pyridones 11
To a solution of dialkyl acetone-1-3-dicarboxylate (1a; 0.95 ml, 1b; 0.72 ml; 5 mmol) in an alcohol (10 ml) was added DMFDMA (0.72 ml, 5.0 mmol) and the mixture was stirred at room temperature for 45 min. Then amine (10; 6 mmol) and one drop of concentrated HC-l were added and stirred under reflux to complete the reaction. After that, the mixture was concentrated under reduced pressure to the oily residue. To this residue tert-buthylmethyl ether was added and the mixture was cooled to 0 oC. The product was separated by filtration and purified by recrystallisation from an appropriate solvent.
Methyl 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (11a)
This compound was prepared from dimethyl aceto-ne-1,3-dicarboxylate (1b; 0.72 ml, 5.0 mmol), methanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and ammonia (10a; 25%, 0,40 ml, 6 mmol), 13.5 h of reflux, in 52% yield, mp = 247-253 °C (from methanol), lit.13 mp = 237-240 °C. 1H NMR (300 MHz, DMSO-dg/TMS) 5: 3.79 (s, 3H: OCH3), 5.61 (s, 1H: H3), 8.02 (s, 1H: Hg), 10.00-12.00 (bs, 2H: NH, OH); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: 51.98 (OCH3), 98.49 (C3), 100.15 (C5), 142.63 (Cg), 163.50, 165.83, 166.22; IR (KBr) v (cm-1): 3443, 3076, 2686, 1694, 1651, 1440; elemental analysis: calcd (%) for C7H7NO4 (169.1): C 49.71, H 4.17, N 8.28; found: C 49.86, H 41.31, N 8.17.
Ethyl 7-amino-2-oxo-1,2-dihydropyrazolo[1,5-c]pyrimidine-4-carboxylate (9)
To a solution of diethyl acetone-1,3-dicarboxylate (1a; 0.38 ml, 2 mmol) in ethanol (4 ml) DMFDMA (0.29 ml, 2 mmol) was added and the mixture was stirred at room temperature for 45 min. Then aminoguanidine hydrogen carbonate (6; 816 mg, 6 mmol) was added and the mixture was stirred under reflux for 15 hours. The reaction mixture was cooled, diluted with ethyl acetate (100 ml), washed with water (100 ml) and brine (3 x 100 ml) and dried over Na1SO4. The mixture was filtered and filtrate concentrated to 5 ml, cooled to 0 °C and the product separated. Yield 13%, mp = 293-295 °C (from methanol). 1H NMR (300 MHz, CDCl3/TMS) 5: 1.30 (t, 3H: OCH1CH3, J = 6.9 Hz), 4.23 (q, 2H: OCH1CH3, J = 6.9 Hz), 6.27 (s, 1H: H3), 7.83 (s, 2H: NH1), 8.23 (s, 1H: H^),
Ethyl 4-hydroxy-6-oxo-1,6-dihydropyridine-3-car-boxylate (11b)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and ammonia (10a; 25%, 0,40 ml, 6 mmol), 20 hours at r.t., in 52% yield, mp = 219-221 °C (from ethanol), lit.14 mp = 213 °C. 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.28 (t, 3H: OCH1CH3, J = 7.2 Hz), 4.26 (q, 2H: OCH1CH3, J = 7.2 Hz), 5.61 (s, 1H: H3), 8.02 (s, 1H: Hg), 10.82 (bs, 1H: OH), 11.75 (bs, 1H: NH); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: 14.01 (OCH1CH3), 60.90 (OCH1CH3), 98.50 (C3), 99.99 (C5), 142.50 (Cg), 163.58, 165.^6, 166.11; IR (ICBr) v (cm-1): 3421, 3068, 1661, 1316; elemental analysis: calcd (%) for C8H9NO4 (183.2): C 52.46, H 4.95, N 7.65; found: C 5^.52, H 4.80, N 7.53.
Methyl 4-hydroxy-1-methyl-6-oxo-1,6-dihydrop-yridine-3-carboxylate (11c)
This compound was prepared from dimethyl aceto-ne-1,3-dicarboxylate (1b; 0.72 ml, 5.0 mmol), methanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and methylamine (10c; 12 M, 0.50 ml, 6 mmol), 1.5 h of reflux, in 93% yield, mp = 148-151 °C (from methanol) 1H NMR (300 MHz, DMSO-d6/TMS) 5: 3.42 (s, 3H: NCH3), 3.80 (s, 3H: OCH3), 5.66 (s, 1H: H3), 8.47 (s, 1H: H6), 10.00-12.00 (bs, 1H: OH); 13C NMR (75.5 MHz, DMSO-d6/TMS), 5: 36.48 (NCH3), 51.99 (OCH3), 97.67 (C3), 99.78 (C5), 146.51 (C6), 162.71, 165.14, 166.19; IR (KBr) V (cm-1): 3418, 3054, 1693, 1453; elemental analysis: cal-cd (%) for C8H9NO4 (183.2): C 52.46, H 4.95, N 7.65; found: C 52.37, H 5.01, N 7.75.
Ethyl 4-hydroxy-1-methyl-6-oxo-1,6-dihydropyri-dine-3-carboxylate (11d)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1; 0.95 ml, 5.0 mmol), methanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and methylamine (10c; 12 M, 0.50 ml, 6 mmol), 1 hour of reflux, in 63% yield, mp = 109-113 °C (from MTBE), lit.15 mp (not reported). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.30 (t, 3H: OCH2CH3, J = 7.2 Hz), 3.43 (s, 3^: NCH3), 4.29 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.68 (s, 1H: H3), 8.49 (s, 1H: Hg), 10.60-1(3.85 (bs, 1H: OH); 13C NMR (75.5 MHz, D6MSO-d6/TMS), 5: 14.09 (OCH2CH3), 36.52 (NCH3), 60.94 (OCH2CH3), 97.66 (C3), 99.68 (C5), 146.34 (Cg), 162.76, 165.29, 166.11; IR (KBr) v (cm^1): 3422, 1694, 1560, 1307; elemental analysis: calcd (%) for C5H11NO4 (197.2): C 54.82, H 5.62, N 7.10; found: C 54.79, H 5.58, N 7.12.
Ethyl 4- hydroxy-1-(2- hydroxyethyl)-6-ox o-1,6-dihydropyridine-3-carboxylate (11e)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and ethanolamine (10e; 0.37 ml, 6 mmol), 24 hours of reflux, in 23% yield, mp = 157-161 °C (from toluene). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.30 (t, 3H: OCH2CH3, J = 6.9Hz), 3.58 (m, 2H: NCH2), 3.97 (m, 2H: CH2OH), 4.29 (q, 2H: OCH2CH3, J = 6.9 Hz), 4.91 (t, 1H: CH2OH, J = 5.4 Hz), 5.69 (s, 1^: H3), 8.34 (s, 1H: H,), 10.75 (bs, 1H: OH); 13C NMR (75.5 MHz, DMSO-dg/TlMS), 5: 14.34 (OCH2CH3), 51.44, 58.63, 61.36, 98.14, ^9.93, 146.93, 162.88, 165.57, 166.31; IR (KBr) v (cm-1): 3268, 3055, 1685, 1317, 844; elemental analysis: calcd (%) for C1oH13NO5 (227.2): C 52.86, H 5.77, N 6.16; found: C 52.86, H 5.42, N 5.84.
Ethyl 4-hydroxy-1-isopropyl-6-oxo-1,6-dihydrop-yridine-3-carboxylate (11f)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1b; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and isopropylamine
(10f; 0.52 ml, 6 mmol), 3.5 hours of reflux, in 56% yield, mp = 152-156 °C (from MTBE). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.31 (m, 9H: OCH2CH3, 2 x CH3 ), 4.29 (q, 2H: OCH2CH3, J = 7.2 Hz), 4.95 (p, 1H: CH J = 6.9 Hz), 5.69 (s, 1H: ^3), 8.25 (s, 1H: Hg), 10.76 (bs, 1H: OH); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: 14.07 (OCH2CH3), 21.02 (2 x CH3), 46.96 (CH), 60.96 (OCH2CH3), 98.01 (C3), 100.74 (C5), 141.27 (Cg), 162.01, 164.48, 165.78; IR (KBr) v (cm-1): 3448, 1693, 1659, 1318, 1241, 780; elemental analysis: calcd (%) for C11H15NO4 (225.2): C 58.66, H 6.71, N 6.22; found: C 58.82, H 6.67, N 6.26.
Ethyl 1-benzyl-4-hydroxy-6-oxo-1,6-dihydropyridi-ne-3-carboxylate (11g)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) benzylamine (10g; 0.65 ml, 6 mmol), 2.5 hours of reflux, in 16% yield, mp = 108-112 °C (from n-butyl chloride). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.29 (t, 3H: OCH2CH3, J = 6.9 Hz), 4.28 (q, 2H: OCH2CH3, J = 6.9 Hz), 5.16 (s, 2H: CH2Ph), 5.74 (s, 1H: H3), 7.25^7.35 (m, 5H: Ph), 8.59 (s, 1H: Hg), 10.65-10.90 (l^s, 1H: OH); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: 14.06 (OCH2CH3), 50.82 (CH2Ph), 60.96 (OCH2CH3), 98.23 (C3), 100.84 (C5), 127.43, 127.51, 128.5^, 137.0, 145.67, 162.22, 165.25, 165.75; IR (KBr) V (cm-1): 2985, 1687, 1655, 1560, 1321; elemental analysis: calcd (%) for C15H15NO4 (273.3): C 65.92, H 5.53, N 5.13; found: C 65.72, ìì 5.42, N 5.31.
Ethyl 1-(dim e thy lam in o)-4- hydroxy-6-ox o-1,6-dihydropyridine-3-carboxylate (11h)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and 1,1-dimethylhy-drazine (10h; 0.46 ml, 6 mmol), 2 hours of reflux, in 18% yield, mp = 95-105 °C (from MTBE). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.29 (t, 3H: OCH2CH3, J = 7.2 Hz) , 2.95 (s, 6H: N(CH3)2), 4.26 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.67 (s, 1H: H3), ^.21 (s, 1H: Hg), 10.8(( (bs, 1H: OH); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: 13.98 (OCH2CH3), 44.07 (N(CH3)2), 60.96 (OCH2CH3), 99.73 (C3), 100.02 (C5), 147.05 (Cg), 162.24, 164.85, 1^5.05; IR (KBr) V (cm-1): 3463, 3050, 1693, 1557, 1278, 1234, 1139, 776; elemental analysis: calcd (%) for C10H14N2O4 (226.2): C 53.09, H 6.24, N 12.38; found: C 52.68, HH 6.02, N 11.80.
Ethyl 4-hydroxy-6-oxo-1-phenyl-1,6-dihydropyri-dine-3-carboxylate (11i)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and aniline (10i; 0.55 ml, 6 mmol), 24 hours of reflux, in 23% yield, mp = 95-97 °C (from n-butyl chloride). 1H NMR (300 MHz,
DMSO-dg/TMS) 5: 1.26 (t, 3H: OCH2CH3 , J = 7.2 Hz), 4.26 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.78 (s, 1H: H3), 7.40-7.55 (m, 5H: Ph), 8.23 (s, 1H: Hg), 10.50-11.40 (t»s, 1H: OH); 13C NMR (75.5 MHz, DMSO-d./TMS), 5: 13.98 (OCH2CH3), 60.97 (OCH2CH3), 98.35 (C3), 101.38 (C5), 126.977, 1^8.57, 129.05, 139.80, 145.29, 161.94, 165.32, 165.45; IR (KBr) v (cm-1): 3100, 1673, 1551, 1455, 1102; elemental analysis: calcd (%) for C14H13NO4 (259.3): C 64.86, H 5.05, N 5.40; found: C 64.91, H 4.91, N 5.39.
Ethyl 4-hydroxy-6-oxo-1-(phthalazin-1-ylamino)-1,6-dihydropyridine-3-carboxylate (11j)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and 1-hydrazinopht-halazine (10j; 961 mg, 6 mmol), 2.5 hours of reflux, in 32% yield, mp = 264-268 °C (from DMF). 1H NMR (300 MHz, CF3COOD/ TMS) 5: 1.28 (t, 3H: OCH2CH3, J = 7.2 Hz), 4.27 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.80 (s, 1H: H3), 7.80-7.95 (m, 3H: Het), 8.23 (s, 1H: H,), 8.29 (s, 1H: Het), 8.36 (d, 1H: Het), 10.66 (bs, 1H: OH), 12.02 (bs, 1H: NH); 13C NMR (75.5 MHz, CF3COOD/TMS), 5: 13.99 (OCH2CH3), 60.90 (OCH2CH3),399.08 (C3), 99.43 (C5), 124.28, 124.46, 126.64, 126.72, 132.12, 133.14, 138.97, 143.44, 150.89, 159.46, 164.17, 166.19; IR (KBr) V (cm-1): 3173, 1689, 1658, 1536, 1467, 1282; MS (M+) m/z: 326; elemental analysis: calcd (%) for C1gH14N4O4 (326.3): C 58.89, H 4.32, N 17.17; found: C 58.90, H 4.38, N 17.26.
Ethyl 1-(4-chlorophthalazin-1-ylamino)-4-hydroxy -6-oxo-1,6-dihydropyridine-3-carboxylate (11k)
This compound was prepared from diethyl acetone-1,3-dicarboxylate (1a; 0.95 ml, 5.0 mmol), ethanol (10 ml), DMFDMA (0.72 ml, 5.0 mmol) and 1-chloro-4-hydrazinophthalazine (10k; 1168 mg, 6 mmol), 1 hour at r.t. in 29% yield, mp = 268-270 °C (from DMF). 1H NMR (300 MHz, CF3COOD/ TMS) 5: 1.47 (t, 3H: OCH2CH3 , J = 7.2 Hz), 4.58 (q, 2H: OCH2CH3, J = 7.2 Hz), 6.56 (s, 1H: H3), 8.50-8.55 (m, 2H: Hejt), 8.70-8.75 (m, 2H: Het), 8.76 (s, 1H: H,), 11.51 (bs, 2H: OH , NH); 13C NMR (75.5 MHz, CF3CO6OD/ TMS), 5: 14.51 (OCH2CH3), 66.46 (OCH2CH3), 102.74, 107.90, 122.09, 12(5.48, 129.77, 131.01, 140.65, 141.22, 148.06, 154.00, 156.53, 166.78, 169.09, 173.24; IR (KBr) v (cm-1): 3411, 1693, 1662, 1536, 1468, 1279; MS (MH+) m/z: 361; elemental analysis: calcd (%) for C15H13ClN4O4 (360.8): C 53.27, H 3.63, N 15.53; found: C 53.49, H 3.65, N 15.43.
2. 3. General Procedure for the Synthesis of Compounds 14.
To the solution of compound 11 (1 mmol) in glacial acetic acid (4 ml ) was added methyl 2-benzoylamino-3-dimethylaminopropenoate (12; 248 mg, 1 mmol) and the resulting solution was stirred under reflux to complete the
reaction. The mixture was cooled and the product was separated by filtration and purified by recrystallisation from an appropriate solvent.
Methyl 3-benzamido-6-methyl-2,5-dioxo-5,6-dihy-dro-2H-pyrano[3,2-c]pyridine-8-carboxylate (14a)
This compound was prepared from methyl 4-hy-droxy-6-oxo-1,6-dihydropyridine-3-carboxylate (11a; 169mg, 1.0 mmol), 16 hours of reflux, in 19% yield, mp = 287-290 °C (from acetic acid). 1H NMR (300 MHz, DM-SO-dg/TMS) 5: 3.60 (s, 3H: NCH3), 3.84 (s, 3H: OCH3), 7.50-7.70 (m, 3H: Ph), 7.95 (m, 2H: Ph), 8.61 (s, 1H: H4 or H7), 8.66 (s, 1H: H4 or H7), 9.74 (bs, 1H: NH); 13C NMR (75.5 MHz, DMSO-d./TMS), 5: 37.34 (NCH3), 52.06 (OCH3), 100.70, 107.43, 122.95, 123.55, 127.72,
128.57,	132.26, 133.39, 146.19, 155.42, 156.52, 159.54, 161.96, 166.04; IR (KBr) v (cm-1): 3397, 3070, 1726, 1703, 1676, 1649, 1547, 1313; elemental analysis: calcd (%) for C18H14N2O5 (354.3): C 61.02, H 3.98, N 7.91; found: C 61.044, ìì 3(56, N 7.78.
Ethyl 3-benzamido-6-methyl-2,5-dioxo-5,6-dihy-dro-2H-pyrano[3,2-c]pyridine-8-carboxylate (14b)
This compound was prepared from ethyl 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylate (11b; 183 mg, 1.0 mmol), 1 hour of reflux, in 48% yield, mp = 267-270 °C (from acetic acid). 1H NMR (300 MHz, DMSO-d6/TMS) 5: 1.33 (t, 3H: OCH2CH3, J = 6.9 Hz), 3.61 (s, 3H: NCH3), 4.31 (q, 2H: OCìì2CH3, J = 6.9 Hz), 7.50-7.70 (m, 3H: Ph), 7.95 (m, 2H: Ph), 8.62 (s, 1H: H4 or H7), 8.65 (s, 1H: H4 or H7), 9.77 (bs, 1H: NH); 13C NMR (75.5 MHz, DMSO-dg/^MS), 5: 14.14 (OCH2CH3), 37.33 (NCH3), 60.76 (OCH2CH3), 100.93, 107.44, 122.94, 123.49, 127.69, 128.56, 132.24, 133.38, 145.97, 155.46, 156.51, 159.52, 161.38, 166.00; IR (KBr) v (cm-1): 3396, 3071, 1726, 1650, 1519, 1307; elemental analysis: calcd (%) for C15H15N2O5 (368.3): C 61.96, H 4.38, N 7.61; found: C 62.04, H 4.37, N 7.43.
Ethyl 3-benzamido-6-isopropyl-2,5-dioxo-5,6-dihydro-2H-pyrano[3,2-c]pyridine-8-carboxylate (14c)
This compound was prepared from ethyl 4-hy-droxy-1-isopropyl-6-oxo-1,6-dihydropyridine-3-car-boxylate (11f; 225mg, 1.0 mmol), 9 hours of reflux, in 39% yield, mp = 192-194 °C (from diethyl ether). 1H NMR (75.5 MHz, DMSO-dg/TMS) 5: 1.34 (t, 3H: OCH2CH3,J = 7.2 Hz), 1.40 (d, 6H: 2 x CH3 J = 6.9 Hz), 4.33 (q, 2H: OCH2CH3, J = 7.2 Hz), 5.07 (p, 1H: CH, J = 6.9 Hz), 7.50-7.70 (m, 3H: Ph), 7.95 (m, 2H: Ph), 8.41 (s, 1H: H4 orH7), 8.64 (s, 1H: H4 orH7), 9.77 (bs, 1H: NH); 13C NNMR (300 MHz, DMSO-dg/TMS), 5: 14.12 (OCH2CH3), 20.94 (2 x CH3), 468.89 (CH), 60.95 (OCH2CH3), 101.89, 107.72, 123.05, 123.76, 127.72,
128.58,	132.26, 133.38, 140.98, 154.90, 156.53, 158.94, 161.57, 166.01; IR (KBr) v (cm-1): 3408, 1654, 1521, 1248; MS (M+) m/z: 396; elemental analysis: calcd (%)
for C21H20N2Og (396.4): C 63.63, H 5.09, N 7.07; found: C 63.23, H 4.76, N 6.99.
Ethyl 6-(2-acetoxyethyl)-3-benzamido-2,5-dioxo-5,6-dihydro-2H-pyrano[3,2-c]pyridine-8-carboxylate (14d)
This compound was prepared from ethyl 4-hydroxy-1-(2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxy-late (11e; 227 mg, 1.0 mmol), 9 hours of reflux, in 82% yield, mp = 218-224 °C (from acetic acid). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.33 (t, 3H: OCH2CH3, J = 6.9 Hz), 1.98 (s, 3H: COCH3), 4.35 (m, 6H: NCH2CH2O, OCH2CH3), 7.50-7.70 (m, 3H: Ph), 7.95 (m, 2H: Ph), 8.60 (s, 1H: H4 orH7), 8.62 (s, 1H: H4 orH7), 9.79 (bs, 1H: NH); 13C NMR (75.5 MHz, DMSO-dg/TMS), 5: ?14.12 (OCH2CH3), 20.49, 48.21, 60.87, 61.13, 101.41, 107.76, 123.1^, 123.39, 127.74, 128.59, 132.29, 133.38, 145.56, 155.47, 156.45, 159.24, 161.31, 166.05, 170.06; IR (KBr) v (cm-1): 3383, 3071, 1742, 1699, 1528, 1235; MS (M+) m/z: 440; elemental analysis: calcd (%) for C22H20N2O8 (440.4): C 60.00, H 4.58, N 6.36; found: C 59.83, H 4.58, N 6.02.
2. 4. General Procedure for Preparation of Compounds 17
To the solution of dimethyl malonate (0.46 ml, 2 mmol) in toluene (8 ml) was added DMFDMA (0.66 ml) and stirred under reflux for 0.5 h. Toluene was evaporated to obtain crude compound 15, which was without purification used in further experiments. Then glacial acetic acid (8 ml) and compound 11 (2 mmol) were added and stirred under reflux to complete the reaction. The mixture was cooled and the product was separated by filtration and purified by recrystallisation from an appropriate solvent.
Methyl (E)-4-hydroxy-5-(3-methoxy-3-oxoprop-1-enyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (17a)
This compound was prepared from methyl 4-hy-droxy-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (11c; 366 mg, 2.0 mmol), 16 hours of reflux, in 23% yield, mp = 210-214 °C (from toluene). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 3.52 (s, 3H: NCH3), 3.69 (s, 3H: OCH3), 3.90 (s, 3H: OCH3), 7.09 (d, 1H: CH= CHCOOM-e, J = 15.9 Hz), 7.83 (d, 1H: CH=CHCOOMe, J = 15.9 Hz), 8.72 (s, 1H: Hg), 11.70 (bs, 1H: OH); 13C NMR (75.5 MHz, DMSO-d6/TM6 S), 5: 37.35 (NCH3), 51.22 (OCH3), 52.67 (OCH3), 97.49, 104.23, 117.45, 134.52, 146.85, 161.26, 165.^7, 167.78, 168.13; IR (KBr) v (cm-1): 3420, 3084, 1702, 1681, 1552, 1449; MS (MH+) m /z: 268; elemental analysis: calcd (%) for C12H13NOg (267.2): C 53.93, H 4.90, N 5.24; found: C 54.^^, ^ 4.84t, N 5.20.
Ethyl (E)-4-hydroxy-1-isopropyl-5-(3-methoxy-3-oxoprop-1-enyl)-6-oxo-1,6-dihydropyridine-3-carboxy-late (17b)
This compound was prepared from ethyl 4-hydroxy-1-isopropyl-6-oxo-1,6-dihydropyridine-3-carboxylate (11f; 450 mg, 2.0 mmol), 1 hour of reflux, in 56% yield, mp = 140-147 °C (from methanol). 1H NMR (300 MHz, DMSO-dg/TMS) 5: 1.35 (m, 9H: OCH2CH3, 2 x CH3), 3.69 (s, 36H: NCH3), 4.38 (q, 2H: OCH2C2H3,3J = 7.2 Hz3), 5.04 (p, 1H: CH J = 6.9 Hz), 7.09 (d, 1H: CH=CHCOOM-e, J = 15.9 Hz), 7.84 (d, 1H: CH=CHCOOMe, J = 15.9 Hz), 8.41 (s, 1H: Hg), 11.80 (bs, 1H: OH); 13C NMR (75.5 MHz, DMSO-dg/T]VIS), 5: 13.91 (OCH2CH3), 21.00 (2 x CH3), 48.36 (CH), 51.19 (OCH3), 61.95 (OCH2CH3), 98.25, 104.43, 117.66, 134.62, 141.90, 160.59, 164.80, 167.70, 167.75; IR (KBr) v (cm-1): 2987, 1706, 1612, 1334, 1277; elemental analysis: calcd (%) for C15H19NOg (309.3): C 58.25, H 6.19, N 4.53; found: C 58.4^, H 6.10, N 4.58.
3. Acknowledgement
Financial support from the Slovenian Research Agency, Slovenia (grants P1-0179, and J1-6689-0103-04) is gratefully acknowledged. Financial support of pharmaceutical companies LEK- SANDOZ, Ljubljana, and KRKA, Novo mesto is fully appreciated.
4. References
1.	a) B. Stanovnik, J. Svete, Pyrazoles, in: Houben-Weyl: Methods of Molecular Transformations, Georg Thieme Verlag, Stuttgart 2006, Vol. 12, Vol. Ed. R. Neier, pp. 15-225; b) J. Elguero, Pyrazoles and their Benzo Derivatives, In Comprehensive Heterocyclic Chemistry. Eds.: A. R. Katritzky, C. W. Rees; Pergamon, Oxford, 1984, Vol. 5, p. 167-303; c) J. El-guero,Pyrazoles, In Comprehensive Heterocyclic Chemistry. Eds.: A. R. Katritzky, C. W. Rees; Pergamon, Oxford, 1996, Vol. 3, pp. 1-75
2.	a) G. Hajos, Z. Riedl, Azaindolizines with Two Nitrogen Atoms in the Five-Membered Ring, In: Houben-Weyl: Methods of Molecular Transformations; Georg Thieme Verlag, Stuttgart 2006, Vol 12, Vol. Ed. R. Neier, pp 613-678; b) J. V. Greenhill, Pyrazoles with Fused Six-Membered Heterocyclic Ring, In: Comprehensive Heterocyclic Chemistry, Eds. A. R. Katritzky, C. W. Rees, Pergamon Press, Oxford 1984, Vol. 5, Vol. Ed. K. T. Potts, pp. 305-343; c) D. R. Sliskovic, Bicyc-lic 5-6 Systems with One Ring Junction Nitrogen Atom: Two Extra Hetero Atoms 1:1; In: Comprehensive Heterocyclic Chemistry II, Eds. A. R. Katritzky, C. W. Rees, E. F. V. Scri-ven, Elsevier Science Ltd., Oxford 1996, Vol. 8, Vol. Ed. G. Jones, pp.345-3g5;
3.	S. P. Stanforth, Bicyclic 6-6 Systems: Two Heteroatoms 1:1, In: :Comprehensive Heterocyclic Chemistry II, Eds. A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Elsevier Science Ltd., Oxford 1996, Vol. 8, Vol. Ed. G. Jones, pp.345-3g5.
4.	For reviews see: a) B. Stanovnik, J. Svete, Chem. Revs. 2004,
104, 1422-1480; b) B. Stanovnik, J. Svete, Synlett 2000, 1077-1091.
5. a) J. Wagger, D. Bevk, A. Meden, J. Svete, B. Stanovnik, Helv. Chim. Acta 2006, 89, 140-148; b) J. Wagger, U. Grošelj, A. Meden, B. Stanovnik, J. Svete, Tetrahedron: Asymmetry 2007, 18, 464-475; c) J. Wagger, U. Grošelj, A. Meden, J. Svete, B. Stanovnik, Tetraahedron, 2008, 64, 1801-1815; d) J. Wagger, J. Svete, B. Stanovnik, Synthesis, 2008, 1426-1442.
g. For a review see: B. Stanovnik, J. Svete, Mini-Rev. Org. Chem. 2005, 2, 111-114.
7.	D. Bevk, U. Grošelj, A. Meden, J. Svete, B. Stanovnik, Helv. Chim. Acta 2007, 90, 1727-1744.
8.	S. Zupančič, J. Svete, B. Stanovnik, Heterocycles 2000, 53, 2033-2042.
9.	a) D. Bevk, R. Jakše, A. Golobič, L. Golič, A. Meden, J. Svete, B. Stanovnik, Heterocycles 2004, 63, 609-629; b) D.
Bevk, R. Jakše, J. Svete, A. Golobič, L. Golič, B. Stanovnik, Heterocycles 2003, 61, 197-112.
10.	D. Bevk, L. Golič, A. Golobič, J. Svete, B. Stanovnik, Heterocycles 2005, 66, 107-118.
11.	D. Bevk, L. Grošelj, A. Meden, J. Svete, B. Stanovnik, Tetrahedron 2006, 62, 811g-8121.
12.	For a review see: D. Bevk, J. Svete, B. Stanovnik, Enamino-nes and Related Compounds in the Synthesis of Pyrazoles, in: Modern Approaches to the Synthesis of O- and N-Hete-rocycles. Eds. T. S. Kaufman, E. L. Larghi, Trivandrum 2007, Vol 2, pp. 72-88.
12. R. E. Leard, III, J. H. Bedenbaugh, A. O. Bedenbaugh, J. He-terocycl. Chem 1983, 20, 1262-1266.
14.	G. Errera, Chem. Ber. 1898, 31, 1g81-1g91.
15.	E. M. Wallace, J. Lyssikatos, J. F. Blake, J. Seo, H. W. Yang, T. C. Yeh, M. Perrier, H. Jarski, V. Marsh, G. Poch, M. G. Livingston, J. Otten, G. Hingorani, R. Woessner, P. Lee, J. Winkler, K. Koch, J. Med. Chem.; 2006; 49, 441-444.
Povzetek
V članku so opisane pretvorbe dietil 1-dimetilamino-3-oksobut-1-en-2,4-dicarboksilata (2a) s hidrazini 3a-g v 1-substi-tuirane 4-etoksikarbonil-5-(etoksikarbonilmetil)pirazole 5a-g, z aminogvanidinom (6) v 7-amino-2-etoksikarbonil-1H,2H-pi^azolo[1,2-c]pi^imidin-5-on (9) in z amini 10a-k v 4-hidroksipi^idin-1(1H)-one 11a-k. Iz spojin 11 nastanejo pri reakicji z (Z)-1-benzoilamino-2-dimetuilaminopropenoatom (12) g-substituirani 2-benzoilamino-1,5-diokso-5,g-di-hidro-1H-pirano[2,1-c]pi^idin-8-karboksilati.