KR101473081B1 - Cyclic β-enaminoamides from Cyclic 2-diazo-1,3-dicarbonyls and Its Conversion to Uracil Derivatives - Google Patents

Abstract

The present invention relates to a method for the synthesis of one-pots of beta-enaminoamide derivatives using diazodicarbonyl and amines and to the resulting beta-enaminoamide derivative under additional reaction with triphosgene in the presence of K ₂ CO ₃ to produce uracil derivatives More particularly, the present invention relates to a method for synthesizing a beta-enaminoamide derivative at a higher reaction yield by using toluene as a solvent for each reaction and a method for synthesizing a beta-enaminoamide derivative of a starting material, Thereby providing a method for synthesizing an uracil derivative by displacement.

Description

Synthesis of cyclic beta-enaminoamide derivatives and uracil derivatives starting from cyclic 2-diazo-1,3-dicarbonyl compounds {Cyclic beta-enaminoamides from cyclic 2-diazo-1,3-dicarbonyls and Its Conversion to Uracil Derivatives}

The present invention relates to a synthesis method for easily and efficiently synthesizing a beta-enaminoamide derivative as a one-pot by using cyclic 2-diazo-1,3-dicarbonyl and a primary amine, - N is the amino amide derivative under K ₂ CO ₃ present on the synthesis method for conversion to uracil derivatives by the tri-phosgene and additional reaction.

Decomposition of diazocarbonyl compounds has been widely used in organic synthesis, and the addition of transition metal-catalysed rings of diazocarbonyl is an important synthesis method in the heterocyclic reaction.

In addition, thermodynamic, optical, and transition metal-catalyzed wolf shifts are well known reactions, and are useful for homologation and ring reduction of carboxylic acids. In addition, cyclic 2-diazo-1,3-dicarbonyl is converted to a wolf ring by heat / light transfer of the nucleophilic nucleophile through the alpha-oxoketene in the transition state. Is well known in the art.

Recently, a method has been reported for converting cyclic 2-diazo-l, 3-dicarbonyl into beta-ketoamide through the transfer of wolf under the presence of amines using microwaves.

It is also possible to synthesize a cyclic diazodicarbonyl compound with a heterocycle and a beta-substituted alpha-halo with a rhodium (II) -catalyzed reaction using nitrile, isocyanate, ketone, vinyl ether and halide as substrates And the rhodium (II) -catalyzed Wolf transfer of diazoquinoline dion can form oxynes.

Beta-enaminoamide derivative compounds are widely used as synthetic intermediates for various medicines and agricultural chemicals. However, although various methods have been reported, a simple and efficient method for synthesizing beta-enaminoamide derivatives and uracil derivatives is needed.

See Lee, Y. R .; Hwang, J. C. Eur. J. Org. Chem. 2005, which discloses a method for synthesizing beta-aminoamide derivatives of various stages using a metal catalyst, and does not disclose a method for synthesizing a one-pot beta-enaminoamide derivative, Patent Publication No. 10-2010-0068289 (published on Jun. 22, 2010) includes a method of synthesizing various stages of uracil derivatives, but does not disclose a method of synthesizing one-poturacil derivatives.

Therefore, the inventor of the present invention intends to provide a simple and efficient method for synthesizing a cyclic beta-enaminoamide derivative and a method for synthesizing a uracil derivative.

In order to solve the above problems, the present invention relates to a process for the production of cyclic 2-diazo-1,3-dicarbonyl compound represented by the formula (1) by reacting R ₂ NH ₂ with cyclic beta-enaminoamide Pot synthesis of a cyclic beta-enaminoamide derivative which produces a derivative of the cyclic beta-enaminoamide derivative.

[Chemical Formula 1]

(2)

In Formula 1, R ₁ is each independently hydrogen, C ₁ -C ₆ alkyl or aryl,

R ₂ each independently is hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ arylalkyl or aryl.

Also, the present invention provides a method for synthesizing uracil derivatives, which comprises reacting the synthesized beta-enaminoamide derivatives with a triphosgene in the presence of K ₂ CO ₃ to produce uracil derivatives represented by the following formula (3).

(3)

In Formula 3, R ₁ is each independently hydrogen, C ₁ -C ₆ alkyl or aryl,

R ₂ each independently is hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ arylalkyl or aryl.

According to the present invention, there is provided a method for synthesizing a beta-enaminoamide derivative simply and efficiently by using a thermodynamic transfer of a Wittig transposition of a cyclic diazodicarbonyl compound in the presence of a primary amine, The present invention provides a one-pot synthesis method for efficiently converting an aminoamide derivative into an uracil derivative.

The inventors of the present invention have found that a simple and efficient method for synthesizing a beta-enaminoamide derivative can be synthesized by reacting diazodicarbonyl with an amine at a good efficiency at a room temperature as a one-pot, Thereby completing the present invention.

Thus, the present invention is a cyclic 2-diamine crude 1,3-carbonyl compound and R ₂ annular beta of the formula (2) of reacting the NH ₂ of the formula 1 for producing a cyclic amide derivative amino yen Beta-enaminoamide derivatives of the invention.

[Chemical Formula 1]

(2)

In Formula 1, R ₁ is each independently hydrogen, C ₁ -C ₆ alkyl or aryl,

R ₂ can each independently be hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ arylalkyl or aryl.

The number of carbon atoms of the alkyl group of the amine is 1-10, and it may be any one selected from among 1-propylamine, 1-butylamine, cycloethylamine, 2-phenylethylamine, benzylamine, tryptamine or aniline , Each reaction is allowed to react with 2.2-2.5 equivalents of amine, more preferably 2.2 equivalents, but is not limited thereto.

In the present reaction, at least one solvent selected from the group consisting of toluene and para-xylene can be used as a solvent, but the solvent is not limited thereto.

The reaction temperature may be 90-150 ° C, more preferably 100-120 ° C when toluene is used, or 130-150 ° C when para-xylene is used, but is not limited thereto .

More specifically, the one-pot synthesis reaction of the beta-enaminoamide derivatives according to the present invention is carried out by reacting the cyclic 2-diazo-1,3-dicarbonyl and the primary amine with the starting material, Para-xylene as a solvent, or a mixture thereof at a temperature of 90-150 DEG C, and under the above conditions, the cyclization reaction is carried out through the transfer of thermodynamic wolf sites to give the following Reaction Scheme 1 Beta-enaminoamide derivatives can be prepared.

The following Reaction Scheme 1 relates to a method for producing N-propyl-2- (propylamino) cyclopen-1-yl) carboxamide ( 4 ) in Example 1-1.

[Reaction Scheme 1]

Referring to Reaction Scheme 1, the cyclic 2-diazo-1,3-dicarbonyl compound 1 is used as a starting material to remove the nitrogen by heating to produce a carbene intermediate 26 . Alpha-oxoketene 27 via 1,2-transfer of compound 26 , followed by reaction with 1-propylamine to produce compound 28 . The carbonyl group of compound 28 can be reacted with 1-propylamine to give the final product 4 .

Also, the present invention provides a method for synthesizing uracil derivatives, which comprises reacting the synthesized beta-enaminoamide derivatives with a triphosgene in the presence of K ₂ CO ₃ to produce uracil derivatives represented by the following formula (3).

(3)

In Formula 3, R ₁ is each independently hydrogen, C ₁ -C ₆ alkyl or aryl,

R ₂ can each independently be hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ arylalkyl or aryl.

In the present reaction, at least one solvent selected from the group consisting of toluene and para-xylene can be used as a solvent, but the solvent is not limited thereto.

The reaction temperature is 90-150 ° C, more preferably 100-120 ° C when toluene is used, and 130-150 ° C when para-xylene is used, but the present invention is not limited thereto.

More specifically, when the beta-enaminoamide derivative according to the present invention is subjected to an additional reaction with the triphosgene in the presence of K ₂ CO ₃ , the reaction can be carried out by using a toluene, para-xylene, Lt; RTI ID = 0.0 > 150 C < / RTI >

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Experimental Example >

The following experimental examples are intended to provide experimental examples that are commonly applied to the respective embodiments according to the present invention.

One. General Information

All experiments were performed under nitrogen gas. A silica gel plate (Art. 5554) previously coated with Merck, a fluorescent marker, was used for TLC analysis. Flash column chromatography was performed using Silica gel 9385 (Merck). All ¹ H and ¹³ C NMR spectra were recorded on CDCl ₃ on a Bruker Model ARX spectrometer at 300 and 75 MHz, respectively. All IR spectra were recorded on a Jasco FTIR 5300 spectrophotometer. HRMS and MS data were performed at Korea Basic Science Institute.

2. 2- Diazo cyclohexane -1,3- From the dion ion (1)  The annular beta- Enaminoamide  Review of Proper Solvents in the Preparation of Derivatives (4)

A suitable solvent for the thermodynamic reaction of 2.2 equivalents of 2-diazo cyclohexane-1,3-dione ( 1 ) and 1-propylamine represented by the following reaction formula 1 was examined.

[Reaction Scheme 2]

Each solvent used, reaction time and yield are shown in Table 1 below.

[Table 1]

Referring to Table 1, it was found that when the reaction was refluxed in THF, acetonitrile or benzene solvent at 66 ° C, 82 ° C and 80 ° C for 12 hours, the reaction was not performed. In the case of refluxing in toluene at 110 ° C for 6 hours, the beta-enaminoamide derivative ( 4 ) was obtained in 67% yield after column chromatography and para-xylene was refluxed at 140 ° C for 6 hours , The beta- enaminoamide derivative ( 4 ) was obtained in a high yield of 60%. Both of toluene and para-xylene were excellent in yield, but in the following examples, the reaction was carried out by refluxing at 110 ° C with toluene as a solvent.

Therefore, in the following, the reaction was carried out by refluxing the cyclic diazodicarbonyl compound 1-3 at 110 DEG C with toluene as a solvent.

< Example  1> Beta- Enaminoamide  Derivatization method

end. 2- Diazo cyclohexane -1,3- Diaion (1) and  However, Enaminoamide  Production of derivatives and yields of the products

The type of amine, the reaction time, the yield of the product and the yield of the product obtained by reacting with the 2-diazo cyclohexane-1,3-dione ( 1 ) shown in Table 2 below are shown in Table 2 below.

 [Table 2]

Referring to the above Table 2, it was confirmed that, when the 2-diazo cyclohexane-1,3-dione ( 1 ) was reacted with 1-butylamine for 5 hours, the product 5 was obtained in a yield of 53% On the other hand, when reacted with cyclohexanemethylamine for 7 hours, the product 6 was obtained in a yield of 59% (see entry 2). When 2-phenylethylamine was reacted with benzylamine, the product 7 and the product 8 were obtained in a yield of 57% and 83%, respectively (see entry 3-4). Upon reaction with tryptamine having an indole moiety for 7 hours, the product 9 was obtained in 61% yield (see entry 5). Upon reaction with aniline for 5 hours, the product 10 was obtained in a yield of 64% (see entry 6).

I. Other Diazodicarbonyl (2-3) and Amine  Using beta - Enaminoamide  Production of derivatives and yields of the products

Table 3 shows the types of amine, reaction time, products and yields of the products reacted with diazodicarbonyl ( 2-3 ) shown in Table 3 below.

[Table 3]

Referring to Table 3, it was found that the product 11-24 was obtained in a yield of 52% -81% by reacting diazodicarbonyl ( 2-3 ) with each amine (see entry 7-20).

All. And my reaction conditions and product analysis

The above and the reaction were carried out in a toluene solution (5 mL), amine (2.2 mmol) was added to a solution of cyclic diazodicarbonyl (1.0 mmol), and the mixed solution was heated at 110 ° C. Respectively. The end of the reaction was known by TLC. For the lipophilic group, the solution was removed under reduced pressure and purified by silica gel column chromatography. At this time, n-hexane / ethyl acetate (10: 1) was used as an eluent.

The reaction conditions and the product analysis results shown in the above Reaction formulas 2, 2 and 3 are shown in more detail below.

< Example  1-1> N-Propyl-2- ( Propyl amino ) Cytero pen -One- Tencarpamide  (4)

Treatment of 1-propylamine (130 mg, 2.2 mmol) with 2-diamocyclohexane-1,3-dione ( 1 ) (138 mg, 1.0 mmol) and refluxing in toluene for 6 hours afforded compound 4 (141 mg, 67%) as a solid; mp 56-58 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 7.90 (1H, br s), 4.83 (1H, br s), 3.24-3.17 (2H, m), 3.09-3.03 (2H, m), 2.51 (2H, t, J = 7.8 Hz), 2.38 (2H, t, J = 7.2 Hz), 1.88-1.78 (2H, m), 1.56-1.44 (4H, m), 0.93-0.87 (6H, m); ^{13 C NMR (75 MHz, CDCl} 3): δ 169.0, 161.6, 93.2, 46.3, 40.6, 31.8, 29.3, 24.3, 23.5, 20.7, 11.5, 11.4; IR (KBr): 3352, 2960, 1630, 1525, 1447, 1289, 1144 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₂ H ₂₂ N ₂ O: 210.1732, found: 210.1734.

< Example  1-2> N-Butyl-2- ( Butylamino ) Cyclopene -One- Tencarpamide  (5)

Butylamine (161 mg, 2.2 mmol) was treated with 2-diamo cyclohexane-1,3-dione ( 1 ) (138 mg, 1.0 mmol) and refluxed in toluene for 5 hours, compound 5 Was obtained as a liquid (126 mg, 53%); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.84 (1H, br s), 4.79 (1H, br s), 3.23-3.16 (2H, m), 3.09-3.02 (2H, m), 2.47 (2H, (2H, m), 1.48-1.38 (4H, m), 1.34-1.24 (4H, m), 0.87-0.81 (6H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.1, 161.7, 93.2, 44.3, 38.7, 33.3, 32.5, 31.9, 29.3, 20.8, 20.3, 20.1, 14.0, 13.9; IR (neat): 3322, 2955, 1632, 1530, 1453, 1280, 1146 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₄ H ₂₆ N ₂ O: 238.2045, found: 238.2044.

< Example  1-3> N- ( Cyclohexylmethyl )-2-( Cyclohexylmethylamino ) Cyclopene -One- Tencarpamide ( 6) of  Produce

When cyclohexanemethylamine (249 mg, 2.2 mmol) was treated with 2-diazocyclohexane-1,3-dione ( 1 ) (138 mg, 1.0 mmol) and refluxed in toluene for 7 hours, 6 was obtained (188 mg, 59); mp 96-98 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 7.98 (1H, br s), 4.87 (1H, br s), 3.07 (2H, t, J = 6.6 Hz), 2.91 (2H, t, J = 6.6 Hz ), 2.48 (2H, t, J = 7.5 Hz), 2.38 (2H, t, J = 7.2 Hz), 1.86-1.76 (2H, m), 1.74-1.59 (10H, m), 1.47-1.32 m), 1.24-1.04 (6H, m), 0.92-0.82 (4H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.1, 161.7, 93.0, 51.3, 45.2, 39.4, 38.4, 31.9, 31.0, 30.9, 29.4, 26.6, 26.5, 26.0, 25.9 20.7; IR (KBr): 3318, 2917, 2851, 2664, 2345, 1741, 1631, 1523, 1447, 1268 cm- ¹ ; HRMS m / z (M ⁺ ) C ₂₀ H ₃₄ N ₂ O: 318.2671, found: 318.2669.

< Example  1-4> N- Penetil -2-( Phenethylamino ) Cyclopene -One- Tencarpamide  (7)

Phenylethylamine (267 mg, 2.2 mmol) was added to 2-diamo cyclohexane-1,3-dione ( 1 ) (138 mg, 1.0 mmol) and refluxed in toluene for 6 hours, 7 (191 mg, 57%); ¹ H NMR (300 MHz, CDCl ₃ ):? 8.03 (1H, br s), 7.31-7.16 (10H, m), 4.87 (1H, br s), 3.55-3.49 (2H, m), 3.39-3.32 2H, m), 2.84-2.78 (4H, m), 2.41 (2H, t, J = 7.5 Hz), 2.28 (2H, t, J = 7.2 Hz), 1.81-1.72 (2H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 168.7, 161.3, 139.4, 139.0, 128.8, 128.7, 128.5, 128.4, 126.3, 126.2, 93.7, 46.3, 39.9, 38.0, 36.3, 31.5, 28.9, 20.5; IR (neat): 3315, 3026, 2934, 1630, 1518, 1448, 1276, 748 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₂₂ H ₂₆ N ₂ O: 334.2045, found: 334.2042.

< Example  1-5> N-benzyl-2- ( Benzylamino ) Cyclopene -One- Of Tencarpamide (8)  Produce

Benzylamine (236 mg, 2.2 mmol) was added to 2-diazocyclohexane-1,3-dione ( 1 ) (138 mg, 1.0 mmol) and refluxed in toluene for 5 hours to obtain liquid compound 8 (254 mg, 83%; ¹ H NMR (300 MHz, CDCl ₃ ):? 8.29 (1H, br s), 7.23-7.12 (10H, m), 5.18 (2H, t, J = 7.5 Hz), 2.33 (2H, t, J = 7.2 Hz), 1.78-1.68 , m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 168.7, 161.8, 139.8, 139.7, 128.7, 128.6, 127.6, 127.2, 127.1, 126.9, 94.3, 48.3, 42.8, 31.8, 29.3, neat): 3319, 3028, 2925, 1631, 1515, 1448, 1281, 735 cm ^-1 ; HRMS m / z (M ⁺ ) C ₂₀ H ₂₂ N ₂ O: 306.1732, found: 306.1731.

< Example  1-6> N- (2- (lH-Indol-3-yl) ethyl) -2- (2- (lH- Ethylamino ) Cyclopene -One- (9) &lt; / RTI &gt;  Produce

Tripmatine (352 mg, 2.2 mmol) was added to the 2-diazocyclohexane-1,3-dione ( 1 ) (138 mg, 1.0 mmol) and refluxed in toluene for 7 hours to obtain solid compound 9 (251 mg, 61%); mp 80-82 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 8.89 (1H, br s), 8.57 (1H, br s), 8.24 (1H, t, J = 6.0 Hz), 7.77-7.71 (2H, m), 7.48 M), 7.02 (2H, s), 5.25 (1H, t, J = 5.7 Hz), 3.82-3.76 (2H, m), 3.62-3.55 m), 2.65-2.59 (2H, m), 2.44-2.39 (2H, m), 1.96-1.86 (2H, m); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 169.2, 161.9, 136.5, 136.4, 127.5, 127.2, 122.7, 122.4, 121.9, 121.8, 119.2, 119.1, 118.7, 118.5, 113.0, 112.4, 111.5, 111.4, , 39.6, 31.9, 29.2, 27.1, 25.9, 20.6; IR (KBr): 3413, 3297, 3058, 2931, 1730, 1626, 1521, 1445, 1276, 1100 cm ^-1 ; HRMS m / z (M ⁺ ) C ₂₆ H ₂₈ N ₄ O: 412.2263, found: 412.2261.

< Example  1-7> N- Phenyl -2-( Phenylamino ) Cyclopene -One- (10) &lt; / RTI &gt;  Produce

Aniline (205 mg, 2.2 mmol) was added to the 2-diazocyclohexane-1,3-dione ( 1 ) (138 mg, 1.0 mmol) and refluxed in toluene for 5 hours to obtain a solid compound 10 (178 mg, 64%); mp 128-130 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 10.37 (1H, br s), 7.47-6.97 (10H, m), 6.71 (1H, br s), 2.83-2.78 (2H, m), 2.59-2.55 ( 2H, m), 1.94-1.89 (2H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 166.6, 159.4, 141.1, 138.6, 129.3, 129.0, 123.7, 122.9, 120.8, 120.2, 98.5, 33.7, 29.1, 21.7; IR (KBr): 3242, 3044, 2956, 2360, 1596, 1431, 1237, 1144, 754 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₈ H ₁₈ N ₂ O: 278.1419, found: 278.1421.

< Example  1-8> 4- Phenyl -N-propyl-2- ( Propyl amino ) Cyclopene -One- Tencarpamide (11)

Propylamine (130 mg, 2.2 mmol) was added to diazodicarbonyl ( 2 ) (214 mg, 1.0 mmol) and refluxed in toluene for 8 hours to obtain liquid compound 11 (157 mg, 55 %); ¹ H NMR (300 MHz, CDCl ₃ ):? 7.92 (1H, br s), 7.28-7.10 (5H, m), 4.78 (1H, br s), 3.45-3.34 (2H, m), 3.07-3.00 (2H, m), 2.99-2.91 (1H, m), 2.85-2.78 (1H, m), 2.65-2.57 1.51-1.42 (4H, m), 0.89-0.83 (6H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 168.9, 160.2, 146.1, 128.6, 126.9, 126.4, 92.4, 46.5, 40.8, 40.7, 40.0, 38.2, 24.5, 23.6, 11.6, 11.5; IR (neat): 3337, 2961, 1632, 1527, 1267, 1148 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₈ H ₂₆ N ₂ O: 286.2045, found: 286.2047.

< Example  1-9> N-Butyl-2- ( Butylamino )-4- Phenylcyclopene -One- (12) &lt; / RTI &gt;  Produce

Butylamine (161 mg, 2.2 mmol) was added to diazodicarbonyl ( 2 ) (214 mg, 1.0 mmol) and refluxed in toluene for 7 hours to obtain liquid compound 12 (195 mg, 62 %); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.94 (1H, br s), 7.32-7.12 (5H, m), 4.78 (1H, br s), 3.48-3.36 (1H, m), 3.32-3.18 ( M), 3.16-3.04 (2H, m), 3.02-2.93 (1H, m), 2.86-2.79 (1H, m), 2.67-2.59 1.5-e 1.41 (4H, m), 1.37-1.28 (4H, m), 0.92-0.82 (6H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 168.8, 160.0, 146.1, 128.6, 126.9, 126.4, 92.4, 44.3, 40.7, 39.9, 38.6, 38.2, 33.3, 32.4, 20.3, 20.0, 14.0, 13.9; IR (neat): 3325, 2954, 1632, 1522, 1445, 1282, 1147 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₂₀ H ₃₀ N ₂ O: 314.2358, found: 314.2356.

< Example  1-10> N- ( Cyclohexylmethyl )-2-( Cyclohexylmethylamino )-4- Phenylcyclopene -One- (13) &lt; / RTI &gt;  Produce

Cyclohexanemethylamine (249 mg, 2.2 mmol) was added to diazodicarbonyl ( 2 ) (214 mg, 1.0 mmol) and refluxed in toluene for 7 hours to give solid compound 13 (205 mg , 52; mp 112-114 C; ¹ H NMR (300 MHz, CDCl ₃ ):? 7.99 (1H, br s), 7.25-7.10 (5H, m), 4.82 (1H, br s), 3.43-3.32 (1H, m), 3.11-2.98 (2H, m), 2.93-2.75 (4H, m), 2.61-2.44 (2H, m), 1.72-1.52 1.19-1.02 (6H, m), 0.90-0.76 (4H, m); 13 C NMR (75 MHz, CDCl 3): δ 168.7, 160.1, 145.9, 128.5, 126.8, 126.3, 92.1, 51.2, 45.1, 40.6, IR (KBr): 3323, 3060, 3026, 2922, 2849, 2357, 1738, 1633, 1588, 1521, 1447, 1259, 1181 ^{, 1150, 762 cm -1; HRMS} m / z (M +) C 26 H 38 N 2 O: 394.2984, found: 394.2986.

< Example  1-11> N- Penetil -2-( Phenethylamino )-4- Phenylcyclopene -One- (14) &lt; / RTI &gt;  Produce

2-phenylethylamine (267 mg, 2.2 mmol) was added to diazodicarbonyl ( 2 ) (214 mg, 1.0 mmol) and refluxed in toluene for 8 hours to obtain liquid compound 14 (222 mg , 54%); ^{1 H NMR (300 MHz, CDCl} 3): δ 8.05 (1H, br s), 7.28-7.12 (15H, m), 4.79 (1H, br s), 3.49-3.44 (2H, m), 3.33-3.26 ( 2H, m), 2.99-2.89 (1H, m), 2.78-2.74 (4H, m), 2.69-2.56 (2H, m), 2.47-2.31 (2H, m); ^{13 C NMR (75 MHz, CDCl} 3): δ 168.7, 160.0, 145.9, 139.5, 139.1, 129.0, 128.9, 128.8, 128.7, 128.6, 128.5, 126.9, 126.5, 126.4, 92.9, 46.5, 40.6, 40.2, 39.8, 38.3, 37.9, 36.4; IR (neat): 3312, 3027, 2928, 1632, 1521, 1451, 1266, 751 cm &lt; ^{-1 &} gt ;; ^{HRMS m / z (M +)} C 28 H 30 N 2 O: 410.2358, found: 410.2356.

< Example  1-12> N-Benzyl-2- ( Benzylamino )-4- Phenylcyclopene -One- Of tricarboxamide (15)  Produce

Benzylamine (236 mg, 2.2 mmol) was added to diazodicarbonyl ( 2 ) (214 mg, 1.0 mmol) and refluxed in toluene for 7 hours to obtain liquid compound 15 (240 mg, 63% ; ^{1 H NMR (300 MHz, CDCl} 3): δ 8.36 (1H, t, J = 6.3 Hz), 7.28-7.07 (15H, m), 5.13 (1H, t, J = 5.7 Hz), 4.44-4.40 (2H m), 4.29 (2H, d, J = 6.6Hz) 3.42e3.31 (1H, m), 2.96e2.78 (2H, m), 2.64e2.45 (2H, m); ^{13 C NMR (75 MHz, CDCl} 3): δ 168.5, 160.4, 145.8, 139.7, 139.5, 128.8, 128.7, 128.6, 127.8, 127.4, 127.3, 127.0, 126.9, 126.5, 93.5, 48.4, 43.1, 40.7, 39.9, 38.2; IR (neat): 3325, 3060, 2926, 1632, 1520, 1449, 1263, 736 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₂₆ H ₂₆ N ₂ O: 382.2045, found: 382.2043.

< Example  1-13> N- (2- (1H-Indol-3-yl) ethyl) -2- (2- (1H- Ethylamino )-4- Phenylcyclopene -One- Of Tencarpamide (16)  Produce

(352 mg, 2.2 mmol) was added to diazodicarbonyl ( 2 ) (214 mg, 1.0 mmol) and refluxed in toluene for 7 hours to obtain solid compound 16 (293 mg, 60% ); mp 87-89 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 8.12 (1H, br s), 7.99 (2H, br s), 7.61-7.52 (2H, m), 7.33-6.98 (13H, m), 4.93 (1H, (1H, m), 2.69 (2H, m), 3.64-3.57 (2H, m), 3.45-3.40 -2.62 (1H, m), 2.51-2.43 (1H, m), 2.36-2.30 (1H, m); ^{13 C NMR (75 MHz, CDCl} 3): δ 168.9, 160.4, 145.8, 136.5, 128.6, 127.4, 127.1, 126.9, 126.4, 122.8, 122.3, 121.9, 121.8, 119.3, 119.2, 118.8, 118.5, 113.0, 112.4, 111.5, 111.4, 92.6, 45.1, 40.5, 39.9, 39.5, 37.5, 27.2, 25.9; IR (KBr): 3414, 3053, 2922, 2346, 1740, 1629, 1519, 1445, 1268, 1096, 910, 739 cm ^-1 ; HRMS m / z (M ⁺ ) C ₃₂ H ₃₂ N ₄ O: 488.2576, found: 488.2578.

< Example  1-14> N, 4- Diphenyl -2-( Phenylamino ) Cyclopene -One- Of tricarboxamide (17)  Produce

Aniline (205 mg, 2.2 mmol) was added to diazodicarbonyl ( 2 ) (214 mg, 1.0 mmol) and refluxed in toluene for 6 hours to give liquid compound 17 (195 mg, 55%); ^{1 H NMR (300 MHz, CDCl} 3): δ 10.42 (1H, br s), 7.45-7.25 (2H, m), 7.28-6.95 (11H, m), 6.71 (1H, br s), 6.61-6.58 ( 2H, m), 3.53-3.42 (1H, m), 3.24-3.15 (1H, m), 2.99-2.91 (2H, m), 2.73-2.67 (1H, m); ^{13 C NMR (75 MHz, CDCl} 3): δ 166.4, 157.6, 146.2, 144.8, 140.5, 138.3, 129.2, 129.1, 128.8, 128.6, 126.8, 126.5, 123.5, 123.0, 120.6, 119.9, 118.4, 115.0, 97.1, 41.4, 41.3, 37.4; IR (neat): 3362, 3055, 2922, 2356, 1630, 1499, 1437, 1243, 754 cm ^-1 ; HRMS m / z (M ⁺ ) C ₂₄ H ₂₂ N ₂ O: 354.1732, found: 354.1732.

< Example  1-15> 4,4- Dimethyl -N-propyl-2- ( Propyl amino ) Cyclopene -One- Tecarvamide (18)

Diamond Division di-carbonyl (3) (166 mg, 1.0 mmol) in 1-propyl amine (130 mg, 2.2 mmol) in the case where toluene was refluxed for 8 hours, to obtain a liquid compound 18 (155 mg, 65% ); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.85 (1H, br s), 4.76 (1H, br s), 3.23-3.17 (2H, m), 3.06-2.99 (2H, m), 2.33 (2H, s), 2.20 (2H, s), 1.56-1.44 (4H, m), 1.05 (6H, s), 0.93-0.87 (6H, m); ^{13 C NMR (75 MHz, CDCl} 3): δ 169.1, 160.0, 92.1, 46.3, 46.1, 44.3, 40.4, 35.5, 29.8. 24.3, 23.3, 11.4, 11.3; IR (neat): 3323, 2957, 1633, 1526, 1446, 1286, 1168 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₄ H ₂₆ N ₂ O: 238.2045, found: 238.2044.

< Example  1-16> N-Butyl-2- ( Butylamino ) -4,4- Dimethylcyclopene -One- Of tricarboxamide (19)  Produce

Butylamine (161 mg, 2.2 mmol) was added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) and refluxed in toluene for 6 hours to obtain liquid compound 19 (168 mg, 63%); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.78 (1H, br s) 4.71 (1H, br s), 3.22-3.15 (2H, m), 3.02-2.98 (2H, m), 2.28 (2H, s ), 2.15 (2H, s), 1.46-1.36 (4H, m), 1.33-1.24 (4H, m), 1.05 (6H, s), 0.87-0.81 (6H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.2, 160.0, 92.2, 46.5, 44.5, 44.1, 38.6, 35.6, 33.3, 32.4, 30.0, 20.2, 19.9, 13.9, 13.8; IR (neat): 3319, 2953, 1633, 1524, 1444, 1282, 1166 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₆ H ₃₀ N ₂ O: 266.2358, found: 266.2354.

< Example  1-17> N- ( Cyclohexylmethyl )-2-( Cyclohexylmethylamino ) -4,4- Dimethylcyclopene -1-heptene Carboxamide (20 )

Cyclohexanemethylamine (249 mg, 2.2 mmol) was added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) and refluxed in toluene for 7 hours to give solid compound 20 (204 mg , 59%); mp 85-87 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 7.93 (1H, br s), 4.79 (1H, br s), 3.06 (2H, t, J = 6.6 Hz), 2.88 (2H, t, J = 6.6 Hz ), 2.30 (2H, s), 2.19 (2H, s), 1.80-1.56 (10H, m), 1.44-1.36 0.96-0.81 (4 H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.2, 160.2, 91.9, 51.1, 46.5, 45.0, 44.4, 39.3, 38.2, 35.6, 30.9, 30.8, 29.9, 26.5, 26.4, 25.9, 25.8; IR (KBr): 3316, 2920, 2854, 2666, 2344, 1632, 1523, 1448, 1272 cm ^-1 ; HRMS m / z (M ⁺ ) C ₂₂ H ₃₈ N ₂ O: 346.2984, found: 346.2982.

< Example  1-18> 4,4- Dimethyl -N- Penetil -2-( Phenethylamino ) Cyclopene -One- Tencarpamide (21)

2-phenylethylamine (267 mg, 2.2 mmol) was added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) and refluxed in toluene for 5 hours to obtain liquid compound 21 (196 mg, 54%); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.91 (1H, t, J = 6.0 Hz), 7.24-7.07 (10H, m), 4.73 (1H, t, J = 5.4 Hz), 3.46-3.39 (2H m), 3.22-3.20 (2H, m), 2.75-2.68 (4H, m), 2.11 (2H, s), 1.99 (2H, s), 0.95 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.0, 160.0, 139.6, 139.1, 128.9, 128.8, 128.6, 128.5, 126.4, 126.3, 92.8, 46.4, 46.3, 44.3, 40.1, 38.2, 36.4, 35.5, 29.9; IR (neat): 3325, 3062, 2950, 1633, 1516, 1448, 1282 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₂₄ H ₃₀ N ₂ O: 362.2358, found: 362.2361.

< Example  1-19> N-Benzyl-2- ( Benzylamino ) -4,4- Dimethylcyclopene -One- (22) &lt; / RTI &gt;  Produce

Benzylamine (236 mg, 2.2 mmol) was added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) and refluxed in toluene for 5 hours to give solid compound 22 (271 mg, 81% ; mp 69-71 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 8.24 (1H, br s), 7.29-7.14 (10H, m), 5.06 (1H, br s), 4.41 (2H, d, J = 5.7 Hz), 4.26 (2H, d, J = 6.6 Hz), 2.28 (2H, s), 2.18 (2H, s), 1.02 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ ):? 168.8, 160.3, 139.7, 139.4, 128.5, 127.6, 127.0, 126.9, 126.6, 93.2, 48.1, 46.3, 44.4, 42.8, 35.8, 29.8; IR (KBr): 3351, 3060, 2945, 1628, 1518, 1430, 1259, 612 cm ^-1 ; HRMS m / z (M ⁺ ) C ₂₂ H ₂₆ N ₂ O: 334.2043, found 334.2043.

< Example  1-20> N- (2- (1H-Indol-3-yl) ethyl) -2- (2- (1H- Ethylamino ) -4,4- Dimethylcyclopene -1-thiocarboxamide ( 23)  Produce

Tripidamine (352 mg, 2.2 mmol) was added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) and refluxed in toluene for 7 hours to give solid compound 23 (268 mg, 61% ; mp 69-71 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 8.56 (1H, br s), 8.23 (1H, br s), 7.90 (1H, t, J = 6.0 Hz), 7.48-7.40 (2H, m), 7.20 M), 6.74 (2H, s), 4.88 (1H, t, J = 6 Hz), 3.52-3.46 (2H, m), 3.29-3.23 (2H, m), 2.87-2.76 , &lt; / RTI &gt; m), 2.13 (2H, s), 1.94 (2H, s), 0.89 (6H, s); ^{13 C NMR (75 MHz, CDCl} 3): δ 169.4, 160.6, 136.5, 127.5, 127.1, 122.7, 122.4, 121.9, 121.7, 119.2, 119.1, 118.8, 118.4, 113.0, 112.3, 111.5, 111.4, 92.5, 46.5, 44.9, 44.2, 39.6, 35.5, 29.9, 27.1, 25.9; IR (KBr): 3410, 3285, 2938, 1908, 1730, 1629, 1521, 1445, 1279, 1100 cm- ¹ ; ^{HRMS m / z (M +)} C 28 H 32 N 4 O: 440.2576, found: 440.2579.

< Example  1-21> 4,4- Dimethyl -N- Phenyl -2-( Phenylamino ) Cyclopene -One- Tencarpamide (24)

Aniline (205 mg, 2.2 mmol) was added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) and refluxed in toluene for 5 hours to give solid compound 24 (193 mg, 63%); mp 140-142 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 10.41 (1H, br s), 7.51-6.97 (10H, m), 6.71 (1H, br s), 2.69 (2H, s), 2.44 (2H, s) , 1.18 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ ):? 166.9, 157.7, 140.8, 138.4, 129.1, 128.9, 123.4, 122.7, 120.5, 119.9, 97.2, 48.1, 43.9, 36.7, 29.5; IR (KBr): 3361, 3055, 2953, 1628, 1500, 1434, 1244, 1182 cm ^-1 ; HRMS m / z (M ⁺ ) C ₂₀ H ₂₂ N ₂ O: 306.1732, found: 306.1734.

< Example  1-22> N-Benzyl-4,4- Dimethyl -2- Oxocyclopentanecarboxamide (25) Manufacturing

Benzylamine (107 mg, 1.0 mmol) was added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) and refluxed in toluene for 4 hours to obtain a liquid compound 25 (196 mg, 80% ; ^{1 H NMR (300 MHz, CDCl} 3) δ 7.26-7.16 (5H, m), 7.10 (1H, br s), 4.44-4.28 (2H, m), 3.14 (1H, t, J = 9.6 Hz), 2.30 -1.95 (4H, m), 1.08 (3H, s), 0.97 (3H, s); ¹³ C NMR (75 MHz, CDCl3):? 216.3, 167.0, 138.3, 128.8, 127.8, 127.5, 53.9, 53.7, 43.8, 39.4, 34.2, 28.9, 27.9; IR (neat): 3306, 2954, 2357, 1740, 1648, 1537, 1455, 1365, 1232, 1126 cm ^-1 ; HRMS m / z (M ⁺ ) C ₁₅ H ₁₉ NO ₂ : 245.1416, found: 245.1414.

< Comparative Example  1> Diazodicarbonyl  3 and benzylamine. Keto Amide  Produce

In addition to diamond crude reaction of carbonyl embodiment the die using a carbonyl 3 Example 1 was carried out and the reaction represented by the following reaction scheme 3 a.

[Reaction Scheme 3]

Referring to Reaction Scheme 3 above, when diazodicarbonyl 3 and 1 equivalent of benzylamine are refluxed in toluene for 4 hours, beta-ketoamide 25, which is not cyclic beta-enaminoamide derivative 22 of the present invention, 80% yield.

The reaction was carried out under the following conditions.

To a solution of compound 22 (100 mg, 0.30 mmol) in wet ethanol (5 mL) is added para-toluenesulfonic acid monohydrate (6 mg) and refluxed for 12 hours. After warming to room temperature, water (25 mL) was added and the solution was extracted with EtOAc (3 x 25 mL). The organic layer was washed with NaHCO ₃ solution (30 mL) and dried / concentrated with anhydrous MgSO ₄ . The residue was purified by column chromatography on silica gel. Liquid compound 25 (62 mg, 84%) was obtained using n-hexane / EtOAc (10: 1) as eluent.

< Comparative Example  2> Diazodicarbonyl  3 and 1- Propylamine , &Lt; / RTI &gt; benzylamine &lt; RTI ID = Enaminoamide  Production of derivatives

Diazodicarbonyl 3 , the reaction represented by the following reaction formula 4 was carried out in addition to the reaction of Example 1 above.

 [Reaction Scheme 4]

Propylamine (59 mg, 1.0 mmol) and benzylamine (107 mg, 1.0 mmol) were added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) when refluxing for hours, beta- and 31 (14 mg amide 25 (22 mg, 9%) , - ¥ amino amide derivatives 29 and 30 (92 mg, 32%) was obtained in the isomer ratio of 84:16, keto 7%) was obtained in a ratio of 60:40 and was obtained with insoluble trace amounts of beta- enaminoamide derivatives 18 and 22 .

The results of each product analysis described in Scheme 4 are shown in more detail below.

Compound ^{29: 1 H NMR (300 MHz} , CDCl 3): δ 7.85 (1H, br s) 7.23-7.18 (5H, m), 5.01 (1H, br s), 4.40 (2H, d, J = 5.7 Hz) , 3.03-2.96 (2H, m), 2.29 (2H, s), 2.16 (2H, s), 1.49-1.42 ); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.1, 160.9, 139.9, 128.7, 127.8, 126.9, 92.1, 46.7, 46.4, 44.5, 43.0, 35.9, 30.1, 24.6, 11.5; HRMS (FAB) m / z (M + H @ ⁺ ) C ₁₈ H ₂₇ N ₂ O: 287.2123, found: 287.2126.

Compound ^{30: 1 H NMR (300 MHz} , CDCl 3): δ 8.22 (1H, br s), 7.23-7.18 (5H, m), 5.10 (1H, br s), 4.25 (2H, d, J = 6.6 Hz ), 3.03-2.96 (2H, m), 2.27 (2H, s), 2.18 (2H, s), 1.49-1.42 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.1, 160.9, 139.9, 128.8, 127.9, 127.2, 94.0, 48.3, 46.6, 44.6, 43.1, 35.9, 30.0, 24.3, 11.5; IR (neat): 3315, 3061, 3029, 2953, 2869, 1633, 1588, 1517, 1448, 1282, 1168, 734 cm @ ^-1 ; HRMS m / z (FAB) (M + H @ ⁺ ) C ₁₈ H ₂₇ N ₂ O: 287.2123, found: 287.2126.

Compound 25 : &lt; ¹ &gt; H NMR, &lt; ¹³ &gt; C NMR and IR spectra of this compound were the same as those of Compound 24 above. HRMS m / z (FAB) (M + H @ ⁺ ) C ₁₅ H ₂₀ NO ₂ : 246.1494, found: 246.1492.

Compound ^{31: 1 H NMR (300 MHz} , CDCl 3) δ 7.08 (1H, br s), 4.44-4.28 (2H, m), 3.19-3.07 (1H, m), 2.35-1.95 (4H, m), 1.48 -1.41 (2H, m), 1.08 (3H, s), 0.98 (3H, s), 0.84 (3H, t, J = 7.5 Hz); ^{13 C NMR (75 MHz, CDCl} 3): δ 216.1, 167.8, 53.6, 43.4, 41.2, 39.1, 33.9, 28.6, 27.6, 22.6, 11.3; HRMS m / z (M ⁺ ) C ₁₅ H ₁₉ NO ₂ : 245.1416, found: 245.1414 and HRMS (FAB) m / z (M + H ⁺ ) C ₁₁ H ₂₀ NO ₂ : 198.1494, found: 198.1497.

< Example  2> Beta- Enaminoamide  Derivative Uracil  Derivative synthesis and yield of the compound

Beta-enaminoamide derivatives were further reacted with the triphosgene in the presence of K ₂ CO ₃ to synthesize uracil derivatives substituted at positions 5 and 6 of the beta- enaminoamide derivatives. The beta-enaminoamide derivatives used and the reaction time, yields of the compounds and their compounds are shown in Table 4 below.

[Table 4]

Propylamine (59 mg, 1.0 mmol) and benzylamine (107 mg, 1.0 mmol) were added to diazodicarbonyl ( 3 ) (166 mg, 1.0 mmol) when refluxing for hours, beta- and 31 (14 mg amide 25 (22 mg, 9%) , - ¥ amino amide derivatives 29 and 30 (92 mg, 32%) was obtained in the isomer ratio of 84:16, keto 7%) was obtained in a ratio of 60:40 and was obtained with insoluble trace amounts of beta- enaminoamide derivatives 18 and 22 .

The results of each product analysis described in Scheme 4 are shown in more detail below.

Compound ^{29: 1 H NMR (300 MHz} , CDCl 3): δ 7.85 (1H, br s) 7.23-7.18 (5H, m), 5.01 (1H, br s), 4.40 (2H, d, J = 5.7 Hz) , 3.03-2.96 (2H, m), 2.29 (2H, s), 2.16 (2H, s), 1.49-1.42 ); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.1, 160.9, 139.9, 128.7, 127.8, 126.9, 92.1, 46.7, 46.4, 44.5, 43.0, 35.9, 30.1, 24.6, 11.5; HRMS (FAB) m / z (M + H @ ⁺ ) C ₁₈ H ₂₇ N ₂ O: 287.2123, found: 287.2126.

Compound ^{30: 1 H NMR (300 MHz} , CDCl 3): δ 8.22 (1H, br s), 7.23-7.18 (5H, m), 5.10 (1H, br s), 4.25 (2H, d, J = 6.6 Hz ), 3.03-2.96 (2H, m), 2.27 (2H, s), 2.18 (2H, s), 1.49-1.42 Hz); ¹³ C NMR (75 MHz, CDCl ₃ ):? 169.1, 160.9, 139.9, 128.8, 127.9, 127.2, 94.0, 48.3, 46.6, 44.6, 43.1, 35.9, 30.0, 24.3, 11.5; IR (neat): 3315, 3061, 3029, 2953, 2869, 1633, 1588, 1517, 1448, 1282, 1168, 734 cm @ ^-1 ; HRMS m / z (FAB) (M + H @ ⁺ ) C ₁₈ H ₂₇ N ₂ O: 287.2123, found: 287.2126.

Compound 25 : &lt; ¹ &gt; H NMR, &lt; ¹³ &gt; C NMR and IR spectra of this compound were the same as those of Compound 24 above. HRMS m / z (FAB) (M + H @ ⁺ ) C ₁₅ H ₂₀ NO ₂ : 246.1494, found: 246.1492.

Compound ^{31: 1 H NMR (300 MHz} , CDCl 3) δ 7.08 (1H, br s), 4.44-4.28 (2H, m), 3.19-3.07 (1H, m), 2.35-1.95 (4H, m), 1.48 -1.41 (2H, m), 1.08 (3H, s), 0.98 (3H, s), 0.84 (3H, t, J = 7.5 Hz); ^{13 C NMR (75 MHz, CDCl} 3): δ 216.1, 167.8, 53.6, 43.4, 41.2, 39.1, 33.9, 28.6, 27.6, 22.6, 11.3; HRMS m / z (M ⁺ ) C ₁₅ H ₁₉ NO ₂ : 245.1416, found: 245.1414 and HRMS (FAB) m / z (M + H ⁺ ) C ₁₁ H ₂₀ NO ₂ : 198.1494, found: 198.1497.

< Example  2> Beta- Enaminoamide  Derivative Uracil  Derivative synthesis and yield of the compound

Beta-enaminoamide derivatives were further reacted with the triphosgene in the presence of K ₂ CO ₃ to synthesize uracil derivatives substituted at positions 5 and 6 of the beta- enaminoamide derivatives. The beta-enaminoamide derivatives used and the reaction time, yields of the compounds and their compounds are shown in Table 4 below.

[Table 4]

Referring to Table 4 above, when Compound 8 was treated with 1.1 equivalents of triphosgene and refluxed in toluene for 10 hours, uracil derivative 34 was obtained in a yield of 42% (see entry 1). On the other hand, when compounds 12, 13, 15, and 18-20 were reacted, the uracil derivative 35-40 was obtained in a yield of 40-54% (see entry 2-7).

More specifically, K ₂ CO ₃ (5 eq.) And triphosgene (1.1 eq.) Were added to a solution of exo-enaminoamide (0.13-0.40 mmol) on toluene (5 mL). The mixed solution was heated to 110 DEG C in a sealed tube until the reaction was terminated. The end of the reaction was known by TLC. The solution was removed under reduced pressure, and water (25 mL) was added and extracted with EtOAc (3 x 25 mL). The organic layer was dried / concentrated using anhydrous MgSO ₄ and purified by column chromatography on silica gel. At this time, n-hexane / ethyl acetate (10: 1) was used as an eluent.

The reaction conditions and the product analysis results shown in Table 4 are shown in more detail below.

< Example  2-1> 1,3- Dibenzyl -6,7- Dihydro -1H- Cyclopenta [d] pyrimidine 2,4 (3H, 5H) - Of the diaion 34  Produce

To the compound 8 (100 mg, 0.33 mmol) was added triphosgene (107 mg, 0.36 mmol) and refluxed in toluene in the presence of K ₂ CO ₃ (228 mg, 1.65 mmol) for 10 hours to obtain a liquid compound 34 (46 mg, 42%); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.49-7.46 (10H, m), 5.15 (2H, s), 4.97 (2H, s), 2.77-3.69 (4H, m), 2.04-1.94 (2H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 160.7, 154.8, 153.0, 137.2, 136.1, 128.9, 128.8, 128.3, 127.8, 127.4, 126.7, 112.2, 49.3, 44.6, 32.3, 27.7, 21.0; IR (neat): 3328, 3031, 2953, 2359, 1695, 1656, 1482, 1389, 1354, 1075, 1029, 912, 818, 734, 701 cm- ¹ ; HRMS m / z (M ⁺ ) C ₂₁ H ₂₀ N ₂ O ₂ : 332.1525, found: 332.1525.

< Example  2-2> 1,3- Dibenzyl -6,7- Dihydro -1H- Cyclopenta [d] pyrimidine 2,4 (3H, 5H) - Of the diaion (35)  Produce

Triphosgene (72 mg, 0.24 mmol) was added to compound 12 (70 mg, 0.22 mmol) and refluxed in toluene in the presence of K ₂ CO ₃ (152 mg, 1.09 mmol) for 8 hours to give liquid 35 (30 mg, 40%); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.34-7.20 (5H, m), 3.96-3.91 (2H, m), 3.79-3.62 (3H, m), 3.32-3.16 (2H, m), 2.98- 2.80 (2H, m), 1.68-1.56 (4H, m), 1.40-1.30 (4H, m), 0.96-0.88 (6H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 160.7, 152.8, 152.5, 144.2, 128.8, 126.8, 126.7, 110.7, 46.5, 41.3, 40.4, 35.9, 31.1, 29.8, 20.3, 20.0, 13.8, 13.7; IR (neat): 2956, 2868, 2358, 1696, 1656, 1484, 1364, 1323, 1253, 1188, 1079, 763 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₂₁ H ₂₈ N ₂ O ₂ : 340.2151, found: 340.2154.

< Example  2-3> 1,3- Bis ( Cyclohexylmethyl ) -6- Phenyl -6,7- Dihydro -1H- Cyclopenta [d] pyrimidine -2,4 (3H, 5H) - Of the diaion 36  Produce

Compound 13 (158 mg, 0.40 mmol) tri-phosgene (131 mg, 0.44 mmol) the case in which at toluene reflux 4 hours in a _{K 2 CO 3 (276 mg,} 2 mmol) there was added, liquid compound 36 to yield (72 mg, 43%); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.29-7.15 (5H, m), 3.81-3.69 (2H, m), 3.67-3.55 (1H, m), 3.54-3.43 (2H, m), 3.26- 3.11 (2H, m), 2.92-2.76 (2H, m), 1.77-1.50 (12H, m), 1.22-1.03 (6H, m), 0.99-0.76 (4H, m); ^{13 C NMR (75 MHz, CDCl} 3): δ 161.1, 153.2, 152.9, 150.2, 144.1, 128.7, 126.7, 110.5, 52.8, 47.1, 41.3, 10.9, 37.3, 36.3, 35.9, 30.8, 30.7, 26.3, 26.1, 25.8, 25.7; IR (neat): 2924, 2851, 2356, 1697, 1657, 1482, 1395, 1355, 1268, 1144, 1108, 1078, 762 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₂₇ H ₃₆ N ₂ O ₂ : 420.2777, found: 420.2780.

< Example  2-4> 1,3- Dibenzyl -6- Phenyl -6,7- Dihydro -1H- Cyclopenta [d] pyrimidine -2,4 (3H, 5H) - The dion (37)  Produce

To the compound 15 (50 mg, 0.13 mmol) was added triphosgene (43 mg, 0.14 mmol) and refluxed in toluene in the presence of K ₂ CO ₃ (90 mg, 0.65 mmol) for 5 hours to obtain the liquid compound 37 (28 mg, 52%); ^{1 H NMR (300 MHz, CDCl} 3): δ 7.80-7.41 (15H, m), 5.46 (2H, s), 5.36-5.17 (2H, m), 3.94-3.83 (1H, m), 3.52-3.44 ( 2H, &lt; / RTI &gt; m), 3.19-3.07 (2H, m); ^{13 C NMR (150 MHz, CDCl} 3): δ 160.5, 153.3, 153.0, 143.9, 137.2, 135.9, 129.1, 128.9, 128.7, 128.4, 127.9, 127.5, 126.8, 126.7, 126.6, 111.2, 49.3, 44.7, 41.2, 40.4, 36.0; IR (neat): 3038, 2944, 2344, 2252, 1656, 1482, 1345, 1189, 1080, 912, 733 cm &lt; ^{-1 &} gt ;; ^{HRMS m / z (M +)} C 37 H 24 N 2 O 2: 408.1838, found: 408.1836.

< Example  2-5> 6,6- Dimethyl -1,3- Die profile -6,7-dihydro-lH- Cyclopenta [d] pyrimidine -2,4 (3H, 5H) -dione (38)

Triphosgene (69 mg, 0.23 mmol) was added to compound 18 (50 mg, 0.21 mmol) and refluxed in toluene in the presence of K ₂ CO ₃ (145 mg, 1.05 mmol) for 10 hours to give liquid 38 (25 mg, 45%); ^{1 H NMR (300 MHz, CDCl} 3): δ 3.86 (2H, t, J = 7.5 Hz), 3.62 (2H, t, J = 7.5 Hz), 2.61 (2H, s), 2.51 (2H, s), 1.68-1.55 (4H, m), 1.17 (6H, s), 0.94-0.88 (6H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 161.3, 153.0, 152.5, 110.4, 48.0, 46.7, 42.8, 42.4, 37.4, 29.6, 22.2, 21.0, 11.4, 11.1; IR (neat): 3356, 2959, 2871, 1697, 1657, 1482, 1366, 1263, 1074, 765 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₅ H ₂₄ N ₂ O ₂ : 264.1838, found: 264.1836.

< Example  2-6> 1,3- Dibutyl -6,6- Dimethyl -6,7- Dihydro -1H- Cyclopenta [d] pyrimidine -2,4 (3H, 5H) -dione (39)

Triphosgene (75 mg, 0.25 mmol) was added to compound 19 (60 mg, 0.23 mmol) and refluxed in toluene in the presence of K ₂ CO ₃ (159 mg, 1.15 mmol) for 10 hours to give liquid 39 (29 mg, 43%); ^{1 H NMR (300 MHz, CDCl} 3): δ 3.90 (2H, t, J = 7.5 Hz), 3.65 (2H, t, J = 7.5 Hz), 2.60 (2H, s), 2.51 (2H, s), 1.64-1.53 (4H, m), 1.38-1.30 (4H, m), 1.17 (6H, s), 0.96-0.89 (6H, m); ¹³ C NMR (75 MHz, CDCl ₃ )?: 161.2, 152.8, 152.5, 110.5, 46.7, 46.3, 42.5, 41.2, 37.4, 31.1, 29.8, 29.6, 20.2, 20.0, 13.7, 13.6; IR (neat): 3335, 2955, 1695, 1658, 1482, 1366, 1317, 1255, 1135, 1079, 766 cm &lt; ^{-1 &} gt ;; HRMS m / z (M ⁺ ) C ₁₇ H ₂₈ N ₂ O ₂ : 292.2151, found: 292.2148.

< Example  2-7> 1,3- Bis ( Cyclohexylmethyl ) -6,6-dimethyl-6,7- Dihydro -1H- Cyclopenta [d] pyrimidine -2,4 (3H, 5H) - Of the diaion 40  Produce

To the compound 20 (100 mg, 0.29 mmol) was added triphosgene (95 mg, 0.32 mmol) and refluxed in toluene in the presence of K ₂ CO ₃ (200 mg, 1.45 mmol) for 4 hours to obtain liquid compound 39 (58 mg, 54%); ^{1 H NMR (300 MHz, CDCl} 3): δ 3.75 (2H, d, J = 3.6 Hz), 3.47 (2H, d, J = 3.6 Hz), 2.59 (2H, s), 2.50 (2H, s), 1.80-1.59 (12H, m), 1.21-1.08 (12H, m), 1.04-0.89 (4H, m); ¹³ C NMR (75 MHz, CDCl ₃ ):? 161.7, 153.5, 153.2, 110.4, 53.6, 52.9, 47.5, 47.3, 42.6, 37.6, 37.4, 36.5, 31.0, 30.9, 29.7, 26.6, 26.4, 26.0, 25.9; IR (neat): 3053, 2924, 2851, 2358, 1697, 1657, 1480, 1394, 1357, 1314, 1267, 1171, 1142, 1105, 734 cm ^-1 ; ^{HRMS m / z (M +)} C 23 H 36 N 2 O 2: 372.2777, found: 372.2779.

< Example  3> Beta- Enaminoamide  Using derivative 22 Uracil  Production of derivatives

In addition to the uracil derivative, the uraacyl derivative 32 of the following reaction scheme 5 can be synthesized using the beta- enaminoamide derivative 22 of Table 2. Referring to Reaction Scheme 5 below, It was found that additional reactions could occur depending on the conditions.

[Reaction Scheme 5]

Referring to Reaction Scheme 5, when 1.1 equivalents of triphosgene and 5 equivalents of K ₂ CO ₃ are treated with beta-enaminoamide derivative 22 and then refluxed in toluene for 10 hours, uracil derivative 32 is reduced to 52% Yield. &Lt; / RTI &gt; Treatment of the uracil derivative 32 with ammonium formate salt and 10% Pd / C gave 33 (61%) by deprotection via catalytic hydrogenation. 22 was refluxed in wet ethanol for 12 hours using para-TsOH-treated metal-free catalyst, beta-ketoamide 25 was obtained in 84% yield.

The reaction conditions and product analysis results shown in Scheme 5 are shown in more detail below.

< Comparative Example  3-1> 1,3- Dibenzyl -6,6- Dimethyl -6,7- Dihydro -1H- Cyclopenta [d] pyrimidine -2,4 (3H, 5H) - da Ion (3 2)

Compound 22 (100 mg, 0.30 mmol) tri-phosgene (98 mg, 0.33 mmol) was added to toluene _{K 2 CO 3 (207 mg,} 1.5 mmol) when refluxed for 10 hours in the presence, liquid compound 32 (56 in mg, 52%); ¹ H NMR (300 MHz, CDCl ₃ ):? 7.49-7.14 (10H, m), 5.14 (2H, s), 4.94 (2H, s), 2.53 (4H, s), 1.10 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 162.3, 153.4, 153.0, 137.3, 136.1, 129.1, 128.9, 128.3, 127.8, 126.6, 110.9, 49.1, 46.8, 44.6, 42.4, 37.5, 29.4; IR (neat): 3332, 3031, 2954, 2358, 1697, 1656, 1481, 1389, 1261, 1074, 1028 cm- ¹ ; HRMS m / z (M ⁺ ) C ₂₃ H ₂₄ N ₂ O ₂ : 360.1838, found: 360.1840.

< Comparative Example  3-2> 3-Benzyl-6,6- Dimethyl -6,7- Dihydro -1H- Cyclopenta [d] pyrimidine -2,4 (3H, 5H) - Of the diaion 33  Produce

After refluxing Compound 32 (100 mg, 0.28 mmol), ammonium formate (10 mL of a solution of 0.4 N formaldehyde on dry methanol) and 10% Pd / C (319 mg) for 15 hours, filter the mixture using filter paper Afterwards, the solid residue was washed with methanol (50 mL) and and CHCl ₃ (50 mL). The solution was removed under reduced pressure and silica gel column chromatography with chloroform / methanol (99: 1) as eluent gave solid 33 (46 mg, 61%) as a solid; mp 213-215 [deg.] C; ^{1 H NMR (300 MHz, CDCl} 3): δ 10.10 (1H, br s), 7.40-7.37 (2H, m), 7.24-7.18 (3H, m), 5.02 (2H, s), 2.44 (4H, s ), 1.11 (6H, s); ¹³ C NMR (75 MHz, CDCl ₃ ):? 161.7, 154.1, 151.8, 137.3, 129.2, 128.5, 127.8, 110.8, 46.2, 43.9, 42.4, 38.2, 29.8. IR (KBr): 3247, 3030, 2953, 2861, 1708, 1641, 1531, 1435, 1330, 1261, 1071 cm- ¹ ; HRMS m / z (M ⁺ ) C ₁₆ H ₁₈ N ₂ O ₂ : 270.1368, found: 270.1369.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

Reacting a cyclic 2-diazo-1,3-dicarbonyl compound represented by the following formula (1) with R ₂ NH ₂ at 90-150 ° C in a solvent selected from toluene or para- One - pot synthesis of cyclic beta - enaminoamide derivatives to produce cyclic beta - enaminoamide derivatives.
[Chemical Formula 1]

(2)

In Formula 1, R ₁ is each independently hydrogen, C ₁ -C ₆ alkyl or aryl,
R ₂ are each independently hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ arylalkyl or aryl. The method according to claim 1,
The cyclic 2-diazo-1,3-dicarbonyl can be prepared by reacting 2-diazo cyclohexane-1,2-dione, 2-diamocyclohexane- Diamino-5-dimethylcyclohexane-1,2-dione, wherein the cyclic beta-enaminoamide derivative is one selected from the group consisting of: The method according to claim 1,
The cyclic beta-enaminoamide derivative may be selected from the group consisting of N-propyl-2- (propylamino) cyclopen-1-ene carboxamide, N-butyl- 2- (butylamino) cyclopen- N-phenethyl-2- (phenethylamino) cyclopen-1-yl &lt; / RTI &gt; carboxamide, N (cyclohexylmethyl) Yl) ethyl) -2- (2- (lH-indol-3-yl) -benzylamino) cyclopen- (Phenylamino) cyclopen-1-yl &lt; / RTI &gt; carboxamide, (Cyclohexylmethylamino) -4-phenylcyclophen-1-yl &lt; / RTI &gt; carboxamide, N- Phenylcyclo-1-ene-carboxamide, N-phenethyl-2- (phenethylamino) (2- (1H-indol-3-yl) ethyl) -2-phenylcarbamoyl- - (2- (lH-indol-3-yl) ethylamino) -4-phenylcyclophen-l- 2- (propylamino) cyclopene-1-teocarbamide, N-butyl-2- (butylamino) -4,4-dimethylcyclopene- (Cyclohexylmethyl) -2- (cyclohexylmethylamino) -4,4-dimethylcyclophen-1-yl) carboxamide, 4,4-dimethyl-N- N-benzyl-2- (benzylamino) -4,4-dimethylcyclophen-1-yl) carboxamide, N- ( Yl) ethyl) -2- (2- (lH-indol-3-yl) ethylamino) -4,4-dimethylcyclophen- - dimethyl-N-phenyl-2- (phenylamino) cyclopentane -1-thiocarboxamide, wherein the cyclic beta-enaminoamide derivative is one selected from the group consisting of: delete delete The beta-enaminoamide derivative synthesized in claim 1 in a solvent selected from toluene or para-xylene is further reacted with a triphosgene in the presence of K ₂ CO ₃ at 90-150 ° C. to produce a uracil derivative represented by the following formula Of the uracil derivative.
(3)

In Formula 3, R ₁ is each independently hydrogen, C ₁ -C ₆ alkyl or aryl,
R ₂ are each independently hydrogen, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ arylalkyl or aryl. delete delete