CN102093338A - N-acyl cyclic urea derivative and preparation method thereof - Google Patents
N-acyl cyclic urea derivative and preparation method thereof Download PDFInfo
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- CN102093338A CN102093338A CN2010105788234A CN201010578823A CN102093338A CN 102093338 A CN102093338 A CN 102093338A CN 2010105788234 A CN2010105788234 A CN 2010105788234A CN 201010578823 A CN201010578823 A CN 201010578823A CN 102093338 A CN102093338 A CN 102093338A
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- imidazolone
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Abstract
The invention relates to a preparation method of an N-acyl cyclic urea compound, belonging to the technical field of chemical preparation. The structural general formula of the N-acyl cyclic urea compound is disclosed in the specification. The preparation method comprises the following step of: reacting for 0.5-41 hours at 0-110 DEG C by using 1-[(6-chlorine-3-pyridine) methyl]-2-imidazolone and different kinds of acyl chlorides as raw materials and organic amine as a catalyst and an acid binding agent to synthesize the novel N-acyl cyclic urea compound with higher productivity in one step. The method has the advantages of one-step synthesis, single product, short reaction time and simpleness and convenience for post treatment. The compound probably has potential application values in the fields of organic synthesis intermediates, medicines, pesticides, and the like.
Description
Technical field
The present invention relates to the chemical preparation technical field, specifically a kind of preparation method of N-acyl group cyclic urea derivatives.
Background technology
Acylurea is the important medicine of a class, pesticide intermediate.This compounds have suppress methionine(Met) kinase activity, effect such as anticancer (
Bioorg. Med. Chem. Lett. 2008,18,1945 ~ 1951;
Bioorg. Med. Chem. Lett.2008,18,3224 ~ 3229), also shown simultaneously at aspects such as weeding, desinsection, antibiotic, plant growth regulating good biological activity (
Organic chemistry, 2010,30,132 ~ 136).Acyl urea compound has become one of novel agrochemical hot of research and development field in recent years, existing up to now acylurea analog derivative successfully realized commercialization (
Organic chemistry,2004,24,227 ~ 230;
Agricultural chemicals2009,48,625 ~ 628).
Heterogeneous ring compound is widespread in nature, much have tangible biological activity (
Bioorg. Med. Chem. 2007,15,7108), wherein N-acyl group cyclic urea derivatives be important organic synthesis intermediate (
CN 1446803;
CN 1473817;
EP 0240370), be widely used in fields such as medicine, agricultural chemicals, however at present less about the synthetic report of this compounds.In view of acyl group ureas and heterogeneous ring compound excellent activity at field of medicaments, develop new, synthetic method is simple-the acyl group cyclic urea derivatives causes that people pay close attention to widely.
Summary of the invention
The object of the present invention is to provide a kind of novel N-acyl group cyclic urea derivatives and preparation method thereof; use 1-[(6-chloro-3-pyridine) methyl]-2-imidazolone and different types of acyl chlorides be raw material; one-step synthesis N-acyl group cyclic urea derivatives; step is simple; post-reaction treatment is convenient; productive rate reaches more than 80%, has better industrial application prospect.
N-acyl group cyclic urea derivatives provided by the invention can be represented with following general structure:
Wherein R is alkyl, aromatic group, haloalkyl or nitrogen heterocyclic ring class group; Alkyl comprises: methyl, ethyl, sec.-propyl and amyl group etc., aromatic group comprises: phenyl, 4-nitrophenyl and 4-chloro-phenyl-etc.
The preparation method of N-acyl group cyclic urea derivatives provided by the invention is as follows:
Key step:
With 1-[(6-chloro-3-pyridine) methyl]-the 2-imidazolone; organic amine; solvent such as toluene; methylene dichloride; trichloromethane; tetrahydrofuran (THF); acetonitrile or acetone mix; under magnetic agitation, slowly add different types of acyl chlorides; reacted 0.5 ~ 41 hour down at 0 ~ 110 ℃; after reaction finishes; be cooled to room temperature; boil off solvent under the decompression, add methylene dichloride, organic phase is respectively with saturated sodium bicarbonate solution and saturated nacl aqueous solution extraction; separatory; merge organic phase, removal of solvent under reduced pressure, head product is through washing; recrystallization purification final vacuum is dry must described N-acyl group cyclic urea derivatives.
Reaction raw materials acyl chlorides and 1-[(6-chloro-3-pyridine) methyl]-mol ratio of 2-imidazolone is 1:1 ~ 2:1.
Temperature of reaction is between 0 ~ 110 ℃, and preferred temperature is 20 ~ 80 ℃.
Reaction solvent is alkane, halogenated alkane, oxygenatedchemicals etc.Acyl chlorides is facile hydrolysis in protic solvent, therefore can not select protic solvent for use.In order under suitable temperature, to react, also to consider the boiling point of solvent.Preferred solvent is methylene dichloride, trichloromethane, tetrahydrofuran (THF), acetone etc.
Reaction times is 0.5 ~ 41 hour.
The consumption of organic amine and 1-[(6-chloro-3-pyridine) methyl]-mol ratio of 2-imidazolone is 0.5:1 ~ 4:1, preferred molar ratio is 1:1 ~ 1.5:1.
The present invention is raw materials used cheap and easy to get, and preparation N-acyl group cyclic urea derivatives step is simple, at 1-[(6-chloro-3-pyridine) methyl]-2-imidazolone basis previous step is synthetic; reaction safety is convenient to operation and productive rate height; simplify industrial equipments greatly, had better industrial application prospect.
Embodiment
The following example can be used to further the present invention be elaborated, but does not mean that restriction the present invention.
Embodiment 1
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); toluene 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into Benzoyl chloride 5.5 mmol (0.7731 g) under stirring; be warming up to reflux temperature then and react 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL, separatory, water extracts with methylene dichloride (10 mL * 3); merge organic phase; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 1.4074 g white solids, and productive rate is 89%.M.p. 77 ~ 78
oC;
1H NMR (CDCl
3, 500 MHz) and δ: 3.42 (t,
J=7.9 Hz, 2H), 4.00 (m, 2H), 4.41 (s, 2H), 7.33 (d,
J=8.2 Hz, 1H), 7.43 (t,
J=7.7 Hz, 2H), 7.52 (t,
J=7.5 Hz, 1H), 7.59 ~ 7.62 (m, 3H), 8.32 (d,
J=2.2 Hz, 1H);
13C NMR (CDCl
3, 125 MHz) and δ: 40.56,44.61,124.60,127.52,128.61,130.48,131.41,134.24,138.83,149.25,151.34,154.25,170.15; IR (KBr) ν: 3004,2997,2910,1725,1689,1592,1459,1436,1356,1263,762,662 cm
-1; Ultimate analysis (Anal. calcd for) C
16H
14ClN
3O
2: calculated value C 60.86, H 4.47, and N 13.31; Measured value C 60.93, H 4.54, and N 13.24.
Embodiment 2
?
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); tetrahydrofuran (THF) 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into Benzoyl chloride 5.5 mmol (0.7731 g) under stirring; be warming up to reflux temperature then and react 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL, separatory, water extracts with methylene dichloride (10 mL * 3); merge organic phase; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 1.3097 g white solids, and productive rate is 83%.
Embodiment 3
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); toluene 10 mL; acid binding agent pyridine 5 mmol (0.3955 g); in room temperature; splash into Benzoyl chloride 5.5 mmol (0.7731 g) under stirring; be warming up to reflux temperature then and react 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL, separatory, water extracts with methylene dichloride (10 mL * 3); merge organic phase; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 1.0006 g white solids, and productive rate is 64%.
Embodiment 4
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); tetrahydrofuran (THF) 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into parachlorobenzoyl chloride 7.5 mmol (1.3126 g) under stirring; be warming up to reflux temperature then and react 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL; separatory; water extracts with methylene dichloride (10 mL * 3); merge organic phase; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 1.7064 g white solids, and productive rate is 94%.M.p. 120 ~ 121
oC;
1H NMR (CDCl
3, 500 MHz) and δ: 3.43 (d,
J=7.9 Hz, 2H), 4.00 (t,
J=7.9 Hz, 2H), 4.41 (s, 2H), 7.33 (d,
J=8.2 Hz, 1H), 7.39 (d,
J=8.45 Hz, 2H), 7.55 (m, 2H), 7.60 (m, 1H), 8.31 (s, 1H);
13C NMR (CDCl
3, 125 MHz) and δ: 40.53,44.61,124.61,127.82,129.30,130.19,130.31,131.79,132.46,137.66,138.82,149.23,151.37,154.13,169.01; IR (KBr) ν: 3063,3010,2964,2944,2900,1728,1665,1595,1483,1466,1340,1273,845,629 cm
-1; Ultimate analysis (Anal. calcd for) C
16H
13Cl
2N
3O
2: calculated value C 54.87, H 3.74, and N 12.00; Measured value C 55.02, H 3.97, and N 11.75.
Embodiment 5
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); tetrahydrofuran (THF) 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into paranitrobenzoyl chloride 5.5 mmol (1.0206 g) under stirring; be warming up to reflux temperature then and react 41 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL; separatory, water merges organic phase with methylene dichloride (10 mL * 3) extraction; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter.The eluent that head product uses sherwood oil: ethyl acetate=2:1 through column chromatography purify 1.415 g white solids, separation yield is 80%.M.p. 187 ~ 188
oC;
1H NMR (CDCl
3, 500 MHz) and δ: 3.48 (t,
J=7.9 Hz, 2H), 4.05 (t,
J=7.9 Hz, 2H), 4.41 (s, 2H), 7.35 (d,
J=8.2 Hz, 1H), 7.59 (m, 1H), 7.72 (t,
J=4.3 Hz, 2H), 8.29 (m, 3H);
13C NMR (CDCl
3, 125 MHz) and δ: 40.27,40.64,44.70,122.87,124.72,129.36,130.01,138.85,140.22,149.13,149.32,151.63,153.82,168.02; IR (KBr) ν: 3106,3050,2924,2858,1728,1675,1526,1459,1353,1260,845,623 cm
-1; Ultimate analysis (Anal. calcd for) C
16H
13ClN
4O
4: calculated value C 53.27, H 3.63, and N 15.53; Measured value C 53.49, H 3.997, and N 15.54.
Embodiment 6
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); tetrahydrofuran (THF) 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into Acetyl Chloride 98Min. 10 mmol (0.7850 g) under stirring; be warming up to reflux temperature then and react 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL, separatory, water extracts with methylene dichloride (10 mL * 3); merge organic phase; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 0.6929 g white solid, and productive rate is 54%.m.p.?90~91?
oC;?
1H?NMR?(CDCl
3,500?MHz)?δ:?2.52?(s,?3H),?3.32?(t,?
J=8.1?Hz,?2H),?3.83?(m,?2H),?4.43?(s,?2H),?7.34?(d,?
J=8.2?Hz,?1H),?7.63?(dd,?
J=2.4,?2.3?Hz,?1H),?8.31?(d,?
J=2.3?Hz,?1H);?
13C?NMR?(CDCl
3,?125?MHz)?δ:?23.27,?39.34,?40.39,?44.57,?124.61,?130.48,?138.87,?149.12,?151.16,?154.83,?170.52;?IR?(KBr)?ν:?2977,?2943,?2927,?2897,?1728,?1668,?1586,?1502,?1449,?1392,?1267,?854,?616?cm
-1;?HRMS?calcd?for?C
11H
12ClN
3O
2?253.0618;?found?253.0616。
Embodiment 7
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); tetrahydrofuran (THF) 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into propionyl chloride 10 mmol (0.9253 g) under stirring; be warming up to reflux temperature then and react 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL, separatory, water extracts with methylene dichloride (10 mL * 3); merge organic phase; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 1.1206 g white solids, and productive rate is 84%.M.p. 59 ~ 60
oC;
1H NMR (CDCl
3, 500 MHz) and δ: 1.16 (m, 3H), 2.95 (q,
J=7.3 Hz, 2H), 3.31 (t,
J=8 Hz, 2H), 3.83 (t,
J=8 Hz, 2H), 4.42 (s, 2H), 7.62 (dd,
J=2,6 Hz, 1H), 8.31 (d,
J=2 Hz, 1H);
13C NMR (CDCl
3, 125 MHz) and δ: 8.56,28.74,39.44,40.49,44.54,124.56,130.49,138.79,149.21,151.21,154.84,174.39; IR (KBr) ν: 2984,2947,2904,2877,1728,1669,1592,1572,1466,1439,1390,762,679 cm
-1; Ultimate analysis (Anal. calcd for) C
12H
14ClN
3O
2: calculated value C 53.84, H 5.27, and N 15.70; Measured value C 53.70, H 5.13, and N 15.39.
Embodiment 8
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone (1) 5 mmol (1.0575 g); tetrahydrofuran (THF) 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into caproyl chloride 6 mmol (0.8077 g) under stirring; be warming up to reflux temperature then and react 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and saturated sodium bicarbonate solution 80 mL, separatory, water extracts with methylene dichloride (10 mL * 3); merge organic phase; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 1.2969 g white solids, and productive rate is 89%.m.p.?44~45?
oC;?
1H?NMR?(CDCl
3,?500?MHz)?δ:?0.91?(m,?3H),?1.36?(d,?
J=3.6?Hz,?4H),?1.68?(t,?
J=6.1?Hz,?2H),?2.96?(m,?2H),?3.24?(t,?
J=8.1?Hz,?2H),?3.85?(m,?2H),?4.45?(s,?2H),?7.36?(d,?
J=8.3?Hz,?1H),?7.65?(dd,?
J=2.3,?5.9?Hz,?1H),?8.34?(d,?
J=1.7?Hz,?1H);?
13C?NMR?(CDCl
3,?125?MHz)?δ:?13.87,?22.36,?24.28,?31.37,?35.18,?39.46,?40.46,?44.59,?124.56,?130.50,?138.76,?149.23,?151.26,?154.81,?173.76;?IR?(KBr)?ν:?2957,?2931,?2871,?1722,?1672,?1479,?1463,?1393,?812,?605?cm
-1;?HRMS?calcd?for?C
15H
20ClN
3O
2 309.1244;?found?309.1243。
Embodiment 9
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone 5 mmol (1.0575 g); tetrahydrofuran (THF) 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into isobutyryl chloride 10 mmol (1.065 g) under stirring; back flow reaction 1 h; be cooled to room temperature; removal of solvent under reduced pressure; add methylene dichloride 15 mL and wash methylene dichloride (10 mL * 3) extraction of separatory, water with saturated sodium bicarbonate solution 100 mL; merge organic phase; organic phase is washed with saturated nacl aqueous solution 100 mL, separatory, anhydrous magnesium sulfate drying organic phase; filter; removal of solvent under reduced pressure, head product are through the anhydrous diethyl ether washing for several times; filter; vacuum-drying gets 1.225 g white solids, and productive rate is 87%.
1H NMR (CDCl
3, 400 MHz) and δ: 1.18 (d,
J=6.4 Hz, 6H), 3.33 (t,
J=8.2 Hz, 2H), 3.86 (m, 3H), 4.45 (s, 2H), 7.35 (d,
J=8 Hz, 1H), 7.64 (d,
J=8 Hz, 1H), 8.33 (s, 1H);
13C NMR (CDCl
3, 100 MHz) and δ: 19.16,32.39,39.79,40.46,44.70,124.64,130.61,138.87,149.31,151.30,154.58,178.06; Ultimate analysis (Anal. calcd for) C
13H
16ClN
3O
2: calculated value C 55.42, H 5.72, and N 14.91; Measured value C 54.23, H 5.67, and N 14.98.
Embodiment 10
In 100 mL, two neck flasks, add pyridine-3-carboxylic acid (0.6165 g, 5 mmol) under room temperature, the nitrogen protection, constantly stir down, add SOCl
2(14.0 mL), oil bath slowly is warming up to 76 ℃, and 76 ℃ of backflows of steady temperature were reacted after 3 hours, and the intact SOCl of unreacted is removed in decompression
2, obtain the hydrochloride of white solid pyridine-3-acyl chlorides.The hydrochloride of pyridine-3-acyl chlorides of obtaining above added under the room temperature nitrogen protection contains 1-[(6-chloro-3-pyridine) methyl]-dichloromethane solution (10 mL) of 2-imidazolone (0.4123g, 2 mmol), acid binding agent triethylamine 2 mmol (0.2020 g) in.Slowly be warming up to 40 ℃ of 1 h that reflux.Be cooled to room temperature, add methylene dichloride 15 mL, with saturated sodium bicarbonate solution 100 mL washing, separatory, inorganic methylene dichloride (20 mL * 3) extraction, the merging organic phase used mutually, organic phase is washed with saturated nacl aqueous solution 100 mL, separatory, anhydrous magnesium sulfate drying organic phase, removal of solvent under reduced pressure, thick product gets yellow solid through column chromatography, eluent is ethyl acetate: sherwood oil=2.5:1, and vacuum-drying gets 0.3348 g yellow solid, and productive rate is 53%.
1H?NMR?(CDCl
3,?400?MHz)?δ:?3.46?(t,?
J=7.8?Hz,?2H),?4.04?(t,?
J=7.8?Hz,?2H),?4.42?(s,?2H),?7.34?(s,?2H),?7.37?(t,?
J=6?Hz,?1H),?7.62?(d,?
J=8.4?Hz,?1H),?7.91?(d,?
J=7.6?Hz,?1H),?8.32?(s,?1H),?8.72?(d,?
J=4.4?Hz,?1H),?8.82?(s,?1H)?;?
13C?NMR?(CDCl
3,100?MHz)?δ:?40.41,?40.62,?44.70,?122.41,?124.72,?130.22,?130.27,?136.21,?138.90,?149.31,?149.51,?151.49,?151.86,?154.06,?167.87。
Embodiment 11
In 100 mL, two neck flasks, add pyrazoles acid (0.9425 g, 5 mmol) under room temperature, the nitrogen protection, constantly stir down, add SOCl
2(14.0 mL), oil bath slowly is warming up to 76 ℃, and 76 ℃ of backflows of steady temperature were reacted after 7 hours, and remaining SOCl is removed in decompression
2, obtain brown liquid pyrazoles acyl chlorides.The pyrazoles acyl chlorides that obtains above is dissolved in the dry methylene dichloride of crossing of 10 mL; under ice bath, nitrogen protection, above-mentioned solution slowly splashed into and contains 1-[(6-chloro-3-pyridine) methyl]-dichloromethane solution (10 mL) of 2-imidazolone (0.4123g, 2 mmol), acid binding agent triethylamine 2 mmol (0.2020 g) in.Slowly be warming up to 40 ℃ of 5 h that reflux after dropwising.Be cooled to room temperature, add methylene dichloride 15 mL, with saturated sodium bicarbonate solution 100 mL washing, separatory, inorganic methylene dichloride (20 mL * 3) extraction, the merging organic phase used mutually, organic phase is washed with saturated nacl aqueous solution 100 mL, separatory, anhydrous magnesium sulfate drying organic phase, filter, removal of solvent under reduced pressure, thick product gets pure product through column chromatography, and eluent is ethyl acetate: sherwood oil=3:1, vacuum-drying gets 0.267 g glassy yellow transparent solid, and productive rate is 35%.
1H NMR (CDCl
3, 400 MHz) and δ: 1.26 (t,
J=7.4 Hz, 3H), 2.65 (dd,
J=7.2,7.6 Hz, 2H), 3.45 (t,
J=7.6 Hz, 2H), 3.89 (s, 3H), 4.01 (t,
J=7.6 Hz, 2H), 4.46 (s, 2H), 7.35 (d,
J=8.4 Hz, 1H), 7.65 (d,
J=8.4 Hz, 1H), 8.33 (s, 1H);
13C NMR (CDCl
3, 100 MHz) and δ: 12.78,19.19,38.56,40.27,40.78,44.58,110.03,124.72,130.23,132.98,138.89,149.27,149.65,151.54,152.98,159.16; Ultimate analysis (Anal. calcd for) C
16H
17Cl
2N
5O
2: calculated value C 50.27, H 4.48, and N 18.32; Measured value C 50.59, H 4.77, and N 17.64.
Embodiment 12
At N
2Protection adds 1-[(6-chloro-3-pyridine down in two mouthfuls of flasks of 100 mL) methyl]-2-imidazolone 5 mmol (1.0575 g); methylene dichloride 10 mL; acid binding agent triethylamine 5 mmol (0.5050 g); in room temperature; splash into chloroacetyl chloride 10 mmol (1.13 g) under stirring; room temperature reaction 1 h; after reaction finishes; add methylene dichloride 15 mL; and respectively with each the 100 mL washing of distilled water saturated sodium bicarbonate solution; separatory merges organic phase, and organic phase is washed with saturated nacl aqueous solution 100 mL; separatory; the anhydrous magnesium sulfate drying organic phase is filtered removal of solvent under reduced pressure; head product is through ethyl acetate and the dry 0.8994 g pale solid that gets of normal hexane recrystallization final vacuum, and productive rate is 63%.
1H NMR (CDCl
3, 400 MHz) and δ: 3.41 (t,
J=8 Hz, 2H), 3.90 (t,
J=8 Hz, 2H), 4.45 (s, 2H), 4.77 (s, 2H), 7.36 (d,
J=8.4 Hz, 1H), 7.63 (d,
J=8 Hz, 1H), 8.33 (s, 1H);
13C NMR (CDCl
3, 100 MHz) and δ: 39.60,40.83,43.33,44.60,124.63,130.02,138.77,149.24,151.43,154.22,166.13; Ultimate analysis (Anal. calcd for) C
11H
11Cl
2N
3O
2: calculated value C 45.85, H 3.85, and N 14.58; Measured value C 46.19, H 3.76, and N 14.17.
Embodiment 13
In 100 mL, two neck flasks, add time acid (1.2132 g, 5 mmol) under room temperature, the nitrogen protection, constantly stir down, add SOCl
2(14.0 mL), oil bath slowly is warming up to 76 ℃, and 76 ℃ of backflows of steady temperature were reacted after 3 hours, and the intact SOCl of unreacted is removed in decompression
2, obtain white solid time acyl chlorides.The time acyl chlorides that obtains above added under the room temperature nitrogen protection contains 1-[(6-chloro-3-pyridine) methyl]-dichloromethane solution (10 mL) of 2-imidazolone (0.4123g, 2 mmol), acid binding agent triethylamine 2 mmol (0.2020 g) in.Slowly be warming up to 40 ℃ of 1 h that reflux.Be cooled to room temperature, add methylene dichloride 15 mL, add solution of potassium carbonate 100 mL washing then, separatory, water extracts with methylene dichloride (20 mL * 3), merge organic phase, anhydrous magnesium sulfate drying filters, removal of solvent under reduced pressure, thick product is through the ether recrystallization, and vacuum-drying gets 0.4865 g white solid, and productive rate is 56%.
1H?NMR?(CDCl
3,?400?MHz)?δ:?1.28?(s,?3H),?1.38?(s,?3H),?2.25?(t,?
J=8.8?Hz,?1H),?3.33?(t,?
J=7.8?Hz,?2H),?3.59?(d,?
J=8.4?Hz,?1H),?3.84?(t,?
J=8?Hz,?2H),?4.46?(dd,?
J=15.2,?15.6?Hz,?2H),?7.03?(d,?
J=9.6?Hz,?1H)?,?7.36?(d,?
J=8.4?Hz,?1H),?7.65?(d,?
J=8.4?Hz,?1H),?8.34?(s,?1H);?
13C?NMR?(CDCl
3,100?MHz)?δ:?15.18,?28.38,?29.96,?31.93,?33.27,?39.85,?40.36,?44.75,?120.54?(d,?
J=270?Hz,?1C),?120.88?(d,?
J=37?Hz,?1C),?124.68,?130.47,?131.14?(t,?
J=4.5?Hz,?1C),?138.88,?149.27,?151.37,?155.02,?169.78;?HRMS?calcd?for?C
18H
18Cl
2N
3O
2?F
3 435.0728;?found?435.0727。
Claims (4)
1. N-acyl group cyclic urea derivatives is characterized in that the structure of such N-acyl group ring urea has following general structure:
Wherein R is alkyl, aromatic group, haloalkyl or nitrogen heterocyclic ring class group.
2. method for preparing the described N-acyl group of claim 1 cyclic urea derivatives; it is characterized in that this method is to add 1-[(6-chloro-3-pyridine in reaction vessel) methyl]-2-imidazolone, organic amine, solvent slowly add different acyl chlorides under magnetic agitation, 0 ~ 110
oC reacted 0.5 ~ 41 hour down, after reaction finishes, be cooled to room temperature, removal of solvent under reduced pressure adds methylene dichloride, and organic phase is respectively with saturated sodium bicarbonate solution and saturated nacl aqueous solution extraction, separatory, merge organic phase, removal of solvent under reduced pressure, through washing, recrystallization purification final vacuum dry described N-acyl group cyclic urea derivatives; Wherein: acyl chlorides and 1-[(6-chloro-3-pyridine) methyl]-mol ratio of 2-imidazolone is 1:1 ~ 2:1; Organic amine and 1-[(6-chloro-3-pyridine) methyl]-mol ratio of 2-imidazolone is 0.5:1 ~ 4:1, solvent and 1-[(6-chloro-3-pyridine) methyl]-mol ratio of 2-imidazolone is 15:1 ~ 20:1.
3. preparation method according to claim 2 is characterized in that: described organic amine is triethylamine, tripropylamine, n-Butyl Amine 99 or pyridine.
4. according to the described preparation method of claim 2, it is characterized in that: described solvent is toluene, methylene dichloride, trichloromethane, tetrahydrofuran (THF), acetonitrile or acetone.
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