CN1510033A - Synthesis of asymmetric dipyridyl substituted urea derivatives - Google Patents
Synthesis of asymmetric dipyridyl substituted urea derivatives Download PDFInfo
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- CN1510033A CN1510033A CNA021569746A CN02156974A CN1510033A CN 1510033 A CN1510033 A CN 1510033A CN A021569746 A CNA021569746 A CN A021569746A CN 02156974 A CN02156974 A CN 02156974A CN 1510033 A CN1510033 A CN 1510033A
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Abstract
A process for synthesizing the unsymmetrical dipyridinyl substituted urea derivative features the reaction between aminopyridine derivative, nitropyridine derivative, Se or SeO2 as catalyst, and triethylamine as cocatalyst in organic solvent at 50-200 deg.C in a sealed high-pressure reactor for 2-20 hr. Its advantages are simple process and high output rate.
Description
Technical field
The present invention relates to the synthetic method of asymmetric bipyridyl substituted carbamide derivative, the method for particularly a kind of selenium or tin anhydride catalyzed carbonylation is used for synthetic asymmetric bipyridyl substituted carbamide derivative.
Technical background
(pyridine carbamide derivative CONH-) has certain bio-physiological activity to contain peptide bond.As N-benzoyl-N '-pyridyl carbamide derivative is class efficient pesticides [document: US4,405,552; EP8,880; DE3,126,263; US4,264,605; JP62,155,260; JP55,011,537; CA1,131,232 etc.]; N-phenyl-N '-pyridyl carbamide derivative is a class significant herbicide and plant-growth regulator [document: EP401,168; US438,054; The communication of plant physiology, 1989, (1), 17～19 etc.]; N-phenyl-N '-nitrogen pyridine oxide base carbamide derivative is class plant-growth regulator [document: US4,787,931 efficiently too; WO8,702,665; WO8,403,884 etc.].In the pharmacology of routine, can obtain higher bio-physiological activity usually with the pyridyl substituted-phenyl.Based on this idea, we have synthesized a series of asymmetrical bipyridyl substituted carbamide derivatives first.The method of present conventional pyridine synthesis carbamide derivative mainly adopts the isocyanic ester method of phosgene or class phosgene, and its weak point is that phosgene has severe toxicity, produces the big chloride by-product of macro-corrosion in the reaction process, not only the also easy contaminate environment of severe corrosion equipment.And the method for conventional pyridine synthesis carbamide derivative mainly adopts the method for three-step-march, this type of obvious complex operation, and total recovery is also not too high.Document [Tetrahedron Lett, 1999,40 (26), 4845～4846; CN01103688.5; CN01134394.X; CN02109056.5] reported the preparation method of asymmetric replacement urea, but also be not used in the asymmetric bipyridyl substituted carbamide derivative of preparation.
Summary of the invention
The objective of the invention is to, provide a kind of reaction conditions gentleness, selenium or tin anhydride catalysis of carbonyl that cost is low to be combined to asymmetric bipyridyl substituted carbamide derivative.
For achieving the above object, technical scheme of the present invention is as follows: the novel method that a kind of synthetic asymmetric bipyridyl substituted carbamide derivative is provided, it is a raw material with the nitropyridine that replaces under the situation about existing at CO and the aminopyridine analog derivative of replacement, with selenium or tin anhydride is catalyzer, organic basess such as triethylamine are promotor, react in enclosed autoclave in organic solvent; Reaction formula is as follows:
Wherein:
Substituent R on the nitropyridine
1Can be one or more inertia groups or be hydrogen atom;
Substituent R on the aminopyridine analog derivative
2Can be one or more gives electronics and/or electron-withdrawing group or is hydrogen atom;
The mole dosage of catalyzer selenium or tin anhydride is 0.1～20% of a substrate;
The mol ratio of reaction substrate and solvent is: 1: 1 to 1: 50;
Reaction times is: 2～20 hours;
Temperature of reaction is: 50～200 ℃;
Reaction of carbon monoxide pressure is gauge pressure 1～10.0Mpa;
Product separates: can adopt separation methods such as recrystallization or column chromatography.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, the substituent R on its described reactant nitropyridine base
1Can be one or more inertia groups as inertia groups such as alkyl, alkoxyl group, alkylthio, dialkylaminos.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, the nitro on its described reactant nitropyridine base can be positioned at the position of substitution variant on the pyridyl.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, R in its described reactant aminopyridine analog derivative
2Can be to electron substituent group as methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, phenyl etc., or can be electron-withdrawing substituent as halogen, trifluoromethyl, cyano group, carboxyl, formyl radical, ethanoyl etc.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, X on its described reactant aminopyridine analog derivative ring can be one or more heteroatomss such as nitrogen-atoms and/or carbon atom, and heteroatoms X can be positioned at the position of substitution variant on the pyridyl, thus form as: the derivative of aminopyridine, aminopyrimidine, amino pyrazine, amino pyridazine, aminotriazine, aminooimidazole, amino-pyrazol, aminothiazole, amino triazole, amino tetrazole etc.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, its described reactant carbon monoxide can use the industrial carbon monoxide tail gas that contains air, nitrogen, carbonic acid gas and/or water vapor, and wherein the content sum of air, nitrogen, carbonic acid gas and/or water vapor is not more than 10% of cumulative volume.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, its described organic solvent are one or more polarity or nonpolar inert solvent; Its polar solvent is toluene, tetrahydrofuran (THF), N, N '-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or chloroform etc., and non-polar solvent is hexane or benzene etc.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, its described trimethylamine can be triethylamine, 1,8-diaza-bicyclo (5,4,0)-11-carbon-7-alkene, 1,5-diaza-bicyclo (4,3,0)-and 5-nonene, 1,4-diaza-bicyclo (2,2,2) octane, N-crassitude (NMP) or TERTIARY BUTYL AMINE.Its mole dosage is 10～200% of a reaction substrate.
The synthetic method of described asymmetric bipyridyl substituted carbamide derivative, its described reaction product are when separation and purification, and the solvent that is used for recrystallization can be selected the aqueous solution, dehydrated alcohol, trichloromethane and the N of 60% dehydrated alcohol, dinethylformamide etc. for use; Can use unmodified packed column during column chromatography, be leacheate with sherwood oil and ethyl acetate or toluene and ethyl acetate etc.
The present invention has following advantage:
1. cost is low.Catalyzer is inexpensive, and facility investment is few, easily operation.
2. reaction conditions gentleness.Do not use deleterious phosgene, the three wastes are few, production easy to clean.
3. catalyzer is recyclable uses again.
Embodiment
Below by embodiment in detail the present invention is described in detail, but the present invention is not limited to following embodiment.
1-(2-pyridyl)-3-(6-methoxyl group-3-pyridyl) urea is synthetic under the embodiment 1 selenium catalysis
In the stainless steel autoclave of 100ml, add 2-methoxyl group-5-nitropyridine (10mmol), selenium (0.5mmol), 2-aminopyridine (10mmol), triethylamine (10mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 130 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (1: 1), concentrate eluant gets product, m.p.178～180 ℃, yield is 74.5%.
Asymmetric bipyridyl substituted carbamide derivative is synthetic under the embodiment 2 selenium catalysis
Embodiment is summarized as follows with tabulated form: (its reaction conditions and step are with embodiment 1)
Table 1: the carbonylation of 2-methoxyl group-5-nitropyridine and aminopyridine analog derivative under the selenium catalysis
The synthetic asymmetric two pyridine carbamide derivatives of reaction
Preface
The fusing point productive rate
The substrate product
Number
(℃) (％)
1-(2-pyridyl)-3-(6-methoxyl group-3-pyridyl) urea is synthetic under the embodiment 3 tin anhydride catalysis
In the stainless steel autoclave of 100ml, add 2-methoxyl group-5-nitropyridine (10mmol), tin anhydride (0.5mmol), 2-aminopyridine (10mmol), triethylamine (10mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 130 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (1: 1), concentrate eluant gets product, m.p.178～180 ℃, yield is 77.1%.
Asymmetric bipyridyl substituted carbamide derivative is synthetic under the embodiment 4 tin anhydride catalysis, and its reaction conditions and step are with embodiment 3, and gained the results are shown in table 2:
Table 2: 2-methoxyl group-5-nitropyridine and aminopyridine analog derivative under the tin anhydride catalysis
Carbonylation reaction synthesizes asymmetric two pyridine carbamide derivatives
Preface
The fusing point productive rate
The substrate product
Number
(℃) (％)
Asymmetric bipyridyl substituted carbamide derivative is synthetic under the embodiment 5 selenium catalysis differential responses conditions, with the example that synthesizes of 1-(2-pyridyl)-3-(6-methoxyl group-3-pyridyl) urea, the result of implementation of (its reactions steps is with embodiment 1) is listed in table 3 under reaction conditionss such as different reaction ratios, reaction times, pressure, temperature.But the present invention is not limited to following embodiment.
Table 3: when the character of temperature of reaction, catalyst levels, alkali and consumption, CO pressure and reaction
Between etc. condition to the reaction influence
Catalysis meter reaction yield
Preface temperature alkali CO pressure
The consumption time (%)
Number (℃) (mmol) (MPa)
(mmol) (h)
27 110 0.5 TEA(10) 3.0 4 68.1
28 130 0.5 TEA(10) 3.0 4 74.5
29 150 0.5 TEA(10) 3.0 4 75.1
30 170 0.5 TEA(10) 3.0 4 75.8
31 130 0.01 TEA(10) 3.0 4 68.1
32 130 0.05 TEA(10) 3.0 4 69.6
33 130 0.1 TEA(10) 3.0 4 73.1
34 130 1.0 TEA(10) 3.0 4 76.3
35 130 0.5 TEA(/) 3.0 4 8.3
36 130 0.5 TEA(5) 3.0 4 52.6
37 130 0.5 TEA(15) 3.0 4 75.2
38 130 0.5 TEA(20) 3.0 4 76.8
39 130 0.5 NMP(10) 3.0 4 76.1
40 130 0.5 DABCO 3.0 4 76.6
(10)
41 130 0.5 DBN(10) 3.0 4 77.6
42 130 0.5 DBU(10) 3.0 4 78.7
43 130 0.5 TEA(10) 1.0 4 19.2
44 130 0.5 TEA(10) 2.0 4 64.3
45 130 0.5 TEA(10) 4.0 4 75.9
46 130 0.5 TEA(10) 5.0 4 76.3
47 130 0.5 TEA(10) 3.0 1 55.6
48 130 0.5 TEA(10) 3.0 2 71.5
49 130 0.5 TEA(10) 3.0 6 74.9
50 130 0.5 TEA(10) 3.0 8 75.1
51 130 0.5 TEA(10) 3.0 10 75.0
Reaction conditions: 2-methoxyl group-5-nitropyridine, 10mmol; The 2-aminopyridine, 10mmol; Selenium, 0.01-1.0mmol; Organic bases, 0-20mmol; CO, 1.0-5.0MPa; Toluene, 10ml; Temperature, 110-170 ℃; Reaction times, 1.0-10.0h.
TEA: triethylamine (Triethylamine)
NMP:N-crassitude (N-Methylpyrrolidine)
DABCO:1,4-diaza-bicyclo [2,2,2] octane (1,4-Diazabicyclo[2,2,2] octane)
DBN:1,5-diaza-bicyclo [4,3,0]-5-nonene (1,5-Diazabicyclo[4,3,0] non-5-ene)
DBU:1,8-diaza-bicyclo [5,4,0]-11 carbon-7-alkene (1,8-Diazabicyclo[5,4,0] undec-7-ene)
Claims (9)
1. the novel method of a synthetic asymmetric bipyridyl substituted carbamide derivative, it is characterized in that, being raw material with the nitropyridine that replaces and the aminopyridine analog derivative of replacement under the situation about existing at CO, with selenium or tin anhydride is catalyzer, organic basess such as triethylamine are promotor, react in enclosed autoclave in organic solvent; Reaction formula is as follows:
Wherein:
Substituent R on the nitropyridine
1Can be one or more inertia groups or be hydrogen atom;
Substituent R on the aminopyridine analog derivative
2Can be one or more gives electronics and/or electron-withdrawing group or is hydrogen atom;
The mole dosage of catalyzer selenium or tin anhydride is 0.1～20% of a substrate;
The mol ratio of reaction substrate and solvent is: 1: 1 to 1: 50;
Reaction times is: 2～20 hours;
Temperature of reaction is: 50～200 ℃;
Reaction of carbon monoxide pressure is gauge pressure: 1～10.0Mpa;
Product separates: can adopt separation methods such as recrystallization or column chromatography.
2. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative is characterized in that, the substituent R on the described reactant nitropyridine base
1Can be one or more inertia groups as inertia groups such as alkyl, alkoxyl group, alkylthio, dialkylaminos.
3. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative is characterized in that, the nitro on the described reactant nitropyridine base can be positioned at the position of substitution variant on the pyridyl.
4. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative is characterized in that, R in the described reactant aminopyridine analog derivative
2Can be to electron substituent group as methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, phenyl etc., or can be electron-withdrawing substituent as halogen, trifluoromethyl, cyano group, carboxyl, formyl radical, ethanoyl etc.
5. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative, it is characterized in that, X on the described reactant aminopyridine analog derivative ring can be one or more heteroatomss such as nitrogen-atoms and/or carbon atom, and heteroatoms X can be positioned at the position of substitution variant on the pyridyl, thus form as: the derivative of aminopyridine, aminopyrimidine, amino pyrazine, amino pyridazine, aminotriazine, aminooimidazole, amino-pyrazol, aminothiazole, amino triazole, amino tetrazole etc.
6. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative, it is characterized in that, described reactant carbon monoxide can use the industrial carbon monoxide tail gas that contains air, nitrogen, carbonic acid gas and/or water vapor, and wherein the content sum of air, nitrogen, carbonic acid gas and/or water vapor is not more than 10% of cumulative volume.
7. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative is characterized in that, described organic solvent is one or more polarity or nonpolar inert solvent; Its polar solvent is toluene, tetrahydrofuran (THF), N, N '-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or chloroform etc., and non-polar solvent is hexane or benzene etc.
8. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative, it is characterized in that described trimethylamine can be triethylamine, 1,8-diaza-bicyclo (5,4,0)-and 11-carbon-7-alkene, 1,5-diaza-bicyclo (4,3,0)-5-nonene, 1,4-diaza-bicyclo (2,2,2) octane, N-crassitude (NMP) or TERTIARY BUTYL AMINE.Its mole dosage is 10～200% of a reaction substrate.
9. the synthetic method of asymmetric according to claim 1 bipyridyl substituted carbamide derivative, it is characterized in that, described reaction product is when separation and purification, and the solvent that is used for recrystallization can be selected the aqueous solution, dehydrated alcohol, trichloromethane and the N of 60% dehydrated alcohol, dinethylformamide etc. for use; Can use unmodified packed column during column chromatography, be leacheate with sherwood oil and ethyl acetate or toluene and ethyl acetate etc.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009048752A3 (en) * | 2007-10-09 | 2009-05-28 | Dow Agrosciences Llc | Insecticidal substituted azinyl derivatives |
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2002
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009048752A3 (en) * | 2007-10-09 | 2009-05-28 | Dow Agrosciences Llc | Insecticidal substituted azinyl derivatives |
| JP2011500574A (en) * | 2007-10-09 | 2011-01-06 | ダウ アグロサイエンシィズ エルエルシー | Insecticidal substituted azinyl derivatives |
| US8013154B2 (en) | 2007-10-09 | 2011-09-06 | Niyaz Noormohamed M | Insecticidal substituted azinyl derivatives |
| US8455649B2 (en) | 2007-10-09 | 2013-06-04 | Dow Agrosciences, Llc | Insecticidal substituted azinyl derivatives |
| US8507671B2 (en) | 2007-10-09 | 2013-08-13 | Dow Agrosciences Llc | Insecticidal substituted azinyl derivatives |
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