CN1123565C - Process for preparing unsymmetric phenyl substituted urea - Google Patents
Process for preparing unsymmetric phenyl substituted urea Download PDFInfo
- Publication number
- CN1123565C CN1123565C CN 99112869 CN99112869A CN1123565C CN 1123565 C CN1123565 C CN 1123565C CN 99112869 CN99112869 CN 99112869 CN 99112869 A CN99112869 A CN 99112869A CN 1123565 C CN1123565 C CN 1123565C
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- CN
- China
- Prior art keywords
- urea
- phenyl substituted
- substituted urea
- preparation
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000004202 carbamide Substances 0.000 title claims abstract description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 15
- 150000003672 ureas Chemical class 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title 1
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- GWEHVDNNLFDJLR-UHFFFAOYSA-N 1,3-diphenylurea Chemical class C=1C=CC=CC=1NC(=O)NC1=CC=CC=C1 GWEHVDNNLFDJLR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000012442 inert solvent Substances 0.000 claims abstract description 5
- 239000000463 material Substances 0.000 claims abstract description 4
- 238000006073 displacement reaction Methods 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 16
- -1 phenyl-substituted urea Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 238000005292 vacuum distillation Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- LUBJCRLGQSPQNN-UHFFFAOYSA-N 1-Phenylurea Chemical compound NC(=O)NC1=CC=CC=C1 LUBJCRLGQSPQNN-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 238000007789 sealing Methods 0.000 description 5
- 238000003556 assay Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
- 239000010935 stainless steel Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 238000005649 metathesis reaction Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- RECCURWJDVZHIH-UHFFFAOYSA-N (4-chlorophenyl)urea Chemical compound NC(=O)NC1=CC=C(Cl)C=C1 RECCURWJDVZHIH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 238000005810 carbonylation reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- VFVKGALKOKTPEA-UHFFFAOYSA-N 1,3-dibutyl-1-phenylurea Chemical compound CCCCNC(=O)N(CCCC)C1=CC=CC=C1 VFVKGALKOKTPEA-UHFFFAOYSA-N 0.000 description 1
- 102100030492 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1 Human genes 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101100408465 Homo sapiens PLCE1 gene Proteins 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012822 chemical development Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- UICIJOHWFFTRLI-UHFFFAOYSA-N n-phenylpiperidine-1-carboxamide Chemical class C1CCCCN1C(=O)NC1=CC=CC=C1 UICIJOHWFFTRLI-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
一种不对称苯基取代脲的制备方法，是用对称的取代或非取代的二苯基脲与有机胺起置换反应得到不对称的苯基取代脲，其特征在于：反应在密封的高压釜，情性溶剂中70～200℃条件下进行，二苯基脲与有机胺的物料比为1∶1～1∶10(mol)。本发明产率高，产品质量稳定，后序分离容易。A kind of preparation method of unsymmetrical phenyl substituted urea, it is to use symmetrical substituted or non-substituted diphenyl urea and organic amine to carry out displacement reaction to obtain unsymmetrical phenyl substituted urea, it is characterized in that: react in sealed autoclave , carried out in an inert solvent at 70-200° C., and the material ratio of diphenylurea to organic amine is 1:1-1:10 (mol). The invention has high yield, stable product quality and easy subsequent separation.
Description
The present invention relates to utilize the replacement(metathesis)reaction of symmetric phenylurea and organic amine to prepare the method for asymmetric phenylurea.
Asymmetry substitute urea is the broad-spectrum compound of a class, owing to contain the different peptide bonds that replace in the structure (CONH-), so most biologically active.As the asymmetry substitute urea unit is the common constitutional features of many enzyme inhibitorss and biosimulation peptide, and asymmetric phenyl substituted urea is the weedicide of the last class outbalance of agricultural etc.Synthetic the earliest substitute urea compound is to utilize phosgene or based on the class material (as isocyanide ester and urea chloride) of phosgene, because phosgene has severe toxicity, and generate a large amount of chloride refuses in the reaction process, thereby the difficulty that causes equipment corrosion and deal with in a large number.In the past few decades, people seek the route of synthesis that can replace phosgene always, mainly are the carbonic acid derivativess that utilizes some symmetries or asymmetric replacement, and some chloro-formic ester compounds.But many phosgene of getting back to again get in them.Along with C
1CHEMICAL DEVELOPMENT is directly utilized the carbonylation reaction of CO to synthesize the method that replaces urea and is found and obtains broad research.Wherein more research concentrates on the reducing carbonyl of the nitro-compound of precious metal (as palladium, ruthenium, rhodium) and their compound as catalyst and the oxidation carbonylation of amine, generally needs higher temperature and pressure.Document Y.Furuya and K.Itoho, Chem.Ind. (London), 359 (1967) and K.Ramadas and N.Srinivasan, Org.Prep.Preced.Int, 25 (5), 600 (1993) have introduced a kind of replacement(metathesis)reaction of symmetric phenylurea and organic amine of utilizing also can prepare asymmetric phenylurea well, this reaction is to carry out under the condition of atmospheric pressure reflux, have only primary amine to react under this reaction conditions with symmetric phenylurea, and need make catalyzer with triethylamine, the time that reaction needed is long, need use the high boiling solvent as DMF so in addition, thereby cause the difficulty in the separation.
The object of the present invention is to provide a kind of preparation method of asymmetric phenyl substituted urea, this method productive rate height, constant product quality, postorder separates easily.
The invention provides a kind of preparation method of asymmetric phenyl substituted urea, be to play replacement(metathesis)reaction with the diphenyl urea of symmetric replacement or non-replacement and organic amine to obtain asymmetric phenyl substituted urea, it is characterized in that: the autoclave that is reflected at sealing, carry out under 70～200 ℃ of conditions in the inert solvent, the material ratio of diphenyl urea and organic amine is 1: 1～1: 10 (mol).
Reaction formula is:
Separated product is come with underpressure distillation in the reaction back, and the present invention need not use any catalyzer, and the reaction times is shorter, and reaction yield and selectivity are good, and product separates simple.Substituent X on the phenyl can be one or more and gives electronics or electrophilic group; The organic amine scope here is wider, wherein R
1, R
2Can be the alkyl of H, replacement or non-replacement, or NR
1R
2Can be heterocycle such as pyrrolidyl, piperidyl and morphine quinoline base etc.; Solvent can use any polarity or nonpolar inert solvent or its mixture.
Raw material of the present invention is simple, need not to use any catalyzer, the productive rate height, and constant product quality, postorder separates easily, and technology difficulty is low, does not have corrosion, and investment goods is few, easily operation.
Below by embodiment in detail the present invention is described in detail.
Embodiment 1
In 70 milliliters stainless steel autoclave, add N, and N '-diphenyl urea (1.06g, 5mmol), Isopropylamine (1.5g, 25mmol) with toluene solvant 10g, sealing put it into the interior stirring reaction of the oil bath that rises to 150 ℃ 2 hours, was cooled to room temperature, open still, with the gained solution decompression concentrate solid, drying, weigh 0.81g product N-sec.-propyl-N '-phenylurea, the HPLC purity assay is 99%, and calculating productive rate is 90.1%.Stratographic analysis Waters HPLC analyser, Spherisorb C
18Post is a moving phase with the methanol-water.
Embodiment 2
In 70 milliliters stainless steel autoclave, add N, and N '-diphenyl urea (1.06g, 5mmol), Di-n-Butyl Amine (3.23g, 25mmol) with toluene solvant 10g, sealing put it into the interior stirring reaction of the oil bath that rises to 150 ℃ with 2 hours, be cooled to room temperature, open still, with the gained solution decompression concentrate solid, drying, weigh 1.18g product N, N '-di-n-butyl-N '-phenylurea, the PPLC purity assay is 99%, calculating productive rate is 94.2%.
Embodiment 3
Add N at 70 milliliters stainless steel autoclaves, N '-diphenyl urea (1.06g, 5mmol), piperidines (2.13g, 25mmol) and toluene solvant 10g, sealing, put it into the interior stirring reaction of the oil bath that rises to 150 ℃ with 2 hours, be cooled to room temperature, open still, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, weigh 0.95g product phenylamino carbonyl piperidines, the HPLC purity assay is 99%, calculating productive rate is 92.2%.
Embodiment 4
In 70 milliliters stainless steel autoclave, add N, N '-two (4-chloro-phenyl-) urea (1.40g, 5mmol), n-Butyl Amine 99 (1.83g, 25mmol) and toluene solvant 10g, sealing, put it into the interior stirring reaction of the oil bath that rises to 150 ℃ with 2 hours, be cooled to room temperature, open still, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, weigh 1.10g product N-normal-butyl-N '-(4-chloro-phenyl-) urea, the HPLC purity assay is 99%, calculating productive rate is 96.1%.
Claims (5)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99112869 CN1123565C (en) | 1999-04-22 | 1999-04-22 | Process for preparing unsymmetric phenyl substituted urea |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99112869 CN1123565C (en) | 1999-04-22 | 1999-04-22 | Process for preparing unsymmetric phenyl substituted urea |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1271725A CN1271725A (en) | 2000-11-01 |
| CN1123565C true CN1123565C (en) | 2003-10-08 |
Family
ID=5276119
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99112869 Expired - Fee Related CN1123565C (en) | 1999-04-22 | 1999-04-22 | Process for preparing unsymmetric phenyl substituted urea |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1123565C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201733620A (en) | 2015-12-11 | 2017-10-01 | 國立大學法人靜岡大學 | Oil gelling agent |
-
1999
- 1999-04-22 CN CN 99112869 patent/CN1123565C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1271725A (en) | 2000-11-01 |
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