CN109293530A - Chiral bisamide ester intermediate, chiral double urea ligands and the preparation method and application thereof - Google Patents
Chiral bisamide ester intermediate, chiral double urea ligands and the preparation method and application thereof Download PDFInfo
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- CN109293530A CN109293530A CN201811336664.XA CN201811336664A CN109293530A CN 109293530 A CN109293530 A CN 109293530A CN 201811336664 A CN201811336664 A CN 201811336664A CN 109293530 A CN109293530 A CN 109293530A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/52—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
- C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of chiral bisamide ester intermediates and chiral double urea ligands and preparation method thereof, belong to chemosynthesis technical field.The present invention is first with chirality 1,2- hexichol ethylenediamine and phenyl chloroformate for raw material, and pyridine is catalyst, and using methylene chloride as solvent, high yield prepares bisamide ester intermediate, and then it is reacted synthesising target compound with diisopropylamine in dimethyl sulfoxide.Raw material and catalyst used in the present invention are cheap, substantially reduce synthesis cost, and reaction condition is mildly easily-controllable under the catalyst system, have many advantages, such as that experimental arrangement is simple and effective, avoid many and diverse post processor.The present invention has raw material cheap and easy to get, and post-processing is simple, and to the Small side effects of environment, and gained chiral ligand has potential application in the synthesis of chiral metal catalyst and asymmetric syntheses chemical aspect.
Description
Technical field
The present invention relates to a kind of preparation methods of chiral double urea class ligands, particularly relate to utilize chirality 1,2- hexichol second two
Amine is chiral source, obtains the novel chiral ligands of chiral double urea structures by two-step reaction, it has and metal ligand structure
The advantages that single and stabilization, space orientation effect is good, belong to chemosynthesis technical field.
Background technique
After " reaction stops " event of the sixties in last century occurs, the chiral compound of people has more deep and complete
The understanding in face, and the synthesis and separation of chiral compound have further research.Wherein, not by chiral catalyst catalysis
Symmetric response, synthesis of chiral substance are to obtain the main means of chipal compounds.The design of chiral catalyst synthesizes then to or not
Claim reaction that there is decisive role.Common chiral ligand mainly has following a few classes: chiral organophosphor ligand, chiral double hydroxyls are matched
Body, chiral nitrogen-containing ligands and chiral nitrogen phosphorus ligand etc..Wherein most species of chiral nitrogen-containing ligands and locating effect is relatively
It is good, it has been widely used in many asymmetry organic synthesis reaction (Ryken, S.A.；Schafer,L.L.Acc.Chem.
Res.2015,48,2576-2586；Kobayashi,S.；Sugiura,M.；Kitagawa,H.；Lam,W.W.-
L.Chem.Rev. 2002,102,2227-2302).Although people have carried out relevant grind to the synthesis of urea class ligand
Study carefully work (DiPucchio, R.C.；S.C.；Schafer,L.L.Angew.Chem.Int.Ed.2018,57,3469-
3472), but the research about chiral double urea ligands is there is not yet document report.
Chiral double urea ligands are to be connected two urea derivatives with same or similar structure using chiral source
Come, locating effect can be played using the big steric hindrance of chiral source by having the advantage that, two urea structures spaces are mutually made
The selectivity of reaction about can be improved, big seeking group will be especially introduced on terminal nitrogen atom and can be greatly improved and is entirely matched
The spatial selectivity of body, and then improve the stereoselectivity of asymmetric reaction；Two nitrogen-atoms of urea itself can with metal at
Key, can also be coordinated in the form of amide from metal and other nitrogen-atoms plays space orientation by the different group of connection and makees
With.People have carried out certain research work to urea ligand in recent years, but the research of chiral urea ligand, especially hand
Property double urea ligand research be still in the starting stage, therefore the double urea ligands of synthesis of chiral have the synthesis of chipal compounds
It is of great significance.
Summary of the invention
The present invention preferably 1,2- hexichol ethylenediamine is chiral source, is obtained most preferably by the comparison to three different synthetic routes
Chiral ligand synthetic method.Experiment is found, organic solvent such as toluene, methanol, three chloromethanes are selected in the synthesis of chiral ligand
Alkane or ethyl alcohol etc., reaction effect is bad, is difficult high yield and obtains product and have certain side effect to environment.Using dimethyl sulfoxide
For solvent, reaction yield is relatively preferable, and avoids complicated post-processing problem.
The present invention is divided into the synthesis of two steps, first mixes 1,2- hexichol ethylenediamine and phenyl chloroformate in methylene chloride,
Controlling reaction temperature is 0 DEG C or so reaction, and suitable pyridine is added as catalyst, can obtain bisamide phenyl ester with high yield
Intermediate, and the property stabilization of intermediate is conducive to subsequent operation.Then by separation product and diisopropylamine in diformazan Asia
It is mixed in sulfone and is incorporated in stirring 4-6 hours under room temperature, then the target product of available preferable yield.In addition, this research was once
It attempts to replace phenyl chloroformate using ethyl chloroformate, discovery can obtain intermediate product with high yield, but in subsequent reaction
In only low-yield obtain target product, and be easy to generate intractable g., jelly-like compound in last handling process, especially
It is to be hardly obtained target product using methylene chloride and chloroform as when solvent.Then we are by consulting text
It offers and utilization (BOC) has also been attempted2O replaces phenyl chloroformate to carry out the synthesis of chiral ligand, it is found that single step reaction hardly results in mesh
Product is marked, tracing it to its cause be that group with imine moiety has reactivity more higher than chiral diamine, and then generates symmetrical configuration
Single urea compounds, therefore chiral source cannot participate in reacting, and the purpose of synthesis of chiral ligand is not achieved.
To sum up, the present invention synthesizes centre by reacting with phenyl chloroformate with chirality 1,2- hexichol ethylenediamine for chiral source
Compound, and then it is obtained into chiral double urea ligands with the higher diisopropyl imine reaction of activity, program raw material is cheap
It is easy to get, synthesis step is simple and effective, and the double urea ligands of synthesis of chiral of energy high yield, has good use value and reference
Meaning.
Further: the present invention relates to a kind of preparation methods of chiral double urea ligands comprising following steps:
(1) preparation of chiral bisamide ester intermediate:
In the flask of 100ml, by 10mmol1,2- hexichol ethylenediamine is dissolved in 50mL methylene chloride, controls mixture temperature
Degree is 0 DEG C or so, and pyridine is added dropwise into reaction mixture, 20mmol phenyl chloroformate is then added dropwise, is warming up to wait be added dropwise
It is stirred at room temperature 4-6 hours.TLC tracks reaction process, to after the reaction was completed, 1molL be added-1Hydrochloric acid 20mL, then will be organic
1molL is mutually used respectively-1Hydrochloric acid 20mL, saturated common salt water washing, organic phase is dry with anhydrous sodium sulfate, and solvent is spin-dried for, is obtained
To intermediate product without further purification, purity is greater than 95%；
(2) synthesis of chiral double urea ligands:
3.25mmol intermediate product is dissolved in 10mL dimethyl sulfoxide, 16.25mmol dimethyleneimine syringe is careful
It is added dropwise, after being added dropwise to complete, is stirred at room temperature until there is white precipitate precipitation, methylene chloride 30mL is added into reaction system, it will
Organic phase uses 1molL respectively-1Hydrochloric acid 50mL, water 50mL, 1molL-1Sodium hydroxide 50mL and saturated salt solution 50mL wash
It washs, organic phase is dry with anhydrous sodium sulfate, obtains crude product, and obtaining white crystal by ethyl alcohol recrystallization is sterling.
It is original with 1,2- hexichol ethylenediamine and phenyl chloroformate in a kind of preparation method of above-mentioned chiral double urea ligands
Material, and 1,2- hexichol ethylenediamine and phenyl chloroformate the mass ratio of the material are 1:2, pyridine are catalyst, and pyridine catalyst dosage
Only substrate 10mol%, carries out reaction synthesizing amide ester intermediate in methylene chloride, and the synthesis yield of intermediate is higher and not
Need complicated post processor.In addition, only needing to react at room temperature in ligand synthesis, ligand synthetic reaction will avoid as far as possible
The generation of by-product.
Preferably, above-mentioned intermediate preparation reaction temperature is 0-25 DEG C.
A kind of chiral double urea ligands are synthesized in the synthesis of chiral metal organic compound and asymmetry catalysis in the present invention
Chemical aspect has potential application.
Excellent beneficial effect of the invention is as follows:
1, raw material and catalyst are cheap and easy to get, and experimental arrangement less pollution, experimental implementation is simple and effective, and product is easily purified,
With very high practical value and academic significance.
2, the reaction only needs pyridine as catalyst, and reaction condition is mildly easily-controllable, and reaction yield is high, after simple
Reason can obtain product.
3, the reaction carries out in methylene chloride and dimethyl sulfoxide respectively, can be obtained by the reaction condition not higher than room temperature
To target product, the validity of Atom economy, combined coefficient is embodied.
4, the double urine of pure chirality can be obtained only by simple recrystallization operation in chiral double urea ligands in the reaction
Plain ligand.
5, chiral double urea ligands prepared by the present invention, chemical property is stablized, in the synthesis of chiral metal organic compound
It is had potential application with asymmetry catalysis synthesis chemical aspect.
Specific embodiment
Below with reference to embodiment, the present invention is further described.
Embodiment:
By 10mmol1,2- hexichol ethylenediamine is dissolved in the flask of 50mL methylene chloride, and control mixture temperature is 0 DEG C of left side
The right side, then pyridine is added dropwise in reaction mixture, and pyridine dosage is only substrate 10mol%, then by phenyl chloroformate 20
Mmol is added drop-wise in reaction system, is stirred at room temperature 4-6 hours wait be added dropwise to be warming up to.TLC tracking test process, wait react
1molL is added in Cheng Hou-1Hydrochloric acid 20mL, then organic phase is used into 1molL respectively-1Hydrochloric acid 20mL, saturated salt solution 20mL washes
It washs and dry with anhydrous sodium sulfate, solvent is spin-dried for, obtain the higher white intermediate product of purity without further purification, yield
It is 90%, purity is greater than 95%.
Product confirmation:
White solid；1HNMR(CDCl3,400MHz,ppm):δ7.42-7.46(m,2H,ArH),7.28-7.38(m,10H,
), ArH 7.14-7.22 (m, 8H, ArH), 6.18 (br, s, 2H, NH), 5.15 (d, J=3.6Hz, 2H, CH)；13C NMR
(CDCl3,100MHz,ppm):δ154.9,151.4,151.3,143.6,129.6,129.5,129.0,128.5,128.3,
126.6, 126.4,126.1,125.6,125.4,121.5,121.4,121.0,63.3；Anal.Calc.for C28H24N2O4
(452.17):C 74.32,H 5.35,N 6.19；Found:C 74.20,H 5.51,N 5.88.
3.25mmol intermediate product is dissolved in 10mL dimethyl sulfoxide, 16.25mmol dimethyleneimine syringe is careful
It is added dropwise, after being added dropwise to complete, is stirred at room temperature until there is white precipitate precipitation, methylene chloride 30mL is added into reaction system, it will
Organic phase uses 1molL respectively-1Hydrochloric acid 50mL, water 50mL, 1molL-1Sodium hydroxide 50mL and saturated salt solution 50mL wash
It washs, and dry by anhydrous sodium sulfate, obtains crude product, and obtaining white crystal by ethyl alcohol recrystallization is sterling.
Product confirmation:
Light yellow solid powder；1H NMR(CDCl3,400MHz,ppm):δ7.31-7.37(m,6H,ArH),7.21-7.27
(m, 4H, ArH), 5.53 (s, 2H, NH), 5.12 (d, J=9.6Hz, 2H, CH), 3.34-3.44 (m, 4H, NCH), 1.48 (d, J
=6.4Hz, 12H, CH3), 1.35 (d, J=6.8Hz, 6H, CH3), 1.10 (d, J=5.6Hz, 6H, CH3)；13C NMR
(CDCl3,100MHz,ppm):δ156.6,143.6,128.7,128.6,128.4,128.3,126.5,126.4,62.9,
56.7, 20.6；Anal.Calc.for C28H42N4O2(466.34):C 72.07,H 9.07,N 12.01；Found:C
71.89,H 8.87,N 12.32。
Claims (4)
1. a kind of chirality bisamide ester intermediate and chiral double urea ligands, structural formula is as shown in formula 1, formula 2:
2. a kind of preparation method of chiral double urea ligands, it is characterized in that the following steps are included:
(1) preparation of chiral bisamide ester intermediate:
By 10mmol1,2- hexichol ethylenediamine is dissolved in the flask of the methylene chloride containing 50mL, and control mixture temperature is 0 DEG C or so,
The pyridine of 10mol% is added dropwise in the reaction mixture again, 20mmol phenyl chloroformate is carefully then added drop-wise to reactant
It in system, is warmed to room temperature, reacts about 4-6 hours wait be added dropwise；TLC tracking test process, to after the reaction was completed, 1molL be added-1
Hydrochloric acid 20mL, extract organic phase, then it used into 1molL respectively-1Hydrochloric acid 20mL, saturated salt solution 20mL washing, separate
It is dry with anhydrous sodium sulfate to organic phase, solvent is spin-dried for, the white intermediate product carboxylic acid amide esters that purity is greater than 95% are obtained；
(2) preparation of chiral double urea ligands:
3.25mmol intermediate amide ester is dissolved in 10mL dimethyl sulfoxide, by the dimethyleneimine syringe of 16.25mmol
It is slowly added dropwise, after being added dropwise to complete, is stirred at room temperature until there is white precipitate precipitation, methylene chloride is added into reaction system
Organic phase is used 1molL by 30mL respectively-1Hydrochloric acid 50mL, water 50mL, 1molL-1Sodium hydroxide 50mL and saturated salt solution
50mL washing obtains the drying of organic phase anhydrous sodium sulfate, obtains crude product, and obtain white crystal i.e. by ethyl alcohol recrystallization
For sterling.
3. the preparation method of a kind of chiral double urea ligands as claimed in claim 2, it is characterized in that the preparation of above-mentioned intermediate is anti-
Answering temperature is 0-25 DEG C.
4. a kind of double urea ligands of chirality described in claim 1 are closed in the synthesis of chiral metal organic compound and asymmetry catalysis
There is potential application at chemical aspect.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3541260A1 (en) * | 1985-11-22 | 1987-05-27 | Bayer Ag | N- (4-TERT.-BUTOXY-PHENYL) UREAS |
| CA2215585C (en) * | 1996-09-17 | 2004-04-20 | Boehringer Ingelheim (Canada) Ltd. | Practical synthesis of urea derivatives |
| CN103293176A (en) * | 2013-05-21 | 2013-09-11 | 中国科学院福建物质结构研究所 | Method for measuring optical purity of chiral carboxylic acid |
| CN103880737A (en) * | 2014-02-27 | 2014-06-25 | 浙江泰达作物科技有限公司 | Preparation method of 1-(2-chloro-4-pyridyl)-3-phenylurea |
| CN103880738A (en) * | 2014-02-27 | 2014-06-25 | 浙江泰达作物科技有限公司 | Preparation method of 1-(2-chloro-4-pyridyl)-3-phenylurea |
-
2018
- 2018-11-12 CN CN201811336664.XA patent/CN109293530A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3541260A1 (en) * | 1985-11-22 | 1987-05-27 | Bayer Ag | N- (4-TERT.-BUTOXY-PHENYL) UREAS |
| CA2215585C (en) * | 1996-09-17 | 2004-04-20 | Boehringer Ingelheim (Canada) Ltd. | Practical synthesis of urea derivatives |
| CN103293176A (en) * | 2013-05-21 | 2013-09-11 | 中国科学院福建物质结构研究所 | Method for measuring optical purity of chiral carboxylic acid |
| CN103880737A (en) * | 2014-02-27 | 2014-06-25 | 浙江泰达作物科技有限公司 | Preparation method of 1-(2-chloro-4-pyridyl)-3-phenylurea |
| CN103880738A (en) * | 2014-02-27 | 2014-06-25 | 浙江泰达作物科技有限公司 | Preparation method of 1-(2-chloro-4-pyridyl)-3-phenylurea |
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| BOUNKHAM THAVONEKHAM等: ""A Practical Synthesis of Ureas from Phenyl Carbamates"", 《SYNTHESIS》 * |
| DAVID C. LEITCH等: ""Zirconium Alkyl Complexes Supported by Ureate Ligands: Synthesis, Characterization, and Precursors to Metal-Element Multiple Bonds"", 《ORGANOMETALLICS》 * |
| F. TOUCHARD等: ""Ureas and thioureas as Rh-ligands for the enantioselective hydride transfer reduction of acetophenone"", 《JOURNAL OF MOLECULAR CATALYSIS A: CHEMICAL》 * |
| PATRICK GAMEZ等: ""Homogeneous and Heterogeneous Pd-catalyzed Enantioselective Alkylation with C2-symmetric Chiral Nitrogen Ligands"", 《TETRAHEDRON: ASYMMETRY》 * |
| TATSUYA SHONO等: ""A Novel Method for Stereqselective Synthesis of (IR,2R)-Diarylethylenediamines by Reductive Intramolecular Coupling of Aromatic Diimines"", 《TETRAHEDRON LETTERS》 * |
| 刘先勤: ""芳香脲类化合物的合成及其在醇中稳定性研究"", 《中国优秀硕士学位论文全文数据库工程科技I辑》 * |
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