CN109824600B - Method for synthesizing chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine compound - Google Patents
Method for synthesizing chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine compound Download PDFInfo
- Publication number
- CN109824600B CN109824600B CN201711181516.0A CN201711181516A CN109824600B CN 109824600 B CN109824600 B CN 109824600B CN 201711181516 A CN201711181516 A CN 201711181516A CN 109824600 B CN109824600 B CN 109824600B
- Authority
- CN
- China
- Prior art keywords
- palladium
- chiral
- catalyst
- ligand
- cyclic urea
- 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.)
- Active
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a method for synthesizing chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine compounds,
in the formula: r is hydrogen, alkyl or aryl of C1-C6; r' is aryl, heteroaryl or alkyl containing substituent, and the substituent on the aryl or heteroaryl is F, Cl or CF3One substituent or two substituents or three substituents in Me and MeO; the chiral cyclic urea is synthesized by asymmetrically hydrogenating the 2-hydroxypyrimidine compound by adopting a cheap and easily-obtained palladium catalyst with stable air, and the enantiomeric excess of the chiral cyclic urea can reach 94%. The method has the advantages of simple, convenient, practical and feasible operation, high yield, environmental friendliness, greenness, mild reaction conditions and potential practical application value.
Description
Technical Field
The invention relates to a method for synthesizing chiral cyclic urea by catalyzing asymmetric hydrogenation of a 2-hydroxypyrimidine compound with high enantioselectivity by using a palladium catalysis system.
Background
The asymmetric hydrogenation of aromatic heterocyclic compounds has been greatly developed in recent years. Various heteroaromatic compounds such as: isoquinoline, pyridine, quinoline, pyrazine and the like can all obtain corresponding heterocyclic compounds through asymmetric catalysis, wherein the corresponding heterocyclic compounds can be obtained through asymmetric catalysis (refer to the first publication, (a) Lu, S.M.; Wang, Y.Q.; Han, X.W.; Zhou, Y.G.Angew.chem.Int.Ed.2006, 45,2260.(b) Ye, Z-S.; Chen, M.W.; Chen, Q.A.; Shi L.; Duan, Y.; Zhou, Y.G.Angew.chem.Int.Ed.2012, 51,10181.(c) Wang, W.B.; Lu S.M.; Yang, P.Y.; Han, X.W.; Zhou Y.J.am.Soc.; Lu S-M.; Yang.P.Y.; Han, X.W.; Zhou Y.J.C.; Chen J.S.125, W.; W.M.I.E.E.E.E.E.E.D.; F.; W.E.E.I.; F.E.E.I.I.52, W.; F.; F.I.I. F.; F.I.I.I.I.. The challenges are: firstly, aromatic compounds have strong stability and generally require relatively harsh conditions to react, and the enantioselectivity of the reaction is difficult to control under the conditions; secondly, the aromatic heterocyclic compound usually contains heteroatoms which are easy to coordinate with the catalyst, such as nitrogen, oxygen, sulfur and the like, and is easy to cause catalyst poisoning and inactivation; and thirdly, secondary coordination groups are usually lacking in the aromatic compounds, which is not favorable for the action of substrates and catalysts. If a functional group (such as hydroxyl, sulfydryl, amino and the like) with potential isomerization is introduced into the ortho position of the aromatic heterocyclic nitrogen, the aromaticity, the chemical activity, the biological property and the like of the aromatic compound are obviously influenced. It is worth mentioning that when hydroxyl group is introduced at position 2 of pyrimidine, there is an isomerization equilibrium of alcoholic and ketone type, in protic solvents, the isomerization equilibrium system is mostly ketone type, when acidic condition exists in the system, the proportion of ketone type structure is larger than the percentage of alcoholic structure, on the other hand, the aromatic character of ketone type structure is reduced compared to alcoholic structure, thus improving the activity of substrate to some extent, and we speculate that this type of substrate is easier to be hydrogenated in palladium catalytic hydrogenation system.
In 2015, the Glorius group developed a ruthenium/N-heterocyclic carbene complex to catalyze the hydrogenation of pyridone substrates, which gave cyclic lactams in excellent yields, but with poor enantioselectivity (ref: Wysocki, J.; Schlephorst, C.; Glorius. F. Synlett.2015,26,1557.);
subsequently, the week group successfully achieved palladium-catalyzed asymmetric hydrogenation of 3-hydroxypyrazole using a palladium catalytic system with good results, but the substrate range was limited to fluorine-containing compounds (reference three: Chen, Z. -P.; Chen, M. -W.; Shi, L.; Yu, C. -B.; Zhou, Y. -G.Chem.Sci.2015,6,3415.).
Disclosure of Invention
The invention aims to provide a method for synthesizing a chiral cyclic urea compound by palladium-catalyzed asymmetric hydrogenation of a 2-hydroxypyrimidine compound, and the technical scheme adopted by the invention is as follows: a method of synthesizing a chiral cyclic urea, characterized by: catalyzing the asymmetric hydrogenation of a 2-hydroxypyrimidine compound to prepare the catalyst, wherein the catalyst is a complex of a palladium metal precursor and a chiral ligand;
in the formula:
r is hydrogen, alkyl or aryl of C1-C6;
r' is aryl, heteroaryl or alkyl containing substituent groups;
the substituent is F, Cl, Br, CF3At least one of Me and MeO.
Preferably the process comprises two stages:
(1) catalyst preparation
Mixing a palladium metal precursor, a chiral ligand and an organic solvent, stirring at normal temperature for 15-30 minutes, and removing the solvent under reduced pressure to obtain a catalyst;
(2) asymmetric hydrogenation reaction
Adding the obtained catalyst, additive and organic solvent into a 2-hydroxypyrimidine substrate, neutralizing, transferring into an autoclave, charging hydrogen gas at 400-1200 psi, and stirring at 40-100 ℃ for 12-24 hours to obtain the product.
The palladium metal precursor is preferably selected from palladium acetate or palladium trifluoroacetate.
The organic solvent is preferably at least one selected from the group consisting of toluene, dichloromethane, methanol, trifluoroethanol, ethanol, and tetrahydrofuran.
The additive is preferably one selected from benzoic acid, p-toluenesulfonic acid monohydrate, (D) -camphorsulfonic acid, and (L) -camphorsulfonic acid.
Preferably, the chiral ligand is a chiral diphosphine ligand. The chiral diphosphine ligand is selected from (1R,1 'R, 2S, 2' S) -DuanPhos, (S, S) -MeDuPhos, (R) -DifluorPhos, (R) -SynPhos, (R) - (S) -PPF-PtBu2,(R)-(S)-Cy2PF-PtBu2(R) - (S) -JosiPhos, more preferably a bisphosphine ligand: (R) - (S) -PPF-PtBu2And (R) - (S) -JosiPhos.
Preferably, the feeding proportion of the method is as follows: the molar ratio of palladium trifluoroacetate to chiral ligand to additive to substrate is as follows: 0.01-0.05: 0.011-0.055: 0.05-0.20: 1.
Advantageous effects
The method adopts the cheap and easily-obtained palladium catalyst with stable air to synthesize the chiral cyclic urea by the asymmetric hydrogenation of the 2-hydroxypyrimidine compound, has the advantages of simple, convenient, practical and feasible operation, high yield, environmental friendliness, greenness, mild reaction conditions and potential practical application value:
1. the reaction system is clean, the enantioselectivity of the product is good, and the chiral cyclic urea compound can be obtained with 94% enantioselectivity;
2. the catalyst is convenient to prepare, cheap, stable in air, and simple and practical in reaction operation;
3. the hydrogenation reaction condition is mild, clean, green and good in atom economy.
Detailed Description
The present invention will be described in detail by way of examples, which are given as alternatives, but are not limited thereto.
The catalyst is a complex of a palladium metal precursor and a diphosphine ligand. Both palladium metal precursors and bisphosphine ligands are commercially available and do not require any treatment.
Examples 1 to 11: optimization of mono-substituted substrate hydrogenation reaction conditions
Putting palladium trifluoroacetate (1 mol% -5 mol% of substrate dosage) and chiral diphosphine ligand (1.1 mol% -5.5 mol% of substrate dosage) into a reaction bottle, adding an organic solvent (1.0-4.0mL) after nitrogen replacement, stirring at room temperature for 30 minutes, removing the organic solvent under reduced pressure, transferring the catalyst into the reaction bottle in which the substrate 1a (0.2mmol) and an additive (5 mol% -20 mol% of substrate dosage) are placed in advance by using the organic solvent (1.0-2.0mL), transferring the reaction bottle into a reaction kettle, introducing hydrogen (400psi-1200psi), and reacting at 40-100 ℃ for 24 hours; releasing hydrogen, removing the solvent, and directly performing column chromatography separation to obtain a target product, wherein the reaction formula and the ligand structure are as follows:
note: in the formula, Pd (OCOCF)3)2Palladium trifluoroacetate, chiral ligand, Additive and SolventIs a solvent.
The yield was the conversion, the enantiomeric excess of the product was determined by chiral liquid chromatography and is detailed in table 1.
TABLE 1 asymmetric hydrogenation optimization of 2-hydroxypyrimidine 1aa
Examples 12 to 17: synthesis of chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine
Palladium trifluoroacetate (3.0 mol% of substrate) and (R) - (S) -PPF-P were put into a reaction flasktBu2(3.3 mol% of the amount of the substrate), replacing with nitrogen, adding an organic solvent (1.0mL), and stirring at room temperature for 30 minutes; removing the solvent under reduced pressure, transferring the solution into an ampoule with a substrate 1(0.3mmol) and benzoic acid (10 mol%) by using an organic solvent (3.0mL), transferring the ampoule into a reaction kettle, introducing hydrogen (1000psi), and reacting at 80 ℃ for 24 hours; releasing hydrogen, removing the solvent, and directly performing column chromatography separation to obtain a pure product, wherein the reaction formula is as follows:
note: in the formula, Pd (OCOCF)3)2Is palladium trifluoroacetate, chiral ligand is chiral ligand, PhCO2H is benzoic acid and TFE is trifluoroethanol.
The yields were isolated and the enantiomeric excess of the product was determined by chiral liquid chromatography, see table 2.
TABLE 2 Synthesis of chiral Cyclic Urea 2 by Palladium catalyzed asymmetric hydrogenationa
112.8,111.2,54.8,54.4,37.81,29.9.
CD2Cl2)158.9,143.9,130.1,129.2,127.6,56.8,47.8,41.7,22.9.
Claims (6)
1. A method of synthesizing a chiral cyclic urea, characterized by: catalyzing the asymmetric hydrogenation of a 2-hydroxypyrimidine compound to prepare the catalyst, wherein the catalyst is a complex of a palladium metal precursor and a chiral ligand;
in the formula:
r is hydrogen;
r' is aryl, heteroaryl or alkyl containing substituent groups;
the substituent is F, Cl, Br, CF3At least one of Me and MeO;
the palladium metal precursor is selected from palladium acetate or palladium trifluoroacetate;
the additive is one of benzoic acid, p-toluenesulfonic acid monohydrate, (D) -camphorsulfonic acid and (L) -camphorsulfonic acid.
2. The method of claim 1, wherein: the method comprises two stages:
(1) catalyst preparation
Mixing a palladium metal precursor, a chiral ligand and an organic solvent, stirring at normal temperature for 15-30 minutes, and removing the organic solvent under reduced pressure to obtain a catalyst;
(2) asymmetric hydrogenation reaction
Adding the obtained catalyst, additive and organic solvent into a 2-hydroxypyrimidine substrate, transferring the substrate into a high-pressure kettle, filling hydrogen gas at 400-1200 psi, and stirring at 40-100 ℃ for 12-24 hours to obtain the product.
3. The method of claim 2, wherein: the organic solvent is at least one selected from the group consisting of toluene, dichloromethane, methanol, trifluoroethanol, ethanol and tetrahydrofuran.
4. The method of claim 1 or 2, wherein: the chiral ligand is a chiral diphosphine ligand.
5. The method of claim 4, wherein: the chiral diphosphorus ligand is selected from (1)R,1’R,2S,2’S)-DuanPhos, (S,S)-MeDuPhos, (R)-DifluorPhos, (R)-SynPhos, (R)-(S)-PPF-P t Bu2,(R)-(S)-Cy2PF-P t Bu2, (R)-(S)-JosiPhos。
6. The method of claim 1, wherein: the method comprises the following feeding proportions: the mole ratio of the palladium metal precursor, the chiral ligand, the additive and the 2-hydroxypyrimidine compound is as follows: 0.01-0.05: 0.011-0.055: 0.05-0.20: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711181516.0A CN109824600B (en) | 2017-11-23 | 2017-11-23 | Method for synthesizing chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711181516.0A CN109824600B (en) | 2017-11-23 | 2017-11-23 | Method for synthesizing chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109824600A CN109824600A (en) | 2019-05-31 |
| CN109824600B true CN109824600B (en) | 2020-10-02 |
Family
ID=66858575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711181516.0A Active CN109824600B (en) | 2017-11-23 | 2017-11-23 | Method for synthesizing chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109824600B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112574014B (en) * | 2019-09-29 | 2022-03-11 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral beta-hydroxy ketone by palladium-catalyzed asymmetric reduction |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838522A (en) * | 2011-06-21 | 2012-12-26 | 中国科学院大连化学物理研究所 | Chiral pyrroline synthetic method by palladium-catalyzed asymmetric hydrogenation |
| CN104710406A (en) * | 2013-12-13 | 2015-06-17 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by iridium |
| WO2015142001A2 (en) * | 2014-03-21 | 2015-09-24 | 충남대학교산학협력단 | Compound having cardiotonic activity and pharmaceutical composition for preventing or treating heart failure, containing same |
| CN105017150A (en) * | 2014-04-23 | 2015-11-04 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclohexanediamine through asymmetric hydrogenation of palladium-catalyzed quinoline-3-amine |
| CN105859622A (en) * | 2015-01-22 | 2016-08-17 | 中国科学院大连化学物理研究所 | Method for palladium-catalysis asymmetric hydrogenation synthesis of chiral fluorinated pyrazolone derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2803298A1 (en) * | 1999-12-30 | 2001-07-06 | Adir | NOVEL LINEAR OR CYCLIC UREAS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
2017
- 2017-11-23 CN CN201711181516.0A patent/CN109824600B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838522A (en) * | 2011-06-21 | 2012-12-26 | 中国科学院大连化学物理研究所 | Chiral pyrroline synthetic method by palladium-catalyzed asymmetric hydrogenation |
| CN104710406A (en) * | 2013-12-13 | 2015-06-17 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclic amine through catalyzing asymmetric hydrogenation of quinolin-3-amine by iridium |
| WO2015142001A2 (en) * | 2014-03-21 | 2015-09-24 | 충남대학교산학협력단 | Compound having cardiotonic activity and pharmaceutical composition for preventing or treating heart failure, containing same |
| CN105017150A (en) * | 2014-04-23 | 2015-11-04 | 中国科学院大连化学物理研究所 | Method for synthesizing chiral cyclohexanediamine through asymmetric hydrogenation of palladium-catalyzed quinoline-3-amine |
| CN105859622A (en) * | 2015-01-22 | 2016-08-17 | 中国科学院大连化学物理研究所 | Method for palladium-catalysis asymmetric hydrogenation synthesis of chiral fluorinated pyrazolone derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109824600A (en) | 2019-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5923105B2 (en) | Chiral spiro-pyridylamidophosphine ligand compound, synthesis method thereof and use thereof | |
| Wang et al. | Asymmetric Lewis acid catalysis directed by octahedral rhodium centrochirality | |
| Yang et al. | A palladium-catalyzed enantioselective addition of arylboronic acids to cyclic ketimines | |
| JP5685071B2 (en) | Novel ruthenium complex and method for producing optically active alcohol compound using the same as catalyst | |
| CN103059064B (en) | Chiral diphosphine ligand and chiral catalyst and preparation, application method | |
| Mechler et al. | Homo-and Heterobimetallic Pd–, Ag–, and Ni–Hybrid Salen–Bis-NHC Complexes | |
| JP4426012B2 (en) | Process for the enantioselective hydrogenation of homogeneous ester and acid compounds and use of hydrogenation products | |
| Genoni et al. | Synthesis of an advanced precursor of Rivastigmine: Cinchona-derived quaternary ammonium salts as organocatalysts for stereoselective imine reductions | |
| CN102030721B (en) | Method for synthesizing chiral benzosultam via palladium-catalytic asymmetric hydrogenation | |
| US20140187809A1 (en) | Novel ruthenium complex and process for producing optically active alcohol compound using same as catalyst | |
| Makra et al. | Achiral amine additives in the enantioselective hydrogenation of aliphatic α, β-unsaturated acids over cinchonidine-modified Pd/Al2O3 catalyst | |
| CN109824600B (en) | Method for synthesizing chiral cyclic urea by palladium-catalyzed asymmetric hydrogenation of 2-hydroxypyrimidine compound | |
| EP1867654A1 (en) | Process for production of optically active quinuclidinol | |
| JP5276093B2 (en) | Method for producing optically active amino alcohol compound | |
| CN102336698A (en) | Method for synthesizing chiral indoline through palladium-catalyzed asymmetric hydrogenation | |
| CN101260085B (en) | Catalytic asymmetric hydrogenation synthesis method for chiral gamma-sultam | |
| JP2013526493A (en) | Process for the hydrogenation of ketoesters | |
| CN114685461A (en) | Crown ether-containing chiral o-diamine compound, transition metal complex and chiral biaryl compound, and preparation method and application thereof | |
| CN109824601B (en) | Method for synthesizing chiral cyclic urea through asymmetric hydrogenation of iridium-catalyzed 2-hydroxypyrimidine compound | |
| Jin et al. | Synthesis of BINAP ligands with imidazole tags for highly enantioselective Ru-catalyzed asymmetric hydrogenation of β-keto esters in ionic liquid systems | |
| CN113979982A (en) | Preparation method and application of chiral dihydrochromone-2-carboxylic acid compound and derivative thereof | |
| CN109574867B (en) | Method for synthesizing chiral tertiary amine by asymmetric hydrogenation of ruthenium-catalyzed arylamine compound | |
| CN113527367A (en) | Chiral diphosphine ligand rhodium complex containing tetra (3, 5-bistrifluoromethylphenyl) boron anion and preparation method and application thereof | |
| CN113979983A (en) | Asymmetric synthesis method of fidarestat key intermediate | |
| JP5507931B2 (en) | Method for producing optically active alcohol having aromatic heterocycle |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |