CN110551033B - Method for preparing chiral amine through asymmetric reductive amination of ketone - Google Patents
Method for preparing chiral amine through asymmetric reductive amination of ketone Download PDFInfo
- Publication number
- CN110551033B CN110551033B CN201810547088.7A CN201810547088A CN110551033B CN 110551033 B CN110551033 B CN 110551033B CN 201810547088 A CN201810547088 A CN 201810547088A CN 110551033 B CN110551033 B CN 110551033B
- Authority
- CN
- China
- Prior art keywords
- chiral
- amine
- ketone
- reductive amination
- asymmetric reductive
- 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
Classifications
-
- 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
- B01J31/22—Organic complexes
- B01J31/2282—Unsaturated compounds used as ligands
- B01J31/2295—Cyclic compounds, e.g. cyclopentadienyls
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/06—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid
- C07C227/08—Formation of amino groups in compounds containing carboxyl groups by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid by reaction of ammonia or amines with acids containing functional groups
-
- 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
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4277—C-X Cross-coupling, e.g. nucleophilic aromatic amination, alkoxylation or analogues
-
- 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
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/827—Iridium
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for preparing chiral amine by asymmetric reductive amination of ketone, which takes a complex prepared in situ by reacting a chiral phosphine-phosphoramidite ligand with a metal iridium precursor as a catalyst, and prepares the chiral amine by direct asymmetric reductive amination of the ketone and the amine. The ligand of the invention has simple preparation, low catalyst consumption and simple and convenient operation, can realize continuous operation, is suitable for preparing chiral amine on a large scale, has the enantiomeric excess value of the product of more than 80 percent, and can meet the requirement of being used as a pesticide intermediate. The invention has better result for 500000 of 2-ethyl-6-methylaniline/catalyst (S/C) in the synthesis of the metolachlor intermediate, reaches 95 percent of yield and 80 percent of enantioselectivity, and has good industrial practicability.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing chiral amine through asymmetric reductive amination of ketone.
Background
Chiral amine compounds are important organic synthetic intermediates useful in the preparation of a variety of natural and unnatural compounds having biological activity. In recent years, the main methods for synthesizing chiral amines include asymmetric hydrogenation and asymmetric reductive amination of imines, enamines. The asymmetric reductive amination is a green, environment-friendly and efficient method for synthesizing the chiral amine compound. It is prepared through the direct reaction of ketone compound and amine source in the presence of chiral catalyst and other assistant to produce chiral amine compound. The reaction omits the step of preparing imine or enamine intermediate in asymmetric hydrogenation, and improves the yield of chiral amine and the atom economy of the reaction.
In 1999, Hans-Peter Jalett (Jalett H.P., Spindler F., Hanreich R.G.US5886225[ P ],1999) and others successfully catalyzed asymmetric hydrogenation of imine by ferrocene diphosphine ligand to synthesize chiral metolachlor, attempted to react 2-methoxy acetone with 2-ethyl-6-methylaniline, catalyzed by Ir-Xyl iPhos to obtain chiral metolachlor, and obtained 99% yield and 76% enantioselectivity. This is the first success of an asymmetric reductive amination reaction in the true sense. However, since the substrate ketone can be reduced into the corresponding alcohol, the substrate amine or chiral amine product can be complexed with the transition metal, thereby inhibiting the catalytic activity of the catalyst; because the dosage of the catalyst is 100 times of that of the catalyst for the asymmetric reduction of the imine, the method for the asymmetric reduction of the imine is adopted in the industrial production. But the research results of the chiral amine compound create a new reaction idea for the synthesis of the chiral amine.
In 2003, Yongxiang CHi (Y.X.Chi, Y.G.Zhou, X.M.Zhang J.org.chem.2003,68,4120-4122) reported that 4-methoxyaniline as an amine source and aromatic ketone are subjected to direct asymmetric reductive amination reaction, and a chiral alpha-arylamine product can be obtained under the catalysis of Ir- (S, S) -f-Binaphine, wherein the product yield is more than 93%, and the enantioselectivity is up to 96%, however, the catalytic system is not suitable for aliphatic ketone.
Therefore, the development of the catalyst with high activity, high stereoselectivity and wide asymmetric reductive amination applicable to the substrate has very important significance.
Disclosure of Invention
The invention aims to provide a method for preparing chiral amine by catalyzing asymmetric reductive amination of ketone by using an iridium/chiral phosphine-phosphoramidite ligand system.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for preparing chiral amine by asymmetric reductive amination of ketone adopts a chiral catalyst Ir-L, and the ketone and the amine are directly subjected to asymmetric reductive amination to prepare the chiral amine;
the chiral catalyst Ir-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and chiral phosphine-phosphoramidite in a solvent.
A method for preparing chiral amine by asymmetric reductive amination of ketone comprises the following steps:
under the protection of nitrogen, dissolving an iridium-cyclooctadiene complex and a chiral phosphine-phosphoramidite ligand in a solvent, stirring for 10 minutes at room temperature, adding a substrate amine, ketone and an additive which are dissolved in the solvent, placing the mixture in a high-pressure reaction kettle, carrying out hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting for 1-24 hours at 20-100 ℃, slowly releasing the hydrogen, and separating by using a silica gel column after removing the solvent to obtain the product chiral amine.
The solvent is dichloromethane, 1, 2-dichloroethane or toluene;
the additive is isopropyl titanate, ethyl titanate or methyl titanate;
the substrate amine is: r3NH2Wherein R is3Is H, C1～C10Alkyl radical, C3～C12Cycloalkyl radical, C6-C30Aromatic groups with or without N, S, O, P functional groups.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the ketones and the chiral amines produced according to the invention have the following structures:
in the formula:
R1is C1～C10Alkyl radicals such as CH3、CH3CH2Etc. C3～C12Cycloalkyl radicals such as cyclopentyl, cyclohexyl, etc., or C containing one or more functional groups of N, S, O, P1～C10Alkyl such as methoxymethyl, ethoxymethyl, etc., or C containing one or more functional groups of N, S, O, P3～C10Cycloalkyl groups such as 2-tetrahydrofuryl, 4-tetrahydrofuryl, etc.; or aryl or the like C6-C30Aromatic groups such as phenyl, 4-methoxyphenyl, etc., which may or may not contain N, S, O, P, etc.; or ester groups such as COOCH3、COOCH2CH3Etc. of
R2Is H, C1-C40Alkyl or aryl within;
R3is H, C1～C10Alkyl radicals such as CH3、CH3CH2Etc. C3～C12Cycloalkyl radicals, e.g. cyclopentyl, cyclohexyl, etc., or aryl radicals, e.g. C6-C30Aromatic groups containing or not containing N, S, O, P functional groups, such as phenyl, 4-methoxyphenyl, 2-ethyl-6-methylphenyl, 2, 6-dimethylphenyl, and the like.
The phosphine-phosphoramidite ligand related by the invention has the following structure:
in the formula, R1Is H; alkyl and cycloalkyl radicals and the like C1～C40Aliphatic groups with or without functional groups such as N, S, O, P; benzyl radical or the like C7-C60A combination of aromatic groups and aliphatic groups, which may or may not contain N, S, O, P functional groups; aryl radicals and the like C60-C64Aromatic groups with or without functional groups such as N, S, O, P; r2Is H, C7-C60An internal alkyl or aryl group.
Ar is C6-C60Aromatic groups with or without N, S, O, P functional groups.
The X group is: chiral or achiral aliphatic groups with or without functional groups such as N, S, O, P; aromatic groups with or without functional groups such as N, S, O, P; chiral or achiral biphenyl, binaphthyl or tetrahydrobinaphthyl aromatic groups containing or not containing N, S, O, P functional groups.
The iridium-cyclooctadiene complex is: [ Ir (COD) Cl]2、Ir(COD)2BF4Or Ir (COD)2BARF。
The iridium concentration in the reaction system is 0.0001-0.01mol/l, and the molar ratio of the ligand to the iridium is 1-5: 1.
the molar ratio of the amine substrate to the catalyst is 100-500000: 1.
the molar ratio of the amine substrate to the ketone is: 0.5-1.5:1, the molar ratio of amine substrate to additive being 1: 1 to 5.
The invention has the beneficial effects that: compared with other methods for synthesizing chiral amine, the method for synthesizing the chiral phosphine-phosphoramidite ligand for reductive amination for the first time is simple in synthesis, low in price and suitable for kilogram-level production, an iridium/chiral phosphine-phosphoramidite system is high in catalytic activity and enantioselectivity, the enantiomeric excess value (ee value) of a product reaches more than 80%, the reductive amination reaction is simple to operate, mild in condition and high in atom economy, and the method is suitable for industrial production, has a good result that 2-ethyl-6-methylaniline/a catalyst (S/C) is 500000 in the synthesis of the metolachlor intermediate, achieves 95% of yield and 80% of enantioselectivity, and has good industrial practicability.
Detailed Description
The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker NMR and High Performance Liquid Chromatography (HPLC) was measured by Agilent1100 series HPLC. Column for GC analysis: beta-DEX 120.
Example 1
Under the protection of nitrogen gas, [ Ir (COD) Cl]2(0.0025mmol,0.5 mol%), chiral phosphine-phosphoramidite ligand (shown in the above formula) (0.0055mmol,1.1 mol%) was dissolved in toluene (1.0mL), stirred at room temperature for 10 minutes, added with a toluene (1.0mL) solution of the substrates 2, 6-dimethylaniline (0.5mmol) and acetophenone (0.6mol) and 0.2mL isopropyl titanate, placed in an autoclave, replaced with hydrogen for 3 times, and then reacted at 50 ℃ for 12 hours with hydrogen gas to 50 atm. Slowly releasing hydrogen, removing the solvent, and separating by using a silica gel column to obtain the product.
The product was analyzed and the NMR and HPLC data are as follows:
98％yield.97％ee was determined by chiral HPLC(chiralcel OJ-H,n-hexane/i-PrOH＝90/10,1.0mL/min,254nm,40℃):tR(major)＝4.9min,tR(minor)＝5.4min.[α]D 25＝-158(c＝1.42in CHCl3).1H NMR(400MHz,CDCl3):δ＝1.54(d,J＝6.8Hz,3H),2.19(s,6H),3.22(br,1H),4.34(q,J＝6.8Hz,1H),6.81(t,J＝7.2Hz,1H),6.97(d,J＝7.2Hz,2H),7.25-7.27(m,1H),7.31-7.32(m,4H)；13C NMR(100MHz,CDCl3):δ＝19.1,22.9,57.0,121.8,121.9,126.3,126.4,127.1,127.2,128.6,128.7,129.0,129.1,129.6,145.2,145.5。
the detection result shows that the product is as follows: 2, 6-dimethyl-N- (1-phenylethyl) aniline.
Example 2
The reaction conditions in example 1 were changed from chiral phosphine-phosphoramidite ligand to B, and the reaction was performed as in example 1 to obtain 2, 6-dimethyl-N- (1-phenylethyl) aniline with a yield of 98% and an enantioselectivity of 90% ee. Ligand B has the following structure:
example 3
The reaction conditions in example 1 were changed to C for the chiral phosphine-phosphoramidite ligand, and the reaction was performed as in example 1 to give 2, 6-dimethyl-N- (1-phenylethyl) aniline in 98% yield and 80% enantioselectivity. Ligand C has the structure:
example 4
The reaction conditions in example 1 were changed to D for the chiral phosphine-phosphoramidite ligand, and the reaction was performed as in example 1 to obtain 2, 6-dimethyl-N- (1-phenylethyl) aniline with a yield of 98% and an enantioselectivity of 90% ee. Ligand D has the structure:
example 5
The reaction conditions H in example 1 were2The pressure was changed to 20 atmospheres, and the remainder was the same as in example 1, giving 2, 6-dimethyl-N- (1-phenylethyl) aniline in 90% yield and 97% ee enantioselectivity.
Example 6
The substrate to catalyst ratio in example 1 was changed to 1000S/C, i.e.: [ Ir (COD) Cl]2(0.00025mmol,0.05 mol%), chiral phosphine-phosphoramidite ligand (0.00055mmol,0.11 mol%), enantioselectivity of the product 2, 6-dimethyl-N- (1-phenylethyl) aniline obtained by the reaction was 97% ee.
Example 7
The substrate to catalyst ratio in example 1 was changed to S/C10000, i.e.: [ Ir (COD) Cl]2(0.000025mmol,0.005 mol%), chiral phosphine-phosphinidene amide ligand (0.000055mmol,0.011 mol%), reaction conditions H2The pressure was 80 atm, the reaction temperature was 90 ℃ and the reaction time was 36 hours, and the enantioselectivity of the product 2, 6-dimethyl-N- (1-phenylethyl) aniline obtained by the reaction was 93% ee in the same manner as in example 1.
Example 8
The substrate in the example 1 is changed into p-nitroacetophenone, and the reaction is carried out in the same way as the example 1 to obtain the product 2, 6-dimethyl-N- (1- (4-nitrophenyl) ethylideneaniline.
The product was analyzed and the NMR and HPLC data are as follows:
99％yield.96％ee was determined by chiral HPLC(chiralpak AD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(major)＝5.4min,tR(minor)＝7.5min.[α]D 25＝-233(c＝1.90in CHCl3).1H NMR(400MHz,CDCl3):δ＝1.57(d,J＝6.8Hz,3H),2.16(s,6H),3.13(br,1H),4.40(q,J＝6.8Hz,1H),6.81(t,J＝7.2Hz,1H),6.96(d,J＝7.2Hz,2H),7.45(d,J＝8.8Hz,2H),8.15(d,J＝8.8Hz,2H)；13C NMR(100MHz,CDCl3):δ＝19.0,22.9,56.5,122.1,123.6,127.1,129.1,129.3,144.4,146.9,152.9。
example 9
The substrate in example 1 was changed to 3-nitroacetophenone, and the reaction was carried out in the same manner as in example 1 to give 2, 6-dimethyl-N- (1- (3-nitrophenyl) ethylaniline).
The product was analyzed and the NMR and HPLC data are as follows:
98％yield.99％ee was determined by chiral HPLC(chiralpak AD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(minor)＝10.3min,tR(major)＝10.9min.[α]D 25＝-141(c＝1.88in CHCl3).1H NMR(400MHz,CDCl3):δ＝1.58(d,J＝6.8Hz,3H),2.19(s,6H),3.20(br,1H),4.43(q,J＝6.8Hz,1H),6.82(t,J＝7.6Hz,1H),6.97(d,J＝7.6Hz,2H),7.45(t,J＝7.6Hz,1H),7.62(d,J＝7.6Hz,1H),8.10(d,J＝7.6Hz,1H),8.24(s,1H)；13C NMR(100MHz,CDCl3):δ＝19.0,23.0,56.3,121.0,122.0,122.2,129.1,129.3,129.4,132.7,144.3,147.5,148.3。
example 10
The substrate in the example 1 is changed into butanone, and the reaction is carried out in the same way as the example 1 to obtain the product N-isobutyl-2, 6-dimethylaniline.
The product was analyzed and the GC and NMR data are shown below:
94％yield.90％ee was determined by chiral GC(chiralβ-DEX 120column(0.25mm x 30m),column temp.:90℃,carrier gas:N2):tR(major)＝20.1min,tR(minor)＝20.8min.[α]D 25＝-41(c＝0.96in CHCl3).1HNMR(400MHz,CDCl3):δ＝0.98(t,J＝7.2Hz,3H),1.07(d,J＝6.4Hz,3H),1.37-1.44(m,1H),1.58-1.64(m,1H),2.28(s,6H),2.84(br,1H),3.21(q,J＝6.8Hz,1H),6.80(t,J＝7.2Hz,1H),6.99(d,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3):δ＝7.1,15.3,17.1,27.2,50.1,117.4,125.1,141.5。
example 11
The substrate in the example 1 is changed into methoxy acetone, and the reaction is carried out in the same way as the example 1 to obtain the product N- (1-methoxy-2-propyl) -2, 6-dimethylaniline.
The product was analyzed and the GC and NMR data are shown below:
95％yield.96％ee was determined by chiral GC(chiralβ-DEX 120 column,column temp.:85℃,carrier gas:N2):tR(major)＝69.8min,tR(minor)＝71.4min.[α]D 25＝9.5(c＝1.31in CHCl3).1HNMR(400MHz,CDCl3):δ＝1.20(d,J＝6.0Hz,3H),2.30(s,6H),3.35-3.80(m,7H),6.82(t,J＝7.2Hz,1H),6.99(d,J＝7.2Hz,2H)；13C NMR(100MHz,CDCl3):δ＝18.6,18.7,52.4,59.0,76.3,121.5,128.8,129.4,145.0。
example 12
The substrate in the example 1 is changed into acetone methyl ester, and the reaction is carried out in the same way as the example 1 to obtain the product 2- (2, 6-dimethylphenylamino) methyl propionate.
The product was analyzed and the NMR and HPLC data are as follows:
96％yield.86％ee was determined by chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(minor)＝6.9min,tR(major)＝7.7min.[α]D 25＝-16(c＝1.33in CHCl3).1HNMR(400MHz,CDCl3):δ＝1.38(d,J＝7.2Hz,3H),2.31(s,6H),3.68(s,3H),4.00(q,J＝7.2Hz,1H),6.81(t,J＝7.6Hz,1H),6.97(d,J＝7.6Hz,2H)。
example 13
The substrate in the example 1 is changed into propiophenone, and the rest is reacted with the substrate in the example 1 to obtain the product 2, 6-dimethyl-N- (1-phenylpropyl) aniline.
The product was analyzed and the NMR and HPLC data are as follows:
97％yield.90％ee was determined by chiral HPLC(chiralcel OJ-H,n-hexane/i-PrOH＝90/10,1.0mL/min,254nm,40℃):tR(major)＝4.4min,tR(minor)＝4.8min.[α]D 25＝-116(c＝1.79in CHCl3).1HNMR(400MHz,CDCl3):δ＝0.91(d,J＝7.2Hz,3H),1.87-1.92(m,1H),2.02-2.05(m,1H),2.18(s,6H),3.30(br,1H),4.07(m,1H),6.78(t,J＝7.2Hz,1H),6.94(d,J＝7.2Hz,2H),7.20-7.31(m,5H)；13CNMR(100MHz,CDCl3):δ＝11.3,19.1,29.8,63.5,121.4,126.3,126.8,127.0,128.4,128.9,129.1,143.9,145.0。
example 14
Under the protection of nitrogen gas, [ Ir (COD) Cl]2(0.000125mmol,0.0001 mol%), chiral phosphine-phosphoramidite ligand (0.000275mmol,0.00022 mol%) was dissolved in toluene (10mL), stirred at room temperature for 10 minutes, added with the substrate 2-ethyl-6-methylaniline (0.125mol) and a solution of methoxyacetone (0.15mol) and isopropyl titanate (0.1375mol) in toluene (50mL), placed in an autoclave, displaced with hydrogen for 3 times, and then reacted at 100 ℃ for 12 hours while passing hydrogen to 80 atmospheres. Slowly releasing hydrogen, removing solvent, and separating with silica gel column to obtain the product (S) -2-ethyl-N- (1-methoxy-2-propyl) -6-methylaniline.
The product was analyzed and the NMR and HPLC data are as follows:
95％yield.80％ee was determined by chiral HPLC(chiralcel OD-H,n-hexane/i-PrOH＝99/1,1.0mL/min,254nm,40℃):tR(minor)＝4.4min,tR(major)＝4.8min.[α]D 25＝8.8(c＝1.0in CHCl3).1HNMR(400MHz,CDCl3):δ＝1.18(d,J＝5.6Hz,3H),1.23(t,J＝7.6Hz,3H),2.29(s,3H),2.65(q,J＝7.6Hz,2H),3.34-3.38(m,6H),6.87(t,J＝7.6Hz,1H),7.00(dd,J＝7.6,15.2Hz,2H)。
Claims (6)
1. a method for preparing chiral amine by asymmetric reductive amination of ketone is characterized in that; the method adopts a chiral catalyst Ir-L, and adopts ketone and amine to prepare chiral amine through direct asymmetric reductive amination, wherein the ketone and the prepared chiral amine respectively have the following structures:
R1is C1～C10Alkyl radical, C3～C12Cycloalkyl or C containing one or more heteroatoms of N, S, O, P1～C10An alkyl group;
R2is H, C1-C40Alkyl or aryl within;
R3is (2-methyl-6-ethyl) phenyl or (2, 6-dimethyl) phenyl;
the chiral catalyst Ir-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and chiral phosphine-phosphoramidite in a solvent, wherein the chiral phosphine-phosphoramidite ligand L has the following structural general formula:
in the formula, R1Is H or alkyl;
R2is H or C7～C60An alkyl group;
ar is phenyl;
the X group is a chiral binaphthyl aromatic group.
2. The method for preparing chiral amine by asymmetric reductive amination of ketone according to claim 1, which is characterized in that the method specifically comprises:
under the protection of nitrogen, dissolving an iridium-cyclooctadiene complex and a chiral phosphine-phosphoramidite ligand L in a solvent, stirring for 10 minutes at room temperature, adding substrate amine, ketone and an additive which are dissolved in the solvent, placing the mixture into a high-pressure reaction kettle, carrying out hydrogen replacement for 3 times, then introducing hydrogen to 20-100bar, reacting for 1-24 hours at 20-100 ℃, slowly releasing the hydrogen, and separating by using a silica gel column after removing the solvent to obtain a product chiral amine;
the solvent is dichloromethane, 1, 2-dichloroethane or toluene;
the additive is isopropyl titanate, ethyl titanate or methyl titanate;
the substrate amine R3NH2In R3Is (2-methyl-6-ethyl) phenyl or (2, 6-dimethyl) phenyl.
3. The process for the preparation of chiral amines by the asymmetric reductive amination of ketones according to claim 1 or 2, characterized in that said iridium-cyclooctadiene complex is [ Ir (COD) Cl]2、Ir(COD)2BF4Or Ir (COD)2BARF。
4. The method for preparing chiral amine by asymmetric reductive amination of ketone as claimed in claim 2, wherein the iridium concentration in the reaction system is 0.0001-0.01mol/L, and the molar ratio of the chiral phosphine-phosphoramidite ligand to iridium is 1-5: 1.
5. the method for preparing chiral amine by asymmetric reductive amination of ketone according to claim 2, wherein the molar ratio of the amine substrate to the chiral catalyst Ir-L is 100-500000: 1.
6. the method for preparing chiral amine by asymmetric reductive amination of ketone according to claim 2, wherein the molar ratio of the amine substrate to the ketone is 0.5-1.5:1, and the molar ratio of the amine substrate to the additive is 1: 1 to 5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810547088.7A CN110551033B (en) | 2018-05-31 | 2018-05-31 | Method for preparing chiral amine through asymmetric reductive amination of ketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810547088.7A CN110551033B (en) | 2018-05-31 | 2018-05-31 | Method for preparing chiral amine through asymmetric reductive amination of ketone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110551033A CN110551033A (en) | 2019-12-10 |
| CN110551033B true CN110551033B (en) | 2022-04-12 |
Family
ID=68734442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810547088.7A Active CN110551033B (en) | 2018-05-31 | 2018-05-31 | Method for preparing chiral amine through asymmetric reductive amination of ketone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110551033B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1951945A (en) * | 2005-10-20 | 2007-04-25 | 中国科学院大连化学物理研究所 | Phosphine-phosphoramidite ligand, its preparation method and uses |
| CN105712812A (en) * | 2016-01-25 | 2016-06-29 | 西北农林科技大学 | Chiral beta-arylamine compounds prepared by asymmetric reductive amination reaction and preparation method of chiral beta-arylamine compounds |
-
2018
- 2018-05-31 CN CN201810547088.7A patent/CN110551033B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1951945A (en) * | 2005-10-20 | 2007-04-25 | 中国科学院大连化学物理研究所 | Phosphine-phosphoramidite ligand, its preparation method and uses |
| CN105712812A (en) * | 2016-01-25 | 2016-06-29 | 西北农林科技大学 | Chiral beta-arylamine compounds prepared by asymmetric reductive amination reaction and preparation method of chiral beta-arylamine compounds |
Non-Patent Citations (1)
| Title |
|---|
| Chiral phosphine-phosphoramidite ligands for highly enantioselective hydrogenation of N-arylimines;Qing Li等;《RSC Adv.》;20151231;第13702–13708页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110551033A (en) | 2019-12-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110551037B (en) | Method for catalyzing asymmetric hydrogenation of imine by iridium/chiral diphosphine system | |
| CN110548546A (en) | Method for catalyzing asymmetric hydrogenation of imine by iridium/linear phosphine-phosphoramidite system | |
| CN112824422B (en) | Chiral ferrocene-indole diphosphine ligand as well as preparation method and application thereof | |
| CN111285775B (en) | Method for applying fructose-derived pyridine alcohol chiral ligand to asymmetric reductive amination of ketone | |
| CN110551033B (en) | Method for preparing chiral amine through asymmetric reductive amination of ketone | |
| CN110551035A (en) | Iridium-catalyzed asymmetric reductive amination method for ketone | |
| CN110551034B (en) | Asymmetric reductive amination method of ketone | |
| CN110551032B (en) | Asymmetric reductive amination method for catalyzing ketone by iridium chiral phosphine-aminophosphine ligand system | |
| CN103483306A (en) | Method for preparing 2-amino-2-chromene derivatives by using polyamino ionic liquid as catalyst | |
| CN111285770B (en) | Asymmetric reductive amination method based on fructose-derived chiral monodentate phosphite ligand ketone | |
| Kumar et al. | Phosphomolybdic acid-Al2O3: A mild, efficient, heterogeneous and reusable catalyst for regioselective opening of oxiranes with amines to β-amino alcohols | |
| Suzuki et al. | Efficient Solvent-and Catalyst-Free Syntheses of Imine Derivatives Applying the Pressure Reduction Technique: Remarkable Change of the Reaction Rate with the Phase Transition | |
| JP4286486B2 (en) | Ruthenium compound, diamine ligand and method for producing optically active alcohol | |
| CN110551036B (en) | Iridium/chiral phosphite ester-pyridine catalyzed imine asymmetric hydrogenation method | |
| CN111285774A (en) | Asymmetric imine hydrogenation method based on chiral monodentate phosphine ligand derived from D-mannitol | |
| CN111285773A (en) | Method for preparing chiral amine based on glucose-derived monodentate phosphite ligand asymmetric hydrogenation | |
| JP5042438B2 (en) | Process for producing β-aminoalcohols having a syn configuration | |
| CN114539319B (en) | Chiral phosphine-dicyclophosphoramidite ligand and preparation method and application thereof | |
| CN112521333A (en) | Synthesis method of chiral 2, 3-disubstituted tetrahydroquinoline derivative | |
| CN112824372A (en) | Copper-catalyzed asymmetric cyclopropanation method of olefin and application thereof | |
| CN109422602A (en) | A kind of method of asymmetric hydrogenation imines preparation Chiral Amine | |
| JPH09110750A (en) | Production of optically active cyclohexanols | |
| CN112824371B (en) | Chiral (E) -2- (1, 3-diaryl allyl) malonic acid dimethyl ester compound and preparation method thereof | |
| EP1421059A1 (en) | Process for the preparation of enantiomerically enriched n-acyl-beta-amino acid derivatives by enantioselective hydrogenation of the corresponding (z)-enamides | |
| JPWO2002055477A1 (en) | Method for producing ruthenium compound, diamine compound and β-amino alcohol |
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 |