阅读说明：本技术 一种铱/手性双膦体系催化亚胺不对称氢化方法 (Method for catalyzing asymmetric hydrogenation of imine by iridium/chiral diphosphine system ) 是由 胡向平 胡信虎 于 2018-05-31 设计创作，主要内容包括：本发明公开了一种铱/手性双膦体系催化亚胺不对称氢化方法,该方法以手性双膦配体与金属铱前驱体反应原位制备配合物为催化剂,亚胺不对称加氢制备手性胺。本发明配体制备简单,催化剂用量低,操作简便,且可实现连续操作,适于大规模制备手性胺,产物的对映体过量值达80％以上,并且本发明对于精异丙甲草胺中间体的合成时2-乙基-6-甲基苯胺/催化剂(S/C)为500000具有较好的结果,达到95％收率,91％对映选择性,具有很好的工业实用性。(the invention discloses an asymmetric hydrogenation method of imine catalyzed by an iridium/chiral diphosphine system, which takes chiral diphosphine ligand and metal iridium precursor to react to prepare a complex in situ as a catalyst, and imine is asymmetrically hydrogenated to prepare chiral amine. The ligand of the invention has simple preparation, low catalyst consumption, simple and convenient operation, can realize continuous operation, is suitable for preparing chiral amine on a large scale, has the enantiomeric excess value of more than 80 percent, has better result for 500000 of 2-ethyl-6-methylaniline/catalyst (S/C) in the synthesis of the metolachlor intermediate, achieves 95 percent of yield and 91 percent of enantioselectivity, and has good industrial practicability.)

1. An asymmetric hydrogenation method of imine catalyzed by an iridium/chiral diphosphine system is characterized in that: the method adopts a chiral catalyst Ir-L, and adopts imine asymmetric hydrogenation to prepare chiral amine; the chiral catalyst Ir-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and a chiral diphosphine ligand in a solvent.

2. The method for the asymmetric hydrogenation of imine by using an iridium/chiral diphosphine system according to claim 1, wherein the method comprises the following steps: the method specifically comprises the following steps:

(1) Adding an iridium-cyclooctadiene complex and a chiral diphosphine ligand into the solvent, stirring the mixture for 2 to 5 hours at room temperature, and carrying out in-situ coordination to generate a chiral catalyst Ir-L;

(2) Under the protection of nitrogen, adding a substrate imine dissolved in a solvent, adding a chiral catalyst Ir-L, placing the mixture into a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting at 20-100 ℃ for 1-24 hours, slowly releasing the hydrogen, removing the solvent, and separating by using a silica gel column to obtain a product chiral amine;

The solvent is dichloromethane, 1, 2-dichloroethane or toluene;

The substrate imine is as follows:

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.;

R²Is H, C₁-C₄₀Alkyl or aryl within.

3. The method for the asymmetric hydrogenation of imines catalyzed by an iridium/chiral diphosphine system according to claim 1 or 2, characterized in that; the imine and the resulting chiral amine have the following structures:

In the formula: r¹Is C₁～C₁₀Alkyl radical, C₃～C₁₂Is cycloalkyl, or C containing one or more functional groups of N, S, O, P₁～C₁₀Alkyl, or C containing one or more functional groups of N, S, O, P₃～C₁₀a cycloalkyl group; or C₆-C₃₀Aromatic groups with or without N, S, O, P functional groups; or an ester group;

R²is H, C₁-C₄₀Alkyl or aryl within;

Ar is phenyl, 2-substituted, 3-substituted, 4-substituted, 2, 6-disubstituted, 2,4, 6-trisubstituted aryl and C₆-C₃₀Aromatic groups with or without N, S, O, P functional groups.

4. the method for the asymmetric hydrogenation of imines catalyzed by an iridium/chiral diphosphine system according to claim 1 or 2, wherein: the chiral diphosphine ligand L has the following structural general formula:

Wherein: r is one of phenyl, substituted phenyl, alkyl or cycloalkyl, and R' is one of phenyl, substituted phenyl, alkyl, hydrogen, halogen or cycloalkyl.

5. The method for the asymmetric hydrogenation of imines catalyzed by an iridium/chiral diphosphine system according to claim 1 or 2, wherein: the iridium-cyclooctadiene complex is: [ Ir (COD) Cl]₂、Ir(COD)₂BF₄or Ir (COD)₂BARF。

6. The method for the asymmetric hydrogenation of imine by using an iridium/chiral diphosphine system according to claim 2, wherein the method comprises the following steps: 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.

7. The method for the asymmetric hydrogenation of imine by using an iridium/chiral diphosphine system according to claim 2, wherein the method comprises the following steps: the molar ratio of the imine substrate to the chiral catalyst Ir-L is 100-500000: 1.

8. The method for the asymmetric hydrogenation of imines catalyzed by an iridium/chiral diphosphine system according to claim 1 or 2, wherein: the preparation method of the chiral diphosphine ligand L comprises the following steps:

(1) introducing argon to react (R)_c,S_p) -ppfa (i) and imidazole are dissolved in dehydroacetic acid and heated to 80 ℃ for 8 hours; (R)_c,S_p) The molar ratio of PPFA (I) to imidazole is 1: 1.1-5;

After cooling, neutralizing with an excess saturated sodium bicarbonate solution, extracting with dichloromethane (3 × 50ml), combining organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, removing the solvent, and subjecting the crude product to column chromatography (n-hexane/ethyl acetate/triethylamine ═ 10/10/1) to obtain brown crystals II;

(2) under the condition of introducing argon, dissolving the brown crystal II in diethyl ether, slowly dropwise adding n-BuLi, gradually changing the reaction mixture into a dark red clear solution, and continuously reacting for one hour; dropwise adding diphenyl phosphine chloride, wherein the molar ratio of the brown crystal II, the n-BuLi and the diphenyl phosphine chloride is 1: 1.2-5;

After reacting for two hours, a saturated sodium hydrogencarbonate solution was added, and the organic phase was separated, washed with saturated brine and dried over anhydrous sodium sulfate. Desolventizing, column chromatography (n-hexane/ethyl acetate 10/1), and n-hexane recrystallization to give 0.24g of orange needle crystals I_aNamely chiral diphosphine ligand L.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to an asymmetric hydrogenation method for imine by using an iridium/chiral diphosphine system as a catalyst.

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 preparation of chiral amine compounds by asymmetric catalytic Hydrogenation of imines has been very successful [ (a) H. -U.Blaser, F.Spinder in Handbook of Homogeneous Hydrogenation (eds.: J.G.de Vries, C.J.Elsevier), Wiley-VCH, Weinheim,2007, pp.1193; (b) claver, e.fernandez in Morden Reduction Methods (eds.: p.anderson, i.munsell), Wiley-VCH, Weinheim,2008, pp.237; (c) U.Blaser, F.Spinder in Comprehensive asymmetry catalysis catalysts (eds.: E.Jacobsen, A.Pfaltz, H.Yamamoto), Springer, Berlin,1999, pp.247 ], but the catalytic systems have the problems of low reaction activity, narrow substrate range, harsh reaction conditions and the like, and particularly, for the synthetic route of obtaining the refined metolachlor through asymmetric catalysis, a plurality of different attempts are made by organic chemists at home and abroad to design and synthesize a plurality of asymmetric catalytic catalysts. The preparation of s-metolachlor intermediates by asymmetric hydrogenation of (2-methyl-6-ethylaniline) -imines was found to be a viable and efficient route.

In 1975, Levi et al reported a hydrogenation process for imines, but the enantiomeric excess (ee value) was only 22% (Levi A., Modena G., Scorano G.J.chem.Soc.Commun.1975,1, 6-7). In 1999, Hans-PeterJalett et al catalyzed asymmetric hydrogenation with ferrocene bisphosphine ligand increased its ee value to 76% (Jalett H.P., Spindler F., Hanreich R.G.US5886225[ P ],1999) and achieved industrialization. The method is characterized in that { (R) -1- [ (S) -2-diphenylphosphine cyclopentadienyl iron group ] } ethyl-bis- (3, 5-dimethylphenyl) phosphine is used as a ligand and forms a catalyst precursor with an iridium complex in situ, and the asymmetric hydrogenation of 2-methyl-6-ethyl-N-methyleneaniline is catalyzed in the presence of acid and tetrabutylammonium iodide at 50 ℃ and 80 atmospheres of hydrogen pressure to obtain chiral amine with the highest ee of 76%. However, the synthesis of the ligand used in this reaction is difficult, and the hydrogenation system requires a large amount of acid and requires high equipment. Therefore, the development of the catalyst for preparing the chiral amine with high activity, high stereoselectivity and low cost has very important significance.

disclosure of Invention

The invention aims to provide a method for catalyzing asymmetric hydrogenation of imine by an iridium/chiral diphosphine system.

In order to achieve the purpose, the technical scheme of the invention is as follows:

An asymmetric hydrogenation method of imine catalyzed by iridium/chiral diphosphine system, which adopts chiral catalyst Ir-L to prepare chiral amine by asymmetric hydrogenation of imine; the chiral catalyst Ir-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and a chiral diphosphine ligand in a solvent.

An asymmetric hydrogenation method of imine catalyzed by an iridium/chiral diphosphine system comprises the following steps:

(1) adding an iridium-cyclooctadiene complex and a chiral diphosphine ligand into the solvent, stirring the mixture for 2 to 5 hours at room temperature, and carrying out in-situ coordination to generate a chiral catalyst Ir-L;

(2) Under the protection of nitrogen, adding a substrate imine dissolved in a solvent, adding a chiral catalyst Ir-L, placing the mixture into a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting at 20-100 ℃ for 1-24 hours, slowly releasing the hydrogen, removing the solvent, and separating by using a silica gel column to obtain a product chiral amine;

the solvent is dichloromethane, 1, 2-dichloroethane or toluene;

the substrate imine is as follows:

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.;

R²Is H, C₁-C₄₀Alkyl or aryl within;

in order to achieve the purpose, the technical scheme of the invention is as follows:

the imines 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.;

R²Is H, C₁-C₄₀alkyl or aryl within;

Ar is C such as phenyl, 2-substituted, 3-substituted, 4-substituted, 2, 6-disubstituted, 2,4, 6-trisubstituted aryl, etc₆-C₃₀Aromatic groups containing or not containing N, S, O, P functional groups such as 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-6-ethylphenyl, thiophene, etc.

The structural general formula of the chiral diphosphine ligand L is as follows:

wherein: r is one of phenyl, substituted phenyl, alkyl or cycloalkyl, and R' is one of phenyl, substituted phenyl, alkyl, hydrogen, halogen or cycloalkyl.

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 imine substrate to the catalyst is 100-500000: 1.

The ligand synthesis method related by the invention is shown as the following reaction equation:

The preparation method of the chiral diphosphine ligand L comprises the following steps:

(1) introducing argon to react (R)_c,S_p) -ppfa (i) and imidazole are dissolved in dehydroacetic acid and heated to 80 ℃ for 8 hours; (R)_c,S_p) The molar ratio of PPFA (I) to imidazole is 1: 1.1-5;

Cooling, neutralizing with excessive saturated sodium bicarbonate solution, extracting with dichloromethane (3 × 50ml), mixing organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, removing solvent, and subjecting the crude product to column chromatography (n-hexane/ethyl acetate/triethylamine: 10/10/1); brown crystals II;

(2) Under the condition of introducing argon, dissolving the brown crystal II in diethyl ether, slowly dropwise adding n-BuLi, gradually changing the reaction mixture into a dark red clear solution, and continuously reacting for one hour; dropwise adding diphenyl phosphine chloride, wherein the molar ratio of the brown crystal II, the n-BuLi and the diphenyl phosphine chloride is 1: 1.2-5;

after reacting for two hours, a saturated sodium hydrogencarbonate solution was added, and the organic phase was separated, washed with saturated brine and dried over anhydrous sodium sulfate. Desolventizing, column chromatography (n-hexane/ethyl acetate 10/1), and n-hexane recrystallization to give 0.24g of orange needle crystals I_anamely chiral diphosphine ligand L.

the invention has the beneficial effects that: compared with other methods for synthesizing chiral amine, the method for synthesizing chiral diphosphine ligand L by imine reductive hydrogenation is simple in synthesis, low in price and suitable for kilogram-level production, an iridium/chiral diphosphine system is high in catalytic activity and enantioselectivity, the enantiomeric excess value (ee value) of a product reaches more than 85%, the reductive amination reaction is simple to operate, mild in conditions 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 S-metolachlor intermediate, achieves 95% of yield and 91% 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. GC analysis conditions were as follows: SE-54, injection port temperature: 250 degrees, detector temperature: initial temperature 50 ℃ for 2 minutes, then 10 ℃ per minute to 250 ℃ and then 5 minutes.