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CN118206454A - Synthesis and application of chiral (2R, 5R) -2, 5-hexamethylenediamine - Google Patents

Synthesis and application of chiral (2R, 5R) -2, 5-hexamethylenediamine Download PDF

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CN118206454A
CN118206454A CN202211617898.8A CN202211617898A CN118206454A CN 118206454 A CN118206454 A CN 118206454A CN 202211617898 A CN202211617898 A CN 202211617898A CN 118206454 A CN118206454 A CN 118206454A
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hexamethylenediamine
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hexanediol
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陈木旺
周永贵
黎红旺
孙蕾
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Dalian Institute of Chemical Physics of CAS
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Dalian Institute of Chemical Physics of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
    • C07C209/42—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitrogen-to-nitrogen bonds
    • 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
    • B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • 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
    • B01J2231/60—Reduction reactions, e.g. hydrogenation
    • B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
    • B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
    • B01J2231/643—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of R2C=O or R2C=NR (R= C, H)
    • 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
    • B01J2531/821—Ruthenium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07B2200/07—Optical isomers

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Abstract

The invention discloses a synthesis and application of chiral (2R, 5R) -2, 5-hexamethylenediamine, which is prepared from (2S, 5S) -2, 5-hexanediol as a raw material by Ms protection on alcohol, then carrying out Mitsunobu reaction with NaN 3, reducing azide into primary amine by lithium aluminum hydride or Pd/C and hydrogen, obtaining (2R, 5R) -2, 5-hexamethylenediamine, then carrying out reaction with [ RuCl 2(η6-benzene)2]2 and (S) -BINAP to prepare ruthenium biphosphol diamine catalyst, and applying the ruthenium biphosphol diamine catalyst to asymmetric hydrogenation of 3-quinine, wherein the enantiomeric excess can reach 99%, and the S/C can reach 30000. The method has the advantages of simple and practical operation, easily obtained raw materials, high enantioselectivity, good yield, green atomic economy, environmental friendliness and the like.

Description

Synthesis and application of chiral (2R, 5R) -2, 5-hexamethylenediamine
Technical Field
The invention relates to a method for synthesizing chiral (2R, 5R) -2, 5-hexamethylenediamine and an application thereof.
Technical Field
Enantiomerically pure chiral diamines are widely found in many natural products and are also the core backbones for many drugs, pesticides, polymers and organic functional materials (Khokhar, a.r.; al-Baker, s.; shamsuddin, s.; siddik, z.h. bioorg.med. Chem. Lett.1997,40,112). Chiral primary diamino complexes are being evaluated as antitumor agents, and alternative cisplatin can reduce toxicity and circumvent drug resistance. The C2-symmetrical diamines are also reported as chiral auxiliary and ligand building blocks for various transition metal catalysts, such as Cu, fe, os, pd, rh, ru, se and Cr, and can be selectively bound to DNA (Tanaka,T.;Tsurutani,K.;Komatsu,A.;Ito,T.;Iida,K.;Fujii,Y.;Nakano,Y.;Usui,Y.;Fukuda,Y.;Chikira,M.Bull.Chem.Soc.Jpn.1997,70,615). and can also be used as HIV protease inhibitors. In view of the importance of C2-symmetric diamine compounds in the pharmaceutical and synthetic chemistry fields, chemists have developed methods to synthesize such compounds, particularly to construct chiral C2-symmetric diamines using environmentally friendly and efficient asymmetric hydrogenation methods, although numerous studies have described diastereoselective synthesis of C2-symmetric chiral diamines, particularly 2, 5-hexamethylenediamine, and the highly enantioselective synthesis of chiral 2, 5-hexamethylenediamine is currently not a very successful example.
In 2000, the Higashiyama group reported that chiral 2, 5-hexamethylenediamine was obtained by starting with D-phenylglycinol as the initial starting material for chiral source, proceeding with two steps of reaction to obtain the target product 3, then reacting with a grignard reagent, but with poor diastereoselectivity, and then removing the protecting group on nitrogen by Pb (OAc) 4 oxidation. (literature) :Yamauchi,T.;Higashiyama,K.;Kubo,H.;Ohmiya,S.Synthesis of C2-symmetrical chiral diamines:diastereoselective addition to bis(1,3-oxazolidinyl)alkanes with Grignard reagents.Tetrahedron Asymmetry2000,11,3003).
From the above examples, there are few successful cases of synthesizing chiral 2, 5-hexamethylenediamine with high enantioselectivity. Thus, developing a high yield, high stereoselective process for synthesizing 2, 5-hexamethylenediamine remains a difficulty and hotspot of current research.
Disclosure of Invention
The invention aims to provide a synthesis method and application of chiral (2R, 5R) -2, 5-hexamethylenediamine, which is prepared from (2S, 5S) -2, 5-hexanediol as a raw material by Ms protection on alcohol, mitsunobu reaction with NaN 3, and reduction of azide into primary amine by lithium aluminum hydride or Pd/C and hydrogen. After (2R, 5R) -2, 5-hexamethylenediamine is obtained, the (2R, 5R) -2, 5-hexamethylenediamine reacts with [ RuCl 2(η6-benzene)2]2 and (S) -BINAP to prepare the ruthenium biphospholoamine catalyst, and the ruthenium biphospholoamine catalyst is applied to asymmetric hydrogenation of triquinine ketone, wherein the enantiomeric excess can reach 99 percent, and the S/C can reach 30000. The method has the advantages of simple and practical operation, easily obtained raw materials, high enantioselectivity, good yield, green atomic economy, environmental friendliness and the like.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
a synthesis method of chiral (2R, 5R) -2, 5-hexamethylenediamine comprises the following steps:
(1) Starting from (2S, 5S) -2, 5-hexanediol, reacting with methylsulfonyl chloride (MsCl) in the presence of triethylamine, and protecting by Ms on alcohol to obtain methylsulfonyl-protected (2S, 5S) -2, 5-hexanediol, wherein the reaction formula is shown in formula I;
(2) The (2S, 5S) -2, 5-hexanediol protected by methylsulfonyl and NaN 3 are subjected to Mitsunobu reaction to obtain an azide compound, wherein the reaction formula is shown as a formula II;
(3) The azide compound is reduced into primary amine through lithium aluminum hydride or Pd/C and hydrogen to obtain (2R, 5R) -2, 5-hexamethylenediamine, and the reaction formula is shown as a formula III.
The reaction formula is as follows:
Based on the above technical scheme, formula one temperature: -50-30 ℃; and (2) the temperature: 30-120 ℃; three temperatures: 0-60 ℃; preferred formula one temperature: -20 ℃; and (2) the temperature: 80 ℃; three temperatures: 25 ℃;
Formula one, formula two, formula three solvents: one or more than two mixed solvents selected from dichloromethane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, chloroform, acetonitrile and azodicarbonamide;
time of formula one, formula two, formula three: 1-72 hours; preferred formula (la) is time: 24h; two times: 24h; formula three times: 8h
Reducing agent of formula three: lithium aluminum hydride or Pd/C and hydrogen;
Hydrogen pressure: 1-10 atmospheres
Based on the above technical scheme, preferably, the method specifically comprises the following steps:
(1) In the formula I, under the protection of nitrogen, a Schlenk bottle is added with a substrate (2S, 5S) -2, 5-hexanediol, triethylamine and a solvent (methylene chloride) (40 mL), and then stirred and dissolved at-50-30 ℃ and then newly distilled methylsulfonyl chloride is added dropwise. Stirring and reacting for 1-72 hours, and obtaining a target product Ms protection substrate through column chromatography;
(2) Adding the Ms protective substrate obtained in the first formula and NaN 3 into a reaction bottle, adding a solvent (N, N-Dimethylformamide (DMF)), heating to 30-120 ℃ and stirring for reaction, and stopping the reaction for 1-72 hours to obtain a target product azide;
(3) In the third formula, the azide compound obtained in the second formula is added into a reaction bottle, newly distilled tetrahydrofuran is added, and then tetrahydrofuran and lithium aluminum hydride are added into a dropping funnel to form a suspension. Then slowly dripping the suspension into a reaction bottle, wherein the reaction temperature is between 0 ℃ and 60 ℃, and stirring for about 1-72 hours to finish the reaction, thereby obtaining the target product (2R, 5R) -2, 5-hexamethylenediamine;
or adding the azide compound obtained in the formula II into a reaction bottle, adding Pd/C and ethyl acetate solvent, putting into a reaction kettle, filling hydrogen into the reaction kettle, wherein the hydrogen pressure is 1-10 atmospheres, and the reaction temperature is between 0 ℃ and 60 ℃. Stirring for about 1-72 hours to finish the reaction, and obtaining the target product (2R, 5R) -2, 5-hexamethylenediamine.
Based on the above technical scheme, preferably, the molar ratio of the (2S, 5S) -2, 5-hexanediol and the methylsulfonyl chloride in the formula I is 1:2-1:4, and the molar ratio of the (2S, 5S) -2, 5-hexanediol and the triethylamine is 1:4-1:8;
The molar ratio of the Ms protective substrate of the formula II to the NaN 3 is 1:2-1:4;
The molar ratio of the N 3 substrate (azide) and the LiAlH 4 is 1:1-1:4; or the molar ratio of N 3 substrate (azide) of formula III to Pd in Pd/C is 1:0.01-1:0.05; pd loading in Pd/C is 5-10wt.
Based on the above technical scheme, preferably, the solvent is used in an amount of 2 to 4 ml per 0.25 mmol of the hydrogenation azide.
Based on the above technical scheme, preferably, the solvent in the step (1) is dichloromethane, the solvent in the step (2) is nitrogen-dimethylformamide, and the solvent in the step (3) is tetrahydrofuran or ethyl acetate, and the result is the best.
The application of the synthesized (2R, 5R) -2, 5-hexamethylenediamine serving as a ligand in the preparation of a ruthenium bisphosphamide catalyst, wherein the ruthenium bisphosphamide catalyst is applied to the asymmetric hydrogenation reaction of 3-quinine ketone, and the reaction formula is as follows:
The invention has the following advantages:
1. the method has the advantages of high reaction activity and enantioselectivity, complete reaction, specific generated products, convenient separation and capability of obtaining high-enantiomer excess pure products.
2. The catalyst is convenient to prepare, and the reaction operation is simple, convenient and practical.
4. The reduction reaction condition is mild, and the post-treatment is simple.
5. After (2R, 5R) -2, 5-hexamethylenediamine is obtained, the (2R, 5R) -2, 5-hexamethylenediamine reacts with [ RuCl 2(η6-benzene)2]2 and (S) -BINAP to prepare the ruthenium biphospholoamine catalyst, and the ruthenium biphospholoamine catalyst is applied to the asymmetric hydrogenation of 3-quinine ketone, wherein the enantiomeric excess can reach 99 percent, and the S/C can reach 30000.
Detailed Description
The invention is described in detail below by way of examples; however, the present invention is not limited to the following examples.
Example 1
Step one: to a Schlenk flask, under nitrogen protection, substrate (2S, 5S) -2, 5-hexanediol (4.3 mmol,1.0 eq), triethylamine (2.4 mL,4.0 eq) (Innochem eq) (purchased) and methylene chloride (4.0 mL) were added and dissolved under stirring at-20℃and then freshly distilled methanesulfonyl chloride (13 mmol,3.0 eq) (methylsulfonyl chloride dissolved in 2mL of methylene chloride) was added dropwise, the system turned yellow from clear and opaque, the cold bath was removed after stirring for three hours, stirring was continued at room temperature, the reaction was followed by a spot-plate tracing, and after the complete disappearance of the starting material was detected by oxidation with potassium permanganate solution, the reaction was stopped (generally the starting material was completely disappeared after 12-14 hours). After the completion of the reaction, 10mL of 2N HCl was added to quench the reaction, and the system was red. The organic phase was then separated and the aqueous phase extracted three times with dichloromethane (20 mL x 3), the organic phases combined, washed once with saturated sodium bicarbonate, saturated sodium chloride each (30 mL each) and then dried over anhydrous sodium sulfate. And (3) evaporating and spin-drying the solvent by spin to obtain a target product Ms to protect the substrate, so as to obtain quantitative yield, and directly putting the product into the next reaction.
Step two: the Ms-protected substrate (4.3 mmol,1.0 eq) obtained in the above step and NaN 3 (13.0 mmol,3.0 eq) were added to a reaction flask, 8mL of N, N-Dimethylformamide (DMF) was added, and the mixture was heated to 80℃and stirred. The reaction was performed for about 36 hours with the reaction starting material completely disappeared as measured by NMR. The reaction was stopped, cooled to room temperature, quenched by the addition of 15mL of water, and extracted three times with dichloromethane (60 mL. Times.3). The organic phases were combined and then repeatedly washed with water to remove DMF (10 mL x 8), and saturated aqueous sodium chloride (10 mL) was washed once and dried over anhydrous sodium sulfate. The target product of the azide compound (yield 80%) is obtained by rotary evaporation and rotary drying of the solvent and is directly put into the next reaction.
Step three: in a first method, the azide compound (3.5 mmol,1.0 eq) obtained in the previous step was added to a reaction flask, 6mL of freshly distilled tetrahydrofuran was added, and then 4mL of tetrahydrofuran and lithium aluminum hydride (3.6 mmol,1.05 eq) were added to a dropping funnel as a suspension. Then slowly drop-wise into the reaction flask (a large number of bubbles are generated during the drop-wise addition, taking care to control the drop-wise rate, about 30 drops of suspension per minute), and controlling the reaction temperature in the water bath between 20℃and 30 ℃. The system is changed from clear to light grass green. After the completion of the dropwise addition of the tetrahydrofuran solution of lithium aluminum oxide, 4ml of tetrahydrofuran was added to wash the lithium aluminum oxide stained on the wall of the dropping funnel, and then the reaction was completed by continuing stirring at room temperature for about 12 hours (the reaction was followed by a plate). After the reaction was completed, the reaction was quenched by adding water in an ice bath in an amount equal to the weight of lithium aluminum hydride, followed by adding a 15% aqueous NaOH (w/v) solution (equal to the volume of water used for the previous quenching reaction), and then adding water (three times the amount of water used for the previous quenching reaction). After stirring for 15 minutes, the ice bath was removed, and then anhydrous sodium sulfate was directly added to the system to dry. Filtering with diatomite, spin-drying the solvent with a rotary evaporator to obtain the target product (2R, 5R) -2, 5-hexamethylenediamine (yield 89%), and directly putting into the next reaction.
In a second method, pd/C was used to reduce azide, and the azide compound (3.5 mmol,1.0 eq) obtained in the previous step was added to a reaction flask under nitrogen protection, 20mL of ethyl acetate and 10wt% Pd/C210 mg were added, a hydrogen balloon was inserted, and the reaction was stopped by stirring at 25℃for 24 hours. Then Pd/C was filtered with celite, and the solvent was spin-dried with a rotary evaporator to give the target product (2R, 5R) -2, 5-hexamethylenediamine (yield 92%) which was directly put into the next reaction.
Preparation of the catalyst: under the protection of nitrogen, add [ RuCl 2(η6-benzene)2]2 (0.6 mmol,1.0 eq) and (S) -BINAP (1.26 mmol,2.1 eq) and 25mL N, N-dimethylformamide into the reaction tube, react for 15 minutes at 100deg.C, the system is clear red, then cool to room temperature, add (2R, 5R) -2, 5-hexamethylenediamine (1.6 mmol,2.7 eq) and react, the system changes from red clear to pale red to pale yellow turbid. After 21 hours of reaction, the solvent was drained and then pumped with an oil pump at 50 ℃ for a further 40 minutes. 63mL of degassed dichloromethane was added under nitrogen to dissolve the solid, then 125mL of degassed n-hexane was added and the mixture was placed in a refrigerator freezer for recrystallization. After a large amount of solids had been precipitated, the solvent was drained off with a double-ended needle and the residual solvent was drained off to give a yellowish-brown solid (yield 71.3%). Adding the product obtained by the first recrystallization into a branched bottle, adding 40mL of degassed dichloromethane under nitrogen to dissolve the solid, wrapping absorbent cotton at one end of a double-ended needle, filtering, transferring to another dry anaerobic branched bottle, adding 90mL of n-hexane, and freezing in a refrigerator. After a large amount of solids had been precipitated, the solvent was drained off with a double-ended needle and the residual solvent was drained off to give a yellowish-brown solid (overall yield 55%).
Asymmetric hydrogenation of 3-quinuclidinone: weighed amounts of catalyst (2.7 mg, 0.003mmol) and potassium tert-butoxide (67.3 mg,0.6 mmol) as well as substrate 3-quinuclidinone (3.75 g,30.0 mmol), isopropanol 2.0 ml, were added to an amp bottle and stirred for 2-5 minutes. The ampoules were then placed in a stainless steel autoclave and allowed to react at 30℃for 24 hours under 30 atmospheres of hydrogen. Slowly releasing hydrogen, removing solvent by rotary evaporator, and separating by direct column chromatography (volume ratio of petroleum ether and ethyl acetate is 1:1), to obtain pure product, wherein the reaction formula is as follows:
2H),3.01(s,2H),2.76(d,J＝5.2Hz,4H),1.57(brs,2H),1.39–1.23(m,2H),0.46(d,J＝6.4Hz,6H);31P NMR(160MHz,CDCl3)δ45.7(s).
(R)-3-quinuclidinol:3.71g,99％yield,93％ee,white solid,1H NMR(400MHz,CDCl3)δ1.32–1.41(m,1H),1.42–1.50(m,1H),1.63–1.71(m,1H),1.79–1.85(m,1H),1.91–1.99(m,1H),2.60–2.69(m,2H),2.73–2.83(m,2H),2.87–2.95(m,2H),3.10–3.14(m,1H),3.83–3.87(m,1H). The yield was isolated.
The invention takes (2S, 5S) -2, 5-hexanediol as a raw material, through Ms protection on alcohol, then Mitsunobu reaction is carried out with NaN 3, and then azide is reduced into primary amine through lithium aluminum hydride or Pd/C and hydrogen. After (2R, 5R) -2, 5-hexamethylenediamine is obtained, the (2R, 5R) -2, 5-hexamethylenediamine reacts with [ RuCl 2(η6-benzene)2]2 and (S) -BINAP to prepare the ruthenium biphospholoamine catalyst, and the ruthenium biphospholoamine catalyst is applied to asymmetric hydrogenation of triquinine ketone, wherein the enantiomeric excess can reach 99 percent, and the S/C can reach 30000. The method has the advantages of simple and practical operation, high enantioselectivity, good yield, atomic economy, environmental friendliness and the like.

Claims (8)

1. A synthesis method of chiral (2R, 5R) -2, 5-hexamethylenediamine is characterized by comprising the following steps: the method comprises the following steps:
(1) Starting from (2S, 5S) -2, 5-hexanediol as a raw material, reacting with methylsulfonyl chloride in the presence of triethylamine to obtain methylsulfonyl-protected (2S, 5S) -2, 5-hexanediol, wherein the reaction formula is shown as a first formula;
(2) The (2S, 5S) -2, 5-hexanediol protected by methylsulfonyl reacts with NaN 3 to obtain an azide compound, wherein the reaction formula is shown as a formula II;
(3) The azide compound is reduced into (2R, 5R) -2, 5-hexamethylenediamine by lithium aluminum hydride or Pd/C and hydrogen, and the reaction formula is shown as a formula III;
2. the method of claim 1, wherein:
Reaction temperature of step (1): -50-30 ℃; reaction temperature of step (2): 30-120 ℃; reaction temperature of step (3): 0-60 ℃;
Step (1), (2) and (3) solvents: one or more than two mixed solvents selected from dichloromethane, toluene, tetrahydrofuran, ethyl acetate, 1, 4-dioxane, chloroform, acetonitrile and nitrogen-dimethylformamide;
Reaction time of steps (1), (2) and (3): 1-72 hours;
Step (3) hydrogen pressure: 1-10 atmospheres.
3. The method of claim 1, wherein: the method comprises the following steps:
(1) Under the protection of nitrogen, adding a substrate (2S, 5S) -2, 5-hexanediol, triethylamine and a solvent into a Schlenk bottle, stirring and dissolving at the temperature of-50-30 ℃, then dropwise adding newly-steamed methylsulfonyl chloride, and stirring and reacting for 1-72 hours to obtain a substrate protected by methylsulfonyl;
(2) Adding the methylsulfonyl protected substrate obtained in the step (1) and NaN 3 into a reaction bottle, adding a solvent, heating to 30-120 ℃, and stirring for reaction for 1-72 hours to obtain an azide compound;
(3) Adding the azide compound obtained in the step (2) into a reaction bottle, adding a newly steamed organic solvent, then adding the solvent and lithium aluminum hydride into a dropping funnel to form a suspension, then dripping the suspension into the reaction bottle, and stirring at 0-60 ℃ for about 1-72 hours to obtain a target product;
Or adding the azide compound obtained in the step (2) into a reaction bottle, adding Pd/C and a solvent, putting into a reaction kettle, filling hydrogen into the reaction kettle, wherein the hydrogen pressure is 1-10 atmospheres, and stirring for 1-72 hours at 0-60 ℃ to obtain the target product.
4. A method according to claim 1 or 3, wherein: the molar ratio of the (2S, 5S) -2, 5-hexanediol and the methylsulfonyl chloride in the step (1) is 1:2-1:4, and the molar ratio of the (2S, 5S) -2, 5-hexanediol and the triethylamine is 1:4-1:8
The molar ratio of the Ms protected substrate and NaN 3 in the step (2) is 1:2-1:4;
The molar ratio of the azide compound and the LiAlH 4 in the step (3) is 1:1-1:4; or the molar ratio of the azide compound and Pd/C in the step (3) is 1:0.01-1:0.05.
5. A method according to claim 1 or 2, characterized in that: the solvent is used in an amount of 2 to 4ml of solvent per 0.25 mmole of the hydridoazide.
6. The method of claim 1, wherein: the solvent in the step (1) is dichloromethane, the solvent in the step (2) is nitrogen-dimethylformamide, and the solvent in the step (3) is tetrahydrofuran or ethyl acetate.
7. Use of (2 r,5 r) -2, 5-hexamethylenediamine synthesized by the method of any one of claims 1 to 6 as ligand in the preparation of ruthenium bisphosphine catalyst.
8. The ruthenium bisphosphobiamine catalyst of claim 7, which is used in the asymmetric hydrogenation of 3-quinuclidinone.
CN202211617898.8A 2022-12-15 2022-12-15 Synthesis and application of chiral (2R, 5R) -2, 5-hexamethylenediamine Pending CN118206454A (en)

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