CN110494439B - Chiral biphenyl diphosphine ligand and preparation method thereof - Google Patents

Chiral biphenyl diphosphine ligand and preparation method thereof Download PDF

Info

Publication number
CN110494439B
CN110494439B CN201880023975.2A CN201880023975A CN110494439B CN 110494439 B CN110494439 B CN 110494439B CN 201880023975 A CN201880023975 A CN 201880023975A CN 110494439 B CN110494439 B CN 110494439B
Authority
CN
China
Prior art keywords
compound
formula
mixture
stereoisomer
stereoisomers
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
Application number
CN201880023975.2A
Other languages
Chinese (zh)
Other versions
CN110494439A (en
Inventor
维尔纳·邦拉蒂
冯正川
乔纳森·艾伦·米德洛克
彭坤
朱志斌
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DSM IP Assets BV
Original Assignee
DSM IP Assets BV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by DSM IP Assets BV filed Critical DSM IP Assets BV
Publication of CN110494439A publication Critical patent/CN110494439A/en
Application granted granted Critical
Publication of CN110494439B publication Critical patent/CN110494439B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65525—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring
    • C07F9/65527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a seven-(or more) membered ring condensed with carbocyclic rings or carbocyclic ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to novel chiral biphenyl diphosphine ligands of formula (I), or stereoisomers, or mixtures thereof:
Figure DDA0002226334260000011
wherein R is 1 、R 2 And R 3 Independently is H, alkyl or aryl; r 6 And R 7 Independently is a substituent; and a is independently aryl or heteroaryl optionally substituted with one or more substituents.

Description

Chiral biphenyl diphosphine ligand and preparation method thereof
Technical Field
The present invention relates to chemical products and methods for their preparation. In particular, the present invention relates to a novel chiral biphenyldiphosphine ligand, an intermediate for preparing the ligand, and a method for preparing the same. In addition, the invention also relates to a chiral transition metal catalyst containing the novel chiral biphenyl diphosphine ligand and application of the chiral transition metal catalyst in asymmetric reaction.
Background
Asymmetric catalysis is one of the most efficient methods to obtain large quantities of enantiomerically enriched compounds through the action of chiral catalysts in various asymmetric reactions. For asymmetric synthesis, highly promising candidates are transition metal complexes with chiral ligands. Despite the large number of chiral ligands employed in asymmetric syntheses, only a few have been practically applied by the chemical and pharmaceutical industries in the manufacture of chiral molecules.
Among these ligands, BINAP is one of the commonly used chiral ligands. BINAP has been shown to be highly effective for many asymmetric reactions (Noyori and Takaya, acc. Chern. Res., 1990,23,345; and Olkuma et al, am. Chern. Soc.,1998,120,13529). Related axially asymmetric ligands, such as MeO-BIPHEP and BIPHEMP, have also been used in many asymmetric reactions (Schmid et al, pure & Appl. Chern.,1996,68,131, foricher, heiser, and Schmid, U.S. Pat. Nos. 5,302,738 Michel, european patent application 0667350A1; and Broger et al, WO 92/16536). The structures of BINAP, BIPHEMP and MeO-BIPHEP are shown below.
Figure BDA0002226334250000011
Despite extensive research in this field, there are still a number of reactions in which only moderate enantioselectivities were achieved using these ligands. Thus, there remains a high need to develop novel chiral ligands that are selective and efficient in various asymmetric catalytic reactions and are readily available synthetically.
Disclosure of Invention
The present invention provides a compound of formula (I), or a stereoisomer, or a mixture of stereoisomers thereof, which is a novel chiral biphenyldiphosphine ligand:
Figure BDA0002226334250000021
wherein R is 1 、R 2 And R 3 Independently H, alkyl or aryl;
R 6 and R 7 Independently is a substituent; and is provided with
A is independently aryl or heteroaryl optionally substituted with one or more substituents.
The invention also provides novel intermediates of the compounds of formula (I) of the invention, or stereoisomers, or mixtures thereof, and processes for their preparation.
The present invention also provides a chiral transition metal catalyst comprising: a compound of formula (I) of the present invention, or a stereoisomer thereof, or a mixture of stereoisomers thereof; and transition metals, or ions or complexes thereof.
The invention further provides for the use of the chiral transition metal catalyst of the invention in asymmetric reactions.
Detailed Description
In the present application, the term "alkyl" refers to an unsubstituted or substituted straight or branched chain hydrocarbon group having 1 to 20 carbon atoms, preferably having 1 to 7 carbon atoms. Exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, octyl and the like. Substituted alkyl groups include, but are not limited to, alkyl groups substituted with one or more of the following groups: halogen, cycloalkyl, alkoxy or aryl.
In the present application, the term "aryl" refers to a phenyl group, which may be optionally substituted with 1-4 substituents, such as optionally substituted alkyl, cycloalkyl, halogen or alkoxy.
In this application, the term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing one or two aromatic rings and of which from 5 to 14 atoms, one, two, three, four, or five, unless otherwise specified, are heteroatoms independently selected from N, O and S, and includes thienyl, furyl, pyrrolyl, pyridyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, and the like. Preferably, heteroaryl is furyl or pyridyl.
The term "cycloalkyl" refers to an optionally substituted monocyclic aliphatic hydrocarbon group having 3 to 6 carbon atoms, which may be substituted with one or more substituents such as alkyl, alkoxy or halogen.
The term "alkoxy" refers to alkyl-O-.
The terms "halogen", "halide" or "halo" refer to fluorine, chlorine, bromine and iodine.
In this application, the term "substituent" refers to alkyl, cycloalkyl, alkoxy, or halogen.
In a first aspect, the present invention provides a compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof:
Figure BDA0002226334250000031
wherein R is 1 、R 2 And R 3 Independently is H, alkyl or aryl;
R 6 and R 7 Independently is a substituent; and is
A is independently aryl or heteroaryl optionally substituted with one or more substituents.
Preferably, R 1 、R 2 、R 3 、R 6 And R 7 Independently H or alkyl, more preferably independently H.
Preferably, A is phenyl optionally substituted with one or more substituents, and more preferably, A is
Figure BDA0002226334250000032
More preferably, the compound of formula (I) is the following compound or a mixture thereof:
Figure BDA0002226334250000041
stereoisomers of the compounds of formula (I) include enantiomers and diastereomers. For example, the stereoisomers of the compounds of formula (I) are isomers of formulae (I-1 a) to (I-1 d) or mixtures thereof, due to the chiral centres in the side chains and also the axial chirality of the biphenyl system:
Figure BDA0002226334250000042
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined above.
Preferably, the stereoisomers of the compounds of formula (I) are the following isomers or mixtures thereof:
Figure BDA0002226334250000043
the compounds of the present invention preferably have an optical purity of at least 85% enantiomeric excess (ee) and diastereomeric excess (de), more preferably at least 95% ee and de and most preferably at least 98% ee and de.
In a second aspect, the present invention provides novel intermediates of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof:
Figure BDA0002226334250000051
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined above.
Stereoisomers of the compounds of formula (II) include enantiomers and diastereomers. For example, the stereoisomers of the compounds of the formula (II) are isomers of the formulae (II-1 a) to (II-1 d) or mixtures thereof, owing to the chiral centers in the side chains and also to the axial chirality of the biphenyl system:
Figure BDA0002226334250000052
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined above.
The intermediates of formula (II), or stereoisomers thereof, or mixtures thereof, may be used to prepare compounds of formula (I), or stereoisomers thereof, or mixtures thereof, according to the methods disclosed herein.
In a third aspect, the present invention provides a process for the preparation of a compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, which process comprises:
reducing a compound of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof, to produce a compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof:
Figure BDA0002226334250000053
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined above.
The above reduction can be carried out as is known in the art from phosphine oxides to phosphines (see Damien H rault et al, chem. Soc. Rev.,2015 (44), 2508-2528). In one embodiment, the compound of formula (II) is reduced with a reducing agent such as trichlorosilane in a solvent such as xylene, toluene, and Tetrahydrofuran (THF) in the presence of a base such as trimethylamine and tributylamine to provide the compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof.
In this embodiment, the reducing agent may be added in an amount of 2 to 20 moles, preferably 2 to 10 moles, more preferably 4 to 8 moles per mole of the compound of formula (II), or a stereoisomer thereof or a mixture of stereoisomers thereof; the base may be added in an amount of 2 to 20 moles, preferably 2 to 10 moles, more preferably 4 to 8 moles per mole of the compound of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof.
In this process, the reaction may be carried out at a temperature of 50 ℃ to 200 ℃, preferably 100 ℃ to 160 ℃, more preferably at reflux. Preferably, the reaction may be carried out under the protection of an inert gas such as nitrogen or argon.
The product of the process, i.e. the compound of formula (I), or a stereoisomer thereof, or a stereoisomeric mixture thereof, can be easily purified from the reaction mixture, for example by extraction, recrystallization and column chromatography, for further use.
In the present invention, the intermediate of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof, may be produced by a process comprising:
1) In the presence of a base (such as trimethylamine (Et) 3 N)) and a catalyst, preferably a palladium catalyst (e.g. PdCl) 2 And Pd (dppf) Cl 2 ) With a compound of formula (III) in a solvent such as toluene and xylene in the presence of a compound of formula (III) of formula HP = O (OR) 8 ) 2 Reacting the compound to produce a compound of formula (III-1); and
Figure BDA0002226334250000061
2) Converting the compound of formula (III-1) to a compound of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof,
Figure BDA0002226334250000071
wherein R is 1 、R 2 、R 3 、R 6 And R 7 As defined above, and R 8 Is alkyl and X is halogen.
In step 1), formula HP = O (OR) 8 ) 2 The compound may be added in an amount of 2 to 10 moles, preferably 2 to 4 moles, per mole of the compound of formula (III); the solvent may be 500 to 2000mL, preferably 800 to 1500mL, more preferably 500mL per mole of the compound of formula (III)Optionally adding 1000mL to 1200 mL; and the base may be added in an amount of 2 to 10 moles, preferably 2 to 5 moles, per mole of the compound of formula (III).
In step 1), the reaction may be carried out under the protection of an inert gas such as nitrogen, and the reaction temperature may be 20 ℃ to 150 ℃, preferably under reflux.
The obtained compound of formula (III-1) can be isolated from the reaction of step 1) by any known method such as extraction, for use in the next step.
In step 2), the conversion can be achieved by Grignard reaction (Grignard reaction) and coupling reaction. In one embodiment of step 2), the conversion comprises a subsequent grignard reaction followed by a coupling reaction, as shown below.
Figure BDA0002226334250000072
In another embodiment of step 2), the conversion comprises a coupling reaction followed by a grignard reaction, as shown below.
Figure BDA0002226334250000081
In the above-described Grignard reaction, a chlorinating agent (such as SOCl) may be added first 2 ) To perform a chlorination reaction in a solvent such as THF in the presence of a catalyst such as Dimethylformamide (DMF), and then adding a grignard reagent (a-MgX, a and X being defined as above) to perform a grignard reaction in a solvent such as THF.
In the coupling reaction, a coupling agent such as Lithium Diisopropylamide (LDA) or 2,2,6,6-tetramethyllithium piperidine (LiTMP) may be added to the reaction mixture, such as FeCl 3 In the presence of an oxidizing agent such as THF or diethyl ether (Et) 2 O) in a solvent.
Preferably, the conversion is carried out under an inert atmosphere, for example under a nitrogen or argon blanket.
In the present invention, the compound of formula (III) may be produced by a process comprising:
a) Reacting a compound of formula (IV) with a compound of formula (V) to obtain a compound of formula (VI);
Figure BDA0002226334250000082
b) Reducing the obtained compound of formula (VI) to obtain a compound of formula (VI-1); and
Figure BDA0002226334250000083
c) Reacting the obtained compound of formula (VI-1) with a compound of formula (V-I) to give a compound of formula (III)
Figure BDA0002226334250000091
Wherein R is 1 、R 2 、R 3 、R 6 、R 7 And X is as defined above; r 4 Is H, alkyl or aryl; and R is 5 Is H.
In step a) of the process, the reaction may be under Mitsunobu reaction conditions, for example under conditions such as triphenylphosphine (PPh) 3 ) And azo compounds such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and 1,1' - (azodicarbonyl) dipiperidine (ADDP) in the presence of a base such as THF or Et 2 O in a solvent.
In step a) of the process, the compound of formula (V) may be added in an amount of 1 to 10 moles, preferably 1 to 4 moles, more preferably 1 to 2 moles per mole of the compound of formula (IV); and the phosphine may be added in an amount of 1 to 10 moles, preferably 1 to 4 moles, more preferably 1 to 2 moles per mole of the compound of formula (IV).
The reaction of step a) of the process may be carried out at a temperature of from 0 ℃ to 100 ℃, preferably from 20 ℃ to 60 ℃.
The resulting product from step a) can be used in the next step after filtration and concentration.
The compounds of formula (IV) and formula (V) are commercially available or synthesized by methods known in the art (see carra s.m.pereira et al, chemical Engineering Science, vol 64, phase 14, 7/15/2009, p 3301-3310).
In step b) of the process, the reduction may be carried out in an ester reduction process known in the art (see Svenja Werkmeister et al, org. Process Res. Dev.,2014,18 (2), pages 289-302).
In one embodiment of step b), the reducing agent used is selected from NaBH 4 And LiAlH 4 And the reducing agent is added in an amount of 1 to 10 moles, preferably 2 to 8 moles, preferably 4 to 6 moles, per mole of the compound of formula (VI-1). In the use of NaBH 4 In the case of a reducing agent, caCl is preferably added in an amount of 2 to 4 mol per mol of the compound of the formula (VI-1) 2 、 MgCl 2 Or ZnCl 2 。
The reaction of step b) of the process may be carried out at a temperature of-10 ℃ to 100 ℃, preferably 0 ℃ to 40 ℃. The resulting product of the compound of formula (VI-1) can be used in the next step after extraction and concentration.
In step c) of the process, the reaction may be carried out under the same Mitsunobu reaction conditions as in step a). The resulting product of the compound of formula (III) can be used in the next step, either purified or not.
Alternatively, the compound of formula (II) may be produced from the compound of formula (VI-1) by a nucleophilic substitution reaction. As an example, the nucleophilic substitution reaction comprises the following steps:
step (c-1): converting the compound of formula (VI-1) to a compound of formula (VI-2) by addition of a leaving group:
Figure BDA0002226334250000101
and
step (c-2): reacting a compound of formula (VI-2) with a compound of formula (V-I) to produce a compound of formula (III),
Figure BDA0002226334250000102
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And X is as defined above and Y is a leaving group, such as a toluene sulfonic acid (Ts) group or a methane sulfonic acid (Ms) group.
In step (c-1), the reaction may be in the presence of a base (such as Et) 3 N) and a leaving group chloride (such as p-toluenesulfonyl chloride or methanesulfonyl chloride).
In step (c-2), the reaction may be at, for example, K 2 CO 3 、CS 2 CO 3 And Na 2 CO 3 In the presence of a base such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), CH 3 CN and acetone.
In a fourth aspect, the present invention provides a chiral transition metal catalyst comprising: a compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof; and transition metals, or ions or complexes thereof:
Figure BDA0002226334250000111
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined above.
The transition metal may be iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium or platinum, especially ruthenium, rhodium or iridium. Preferably, the chiral transition metal catalyst of the present application comprises the metal ruthenium, rhodium or iridium and 1 to 5 moles, preferably 1 to 2 moles, of the compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, per mole of said metal.
The chiral transition metal catalysts of the present application can be obtained by reacting a compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, with a suitable metal salt or a suitable metal complex of a transition metal. The chiral transition metal catalyst may be generated in situ, or it may be isolated prior to use.
The chiral transition metal catalysts of the present invention, obtainable as described herein, are useful for converting prochiral substrates to chiral products under reaction conditions otherwise applicable to asymmetric induction. Thus, in a fifth aspect, the present invention provides a method of converting a prochiral substrate to a chiral product by using the chiral transition metal catalyst of the invention in an asymmetric reaction.
Such asymmetric reactions include, but are not limited to, catalytic hydrogenation, hydrosilylation, hydroboration, hydroformylation, hydrocarboxylation, hydroacylation, heck reactions, and some allyl isomerization and substitution reactions. The preferred reaction for asymmetric induction using the chiral transition metal catalysts of the present application is catalytic hydrogenation. The chiral transition metal catalysts of the present invention are particularly effective when used in the asymmetric catalytic hydrogenation of Cyclic Anhydrides (CAN) to L-Lactones (LAP) as follows:
Figure BDA0002226334250000121
the following examples are intended to further illustrate the invention and should not be construed as limiting the invention.
Examples
Example 1
Figure BDA0002226334250000122
Step I: (R) -2- (3-bromophenoxy) propionic acid methyl ester
To a 250mL dry three-necked round bottom flask equipped with a magnetic stirrer and a thermometer was added under nitrogen atmosphere:
12.3g of L (-) -ethyl lactate (104.0 mmol,1.0 equiv),
28.1g of triphenylphosphine (PPH) 3 107.6mmol,1.03 equivalent),
18.0g of 3-bromophenol (104.0 mmol,1.0 equiv.), and
100mL of Tetrahydrofuran (THF). Then the
21.0g of diisopropyl azodicarboxylate (DIAD, 104.0mmol,1.0 equiv.) was added dropwise to the reaction mixture at 0-10 ℃ and the reaction was allowed to stir overnight at room temperature (16 h). Then THF is removed in vacuo and the remaining crude product is comminuted, in
200mL of petroleum ether (PE, bp =60-90 ℃), triphenylphosphine oxide, and diisopropyl 1,2-hydrazinedicarboxylate were filtered as a white solid, and the solution was concentrated to give the crude product as a colorless oil without further purification (24.8g, 87.3-93.8% yield).
Example 2
Figure BDA0002226334250000131
Step II: (R) -2- (3-bromophenoxy) propan-1-ol
To a 500mL dry three-necked round bottom flask equipped with a magnetic stirrer and a thermometer was added under nitrogen:
10.0g of methyl (R) -2- (3-bromophenoxy) propionate (36.6 mmol,1.0 eq),
8.2g of calcium chloride (73.5mmol, 2.0 equiv.), and
250mL of EtOH at 0 ℃ followed by
5.5g of sodium borohydride (147.0 mmol,4.0 equiv.) were added portionwise over 15min and the reaction was stirred overnight (16 h) and then quenched with water
Quench with 200mL of 1M HCl, remove the solvent in vacuo, and use
Extracted three times with 200mL of ethyl acetate and then Na 2 SO 4 Dried and evaporated to dryness to give a colorless oil (8.0g, 90-95% yield)
Example 3
Figure BDA0002226334250000132
Step III: (R) -1,2-bis (3-bromophenoxy) propane
In a 100mL dry three-necked round bottom flask equipped with a magnetic stirrer and a thermometer under nitrogen protection were added:
5.0g of (R) -2- (3-bromophenoxy) propan-1-ol (21.6 mmol,1.0 eq),
6.3g of triphenylphosphine (24mmol, 1.1 eq.), and
20.0mL of THF. Then the
4.0g of 3-bromophenol (23mmol, 1.05 eq.) and
4.6g of diisopropyl azodicarboxylate (23mmol, 1.05 eq.) after stirring for a further 1h at 23 ℃ the solvent is removed in vacuo and
100mL of petroleum ether and
0.5mL of H 2 O 2 (30%) after stirring for 1h and filtration, the solvent was removed in vacuo to give a colorless oil (6.87g, 82% yield).
Example 4
Figure BDA0002226334250000141
Step III: (R) -1,2-bis (3-bromophenoxy) propane
To a 100mL dry three-necked round bottom flask equipped with a magnetic stirrer and a thermometer was added under nitrogen:
9.2g of (R) -2- (3-bromophenoxy) propan-1-ol (40.0 mmol,1.0 equiv),
4.45g of triethylamine (44.0 mmol,1.1 equiv),
30.0mL of methylene chloride, then
4.8g of methanesulfonyl chloride (42mmol, 1.05 eq) was added dropwise at 0 ℃, the mixture was gradually warmed to room temperature and stirred for an additional 1h, then dichloromethane was removed in vacuo and to another 500mL dry three-necked round bottom flask equipped with a magnetic stirrer and thermometer was added:
150mL of acetonitrile contained in the reaction solution,
6.9g of 3-bromophenol (40.0 mmol,1.0 equiv),
27.6g of potassium carbonate (200.0 mmol,5.0 equiv.) were then refluxed for 1h and added
Methanesulfonate in 10.0mL acetonitrile, the mixture was refluxed overnight (16 h), filtered and washed with
After 50.0mL of acetonitrile, the solvent was removed and the residue was dissolved
50.0mL of methylene chloride in combination with
50.0mL of 1M HCl,
50.0mL of water was washed, then concentrated and separated by flash column to give a colorless oil (12.8 g,81-83% yield).
Example 5
Figure BDA0002226334250000151
Step IV: tetraethyl (((2R) -propane-1,2-diylbis (oxy)) bis (3,1-phenylene)) bis (phosphonate)
To a 50mL dry Schlenk tube equipped with a magnetic stirrer and a rubber septum were added, under a blanket of dry nitrogen:
95.0mg of Pd (dppf) Cl 2 (0.13mmol, 0.01 equivalent),
5.0g of (R) -1,2-bis (3-bromophenoxy) propane (13.0 mmol,1.0 equiv),
4.0mL of diethyl phosphate (31.1mmol, 2.4 equiv),
4.4mL of triethylamine (31.1mmol, 2.4 equivalents), and
13mL of toluene. The solution was then cooled to-78 ℃ under vacuum to remove residual oxygen from the solution. After warming to room temperature under dry nitrogen, the solution was stirred at reflux for 10h. After the mixture is cooled to the room temperature,
50mL of water was added, followed by
50mL of dichloromethane were extracted 3 times and the combined organic solutions were taken up in
Washed with 100mL of brine, washed with Na 2 SO 4 Dried and the solvent removed in vacuo (6.1g, 94% yield).
Example 6
Figure BDA0002226334250000152
Step V: ((2R) -propane-1,2-diylbis (oxy)) bis (3,1-phenylene)) bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine oxide)
To a 250mL dry three-necked round bottom flask equipped with a magnetic stirrer and a thermometer was added under nitrogen:
1.0g of tetraethyl (((2R) -propane-1,2-diylbis (oxy)) bis (3,1-phenylene)) bis (phosphonate) (2.0 mmol,1.0 equiv.) in 3.0mL of thionyl chloride (40.0 mmol,20.0 equiv.) was added under nitrogen
30.0. Mu.L of dimethylformamide (0.4 mmol,0.2 eq). The mixture was stirred at reflux for 18h, during which time
After 12h 15.0. Mu.L of dimethylformamide (8.0 mmol total, 0.3 equiv.) was added. After evaporation of the solvent, the residue is dissolved in
5.0mL of THF and concentration in vacuo (once). The residue was used in the next step without further purification.
At 0 ℃ under nitrogen will be
0.53g of magnesium chips (22.0 mmol,11.0 equivalents) and
6.0g of 5-bromo-1,3-di-tert-butyl-2-methoxybenzene (20.0mmol, 10.0 equiv.) in
A solution of phenylmagnesium bromide prepared as a suspension in 20.0mL of THF was added dropwise to the solution of the residue prepared above. After stirring at room temperature for a further 1.5h, the mixture is used at 0 DEG C
10.0mL of water was quenched and used
50mL of methylene chloride were extracted three times. The combined organic layers were washed with Na 2 SO 4 Dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate =75 to give the product as a white solid (1.94g, 81% yield).
Example 7
Figure BDA0002226334250000161
Step VI: (S) AX ,R)-3,5-t-Bu-4-MeO-LacBIPHEP dioxide
To a 250mL dry three-necked round bottom flask equipped with a magnetic stirrer and a thermometer was added under nitrogen:
6.5mL of the suspension at-78 ℃ over a period of 15min n BuLi (14.4 mmol,3.6 equiv.) was added dropwise to
2.2mL of diisopropylamine (16.0 mmol,4.0 equivalents) in dry form
30mL of THF, whereby the temperature rose to about-50 ℃ and a white precipitate formed (a yellow precipitate was sometimes observed). Replacement of CO by Ice/ethanol bath 2 The bath was cooled with acetone and the reaction mixture was stirred at about-15 ℃ for an additional 30 minutes and then cooled again to-78 ℃. Will be provided with
4.8g (((2R) -propane-1,2-diylbis (oxy)) bis (3,1-phenylene)) bis (3,5-di-tert-butyl-4-methoxyphenyl) phosphine oxide) (4.0 mmol,1.0 equiv.) in
12.0mL of a solution in dry tetrahydrofuran was added dropwise to the reaction mixture, whereupon the temperature rose to about-68 ℃ and a translucent caramel colored solution (sometimes dark green) was obtained. After a further period of 5h at-78 ℃ will be started
1.9g of anhydrous FeCl 3 (12.0 mmol,3.0 equiv.) in
A suspension of 30.0ml in THF is added directly to the reaction mixture in one portion. After the reaction was completed overnight (16 h), the reaction was allowed to proceed at 0 deg.C
Quench with 2.0mL of saturated ammonium hydroxide. After filtration, the solvent was removed on a rotary evaporator. Dissolving the oil residue in
40mL of methylene chloride was washed with 2N aqueous HCl, brine and anhydrous Na 2 SO 4 Dried and concentrated. The product was isolated by flash column (petroleum ether/ethyl acetate =75/25, 48.7-68.3% yield).
Example 8
Figure BDA0002226334250000171
Step VII: (S) AX ,R)-3,5-t-Bu-4-MeO-LacBIPHEP
To a 10mL dry Schlenk tube equipped with a magnetic stirrer and a rubber septum were added under nitrogen:
490mg of (S) Ax R) -3,5-t-Bu-4-MeO-LacBIPHEP dioxide (0.41 mmol,1.0 equiv),
720. Mu.l of tributylamine (3.0 mmol,7.4 equiv.), and
3.5 μ L of degassed xylene. Then the
290 μ L of trichlorosilane (2.9 mol,7.0 equiv) was added under reflux and another 3 h was stirred. After cooling to 0 c, the mixture was cooled,
6.0mL of 30% aqueous NaOH solution was added and the mixture was stirred at 60 ℃ until the organic and aqueous layers became clear. The organic product is used
10.0mL of degassed toluene were extracted three times and the combined organic layers were successively washed with
10.0mL of water, saturated aqueous NaCl and washed with anhydrous Na 2 SO 4 And drying.
The organic layer was concentrated on a rotary evaporator, followed by vacuum distillation to give a crude product containing traces of tributylamine. The residue is used
1.0mL of cold hexane was washed three times to give the pure product as a white powder (477mg, 99% yield).
Example 9: asymmetric hydrogenation of CAN to LAP
Figure BDA0002226334250000181
Will be provided with
1.25g of CAN,
2.5mg of [ Ir (COD) Cl] 2 、
9.1mg of (S) Ax R) -3,5-t-Bu-4-MeO-LacBIPHEP and
a mixture of 10mL of THF was charged to a 35mL autoclave, sealed, then flushed three times with nitrogen and 80 bar of hydrogen was introduced. After heating at 70 ℃ for 18h with shaking, the reaction was cooled to room temperature and the final pressure was 24.1 bar.
Conversion and chemoselectivity, diastereoselectivity and enantiomeric purity were determined by HPLC. Conversion >99% and enantiomeric excess 95% (L).
Example 10
Figure BDA0002226334250000191
600mg of CAN,
6.0mg of [ Ir (COD) Cl] 2 、
22.0mg
Figure BDA0002226334250000192
BINAP and
a mixture of 10mL of THF was charged to a 35mL autoclave, sealed, then flushed three times with nitrogen and 80 bar of hydrogen was introduced. After heating at 70 ℃ for 18h with shaking, the reaction was cooled to room temperature and the final pressure was 24.1 bar.
Conversion and chemoselectivity, diastereoselectivity and enantiomeric purity were determined by HPLC. Conversion >99%, lactone yield 44%, enantiomeric excess 73.8% (D).

Claims (21)

1. A compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof:
Figure DEST_PATH_IMAGE001
wherein R is 1 、R 2 And R 3 Independently H, alkyl or aryl;
R 6 and R 7 Independently is H or alkyl; and is
A is independently aryl or heteroaryl optionally substituted with one or more substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, and halogen.
2. The compound of claim 1, wherein R 1 、R 2 、R 3 、R 6 And R 7 Independently is H or C 1-7 An alkyl group; and A is phenyl optionally substituted with one or more substituents selected from C 1-7 Alkyl radical, C 3-6 Cycloalkyl, C 1-7 Alkoxy and halogen.
3. The compound of claim 1 or 2, wherein a is phenyl, or
Figure 955471DEST_PATH_IMAGE002
。
4. The compound according to claim 1 or 2, wherein the compound of formula (I) is the following compound or a mixture thereof:
Figure DEST_PATH_IMAGE003
。
5. the compound of claim 1 or 2, wherein the stereoisomer is an isomer of formulae (I-la) to (I-1 d) or a mixture thereof:
Figure 731666DEST_PATH_IMAGE004
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And a is as defined in any one of claims 1-2.
6. The compound according to claim 1 or 2, wherein the stereoisomer is the following isomer or a mixture thereof:
Figure DEST_PATH_IMAGE005
。
7. a compound of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof
Figure 183507DEST_PATH_IMAGE006
Wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined in any one of claims 1 to 6.
8. The compound of claim 7, wherein the stereoisomer is an isomer of formulae (II-1 a) to (II-1 d) or a mixture thereof:
Figure DEST_PATH_IMAGE007
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined in any one of claims 1 to 6.
9. A method of producing a compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof, the method comprising:
reducing a compound of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof, to produce the compound of formula (I), or a stereoisomer thereof, or a mixture of stereoisomers thereof:
Figure 155880DEST_PATH_IMAGE008
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined in any one of claims 1 to 6, and
wherein the compound of formula (II), or a stereoisomer, or a mixture of stereoisomers thereof, is produced by a process comprising:
1) In the presence of a base and a catalystReacting a compound of formula (III) with a compound of formula HP = O (OR) in a solvent 8 ) 2 Reacting the compound to produce a compound of formula (III-1); and
Figure DEST_PATH_IMAGE009
2) Converting a compound of formula (III-1) to a compound of formula (II), or a stereoisomer thereof, or a mixture of stereoisomers thereof,
Figure 360465DEST_PATH_IMAGE010
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And A is as defined in any one of claims 1 to 6, and R 8 Is alkyl and X is halogen.
10. The method of claim 9, wherein R 8 Is C 1-7 An alkyl group.
11. The process according to claim 9 or 10, wherein the solvent is selected from toluene and xylene.
12. The process according to claim 9 or 10, wherein the base is trimethylamine.
13. The method of claim 9 or 10, wherein the catalyst is a palladium catalyst.
14. The method of claim 13, wherein the palladium catalyst is selected from PdCl 2 And Pd (dppf) Cl 2 。
15. The method of claim 9, wherein the conversion of step 2) is achieved by a grignard reaction and a coupling reaction.
16. The method of claim 9, 10 or 15, wherein the compound of formula (III) is produced by a method comprising:
a) Reacting a compound of formula (IV) with a compound of formula (V) to obtain a compound of formula (VI);
Figure DEST_PATH_IMAGE011
b) Reducing the obtained compound of formula (VI) to obtain a compound of formula (VI-1); and
Figure 41983DEST_PATH_IMAGE012
c) Reacting the obtained compound of formula (VI-1) with a compound of formula (V-I) to produce said compound of formula (III),
Figure DEST_PATH_IMAGE013
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And X is as defined in claim 9 or 10; r is 4 Is H, alkyl or aryl; and R is 5 Is H.
17. The method of claim 16, wherein R 4 Is H, C 1-7 Alkyl or aryl.
18. The method of claim 16, wherein the compound of formula (III) is produced from a compound of formula (VI-1) by:
step (c-1): converting said compound of formula (VI-1) to a compound of formula (VI-2) by addition of a leaving group:
Figure 715540DEST_PATH_IMAGE014
and an
Step (c-2): reacting the compound of formula (VI-2) with the compound of formula (V-I) to produce the compound of formula (III),
Figure DEST_PATH_IMAGE015
wherein R is 1 、R 2 、R 3 、R 6 、R 7 And X is as defined in claim 16 and Y is a leaving group.
19. The method of claim 18, wherein the leaving group is a toluene sulfonic acid (Ts) group or a methane sulfonic acid (Ms) group.
20. A chiral transition metal catalyst comprising a compound according to any one of claims 1-6, and a transition metal, or an ion or complex thereof, wherein the transition metal is selected from the group consisting of: iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium or platinum.
21. A method for converting a prochiral substrate to a chiral product in an asymmetric catalytic hydrogenation reaction by using the chiral transition metal catalyst of claim 20, wherein the prochiral substrate is CAN and the chiral product is LAP,
Figure 44934DEST_PATH_IMAGE016
。
CN201880023975.2A 2017-04-11 2018-04-09 Chiral biphenyl diphosphine ligand and preparation method thereof Active CN110494439B (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN2017080063 2017-04-11
CNPCT/CN2017/080063 2017-04-11
PCT/EP2018/059021 WO2018189107A1 (en) 2017-04-11 2018-04-09 A new chiral biphenyl diphosphine ligand and process for preparation thereof

Publications (2)

Publication Number Publication Date
CN110494439A CN110494439A (en) 2019-11-22
CN110494439B true CN110494439B (en) 2022-11-08

Family

ID=61913181

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201880023975.2A Active CN110494439B (en) 2017-04-11 2018-04-09 Chiral biphenyl diphosphine ligand and preparation method thereof

Country Status (2)

Country Link
CN (1) CN110494439B (en)
WO (1) WO2018189107A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR3095974B1 (en) 2019-05-17 2022-05-20 Safran Helicopter Engines DEVICE AND METHOD FOR ADDITIVE MANUFACTURING BY POWDER BED LASER FUSION
CN111205208B (en) * 2020-01-16 2021-12-17 郑州恒诚仪器耗材有限公司 Cyclohexane-1, 3-diketone compound and synthetic method and application thereof
WO2021143617A1 (en) * 2020-01-16 2021-07-22 郑州手性药物研究院有限公司 Cyclohexadiene oxime ether compound, synthesis method therefor and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004111063A2 (en) * 2003-06-13 2004-12-23 Lanxess Deutschland Gmbh Chiral ligands for application in asymmetric syntheses
CN1704421A (en) * 2004-05-10 2005-12-07 兰克赛斯德国有限公司 Cirality diphosphaneterpene and transition metal complex thereof
CN101048419A (en) * 2004-10-26 2007-10-03 巴斯福股份公司 Ligands for use in asymmetric hydroformylation
CN101230075A (en) * 2008-02-22 2008-07-30 武汉大学 Central chirality induced axial chirality diphosphine ligand and method for synthesizing same

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE135008T1 (en) 1991-03-15 1996-03-15 Hoffmann La Roche CHIRAL PHOSPHINS
ATE141278T1 (en) 1991-03-15 1996-08-15 Hoffmann La Roche DIPHOSPHONIC ACID DERIVATIVES AS INTERMEDIATE PRODUCTS FOR THE PRODUCTION OF DIPHOSPHONE LIGANDS
US5536858A (en) 1994-02-12 1996-07-16 Hoffmann-La Roche Inc. Tetrasulfonated diphosphine compounds and metal complexes thereof for asymmetric catalytic reactions
US7094725B2 (en) * 2003-07-11 2006-08-22 The Hong Kong Polytechnic University Biphenyldiphosphine compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004111063A2 (en) * 2003-06-13 2004-12-23 Lanxess Deutschland Gmbh Chiral ligands for application in asymmetric syntheses
CN1704421A (en) * 2004-05-10 2005-12-07 兰克赛斯德国有限公司 Cirality diphosphaneterpene and transition metal complex thereof
CN101048419A (en) * 2004-10-26 2007-10-03 巴斯福股份公司 Ligands for use in asymmetric hydroformylation
CN101230075A (en) * 2008-02-22 2008-07-30 武汉大学 Central chirality induced axial chirality diphosphine ligand and method for synthesizing same

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Recoverable Catalysts for Asymmetric Organic Synthesis;Qing-Hua Fan et al.;《 Chem. Rev.》;20020918;第102卷;第3385-3466页 *

Also Published As

Publication number Publication date
CN110494439A (en) 2019-11-22
WO2018189107A1 (en) 2018-10-18

Similar Documents

Publication Publication Date Title
JP4488739B2 (en) P-chiral phosphoranes and phosphocyclic compounds and their use in asymmetric catalysis
KR20000016597A (en) Asymmetric synthesis catalyzed by transition metal complexes with cyclic chiral ligands
KR100384411B1 (en) Chiral ligand in heteroaromatic diphosphine
CN110494439B (en) Chiral biphenyl diphosphine ligand and preparation method thereof
CA2382779C (en) Chiral ligands, transition-metal complexes thereof and uses thereof in asymmetric reactions
KR20130079319A (en) Ruthenium complex and method for preparing optically active alcohol compound
WO2005108407A1 (en) Cycloolefin phosphine ligands and their use in catalysis
US20150018555A1 (en) Novel chiral nitrogen-phosphorus ligands and their use for asymmetric hydrogenation of alkenes
JP5454756B2 (en) Diphosphine compounds, transition metal complexes thereof, catalysts containing the transition metal complexes, phosphine oxide compounds and diphosphine oxide compounds
AU2011301115B2 (en) Biaryl diphosphine ligands, intermediates of the same and their use in asymmetric catalysis
CN111925356B (en) Synthesis method and application of chiral quinoline-imidazoline ligand
US6333291B1 (en) Optically active diphosphine compound, production intermediate thereof, transition metal complex containing the compound as ligand and asymmetric hydrogenation catalyst containing the complex
JP7464234B2 (en) Method for producing highly optically active allene carboxylic acid compounds having axial asymmetry
EP0732337B1 (en) Optically active asymmetric diphosphine and process for producing optically active substance in its presence
CN102553646B (en) Chiral diamine diphosphine metal compound catalysts as well as preparation method and application thereof
Šebesta et al. Influence of structural changes in ferrocene phosphane aminophosphane ligands on their catalytic activity
JP4562736B2 (en) Method for producing optically active alcohol
ES2551894T3 (en) Paracyclofan-based ligands, their preparation and use in catalysis
Wu Development of Methods for Stereoselective Carbon-Carbon Bond Formation
JP2012031119A (en) Axially chiral isoquinoline derivative, its production method, and asymmetric synthesis method
Abell Development of tethered bis (8-quinolinato) aluminum complexes and applications to catalytic asymmetric reactions
CN112876376A (en) Synthesis method of allyl aryl compound
JP5546294B2 (en) Axial asymmetric phosphine compound and method for producing the same
Yuan Asymmetric synthesis of functionalized chiral diphosphines via organopalladium promoted hydrophosphination and diels-alder reactions
Liu Asymmetric synthesis of chiral phosphines and arsines promoted by organometallic complexes

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