Preparation method and application of phosphine ligand palladium metal complex

Abstract

The invention discloses a preparation method and application of a phosphine ligand palladium metal complex. Specifically, the invention provides a phosphine ligand as shown in a formula I or I'or a racemate thereof. The phosphine coordination palladium metal complex is applied to an asymmetric Suzuki-Miyaura coupling reaction, various ortho-tetra-substituted biaryl compounds can be obtained with low cost, high yield and high enantioselectivity, and the reaction conditions are mild.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing a phosphine ligand palladium metal complex and its application in Suzuki-miyaura coupling reaction. BACKGROUND

[0002] Tetra-substituted axially chiral biaryl compounds play an important role in optoelectronic materials, synthesis of natural products and drug molecules. Suzuki-miyaura coupling reaction is the most direct way to construct such tetra-substituted axially chiral compounds. Chiral phosphine ligands can regulate the reactivity and enantioselectivity in Suzuki-miyaura coupling reaction, so the structure of phosphine ligands and their palladium metal complexes is very important for the construction of tetra-substituted axially chiral compounds.

[0003] In the past few decades, scientists have developed a series of methods to construct tetra-substituted axially chiral compounds (Angew. Chem. Int. Ed. 2009, 48, 2708 – 2710; Angew. Chem. Int. Ed. 2017, 56, 4777; J. Am. Chem. Soc. 2002, 124, 13396; Eur. J. Org. Chem. 2014, 6676; Chem. Eur. J. 2006, 12, 9346; Org. Lett. 2010, 12, 1072.). In 2020, Tang Wenjun's group reported a method for synthesizing tetra-substituted axially chiral compounds by using secondary interactions between ligands and substrates to induce product chirality (J. Am. Chem. Soc. 2020, 142, 8036-8043.). In 2022, Tang Wenjun's group again applied such weak interactions to the synthesis of tetra-substituted axially chiral compounds containing nitro groups (Nat. Commun. 2022, 13, 4577.). Such weak interactions are achieved through hydrogen bonding between the hydroxyl group on BaryPhos and the substrate. Although the BaryPhos / Pd2(dba)3 catalytic system can obtain tetra-substituted biaryl compounds with excellent yield and enantioselectivity, it is found in actual use that the high palladium dosage of the BaryPhos / Pd2(dba)3 catalyzed coupling reaction leads to high catalyst cost, and the compound is difficult to crystallize during the production of BaryPhos. In order to solve the problems of high production cost of tetra-substituted axially chiral biaryl compounds and difficulty in crystallization during the production of BaryPhos, the present application introduces two types of BaryPhos series palladium metal complexes. SUMMARY

[0004] The technical problem this invention aims to solve is to overcome the high catalyst consumption and high production cost in the synthesis of ortho-tetrasubstituted biaryl compounds, as well as the difficulty in crystallization during the BaryPhos production process, by providing a method for preparing phosphine ligand palladium metal complexes. When applied to the asymmetric Suzuki-Miyaura coupling reaction, the phosphine ligand palladium metal complexes of this invention can yield a variety of ortho-tetrasubstituted biaryl compounds with low cost, high yield, and high correspondence selectivity, under mild reaction conditions.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a phosphine ligand or a racemate thereof as shown in Formula I or I':

[0007] ;

[0008] Among them, the standard The phosphorus atom has a configuration of R or S; The carbon atom has a configuration of R or S;

[0009] R 1 R 3 and R 5 Independently hydrogen, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~30 cycloalkyl, R 1-1a Replacement C 3~30 cycloalkyl, C6~ 30 Aryl or R 1-1b Replacement C6~ 30 Aryl; the C 1~10 The heteroatom in the heteroalkyl group is selected from one or more of O, S and N, and the number of said heteroatoms is 1, 2, 3, 4, 5 or 6; when the number of heteroatoms is multiple, the heteroatoms may be the same or different;

[0010] R 2 and R 4 Independently for H and C 1~10 Alkyl, C 1~10 Heteroalkyl, C 3~30 cycloalkyl, R 2-1a Replacement C 3~30 cycloalkyl, C6~ 30 Aryl or R 2-1b Replacement C6~ 30 Aryl; the C 1~10 The heteroatom in the heteroalkyl group is selected from one or more of O, S and N, and the number of said heteroatoms is 1, 2, 3, 4, 5 or 6; when the number of heteroatoms is multiple, the heteroatoms may be the same or different;

[0011] Each R 1-1a and each R 2-1a Independently for C 1~10 Alkyl; R 1-1a and R 2-1a The number is independently one or more; when R 1-1a and R 2-1a The number is independently multiple, R 1-1a and R 2-1a Independently the same or different;

[0012] Each R 1-1b and each R 2-1b Independently for C 1~10 Alkyl, C 1~10 Alkyl or C6~ 30 Aryl; each R 1-1b and each R 2-1b The number is independently one or more, when each R 1-1b and each R 2-1b The number is independently multiple, R 1-1b and R 2-1b Independently the same or different;

[0013] R 6 and R 7 Independently for H and C 1~10 Alkyl, hydroxyl substituted C 1~10 Alkyl, C 3~30 cycloalkyl or C6~ 30 Aryl;

[0014] R 8 Hydroxyl group, C 1~10 Alkyl, hydroxyl substituted C 1~10 Alkyl, C 1~10 Alkoxy, C 3~30 cycloalkyl, mercapto, or C6~ 30 Aryl, of which R 10 and R 11 Independently H or C 1~4 alkyl;

[0015] R 9 C 1~10 Alkyl, C 3~30 cycloalkyl or C6~ 30 Aryl;

[0016] R 8 Hydroxyl group, C 1~10 Alkoxy, Or when thiol, R 8 Through the coordination of heteroatoms N, O, or S with Pd;

[0017] X can be F, Cl, Br, I, or OTf independently.

[0018] In one embodiment, certain groups in the phosphine ligand or its racemate as shown in Formula I or I' are defined as follows, and the definitions of groups not mentioned are as described in any embodiment of the present invention.

[0019] When the R 1 R 3 and R 5 Independently for C 1~10 When alkyl, the C 1~10 Alkyl groups can be C 1~6 Alkyl, preferably C 1~3 Alkyl group. The C... 1~3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, preferably methyl or isopropyl.

[0020] When the R 1 R 3 and R 5 Independently for C 1~10 When it is a heteroalkyl group, the C 1~10 Heteroalkyl groups can be C 1~6 Heteroalkyl groups.

[0021] When the R 1 R 3 and R 5 Independently for C 3~30 When cycloalkyl, the C 3~30 Cycloalkyl groups can be C 3~10 Cycloalkyl.

[0022] When the R 1 R 3 and R 5 Independently for R 1-1a Replacement C 3~30 When cycloalkyl, the R 1-1a Replacement C 3~30 C in cycloalkyl 3~30 Cycloalkyl groups can be C 3~10 Cycloalkyl.

[0023] When the R 1 R 3 and R 5 Independently C6~ 30 In the aryl case, the C6~ 30 Aryl groups can be C 6~14 Aryl.

[0024] When the R 1 R 3 and R 5 Independently for R 1-1b Replacement C6~30 When aryl, the R 1-1b Replacement C6~ 30 C6 in aryl 30 Aryl groups can be C 6~14 Aryl.

[0025] When the R 2 and R 4 Independently for C 1~10 When alkyl, the C 1~10 Alkyl groups can be straight-chain C 1~10 Alkyl or branched C 3~10 Alkyl groups, preferably branched C4 groups 3~10 Alkyl group. Wherein, the straight-chain C 1~10 Alkyl groups can be straight-chain C 1~6 Alkyl groups, preferably straight-chain C 1~3 Alkyl group. The branched C 3~10 Alkyl groups can be branched C-chains. 3~6 Alkyl groups, preferably branched C4 groups 3~5 Alkyl group. The branched C 3~5 Alkyl groups can be isopropyl, , , , , , , or Isopropyl or .

[0026] When the R 2 and R 4 Independently for C 3~30 When cycloalkyl, the C 3~30 Cycloalkyl groups can be C 3~10 Cycloalkyl, preferably C 3~6 Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0027] When the R 2 and R 4 Independently for R 2-1a Replacement C 3~30 When cycloalkyl, R 2-1a Replacement C 3~30 C in cycloalkyl 3~30 Cycloalkyl groups can be C 3~10 Cycloalkyl, preferably C 3~6 Cycloalkyl. The C... 3~6 The cycloalkyl group can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopentyl.

[0028] When the R 2 and R 4 Independently for R2-1a Replacement C 3~30 When cycloalkyl, the R 2-1a Replacement C 3~30 R in cycloalkyl 2-1a The number can be 1, 2, 3, or 4, with 4 being preferred. When the R... 2-1a When the number of replacements is multiple, the R 2-1a The same is preferred.

[0029] When the R 2-1a C 1~10 When alkyl, the C 1~10 Alkyl groups can be C 1~6 Alkyl, preferably C 1~3 Alkyl group. The C... 1~3 The alkyl group may be methyl, ethyl, n-propyl or isopropyl, with methyl being preferred.

[0030] When the R 2 and R 4 Independently for R 2-1a Replacement C 3~30 When cycloalkyl, the R 2-1a Replacement C 3~30 Cycloalkyl groups can be C 1~3 Alkyl-substituted C 3~6 Cycloalkyl groups, further preferred .

[0031] When the R 2 and R 4 Independently C6~ 30 In the aryl case, the C6~ 30 Aryl groups can be C 6~20 Aryl, preferably C 6~14 Aryl, more preferably phenyl.

[0032] When the R 1 R 2 R 3 R 4 and R 5 Independently for R 2-1b Replacement C6~ 30 When aryl, the R 2-1b Replacement C6~ 30 C6 in aryl 30 Aryl groups can be C 6~20 Aryl, preferably C 6~14 Aryl.

[0033] When the R 6 and R 7 Independently for C 1~10 When alkyl, the C 1~10 Alkyl groups can be C 1~6Alkyl, preferably C 1~3 Alkyl group. The C... 1~3 The alkyl group can be methyl, ethyl, n-propyl, or isopropyl.

[0034] When the R 6 and R 7 C that is independently substituted with a hydroxyl group 1~10 When alkyl, the C-substituted hydroxyl group 1~10 C in alkyl 1~10 Alkyl groups can be C 1~6 Alkyl, preferably C 1~3 Alkyl group. The C... 1~3 The alkyl group can be methyl, ethyl, n-propyl or isopropyl, with methyl being preferred.

[0035] When the R 6 and R 7 Independently for C 3~30 When cycloalkyl, the C 3~30 Cycloalkyl groups can be C 3~10 Cycloalkyl.

[0036] When the R 6 and R 7 Independently C6~ 30 In the aryl case, the C6~ 30 Aryl groups can be C6~ 20 Aryl.

[0037] When the R 8 C 1~10 When alkyl, the C 1~10 Alkyl groups can be C 1~6 Alkyl, preferably C 1~3 Alkyl group. The C... 1~3 The alkyl group can be methyl, ethyl, n-propyl or isopropyl, with methyl being preferred.

[0038] When the R 8 C substituted with hydroxyl group 1~10 When alkyl, the C-substituted hydroxyl group 1~10 C in alkyl 1~10 Alkyl groups can be C 1~6 Alkyl, preferably C 1~3 Alkyl group. The C... 1~3 The alkyl group can be methyl, ethyl, n-propyl or isopropyl, with methyl being preferred.

[0039] When the R 8 C substituted with hydroxyl group 1~10 When alkyl, the C-substituted hydroxyl group 1~10 The number of hydroxyl groups in an alkyl group can be one.

[0040] When the R 8 Independently for C1~10 When alkoxy is present, the C 1~10 Alkoxy groups can be C 1~6 Alkoxy, preferably C 1~3 Alkyl groups. The C 1~3 The alkoxy group can be methoxy, ethoxy, n-propoxy, or isopropoxy, with methoxy being preferred.

[0041] When the R 8 for At that time, the Can be , , or Preferred .

[0042] When the R 8 C 3~30 When cycloalkyl, the C 3~30 Cycloalkyl groups can be C 3~10 Cycloalkyl.

[0043] When the R 8 C6~ 30 In the aryl case, the C6~ 30 Aryl groups can be C6~ 20 Aryl.

[0044] When R 9 C 1~10 When alkyl, the C 1~10 Alkyl groups can be straight-chain C 1~10 Alkyl or branched C 3~10 Alkyl groups, preferably branched C4 groups 3~10 Alkyl group. Wherein, the straight-chain C 1~10 Alkyl groups can be straight-chain C 1~6 Alkyl groups, preferably straight-chain C 1~3 Alkyl group. The branched C 3~10 Alkyl groups can be branched C-chains. 3~6 Alkyl groups, preferably branched C4 groups 3~4 Alkyl group. The branched C 3~4 Alkyl groups can be isopropyl, , It can be either tert-butyl or tert-butyl.

[0045] When the R 9 C 3~30 When cycloalkyl, the C 3~30 Cycloalkyl groups can be C 3~10 Cycloalkyl.

[0046] When the R 9 C6~ 30 In the aryl case, the C6~ 30 Aryl groups can be C6~20 Aryl.

[0047] When the R 10 and R 11 Independently for C 1~4 When alkyl, the C 1~4 Alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, , Or tert-butyl.

[0048] In one embodiment of the present invention, the phosphine ligand as shown in Formula I is a phosphine ligand as shown in Formula I-1 or I-2:

[0049] or .

[0050] In one embodiment of the present invention, the phosphine ligand as shown in Formula I' is a phosphine ligand as shown in Formula I'-1 or I'-2:

[0051] or .

[0052] In one embodiment of the present invention, R 1 and R 5 Independently for C 1~10 Alkyl, such as C 1~3 Alkyl groups, such as methyl groups.

[0053] In one embodiment of the present invention, R 1 and R 5 same.

[0054] In one embodiment of the present invention, R 2 and R 4 Independently for H and C 3~30 cycloalkyl, R 2-1a Replacement C 3~30 cycloalkyl or C6~ 30 Aryl.

[0055] In one embodiment of the present invention, R 2 and R 4 Independently for H and C 3~6 cycloalkyl, C6~ 14 Aryl or R 2-1a Replacement C 3~6 cycloalkyl, such as C 3~6 Cycloalkyl.

[0056] In one embodiment of the present invention, R 2 and R 4 same.

[0057] In one embodiment of the present invention, R2-1a Independently for C 1~3 Alkyl groups, such as methyl groups.

[0058] In one embodiment of the present invention, R 2 and R 4 Independently, it is H, phenyl, cyclopentyl, cyclohexyl or .

[0059] In one embodiment of the present invention, R 3 It is hydrogen.

[0060] In one embodiment of the present invention, R 6 and R 7 Independently for H and C 1~10 alkyl or hydroxy substituted C 1~10 alkyl.

[0061] In one embodiment of the present invention, R 6 and R 7 Independently for C 1~10 Alkyl, such as C 1~3 alkyl.

[0062] In one embodiment of the present invention, R 6 and R 7 It can be methyl, ethyl, or isopropyl on its own.

[0063] In one embodiment of the present invention, R 8 Hydroxyl group, C 1~10 Alkyl, C 1~10 alkoxy or .

[0064] In one embodiment of the present invention, R 8 hydroxyl or .

[0065] In one embodiment of the present invention, R 10 and R 11 C 1~4 Alkyl groups, such as methyl groups.

[0066] In one embodiment of the present invention, R 8 hydroxyl or .

[0067] In one embodiment of the present invention, R 9 C 1~10 Alkyl group, preferably C 1~6 Alkyl groups, such as tert-butyl groups.

[0068] In one embodiment of the present invention, for , , , , , , or .

[0069] In one embodiment of the present invention, for .

[0070] In one embodiment of the present invention, in the compound represented by formula I or I', for , , , or .

[0071] In one embodiment of the present invention, in the compound represented by formula I or I', for .

[0072] In one embodiment of the present invention, X is Cl, Br, I or OTf.

[0073] In one embodiment of the present invention,

[0074] R 1 and R 5 Independently for C 1~10 alkyl;

[0075] R 2 and R 4 Independently for C 1~10 Alkyl, C 3~30 cycloalkyl, R 2-1a Replacement C 3~30 cycloalkyl or C6~ 30 Aryl;

[0076] R 3 It is hydrogen;

[0077] R 6 and R 7 Independently for H and C 1~10 alkyl or hydroxy substituted C 1~10 alkyl;

[0078] R 8 Independently hydroxyl, C 1~10 Alkyl, C 1~10 alkoxy or ;

[0079] R 9 C 1~10 Alkyl; and, X is Cl, Br, I or OTf.

[0080] In one embodiment of the present invention,

[0081] R 1 and R 5 Independently for C 1~10 alkyl;

[0082] R 2 and R 4 Independently for C 3~10 cycloalkyl or R 2-1a Replacement C 3~10 cycloalkyl;

[0083] R 3 It is hydrogen;

[0084] R 6 and R 7 Independently for C 1~10 alkyl;

[0085] R 8 Independently, it is a hydroxyl group;

[0086] R 9 C 1~10 Alkyl; and, X is Cl, Br, I or OTf.

[0087] In one embodiment of the present invention, the phosphine ligand as shown in Formula I is selected from any of the following compounds:

[0088] .

[0089] The present invention also provides a method for preparing a phosphine ligand or its racemate as shown in Formula I or I', comprising the following steps:

[0090] The palladium precursor undergoes a coordination complexation reaction in a solvent with a compound or racemate of Formula I-0 to obtain the phosphine ligand or racemate of Formula I.

[0091] The palladium precursor is (COD)PdCl2, palladium diacetonitrile, palladium dichloride, palladium dichloride, palladium dibromide, palladium diiodide, or palladium trifluoromethanesulfonate (Pd(OTf)2).

[0092] Alternatively, the palladium precursor of formula Pd-G3 is subjected to a coordination complexation reaction in a solvent with a compound of formula I-0 or its racemate to obtain the phosphine ligand of formula I' or its racemate.

[0093]

[0094] in, R 1 R 2 R 3 R4 R 5 R 6 R 7 R 8 and R 9 The definitions are as described in the previous scheme.

[0095] In one embodiment of the present invention, the coordination complexation reaction is carried out under an inert atmosphere, such as a nitrogen atmosphere.

[0096] In one embodiment of the present invention, in the coordination complexation reaction, the organic solvent is a haloalkane solvent and / or an ether solvent, for example, the haloalkane solvent is dichloromethane; and the ether solvent is tetrahydrofuran.

[0097] The amount of organic solvent used is the conventional amount used in the art, provided that it does not affect the reaction.

[0098] In one embodiment of the present invention, the temperature of the coordination complexation reaction is 10-50°C, for example 20-30°C, for example 25°C.

[0099] In one embodiment of the present invention, after the coordination complexation reaction is completed, a pulping and purification step is further included, for example, using petroleum ether for pulping to obtain a phosphine ligand or its racemate as shown in Formula I', preferably obtaining a single crystal of a phosphine ligand or its racemate as shown in Formula I'.

[0100] The present invention also provides a single crystal of a compound as shown in Formula I-1:

[0101] The single crystal belongs to the orthorhombic crystal system, and the unit cell parameters of the single crystal are: , , , , , .

[0102] In one embodiment of the present invention, the single-crystal parameters of the compound represented by Formula I-1 are shown in Table 1:

[0103] The present invention also provides the application of a phosphine ligand or its racemate as shown in Formula I or I' as a metal ligand in a Suzuki-Miyaura coupling reaction, wherein the Suzuki-Miyaura coupling reaction comprises the following steps: in the presence of the phosphine ligand or its racemate as shown in Formula I or I' and a basic reagent, compound C and compound D undergo a Suzuki-Miyaura coupling reaction in a solvent to obtain compound E and compound ent-E;

[0104] ;

[0105] in," and "and" and ", all indicate that this group has axial chirality;

[0106] Q is either C or N;

[0107] X is a halogen;

[0108] M is , Or -BF3K;

[0109] When Q is C, R 15 C 1~10 Alkyl groups, -CHO groups, or halogens;

[0110] When Q is N, R 15 It may be absent or contain oxygen;

[0111] R 19 C 1~10 Alkyl groups, -CHO groups, or halogens;

[0112] R 20 and R 24 Independently for C 1~10 Alkyl, C 1~10 Alkyl groups or -CHO;

[0113] R 16 R 17 R 18 R 21 R 22 and R 23 Independently, H, F, nitro, C 1~10 Alkyl, C 1~10 Alkyl group or -C(O)OC 1~10 alkyl;

[0114] The molar ratio of the phosphine ligand or its racemate as shown in Formula I or I' to compound C is 0.0001 - 0.01.

[0115] In one embodiment of the present invention, in the Suzuki-Miyaura coupling reaction, X is Cl, Br, or I, for example, Br.

[0116] In one embodiment of the present invention, in the Suzuki-Miyaura coupling reaction, M is... Or -BF3K.

[0117] In one embodiment of the present invention, in the Suzuki-Miyaura coupling reaction, R 15 R 19R 20 and R 24 In, the C 1~10 Alkyl groups are independently C 1~6 Alkoxy groups, such as C 1~3 Alkyl groups, such as methoxy groups.

[0118] In one embodiment of the present invention, in the Suzuki-Miyaura coupling reaction, R 16 R 17 R 18 R 21 R 22 and R 23 In, the C 1~10 Alkyl groups are independently C 1~6 Alkyl, such as C 1~3 Alkyl groups, such as methyl groups.

[0119] In one embodiment of the present invention, in the Suzuki-Miyaura coupling reaction, R 16 R 17 R 18 R 21 R 22 and R 23 In, the C 1~10 Alkoxy independently C 1~6 Alkoxy groups, such as C 1~3 Alkyl groups, such as methoxy groups.

[0120] In one embodiment of the present invention, Q is C, R 15 -CHO;R 19 C 1~10 Alkyl group.

[0121] In one embodiment of the present invention, Q is N, R 15 For oxygen, R 19 It is a halogen.

[0122] In one embodiment of the present invention, R 20 -CHO;R 24 C 1~10 Alkyl group.

[0123] In one embodiment of the present invention, R 20 C 1~10 Alkyl; R 24 C 1~10 Alkyl group.

[0124] In one embodiment of the present invention, Q is C, R 15 -CHO;R 19 C 1~10 Alkoxy; R 20-CHO;R 24 C 1~10 Alkyl group.

[0125] In one embodiment of the present invention, Q is N, R 15 For oxygen, R 19 It is a halogen; R 20 C 1~10 Alkyl; R 24 C 1~10 Alkyl group.

[0126] In one embodiment of the present invention, R 16 R 17 and R 18 H, F, C independently 1~10 Alkyl group or -C(O)OC 1~10 alkyl.

[0127] In one embodiment of the present invention, R 21 R 22 and R 23 For H.

[0128] In one embodiment of the present invention, the molar ratio of the compound as shown in Formula I to the compound C is 0.0009-0.0021, for example 0.001 or 0.002.

[0129] The conditions and procedures for the Suzuki-Miyaura coupling reaction can be the conventional conditions and procedures for this type of reaction in the art, and the following conditions are preferred in this invention:

[0130] The alkaline reagent is preferably an inorganic weak base. The inorganic weak base is preferably one or more of alkali metal carbonates, alkali metal fluorides, and alkali metal phosphates, more preferably alkali metal phosphates or alkali metal carbonates, and even more preferably potassium phosphate or potassium carbonate.

[0131] The molar ratio of the alkaline reagent to compound C is preferably 1 to 5, for example, 3.

[0132] The molar ratio of compound D to compound C is preferably 1 to 4, for example 1.2.

[0133] In the Suzuki-Miyaura coupling reaction, the amount of solvent used is not specifically limited, as long as it does not affect the reaction.

[0134] In the Suzuki-Miyaura coupling reaction, the solvent is preferably a mixture of an organic solvent and water. The organic solvent is preferably one or more of aromatic solvents, alcohol solvents, amide solvents, ether solvents, and sulfoxide solvents, more preferably aromatic solvents. Toluene is a preferred aromatic solvent. n-Butanol and / or 3-pentanol are preferred alcohol solvents. N,N-dimethylformamide is a preferred amide solvent. Tetrahydrofuran and / or dioxane are preferred ether solvents. Dimethyl sulfoxide is a preferred sulfoxide solvent.

[0135] The preferred volume ratio of the organic solvent to water is (4-10):1, for example, 5:1.

[0136] In the Suzuki-Miyaura coupling reaction, the reaction temperature is preferably 40-100°C, more preferably 55-65°C, for example 60°C.

[0137] In the Suzuki-Miyaura coupling reaction, compound C is preferably any of the following compounds: , or .

[0138] In the Suzuki-Miyaura coupling reaction, compound D is preferably any of the following compounds: or .

[0139] In one embodiment, compound C is The compound D is The phosphine ligand is phosphine ligand I-1, I-2, I-6 or I-9.

[0140] In one embodiment, compound C is The compound D is The phosphine ligand is phosphine ligand I-1, I-6 or I-7.

[0141] In one embodiment, compound C is The compound D is The phosphine ligand is phosphine ligand I-1 or I-2.

[0142] In the Suzuki-Miyaura coupling reaction, the progress of the reaction can be monitored using conventional methods in the art (e.g., TIC, HPLC, LC-MS), generally with the disappearance or non-disappearance of compound III as the endpoint. The reaction time is preferably 4-24 hours, more preferably 8-20 hours.

[0143] In this invention, the term "chiral atom" refers to an atom C or P that is attached to different substituents; in this case, the atom C or P is called a chiral atom. In this invention, "RS configuration" is a term from the RS systematic nomenclature for chiral atoms. The specific RS systematic nomenclature is as follows: when the a, b, c, and d groups attached to the central C or P atom are different groups, the molecule is chiral. Assuming the four substituents in the molecule are arranged in the CIP sequence a>b>c>d, if the smallest d group is placed furthest from the observer, and the other three groups are observed in the order a, b, and c, and a→b→c is observed in a clockwise direction, then the configuration of this carbon center is defined as R (Latin: rectus); otherwise, it is considered S (Latin: sinister).

[0144] In this invention, the term "alkyl" unless otherwise specified refers to a saturated straight-chain or branched monovalent hydrocarbon group with a specified number of carbon atoms, such as C1-C2. 10 Alkyl refers to an alkyl group having 1 to 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl).

[0145] In this invention, the terms "alkoxy" or "phenoxy" refer to alkyl or phenyl groups that are connected to other parts of a molecule via oxygen bridges.

[0146] In this invention, the term "cycloalkyl" or "cycloalkane" refers to a non-aromatic saturated or unsaturated cycloalkyl group having a specified number of ring carbon atoms. The cycloalkyl group can be monocyclic or polycyclic (e.g., bicyclic and tricyclic), and can have fused, spirocyclic, and bridged ring structures. The cycloalkyl group optionally contains one or more double or triple bonds. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Cycloalkyl groups also include polycyclic cycloalkyl structures, wherein the polycyclic structure optionally includes a saturated or partially unsaturated cycloalkyl group fused with a saturated or partially unsaturated cycloalkyl or heterocyclic or aryl or heteroaryl ring. Bicyclic carbon rings having 7 to 12 atoms can be arranged, for example, as bicyclic [4,5], [5,5], [5,6] or [6,6] systems, or as bridging ring systems such as bis[2.2.1]heptane, bicyclic [2.2.2]octane and bicyclic [3.2.2]nonane.

[0147] In this invention, the term "heterocyclic" refers to a non-aromatic saturated or partially unsaturated cyclic hydrocarbon group formed by replacing at least one cyclic carbon atom in a cycloalkane (as defined in this invention) with a heteroatom selected from N, O and S.

[0148] In this invention, the term "aryl" or "aromatic ring" refers to any stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbocyclic ring containing up to seven atoms in each ring, wherein at least one ring is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl, phenanthryl, anthracene, or acenaphthyl. It is understood that in cases where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage occurs through the aromatic ring.

[0149] In this invention, the term "heteroaryl" or "heteroary ring" refers to a stable monocyclic or polycyclic (e.g., bicyclic or tricyclic) carbon ring, each ring containing up to seven atoms, wherein at least one ring is an aromatic ring and contains at least one heteroatom selected from O, N, and S. Heteroaryl groups can be linked to other parts of a molecule via heteroatoms or carbon atoms. Examples of heteroaryl groups include, but are not limited to, acridinel, carbazolyl, cyclophosphinl, quinoxalinl, pyrazolyl, indolyl, benzotriazolyl, and furanyl.

[0150] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0151] The reagents and raw materials used in this invention are all commercially available.

[0152] The positive and progressive effects of this invention are as follows: the compound of this invention, as shown in Formula I, or its racemate, as a catalyst in the Suzuki-Miyaura coupling reaction (especially the sterically hindered coupling reaction), can obtain axially chiral tetrasubstituted biaryl compounds in high yield under the condition of low palladium metal catalyst dosage, and has strong economic and practicality. Detailed Implementation

[0153] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0154] Chiral monophosphine ligands L1, L2, L3, L4, L5, L6, L7, L8, and L9 were prepared and synthesized with reference to patents CN 111662331 B and CN114751937 B.

[0155] Example 1

[0156] Preparation method of palladium metal complex I-1

[0157]

[0158] Take a clean 250 mL three-necked reaction flask, add ligand L1 (5.25 g, 10 mmol, 1.1 eq) and (COD)PdCl2 (2.6 g, 9.091 mmol, 1.0 eq), and purge with nitrogen three times. Then add THF (60 mL) to the reaction flask and react at room temperature for 12 h or stir until the system becomes clear and transparent. After the reaction is complete, evaporate the THF to dryness under nitrogen protection, then add degassed petroleum ether (100 mL) and stir for 2-3 hours. Finally, filter to obtain 6.3 g of deep yellow solid, yield: 89%. 31 P NMR: 64.

[0159] Preparation of I-1 crystals: 100 mg of yellow solid I-1 was placed in a 25 mL Shrek tube, which was then purged with nitrogen three times. Dichloromethane (3 mL) was added to the Shrek tube until the system dissolved and became clear and transparent. Then, petroleum ether (3 mL) was added to the Shrek tube. The Shrek tube was placed in a glove box, and a hole was punched in the rubber stopper with a 2.5 mL syringe needle to allow the solvent to evaporate slowly. Two days later, yellow transparent crystals of compound I-1 precipitated in the system.

[0160] Table 1 shows the single-crystal parameters of the compounds shown in Formula I-1.

[0161] .

[0162] Subsequent palladium complexes I-2, I-3, I-4, I-5, I-6, I-7, and I-8 were synthesized following the procedure in I-1. The chemical shifts and yields of the phosphine spectra are shown in the table below:

[0163]

[0164] Example 2

[0165] Preparation method of palladium metal complex I-9

[0166]

[0167] Compound Pd-G3 was synthesized according to the reference NC Bruno.; SL Buchwald, Org. Lett. 2013, 15, 11, 2876–2879.

[0168] Take a clean 25 mL Shrek tube and add ligand L1 (525 mg, 1.0 mmol, 2.2 eq) and Pd-G3 (370 mg, 0.5 mmol, 1.0 eq) to the reaction flask, purging with nitrogen three times. Then add DCM (6 mL) to the reaction flask and react at room temperature for 12 h. After the reaction is complete, remove 5 mL of dichloromethane under nitrogen protection, then add degassed petroleum ether (6 mL) and stir for 2-3 hours. Finally, filter to obtain 600 mg of gray solid, yield: 67%. 31 P NMR: 50.

[0169] Subsequent palladium complexes I-10, I-11, and I-128 were synthesized following the same procedure as complex I-8. The chemical shifts and yields of the phosphine spectra are shown in the table below.

[0170]

[0171] Example 3

[0172] Using the complexes I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, and I-12 prepared in Examples 1 and 2 as catalysts, an asymmetric Suzuki-Miyaura coupling reaction involving aryl halide 1 and potassium arylfluoroborate 2 was conducted to prepare axially chiral ortho-tetrasubstituted biaryl compound 3.

[0173]

[0174] The reaction procedure is as follows: 2-Bromo-3,4-dimethoxybenzaldehyde (4, 120 mg, 0.48 mmol), potassium 2-formyl-6-methoxyphenyltrifluoroborate (5, 136 mg, 0.56 mmol), and potassium phosphate (312 mg, 1.44 mmol) were added to a 25 mL Schlenk tube. The tube was purged three times, and the air in the Schlenk tube was replaced with nitrogen. Under nitrogen protection, degassed toluene (8 mL), deionized water (1.6 mL), and complex 2 (0.4 mg, 0.1 mol%) were added sequentially. The reaction system was heated at 60 °C. o Stirring at C for 15 hours and then cooling to room temperature. Saturated brine was added to the reaction system, and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to a colorless waxy solid (S)-5,6,6'-trimethoxybiphenyl-2,2'-dialdehyde (6), yielding 120 mg, with a yield of 82%.

[0175] The enantiomeric excess (ee) was determined by chiral high-performance liquid chromatography (HPLC), and the ee value was 94%. HPLC conditions: chiral AD-H column, 25℃, flow rate: 1 mL / min, hexane / isopropanol: 70 / 30, 210 nm, 6.70 min (S), 9.67 min (R). 1 H NMR (500 MHz, CDCl3) δ 9.70 (s, 1H), 9.50 (s, 1H), 7.85 (d, J = 8.6Hz, 1H), 7.68 (dd, J = 7.8, 1.0 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.23 (dd,J = 8.2, 0.8 Hz, 1H), 7.11 (d,J = 8.6 Hz, 1H), 3.99 (s, 3H), 3.76 (s, 3H), 3.50 (s, 3H).

[0176] Comparison of the effects of different metal complexes with Pd2(dba)3 / BaryPhos:

[0177]

[0178] The conditions and procedures for Comparative Example 1 were the same as those for Example 3, except that the palladium complex was replaced with Pd2(dba)3 / BaryPhos (added in a non-complex form).

[0179] Example 4

[0180] The reaction steps are the same as those in Example 3. The reactions were compared using palladium complexes I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, and I-12 prepared in Examples 1 and 2 as catalysts, and Pd2(dba)3 / BaryPhos as a catalyst.

[0181]

[0182] (S)-3-fluoro-6,6'-dimethoxybiphenyl-2,2'-dialdehyde (5) enantiomeric excess (ee) was determined by chiral high-performance liquid chromatography (HPLC), and the ee value was 90%; HPLC conditions: chiral AD-H column, 25℃, flow rate: 1 mL / min, n-hexane / isopropanol: 85 / 15, 250 nm, 8.00 min (S), 12.55 min (R); 1H NMR (400 MHz, CDCl3) δ 9.96(s, 1H), 9.67 (s, 1H), 7.64 (dd, J = 7.8, 1.0 Hz, 1H), 7.52 (t, J = 8.0 Hz,1H), 7.26–7.13 (m, 3H), 3.73 (s, 3H), 3.68 (s, 3H).

[0183] Comparison of effects of metal complexes with different structures and BaryPhos:

[0184]

[0185] The conditions and operations of Comparative Examples 3 and 4 were the same as those of Example 4, except that the palladium complex was replaced with Pd2(dba)3 / BaryPhos (added in non-complex form).

[0186] Example 5

[0187] The reaction steps are the same as those in Example 3. The reactions were compared using palladium complexes I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, and I-12 prepared in Examples 1 and 2 as catalysts, and Pd2(dba)3 and BaryPhos as catalysts.

[0188]

[0189] (S)-3-fluoro-2-(2-methoxy-6-methylphenyl)-5-(methoxycarbonyl)pyridine-1-oxide (8) Enantiomeric excess (ee) was determined by chiral high-performance liquid chromatography (HPLC). HPLC conditions: chiral OD-H column, 25 °C, flow rate: 0.7 mL / min, n-hexane / isopropanol: 70 / 30, 250 nm, 8.38 min (S), 14.42 min (R); 1 H NMR (600 MHz, CDCl3) δ 8.46 (s, 1H), 7.2-7.14 (m, 2H), 7.1-7.05 (m, 2H), 3.9 (s, 4H), 3.79 (s, 3H), 2.57 (s, 3H).

[0190] Comparison of effects of metal complexes with different structures and BaryPhos:

[0191]

[0192] The conditions and operations of Comparative Example 5 were the same as those of Example 5, except that the palladium complex was replaced with Pd2(dba)3 / BaryPhos (added in non-complex form). It can be seen that when using the palladium complex, most of the yields and ee values ​​are higher than those of the uncomplexed catalyst.

[0193] As can be seen from Examples 3-5, by comparing the palladium complex with the Pd2(dba)3 / BaryPhos catalyst system, it can be seen that using the palladium complex as a catalyst can significantly reduce the amount of palladium catalyst used in the asymmetric Suzuki-miyaura coupling reaction without reducing the yield and ee value.

Claims

1. A phosphine ligand as shown in formula I or I' or a racemate thereof: ； wherein Standard The phosphorus atom has a configuration of R or S; The carbon atom has a configuration of R or S; R 1 , R 3 , and R 5 are independently hydrogen, C 1~10 alkyl, C 1~10 heteroalkyl, C 3~30 cycloalkyl, R 1-1a substituted C 3~30 cycloalkyl, C6- 30 aryl, or R 1-1b substituted C6- 30 aryl; the heteroatoms in said C 1~10 heteroalkyl are selected from one or more of O, S, and N, the number of heteroatoms being 1, 2, 3, 4, 5, or 6; when the number of heteroatoms is plural, the heteroatoms are the same or different; R 2 and R 4 independently H, C 1~10 alkyl, C 1~10 heteroalkyl, C 3~30 cycloalkyl, R 2-1a substituted C 3~30 cycloalkyl, C6- 30 aryl, or R 2-1b substituted C6- 30 aryl; the heteroatoms in said C 1~10 heteroalkyl are selected from one or more of O, S, and N, the number of heteroatoms being 1, 2, 3, 4, 5, or 6; when the number of heteroatoms is more than one, the heteroatoms are the same or different. each R 1-1a and each R 2-1a independently is C 1~10 alkyl; R 1-1a and R 2-1a number independently is one or more; when R 1-1a and R 2-1a number independently is more, R 1-1a and R 2-1a independently are the same or different; each R 1-1b and each R 2-1b independently is C 1~10 alkyl, C 1~10 alkoxy or C6~ 30 aryl; each R 1-1b and each R 2-1b independently is 1 or more, when each R 1-1b and each R 2-1b independently is more than one, R 1-1b and R 2-1b are independently the same or different. R 6 and R 7 are independently H, C 1~10 alkyl, hydroxy-substituted C 1~10 alkyl, C 3~30 cycloalkyl or C6~ 30 aryl; R 8 hydrogen, C 1~10 alkyl, hydroxy-substituted C 1~10 alkyl, C 1~10 alkoxy, , C 3~30 cycloalkyl, mercapto or C6 30 aryl, wherein R 10 and R 11 are independently H or C 1~4 alkyl; R 9 is C 1~10 alkyl, C 3~30 cycloalkyl or C6~ 30 aryl; R 8 is hydroxy, C 1~10 alkoxy, or thiol, R 8 coordinates to the Pd through the heteroatom N, O or S therein; X is independently F, Cl, Br, I or OTf.

2. The phosphine ligand or its racemate as shown in Formula I or I' as claimed in claim 1, characterized in that, The phosphine ligand as shown in formula I is a phosphine ligand as shown in formula I-1 or I-2: or ; Or, the phosphine ligand as shown in formula I' is a phosphine ligand as shown in formula I'-1 or I'-2: or .

3. The phosphine ligand of formula I or I' according to claim 1, wherein which satisfies one or more of the following conditions: (1) R 1 and R 5 are independently C 1~10 alkyl, for example C 1~3 alkyl; (2) R 1 and R 5 are the same; (3) R 2 and R 4 are independently H, C 3~30 cycloalkyl, R 2-1a substituted C 3~30 cycloalkyl or C6~ 30 aryl; preferably, R 2 and R 4 are independently H, C 3~6 cycloalkyl, C6~ 14 aryl or R 2-1a substituted C 3~6 cycloalkyl, for example C 3~6 cycloalkyl; (4) R 2 and R 4 are the same; (5) R 2-1a independently C 1~3 alkyl; (6) R 6 and R 7 independently H, C 1~10 alkyl or hydroxy-substituted C 1~10 alkyl; preferably, R 6 and R 7 independently C 1~10 alkyl, for example C 1~3 alkyl; (7) R 8 is hydroxy, C 1~10 alkyl, C 1~10 alkoxy or ; preferably R 8 is hydroxy or ; (8) R 10 and R 11 is C 1~4 alkyl, for example methyl; (9) R 9 is C 1~10 alkyl, preferably C 1~6 alkyl; (10) X is Cl, Br, I or OTf.

4. The phosphine ligand of formula I or I' according to claim 1, wherein which satisfies one or more of the following conditions: (1) R 1 and R 5 is methyl; (2) R 2 and R 4 is H, phenyl, cyclopentyl, cyclohexyl or ; (3) R 3 is hydrogen; (4) R 6 and R 7 is independently methyl, ethyl or isopropyl; (5) R 8 is hydroxyl or ; (6) R 9 is tert-butyl.

5. The phosphine ligand of formula I or I' according to claim 1, wherein The phosphine ligand as shown in formula I is selected from any one of the following compounds: ； Preferably, the compound as shown in formula I-1 is in a single crystal form: the single crystal belongs to the orthorhombic system, and the unit cell parameters of the single crystal are a = 8. 1 A, b = 10. 1 A, c = 23. 1 A, α = 90°, β = 90°, γ = 90°. , , , , , .

6. A process for the preparation of a phosphine ligand of the formula I or I' ###0001### I I' or a racemate thereof, characterized in that which comprises the following steps: a coordination complex reaction of a metal palladium precursor in a solvent with a compound as shown in formula I-0 or a racemate thereof, to obtain the phosphine ligand as shown in formula I or a racemate thereof; The metal palladium precursor is (COD)PdCl2, diacetonitrile palladium dichloride, palladium dichloride, palladium dibromide, palladium diiodide or palladium triflate; Or, a coordination complex reaction of a metal palladium precursor as shown in formula Pd-G3 in a solvent with a compound as shown in formula I-0 or a racemate thereof, to obtain the phosphine ligand as shown in formula I' or a racemate thereof; ； wherein , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each as defined in any one of claims 1-5.

7. The process for the preparation of a phosphine ligand according to claim 6, of formula I or I', or a racemate thereof, characterized in that, which satisfies one or more of the following conditions: (1) The coordination complex reaction is carried out under an inert atmosphere, such as nitrogen atmosphere; (2) The organic solvent is a halogenated alkane solvent and / or an ether solvent, for example, the halogenated alkane solvent is dichloromethane; the ether solvent is tetrahydrofuran; (3) The temperature of the coordination complex reaction is 10-50℃, for example, 20-30℃, for example, 25℃; (4) After the coordination complex reaction, a beating and purifying step is further included, for example, beating with petroleum ether, to obtain the phosphine ligand as shown in formula I' or a racemate thereof, preferably, a single crystal of the phosphine ligand as shown in formula I' or a racemate thereof. 8.Use of a phosphine ligand as shown in formula I or I' or a racemate thereof as a metal ligand in a Suzuki-Miyaura coupling reaction, which comprises the following steps: a Suzuki-Miyaura coupling reaction of a compound C and a compound D in a solvent in the presence of the phosphine ligand as shown in formula I or I' or a racemate thereof and a basic reagent, to obtain a compound E and a compound ent-E; ； wherein " with " and with ", both mean that the group has axial chirality; Q is C or N; X is halogen; M is , or -BF3K; When Q is C, R 15 C 1~10 Alkyl groups, -CHO groups, or halogens; when Q is N, R 15 is absent or oxygen; R 19 is C 1~10 alkoxy, -CHO or halogen; R 20 and R 24 independently C 1~10 alkyl, C 1~10 alkoxy or -CHO; R 16 , R 17 , R 18 , R 21 , R 22 , and R 23 are independently H, F, nitro, C 1~10 alkyl, C 1~10 alkoxy, or -C(O)O-C 1~10 alkyl; The molar ratio of the phosphine ligand as shown in formula I or I' or a racemate thereof to the compound C is 0.0001-0.

01.

9. Use according to claim 8, wherein the compound is ###0002### The Suzuki-Miyaura coupling reaction satisfies one or more of the following conditions: (1) X is Cl, Br or I, for example, Br; (2) M is or -BF3K; (3) Q is C, R 15 is -CHO; R 19 is C 1~10 alkoxy; or, Q is N, R 15 is oxygen, R 19 is halogen; (4) R 20 is -CHO; R 24 is C 1~10 alkyl; or R 20 is C 1~10 alkyl; R 24 is C 1~10 alkyl; or R (5) R 16 R 17 and R 18 H, F, C independently 1~10 Alkyl group or -C(O)OC 1~10 alkyl; (6) R 21 , R 22 , and R 23 are H; (7) The molar ratio of the compound as shown in formula I to the compound C is 0.0009-0.0021, for example, 0.001 or 0.002; (8) The basic reagent is one or more of metal carbonate, alkali metal fluoride salt and alkali metal phosphate, preferably, alkali metal phosphate or alkali metal carbonate, further preferably, potassium phosphate or potassium carbonate; (9) The molar ratio of the basic reagent to the compound C is 1-5, for example, 3; (10) the molar ratio of the compound D to the compound C is 1 to 4, for example 1.2; (11) the solvent is preferably a mixed solvent of an organic solvent and water; the organic solvent is preferably one or more of an aromatic hydrocarbon solvent, an alcohol solvent, an amide solvent, an ether solvent, and a sulfoxide solvent, more preferably an aromatic hydrocarbon solvent; preferably, the volume ratio of the organic solvent to water is preferably (4-10): 1, for example 5: 1; more preferably, the aromatic hydrocarbon solvent is toluene; the alcohol solvent is n-butanol and / or 3-pentanol; the amide solvent is N,N-dimethylformamide; the ether solvent is tetrahydrofuran and / or dioxane; the sulfoxide solvent is dimethyl sulfoxide; (12) the reaction temperature is preferably 40-100°C, more preferably 55-65°C, for example 60°C.

10. The use according to claim 8, wherein the compound is ###00010### The Suzuki-Miyaura coupling reaction meets one or more of the following conditions: (1) the compound C is , or ; (2) the compound D is or .

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