CN103193830A - Preparation method of chiral ferrocene phosphine ligand - Google Patents

Abstract

The invention discloses a preparation method of a chiral phosphine ligand, which uses BuLi to lithiate Ugi's amine at room temperature to obtain ortho-activated Ugi's amine, and then place it in an environment below -60°C, slowly After injecting PCl _3, rise to room temperature and react overnight to generate a suspension of dichlorides. After adding excess lithium compound RLi or Grignard reagent RMgX, react to obtain a chiral phosphine ligand, or add equimolar RLi or RMgX, and slowly rise to After reacting at room temperature, an excess of RLi or RMgX was added to react to obtain a chiral phosphine ligand. The invention can conveniently introduce various substituents on the phosphorus atom, thereby conveniently changing the electronic and stereoscopic properties of the phosphine ligand.

Description

Preparation method of chiral ferrocene phosphine ligand

technical field

The invention relates to a synthesis method of a chiral ferrocene phosphine ligand, belonging to the technical field of organic synthesis.

Background technique

Chiral ferrocenephosphine ligands are a very important class of ligands in the field of asymmetric catalysis (Arrayás R G, Angew. Chem. Int. Ed. 2006, 45, 7675-7676.). 1-(2-diphenylphosphino) ferrocenyl- N , N -dimethylethylamine (PPFA) compound itself is a class of excellent ligands, (Hayashi T, Tetrahedron Letters. 1974, 15, 4405 -4408.), while PPFA compounds are also used to synthesize many chiral ferrocene phosphine ligands, such as: Josiphos (Togni A, J. Am. Chem. Soc. 1994, 116, 4062-4066.) and BoPhoz (Boaz, N. W. Org. Lett. 2002, 4 , 2421). The known synthetic methods of PPFA compounds are all Ugi's amine diastereoselective lithiation, and then react with diaryl (alkyl) phosphine chloride (Hayashi T, Bull. Chem. Soc. Jpn. 1980, 53 , 1138-1151.). A disadvantage of the known synthesis methods of PPFAs is that many diaryl(alkyl)phosphine chlorides are not readily available.

Since the synthesis of P-chiral ligands is more difficult than other chiral ligands, there are fewer types of ligands developed. Since the chiral center of P-chiral ligands is closer to the transition metal, better stereoselectivity is often achieved. Therefore, a simple method for synthesizing P-chiral substances has been the direction of chemists' efforts. A known method for the synthesis of ferrocene P-chiral phosphine ligands is: diastereoselective lithiation of Ugi's amines, followed by reaction with aryl (alkyl) phosphine dichlorides, followed by reaction with a Reaction of organometallic reagents (Chen W, J. Am. Chem. Soc. 2006 , 128, 3922 . ). This method has the advantages of high stereoselectivity, high yield, and simple operation. Many excellent ligands such as Trifer (Chen W, Angew. Chem. Int. Ed. 2007, 46, 4141), ChenPhos (WO2007116081.) and C1-Trifer (WO2008101868.). However, the disadvantage of this method is that many aryl(alkyl)phosphine dichlorides are not readily available, and the substituents on the phosphorus atom can only be changed to a limited extent.

It is well known that the electronic and steric properties of chiral phosphine ligands play a decisive role in catalytic activity and enantioselectivity. Different substrates and different catalytic reactions have different requirements for the electronic and steric properties of chiral phosphine ligands. Therefore, the development It is of great significance to facilitate the synthesis of various phosphine ligands with different electronic and steric properties.

Contents of the invention

The purpose of the present invention is to provide a preparation method of chiral ferrocene phosphine ligand with simple and convenient synthesis method.

The realization process of the present invention is as follows:

The preparation method of the compound shown in general structural formula (I), is characterized in that comprising the following steps:

R ₁ and R ₂ are independently selected from C1-C25 alkyl groups,

or aryl, such as:

or heteroaryl, such as:

or cycloalkyl, such as:

or ferrocenyl, such as:

(1) The organometallic lithium reagent activates the R -configuration or S- configuration Ugi′s amine and reacts with PCl ₃ to obtain the dichloride (II);

(2) Add RLi or RMgX in an amount 2 to 3 times the amount of the dichloride (II), and react to obtain a compound shown in the general structural formula (I) without P-chirality, where R=R ₁ =R ₂ , X is halogen;

Alternatively, first add 1-1.05 times the molar amount of dichloride (II) R ₁ Li or R ₁ MgX to react to obtain monochloride (III), and then add excess R ₂ Li or R ₂ MgX to react to obtain P-chiral The compound shown in general formula (I), wherein R ₁ ≠ R ₂ ,

。

.

In the above step (1), the organometallic lithium reagent is methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, hexyllithium or phenyllithium; adding the organometallic lithium reagent to activate the Ugi's amine reaction solvent It is methyl tert-butyl ether, diethyl ether, toluene or tetrahydrofuran, and the temperature is -15°C to 35°C; the temperature for adding PCl ₃ is -120°C to -60°C, and the reaction time is 6 to 18h.

In the above step (2), the temperature for adding RLi or RMgX is -60°C to 35°C. The temperature at which R ₁ Li or R ₁ MgX is added is -120°C to -60°C, and the reaction takes 1 to 6 hours after rising to room temperature. The temperature for adding R ₂ Li or R ₂ MgX is -60°C to 35°C, the amount of R ₂ Li or R ₂ MgX is 1-2 times that of the monochloride (III), and react for 4-16 hours after rising to room temperature .

Advantages and positive effects of the present invention: various substituents can be conveniently introduced on the phosphorus atom, and the electronic and stereoscopic properties of the phosphine ligand can be easily changed, thereby maximally expanding the scope of application of the phosphine ligand in unpaired catalytic reactions .

Detailed ways

Use BuLi to lithiate Ugi's amine at room temperature to obtain ortho-activated Ugi's amine, then place it below -60°C, slowly inject PCl ₃ and rise to room temperature to react to form a suspension of dichloride. The phosphine reagent is PCl ₃ , and the lithium reagent used in the reaction is an organometallic lithium reagent, such as: methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, hexyllithium or phenyllithium. The solvent used in the reaction is methyl tert-butyl ether, diethyl ether, toluene or tetrahydrofuran, etc.; the reaction temperature during lithiation is -15°C to 35°C, the temperature for adding _PCl3 is -120°C to -60°C, and the reaction time is 6 to 60°C. 18h, the synthetic route is as follows:

)与 (

)路线分别生成非P-手性和P-手性的(R)-S-PPFA类化合物： according to(

)and (

) route generates non-P-chiral and P-chiral ( R ) -S -PPFA compounds respectively:

( ) Add excess lithium compound RLi or Grignard reagent RMgX under low temperature conditions, then raise the temperature to reflux reaction to obtain PPFA compounds without P-chirality, the reaction time is 4-16h, the amount of substance of RLi or RMgX is dichloro 2 to 3 times of the R of the substitute is an aliphatic hydrocarbon group, a heterocyclic ring or an aromatic hydrocarbon group, and the synthetic route is as follows:

) 在-60℃以下加入等摩尔的RLi或RMgX，然后缓慢升至室温反应2h，反应所用溶剂为甲基叔丁基醚、乙醚、甲苯或四氢呋喃等；加入RLi或RMgX的物质的量为二氯代物的1～1.05倍，缓慢升至室温反应得到单氯代物悬浊液时间为1～6h；再在低温下加入过量的RLi或RMgX，然后升温至回流反应4-16h得到P-手性的PPFA类化合物，R′Li或R′MgX的物质的量为单氯代物的1～2倍，升温至回流反应时间为4-16h；R和R′不相同，合成路线如下： (

) Add equimolar RLi or RMgX below -60°C, then slowly rise to room temperature and react for 2 hours. The solvent used in the reaction is methyl tert-butyl ether, diethyl ether, toluene or tetrahydrofuran, etc.; 1-1.05 times that of chlorinated compounds, slowly rise to room temperature and react to obtain mono-chlorinated compound suspension. The PPFA compound, the amount of R'Li or R'MgX is 1 to 2 times that of the monochloride, and the reaction time is 4-16h when the temperature is raised to reflux; R and R' are different, and the synthetic route is as follows:

Example 1: Preparation of ( R ) -S -1-(2-diphenylphosphino)ferrocenyl- N , N -dimethylethylamine 1

Add 2.57 g (10 mmol) of ( R )-Ugi's amine to a 250 mL three-necked flask, inject 40 mL of dried methyl tert-butyl ether with a syringe after vacuuming/nitrogen flushing cycle, and place in an ice-water bath Stir until dissolved, slowly inject 11 mL of s -BuLi (1 M , 11 mmol), react in an ice-water bath for 2 h to form a brick-red floc precipitate, place the three-necked flask in a low-temperature reactor at -78 °C, and slowly inject the solution Add 0.96 mL (11 mmol) of PCl ₃ in 10 mL of methyl tert-butyl ether to room temperature and react overnight to obtain a suspension of the dichloro compound.

Add 2.4 mL (23 mmol) of bromobenzene into a 100 mL single-necked bottle, inject 40 mL of dried methyl tert-butyl ether with a syringe after vacuum/nitrogen cycle, and place in a low-temperature reactor at -40°C to stir Until dissolved, slowly inject 15 mL of n -BuLi (1.6 M, 24 mmol), slowly rise to room temperature and react for 2 hours to form phenyllithium.

Place the suspension of the dichloride in a low-temperature reactor at -20°C, add the phenyllithium compound into the suspension of the dichloride with a double needle, raise the temperature to reflux for 8 hours, remove the insoluble matter by filtration, and then use water, Washed with saturated brine, evaporated to dryness, and column chromatography gave 2.4 g of an orange-red solid product with a yield of 54.4%.

 -350.9 (c = 0.25, CHCl₃); ¹H NMR (500 Hz, CDCl₃)：δ 7.62-7.56 (m, 2H), 7.37-7.32 (m, 3H), 7.22-7.14 (m, 5H), 4.37 (s, 1H), 4.25-4.24 (m, 1H), 4.16-4.14 (dd, J = 2.5, 2.5 Hz, 1H), 3.94 (s, 5H), 3.86 (s, 1H), 1.77 (s, 6H), 1.27-1.26 (d, J = 7 Hz, 3H)。 mp 141-143°C;

-350.9 (c = 0.25, CHCl ₃ ); ¹ H NMR (500 Hz, CDCl ₃ ): δ 7.62-7.56 (m, 2H), 7.37-7.32 (m, 3H), 7.22-7.14 (m, 5H), 4.37 (s, 1H), 4.25-4.24 (m, 1H), 4.16-4.14 (dd, J = 2.5, 2.5 Hz, 1H), 3.94 (s, 5H), 3.86 (s, 1H), 1.77 (s, 6H), 1.27-1.26 (d, J = 7 Hz, 3H).

Example 2: Preparation of ( R ) -S -1-[2-bis(3,5-dimethylphenyl)phosphino]ferrocenyl- N , N -dimethylethylamine 2

The preparation method was the same as in Example 1, and 2.2 g of orange-red oil was obtained, with a yield of 44.2%.

 -278.5 (c = 0.25, CHCl₃); ¹H NMR (500 Hz, CDCl₃) δ 7.25-7.23 (m, 2H), 6.98 (s, 1H), 6.80-6.78 (m, 3H), 4.35 (s, 1H), 4.23-4.22 (m, 1H), 4.10-4.08 (dd, J = 2.5, 2.5 Hz, 1H), 3.92 (s, 5H), 3.87 (s, 1H), 2.32 (s, 6H), 2.18 (s, 6H), 1.81 (s, 6H), 1.28-1.27 (d, J = 7 Hz, 3H)。

-278.5 (c = 0.25, CHCl ₃ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.25-7.23 (m, 2H), 6.98 (s, 1H), 6.80-6.78 (m, 3H), 4.35 (s , 1H), 4.23-4.22 (m, 1H), 4.10-4.08 (dd, J = 2.5, 2.5 Hz, 1H), 3.92 (s, 5H), 3.87 (s, 1H), 2.32 (s, 6H), 2.18 (s, 6H), 1.81 (s, 6H), 1.28-1.27 (d, J = 7 Hz, 3H).

Example 3: Preparation of ( R ) -S -1-[2-bis(3,5-di-tert-butylphenyl)phosphino]ferrocenyl- N , N -dimethylethylamine 3

The preparation method was the same as in Example 1, and 3.1 g of a yellow foamy solid was obtained, with a yield of 46.6%.

 -246.8 (c = 0.25, CH₂Cl₂); ¹H NMR (500 Hz, CDCl₃) δ 7.65-7.55 (dd, J = 2, 1.5 Hz, 2H), 7.44 (s, 1H), 7.25-7.21 (m, 3H), 4.37 (s, 1H), 4.26 (s, 1H), 4.21-4.17 (dd, J = 3, 2.5 Hz, 1H), 3.97 (s, 5H), 3.90 (s, 1H), 1.73 (s, 6H), 1.36 (s, 18H), 1.34-1.30 (d, J = 6.5 Hz, 3H), 1.26 (s, 18H); ³¹P NMR (202 Hz, CDCl₃) δ -22.78 (s).

-246.8 (c = 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.65-7.55 (dd, J = 2, 1.5 Hz, 2H), 7.44 (s, 1H), 7.25-7.21 (m, 3H), 4.37 (s, 1H), 4.26 (s, 1H), 4.21-4.17 (dd, J = 3, 2.5 Hz, 1H), 3.97 (s, 5H), 3.90 (s, 1H), 1.73 (s, 6H), 1.36 (s, 18H), 1.34-1.30 (d, J = 6.5 Hz, 3H), 1.26 (s, 18H); ³¹ P NMR (202 Hz, CDCl ₃ ) δ -22.78 (s ).

Example 4: Preparation of ( R ) -S -1-[2-bis(4-bromophenyl)phosphino]ferrocenyl- N , N -dimethylethylamine 4

The preparation method was the same as in Example 1, and 1.38 g of a yellow foamy solid was obtained, with a yield of 23.1%.

-302.8 (c = 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.52-7.46 (d, J = 7.5 Hz, 2H), 7.44-7.36 (m, 2H), 7.34-7.28 (d, J = 7.5 Hz, 2H), 7.04-6.98 (m, 2H), 4.39 (s, 1H), 4.20 (s, 1H), 4.15-4.10 (d, J = 4.5 Hz, 1H), 3.96 ( s, 5H), 3.77 (s, 1H), 1.76 (s, 6H), 1.16-1.12 (d, J = 3 Hz, 3H); ³¹ P NMR (202 Hz, CDCl ₃ ) δ -24.36 (s).

Example 5: Preparation of ( R ) -S -1-[2-(bis(2-thienyl)phosphino]ferrocenyl- N , N -dimethylethylamine 5

The preparation method was the same as in Example 1, the orange-red solid product was 2.38 g, and the yield was 52.5%.

 -424 (c = 0.25, CH₂Cl₂); ¹H NMR (500 Hz, CDCl₃) δ 7.60-7.56 (d, J = 5 Hz, 1H), 7.52-7.46 (m, 1H), 7.36-7.32 (d, J = 5 Hz, 1H), 7.15-7.05 (m, 2H), 7.00-6.90 (m, 1H), 4.37 (s, 1H), 4.32 (s, 1H), 4.27 (s, 1H), 4.20-4.10 (m, 1H), 3.95 (s, 5H), 1.80 (s, 6H), 1.30-1.20 (d, J = 7 Hz, 3H); ³¹P NMR (202 Hz, CDCl₃) δ -52.08 (s)。 mp 118.6-119.8℃;

-424 (c = 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.60-7.56 (d, J = 5 Hz, 1H), 7.52-7.46 (m, 1H), 7.36-7.32 (d, J = 5 Hz, 1H), 7.15-7.05 (m, 2H), 7.00-6.90 (m, 1H), 4.37 (s, 1H), 4.32 (s, 1H), 4.27 (s, 1H), 4.20-4.10 (m, 1H), 3.95 (s, 5H), 1.80 (s, 6H), 1.30-1.20 (d, J = 7 Hz, 3H); ³¹ P NMR (202 Hz, CDCl ₃ ) δ -52.08 (s).

Example 6: Preparation of ( R ) -S -1-[2-bis(4-phenylphenyl)phosphino]ferrocenyl- N , N -dimethylethylamine 6

The preparation method was the same as in Example 1, and 2.5 g of an orange-yellow solid was obtained, with a yield of 42.0%.

mp 95.6-97℃; -387.6 (c = 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.80-7.74 (m, 2H), 7.72-7.66 (m, 4H), 7.66-7.62 (d, J = 7.5 Hz, 2H), 7.54-7.32 (m, 10H), 4.46 (s, 1H), 4.34 (s, 1H), 4.30-4.20 (dd, J = 2, 1.5 Hz, 1H), 4.04 (s, 5H ), 4.00 (s, 1H), 1.88 (s, 6H), 1.36-1.32 (d, J = 6 Hz, 3H); ³¹ P NMR (202 Hz, CDCl ₃ ) δ -24.35 (s).

Example 7: ( R ) -S -1-[2-Di-n-decylphosphino)]ferrocenyl- N , N -dimethylethylamine 7

The preparation of dichloride is the same as in Example 1.

Add 0.96 g (40 mmol) magnesium strips to a 100 mL three-neck flask with a condenser tube, inject dry diethyl ether and stir slowly, slowly inject 0.8 mL (3.8 mmol) n-bromodecane to initiate the reaction to reflux, and then add dropwise Dissolve 7.5 mL (36.2 mmol) n-bromodecane in 20 mL of anhydrous ether, reflux for reaction for 4 hours after the addition, and let stand for use.

Place the suspension of the dichloride in a low-temperature reactor at -20°C, add the Grignard reagent into the suspension of the dichloride with a double needle, raise the temperature to reflux for 8 hours, remove the insoluble matter by filtration, and then water, saturated Washed with brine, evaporated to dryness and solvent column chromatography gave 2.6 g of an orange-red oily substance, with a yield of 45.7%.

 -92.1 (c = 0.7, CH₂Cl₂); ¹H NMR (500 Hz, CDCl₃) δ 4.26 (s, 1H), 4.19 (s, 1H), 4.11 (s, 1H), 4.10-4.02 (m, 6H), 2.06 (s, 6H), 1.70-1.43 (m, 6H), 1.42-1.16 (m, 33H), 0.92-0.83 (m, 6H); ³¹P NMR (202 Hz, CDCl₃) δ -39.17 (s)。

-92.1 (c = 0.7, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 4.26 (s, 1H), 4.19 (s, 1H), 4.11 (s, 1H), 4.10-4.02 (m , 6H), 2.06 (s, 6H), 1.70-1.43 (m, 6H), 1.42-1.16 (m, 33H), 0.92-0.83 (m, 6H); ³¹ P NMR (202 Hz, CDCl ₃ ) δ - 39.17(s).

Example 8: Preparation of ( R ) -S -1-[2-[( R )-(2-o-methoxyphenyl)(phenyl)]phosphino]ferrocenyl- N , N -dimethyl Ethylamine 8

The preparation of dichloride is the same as in Example 1.

Add 1.25 mL (10 mmol) of o-methoxybromobenzene into a 100 mL single-necked bottle, inject 20 mL of dried methyl tert-butyl ether with a syringe after vacuuming/nitrogen cycle, and place at -40°C Stir in the reactor until dissolved, slowly inject 6.6 mL (1.6 M, 10.56 mmol) of n -BuLi, rise to room temperature and react for 2 hours to generate phenyllithium; place the suspension of dichloride in a low-temperature reactor at -70°C , Add the phenyl lithium compound to the suspension of the dichloride with a double needle, rise to room temperature and react for 2h to obtain the monochloride.

Add 1.26 mL (12 mmol) of bromobenzene into a 100 mL single-necked bottle, inject 20 mL of dried methyl tert-butyl ether with a syringe after vacuuming/nitrogen cycle, and place in a low-temperature reactor at -40°C to stir Until dissolved, slowly inject 8 mL of n -BuLi (1.6 M, 12.8 mmol), rise to room temperature and react for 2 hours to generate lithium compounds; place the suspension of monochlorides in a low-temperature reactor at -20°C, and use a double needle to inject lithium The compound was added to the suspension of monochloride, heated to reflux for 8 hours, filtered to remove insoluble matter, washed with water and saturated brine in turn, and evaporated to dryness. Column chromatography gave 2.1 g of orange-red solid product, 44.6%.

mp 127. -128.4℃; -237.2 (c = 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.36-7.30 (m, 1H), 7.22-7.10 (m, 6H), 6.98-6.92 (m, 1H) , 6.90-6.84 (m, 1H), 4.37 (s, 1H), 4.25 (s, 1H), 4.32-4.05 (dd, J = 2.5, 3 Hz, 1H), 3.97 (s, 5H), 3.96-3.93 (m, 1H), 3.93 (s, 3H), 1.79 (s, 6H), 1.34-1.24 (d, J = 1.5 Hz, 3H); ³¹ P NMR (202 Hz, CDCl ₃ ) δ -40.51 (s) .

Example 9: Preparation of ( R ) -S -1-[2-[( S )-(2-o-methoxyphenyl)(phenyl)]phosphino]ferrocenyl- N , N -dimethyl Ethylamine 9

The preparation of dichloride is the same as in Example 1.

Add 1.05 mL (10 mmol) of bromobenzene into a 100 mL single-necked bottle, inject 20 mL of dried methyl tert-butyl ether with a syringe after vacuuming/nitrogen cycle, and place in a low-temperature reactor at -40°C to stir Until dissolved, slowly inject 6.6 mL (1.6 M, 10.56 mmol) of n -BuLi, rise to room temperature and react for 2 hours to generate phenyllithium; place the suspension of dichloride in a low-temperature reactor at -70°C, and Add the phenyllithium compound to the suspension of the dichloride, rise to room temperature and react for 2 hours to obtain the monochloride.

Add 1.5 mL (12 mmol) of o-methoxybromobenzene into a 100 mL single-necked bottle, inject 20 mL of dried methyl tert-butyl ether with a syringe after vacuuming/nitrogen cycle, and place at -40 °C Stir in the reactor until dissolved, slowly inject n -BuLi 8 mL (1.6 M, 12.8 mmol), rise to room temperature and react for 2 hours to generate lithium compounds; place the monochloride suspension in a -20°C low-temperature reactor, Add the lithium compound into the suspension of the monochloride with double needles, raise the temperature to reflux for 8 hours, remove the insoluble matter by filtration, wash with water and saturated brine successively, and evaporate the solvent to dryness. .

 -106 (c = 0.25, CH₂Cl₂); ¹H NMR (500 Hz, CDCl₃) δ 7.34-7.28 (m, 1H), 7.18-7.08 (m, 2H), 6.98-6.80 (m, 4H), 6.78-6.72 (m, 1H), 6.70-6.65 (m, 1H), 4.39 (s, 1H), 4.26 (s, 1H), 4.20-4.08 (dd, J = 3.5, 3.5 Hz, 1H), 3.97 (s, 5H), 3.90 (s, 1H), 3.58 (s, 3H), 1.84 (s, 6H), 1.35-1.25 (d, J = 6.5 Hz, 3H); ³¹P NMR (202 Hz, CDCl₃) δ -53.36 (s)。 mp 127. -128.4℃;

-106 (c = 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.34-7.28 (m, 1H), 7.18-7.08 (m, 2H), 6.98-6.80 (m, 4H) , 6.78-6.72 (m, 1H), 6.70-6.65 (m, 1H), 4.39 (s, 1H), 4.26 (s, 1H), 4.20-4.08 (dd, J = 3.5, 3.5 Hz, 1H), 3.97 ( ^s , 5H), 3.90 (s, 1H), 3.58 (s, 3H), 1.84 (s, 6H), 1.35-1.25 (d, J = 6.5 Hz, _3H ); ) δ -53.36 (s).

Example 10: Preparation of ( R ) -S -1-[2-[( S )-(3,5-dimethylphenyl)(phenyl)]phosphino]ferrocenyl- N , N -di Methylethylamine 10

The preparation method was the same as in Example 9, 2.3 g of a yellow solid product, and the yield was 49.0%.

mp 177.3-178.6℃; -317.6 (c = 0.25, CH ₂ Cl ₂ ); ¹ H NMR (500 Hz, CDCl ₃ ) δ 7.72-7.60 (m, 2H), 7.44-7.36 (m, 3H), 6.90-6.80 (m, 3H) , 4.43 (s, 1H), 4.28 (s, 1H), 4.22-4.12 (d, J = 4 Hz, 1H), 3.96 (s, 5H), 3.91 (s, 1H), 2.23 (s, 6H), 1.87 (s, 6H), 1.44-1.28 (d, J = 1.5 Hz, 3H).

Claims (7)

1. The preparation method of the compound shown in general structural formula (I), it is characterized in that comprising the following steps:

R ₁ and R ₂ are independently selected from C1-C25 alkyl, or aryl, heteroaryl, cycloalkyl, ferrocenyl, (1) The organometallic lithium reagent activates the R -configuration or S- configuration Ugi′s amine and reacts with PCl ₃ to obtain the dichloride (II);

(2) Add RLi or RMgX in an amount 2 to 3 times the amount of the dichloride (II), and react to obtain a compound shown in the general structural formula (I) without P-chirality, where R=R ₁ =R ₂ , X is halogen; Alternatively, first add 1-1.05 times the molar amount of dichloride (II) R ₁ Li or R ₁ MgX to react to obtain monochloride (III), and then add excess R ₂ Li or R ₂ MgX to react to obtain P-chiral The compound shown in general formula (I), wherein R ₁ ≠ R ₂ ,

. 2. The preparation method of the compound according to claim 1, characterized in that: in step (1), the organometallic lithium reagent is methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, hexyllithium or Phenyllithium. 3. according to the preparation method of the described compound of claim 1, it is characterized in that: in step (1), add organometallic lithium reagent activation Ugi's amine reaction solvent is methyl tert-butyl ether, ether, toluene or tetrahydrofuran, temperature -15°C to 35°C. 4. The preparation method of the compound according to claim 1, characterized in that: in step (1), the temperature of adding PCl ₃ is -120°C ~ -60°C, and the reaction time is 6 ~ 18h. 5. The preparation method of the compound according to claim 1, characterized in that: in step (2), the temperature of adding RLi or RMgX is -60°C to 35°C. 6. The preparation method of the compound according to claim 1, characterized in that: in step (2), the temperature of adding R ₁ Li or R ₁ MgX is -120°C ~ -60°C, after rising to room temperature Reaction 1 ~ 6h. 7. The preparation method of the compound according to claim 1, characterized in that: in step (2), the temperature of adding R ₂ Li or R ₂ MgX is -60°C to 35°C, and the substance of R ₂ Li or R ₂ MgX The amount is 1 to 2 times that of the monochloride (III), and react for 4-16 hours after rising to room temperature.