Di-tert-butyl phosphonium chloride d18, preparation method thereof, phosphine ligand and catalyst

Abstract

The invention discloses di-tert-butyl phosphonium chloride d18 and a preparation method thereof, a phosphine ligand and a catalyst, the method comprises the following steps: S1, dispersing tert-butyl chloro-d9 and magnesium chips in an organic solvent, and initiating a Grignard reaction by an initiator to generate tert-butyl magnesium chloride-d9; the molar ratio of the tertiary butyl chlorine-d9 to the magnesium chips to the initiator is 1: (1.0-1.2): (0.01-0.02); and S2, dissolving phosphorus trichloride in an organic solvent, adding the tert-butyl magnesium chloride-d9 obtained in the S1, reacting to generate di-tert-butyl phosphorus chloride-d18, and separating and purifying to obtain the product. The raw materials are easy to obtain, the reaction conditions are mild and controllable, and industrial enlarged production is facilitated.

Description

Technical Field

[0001] The present invention relates to the technical field of deuterated compound production, and particularly relates to a di-tert-butylphosphine chloride-d18, a preparation method thereof, a phosphine ligand, and a catalyst. Background Art

[0002] Di-tert-butylphosphine chloride (t-Bu2PCl), also known as di-tert-butyl chlorophosphite, is a very important palladium complex ligand in the field of organic synthesis. Generally, it appears as a colorless liquid and can exist stably under normal temperature and pressure. Using di-tert-butylphosphine chloride as a direct ligand or as a raw material for the synthesis of ligand catalysts, it is further widely used in coupling reactions such as C-C, C-N, and C-O. For example, Cu(I)X can be used to catalyze the coupling of di-tert-butylphosphine chloride with phenyl or biphenyl Grignard reagents to obtain ligands of di-tert-butylphenylphosphine. Research shows that in palladium-catalyzed coupling reactions, alkylphosphines with larger volumes are more effective ligands because they can increase the reductive elimination rate in these processes and can be used for more challenging substrate combinations (those with steric hindrance or containing sensitive functional groups). Catalysts or ligands with di-tert-butylphosphine or dicyclohexylphosphine are generally more effective. However, some reactions have higher requirements for the stability of the ligand, and the C-H bond in the coordination may have an adverse effect on the reaction. Utilizing the fact that the C-D bond is more stable than the C-H bond, developing deuterated phosphine ligands is a solution.

[0003] Di-tert-butylphosphine chloride can be used to synthesize phosphine oxide bidentate ligands. CN111647020A discloses a synthesis method of a phosphine oxide bidentate ligand: The reaction system is established under the protection of an inert gas, and generally nitrogen or argon is selected as the inert gas here. Then, starting materials and the reaction solvent tetrahydrofuran are added to a dry reaction vessel. The temperature is maintained at -78°C to -60°C, and deprotonation is carried out with the base LDA, and di-tert-butylphosphorus chloride is slowly added dropwise. After the reaction is complete, a methanol solution of magnesium monoperoxyphthalate hexahydrate is slowly added dropwise to the above mixture. After the reaction ends, the reaction system mixture is filtered through diatomaceous earth, washed, and concentrated to obtain a crude product. Still under the protection of an inert gas, the crude product is dissolved in toluene, triethylamine and trichlorosilane are added, and finally 30% sodium hydroxide solution is added to quench the reaction. Then, through extraction, concentration, and pulping steps, the phosphine oxide bidentate ligand is obtained. Experimental detection shows that the purity of the synthesized ligand can reach more than 97%.

[0004] Furthermore, various palladium catalysts can be synthesized according to different synthesized phosphine ligands for use in various reaction processes such as catalyzing coupling reactions. For example, CN108659054A discloses a preparation method of dichlorobis(tert-butyl)-4-dimethylaminophenylphosphine palladium. First, tert-butylphosphine chloride reacts with a Grignard reagent prepared from N,N-dimethyl-p-haloaniline and magnesium chips to prepare tert-butyl-4-dimethylaminophenylphosphine; second, the product p-tert-butyl-4-dimethylaminophenylphosphine is purified; finally, bis(acetonitrile)palladium dichloride is taken to carry out a complexation reaction with the purified substance to obtain dichlorobis(tert-butyl)-4-dimethylaminophenylphosphine palladium. By purifying tert-butyl-4-dimethylaminophenylphosphine in the above process and reacting it with bis(acetonitrile)palladium dichloride, the yield loss of precious metal palladium can be greatly reduced, the preparation cost can be significantly reduced, and it has good practical value.

[0005] In addition, tert-butylphosphine chloride has good biological activity and can also be used as a component of anticancer drugs and antiviral drugs, with broad application prospects. Summary of the Invention

[0006] The purpose of the present invention is to provide a tert-butylphosphine chloride-d18, its preparation method, a phosphine ligand, and a catalyst, with easily obtainable raw materials and mild and controllable reaction conditions, which are conducive to industrial scale-up production.

[0007] The technical solution adopted by the present invention to solve its technical problems is: A preparation method of tert-butylphosphine chloride-d18, comprising the following steps: S1: Dispersing tert-butyl chloride-d9 and magnesium chips in an organic solvent, and initiating a Grignard reaction with an initiator to generate tert-butylmagnesium chloride-d9; the molar ratio of tert-butyl chloride-d9, magnesium chips, and the initiator is 1:1.0 - 1.2:0.01 - 0.02; S2: Dissolving phosphorus trichloride in an organic solvent, adding the tert-butylmagnesium chloride-d9 obtained in S1, reacting to generate tert-butylphosphine chloride-d18, and obtaining the product through separation and purification.

[0008] For the synthesis route of tert-butylphosphine chloride-d18, its non-deuterated synthesis route is known, but the deuterated synthesis route has not been reported. The present invention uses tert-butyl chloride-d9 as a raw material to carry out a Grignard reaction with magnesium chips to generate tert-butylmagnesium chloride-d9; then reacting with phosphorus trichloride to generate tert-butylphosphine chloride-d18. In the preparation of the Grignard reagent, tert-butyl chloride may reversibly eliminate to obtain isobutene, which will cause a decrease in the deuterium content of tert-butylphosphine chloride-d18 in an environment where active hydrogen exists. Therefore, when using conventional iodine or dibromoethane as an initiator, the conditions within the reaction system need to be strictly controlled. The present application uses a Grignard reagent as an initiator to avoid the problems brought by conventional initiators.

[0009] Preferably, in S1, the initiator is selected from at least one of methylmagnesium chloride and isopropylmagnesium chloride. The amount of the initiator is very small, which can reduce the generation of by-products; and preferably, small molecule Grignard reagents are selected, and the low-boiling by-products generated can be removed by distillation.

[0010] Preferably, S1 is specifically as follows: under nitrogen protection, part of tert-butyl chloride-d9 and magnesium chips are dispersed in an organic solvent, heated to 50-60 °C and stirred evenly, then the initiator and the remaining tert-butyl chloride-d9 are added, and the temperature is raised to 70-75 °C, and the reaction is carried out for 1-2 h. The amount of part of tert-butyl chloride-d9 accounts for 20-30% of the total molar percentage of tert-butyl chloride-d9.

[0011] Preferably, in S2, the molar ratio of tert-butylmagnesium chloride-d9 to phosphorus trichloride is 1:0.2-0.4.

[0012] Preferably, S2 is specifically as follows: phosphorus trichloride is dissolved in an organic solvent, cooled to -40 °C to -50 °C, and tert-butylmagnesium chloride-d9 obtained in S1 is added dropwise. After the addition is completed, the temperature is raised to room temperature and stirred for 10-20 h; then heated to 70-75 °C and refluxed for 2-3 h. Finally, dioxane is added and refluxed at 70-75 °C for 1-2 h to obtain di-tert-butylphosphine chloride-d18.

[0013] Preferably, in S2, the separation and purification are as follows: the reaction solution is filtered, concentrated, and distilled under reduced pressure in sequence to obtain the purified product.

[0014] Preferably, the organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, and n-hexane.

[0015] Di-tert-butylphosphine chloride-d18 is prepared by the described preparation method, and its chemical structural formula is:

[0016] A phosphine ligand is prepared by using the di-tert-butylphosphine chloride-d18, and its chemical structural formula is: 。 The phosphine ligand can be complexed with a transition metal and used as a catalyst, for example, used in combination with palladium acetate.

[0017] A catalyst is prepared by using the di-tert-butylphosphine chloride-d18, and its chemical structural formula is: One of

[0018] The beneficial effects of the present invention are as follows: The raw materials involved in the reaction of the present invention are easily obtained, and the reaction conditions are mild and controllable, which is conducive to industrial scale-up production. The purity of the di-tert-butylphosphine chloride-d18 prepared by the method provided by the present invention is >90%, and the deuterium substitution degree is >99%. Detailed implementation manners

[0019] The technical solutions of the present invention will be further specifically described below through specific examples.

[0020] In the present invention, unless otherwise specified, the raw materials and equipment used can be purchased from the market or are commonly used in the art. The methods in the following examples are all conventional methods in the art unless otherwise specified.

[0021] Example 1 This example provides a method for preparing di-tert-butylphosphine chloride-d18, which includes the following steps: S1: Suspend magnesium chips (4.74 g, 194.84 mmol, 1.1 eq) in tetrahydrofuran (40 mL), under nitrogen protection, and add tert-butyl chloride-d9 with a deuterium substitution degree greater than 99% (4.5 g, 44.28 mmol, 0.25 eq). Heat to 60 °C, stir for 30 minutes, then dropwise add methylmagnesium chloride (3 M solution in tetrahydrofuran) (0.7 mL, 2.1 mmol, 0.012 eq). After the reaction is initiated, slowly dropwise add tert-butyl chloride-d9 (13.5 g, 132.85 mmol, 0.75 eq). After the addition is completed in one hour, raise the temperature to 70 °C and continue to stir for 1 hour to obtain tert-butylmagnesium chloride-d9. Then cool to room temperature, add tetrahydrofuran (18 mL) for dilution, and directly use it for the next reaction.

[0022] S2: Dissolve phosphorus trichloride (5.35 g, 38.97 mmol, 0.22 eq) in tetrahydrofuran (100 mL), cool to -45 °C, and dropwise add the tert-butylmagnesium chloride-d9 prepared in the previous step, maintaining the internal temperature at -30 to -40 °C. After the addition is completed, gradually raise the temperature to room temperature and stir overnight. Then heat to 75 °C and reflux for 2 hours. Cool to 45 °C, add dioxane (40 mL), and continue to reflux for 1 hour to obtain di-tert-butylphosphine chloride-d18; separate and purify to obtain the product.

[0023] After the reaction is completed, filter, concentrate, and distill under reduced pressure the reaction solution to obtain purified di-tert-butylphosphine chloride-d18, 3.1 g, with a yield of 40% (calculated based on phosphorus trichloride), a purity >90%, and a deuterium substitution degree >99%. 31 P{ 1 H}NMR (121.5 MHz, CDCl3) δ 146.6 (s).

[0024] Example 2 - 5 This example provides a preparation method of di - tert - butylphosphine chloride - d18. The preparation process refers to Example 1, with the difference being the control of reactants and various parameters. See Table 1 for details.

[0025] Table 1

[0026] Example 6 This example provides a phosphine ligand, and its synthesis route is shown as follows: Specifically, it includes the following steps: Suspend magnesium chips (0.55 g, 22.7 mmol, 2.17 eq) in tetrahydrofuran (12 mL), under nitrogen protection, heat to 70 °C, slowly add dropwise 2 - bromo - N,N - dimethylaniline (2.4 g, 12.0 mmol, 1.15 eq). After stirring for 30 minutes, the reaction is initiated, and the reaction solution refluxes violently. Then cool down to 60 °C and stir for 30 minutes. Slowly add dropwise 1 - bromo - 2 - chlorobenzene (2 g, 10.5 mmol, 1.0 eq), and then react at 60 °C for 2 hours. Monitor until 1 - bromo - 2 - chlorobenzene disappears, and the reaction solution is cooled to room temperature.

[0027] Add cuprous chloride (0.17 g, 1.78 mmol, 0.17 eq) to the reaction solution. After stirring for 15 minutes, then add dropwise di - tert - butylphosphine chloride - d18 (2.4 g, 12.0 mmol, 1.15 eq). Heat the reaction solution to 60 °C and stir for 16 hours. Quench the reaction solution with water (40 mL), then add ammonia water (12 mL), extract with ethyl acetate (50 mL). Dry the organic phase with anhydrous sodium sulfate, concentrate, and the obtained solid is slurried with cold methanol, and the filtered solid is dried to obtain the product 2'-(bis(2 - (methyl - d3)propan - 2 - yl - 1,1,1,3,3 - d6)phosphoryl)-N,N - dimethyl - [1,1'-biphenyl]-2 - amine (1.5 g, yield 40%).

[0028] Example 6 This example provides a phosphine ligand, which is different from Example 6 in that: Replace Obtain

[0029] Example 7 This example provides a catalyst, which is prepared using the di - tert - butylphosphine chloride - d18 of Example 1, and its chemical structural formula is:

[0030] Example 8 This example provides a catalyst, which is prepared using the di-tert-butylphosphine chloride-d18 of Example 1, and its chemical structural formula is:

[0031] Example 9 This example provides a catalyst, which is prepared using the di-tert-butylphosphine chloride-d18 of Example 1, and its chemical structural formula is:

[0032] The above-described examples are only a preferred solution of the present invention, and do not impose any formal restrictions on the present invention. There are other variations and modifications without exceeding the technical solutions described in the claims.

Claims

1. A preparation method of di-tert-butylphosphine chloride-d18, characterized in that, It includes the following steps: S1: Dispersing tert-butyl chloride-d9 and magnesium chips in an organic solvent, initiating a Grignard reaction with an initiator to generate tert-butylmagnesium chloride-d9; the molar ratio of tert-butyl chloride-d9, magnesium chips, and the initiator is 1:1.0 - 1.2:0.01 - 0.02; S2: Dissolving phosphorus trichloride in an organic solvent, adding the tert-butylmagnesium chloride-d9 obtained in S1, reacting to generate di-tert-butylphosphinous chloride-d18, and obtaining the product through separation and purification.

2. The preparation method according to claim 1, wherein In S1, the initiator is selected from at least one of methylmagnesium chloride and isopropylmagnesium chloride.

3. The preparation method according to claim 1, characterized in that, Specifically, in S1: Under nitrogen protection, disperse part of tert-butyl chloride-d9 and magnesium chips in an organic solvent, heat to 50 - 60 °C and stir evenly, then add the initiator and the remaining tert-butyl chloride-d9, raise the temperature to 70 - 75 °C, and react for 1 - 2 h.

4. The preparation method according to claim 1, characterized in that, In S2, the molar ratio of tert-butylmagnesium chloride-d9 and phosphorus trichloride is 1:0.2 - 0.

4.

5. The preparation method according to claim 1, characterized in that, Specifically, in S2: Dissolve phosphorus trichloride in an organic solvent, cool to -40 °C to -50 °C, dropwise add the tert-butylmagnesium chloride-d9 obtained in S1, after the addition is complete, raise the temperature to room temperature, and stir for 10 - 20 h; then heat to 70 - 75 °C and reflux for 2 - 3 h, finally add dioxane, and continue to reflux at 70 - 75 °C for 1 - 2 h to obtain di-tert-butylphosphinous chloride-d18.

6. The preparation method according to claim 1, characterized in that, In S2, the separation and purification are as follows: Filter the reaction solution successively, concentrate, and perform vacuum distillation to obtain the purified product.

7. The preparation method according to claim 1, characterized in that, The organic solvent is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, and n-hexane.

8. Di-tert-butylphosphine chloride - d18, characterized in that, Prepared by the preparation method according to any one of claims 1 - 7, and its chemical structural formula is:

9. A phosphine ligand, characterized in that, Prepared from the di-tert-butylphosphinous chloride-d18 according to claim 8, and its chemical structural formula is:

10. A catalyst, characterized in that, Prepared from the di-tert-butylphosphinous chloride-d18 according to claim 8, and its chemical structural formula is: One of them.

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