Preparation method of 4-bromo-2-(methylamino) phenyl diethylphosphine oxide

Abstract

The invention discloses a preparation method of 4-bromo-2-(methylamino) phenyl diethylphosphine oxide, and belongs to the technical field of chemical synthesis. The preparation method comprises the following steps: by taking 1, 4-dibromo-2-fluorobenzene as a raw material, carrying out reaction on 1, 4-dibromo-2-fluorobenzene and diethyl phosphorus chloride under the action of tri-n-butyl magnesium lithium to generate 4-bromo-2-fluorophenyl diethyl phosphine; then, 4-bromine-2-fluorophenyl diethyl phosphine fluoroborate and fluoboric acid form 4-bromine-2-fluorophenyl diethyl phosphine fluoroborate; and then carrying out methylamine substitution and phosphine oxidation reaction to obtain the 4-bromo-2-(methylamino) phenyl diethylphosphine oxide. The raw materials are available in the market, the whole route is simple and effective, and a route reference is provided for synthesis of the compounds.

Description

Technical Field

[0001] The invention relates to a preparation method of 4-bromo-2-(methylamino)phenyl diethyl phosphine oxide, belonging to the technical field of pharmaceutical intermediate synthesis. Background Art

[0002]

[0003] Aleniglipron is a small molecule GLP-1 receptor agonist whose pharmacological activity is demonstrated by a cAMP stimulation EC50 value of less than 0.1 nM in the HDB cell line. It holds significant importance in the field of GLP-1 agonists. The GLP-1RA drug market is vast, with strong demand for weight loss products in particular. In 2024, global GLP-1RA drug sales totaled $51.8 billion, with weight loss product sales increasing by 121% to $14.1 billion. According to Evaluate Pharma, GLP-1RA drug sales are expected to reach $130 billion by 2030, with particularly significant growth in demand for weight loss products. 4-Bromo-2-(methylamino)phenyldiethylphosphine oxide is a key raw material for Aleniglipron.

[0004] Regarding the synthesis route of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide, a search of existing literature revealed that patents [WO2021155841A; WO202316546A] reported the use of 1-bromo-3-fluoro-4-iodobenzene as a raw material, reacting it with diethylphosphine oxide under the action of a palladium catalyst to generate 4-bromo-2-fluorophenyldiethylphosphine oxide, which was then reacted with methylamine to generate 4-bromo-2-(methylamino)phenyldiethylphosphine oxide.

[0005] There are few synthetic methods reported so far, with low yields and the use of expensive palladium catalysts. Summary of the Invention

[0006] The present invention is made to solve the above problems, and its purpose is to provide a preparation method with high yield and economical route.

[0007] The present invention provides a method for preparing 4-bromo-2-(methylamino)phenyl diethyl phosphine oxide, comprising the following steps:

[0008] A. 1,4-dibromo-2-fluorobenzene is mixed in tetrahydrofuran, and tri-n-butyl magnesium lithium is added under low temperature conditions, followed by diethylphosphine chloride to obtain 4-bromo-2-fluorophenyl diethylphosphine;

[0009] B. Mixing 4-bromo-2-fluorophenyldiethylphosphine and tetrafluoroboric acid in dichloromethane at room temperature to obtain 4-bromo-2-fluorophenyldiethylphosphine fluoroborate;

[0010] C. Mixing 4-bromo-2-fluorophenyl diethylphosphine fluoroborate with methylamine in a solvent and heating the mixture to obtain 4-bromo-2-(methylamino)phenyl diethylphosphine fluoroborate;

[0011] D. Mix 4-bromo-2-(methylamino)phenyldiethylphosphine fluoroborate, lithium hydroxide and hydrogen peroxide in dioxane at room temperature to obtain the product 4-bromo-2-(methylamino)phenyldiethylphosphine oxide.

[0012] The reaction equation is shown as follows:

[0013]

[0014] The preparation method of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide provided by the present invention may also have the following characteristics: wherein, in step A, the low temperature condition is -10-10°C.

[0015] The preparation method of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide provided by the present invention may also have the following characteristics: in step A, the molar ratio of 1,4-dibromo-2-fluorobenzene, tri-n-butylmagnesium lithium and diethylphosphine chloride is 1:0.35-0.45:1.05-1.35.

[0016] The preparation method of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide provided by the present invention may also have the following characteristics: in step B, the molar ratio of the 4-bromo-2-fluorophenyldiethylphosphine to tetrafluoroboric acid is 1:1-1.2.

[0017] The preparation method of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide provided by the present invention may also have the following feature: in step C, the solvent is dioxane or dimethyl sulfoxide.

[0018] The preparation method of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide provided by the present invention may also have the following feature: in step C, the temperature is raised to 90-120°C.

[0019] The preparation method of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide provided by the present invention may also have the following characteristics: in step C, the molar ratio of the 4-bromo-2-fluorophenyldiethylphosphine fluoroborate to methylamine is 1:10-20.

[0020] The preparation method of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide provided by the present invention may also have the following characteristics: in step D, the molar ratio of the 4-bromo-2-(methylamino)phenyldiethylphosphine fluoroborate, lithium hydroxide and hydrogen peroxide is 1:1-1.5:1.1-1.5.

[0021] The present invention has the following beneficial effects:

[0022] 1. The present invention uses cheap and easily available 1,4-dibromo-2-fluorobenzene as a raw material, has a novel route, good operability and a high overall yield.

[0023] 2. In the present invention, phosphorus is first salted with tetrafluoroboric acid, at which time phosphorus becomes a strong electron-pulling group, which is the nucleophilic SN for the subsequent methylamine Ar Substitution provides favorable conditions.

[0024] 3. The route of the present invention does not require the use of precious metal catalysts, has low route cost and good economic value. Specific embodiments

[0025] The present invention will be further described below by way of specific examples. These embodiments should be understood to be merely illustrative of the present invention and not intended to limit the scope of protection of the present invention. After reading the contents described herein, those skilled in the art may make various changes or modifications to the present invention, and these equivalent variations and modifications also fall within the scope defined by the claims of the present invention.

[0026] Example 1

[0027] Under nitrogen protection, 1,4-dibromo-2-fluorobenzene (12.7 g, 0.05 mol) was mixed in 100 mL of tetrahydrofuran, cooled to 0-5°C, and 28.6 mL of tri-n-butyl magnesium lithium (0.7 M ether / n-hexane solution) was slowly added. The mixture was stirred for 1 hour, followed by the addition of diethyl phosphine chloride (7.5 g, 0.06 mol) and 35 mL of tetrahydrofuran solution. After the addition was complete, the mixture was heated to room temperature and stirred for 4 hours. 50 mL of water was slowly added, the layers were separated, the organic layer was concentrated, and the crude product was distilled under reduced pressure to obtain 11.4 g of 4-bromo-2-fluorophenyldiethylphosphine with a yield of 87% and an HPLC index of 98.6%. 1 HNMR (400MHz, CDCl3): 7.51-7.48(m,1H), 7.42-7.37(m,1H), 7.05-7.01(m,1H), 1.62-1.45(m,4H), 0.98-0.84(m,6H).

[0028] Example 2

[0029] Under nitrogen protection, 4-bromo-2-fluorophenyldiethylphosphine (13.2 g, 0.05 mol) and tetrafluoroboric acid (40%) aqueous solution (12.1 g, 0.055 mol) were mixed in 80 mL of dichloromethane and reacted at room temperature for 2 hours. The dichloromethane was concentrated under reduced pressure, the temperature was lowered to 0-5°C, and the filter cake was washed with n-heptane and dried to obtain 15.8 g of 4-bromo-2-fluorophenyldiethylphosphine fluoroborate in a yield of 90% and an HPLC result of 99.1%.1 HNMR(400MHz, DMSO-d6):7.70-7.66(m,1H),7.61-7.56(m,1H),7.15-7.11(m,1H),1.68-1.50(m,4H),1.03-0.89(m,6H).

[0030] Example 3

[0031] Under nitrogen protection, 4-bromo-2-fluorophenyldiethylphosphine fluoroborate (17.5 g, 0.05 mol) was mixed with 375 mL of 2M methylamine-dioxane solution in an autoclave, heated to 95-100° C. for 3 hours, cooled to room temperature, concentrated, and the crude product was recrystallized from methanol and water, filtered and dried to give 13.6 g of 4-bromo-2-(methylamino)phenyldiethylphosphine fluoroborate in a yield of 75%, and an HPLC purity of 98.8%. 1 HNMR(400MHz, DMSO-d6):7.66-7.62(m,1H),7.21-7.18(d,1H),6.83-6.60(m,2H),2.75(d,3H),1.88-1.80(m,4H),1.06-0.92(m,6H).

[0032] Example 4

[0033] Under nitrogen protection, 4-bromo-2-fluorophenyldiethylphosphine fluoroborate (17.5 g, 0.05 mol) was mixed with 375 mL of 2M methylamine-dimethyl sulfoxide solution in an autoclave, heated to 105-110° C. for 2 hours, cooled to room temperature, concentrated, and the crude product was recrystallized from methanol and water, filtered and dried to give 12.7 g of 4-bromo-2-(methylamino)phenyldiethylphosphine fluoroborate in a yield of 70% and an HPLC purity of 98.4%.

[0034] Example 5

[0035] Under nitrogen, 4-bromo-2-(methylamino)phenyldiethylphosphine fluoroborate (18.1 g, 0.05 mol) and lithium hydroxide (1.44 g, 0.06 mol) were mixed in 80 mL of dioxane, followed by the slow dropwise addition of 30% hydrogen peroxide (7.4 g, 0.065 mol). The reaction was allowed to proceed at room temperature for 2 hours, followed by the addition of 60 mL of saturated sodium bicarbonate solution. The mixture was extracted twice with 150 mL of ethyl acetate. The organic layers were combined and concentrated, and the crude product was recrystallized from petroleum ether / ethyl acetate, filtered, and dried to afford 13.5 g of 4-bromo-2-(methylamino)phenyldiethylphosphine oxide, with a yield of 93% and an HPLC yield of 99.3%. 1HNMR(400MHz, DMSO-d6):7.77-7.74(m,1H),7.13(d,1H),6.81-6.65(m,2H),2.72(d,3H),1.95-1.91(m,4H),1.07-0.91(m,6H).

[0036] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing 4-bromo-2-(methylamino)phenyl diethyl phosphine oxide, characterized in that: The steps include: A. 1,4-dibromo-2-fluorobenzene is mixed in tetrahydrofuran, and tri-n-butyl magnesium lithium is added under low temperature conditions, followed by diethylphosphine chloride to obtain 4-bromo-2-fluorophenyl diethylphosphine; B. Mixing 4-bromo-2-fluorophenyldiethylphosphine and tetrafluoroboric acid in dichloromethane at room temperature to obtain 4-bromo-2-fluorophenyldiethylphosphine fluoroborate; C. Mixing 4-bromo-2-fluorophenyl diethylphosphine fluoroborate with methylamine in a solvent and heating the mixture to obtain 4-bromo-2-(methylamino)phenyl diethylphosphine fluoroborate; D. Mix 4-bromo-2-(methylamino)phenyldiethylphosphine fluoroborate, lithium hydroxide and hydrogen peroxide in dioxane at room temperature to obtain the product 4-bromo-2-(methylamino)phenyldiethylphosphine oxide.

2. The method for preparing 4-bromo-2-(methylamino)phenyldiethylphosphine oxide according to claim 1, wherein: In step A, the low temperature condition is -10-10°C.

3. The method for preparing 4-bromo-2-(methylamino)phenyldiethylphosphine oxide according to claim 1, wherein: In step A, the molar ratio of 1,4-dibromo-2-fluorobenzene, tri-n-butyl magnesium lithium and diethyl phosphine chloride is 1:0.35-0.45:1.05-1.

35.

4. The method for preparing 4-bromo-2-(methylamino)phenyldiethylphosphine oxide according to claim 1, wherein: In step B, the molar ratio of 4-bromo-2-fluorophenyldiethylphosphine to tetrafluoroboric acid is 1:1-1.

2.

5. The method for preparing 4-bromo-2-(methylamino)phenyldiethylphosphine oxide according to claim 1, wherein: In step C, the solvent is dioxane or dimethyl sulfoxide; and the temperature is raised to 90-120°C.

6. The method for preparing 4-bromo-2-(methylamino)phenyldiethylphosphine oxide according to claim 1, wherein: In step C, the molar ratio of 4-bromo-2-fluorophenyldiethylphosphine fluoroborate to methylamine is 1:10-20.

7. The method for preparing 4-bromo-2-(methylamino)phenyldiethylphosphine oxide according to claim 1, wherein: In step D, the molar ratio of 4-bromo-2-(methylamino)phenyldiethylphosphine fluoroborate, lithium hydroxide and hydrogen peroxide is 1:1-1.5:1.1-1.5.

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