Process for preparing abiraterone by one-pot method

Abstract

The invention belongs to the technical field of raw material medicine synthesis, and discloses a process for preparing abiraterone by a one-pot method. The process for preparing abiraterone by the one-pot method comprises the following steps: mixing an aprotic ether solvent, 3-bromopyridine, iodine, magnesium and a catalyst for reaction to obtain a Grignard reagent of the 3-bromopyridine; mixing a Grignard reagent of 3-bromopyridine, a raw material 3, triphenylphosphine, a metal catalyst and an aprotic ether solvent, and reacting to obtain an intermediate 2 solution; and mixing the intermediate 2 solution with an acid solution, and then adjusting the pH value to obtain abiraterone. The process successfully realizes a method for preparing abiraterone by a Grignard reaction, a Kumada reaction, a hydrolysis reaction and a neutralization reaction through a one-pot method, abiraterone is produced from the raw material 3-bromopyridine and the raw material 3 in one step, the requirement of continuous production is met, the requirement of green chemistry is met, pollution is reduced, the yield is increased, and the cost is reduced.

Description

Technical Field

[0001] The invention relates to the technical field of raw material drug synthesis, and in particular to a process for preparing abiraterone by a one-pot method. Background Art

[0002] Abiraterone acetate is an effective and selective oral inhibitor of 17α-hydroxylase-C17,20-lyase (also known as steroid 17α-monooxygenase inhibitor or human cytochrome P45017α), a key enzyme in androgen synthesis, and can be used to treat prostate cancer. Abiraterone acetate is a prodrug of abiraterone, and abiraterone is an intermediate in the synthesis of abiraterone acetate.

[0003] Currently, abiraterone is mainly prepared by the following three methods:

[0004] Method 1: The route is shown below. The preparation of 3-pyridinium zinc bromide needs to be at -78°C, so there are certain limitations for industrial production.

[0005]

[0006] Method 2: The route is shown below, and it also requires very expensive diethyl (3-pyridyl) borane. In addition, the production cost is high, which is not conducive to industrialization.

[0007]

[0008] Method 3: The route is shown below. There are many reaction by-products, the yield is low, the amount of Grignard reagent used is large, and the cost is high.

[0009]

[0010] Therefore, it is an urgent problem to provide a synthesis method of abiraterone that meets the requirements of continuous production and green chemistry, reduces pollution, improves yield, and reduces cost. Summary of the invention

[0011] The object of the present invention is to provide a heat treatment process for improving the superplasticity of duplex stainless steel, so as to improve the elongation of the superplastic deformation of the duplex stainless steel.

[0012] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0013] The present invention provides a one-pot process for preparing abiraterone, comprising the following steps:

[0014] (1) mixing an aprotic ether solvent, 3-bromopyridine, iodine, magnesium and a catalyst to react to obtain a Grignard reagent of 3-bromopyridine;

[0015] (2) mixing a Grignard reagent of 3-bromopyridine, raw material 3, triphenylphosphine, a metal catalyst and a non-protonic ether solvent, and reacting to obtain an intermediate 2 solution;

[0016] (3) mixing the intermediate 2 solution and the acid solution, and then adjusting the pH value to obtain abiraterone;

[0017] The structure of the raw material 3 is shown in Formula 1 below:

[0018]

[0019] Wherein, PG is one of trimethylsilyl (Me3Si-), tert-butyldimethylsilyl (t-BuMe2Si-) or 3,4-dihydro-2H-pyranyl.

[0020] Preferably, in step (1), the ratio of the aprotic ether solvent, 3-bromopyridine, iodine, magnesium and catalyst is 100-150:10-15:0.1-0.15:2-2.5:3-5.

[0021] Preferably, the reaction temperature in step (1) is 15-30° C., the reaction time is 0.5-5 h, and the reaction atmosphere is an inert atmosphere.

[0022] Preferably, the catalyst in step (1) comprises at least one of a brominated alkane or a metal halide.

[0023] Preferably, the mixing process in step (1) comprises:

[0024] First, part of the aprotic ether solvent, iodine, catalyst and magnesium are mixed, dispersed at 20-30° C. for 0.5-1 h, cooled to 15-30° C., and then 3-bromopyridine bromide and the remaining aprotic ether solvent are added.

[0025] Preferably, the aprotic ether solvent in step (1) and the aprotic ether solvent in step (2) independently comprise at least one of 2-methyltetrahydrofuran and tetrahydrofuran;

[0026] And / or, the mass ratio of the 3-bromopyridine in step (1) to the raw material 3, triphenylphosphine, metal catalyst and aprotic ether solvent in step (2) is 10-15:25-35:4-8:1-3:70-75;

[0027] And / or, the metal catalyst in step (2) includes tetrakistriphenylphosphine palladium.

[0028] Preferably, the mixing process in step (2) comprises:

[0029] The raw material 3, triphenylphosphine and aprotic ether solvent are mixed and replaced with nitrogen, and then a metal catalyst is added to continue nitrogen replacement. The temperature is raised to 40-60° C., and the Grignard reagent of 3-bromopyridine is dropped.

[0030] Preferably, the reaction temperature in step (2) is 40-60° C., and the reaction time is 4-8 h.

[0031] Preferably, the mass ratio of the acid solution in step (3) to the Grignard reagent of 3-bromopyridine in step (2) is 13-15:10-15;

[0032] And / or, the concentration of the acid solution in step (3) is 36-38 wt %.

[0033] Preferably, the target pH value in step (3) is 9-10.

[0034] It can be seen from the above technical solution that compared with the prior art, the present invention has the following beneficial effects:

[0035] The invention provides a new process for preparing abiraterone by a one-pot method. The process successfully realizes a one-pot method for preparing abiraterone by a four-step reaction of a Grignard reaction, a Kumada reaction, a hydrolysis and a neutralization reaction, and produces abiraterone acetate from a raw material 3-bromopyridine and a raw material 3 in one step, meets the requirements of continuous production, meets the requirements of green chemistry, reduces pollution, improves the yield and reduces the cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required to be used in the description of the embodiments or the prior art are briefly introduced below.

[0037] Figure 1 is the synthetic route diagram of the present invention;

[0038] Figure 2 It is the HPLC spectrum of abiraterone in Example 1. DETAILED DESCRIPTION

[0039] The present invention provides a one-pot process for preparing abiraterone, comprising the following steps:

[0040] (1) mixing an aprotic ether solvent, 3-bromopyridine, iodine, magnesium and a catalyst to react to obtain a Grignard reagent of 3-bromopyridine;

[0041] (2) mixing a Grignard reagent of 3-bromopyridine, raw material 3, triphenylphosphine, a metal catalyst and a non-protonic ether solvent, and reacting to obtain an intermediate 2 solution;

[0042] (3) mixing the intermediate 2 solution and the acid solution, and then adjusting the pH value to obtain abiraterone;

[0043] The structure of the raw material 3 is shown in Formula 1 below:

[0044]

[0045] PG:A=Me3Si,B=t-BuMe2Si,C=tetrahydro-2H-pyran ,etc Formula 1,

[0046] Among them, PG is trimethylsilyl tert-Butyldimethylsilyl t-BuMe2Si- or 2-tetrahydro-2H-pyranyl One of them.

[0047] In the present invention, the mass ratio of the aprotic ether solvent, 3-bromopyridine, iodine, magnesium and catalyst in step (1) is preferably 100-150:10-15:0.1-0.15:2-2.5:3-5, more preferably 100-130:12-14:0.1-0.13:2.1-2.3:3.5-4.8, and more preferably 100:13.9:0.11:2.11:4.27-4.57.

[0048] In the present invention, the reaction temperature in step (1) is preferably 15 to 30°C, more preferably 18 to 25°C, and more preferably 20 to 22°C; the reaction time is preferably 0.5 to 5h, more preferably 1 to 4h, and more preferably 2 to 3h; the reaction atmosphere is preferably an inert atmosphere; and the inert atmosphere is preferably nitrogen.

[0049] In the present invention, the catalyst in step (1) preferably comprises at least one of a brominated alkane or a metal halide, more preferably a mixture of a brominated alkane and a metal halide;

[0050] The brominated alkane preferably includes at least one of ethyl bromide and propyl bromide;

[0051] The metal halide is preferably lithium chloride;

[0052] The mass ratio of the brominated alkane to the metal halide in the catalyst in step (1) is preferably 0.4-0.6:2.6-4.4, more preferably 0.5-0.58:3.5-4.2, and more preferably 0.54:3.73.

[0053] In the present invention, the mixing process in step (1) comprises:

[0054] First, part of the aprotic ether solvent, iodine, catalyst and magnesium are mixed, dispersed at 20-30° C. for 0.5-1 h, cooled to 15-30° C., and then 3-bromopyridine bromide and the remaining aprotic ether solvent are added.

[0055] In the present invention, after the reaction in step (1) is completed, the obtained product is further cooled to 0-5°C.

[0056] In the present invention, the aprotic ether solvent in step (1) and the aprotic ether solvent in step (2) independently preferably contain at least one of 2-methyltetrahydrofuran and tetrahydrofuran.

[0057] In the present invention, the mass ratio of the 3-bromopyridine in step (1) to the raw material 3, triphenylphosphine, metal catalyst and aprotic ether solvent in step (2) is preferably 10-15: 25-35: 4-8: 1-3: 70-75, more preferably 12-14: 26-32: 4.2-7: 1.2-2.5: 71-74, and more preferably 13.9: 27.6-30.06: 4.23-4.56: 1.5: 72-73.

[0058] In the present invention, the metal catalyst in step (2) includes tetrakistriphenylphosphine palladium.

[0059] In the present invention, the mixing process in step (2) comprises:

[0060] The raw material 3, triphenylphosphine and aprotic ether solvent are mixed and replaced with nitrogen, and then a metal catalyst is added to continue nitrogen replacement. The temperature is raised to 40-60° C., and the Grignard reagent of 3-bromopyridine is dropped.

[0061] In the present invention, the reaction temperature in step (2) is preferably 40-60°C, more preferably 45-55°C, more preferably 46-50°C; the reaction time is preferably 4-8h, more preferably 4.5-7.5h, more preferably 5-6h.

[0062] In the present invention, after the reaction in step (2) is completed, post-treatment is also included:

[0063] The product obtained after the reaction is completed is cooled to 20-30°C, and then water is added for stirring, and then concentrated to remove 2-methyltetrahydrofuran, and then toluene is added for filtration;

[0064] There is no limitation on the amount of water and toluene used.

[0065] In the present invention, the mass ratio of the acid solution in step (3) to the 3-bromopyridine in step (1) is preferably 13-15:10-15, more preferably 13.5-14.8:11-14, and more preferably 14.25-14.4:13.9.

[0066] In the present invention, the concentration of the acid solution in step (3) is preferably 36-38 wt %, more preferably 36.5-37.5 wt %, and more preferably 37 wt %.

[0067] In the present invention, the target pH value in step (3) is preferably 9 to 10, more preferably 9.2 to 9.8, and even more preferably 9.5.

[0068] In the present invention, the specific process of step (3) is as follows: adding an acid solution to the intermediate 2 solution, then heating to 30-50° C. and stirring for 1-3 hours, then cooling to 20-25° C. for washing and filtering, mixing the precipitate obtained by filtration with water, and adjusting the pH at 20-30° C.; after the pH adjustment is completed, filtering the precipitated solid, and washing with water; then adding 150 mL of acetone, stirring at 50-60° C. for 2 hours; cooling to 20-25° C., and then filtering, washing, and drying.

[0069] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0070] Example 1

[0071] Under a nitrogen atmosphere, 0.54 g (8.8 mmol) of bromopropane was added to a mixed system of 80 g of 2-methyltetrahydrofuran (2-MeTHF), 0.11 g of iodine, 3.73 g of lithium chloride, and 2.11 g (88 mmol) of magnesium to obtain a mixture, which was stirred at 30° C. for 0.5 h; after the stirring was completed, the temperature was lowered to 15° C., and a mixed solution of 13.9 g (88 mmol) of 3-bromopyridine and 20 g of 2-MeTHF was added dropwise, and after the addition was completed, the reaction was continued to be stirred at 15° C. for 1 h. After the reaction was completed, the obtained product was cooled to 5° C. to obtain a Grignard reagent of 3-bromopyridine;

[0072] Take 27.60g of raw material 4.23 g of triphenylphosphine and 70 g of 2-MeTHF were placed in a reaction bottle and replaced with nitrogen; 1.15 g of tetrakistriphenylphosphine palladium was added and replaced with nitrogen 5 times; the temperature was raised to 50°C, and the Grignard reagent of 3-bromopyridine was added dropwise. After the addition was completed, the temperature was kept at 55°C for 6 hours. After the reaction was completed, the temperature was lowered to 20°C, 2.69 g of water was added dropwise, and the mixture was stirred for 15 minutes after the addition was completed; the mixture was then concentrated to remove 2-MeTHF, 300 mL of toluene was added, and the mixture was stirred for 2 hours. Filter to obtain an intermediate 2 solution, add 14.25 g of concentrated hydrochloric acid (37 wt%) dropwise to the intermediate 2 solution at room temperature, heat to 40 ° C and stir for 2 h, cool to 20 ° C and filter, wash, transfer the solid into 200 mL of water, control the temperature at 25 ° C, adjust the pH to 9 with a saturated potassium bicarbonate solution, precipitate the solid and then filter, wash with water; then add 150 mL of acetone to the obtained solid, stir at 50 ° C for 2 h; cool to 20 ° C, filter, wash, and dry to obtain 22.05 g of product abiraterone.

[0073] The HPLC spectrogram of Abiraterone in Example 1 is as follows Figure 2 As shown. Figure 2 It can be seen that the retention time 26.760 is the abiraterone product peak.

[0074] Example 2

[0075] Under a nitrogen atmosphere, 0.54 g (8.8 mmol) of bromopropane was slowly added to a mixed system of 80 g of tetrahydrofuran (THF), 0.11 g of iodine, 4.03 g of lithium chloride, and 2.11 g (88 mmol) of magnesium to obtain a mixture, which was stirred at 30°C for 0.5 h; after the stirring was completed, the temperature was lowered to 15°C, and a mixed solution of 13.9 g (88 mmol) of 3-bromopyridine and 20 g of THF was added dropwise. After the addition was completed, the reaction was continued to be stirred at 15°C for 1 h. After the reaction was completed, the obtained product was cooled to 5°C to obtain a Grignard reagent of 3-bromopyridine.

[0076] Take 30.06g of raw material 3B (PG is Triphenylphosphine and 75g THF were placed in a reaction bottle and replaced with nitrogen; 1.15g tetrakistriphenylphosphine palladium was added and replaced with nitrogen 5 times; the temperature was raised to 50°C, and the Grignard reagent of 3-bromopyridine was added dropwise. After the addition was completed, the temperature was kept at 55°C for 6h. After the reaction was completed, the temperature was lowered to 20°C, 2.69g water was added dropwise, and the mixture was stirred for 15 minutes after the addition was completed; then the mixture was concentrated to remove THF, 300mL toluene was added, and the mixture was stirred for 2 hours. Filtering was performed to obtain an intermediate 2 solution, 14.40g concentrated hydrochloric acid (37wt%) was added dropwise to the intermediate 2 solution at room temperature, the temperature was raised to 40°C, and the mixture was stirred for 2h, the temperature was lowered to 20°C, the mixture was filtered, and the intermediate 2 solution was washed. The solid was transferred into 200 mL of water, the temperature was controlled at 25°C, the pH was adjusted to 10 with saturated potassium bicarbonate solution, the solid was precipitated and then filtered and washed with water; 150 mL of acetone was added to the obtained solid, and stirred at 50°C for 2 h; the temperature was lowered, filtered, washed, and dried to obtain 22.05 g of product abiraterone.

[0077] Example 3

[0078] Under a nitrogen atmosphere, 0.54 g (8.8 mmol) of bromopropane was slowly added to a mixed system of 80 g of 2-MeTHF, 0.11 g of iodine, 3.73 g of lithium chloride, and 2.11 g (88 mmol) of magnesium, and the mixture was stirred at 30°C for 0.5 h. After the stirring, the temperature was lowered to 15°C, and a mixed solution of 13.9 g (88 mmol) of 3-bromopyridine and 20 g of 2-MeTHF was added dropwise. After the addition was completed, the reaction was continued to be stirred at 15°C for 1 h. After the reaction was completed, the obtained product was cooled to 5°C to obtain a Grignard reagent of 3-bromopyridine.

[0079] Take 28.00g of raw material 4.53g triphenylphosphine and 70g 2-MeTHF were placed in a reaction bottle and replaced with nitrogen; 1.15g tetrakis triphenylphosphine palladium was added and replaced with nitrogen 5 times. The temperature was raised to 50°C, and the Grignard reagent of 3-bromopyridine was added dropwise. After the addition was completed, the temperature was kept at 55°C for 6h; after the reaction was completed, the temperature was lowered to 20°C, 2.69g water was added dropwise, and the temperature was stirred for 15 minutes after the addition was completed; then the reaction was concentrated to remove 2-MeTHF, 300mL toluene was added, and the mixture was stirred for 2 hours. Filter to obtain the intermediate 2 solution, 14.36g concentrated hydrochloric acid (37wt%) was added dropwise to the intermediate 2 solution at room temperature, the temperature was raised to 40°C and stirred for 2h, the temperature was lowered to 20°C, filtered, and washed. The solid was transferred into 200mL water, the temperature was controlled at 25°C, and the pH was adjusted to 10 with a saturated potassium bicarbonate solution. The precipitated solid was filtered and washed with water; 150 mL of acetone was added to the obtained solid and stirred at 50° C. for 2 h; the solid was cooled, filtered, washed and dried to obtain 22.05 g of product abiraterone.

[0080] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A one-pot process for preparing abiraterone, characterized in that: The following steps are involved: (1) mixing an aprotic ether solvent, 3-bromopyridine, iodine, magnesium and a catalyst to react to obtain a Grignard reagent of 3-bromopyridine; (2) mixing a Grignard reagent of 3-bromopyridine, raw material 3, triphenylphosphine, a metal catalyst and a non-protonic ether solvent, and reacting to obtain an intermediate 2 solution; (3) mixing the intermediate 2 solution and the acid solution, and then adjusting the pH value to obtain abiraterone; The structure of the raw material 3 is shown in Formula 1 below: Wherein, PG is one of trimethylsilyl, tert-butyldimethylsilane or 2-tetrahydro-2H-pyranyl.

2. The one-pot process for preparing abiraterone according to claim 1, characterized in that: As described in step (1) No Proton ethers The mass ratio of the solvent, 3-bromopyridine, iodine, magnesium and the catalyst is 100-150:10-15:0.1-0.15:2-2.5:3-5.

3. The one-pot process for preparing abiraterone according to claim 2, characterized in that: The reaction temperature in step (1) is 15-30° C., the reaction time is 0.5-5 h, and the reaction atmosphere is an inert atmosphere.

4. The one-pot process for preparing abiraterone according to claim 3, characterized in that: The catalyst in step (1) comprises two kinds of brominated alkanes and lithium halides.

5. The one-pot process for preparing abiraterone according to claim 4, characterized in that: The mixing process in step (1) comprises: First, part of the aprotic ether solvent, iodine, catalyst and magnesium are mixed and dispersed at 20-30° C. for 0.5-1 h, cooled to 15-30° C., and then 3-bromopyridine and the remaining aprotic ether solvent are added.

6. The one-pot process for preparing abiraterone according to claim 4 or 5, characterized in that: The aprotic ether solvent in step (1) and the aprotic ether solvent in step (2) independently comprise at least one of 2-methyltetrahydrofuran and tetrahydrofuran; And / or, the mass ratio of the 3-bromopyridine in step (1) to the raw material 3, triphenylphosphine, metal catalyst and aprotic ether solvent in step (2) is 10-15:25-35:4-8:1-3:70-75; And / or, the metal catalyst in step (2) includes tetrakistriphenylphosphine palladium.

7. The one-pot process for preparing abiraterone according to claim 6, characterized in that: The mixing process in step (2) comprises: The raw material 3, triphenylphosphine and aprotic ether solvent are mixed and replaced with nitrogen, and then a metal catalyst is added to continue nitrogen replacement. The temperature is raised to 40-60° C., and the Grignard reagent of 3-bromopyridine is dropped.

8. The one-pot process for preparing abiraterone according to claim 7, characterized in that: The reaction temperature in step (2) is 40-60° C., and the reaction time is 4-8 hours.

9. The one-pot process for preparing abiraterone according to claim 8, characterized in that: The mass ratio of the acid solution in step (3) to the 3-bromopyridine in step (1) is 13-15:10-15; And / or, the concentration of the acid solution in step (3) is 36-38 wt %.

10. The one-pot process for preparing abiraterone according to claim 9, characterized in that: The target pH value in step (3) is 9 to 10.

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