Apactamide intermediate as well as preparation method and application thereof

Abstract

The invention relates to the field of medicinal chemistry, in particular to a novel intermediate compound of apatramide, and a preparation method of apatramide and a novel intermediate of apatramide. According to the preparation method of the apattamide intermediate, the raw materials are easy to obtain, the process steps are simple, the whole steps for preparing apattamide through the intermediate are simple, the yield of the obtained product is high, the yield of apattamide is 80% or above, the purity of apattamide is 99.5% or above, the process cost is greatly reduced, the product quality is improved, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and particularly to a novel intermediate compound of apalutamide, as well as a preparation method of apalutamide and its novel intermediate. Background Art

[0002] Apalutamide is a second-generation non-steroidal androgen receptor (AR) inhibitor developed by Johnson & Johnson. It can effectively prevent androgens from binding to the receptor, prevent the AR from transferring to the cell nucleus of tumor cells, and play a role in inhibiting the growth of tumor cells promoted by androgens. It is used to treat non-metastatic castration-resistant prostate cancer and metastatic castration-sensitive prostate cancer.

[0003] The chemical name of apalutamide is: 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide, and its chemical structure is shown as follows:

[0004]

[0005] The preparation methods of apalutamide include:

[0006] Route 1: In WO2007126765, 2-fluoro-4-aminobenzoylformamide reacts with sodium cyanide and cyclobutanone, and then reacts with 2-cyano-3-trifluoromethylpyridine-5-isothiocyanate under microwave heating to synthesize apalutamide. This reaction uses microwave heating, and sodium cyanide is a highly toxic reagent and thiophosgene is a strongly irritating reagent in this route, so it is difficult to apply this route to industrial production.

[0007]

[0008] Route 1

[0009] The preparation method disclosed in WO2016100652 is as shown in Route 2. This preparation method has a long route and many steps, and is not suitable for industrial scale-up production:

[0010]

[0011] Route 2

[0012] Therefore, aiming at the defects existing in the prior art, there is an urgent need for a synthesis method of apalutamide with easily available raw materials, simple process, suitable for industrial production, high yield and low cost to meet the market demand. Summary of the Invention

[0013] An object of the present invention is to provide an intermediate of apalutamide;

[0014] Another object of the present invention is to provide a method for preparing an apalutamide intermediate;

[0015] The third object of the present invention is to provide a method for preparing apalutamide.

[0016] To achieve the above object, the technical solution of the present invention is:

[0017] Provide an apalutamide intermediate shown in Formula II:

[0018]

[0019] Wherein, R1, R2, R3, R4, R5 are independently selected from H or C 1-6 alkyl, nitro, Cl, Br, I, but not all H at the same time.

[0020] Furthermore, for the apalutamide intermediate shown in Formula II, R1, R2, R3, R4, R5 are independently selected from H or C 1-6 alkyl, nitro, but not all H at the same time;

[0021] Furthermore, R1, R3, R5 are H, and R2, R4 are C 1-6 alkyl;

[0022] Preferably, R2, R4 are methyl.

[0023] Furthermore, R1, R2, R4, R5 are H, and R3 is ethyl, isopropyl, tert-butyl, nitro.

[0024] Specifically, the structure of the compound of Formula II can be as follows:

[0025]

[0026] Furthermore, the present invention provides a method for preparing a compound of Formula II, which is characterized in that reacting a compound of Formula III with compound 6 to obtain a compound of Formula II:

[0027]

[0028] Wherein, X is Cl, Br, I, and R1, R2, R3, R4, R5 are independently selected from H or C 1-6 alkyl, nitro, Cl, Br, I, but not all H at the same time;

[0029] Furthermore, R1, R2, R3, R4, R5 are independently selected from H or C 1-6 alkyl, nitro, but not all H at the same time;

[0030] Furthermore, R1, R3, R5 are H, and R2, R4 are C 1-6 alkyl;

[0031] Preferably, R2 and R4 are methyl groups.

[0032] Furthermore, R1, R2, R4, and R5 are H, and R3 is ethyl, isopropyl, tert-butyl, or nitro.

[0033] Furthermore, the reaction is carried out in the presence of an inorganic base, which can neutralize the acid generated as a by-product during the reaction and liberate the free form of the compound. The inorganic base can be selected from any one or more of metal carbonates and metal bicarbonates;

[0034] Furthermore, the inorganic base can be selected from any one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate, and lithium carbonate.

[0035] Furthermore, the equivalent ratio of the compound of formula III to compound 6 is 1:1 to 4:1;

[0036] Preferably, the equivalent ratio of the compound of formula III to compound 6 is 2:1.

[0037] Furthermore, the reaction temperature is 30 to 70 °C;

[0038] Preferably, the reaction temperature is 40 to 60 °C;

[0039] More preferably, the reaction temperature is 45 to 55 °C.

[0040] The present invention also provides a method for preparing apalutamide: reacting the compound of formula II with compound 7 to obtain apalutamide,

[0041]

[0042] wherein, R1, R2, R3, R4, and R5 are independently selected from H or C 1-6 alkyl, nitro, Cl, Br, I, but not all H at the same time;

[0043] Furthermore, R1, R3, and R5 are H, and R2 and R4 are C 1-6 alkyl;

[0044] Even further, R1, R2, R4, and R5 are H, and R3 is ethyl, isopropyl, tert-butyl, or nitro.

[0045] Furthermore, the equivalent ratio of the compound of formula II to compound 7 is 1:1 to 1:3;

[0046] Preferably, the equivalent ratio of the compound of formula II to compound 7 is 1:2.

[0047] Furthermore, the reaction temperature is 70 to 90 °C;

[0048] Preferably, the reaction temperature is 80 - 85 °C;

[0049] More preferably, the reaction temperature is 80 °C.

[0050] Furthermore, the reaction solvent is selected from the mixed solvent of dimethyl sulfoxide and isopropyl acetate.

[0051] Compared with the prior art, the beneficial effects of the present invention are embodied in:

[0052] The preparation method of the apalutamide intermediate provided by the present invention has easily available raw materials and simple process steps. The overall steps for preparing apalutamide through this intermediate are simple, and the obtained product has a high yield. The yield of apalutamide is above 80%, and the purity is above 99.5%. It greatly reduces the process cost, improves the product quality, and is suitable for industrial production. Description of the Drawings

[0053] Figure 1 1H NMR spectrum of apalutamide intermediate II1 in Example 1;

[0054] Figure 2 Mass spectrum of apalutamide intermediate II1 in Example 1;

[0055] Figure 3 High performance liquid chromatography (HPLC) of apalutamide in Example 5. Detailed Embodiments

[0056] The present invention will be described in detail below. However, the present invention may be embodied in many different forms and should not be limited to the embodiments described herein. The purpose of providing these embodiments is to make the disclosed content more complete and comprehensive. The reagents and raw materials used, unless otherwise provided in the preparation method, are all commercially available. Unless otherwise defined, all scientific and technical terms herein have the same meaning as commonly understood by those skilled in the technical field to which the claimed subject matter belongs.

[0057] In this article, unless otherwise specified, the following terms have the following meanings:

[0058] The term "DMF" refers to N,N - dimethylformamide;

[0059] The term "DMSO" refers to dimethyl sulfoxide;

[0060] The term "TEA" refers to triethylamine;

[0061] The term "IPAc" refers to isopropyl acetate;

[0062] The term "alkyl" can be straight - chain or branched - chain. For example, the term "C 1-6"Alkyl" refers to an alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.

[0063] The compounds used in the examples of the present invention were prepared according to the methods in the prior art, including but not limited to the methods described in Examples 1-3 of CN201711474542.2.

[0064] Example 1. Preparation of Compound II1

[0065]

[0066] Add compound 6 (35.0 g, 131.5 mmol), potassium carbonate (36.3 g, 263.0 mmol), and 350 ml of DMF to a 1 L three-necked round-bottom flask. Replace the air with nitrogen three times, stir and heat to 50 °C, and slowly add p-tert-butylbenzyl chloride (26.4 g, 144.65 mmol). After the addition, keep the temperature at about 50 °C and react for 3 h. After the reaction is completed, cool the system to below 30 °C, filter, wash the filter cake with a small amount of DMF, collect the filtrate, add 350 ml of purified water and 350 ml of ethyl acetate, adjust the pH to about 7 with a 5% aqueous citric acid solution, let it stand for liquid separation, back-extract the aqueous layer with 350 ml of ethyl acetate once, combine the ethyl acetate layers, wash twice with a 10% aqueous ammonium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to dryness at a temperature below 40 °C to obtain an oily substance II1, 53.23 g, with a yield of 98.17%.

[0067] 1 1H NMR (400 MHz, DMSO-d6) δ 7.64 (m, 1H), 7.45 (t, J = 8.8 Hz, 1H), 7.30 - 7.26 (m, 3H), 7.11 (d, J = 8.4 Hz, 2H), 6.21 (d, J = 8.4 Hz, 1H), 5.98 (d, J14.0, 4.0 Hz, 1H), 5.07 (s, 2H), 2.73 (s, 3H), 2.66 - 2.60 (m, 2H), 2.23–2.16 (m, 2H), 2.03 - 1.94 (m, 2H), 1.24 (s, 9H). The 1H NMR spectrum is shown in Figure 1 .

[0068] LC-MS: m / z = 413.28 [M+H] + , and the mass spectrum is shown in Figure 2 .

[0069] Example 2. Preparation of Compound II2

[0070]

[0071] Add compound 6 (35.0 g, 131.5 mmol), sodium carbonate (27.88 g, 263.0 mmol), and 350 ml of DMF to a 1 L three-necked round-bottom flask. Replace the gas with nitrogen three times, stir and heat up to 70 °C, and slowly add p-isopropylbenzyl bromide (56.0 g, 263.0 mmol). After the addition, keep the temperature at about 70 °C and react for 3 h. After the reaction is completed, cool the system to below 30 °C, filter, wash the filter cake with a small amount of DMF, collect the filtrate, add 350 ml of purified water and 350 ml of ethyl acetate, adjust the pH to about 7 with 5% aqueous citric acid solution, let it stand for liquid separation, back-extract the aqueous layer with 350 ml of ethyl acetate once, combine the ethyl acetate layers, wash twice with 10% aqueous ammonium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to dryness at a temperature below 40 °C to obtain 50.08 g of oily substance II2, with a yield of 95.6%. LC-MS: m / z = 399.28 [M+H] + 。

[0072] Example 3. Preparation of Compound II3

[0073]

[0074] Add compound 6 (35.0 g, 131.5 mmol), sodium bicarbonate (22.1 g, 263.0 mmol), and 350 ml of DMF to a 1 L three-necked round-bottom flask. Replace the gas with nitrogen three times, stir and heat up to 45 °C, and slowly add 4-ethylbenzyl chloride (81.3 g, 526.0 mmol). After the addition, keep the temperature at about 45 °C and react for 3 h. After the reaction is completed, cool the system to below 30 °C, filter, wash the filter cake with a small amount of DMF, collect the filtrate, add 350 ml of purified water and 350 ml of ethyl acetate, adjust the pH to about 7 with 5% aqueous citric acid solution, let it stand for liquid separation, back-extract the aqueous layer with 350 ml of ethyl acetate once, combine the ethyl acetate layers, wash twice with 10% aqueous ammonium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to dryness at a temperature below 40 °C to obtain 48.05 g of oily substance II3, with a yield of 95.09%. LC-MS: m / z = 385.38 [M+H] + 。

[0075] Example 4. Preparation of Compound II4

[0076]

[0077] Add compound 6 (35.0 g, 131.5 mmol), potassium carbonate (36.3 g, 263.0 mmol), and 350 ml of DMF to a 1 L three-necked round-bottom flask. Replace the air with nitrogen three times. Stir and heat the mixture to 60 °C. Slowly add 3,5-dimethylbenzyl chloride (20.3 g, 131.5 mmol). After the addition is complete, maintain the temperature at about 60 °C and react for 3 h. After the reaction is complete, cool the mixture to below 30 °C, filter, wash the filter cake with a small amount of DMF, collect the filtrate, add 350 ml of purified water and 350 ml of ethyl acetate, adjust the pH to about 7 with 5% aqueous citric acid solution, let it stand for liquid separation. Extract the aqueous layer with 350 ml of ethyl acetate once. Combine the ethyl acetate layers, wash twice with 10% aqueous ammonium chloride solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at a temperature below 40 °C until dry to obtain 48.25 g of oily substance II4, with a yield of 95.49%. LC-MS: m / z = 385.38 [M + H] + 。

[0078] Example 5. Preparation of Apatamide

[0079]

[0080] Add compound II1 (50.0 g, 121.2 mmol), compound 7 (55.6 g, 242.4 mmol), 50 ml of DMSO, and 100 ml of IPAc to a 500 ml three-necked round-bottom flask in sequence. Stir and heat the mixture to 90 °C and react for 5 h. After the reaction is complete, cool the system to below 30 °C, add 200 ml of 5% aqueous sodium chloride solution and 100 ml of ethyl acetate, stir for liquid separation. Extract the aqueous layer with ethyl acetate twice. Combine the ethyl acetate layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at a temperature below 40 °C until no liquid flows out to obtain an oily substance. Add 750 ml of isopropanol to the oily substance, heat to 80 - 90 °C, stir until clear, cool to about 5 °C, stir for 3 h, filter by suction. Wash the filter cake three times with isopropanol and then dry to obtain 47.16 g of a white solid, with a yield of 81.5% and a purity of 99.76%. HPLC see Figure 3 。

[0081] 11H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J = 1.6 Hz, 1H), 8.75 (d, J = 1.62 Hz, 1H), 8.48 (d, J = 4.4 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.48 (dd, J = 10.4, 1.6 Hz, 1H), 7.39 (dd, J = 8.1, 1.6 Hz, 1H), 2.82 (d, J = 4.4 Hz, 3H), 2.69–2.63 (m, 2H), 2.54–2.45 (m, 2H), 2.02–1.95 (m, 1H), 1.63–1.57 (m, 1H).

[0082] Example 6, Preparation of Apatamide

[0083]

[0084] To a 500 ml three-necked round-bottom flask, successively add Compound II3 (50.0 g, 130.0 mmol), Compound 7 (89.5 g, 130.0 mmol), 50 ml of DMSO, and 100 ml of IPAc. Stir and heat to 85 °C for reaction for 5 h. After the reaction is completed, cool the system to below 30 °C, add 200 ml of 5% aqueous sodium chloride solution and 100 ml of ethyl acetate, stir and separate the layers. The aqueous layer is back-extracted with ethyl acetate twice. Combine the ethyl acetate layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure at a temperature below 40 °C until no liquid flows out to obtain an oily substance. Add 750 ml of isopropanol to the oily substance, heat to 80 - 90 °C, stir until clear, cool to about 5 °C, stir for 3 h, filter by suction. The filter cake is rinsed three times with isopropanol and then dried to obtain 51.1 g of a white solid, with a yield of 82.3% and a purity of 99.71%.

[0085] Example 7, Preparation of Apatamide

[0086]

[0087] To a 500 ml three-necked round-bottom flask, 4 (50.0 g, 130.0 mmol) of Compound II, 7 (89.5 g, 390.0 mmol) of Compound 7, 50 ml of DMSO, and 100 ml of IPAc were successively added, and the mixture was stirred and heated to 70 °C for reaction for 5 h. After the reaction was completed, the system was cooled to below 30 °C, 200 ml of 5% aqueous sodium chloride solution and 100 ml of ethyl acetate were added, and the mixture was stirred and separated into layers. The aqueous layer was back-extracted with ethyl acetate twice, and the ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at a temperature below 40 °C until no liquid flowed out to obtain an oily substance. 750 ml of isopropanol was added to the oily substance, and the mixture was heated to 80-90 °C, stirred until clear, cooled to about 5 °C, stirred for 3 h, filtered, and the filter cake was washed three times with isopropanol and then dried to obtain 52.5 g of a white solid, with a yield of 84.6% and a purity of 99.82%.

[0088] For those skilled in the art, according to the technical solutions and concepts described above, various other corresponding changes and deformations can be made, and all such changes and deformations should fall within the protection scope of the claims of the present invention.

Claims

1. An intermediate of apalutamide shown in Formula II: Among them, R1, R2, R3, R4, and R5 are independently selected from H or C 1-6 alkyl, nitro, Cl, Br, I, provided that they are not all H at the same time.

2. The compound of formula II according to claim 1, wherein, R1, R2, R3, R4, and R5 are independently selected from H or C 1-6 alkyl, nitro, but not H simultaneously.

3. The compound of formula II according to claim 1, wherein, R1, R3, and R5 are H, and R2 and R4 are C 1-6 alkyl group Preferably, R2 and R4 are methyl.

4. The compound of formula II according to claim 1, wherein R1, R2, R4, and R5 are H, and R3 is ethyl, isopropyl, tert-butyl, or nitro.

5. A process for preparing the compound of formula II according to any one of claims 1-4, characterized in that, The compound of Formula III reacts with Compound 6 in the presence of an inorganic base to obtain the compound of Formula II: wherein X is Cl, Br, or I; R1, R2, R3, R4, and R5 are independently selected from H or C 1-6 alkyl, nitro, Cl, Br, I, provided that they are not all H at the same time; Preferably, R1, R2, R3, R4, and R5 are independently selected from H or C 1-6 alkyl, nitro, but not simultaneously H; Preferably, R1, R3, and R5 are H, and R2 and R4 are C 1-6 alkyl group; More preferably, R1, R2, R4, and R5 are H, and R3 is ethyl, isopropyl, tert-butyl, or nitro.

6. The preparation method according to claim 4, wherein The equivalent ratio of the compound of Formula III to Compound 6 is 1:1 to 4:

1.

7. According to the preparation method described in claim 4, characterized in that, The reaction temperature is 30 to 70 °C.

8. A preparation method of apalutamide, characterized in that, The compound of Formula II reacts with Compound 7 to obtain apalutamide: wherein, R1, R2, R3, R4, and R5 are independently selected from H or C 1-6 alkyl, nitro, Cl, Br, I, provided that they are not simultaneously H; Preferably, R1, R2, R3, R4, and R5 are independently selected from H or C 1-6 alkyl, nitro, but not simultaneously H; Preferably, R1, R3, and R5 are H, and R2 and R4 are C 1-6 alkyl More preferably, R1, R2, R4, and R5 are H, and R3 is ethyl, isopropyl, tert-butyl, or nitro.

9. The preparation method according to claim 8, characterized in that The equivalent ratio of the compound of Formula II to Compound 7 is 1:1 to 1:

3.

10. An intermediate compound of apalutamide:

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