A method for synthesizing a thiaspiro compound, an intermediate thereof, and a method for synthesizing the same

Abstract

The application discloses a method for preparing a thio-diazaspiro compound or a pharmaceutically acceptable salt thereof, each step of which has mild reaction conditions and does not require other special equipment, and is suitable for industrial production. The application also provides an intermediate compound, which has a simple preparation process, high yield and high purity, and is beneficial to high yield and high purity of the subsequent product.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically relating to a method for preparing thiodiazaspiro compounds, their intermediates, and the preparation method thereof. Background Technology

[0002] Compound 1, chemically named 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thio-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide (also known as apalutamide), is a second-generation androgen receptor antagonist developed by Johnson & Johnson. It belongs to the thiodiazaspiro compounds and is used for non-metastatic castration-resistant prostate cancer.

[0003]

[0004] Apaltamethamide is a derivative of diaryl thiohydantoin, consisting of a pyridine ring, a benzene ring, a cyclobutane ring, and a thiohydantoin ring system. Its synthesis mainly revolves around the linkage of aryl amines and the construction of the thiohydantoin ring system, as shown below.

[0005]

[0006] Currently, apalutamide is typically synthesized in two ways: "[3+2] type" and "[4+1] type". The "[3+2] type" is shown below.

[0007]

[0008] There are two main methods for the "[3+2] type" synthetic route. One method involves the [3+2] cyclization of α-aminonitrile with thioisocyanate to obtain compound 1, such as the synthetic methods in CN201180009819.9, CN200780019654.7, CN200780020099.X and China Pharmaceutical Industry Journal, 2018, 49(4), as follows:

[0009]

[0010] The synthesis method uses highly toxic sodium cyanide and employs a microwave method, which increases the difficulty of scale-up production in factories and makes it unsuitable for industrial production.

[0011] The second preparation method involves the [3+2] cyclization of α-carbamate and thioisocyanate to obtain compound 1, as detailed in, for example, the synthetic methods disclosed in CN201610985993.1, CN201711271655.2, and CN201711474542.2, as follows:

[0012]

[0013] The yields of each step in this synthetic method are low, the overall production cost is high, the reaction process and post-processing process are cumbersome, and the optimization of intermediate purification in each step is not considered, making it unsuitable for industrial production.

[0014] The synthesis method of apalutamide "[4+1] type" is shown below.

[0015]

[0016] The [4+1] type preparation method of apaltamethrin involves the [4+1] cyclization of an α-aminoamide with a thiocarbonyl compound to obtain compound 1, for example, the synthetic method in CN201580069602.5, specifically as follows:

[0017]

[0018] This synthetic route requires the use of stoichiometric copper salts; and the final [4+1] cyclization step requires the use of relatively expensive thiocarbonyl compounds, resulting in high costs.

[0019] Therefore, providing a method for synthesizing apalutamide that is simple, has few steps, is easy to operate, and has low production costs has become a problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0020] In view of the above-mentioned problems in the prior art, the main purpose of this application is to provide a new method for synthesizing apaltamethasone, which is simple in process, easy to operate, mild in reaction conditions of each step and has no other special equipment requirements, and is suitable for industrial production.

[0021] The first aspect of this application provides a method for preparing compound 8, comprising reacting compound 7 and compound 9 with an amidation reaction in the presence of a condensing agent to obtain compound 4, and then forming a salt of compound 4 to obtain compound 8, wherein the reaction formula is as follows:

[0022]

[0023] In some embodiments, in the preparation method of compound 8 provided in this application, the reaction of compound 4 to obtain compound 8 is carried out at a temperature of 0-30°C. After the reaction is completed, an ethyl acetate solution of hydrogen chloride is added, wherein the molar equivalent ratio of compound 7, compound 9 and the ethyl acetate solution of hydrogen chloride, calculated as hydrogen chloride, is 1.0:1.1-1.5:1.1-2.0; preferably 1.0:1.2:1.5.

[0024] In some embodiments, in the preparation method of compound 8 provided in this application, the condensing agent is selected from thionyl chloride, a combination of EDCI / HOBt / N-methylmorpholine, T3P and 2-oxazolidinone / PCl5; preferably, the condensing agent is a combination of 2-oxazolidinone and PCl5.

[0025] In some embodiments, the preparation method provided in this application further includes a coupling reaction between compound 8 and compound 3 under the action of a catalytic amount of copper salt, an acid-binding agent, a ligand, and an aprotic polar solvent to generate compound 2, the reaction formula of which is:

[0026]

[0027] In some embodiments, the coupling reaction of compound 8 with compound 3 to form compound 2 is a Ullmann coupling reaction.

[0028] In some embodiments, the coupling reaction is carried out at a temperature of 105-130°C; preferably at a temperature of 115-125°C.

[0029] In some embodiments, in the coupling reaction of compound 8 and compound 3 to form compound 2, the copper salt is selected from cuprous chloride, cuprous bromide, cuprous oxide and cuprous iodide; preferably cuprous bromide.

[0030] The acid-binding agent is selected from sodium carbonate, potassium carbonate, cesium carbonate, and potassium tert-butoxide; preferably potassium tert-butoxide.

[0031] The ligand is selected from N,N-dimethylethylenediamine, ethylenediamine, 2-acetylcyclohexanone and tetramethylethylenediamine; preferably tetramethylethylenediamine.

[0032] The aprotic polar solvent is selected from dimethyl sulfoxide, N-methylpyrrolidone, N'N-dimethylformamide and N'N-dimethylacetamide; preferably N'N-dimethylacetamide.

[0033] In some embodiments, in the coupling reaction of compound 8 and compound 3 to form compound 2, the molar ratio of compound 8 to compound 3 is 1.0:1.1 to 1.5; preferably 1.0:1.2.

[0034] In some embodiments, the preparation method provided in this application further includes reacting compound 2 with a thiocarbonyl compound in the presence of an acid-binding agent and a solvent to obtain compound 1, the reaction formula of which is:

[0035]

[0036] The thiocarbonyl compounds have the following structural formula: in,

[0037] R1 and R2 are each independently selected from: methoxy, cyano, chlorine, amino, phenoxy, and pyridoxy, wherein the phenoxy and pyridoxy groups are optionally substituted with halogen, nitro, C1-C3 alkyl, or phenyl groups.

[0038] In some preferred embodiments, Selected from sulfur phosgene and

[0039] In some preferred embodiments, the cyclization reaction is a [4+1] cyclization reaction.

[0040] In some embodiments, the method for preparing compound 1 provided in this application,

[0041] The acid-binding agent is selected from: triethylamine, N'N-diisopropylethylamine, triethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, and tetramethylethylenediamine; preferably, the acid-binding agent is N'N-diisopropylethylamine;

[0042] The solvent for the cyclization reaction is selected from: N'N-dimethylformamide, N'N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, and toluene; toluene is preferred as the solvent.

[0043] The cyclization reaction is carried out at a temperature of 80-130℃; preferably 95-105℃.

[0044] In a second aspect, this application provides compound 8 obtained by the above-described preparation method.

[0045]

[0046] In a third aspect, this application provides compound 2 obtained by the above-described preparation method.

[0047]

[0048] The fourth aspect of this application provides the use of the above-mentioned compound 8 and / or compound 2 in the preparation of compound 1.

[0049] The preparation method provided in this application is simple in steps, with mild reaction conditions in each step, no other special requirements, low cost, and suitable for industrial production. It also has the following advantages:

[0050] (1) By using 2-oxazolidinone and PCl5 as condensing agents and taking advantage of the large steric hindrance of α-amino acid compound 9, a direct amidation reaction was achieved, avoiding the use of α-amino acid protecting groups and simplifying the reaction steps compared with existing technologies. Furthermore, by using free base to form salts (compound 4 → compound 8), the purification of the complex system after direct amidation was achieved, the purification process was optimized, and the stability and good crystallization properties of the amino intermediate were ensured.

[0051] (2) The Ullman coupling reaction with catalytic amount was achieved, which reduced the amount of copper salt used compared with the existing technology, saved R&D costs, and effectively avoided the risk of excessive copper content in intermediates and final product compound 1.

[0052] (3) The method in this application optimizes the [4+1] cyclization process, increasing the yield to 85% and reducing production costs and impurity removal pressure. Detailed Implementation

[0053] The technical solution of this application will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0054] Unless otherwise specified in the embodiments of this application, the conditions shall be performed according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0055] definition

[0056] "C1-C3 alkyl": refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched groups with 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, etc.

[0057] "Optionally substituted" means that the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0058] instrument

[0059] The structure of the compound was determined by nuclear magnetic resonance (NMR). 1It was determined by H) or mass spectrometry (MS).

[0060] 1 H-wave spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (instrument model: BRUKERAVANCE 400 NMR spectrometer); solvent: DMSO-d6; temperature: 22℃.

[0061] LC-MS detection was performed using an Agilent 6120B Ms liquid chromatograph with a single quadrupole, positive ion mode, ESI ionization source, and a scan range of 50 m / z to 3000 m / z.

[0062] The reagent abbreviations used in the examples have the following Chinese meanings:

[0063]

[0064] Example 1: Synthesis of 1-amino-N-(6-cyano-5-trifluoromethylpyridin-3-yl)cyclobutylcarboxamide hydrochloride (Compound 8)

[0065]

[0066] Compound 7 (0.32 mol), compound 9 (0.38 mol), and 2-oxazolidinone (0.38 mol) were dissolved in acetonitrile (0.3 L) under nitrogen protection. The mixture was cooled to 5 ± 5 °C, and phosphorus pentachloride (0.35 mol) was slowly added dropwise while maintaining the temperature at 5 ± 5 °C. After the addition was complete, the temperature was raised to 45 ± 5 °C. Once the reactants had reacted completely, the temperature was slowly lowered to 5 ± 5 °C while maintaining the temperature at 5 ± 5 °C. 1.0 L of saturated sodium bicarbonate aqueous solution was added dropwise. After the addition was complete, the mixture was kept at 25 ± 5 °C, and 0.6 L of ethyl acetate was added. The mixture was stirred for 0.5 hours, allowed to stand and separate into layers, and the organic phase was separated. Anhydrous sodium sulfate was added for drying. The mixture was filtered, and the filtrate was collected. 240 mL of ethyl acetate solution of hydrogen chloride (2 mol / L) was added dropwise, resulting in the precipitation of a white solid. The mixture was stirred for 2 hours and then filtered. The filter cake was dried under vacuum at 40 ± 5 °C to obtain 89 g of compound 8, with a yield of 87%.

[0067] LC-MS: 285 [M+H] + :

[0068] 1 H NMR (400MHz, DMSO-d6) δ9.46(d,J=2.3Hz,1H),8.88(d,J=2.3Hz,1H),2.96-2.84(m,2H),2.50-2.35(m,2H),2.34-2.20(m,1H),2.10-2.00(m,1H).

[0069] Example 2: Synthesis of 4-((1-((6-cyano-5-trifluoromethylpyridin-3-yl)formyl)cyclobutyl)amino)-2-fluoro-N-methylbenzamide (Compound 2)

[0070]

[0071] Compound 8 (0.2 mol), N-methyl-4-bromo-2-fluorobenzamide (compound 3, 0.24 mol), KOAc (0.7 mol), CuBr (0.01 mol), and TMEDA (0.01 mol) were added to 360 mL of DMA. Under nitrogen protection, the mixture was reacted at 120 °C for 3 h. The temperature was then lowered, and 100 mL of concentrated ammonia was added dropwise while maintaining the temperature below 20 °C. Then, 900 mL of purified water was added dropwise, and the mixture was stirred for 1 h after the addition was complete. The mixture was filtered, and the filter cake was washed with 500 mL of purified water. The filter cake was then filtered until no liquid flowed out. The filter cake and 300 mL of ethyl acetate were heated to 75 °C to dissolve the mixture. The mixture was stirred for 15 min, and 300 mL of n-heptane was added dropwise while maintaining the temperature above 70 °C. The addition was completed within 1 h, and the temperature was allowed to cool naturally to room temperature. The temperature was then further lowered to 5-10 °C, and the mixture was stirred for 0.5 h. The mixture was then filtered until no liquid flowed out. The filter cake was dried in a vacuum drying oven at 50°C for 8 hours to obtain product compound 2, totaling 81g, with a yield of 93%.

[0072] LC-MS: 436 [M+H] +

[0073] 1 H NMR (400MHz, DMSO-d6) δ10.7(s,1H),9.3(s,1H),8.77(s,1H),7.69(t,J=4.7Hz1H),7.51(t,J=8.7Hz,1H),7.19 (s,1H),6.33(d,J=8.6Hz,1H),6.17(d,J=13.9Hz,1H),2.81-2.74(m,5H),2.37-2.15(m,2H),2.11-1.76(m,2H).

[0074] Example 3: Synthesis of apalutamide (compound 1)

[0075]

[0076] Compound 2 (0.1 mol) was dissolved in 50 mL of toluene, DIPEA (0.2 mol) was added, and the mixture was heated to 100 °C. A toluene solution of di(2-pyridine)thiocarbonate (0.15 mol of di(2-pyridine)thiocarbonate dissolved in 20 mL of toluene) was slowly added dropwise over 2 hours. The reaction was stopped after reacting at 100 ± 5 °C for 2 hours. The solvent was distilled off to remove most of the liquid, and the mixture was heated to 50-55 °C in a water bath and distilled until no liquid flowed out. 44 mL of isopropanol was added to the solution. Distillation continued at 0-55℃ until no liquid flowed out. The residue was heated to 85℃, and isopropanol (435 mL) was slowly added dropwise. The mixture was stirred for 2 hours, then slowly cooled to 5±5℃ and stirred for 12 hours. The mixture was filtered, and the filter cake was washed twice with 87 mL of isopropanol. 783 mL of isopropanol was added to the filter cake, and the mixture was heated to 85℃ to dissolve it. The mixture was stirred for 30 minutes, then slowly cooled to 25±5℃ and filtered. The filter cake was washed with 87 mL of isopropanol and dried under vacuum at 45℃ for 16 hours to obtain 41 g of compound 1, with a yield of 85%.

[0077] LC-MS: m / z = 478.1 [M+H] +

[0078] 1 H NMR (400MHz, DMSO-d6) δ9.23(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.54–8.39(m,1H),7.92(t,J=8.0Hz,1H),7.50(dd,J=10.5,1.8H z,1H),7.43(dd,J=8.1,1.8Hz,1H),2.89(d,J=4.6Hz,3H),2.78–2.66(m,2H),2.64–2.49(m,2H),2.11–1.98(m,1H),1.72–1.55(m,1H).

[0079] The above description is only a preferred embodiment of the present invention and does not limit the patent scope of the present invention. All equivalent structural transformations made using the present invention specification under the inventive concept of the present invention, or direct / indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. A method for preparing compound 2, comprising reacting compound 7 and compound 9 in the presence of a condensing agent via an amidation reaction to obtain compound 4, and further comprising reacting compound 4 with compound 3 in the presence of a catalytic amount of a copper salt, an acid-binding agent, a ligand, and an aprotic polar solvent to generate compound 2, wherein the reaction formula is as follows: ； The reaction to prepare compound 8 from compound 4 was carried out at a temperature of 0-30°C. After the reaction was completed, an ethyl acetate solution of hydrogen chloride was added, wherein the molar equivalent ratio of compound 7, compound 9 and the ethyl acetate solution of hydrogen chloride, calculated as hydrogen chloride, was 1.0: 1.1~1.5: 1.1~2.

0. The condensing agent is a combination of 2-oxazolidinone and PCl5; The copper salt is selected from cuprous chloride, cuprous bromide, cuprous oxide, and cuprous iodide; The acid-binding agent is selected from potassium acetate; The ligand is selected from N,N-dimethylethylenediamine, ethylenediamine, 2-acetylcyclohexanone, and tetramethylethylenediamine; The aprotic polar solvent is selected from dimethyl sulfoxide, N-methylpyrrolidone, N'N-dimethylformamide, and N'N-dimethylacetamide; The molar ratio of compound 8 to compound 3 is 1.0:1.1~1.5; The molar ratio of compound 8 to the catalytic amount of copper salt is 1:0.05; The coupling reaction of compound 8 with compound 3 to form compound 2 is a Ullmann coupling reaction; the coupling reaction is carried out at a temperature of 105-130 °C.

2. The preparation method according to claim 1, characterized in that, The molar equivalent ratio of the ethyl acetate solution of compounds 7 and 9 to hydrogen chloride, calculated as hydrogen chloride, is 1.0:1.2:1.

5.

3. The preparation method according to claim 1, characterized in that, The copper salt is cuprous bromide.

4. The preparation method according to claim 1 or 3, characterized in that, The ligand is tetramethylethylenediamine.

5. The preparation method according to claim 1 or 3, characterized in that, The aprotic polar solvent is N'N-dimethylacetamide.

6. The preparation method according to claim 1 or 3, characterized in that, The molar ratio of compound 8 to compound 3 is 1.0:1.

2.

7. A method for preparing compound 1, comprising the preparation method according to any one of claims 1-6, further comprising, in the presence of an acid-binding agent and a solvent, subjecting compound 2 to a cyclization reaction with a thiocarbonyl compound to obtain compound 1, wherein the reaction formula is: ， in, Thiocarbonyl compounds are ; The acid-binding agent is selected from triethylamine, N'N-diisopropylethylamine, triethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, and tetramethylethylenediamine; The solvent is selected from N'N-dimethylformamide, N'N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, and toluene; The cyclization reaction is carried out at a temperature of 80-130℃.

8. The preparation method according to claim 7, characterized in that, The acid-binding agent is N'N-diisopropylethylamine.

9. The preparation method according to claim 7 or 8, characterized in that, The solvent is toluene.

10. The preparation method according to claim 7 or 8, characterized in that, The cyclization reaction takes place at a temperature of 95-105℃.

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