A process for the preparation of apsenetant

Abstract

This invention provides a method for preparing apraxitentan, the method comprising the following steps: (1) reacting compound D with compound X in a polar aprotic solvent to obtain intermediate E; (2) reacting intermediate E with ethylene glycol in an organic solvent in the presence of a base to obtain intermediate F; (3) reacting intermediate F with 2-chloro-5-bromopyrimidine in the presence of a base to obtain intermediate G; (4) finally removing the protecting group from intermediate G to obtain apraxitentan; wherein, R is selected from Li, Na or K.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing the endothelin receptor antagonist aprocitentan and its intermediates. Background Technology

[0002] Aprocitentan is a novel endothelin receptor antagonist that selectively blocks endothelin receptors to treat cardiovascular diseases such as pulmonary hypertension. It was jointly developed by Vifor Pharma and Idorsia Pharmaceuticals. It is a dual endothelin receptor antagonist (ERA) that simultaneously blocks endothelin A (ETA) and endothelin B (ETB) receptors, inhibiting endothelin-1 (ET-1)-mediated vasoconstriction, smooth muscle proliferation, and vascular remodeling, thereby lowering blood pressure and improving vascular function.

[0003] The chemical name of acexitentan is: N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]aminosulfonamide, and its chemical formula is: C 16 H 14 Br2N6O4S, molecular weight: 546.19. Its chemical structure is shown below: .

[0004] International patent application WO2009024906 discloses the following synthetic route as an original research paper: .

[0005] In particular, the last step of this route involves removing the protecting group of compound 4 with BCl3 or BBr3. The reaction is carried out at room temperature and BBr3 is added in multiple steps. The operation is complicated and the yield is low, with the yield of the last step being only 29%.

[0006] International patent application WO2015121397 discloses a method for synthesizing apxitentan: .

[0007] This process employs a strategy of introducing a sulfonamide fragment: firstly, a chloropyrimidine intermediate (3) is constructed by nucleophilic substitution of 4,6-dichloro-5-(4-bromophenyl)pyrimidine (1) with 2-(4-bromopyrimidine-2-yloxy)ethanol (2); subsequently, fluorination is performed to convert 4-chloro to 4-fluorine, yielding fluoropyrimidine (4); finally, debenzylation is performed to obtain apraxitentan or its pharmaceutically acceptable salt. The above method involves a fluorine reagent to prepare high-purity fluoropyrimidine compound 4. The fluorination reagent is achieved by excess cesium fluoride and tetra-n-butylammonium fluoride. When compound 4 reacts with the sulfonamide, the residual fluoride anions in the system easily trigger side reactions, directly affecting the purity and quality of the final product, apraxitentan.

[0008] Chinese patent CN120737035A discloses a method for preparing apraxitentan: .

[0009] Starting compound 1 is reacted with a p-methoxybenzyl-substituted sulfonamide under alkaline conditions to obtain intermediate 2; intermediate 2 is then reacted with 2-[(5-bromo-2-pyrimidinyl)oxy]ethanol under alkaline conditions to obtain intermediate 3; alternatively, intermediate 2 is first reacted with ethylene glycol under alkaline conditions, and then reacted with 5-bromo-2-chloropyrimidine or 5-fluoro-2-chloropyrimidine to obtain intermediate 3. Deprotection of intermediate 3 yields the target compound, apxitentan. In the demethylation step, ceric ammonium nitrate (CAN) is used as the demethylating agent. Ceric ammonium nitrate is a strong oxidizing agent, and the apxitentan molecule contains easily oxidized functional groups such as sulfonamide groups, bromoaromatic rings, and pyrimidine rings. During the reaction, it easily triggers oxidation side reactions, generating impurities that are difficult to remove. Simultaneously, the reaction of ceric ammonium nitrate generates a large amount of cerium salt solid waste, increasing the cost of waste treatment.

[0010] Therefore, in the traditional preparation method of apracitentan, the product yield is low, the product purity is not high, the economic cost is high, and waste is easily generated. The above problems urgently need to be solved. Summary of the Invention

[0011] The technical problem this invention aims to solve is to overcome the shortcomings of existing methods for preparing apracitentan, such as low yield, low purity, poor process stability, and high cost. Therefore, this invention provides a method for preparing apracitentan. The method provided by this invention eliminates the need for fluorination with fluorine reagents, is economical, environmentally friendly, and has a lower overall production cost, making it more suitable for the industrial production of apracitentan.

[0012] This invention provides a method for preparing apraxitentan, the method comprising the following steps: .

[0013] Wherein, R is selected from Li, Na, or K; (1) In a polar aprotic solvent, compound D is reacted with compound X to obtain intermediate E; (2) In the presence of a base, intermediate E is reacted with ethylene glycol in an organic solvent to obtain intermediate F; (3) In the presence of a base, intermediate F is reacted with 2-chloro-5-bromopyrimidine to obtain intermediate G; (4) Finally, the protecting group of intermediate G was removed to obtain apxitentan.

[0014] In some implementations, in step (1), the polar aprotic solvent is selected from one or more of DMF, DMSO, NMP, HMPA, and DMAc.

[0015] In some embodiments, in step (2), the base is selected from one or more of sodium carbonate, sodium hydroxide, potassium carbonate, sodium hydride, potassium hydride, and potassium tert-butoxide.

[0016] In some implementations, in step (2), the organic solvent is selected from one or more of DMF, DMSO, NMP, HMPA, and DMAc.

[0017] In some embodiments, in step (3), the base is selected from one or more of sodium carbonate, sodium hydroxide, potassium carbonate, sodium hydride, potassium hydride, and potassium tert-butoxide.

[0018] In some embodiments, in step (3), intermediate F is reacted with 2-chloro-5-bromopyrimidine in a solvent to obtain intermediate G; the solvent is selected from one or more of DMF, DMA, THF, DMSO, DMEA, and dioxane.

[0019] In some embodiments, in step (4), intermediate G is dissolved in an organic solvent, cooled to 0-10°C, and boron tribromide is added to react and prepare apreceptentam. In some embodiments, the ratio of intermediate G to organic solvent is 1:10-15 (g / mL), preferably 1:10 (g / mL). This ratio not only simplifies the procedure and provides mild conditions, but also yields good yield and purity, while minimizing the cost of the target compound.

[0020] In some embodiments, the molar ratio of intermediate G to boron tribromide is 0.2-0.5:1. Preferably, the molar ratio of intermediate G to boron tribromide is 0.25-0.35:1. This ratio not only simplifies the procedure and provides mild conditions, but also yields good yields and purity, while minimizing the cost of the target compound.

[0021] In some embodiments, in step (4), the organic solvent is selected from one or more of dichloromethane, chloroform, acetone, and ethyl acetate. Preferably, the organic solvent is selected from dichloromethane.

[0022] In some implementations, in step (4), intermediate G is dissolved in an organic solvent, cooled to 0-10°C, boron tribromide is added and reacted for 8-36 hours to prepare apraxitentan.

[0023] In some implementations, the reaction time in step (4) is 12-24 hours.

[0024] The present invention also provides a method for preparing intermediate D, the method comprising the following steps: .

[0025] Wherein, R is selected from Li, Na, or K; (a) Compound 1 and compound 2 were reacted in an organic solvent to obtain intermediate A; (b) In the presence of a base, intermediate A is reacted with tert-butylamine in an organic solvent to obtain intermediate B; (c) Intermediate B was prepared into intermediate C under acidic conditions; (d) Intermediate C is reacted with a base in an alcohol solvent to obtain intermediate D.

[0026] In some embodiments, in step (a), the organic solvent is selected from one or more of dichloromethane, chloroform, acetone, and ethyl acetate.

[0027] In some embodiments, in step (b), the organic solvent is selected from one or more of dichloromethane, chloroform, acetone, and ethyl acetate.

[0028] In some embodiments, in step (b), the base is selected from triethylamine, DBU, DIPEA, pyridine, diethylamine, and N-methylmorpholine.

[0029] In some implementations, in step (c), the acid is hydrochloric acid.

[0030] In some embodiments, in step (d), the alcohol solvent is selected from one or more of methanol, ethanol, and n-butanol.

[0031] In some embodiments, in step (d), the base is lithium tert-butoxide, potassium tert-butoxide, or sodium tert-butoxide.

[0032] On the other hand, the present invention also provides a compound having the formula (I) or a salt thereof: .

[0033] On the other hand, the present invention also provides a compound having the formula (II) or a salt thereof: .

[0034] On the other hand, the present invention also provides a compound having the formula (III) or a salt thereof: .

[0035] The beneficial effects of this invention are: This invention prepares apraxitentan via a sulfonation reaction of a pyrimidine compound with a sulfonyl compound salt, eliminating the need for fluorination with a fluorine reagent. Studies have shown that the structure of the sulfonated compound affects the overall yield and purity of the reaction, with N-tert-butylsulfonamide showing the best yield and purity in the preparation steps of compounds E, F, G, and H. In the final step of apraxitentan preparation, the deprotection process is mild, simple, and significantly improves the yield and purity. Using the preparation process described in this application, the final yield of apraxitentan can reach 70%, and the purity can reach 99%. Therefore, the preparation process of apraxitentan described in this invention is simple, has low production costs, and is well-suited for industrial production. Attached Figure Description

[0036] Figure 1 NMR spectrum of compound E in Example 1 1 HNMR.

[0037] Figure 2 NMR spectrum of compound F in Example 1 1 HNMR.

[0038] Figure 3 NMR spectrum of compound G in Example 1 1 HNMR.

[0039] Figure 4 NMR spectrum of compound H in Example 1 1 HNMR. Detailed Implementation

[0040] The invention will now be described in detail with reference to embodiments, but this does not imply any adverse limitation of the present disclosure. The present disclosure has been described in detail herein, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof.

[0041] Unless otherwise specified, all reagents used in this disclosure are commercially available and can be used without further purification.

[0042] Unless otherwise stated, the proportions expressed for mixed solvents are volume-based.

[0043] Unless otherwise stated, % refers to wt%.

[0044] In this article Indicate the linker site. Compounds are named manually or using ChemDraw® software.

[0045] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0046] Abbreviations: DCM: Dichloromethane; Et3N: Triethylamine; t-BuOK: Potassium tert-butoxide; DMSO: Dimethyl sulfoxide; THF: Tetrahydrofuran; DMF: N,N-Dimethylformamide; NMP: Methylpyrrolidone; HMPA: Hexamethylphosphoramide; DMAc: Dimethylacetamide; DMA: N,N-Dimethylacetamide; DMEA: N,N-Dimethylethanolamine; DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene; DIPEA: N,N-Diisopropylethylamine; PE: Petroleum ether; EA: Ethyl acetate.

[0047] Example 1: .

[0048] Step 1: Preparation of intermediate A: Under nitrogen protection, chlorosulfonyl isocyanate (18.3 g) was dissolved in dichloromethane (100 mL), cooled to -20~30℃, and a dichloromethane (100 mL) solution of tert-butanol (14.8 g) was slowly added dropwise. After the addition was complete, the mixture was stirred at -20~30℃ for 0.5~24 h to obtain the reaction solution of intermediate A, which can be directly used in the next step.

[0049] Step 2: Preparation of intermediate B: In a 2 L three-necked flask, tert-butylamine (10.6 g), triethylamine (30.3 g), and dichloromethane (400 mL) were added, and the mixture was cooled to -20 to 30 °C in an ice bath. The reaction solution of compound A was slowly added dropwise. After the addition was complete, the mixture was stirred for 8 to 36 h. After the reaction was completed, the solvent was removed by vacuum concentration. The residue was dissolved in ethyl acetate (1 L), washed successively with water (100 mL) and saturated brine (40 mL), dried the organic phase, filtered, and concentrated under reduced pressure to obtain compound B (yield 92%).

[0050] MS (ESI) m / z: 252.33 (M+H) + .

[0051] Step 3: Preparation of intermediate C: Compound B (28.2 g) was dissolved in hydrochloric acid solution (250 mL) and stirred for 8–36 h. The solvent was evaporated under reduced pressure and dried under high vacuum to obtain white solid C (yield 95%).

[0052] MS (ESI) m / z: 152.21 (M+H)+.

[0053] Step 4: Preparation of intermediate D: Compound C (15.8 g) was dissolved in methanol solution (200 mL), and potassium tert-butoxide (7.5 g) was added and stirred until completely dissolved. The solvent was removed by vacuum distillation, and the residue was dispersed in a low-polarity solvent (500 mL), filtered, washed, and dried to obtain a grayish-white powder D (yield 91%).

[0054] MS (ESI) m / z: 190.30(M+H)+.

[0055] Step 5: Preparation of intermediate E: In a 500 mL three-necked flask, 10 g of 5-(4-bromophenyl)-4,6-dichloropyrimidine, 12.5 g of compound D, and 100 mL of dimethyl sulfoxide were added, and the mixture was stirred at room temperature for 8–36 h. After the reaction was complete, the pH was adjusted to 5–6 with hydrochloric acid, diluted with 500 mL of saturated brine, and extracted with 3 × 1 L of ethyl acetate. The combined organic phases were concentrated, and the crude product was recrystallized from ethyl acetate-methanol to give a white solid E (yield 85%).

[0056] MS (ESI) m / z: 419.6(M+H)+.

[0057] 1H NMR (600 MHz) δ 10.29 (s, 1H), 8.66 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.31 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 1.16 (s, 9H).

[0058] Step 6: Preparation of intermediate F: Ethylene glycol (400 g) and potassium tert-butoxide (56.1 g) were stirred in DMF for 5-10 minutes. This mixture was added to a DMF solution of intermediate E (46.8 g), and the reaction was carried out at 40-110 °C for 8-36 h. The reaction was quenched with ice water and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a white solid intermediate F (yield 90%).

[0059] MS (ESI) m / z: 445.1(M+H)+ .

[0060] 1H NMR (600 MHz) δ 9.82 (s, 1H), 8.51 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.91 (s, 1H), 4.72 (s, 1H), 4.31 (d, J = 5.4Hz, 2H), 3.58 (d, J = 5.8 Hz, 2H), 1.17 (s, 9H).

[0061] Step 7: Preparation of Intermediate G: Intermediate F (44.5 g) was dissolved in tetrahydrofuran (120 mL), potassium carbonate (3 g) was added, and 2-chloro-5-bromopyrimidine (19.3 g) was added. The reaction was carried out for 8–36 hours. The pH was adjusted to 5–5.5 with hydrochloric acid, and the mixture was extracted with ethyl acetate (2 × 400 mL). The organic layer was washed with water (2 × 300 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was recrystallized from methanol (100 mL) to give a white solid G (90% yield).

[0062] MS (ESI) m / z: 601.3(M+H)+.

[0063] 1H NMR (600 MHz) δ 9.86 (s, 1H), 8.70 (s, 2H), 8.51 (s, 1H), 7.54 (d,J = 8.0 Hz, 2H), 7.10 (d,J = 8.0 Hz, 2H), 6.95 (s, 1H), 4.64 (dd, J = 6.1, 3.2 Hz, 2H), 4.57 (dd, J = 6.0, 3.2 Hz, 2H), 1.17 (s, 9H).

[0064] Step 8: Preparation of Apcitentan (H): Intermediate G (1 g) was dissolved in dichloromethane (10 mL), cooled to 0°C, and boron tribromide (1.5 g) was added. The reaction was allowed to proceed for 12 hours. After the reaction was complete, the mixture was carefully quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 3:1) to give compound H (70% yield, 99.07% purity).

[0065] MS (ESI) m / z: 544.9(M+H) + .

[0066] 1 H1 NMR (600 MHz) δ 9.80 (s, 1H), 8.70 (s, 2H), 8.51 (s, 1H), 7.53(d, J = 8.0 Hz, 2H), 7.16 (m, 4H), 4.65 (t, J = 8.0 Hz, 2H), 4.57 (t, J = 8.0Hz, 2H).

[0067] Example 2: Referring to preparation steps 1-7 of Example 1, step 8 is prepared as follows:

[0068] Intermediate G (1 g) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and boron tribromide (1.2 g) was added. The reaction was allowed to proceed for 24 hours. After the reaction was complete, the mixture was carefully quenched with ice water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA = 10:1) to give compound H (68% yield, 98.74% purity).

[0069] Comparative study of the effects of different protecting groups on alpracitentan

[0070] Compound H was prepared according to the preparation process in Example 1, and the preparation process is as follows: .

[0071] The yields and purities of compound H prepared using the following different raw materials are detailed in Table 1.

[0072] Table 1 .

[0073] This invention prepares apraxitentan via a sulfonation reaction of a pyrimidine compound with a sulfonyl compound salt, eliminating the need for fluorination with a fluorine reagent. Studies have shown that the structure of the sulfonated compound affects the overall yield and purity of the reaction, with N-tert-butylsulfonamide showing the best yield and purity in the preparation steps of compounds E, F, G, and H. In the final step of apraxitentan preparation, the deprotection process is mild, simple, and significantly improves the yield and purity. Using the preparation process described in this application, the final yield of apraxitentan can reach 70%, and the purity can reach 99%. Therefore, the preparation process of apraxitentan described in this invention is simple, has low production costs, and is well-suited for industrial production.

[0074] This invention provides a method for preparing apraxitentan, the method comprising the following steps: (1) reacting compound D with compound X in a polar aprotic solvent to obtain intermediate E; (2) reacting intermediate E with ethylene glycol in an organic solvent in the presence of a base to obtain intermediate F; (3) reacting intermediate F with 2-chloro-5-bromopyrimidine in the presence of a base to obtain intermediate G; (4) finally removing the protecting group from intermediate G to obtain apraxitentan; Wherein, R is selected from Li, Na, or K; .

Claims

1. A method for preparing apraxitentan, characterized in that: The method includes the following steps: Where R is selected from Li, Na, or K; (1) In a polar aprotic solvent, compound D is reacted with compound X to obtain intermediate E; (2) In the presence of a base, intermediate E is reacted with ethylene glycol in an organic solvent to obtain intermediate F; (3) In the presence of a base, intermediate F is reacted with 2-chloro-5-bromopyrimidine to obtain intermediate G; (4) Remove the protecting group from intermediate G to obtain apracitentan.

2. The method for preparing apraxitentan according to claim 1, characterized in that: In step (1), the polar aprotic solvent is selected from one or more of DMF, DMSO, NMP, HMPA, and DMAc.

3. The method for preparing apraxitentan according to claim 1, characterized in that: In step (2), the alkali is selected from one or more of sodium carbonate, sodium hydroxide, potassium carbonate, sodium hydride, potassium hydride, and potassium tert-butoxide; the organic solvent is selected from one or more of DMF, DMSO, NMP, HMPA, and DMAc.

4. The method for preparing apraxitentan according to claim 1, characterized in that: In step (3), the alkali is selected from one or more of sodium carbonate, sodium hydroxide, potassium carbonate, sodium hydride, potassium hydride, and potassium tert-butoxide.

5. The method for preparing apraxitentan according to claim 1, characterized in that: In step (3), intermediate F is reacted with 2-chloro-5-bromopyrimidine in a solvent to obtain intermediate G; the solvent is selected from one or more of DMF, DMA, THF, DMSO, DMEA, and dioxane.

6. The method for preparing apraxitentan according to claim 1, characterized in that: In step (4), intermediate G is dissolved in an organic solvent, cooled to 0-10°C, and boron tribromide is added to react and prepare apreceptentam.

7. A method for preparing intermediate D as described in claim 1, characterized in that: The method includes the following steps: ; Wherein, R is selected from Li, Na, or K; (a) Compound 1 and compound 2 were reacted in an organic solvent to obtain intermediate A; (b) In the presence of a base, intermediate A is reacted with tert-butylamine in an organic solvent to obtain intermediate B; (c) Intermediate B was prepared into intermediate C under acidic conditions; (d) Intermediate C is reacted with a base in an alcohol solvent to obtain intermediate D.

8. A compound having the formula (I) or a salt thereof: .

9. A compound having the formula (II) or a salt thereof: .

10. A compound having the formula (III) or a salt thereof: .

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