Synthesis method for sparsentan intermediate

Abstract

Provided is a synthesis method for a sparsentan intermediate, relating to the field of chemical drugs. The synthesis method comprises: compound 1, by means of a chlorination reaction, synthesizing compound 2; compound 2 and compound 3, by means of a substitution reaction, synthesizing compound 4; compound 4, by means of a Miyaura borylation reaction, generating compound 4i; and compound 4i and compound 5, by means of a coupling reaction, synthesizing compound 6. The synthesis method avoids the use of highly toxic and hazardous chemicals, reduces the use of catalysts, and facilitates large-scale production.

Description

A method for synthesizing a sparsentan intermediate

[0001] Priority claim: This invention claims priority to Chinese Patent Application No. 2024114076851, filed on October 9, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of chemical pharmaceuticals, and in particular to a method for synthesizing a sparsentan intermediate. Background Technology

[0003] Sparsentan is a dual-action endothelin-angiotensin receptor antagonist (DEARA), a novel drug that dually blocks endothelin A (ETA) and angiotensin II type 1 (AT1) receptors. Preclinical data indicate that blocking the endothelin A (ETA) and angiotensin II type 1 (AT1) pathways reduces proteinuria, protects podocytes, and prevents glomerular sclerosis and mesangial cell proliferation in a variety of rare chronic kidney diseases.

[0004] The existing route is as follows:

[0005] The synthesis method for 5 is as follows:

[0006] This method requires the synthesis of butyllithium. Meanwhile, this route involves the use of reagents such as methanesulfonyl chloride and carbon tetrachloride, which are highly toxic, have poor safety, and have low yields, making it difficult to scale up production.

[0007] Lin Haibo et al. published an improved synthesis process for sparsentan in the journal *China Pharmaceutical Industry*, using the following route:

[0008] In the preparation of intermediate 12, intermediate 5 reacts with B2Pin2 to synthesize intermediate 6, and then Suzuki coupling is performed using tetra-triphenylphosphine palladium to avoid the use of n-butyllithium. However, this step cannot be completed in one step, and it involves many types of catalysts, is complicated, has low yield, and high cost.

[0009] Chinese patent CN116239588A discloses a method for synthesizing a sparsentan intermediate. The method involves reacting compound RS-5 with methanesulfonyl chloride, followed by reaction with another starting material under cesium carbonate conditions to obtain compound RS-7. This avoids the problem of difficult-to-handle triphenylphosphine, a byproduct of the original patent. Furthermore, the reaction with the other starting material does not require sodium hydride, using the safer cesium carbonate. The route is as follows:

[0010] However, the patent used MsCl in the preparation of RS-6, which is highly toxic and risky, making it unsuitable for large-scale production. Furthermore, it did not improve the reaction route prior to compound RS-5.

[0011] Summary of the Invention

[0012] To address the problems existing in the prior art, the present invention provides a method for synthesizing sparsentan intermediates, comprising the following technical solutions:

[0013] This invention provides a method for synthesizing a sparsentan intermediate, characterized by comprising the following steps:

[0014] A. Compound 1 is synthesized into compound 2 via a chlorination reaction;

[0015] B. Compound 2 and compound 3 synthesize compound 4 through a substitution reaction;

[0016] C. Compound 4 is converted into compound 4i via the Miyaura borylation reaction, and compound 4i is combined with compound 5 via a coupling reaction to synthesize compound 6;

[0017] Specifically, compound 1 is:

[0018] Specifically, compound 2 is:

[0019] Specifically, compound 3 is: Or its pharmaceutically acceptable salt;

[0020] Specifically, compound 4 is:

[0021] Specifically, compound 4i is:

[0022] Specifically, compound 5 is:

[0023] Specifically, compound 6 is:

[0024] Specifically, the R groups in compounds 5 and 6 are independently selected from amino protecting groups or hydrogen atoms;

[0025] Specifically, step A is: reacting compound 1 with SOCl2 via a chlorination reaction;

[0026] Specifically, the molar ratio of compound 1 to SOCl2 is 1:2-3;

[0027] Preferably, the molar ratio of compound 1 to SOCl2 is 1:2.5;

[0028] Specifically, step A is as follows: dissolve compound 1 in a solvent, add SOCl2, stir to react, and obtain compound 2;

[0029] Specifically, the solvent is DCM; and / or

[0030] Specifically, the temperature at which SOCl2 is added is -10℃ to 0℃; and / or

[0031] Specifically, the temperature of the stirring reaction is 20-25°C; and / or

[0032] Specifically, the stirring reaction takes 2-4 hours;

[0033] Specifically, step B is as follows: compound 3 is dissolved in a solvent, sodium hydride is added, the mixture is stirred, and compound 2 is added to react.

[0034] Specifically, the molar ratio of compound 3, sodium hydride, and compound 2 is 1-1.2:2.5:1;

[0035] Preferably, the molar ratio of compound 3, sodium hydride, and compound 2 is 1.2:2.5:1;

[0036] Specifically, the solvent is DMF; and / or

[0037] Specifically, the stirring time is 20-40 minutes; and / or

[0038] Specifically, the reaction temperature is -10℃ to 0℃;

[0039] Specifically, step C is as follows: Compound 4 undergoes a Miyaura borylation reaction under the conditions of adding a base, a catalyst and a boron source reagent to generate compound 4i, and compound 4i and compound 5 are coupled together to synthesize compound 6.

[0040] Specifically, the molar ratio of compound 4, base, boron source reagent, catalyst and compound 5 is 1:2-3:1-1.5:0.3-0.5:1-1.2;

[0041] Preferably, the molar ratio of compound 4, base, boron source reagent, catalyst and compound 5 is 1:3:1.3:0.3:1.1;

[0042] Specifically, the alkali is at least one selected from KOAc and Na2CO3; and / or

[0043] Specifically, the catalyst is at least one of Pd(dppf)Cl2 and Pd(pph3)4; and / or

[0044] Specifically, the boron source reagent is (BPin)2; and / or

[0045] Specifically, the temperature of the Miyaura borylation reaction is 80-90°C; and / or

[0046] Specifically, the Miyaura borylation reaction takes 2-3 hours; and / or

[0047] Specifically, the solvent for the Miyaura borylation reaction and coupling reaction is DME; and / or

[0048] Specifically, the coupling reaction is performed at a temperature of 80-90°C; and / or

[0049] Specifically, the coupling reaction takes 2-3 hours. Beneficial effects:

[0050] (1) It is not necessary to use MSCl to protect the hydroxyl group or use carbon tetrabromide and triphenylphosphine to convert the hydroxyl group to bromine. Using thionyl chloride, the reaction is clean and the post-processing is simple.

[0051] (2) This invention optimizes existing routes, eliminating the use of the highly hazardous chemical n-butyllithium. The steps involve directly using its precursor. The reaction reduces the use of catalysts, making it economical, environmentally friendly, and easy to post-process;

[0052] (3) This invention optimizes the existing route, thereby improving the yield and purity. Detailed Implementation

[0053] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0054] Unless otherwise specified, all reagents used in this invention were purchased from commercially available channels.

[0055] This invention uses compound 1 as the starting material, and the preparation method of compound 1 is described in the background art.

[0056] In some preferred embodiments of the present invention, the reaction route of the method is as follows:

[0057] Example

[0058] Step 1, Preparation of compound 2: 1-bromo-4-(chloromethyl)-2-(ethoxymethyl)benzene

[0059] At 20°C, compound 1 (21.4 g, 87.3 mmol, 1.0 eq.) and dichloromethane (100 mL) were added to a 250 mL single-necked flask. SOCl2 (26.0 g, 218.3 mmol, 2.5 eq.) was slowly added dropwise under ice bath conditions. After the addition was complete, the reaction mixture was slowly heated to 20°C and stirred for 3 hours. Complete conversion of the starting material was confirmed by LC-MS. The mixture was concentrated under reduced pressure until no obvious fractions were observed to obtain compound 2 (23.0 g, purity 95%, yield = 100%).

[0060] 1 H NMR (400MHz, CDCl3) δ7.56-7.49(m,2H),7.17(dd,J=8.2,2.4Hz,1H),4.55(s,4H),3.64(q,J=7.0Hz,2H),1.30(t,J=7.0Hz,3H).

[0061] Step 2, preparation of compound 4: 3-(4-bromo-3-(ethoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

[0062] Under nitrogen protection at 0°C, sodium hydride (8.78 g, 219.5 mmol, 2.5 eq.) was slowly added to a mixture of compound 3 (24.3 g, 105.3 mmol, 1.2 eq.) and DMF (120 mL), and the mixture was stirred for 30 minutes at the same temperature. Compound 2 (23.0 g, 87.8 mmol, 1.0 mmol) was slowly added to the reaction mixture, and the mixture was stirred for 2 hours at the same temperature. After complete conversion of the starting material was confirmed by LCMS, ice water (300 mL) was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate (200 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 4 (29.5 g, purity 96%, yield = 80%).

[0063] 1H NMR (400MHz, CDCl3) δ7.48(d,J=8.2Hz,1H),7.29(d,J=2.3Hz,1H),6.92(dd ,J=8.2,2.3Hz,1H),4.64(s,2H),4.52(s,2H),3.60(q,J=7.0Hz,2H),2.35-2 .23(m,2H),1.97(dddd,J=14.0,11.8,5.3,2.0Hz,6H),1.87-1.75(m,2H),1 .56(tt,J=7.8,6.4Hz,2H),1.34(dd,J=15.0,7.5Hz,2H),0.96-0.76(m,6H).

[0064] Steps 3 and 4 prepare compound 6: 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-[1,1'-biphenyl]-2-sulfonamide

[0065] At 20 °C, compound 4 (7.0 g, 16.7 mmol, 1.0 eq.), KOAc (4.9 g, 50.1 mmol, 3.0 eq.), and (BPin)2 (5.5 g, 21.7 mmol, 1.3 eq.) were dissolved in 49 mL of DME. After evacuating the vacuum and replacing the nitrogen gas three times, Pd(dppf)Cl2 (244 mg, 0.334 mmol, 2%) was added. Under nitrogen protection, the temperature was gradually increased to 85 °C. After 2 hours, LCMS showed that the starting material had disappeared and was completely converted to compound 4i.

[0066] The reaction solution was cooled to room temperature, and water (12 mL), Na₂CO₃ (3.5 g, 33.4 mmol, 2.0 eq.), and compound 5 (7.7 g, 18.4 mmol, 1.1 eq.) were added. After evacuating to nitrogen three times, the reaction solution was heated to 85 °C and stirred for 2 hours. LCMS confirmed complete conversion of the starting material. After cooling to room temperature, ice water (50 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (100 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 6 (7.9 g, purity 99%, yield = 70%), which was a pale yellow oily liquid.

[0067] LCMS:(M+H) + m / z = 681.39;

[0068] 1H NMR (400MHz, CDCl3) δ7.99(dd,J=8.0,1.3Hz,1H),7.57(td,J=7.5,1.4Hz,1H),7.45(td,J=7.8,1.4Hz,1H),7.38(d,J=1.9Hz,1H),7.33-7. 21(m,2H),7.06(dd,J=7.9,1.9Hz,1H),4.75(s,2H),4.46(d,J=11.2Hz,1H),4.41-4.28(m,2H),4.14(d,J=12.8Hz,1H),3.74(dt,J=10.8,4. 5Hz,1H),3.66-3.56(m,1H),3.46(t,J=4.6Hz,2H),3.43-3.37(m,1H),3.37-3.26(m,4H),2.41-2.32(m,2H),2.29(s,3H),2.13-1.94(m,6H) ,1.92(s,3H),1.84(dp,J=12.7,6.1,4.0Hz,2H),1.62(p,J=7.5Hz,2H),1.37(h,J=7.3Hz,2H),1.11(t,J=7.0Hz,3H),0.90(t,J=7.3Hz,3H).

[0069] The method for preparing sparsentan is as follows:

[0070] Sparsentan: 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-[1,1'-biphenyl]-2-sulfonamide

[0071] At room temperature, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N-(4,5-dimethylisoxazol-3-yl)-2'-(ethoxymethyl)-N-[1,1'-biphenyl]-2-sulfonamide (7.9 g, 11.6 mmol, 1.0 eq.) and ethanol (79 mL) were added to a 250 mL three-necked flask, followed by the addition of 6N HCl (40 mL). The reaction mixture was slowly heated to 75-80 °C and stirred for 3 hours. After confirming complete conversion of the starting material by LCMS, the reaction mixture was cooled to room temperature, and the pH was adjusted to 8 by adding 10 M NaOH solution. The mixture was then stirred for 2 hours, and the pH was adjusted to 6 by adding acetic acid. The mixture was extracted twice with ethyl acetate (100 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain N-(3,4-dimethyl-5-isoxazolyl)-2-(4-(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl-2-ethoxymethylphenyl)benzenesulfonamide (6.19 g, purity 99%, yield = 90%) as a white solid.

[0072] LCMS:(M+H) + m / z = 593.5;

[0073] 1 H NMR (400MHz, DMSO-d6) δ10.49 (s, 1H), 8.07 (dd, J = 7.6, 1.7Hz, 1H), 7.74-7.56 (m, 2H), 7.2 7-7.16(m,2H),7.03(dd,J=7.9,1.9Hz,1H),6.95(d,J=7.8Hz,1H),4.75(s,2H),4.02(s,2H ),3.22(p,J=7.0Hz,2H),2.36(t,J=7.5Hz,2H),2.22(s,3H),1.97-1.78(m,6H),1.68(s,5 H),1.53(p,J=7.5Hz,2H),1.36-1.22(m,2H),1.02(t,J=7.0Hz,3H),0.83(t,J=7.3Hz,3H).

[0074] Comparative Example

[0075] The original synthesis route was used, specifically:

[0076] Compound R5 needs to be synthesized through the following reaction:

[0077] Synthesis of compound R5:

[0078] In a 250 mL three-necked flask, 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-((2-methoxyethoxy)methyl)benzenesulfonamide (31.0 g, 73.9 mmol, 1.0 eq.) and anhydrous tetrahydrofuran (200 mL) were added. After the reaction was purged with nitrogen three times, the mixture was cooled to -78 °C in a dry ice-acetone bath. Then, n-butyllithium solution (2.5 mol / L) (35.5 mL, 88.7 mmol, 1.2 eq.) was added dropwise through a constant pressure dropping funnel. After the addition was complete, the reaction was allowed to proceed at -78 °C for 0.5 h. Then, trimethyl borate (9.21 g, 88 mmol, 1.0 eq.) was added. 7 mmol, 1.2 eq.), the reaction was slowly raised to room temperature and reacted for 1 h. LCMS confirmed complete conversion of the starting material. The reaction solution was cooled to room temperature and quenched by adding 6N hydrochloric acid. The reaction was extracted twice with ethyl acetate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (dichloromethane:methanol = 50:1 to 20:1) to obtain a pale yellow oily (2-(N-(4,5-dimethylisoxazol-3-yl)-N-((2-methoxyethoxy)methyl)aminosulfonyl)phenyl)boronic acid (16.0 g, purity 92%, yield 56%).

[0079] Step R1: Synthesis of compound R2

[0080] Compound 1 (6.0 g, 24.5 mmol) was dissolved in toluene (50 mL), and methanesulfonyl chloride (5.6 g, 48.9 mmol) was added at approximately -10 °C. The reaction was stirred at the same temperature for approximately 30 minutes until reduction was complete, and then quenched with ice water to maintain the temperature at approximately 0 °C. The organic layer was separated and washed again with ice water to obtain a toluene solution of compound R2, which was used directly in the next reaction.

[0081] Step R2: Synthesis of Compound 4

[0082] Methyltributylammonium chloride (0.3 g) was added to a toluene solution of compound R2. The resulting mixture was added to a dichloromethane (33 mL) solution of compound 3 (7.4 g, 32 mmol), followed by 10 M NaOH solution (17 mL). The reaction mixture was stirred at 25 °C for 2 hours until compound R2 was no longer detectable by HPLC, and then quenched with water (30 mL). After stirring for about 10 minutes, the organic layer was separated, the aqueous layer was extracted with toluene, the organic phases were combined, washed with water, and concentrated to a small volume. The organic phase was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 4 (6.8 g, purity = 92%, yield = 77.4%).

[0083] Step R3: Synthesis of Compound 6

[0084] Compound 4 (11.7 g, 27.8 mmol, 1.0 eq.), compound R5 (16.0 g, 41.7 mmol, 1.5 eq.), and Na2CO3 (5.9 g, 55.6 mmol, 2.0 eq.) were dissolved in 60 mL of 1,4-dioxane / water (4 / 1) solution under 20 °C. After evacuating to nitrogen three times, Pd(dppf)Cl2 (406 mg, 0.556 mmol, 2%) was added. The mixture was gradually heated to 100 °C under nitrogen protection. After 2 hours, LCMS analysis showed that the starting material had disappeared, indicating complete conversion to compound 6. The reaction solution was cooled to room temperature. Ice water (50 mL) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (100 mL). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound 6 (8.5 g, purity 99%, yield 52%), which was a pale yellow oily liquid.

[0085] Compared to the comparative example, this invention uses thionyl chloride, eliminating the need for protecting the hydroxyl group with methanesulfonyl chloride or converting the hydroxyl group to bromine with carbon tetrabromide and triphenylphosphine. This invention results in a cleaner reaction and simpler post-processing.

[0086] Compared to the comparative example, this invention directly uses compound 5 for the reaction, eliminating the need to use butyllithium to synthesize compound R5 from compound 5, thus avoiding the use of the highly hazardous chemical n-butyllithium and shortening the reaction steps.

[0087] Compared to the comparative example, the synthesis method of the present invention has a higher yield and better purity.

[0088] The purity of the product in step 1 of this invention is 95% and the yield is 100%; the purity of the product in step 2 is 96% and the yield is 80%; and the purity of the product in step 3 is 99% and the yield is 70%.

[0089] The comparative example was produced by consecutively adding steps R1 and R2, with a product purity of 92% and a yield of 77.4%. Step R3 produced a product with a purity of 99% and a yield of 52%. The comparative example required an additional step to synthesize R5, with a product purity of 92% and a yield of 56%.

[0090] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a sparsentan intermediate, characterized in that, Includes the following steps: A. Compound 1 is synthesized into compound 2 via a chlorination reaction; B. Compound 2 and compound 3 synthesize compound 4 through a substitution reaction; C. Compound 4 is converted into compound 4i via the Miyaura borylation reaction, and compound 4i is combined with compound 5 via a coupling reaction to synthesize compound 6; Compound 1 is: Compound 2 is: The compound 3 is: Or its pharmaceutically acceptable salt; Compound 4 is: The compound 4i is: Compound 5 is: Compound 6 is: The R groups in compounds 5 and 6 are independently selected from amino protecting groups or hydrogen atoms.

2. The synthesis method according to claim 1, characterized in that, Step A is: Compound 1 undergoes a chlorination reaction with SOCl2.

3. The synthesis method according to claim 2, characterized in that, The molar ratio of compound 1 to SOCl2 is 1:2-3.

4. The synthesis method according to claim 3, characterized in that, Step A is as follows: Dissolve compound 1 in a solvent, add SOCl2, stir the reaction to obtain compound 2; and / or The solvent is DCM; and / or The SOCl2 is added at a temperature of -10℃ to 0℃; and / or The temperature of the stirring reaction is 20-25°C; and / or The stirring reaction takes 2-4 hours.

5. The synthesis method according to claim 1, characterized in that, Step B is as follows: Compound 3 is dissolved in a solvent, sodium hydride is added, the mixture is stirred, and then compound 2 is added to react.

6. The synthesis method according to claim 5, characterized in that, The molar ratio of compound 3, sodium hydride and compound 2 is 1-1.2:2.5:

1.

7. The synthesis method according to claim 5, characterized in that, The solvent is DMF; and / or The stirring time is 20-40 minutes; and / or The reaction temperature is -10℃ to 0℃.

8. The synthesis method according to claim 1, characterized in that, Step C is as follows: Compound 4 undergoes a Miyaura borylation reaction under the conditions of adding a base, a catalyst and a boron source reagent to generate compound 4i, and compound 4i and compound 5 are coupled together to synthesize compound 6.

9. The synthesis method according to claim 8, characterized in that, The molar ratio of compound 4, base, boron source reagent, catalyst and compound 5 is 1:2-3:1-1.5:0.3-0.5:1-1.

2.

10. The synthesis method according to claim 8, characterized in that, The alkali is at least one of KOAc and Na2CO3; and / or The catalyst is at least one of Pd(dppf)Cl2 and Pd(pph3)4; and / or The boron source reagent is (BPin)2; and / or The Miyaura borylation reaction is performed at a temperature of 80-90°C; and / or The Miyaura borylation reaction takes 2-3 hours; and / or The solvent for the Miyaura borylation and coupling reactions is DME; and / or The coupling reaction is performed at a temperature of 80-90°C; and / or The coupling reaction takes 2-3 hours.

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