Synthesis method of brissentan intermediate

Abstract

The invention provides a synthesis method of a brissentan intermediate, and relates to the field of chemical drugs. The synthesis method comprises the following steps: performing chlorination reaction on a compound 1 to synthesize a compound 2; performing substitution reaction on the compound 2 and the compound 3 to synthesize a compound 4; carrying out Miyaura boronation reaction on the compound 4 to generate a compound 4i, and carrying out coupling reaction on the compound 4i and a compound 5 to synthesize a compound 6. The synthesis method avoids the use of chemicals with high toxicity and danger coefficient, reduces the use of catalysts, and is easy for large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicines, and in particular to a method for synthesizing a sepasentan intermediate. Background Art

[0002] Separsentan is a dual-acting endothelin-angiotensin receptor antagonist (DEARA), a new class of drugs that dually block endothelin type A (ETA) and angiotensin II type 1 (AT1) receptors. Preclinical data show that blocking the endothelin type 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.

[0003] The existing routes are:

[0004]

[0005] Among them, the synthesis method of 5 is:

[0006] This method requires the use of butyl lithium to synthesize At the same time, 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 them difficult to scale up for production.

[0007] Lin Haibo et al. disclosed an improved synthesis process of sepasentan in the Chinese Journal of Pharmaceutical Industry, using the following route:

[0008]

[0009] When preparing intermediate 12, intermediate 5 reacts with B2Pin2 to synthesize intermediate 6, and then tetrakistriphenylphosphine palladium is used for Suzuki coupling, avoiding the use of n-butyl lithium. However, this step cannot be completed in one step, and many types of catalysts are used, the steps are cumbersome, the yield is low, and the cost is high.

[0010] Chinese patent CN116239588A discloses a method for synthesizing a sepasentan intermediate, wherein compound RS-5 is first reacted with methanesulfonyl chloride, and then reacted with another raw material under cesium carbonate conditions to obtain compound RS-7. This avoids the problem of the difficult treatment of the byproduct triphenylphosphine in the original patent reaction, and the reaction with another raw material does not require the use of sodium hydride, and uses safer cesium carbonate. The following route is used:

[0011]

[0012] However, this patent used MsCl in the preparation of RS-6, which is highly toxic and risky, not conducive to large-scale production, and did not improve the reaction route before the compound RS-5. Summary of the invention

[0013] In order to solve the problems existing in the above-mentioned prior art, the present invention provides a method for synthesizing a sepasentan intermediate, comprising the following technical scheme:

[0014] The present invention provides a method for synthesizing a sepasentan intermediate, characterized in that it comprises the following steps:

[0015] A. Compound 1 is synthesized into compound 2 through chlorination reaction;

[0016] B. Compound 2 and compound 3 are reacted to synthesize compound 4;

[0017] C. Compound 4 is subjected to Miyaura borylation reaction to generate compound 4i, and compound 4i and compound 5 are subjected to coupling reaction to synthesize compound 6;

[0018] Specifically, the compound 1 is:

[0019] Specifically, the compound 2 is:

[0020] Specifically, the compound 3 is: or a pharmaceutically acceptable salt thereof;

[0021] Specifically, the compound 4 is:

[0022] Specifically, the compound 4i is:

[0023] Specifically, the compound 5 is:

[0024] Specifically, the compound 6 is:

[0025] Specifically, the R groups in the compound 5 and the compound 6 are independently selected from amino protecting groups or hydrogen atoms;

[0026] Specifically, step A comprises: subjecting compound 1 to a chlorination reaction with SOCl2;

[0027] Specifically, the molar ratio of the compound 1 to SOCl2 is: 1:2-3;

[0028] Preferably, the molar ratio of compound 1 to SOCl2 is 1:2.5;

[0029] Specifically, step A is: dissolving compound 1 in a solvent, adding SOCl2, and stirring to react to obtain compound 2;

[0030] Specifically, the solvent is DCM; and / or

[0031] Specifically, the temperature of adding SOCl2 is -10°C-0°C; and / or

[0032] Specifically, the stirring reaction temperature is 20-25°C; and / or

[0033] Specifically, the stirring reaction time is 2-4h;

[0034] Specifically, step B is: dissolving compound 3 in a solvent, adding sodium hydride, stirring, and adding compound 2 to react;

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

[0036] Preferably, the molar ratio of compound 3, sodium hydride and compound 2 is: 1.2:2.5:1;

[0037] Specifically, the solvent is DMF; and / or

[0038] Specifically, the stirring time is 20-40 min; and / or

[0039] Specifically, the reaction temperature is -10°C-0°C;

[0040] Specifically, step C is: compound 4 is subjected to 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 subjected to coupling reaction to synthesize compound 6;

[0041] Specifically, the molar ratio of the compound 4, the base, the boron source reagent, the catalyst and the compound 5 is: 1:2-3:1-1.5:0.3-0.5:1-1.2;

[0042] Preferably, the molar ratio of the compound 4, the base, the boron source reagent, the catalyst and the compound 5 is: 1:3:1.3:0.3:1.1;

[0043] Specifically, the base is at least one of KOAc and Na2CO3; and / or

[0044] Specifically, the catalyst is at least one of Pd(dppf)Cl2, Pd(pph3)4; and / or

[0045] Specifically, the boron source reagent is (BPin)2; and / or

[0046] Specifically, the temperature of the Miyaura borylation reaction is 80-90°C; and / or

[0047] Specifically, the Miyaura borylation reaction time is 2-3h; and / or

[0048] Specifically, the solvent for the Miyaura borylation reaction and the coupling reaction is DME; and / or

[0049] Specifically, the coupling reaction temperature is 80-90°C; and / or

[0050] Specifically, the coupling reaction time is 2-3h.

[0051] Beneficial effects:

[0052] (1) It is not necessary to use MSCl to protect the hydroxyl group or use carbon tetrabromide and triphenylphosphine to convert the hydroxyl group into bromine. Using thionyl chloride, the reaction is clean and the post-treatment is simple;

[0053] (2) The present invention optimizes the existing route and omits the use of the highly dangerous chemical n-butyl lithium to obtain Steps, directly using its precursor reaction, while reducing the use of catalysts, economical, environmentally friendly and easy to post-process;

[0054] (3) The present invention optimizes the existing route and improves the yield and purity. DETAILED DESCRIPTION

[0055] 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 the embodiments. 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.

[0056] Unless otherwise specified, the reagents used in the present invention were purchased from commercial channels.

[0057] The present invention uses compound 1 as a starting material. The preparation method of compound 1 can be found in the background technology.

[0058] In some preferred embodiments of the present invention, the reaction scheme of the method is as follows:

[0059]

[0060] Example

[0061] Step 1, preparation of compound 2: 1-bromo-4-(chloromethyl)-2-(ethoxymethyl)benzene

[0062]

[0063] 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-mouth bottle, and SOCl2 (26.0 g, 218.3 mmol, 2.5 eq.) was slowly added dropwise under an ice bath. After the addition was completed, the reaction solution was slowly heated to 20°C and stirred for 3 hours. LCMS confirmed that the raw material was completely converted, and the mixture was concentrated under reduced pressure until there was no obvious fraction to obtain compound 2 (23.0 g, purity 95%, yield = 100%).

[0064] 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).

[0065] Step 2, preparation of compound 4: 3-(4-bromo-3-(ethoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

[0066]

[0067] 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 stirred at the same temperature for 30 minutes. Compound 2 (23.0 g, 87.8 mmol, 1.0 mmol) was slowly added to the reaction mixture, and the mixture was stirred at the same temperature for 2 hours. LCMS confirmed that the raw material conversion was complete, ice water (300 mL) was added to the reaction mixture, 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 a 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%).

[0068] 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).

[0069] Steps 3 and 4, preparation of 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

[0070]

[0071] 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 vacuuming and replacing nitrogen three times, Pd(dppf)Cl2 (244 mg, 0.334 mmol, 2%) was added, and the temperature was gradually raised to 85°C under nitrogen protection. After 2 hours, LCMS detected that the raw material disappeared and was completely converted into compound 4i.

[0072] 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 vacuuming and replacing nitrogen three times, the reaction solution was heated to 85 ° C and stirred for 2 hours. LCMS detected that the raw material was completely converted. After cooling to room temperature, ice water (50 mL) was added to the reaction solution, and it 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 a 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 light yellow oily liquid.

[0073] LCMS: (M+H) + ; m / z = 681.39;

[0074] 1 H 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).

[0075] The method for preparing Separsentan is as follows:

[0076] Sepasentan: 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

[0077]

[0078] At room temperature, 4'-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-ene-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 6N HCl (40 mL). The reaction solution was slowly heated to 75-80°C and stirred for 3 hours. LCMS confirmed that the raw material conversion was complete. After the reaction solution was cooled to room temperature, the pH value was adjusted to 8 by adding 10M NaOH solution, and then continued to stir for 2 hours. The pH value was adjusted to 6 by adding acetic acid, and 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 a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give 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.

[0079] LCMS: (M+H) + ; m / z = 593.5;

[0080] 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).

[0081] Comparative Example

[0082] The synthetic route before optimization was adopted, specifically:

[0083]

[0084] Among them, compound R5 needs to be synthesized by the following reaction:

[0085]

[0086] Synthesis of compound R5:

[0087]

[0088] In a 250 ml three-necked flask, add 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), then replace the reaction nitrogen three times, cool to -78 ° C in a dry ice-acetone bath, and then add n-butyl lithium solution (2.5 mol / L) (35.5 mL, 88.7 mmol, 1.2 eq.) through a constant pressure dropping funnel. After the addition is complete, react at -78 ° C for 0.5 h, and then add trimethyl borate (9.21 g, 88 .7mmol, 1.2eq.), the reaction temperature was slowly raised to room temperature, and the reaction was continued for 1h. LCMS confirmed that the raw material was completely converted. The reaction solution was cooled to room temperature, and 6N hydrochloric acid was added to quench the reaction. The mixture was extracted twice with ethyl acetate (100mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a crude product. The crude product was then purified by column chromatography (dichloromethane: methanol = 50:1 to 20:1) to give a light yellow oily (2-(N-(4,5-dimethylisoxazol-3-yl)-N-((2-methoxyethoxy)methyl)sulfamoyl)phenyl)boronic acid (16.0g, purity 92%, yield 56%).

[0089] Step R1: Synthesis of Compound R2

[0090]

[0091] 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 about -10°C. The reaction was stirred at the same temperature for about 30 minutes until the reduction was complete, and then quenched with ice water to maintain the temperature at about 0°C. The organic layer was separated and washed with ice water again to obtain a toluene solution of compound R2, which was directly used in the next step reaction.

[0092] Step R2: Synthesis of compound 4

[0093]

[0094] 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), and 10 M NaOH solution (17 mL) was added. The reaction mixture was stirred at 25 ° C for 2 hours until compound R2 was no longer detected by HPLC analysis, and then quenched with water (30 mL). After stirring for about 10 minutes, the organic layer was separated, the water layer was extracted with toluene, the organic phase was combined and 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 a 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%).

[0095] Step R3: Synthesis of compound 6

[0096]

[0097] At 20°C, 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), and after vacuuming and replacing nitrogen three times, Pd(dppf)Cl2 (406 mg, 0.556 mmol, 2%) was added, and the temperature was gradually raised to 100°C under nitrogen protection. After 2 hours, LCMS detected that the raw material disappeared and was completely converted into compound 6, and the reaction solution was cooled to room temperature. Ice water (50 mL) was added to the reaction solution, and it was extracted twice with ethyl acetate (100 mL), and the organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1:1) to give compound 6 (8.5 g, purity 99%, yield 52%) as a light yellow oily liquid.

[0098] Compared with the comparative example, the present invention uses thionyl chloride, and does not need to use methylsulfonyl chloride to protect the hydroxyl group, or use carbon tetrabromide and triphenylphosphine to convert the hydroxyl group into bromine. The present invention has a clean reaction and simple post-treatment.

[0099] Compared with the comparative example, the present invention directly uses compound 5 for the reaction, and does not need to use butyl lithium to synthesize compound 5 into compound R5, thereby avoiding the use of the highly dangerous chemical n-butyl lithium and shortening the reaction steps.

[0100] Compared with the comparative example, the synthesis method of the present invention has higher yield and better purity.

[0101] The purity of the product in step 1 of the present 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%.

[0102] In the comparative example, steps R1 and R2 are continuously added, and the purity of the product is 92%, and the yield is 77.4%. The purity of the product of step R3 is 99%, and the yield is 52%. The comparative example requires one more step to synthesize R5, and the purity of the product is 92% and the yield is 56%.

[0103] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing a sepasentan intermediate, characterized in that: The following steps are involved: A. Compound 1 is synthesized into compound 2 through chlorination reaction; B. Compound 2 and compound 3 are reacted to synthesize compound 4; C. Compound 4 is subjected to Miyaura borylation reaction to generate compound 4i, and compound 4i and compound 5 are subjected to coupling reaction to synthesize compound 6; The compound 1 is: The compound 2 is: The compound 3 is: or a pharmaceutically acceptable salt thereof; The compound 4 is: The compound 4i is: The compound 5 is: The compound 6 is: The R groups in the compound 5 and the compound 6 are independently selected from an amino protecting group or a hydrogen atom.

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

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

4. The synthesis method according to claim 3, characterized in that Step A is: dissolving compound 1 in a solvent, adding SOCl2, and stirring to react to obtain compound 2; and / or The solvent is DCM; and / or The addition temperature of SOCl2 is -10°C to 0°C; and / or The stirring reaction temperature is 20-25°C; and / or The stirring reaction time is 2-4h.

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

6. The synthesis method according to claim 5, characterized in that The molar ratio of the 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 min; and / or The reaction temperature is -10°C to 0°C.

8. The synthesis method according to claim 1, characterized in that Step C is: compound 4 is subjected to 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 reacted by coupling reaction to synthesize compound 6.

9. The synthesis method according to claim 8, characterized in that The molar ratio of the compound 4, the base, the boron source reagent, the catalyst and the 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 base is at least one of KOAc and Na2CO3; and / or The catalyst is at least one of Pd(dppf)Cl2, Pd(pph3)4; and / or The boron source reagent is (BPin)2; and / or The temperature of the Miyaura borylation reaction is 80-90°C; and / or The Miyaura borylation reaction time is 2-3h; and / or The solvent for the Miyaura borylation reaction and the coupling reaction is DME; and / or The coupling reaction temperature is 80-90°C; and / or The coupling reaction time is 2-3h.

Images