Method for preparing etrasimod

Abstract

The present invention relates to the technical field of pharmaceutical chemistry. Provided in the present invention is a method for preparing etrasimod. The method comprises a coupling-oxidative hydroxylation reaction, a Mitsunobo reaction, a hydrolysis reaction, and a salt formation process. The method for preparing etrasimod provided by the present invention is used for preparing an etrasimod arginine salt. The method has a new process route and a high overall molar yield, and is characterized by a more controllable quality, a high chiral purity, a high atom economy and stable operation.

Description

A method for preparing edema

[0001] This invention claims priority to Chinese Patent Application No. 202510139127X, filed on February 7, 2025, entitled “A Method for Preparing Itrimod”, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical and chemical technology, specifically to a method for preparing ictromod. Background Technology

[0003] Etrasimod is a once-daily oral selective sphingosine-1-phosphate (S1P) receptor modulator. It is used to treat inflammatory bowel diseases, including ulcerative colitis, Crohn's disease, atopic dermatitis, eosinophilic esophagitis, and alopecia areata. With its once-daily oral regimen, it provides rapid onset of action and achieves hormone-free remission and mucosal healing, offering a new treatment option for adult patients with moderate to severe active ulcerative colitis. The structural formula of estradiol is (R)-2-(7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopentadien[b]indol-3-yl)acetic acid, as shown below:

[0004] The currently published preparation processes are as follows:

[0005] As shown in Chinese patent CN103221391A:

[0006] This route uses 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula 1) and ethyl acetate of 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopentadien[b]indole-3(4H)-ylidene) (Formula 2) as raw materials. First, an isotropic ethyl ester is prepared by docking reaction, and then isotropic is obtained by enzymatic hydrolysis. However, the yield is too low.

[0007] As shown in Chinese patent CN108558740A:

[0008] However, the above route has the following drawbacks: (1) the intermediates obtained in the first and second steps are not stable; (2) the overall yield is low, and the yields of the first three steps are all less than 50%; (3) the atom economy is poor, the chiral construction is placed in the hydrolysis step (sixth step), and the S configuration is separated by enzyme catalysis, resulting in a large amount of intermediate waste.

[0009] In summary, given the inherent drawbacks of current technical solutions, such as poor stability of some intermediates, low overall yield, and poor atom economy, providing a new method for preparing edemamod is of great significance to researchers in this field. Summary of the Invention

[0010] To address the aforementioned problems, this invention provides a method for preparing ictromod. By optimizing the preparation method, the obtained product exhibits high yield, high purity, and high chiral purity.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0012] On the one hand, the present invention provides a method for preparing ictromod, the reaction route of which is shown below:

[0013] It includes the following specific steps:

[0014] S1: Compound VII undergoes a boron esterification reaction followed by an oxidation reaction in the presence of an oxidizing agent to obtain compound VIII;

[0015] S2: Compound VIII is mixed with phosphine reagent, azo reagent, and (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol, and subjected to the Mitsunobo reaction in a nonpolar solvent to obtain compound IX;

[0016] S3: Hydrolyze compound IX with alkali to obtain compound X;

[0017] S4: Compound X is salted to obtain compound XI.

[0018] Preferably, the boron esterification reaction described in S1 includes either scheme 1 or scheme 2, specifically:

[0019] Scheme 1 involves a boron esterification reaction of a compound of formula VII, a boron-containing compound, a Lewis base, and a metal catalyst in a solvent, wherein the metal catalyst is selected from at least one of palladium catalysts, nickel catalysts, and copper catalysts;

[0020] Scheme 2 involves the boron esterification reaction of compound VII, boron-containing compound, and butyllithium in an organic solvent.

[0021] Preferably, the boron-containing compound in Scheme 1 or Scheme 2 is selected from at least one of tetrahydroxydiboron, trimethyl borate, triisopropyl borate, dipinacol diboron, pinacol borane, sodium tetrakis[3,5-di(trifluoromethyl)phenyl]borate and 1H-naphtho[1,8-de][1,3,2]diazacyclohexaneborane-2(3H)-pinacol ester;

[0022] More preferably, the boron-containing compound in Scheme 1 or Scheme 2 is tetrahydroxydiboron.

[0023] Preferably, the Lewis base in Scheme 1 is selected from at least one of potassium acetate, potassium phenoxy, and N,N,N′,N′-tetramethylethylenediamine;

[0024] The metal catalyst described in Scheme 1 is selected from at least one of tetra(triphenylphosphine)palladium, tetra(triphenylphosphine)palladium, triacetylacetone palladium, palladium on carbon, bis(diphenylphosphine)ferrocene palladium dichloride, and dichloroditert-butyl-(4-dimethylaminophenyl)phosphine palladium (II);

[0025] The butyllithium mentioned in Scheme 2 is n-butyllithium.

[0026] Preferably, in S1, the oxidant is hydrogen peroxide;

[0027] Preferably, in S2, the nonpolar solvent is toluene;

[0028] Preferably, in S2, the phosphine reagent is selected from at least one of triphenylphosphine, tri-tert-butylphosphine, and tripyridylphosphine; more preferably, the phosphine reagent is triphenylphosphine.

[0029] Preferably, in S2, the azo reagent is selected from at least one of di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dibenzyl azodicarbonate, dicyclohexyl azodicarbonate, and dipiperidine azodicarbonate; more preferably, in S2, the azo reagent is selected from di-tert-butyl azodicarbonate.

[0030] Preferably, in S3, the alkali is selected from at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide; more preferably, in S3, the alkali is selected from sodium hydroxide.

[0031] Preferably, the compound of formula XI is itramod arginine salt, with the following structure:

[0032] Preferably, the compound of formula VII is prepared by the following method:

[0033] Step a: Compound IV is reacted with a carboxylic acid activator and a chiral cofactor in the presence of a base to obtain compound V; wherein the chiral cofactor is selected from at least one of chiral amine compounds and chiral alcohol compounds;

[0034] In the compound of formula V, R is selected from the chiral amino group corresponding to the chiral amine compound or the chiral hydroxyl group corresponding to the chiral alcohol compound;

[0035] Step b: Compound V is dechiralized at a reaction temperature of -10⁻⁵ °C in the presence of hydrogen peroxide and a base to obtain compound VI.

[0036] Step c: The compound of formula VI is reacted with an ethylating agent in the presence of a base and a solvent to obtain the compound of formula VII.

[0037] Preferably,

[0038] In step a, the base is selected from at least one of triethylamine, DIPEA, triethylenediamine, DBU, potassium carbonate, and sodium carbonate; the carboxylic acid activator is selected from at least one of thionyl chloride, phosphorus oxychloride, and tervapotranilyl chloride.

[0039] More preferably, in step a, the base is selected from triethylamine; the carboxylic acid activator is selected from pentanoyl chloride;

[0040] Preferably, in step b, the reaction temperature is -10 to 0°C; more preferably, the reaction temperature is -5 to 0°C.

[0041] Preferably, in step b, the mass ratio of hydrogen peroxide to compound of formula V is 1.5-2.5:1; more preferably, the mass ratio of hydrogen peroxide to compound of formula V is 2:1.

[0042] Preferably, in step b, the alkali is selected from at least one of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethoxide, and sodium methoxide; more preferably, in step b, the alkali is selected from lithium hydroxide.

[0043] Preferably, in step c, the alkali is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, and sodium ethoxide; more preferably, the alkali is potassium carbonate.

[0044] Preferably, in step c, the solvent is selected from at least one of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and acetone; more preferably, the solvent is N,N-dimethylformamide.

[0045] Preferably, in step c, the ethylating agent is selected from at least one of ethane halide and ethyl sulfonate. More preferably, in step c, the ethylating agent is selected from ethane halide. More preferably, in step c, the ethylating agent is bromoethane.

[0046] Preferably, in step a, the chiral prosthetic group is a substituted chiral oxazoline-2-one compound, and R in the compound of formula V is a chiral amino group corresponding to the substituted chiral oxazoline-2-one compound.

[0047] More preferably, in step a, the chiral cofactor is (S)-4-methyl-2-oxazolidinone, (S)-4-isopropyl-2-oxazolidinone, or (S)-4-phenyl-2-oxazolidinone, and R in the compound of formula V corresponds to...

[0048] Preferably, the compound of formula IV is prepared by the following method:

[0049] Step i: The compound of formula I reacts with ethyl haloacetate in the presence of a base to give the compound of formula II;

[0050] Step ii: The compound of formula II reacts with 4-bromophenylhydrazine hydrochloride in the presence of acid to give the compound of formula III;

[0051] Step iii: Compound III is hydrolyzed with alkali and then decarboxylated with acid to obtain compound IV.

[0052] Preferably, in step i, the alkali is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, potassium bicarbonate, and potassium tert-butoxide; more preferably, the alkali is selected from potassium carbonate.

[0053] Preferably, in step ii, the acid is selected from at least one of glacial acetic acid, trifluoroacetic acid, and citric acid; more preferably, the acid is selected from glacial acetic acid.

[0054] Preferably, in step iii, the alkali is selected from at least one of sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate, and potassium carbonate; more preferably, in step iii, the alkali is selected from potassium carbonate.

[0055] Preferably, the acid is selected from at least one of glacial acetic acid, trifluoroacetic acid, citric acid, concentrated sulfuric acid, and hydrobromic acid. More preferably, the acid is selected from at least one of acetic acid and citric acid.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] This invention provides a novel method for preparing ictromod, which has a novel process route, high total molar yield, more controllable quality, high chiral purity, high atom economy, and stable process. Attached Figure Description

[0058] Figure 1 shows the 1H NMR spectrum of compound II.

[0059] Figure 2 shows the 1H NMR spectrum of compound V.

[0060] Figure 3 shows the 1H NMR spectrum of compound VI.

[0061] Figure 4 shows the 1H NMR spectrum of compound VIII.

[0062] Figure 5 shows the 1H NMR spectrum of compound IX.

[0063] Figure 6 shows the 1H NMR spectrum of compound XI. Detailed Implementation

[0064] To make the technical means, creative features, achieved objectives, and effects of this invention readily understandable, the invention is further illustrated below with specific embodiments. However, these embodiments are merely preferred embodiments and not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments described herein without creative effort are all within the scope of protection of this invention. It is worth noting that the raw materials used in this invention are all common commercially available products, and their sources are not specifically limited. The technical and scientific terms used in the embodiments have the meanings commonly understood by those skilled in the art to which this invention pertains.

[0065] Example 1

[0066] Step i: Condensation reaction (preparation of compound II):

[0067] Acetone (7.11 kg), 2-methoxycarbonylcyclopentanone (0.90 kg), and K₂CO₃ (1.75 kg) were added sequentially to a reaction vessel. Ethyl bromoacetate (1.10 kg) was added dropwise at 25-55 °C. After the addition was complete, the reaction was carried out at 50-60 °C for 1 h. A sample was taken and the content of the 2-methoxycarbonylcyclopentanone raw material was found to be less than 1%. The mixture was concentrated under reduced pressure until no more residue was collected, yielding 1.37 kg of a pale yellow oily substance, namely compound II, with a yield of 95%. (m / z+1:229)

[0068] 1 H NMR(400MHz,Chloroform-d)δ4.06(q,J=7.1Hz,2H),3.65(s,3H),2.91(d,J=17.2Hz,1H),2.75(d ,J=17.3Hz,1H),2.57-2.50(m,1H),2.46-2.33(m,2H),2.10-1.93(m,3H),1.19(t,J=7.2Hz,3H).

[0069] Step ii: Fischer indole cyclization (preparative formula III compound):

[0070] Acetic acid (6.83 kg), compound II (1.30 kg), p-bromophenylhydrazine hydrochloride (1.27 kg), and citric acid monohydrate (0.24 kg) were added to a reaction vessel. The mixture was heated to 75-85 °C and reacted for 6 h. After the reaction was completed, MTBE (4.81 kg) and water (19.50 kg) were added, and the mixture was stirred for 15 min. The mixture was allowed to stand and the phases separated. The organic phase was collected and its pH was adjusted to 6-7 with a 5% sodium bicarbonate aqueous solution. Then, it was washed once with water (6.50 kg), dried with anhydrous sodium sulfate, and concentrated under reduced pressure at 45-55 °C until no fraction remained, yielding 1.56 kg of compound III, with a yield of 72%. (m / z+1: 380, 382)

[0071] Step iii: Decarboxylation (preparation of compound IV):

[0072] The compound of formula III was dissolved in ethanol (6.15 kg), and sodium hydroxide aqueous solution (0.91 kg sodium hydroxide dissolved in 3.25 kg water) was added dropwise while maintaining the temperature below 45°C. The reaction was maintained at 40-50°C for 1 hour. After the reaction was completed, the temperature was lowered to 20-30°C, and water (19.5 kg) and MTBE (4.81 kg) were added for extraction. Then, MTBE (7.69 kg) was added, and the pH of the aqueous phase was adjusted to 1-2 with hydrochloric acid. The mixture was separated, and the organic phase was separated. The organic phase was washed twice with water (6.50 kg * 2), concentrated at 50-60°C until no more was collected, and then acetic acid (6.83 kg) was added to the concentrated dry matter. The mixture was heated to 70-80°C and reacted for 2 hours. After the reaction was completed, the temperature was lowered to 20-30°C, and MTBE (7.69 kg) was added. The mixture was then washed with water (13.0 kg * 2). The organic phase was purified by column chromatography and concentrated until no fraction was obtained to give 700 g of compound IV with a purity of 98.13% and a yield of 70%. (m / z+1: 294, 296)

[0073] Step a: Acid-amine condensation resolution (preparative formula V compound):

[0074] DCM (39.7 kg), compound IV (5 kg), (S)-4-phenyl-2-oxazolidinone (2.91 kg), TEA (6.02 kg), and DMAP (0.21 kg) were added sequentially to a reaction vessel. The mixture was purged with nitrogen three times. Pteropenoyl chloride (4.30 kg) was added dropwise at 25-35 °C. After the addition was complete, the mixture was stirred at 25-35 °C for 1 hour. The reaction solution was then washed twice with 3N hydrochloric acid, once with 10% sodium bicarbonate aqueous solution, and once with 15% sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure until no fraction remained. The mixture was crystallized twice using ethyl acetate (18.04 kg) / n-heptane (6.84 kg), filtered, and the filter cake was dried to obtain 3 kg of white solid, compound V, with a purity of 99.88%, a chiral purity of 100%, and a yield of 40%. (m / z+1: 439, 441).

[0075] 1 H NMR(400MHz,Chloroform-d)δ7.55(d,J=1.7Hz,1H),7.44(dd,J=5.0,2.0Hz,3H),7.32- 7.28(m,2H),7.15(dd,J=8.6,1.9Hz,1H),6.93(d,J=8.6Hz,1H),5.53(dd,J=8.8,4.2Hz ,1H),4.76(t,J=8.9Hz,1H),4.31(dd,J=9.0,4.2Hz,1H),3.68-3.60(m,1H),3.45(dd,J =18.3,4.0Hz,1H),3.13(dd,J=18.3,11.1Hz,1H),2.88-2.73(m,3H),2.30-2.17(m,1H).

[0076] Step b: Dechirped prosthetic group (preparation of compound VI):

[0077] Add tetrahydrofuran (21.7 L) to the reactor, then add compound V (1.55 kg), and add 30% hydrogen peroxide (0.80 kg, 2 eq.). Cool to -5 °C, and add an aqueous solution of lithium hydroxide (0.44 kg of lithium hydroxide dissolved in 3.72 kg of water) dropwise to the system. Control the temperature at -10 to -3 °C during the dropwise addition. After the dropwise addition is complete, keep the temperature at -10 to -3 °C for 1 h.

[0078] After the reaction was complete, water (16 kg) was added dropwise to the system, and the temperature was controlled at 0–15 °C. The mixture was then extracted twice with n-heptane (8 L), and the aqueous phase was collected. Methyl tert-butyl ether (15 L) was added to the aqueous phase, and the pH was adjusted to 1–2 with 3N hydrochloric acid. The mixture was stirred thoroughly, and the phases were separated. The upper organic phase was collected and washed once with sodium bisulfite solution (0.18 kg, 4 kg water). The organic phase was collected again, and n-heptane (30 L) was added to it. The mixture was stirred thoroughly, and the solution was added to a filter cylinder and brushed with silica gel (4 kg). The filtrate was collected, and the silica gel was washed with a mixture of methyl tert-butyl ether and n-heptane (1V:2V). The solution was concentrated under reduced pressure until no fraction was obtained, yielding 0.78 kg of compound VI with a purity of 97.62%, a chiral purity of 99.97%, and a yield of 75% (m / z+1: 294, 296).

[0079] 1H NMR (400MHz, DMSO-d6) δ12.27(s,1H),10.87(s,1H),7.49(d,J=1.9Hz,1H),7.29(d,J=8.6Hz,1H),7.09(dd,J=8.6 ,2.0Hz,1H),3.52(dq,J=8.8,6.3,5.8Hz,1H),2.78-2.64(m,4H),2.41(dd,J=16.1,8.7Hz,1H),2.15-2.07(m,1H).

[0080] Step c: Etylation reaction (preparation of compound VII):

[0081] DMF (3.40 kg), compound VI (0.72 kg), and K₂CO₃ (0.85 kg) were added sequentially to a reaction flask. The temperature was raised to 50-60 °C, and bromoethane (0.27 kg) was added dropwise. After the addition was complete, the mixture was kept at 50-60 °C and stirred for 1 h. After the reaction was completed, the temperature was lowered to 20-30 °C, and methyl tert-butyl ether (5.33 kg) and water (7.2 kg) were added to the system. The mixture was stirred until homogeneous, and the phases were separated. The upper organic phase was collected, washed once with water, and once with saturated brine. The supernatant was concentrated until no fraction was obtained, yielding 0.75 kg of compound VII with a purity of 97.63% and a yield of 95%. (m / z+1: 322, 324)

[0082] S1: Coupling-oxidative hydroxylation reaction (preparative compound VIII):

[0083] Tetrahydrofuran (3.36 kg), methanol (2.39 kg), compound VIII (0.75 kg), potassium acetate (0.68 kg), tetrahydroxydiboron (0.31 kg), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (1.7 g) were added sequentially to a reaction vessel. The mixture was heated to 40-45 °C and reacted for 2 h. After the reaction was completed, the temperature was lowered to 0-10 °C, and 30% hydrogen peroxide (0.53 kg) was added dropwise to the system. After the addition was complete, the mixture was kept at 0-10 °C and reacted for 2 h. After the reaction was completed, sodium thiosulfate solution was added dropwise to quench the reaction. The mixture was extracted with methyl tert-butyl ether, washed once with organic phase brine, and concentrated under reduced pressure until no fraction was obtained, yielding 0.54 kg of compound VIII with a purity of 98.65% and a yield of 90% (m / z+1:260).

[0084] 1H NMR(400MHz,Chloroform-d)δ7.15(d,J=8.6Hz,1H),6.85(d,J=2.4Hz,1H),6.67(dd,J=8.6,2.5Hz,1H),4.21(qd,J=7.1, 2.2Hz,2H),3.61-3.47(m,1H),2.84-2.68(m,4H),2.55-2.44(m,1H),2.09(qd,J=6.9,3.3Hz,1H),1.30(t,J=7.1Hz,3H).

[0085] S2: Mitsunobo reaction (preparation of compound IX):

[0086] Toluene (3.3 kg), compound VIII (0.54 kg), (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (0.61 kg), and triphenylphosphine (1.64 kg) were added sequentially to a reaction flask. After the addition was complete, the temperature was raised to 30-40 °C. A toluene solution of DBAD (diethyl azodicarbonate) (0.96 kg DBAD dissolved in 2.36 kg toluene) was added dropwise to the system. After the addition was complete, the reaction was maintained at 30-40 °C for 1 h. After the reaction was completed, 5.4 kg of water was added to quench the reaction. The phases were separated, and the organic phase was washed three times with methanol / water (4V:2V). The organic phase was concentrated under reduced pressure until no fraction was distilled off. 2.13 kg of ethanol was added, and the temperature was raised to 60 °C to dissolve the compound. Crystallization was precipitated by slow cooling, filtered, and dried to obtain 0.71 kg of compound IX with a purity of 98.9% and a yield of 70% (m / z+1:486).

[0087] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),7.73(s,1H),7.69(d,J=8.3Hz,1H),7.59(d,J=8.2Hz,1H ),7.23(d,J=8.8Hz,1H),6.96(d,J=2.3Hz,1H),6.74(dd,J=8.8,2.4Hz,1H),5.11(s,2H),4.13( q,J=7.1Hz,2H),3.51(p,J=7.7,6.4Hz,1H),3.26(p,J=8.3,7.5Hz,1H),2.83-2.60(m,4H),2.5 2-2.41(m,1H),2.15-1.93(m,3H),1.90-1.75(m,2H),1.73-1.53(m,4H),1.20(t,J=7.1Hz,3H).

[0088] S3: Hydrolysis reaction (preparation of compound X):

[0089] Ethanol (2.21 kg) and compound IX (0.71 kg) were added to a reaction flask. Lithium hydroxide aqueous solution (0.12 kg dissolved in 2.13 kg water) was added dropwise to the system at 20-30 °C. After the addition was complete, the reaction was carried out at 20-30 °C for 2 h. After the reaction was complete, methyl tert-butyl ether (2.62 kg) was added and stirred. The phases were separated, and the lower aqueous phase was collected. The pH of the aqueous phase was adjusted to 2-3 with 1N HCl. Ethyl acetate (0.32 kg) was added for extraction. The organic phase was concentrated under reduced pressure to 1 L. Heptane (1.94 kg) was added dropwise, and the mixture was cooled to 0-5 °C and stirred for 1 h. The mixture was filtered, and the filter cake was dried to obtain 0.60 kg of compound X with a purity of 99.96% and a yield of 90% (m / z+1:458).

[0090] S4: Salt formation (preparation of compound XI):

[0091] Isopropanol (7.56 kg) and compound X (600 g) were added to a reaction flask. The temperature was raised to 55-60 °C, and an appropriate amount of seed crystals were added. An aqueous solution of L-arginine (228 g of L-arginine dissolved in 600 g of water) was added dropwise to the system. After the addition was complete, the mixture was stirred at 55-60 °C for 1 h, then cooled to 25 °C and stirred for 10 h. The mixture was filtered, and the filter cake was washed with isopropanol and ethyl acetate to obtain a wet product. The wet product was dried to obtain 700 g of compound XI with a purity of 99.92%, a chiral purity of 99.96%, and a yield of 85%. (m / z-2: 173+456)

[0092] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),7.72-7.65(m,2H),7.59(d,J=8.1Hz,1H),7.21(d,J =8.7Hz,1H),6.90(d,J=2.4Hz,1H),6.67(dd,J=8.7,2.4Hz,1H),5.09(s,2H),3.50-3.30(m ,2H),3.25(q,J=8.4Hz,1H),3.10(s,2H),2.65(dt,J=29.4,8.2Hz,3H),2.45(d,J=6.3Hz,1 H),2.16(dd,J=15.0,8.3Hz,1H),2.08-1.93(m,3H),1.88-1.76(m,3H),1.75-1.44(m,7H).

[0093] Example 2

[0094] S1: Coupling-oxidative hydroxylation reaction (preparative compound VIII):

[0095] Compound VII (321 mg) prepared in Example 1 and tetrahydrofuran (5 mL) were added to the reaction vessel. The mixture was cooled to -78°C, and n-butyllithium (77 mg) and trimethyl borate (125 mg) were added dropwise. The reaction was maintained at this temperature for 1 h. The reaction solution was then quenched in a saturated ammonium chloride solution. The mixture was separated from the liquid. The organic phase was cooled to 0–5°C, and 30% hydrogen peroxide (227 mg) was added dropwise. The reaction was maintained at this temperature for 1 h, and sodium thiosulfate aqueous solution was added to quench the reaction. The mixture was then separated from the liquid and concentrated under reduced pressure to obtain 228 mg of compound VIII with a purity of 98.33% and a yield of 88%.

[0096] Example 3

[0097] S2: Mitsunobo reaction (preparation of compound IX):

[0098] Toluene (3.3 g), compound VIII prepared in Example 1 (0.54 g), (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (0.61 g), and triphenylphosphine (1.64 g) were added sequentially to a reaction flask. After the addition was complete, the temperature was raised to 30-40 °C, and a toluene solution of dipiperidine azodicarbonate (1.05 g of dipiperidine azodicarbonate dissolved in 2.36 g of toluene) was added dropwise to the system. After the addition was complete, the reaction was maintained at 30-40 °C for 1 h. After the reaction was completed, 5.4 g of water was added to quench the reaction, and the phases were separated. The organic phase was washed three times with methanol / water (4V:2V). The organic phase was concentrated under reduced pressure until no fraction was distilled off, and 2.13 g of ethanol was added. The mixture was heated to 60 °C to dissolve the compound, and crystallization was precipitated by slow cooling. The mixture was filtered, dried, and 0.67 g of compound IX was obtained with a purity of 98.9% and a yield of 66%.

[0099] Example 4

[0100] Step a: Acid-amine condensation resolution (preparative formula V compound):

[0101] DCM (39.7 g), compound IV prepared in Example 1 (5 g), (S)-4-methyl-2-oxazolidinone (1.80 g), TEA (6.02 g), and DMAP (0.21 g) were added sequentially to a reaction vessel. The mixture was purged with nitrogen three times. Pteropenoyl chloride (4.30 g) was added dropwise at 25-35 °C. After the addition was complete, the mixture was stirred at 25-35 °C for 1 h. The reaction was then completed. The reaction solution was washed twice with 3N hydrochloric acid, once with 10% sodium bicarbonate aqueous solution, and once with 15% sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure until no fraction was obtained. The mixture was crystallized twice with ethyl acetate (18.04 g) / n-heptane (6.84 g), filtered, and the filter cake was dried to obtain 2.56 g of white solid, namely compound V, with a purity of 99.89%, a chiral purity of 100%, and a yield of 40%.

[0102] Example 5

[0103] Step a: Acid-amine condensation resolution (preparative formula V compound):

[0104] DCM (39.7 g), compound IV prepared in Example 1 (5 g), (S)-4-isopropyl-2-oxazolidinone (2.31 g), TEA (6.02 g), and DMAP (0.21 g) were added sequentially to a reaction vessel. The mixture was purged with nitrogen three times. Pteropenoyl chloride (4.30 g) was added dropwise at 25-35 °C. After the addition was complete, the mixture was stirred at 25-35 °C for 1 h. The reaction was then completed. The reaction solution was washed twice with 3N hydrochloric acid, once with 10% sodium bicarbonate aqueous solution, and once with 15% sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure until no fraction was obtained. The mixture was crystallized twice with ethyl acetate (18.04 g) / n-heptane (6.84 g), filtered, and the filter cake was dried to obtain 2.68 g of white solid, namely compound V, with a purity of 99.79%, a chiral purity of 100%, and a yield of 39%.

[0105] Example 6

[0106] Step a: Acid-amine condensation resolution (preparative formula V compound):

[0107] DCM (39.7 g), compound IV prepared in Example 1 (5 g), (S)-4-phenyl-2-oxazolidinone (2.91 g), potassium carbonate (8.22 g), and DMAP (0.21 g) were added sequentially to a reaction vessel. The mixture was purged with nitrogen three times. Pteropenoyl chloride (4.30 g) was added dropwise at 25-35 °C. After the addition was complete, the mixture was stirred at 25-35 °C for 1 h. The reaction was then completed. The reaction solution was washed twice with 3N hydrochloric acid, once with 10% sodium bicarbonate aqueous solution, and once with 15% sodium chloride aqueous solution. The organic phase was concentrated under reduced pressure until no fraction was obtained. The mixture was crystallized twice with ethyl acetate (18.04 g) / n-heptane (6.84 g), filtered, and the filter cake was dried to obtain 2.61 g of white solid, namely compound V, with a purity of 99.68%, a chiral purity of 100%, and a yield of 35%.

[0108] Example 7

[0109] Step b: Dechirped prosthetic group (preparation of compound VI):

[0110] Tetrahydrofuran (21.7 mL) was added to the reaction vessel, followed by compound V (1.55 g) prepared in Example 1, and 30% hydrogen peroxide (0.80 g, 2.0 eq.). The mixture was cooled to 0 °C, and an aqueous solution of lithium hydroxide (0.44 g lithium hydroxide dissolved in 3.72 g water) was added dropwise to the system, controlling the dropping temperature to -5 to 0 °C. After the addition was complete, the mixture was kept at 0-5 °C for 1 h. After the reaction was completed, an aqueous solution of sodium bisulfite (0.18 g, 4 g water) was added dropwise to quench the reaction, followed by methyl tert-butyl ether (11.10 g). The pH was adjusted to 2-3 with 3N hydrochloric acid, and the mixture was stirred until homogeneous. The phases were separated, and the upper organic phase was collected and concentrated to dryness to obtain 0.72 g of compound VI with a purity of 97.62% and a yield of 69%.

[0111] Comparative Example 1

[0112] S2: Mitsunobo reaction (preparation of compound IX):

[0113] DMF (4 mL), compound VIII prepared in Example 1 (0.54 g), (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (0.6 g), and triphenylphosphine (1.7 g) were added sequentially to the reaction flask. After the addition was complete, the temperature was raised to 30-40 °C, and a toluene solution of dipiperidine azodicarbonate (1.0 g of dipiperidine azodicarbonate dissolved in 2.4 g of toluene) was added dropwise to the system. After the addition was complete, the reaction was maintained at 30-40 °C for 1 h. After the reaction was completed, 5.4 g of water was added to quench the reaction, and the phases were separated. The organic phase was washed three times with methanol / water (4V:2V). The organic phase was concentrated under reduced pressure until no fraction was distilled off, and 2.1 g of ethanol was added. The mixture was heated to 60 °C to dissolve the compound, and crystallization was precipitated by slow cooling. The mixture was filtered, dried, and 0.26 g of compound IX was obtained with a purity of 98.9% and a yield of 26%.

[0114] Comparative Example 2

[0115] Step b: Dechirped prosthetic group (preparation of compound VI):

[0116] Tetrahydrofuran (9.63 g) was added to the reactor, followed by compound V (1.55 g) prepared in Example 1, and 30% hydrogen peroxide (0.80 g, 2 eq.). The mixture was cooled to 0°C, and an aqueous solution of lithium hydroxide (0.44 g lithium hydroxide dissolved in 3.72 g water) was added dropwise. During the dropwise addition, the system temperature rose sharply to 15°C. After the addition was complete, the temperature was lowered to 5°C and the reaction was carried out for 1 hour. The purity was only 53.2% as determined by the central control, and 32% impurities were present.

[0117] Comparative Example 3

[0118] Step b: Dechirped prosthetic group (preparation of compound VI):

[0119] Tetrahydrofuran (14 mL) was added to the reactor, followed by compound V (2 g, 1.0 eq.) prepared in Example 1, and 30% hydrogen peroxide (0.52 g, 1.0 eq.). The mixture was cooled to 0°C, and an aqueous solution of lithium hydroxide (0.38 g of lithium hydroxide dissolved in 3.2 g of water) was added dropwise to the system, maintaining the temperature between 0 and 5°C during the addition. After the addition was complete, the mixture was kept at 0-5°C for 1 hour. Central control monitoring showed the formation of ring-opening impurities.

[0120] Comparative Example 4

[0121] Step b: Dechirped prosthetic group (preparation of compound VI):

[0122] Tetrahydrofuran (1.4 mL) was added to the reactor, followed by compound V (0.2 g, 1.0 eq.) prepared in Example 1, and then 30% hydrogen peroxide (1.6 g, 3.0 eq.). The mixture was cooled to 0°C, and an aqueous solution of lithium hydroxide (0.38 g of lithium hydroxide dissolved in 3.2 g of water) was added dropwise to the system, maintaining the temperature between 0 and 5°C during the addition. After the addition was complete, the mixture was kept at 0-5°C for 1 hour. Central control monitoring showed a significant increase in the formation of peroxide impurities.

[0123] Comparative Example 5

[0124] Step b: Dechirped prosthetic group (preparation of compound VI):

[0125] Tetrahydrofuran (1.4 mL) was added to the reactor, followed by compound V (0.2 g, 1.0 eq.) prepared in Example 1, and 30% hydrogen peroxide (2.1 g, 4.0 eq.). The mixture was cooled to 0°C, and an aqueous solution of lithium hydroxide (0.38 g of lithium hydroxide dissolved in 3.2 g of water) was added dropwise to the system, maintaining the temperature between 0 and 5°C during the addition. After the addition was complete, the mixture was kept at 0-5°C for 1 hour. Central monitoring results showed that the content of peroxide impurities increased compared to Example 4.

[0126] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing ictromod and its salt, characterized in that, The reaction pathway is shown below: It includes the following specific steps: S1: Compound VII undergoes a boron esterification reaction followed by an oxidation reaction in the presence of an oxidizing agent to obtain compound VIII; S2: Compound VIII is mixed with phosphine reagent, azo reagent, and (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol, and subjected to the Mitsunobo reaction in a nonpolar solvent to obtain compound IX; S3: Hydrolyze compound IX with alkali to obtain compound X; S4: Compound X is salted to obtain compound XI.

2. The preparation method according to claim 1, characterized in that, The boron esterification reaction described in S1 includes either Scheme 1 or Scheme 2, specifically: Scheme 1 involves a boron esterification reaction of a compound of formula VII, a boron-containing compound, a Lewis base, and a metal catalyst in a solvent, wherein the metal catalyst is selected from at least one of palladium catalysts, nickel catalysts, and copper catalysts; Scheme 2 involves the boron esterification reaction of compound VII, boron-containing compound, and butyllithium in an organic solvent.

3. The preparation method according to claim 2, characterized in that, The boron-containing compound described in Scheme 1 or Scheme 2 is selected from at least one of tetrahydroxydiboron, trimethyl borate, triisopropyl borate, dipinacol diboron, pinacol borane, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and 1H-naphtho[1,8-de][1,3,2]diazacyclohexaneborane-2(3H)-pinacol borate; The Lewis base described in Scheme 1 is selected from at least one of potassium acetate, potassium phenoxy, and N,N,N′,N′-tetramethylethylenediamine; The metal catalyst described in Scheme 1 is selected from at least one of tetra(triphenylphosphine)palladium, tetra(triphenylphosphine)palladium, triacetylacetone palladium, palladium on carbon, bis(diphenylphosphine)ferrocene palladium dichloride, and dichloroditert-butyl-(4-dimethylaminophenyl)phosphine palladium (II); The butyllithium mentioned in Scheme 2 is n-butyllithium.

4. The preparation method according to claim 1, characterized in that, In S1, the oxidant is hydrogen peroxide; In S2, the nonpolar solvent is toluene; The phosphine reagent is selected from at least one of triphenylphosphine, tritert-butylphosphine, and tripyridylphosphine; The azo reagent is selected from at least one of di-tert-butyl azodicarbonate, diisopropyl azodicarbonate, diethyl azodicarbonate, dibenzyl azodicarbonate, dicyclohexyl azodicarbonate, and dipiperidine azodicarbonate. In S3, the alkali is selected from at least one of sodium hydroxide, lithium hydroxide, and potassium hydroxide.

5. The preparation method according to claim 1, characterized in that, The compound of formula XI is itremod arginine salt, with the structure shown below:

6. The preparation method according to claim 1, characterized in that, Compound VII is prepared by the following method: Step a: Compound IV is reacted with a carboxylic acid activator and a chiral cofactor in the presence of a base to obtain compound V; wherein the chiral cofactor is selected from at least one of chiral amine compounds and chiral alcohol compounds; In the compound of formula V, R is selected from the chiral amino group corresponding to the chiral amine compound or the chiral hydroxyl group corresponding to the chiral alcohol compound; Step b: Compound V is dechiralized at a reaction temperature of -10 to 5°C in the presence of hydrogen peroxide and a base to obtain compound VI. Step c: The compound of formula VI is reacted with an ethylating agent in the presence of a base and a solvent to obtain the compound of formula VII.

7. The preparation method according to claim 6, characterized in that, In step a, the base is selected from at least one of triethylamine, DIPEA, triethylenediamine, DBU, potassium carbonate, and sodium carbonate; the carboxylic acid activator is selected from at least one of thionyl chloride, phosphorus oxychloride, and tervapotranilyl chloride. In step b, the reaction temperature is -10 to 0°C, the mass ratio of hydrogen peroxide to compound V is 1.5-2.5:1, and the alkali is selected from at least one of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethoxide, and sodium methoxide. In step c, the base is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, and sodium ethoxide; the solvent is selected from at least one of N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, and acetone; and the ethylating agent is selected from at least one of haloethane and ethyl sulfonate.

8. The preparation method according to claim 6, characterized in that, In step a, the chiral prosthetic group is a substituted chiral oxazoline-2-one compound, and R in the compound of formula V is a chiral amino group corresponding to the substituted chiral oxazoline-2-one compound.

9. The preparation method according to claim 8, characterized in that, In step a, the chiral cofactor is (S)-4-methyl-2-oxazolidinone, (S)-4-isopropyl-2-oxazolidinone, or (S)-4-phenyl-2-oxazolidinone, and R in the compound of formula V corresponds to...

10. The preparation method according to claim 7, characterized in that, In step a, the base is triethylamine; the carboxylic acid activator is pentanoyl chloride; In step b, the reaction temperature is -5 to 0℃, the mass ratio of hydrogen peroxide to compound V is 2:1, and the alkali is lithium hydroxide; In step c, the base is potassium carbonate; the solvent is N,N-dimethylformamide; and the ethylating agent is bromoethane.

11. The preparation method according to claim 6, characterized in that, The compound of formula IV is prepared by the following method: Step i: The compound of formula I reacts with ethyl haloacetate in the presence of a base to give the compound of formula II; Step ii: The compound of formula II reacts with 4-bromophenylhydrazine hydrochloride in the presence of acid to give the compound of formula III; Step iii: Compound III is hydrolyzed with alkali and then decarboxylated with acid to obtain compound IV.

12. The preparation method according to claim 11, characterized in that, In step i, the alkali is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, potassium bicarbonate, and potassium tert-butoxide; In step ii, the acid is selected from at least one of glacial acetic acid, trifluoroacetic acid, and citric acid; In step iii, the alkali is selected from at least one of sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate, and potassium carbonate; the acid is selected from at least one of glacial acetic acid, trifluoroacetic acid, citric acid, concentrated sulfuric acid, and hydrobromic acid.

13. The preparation method according to claim 12, characterized in that, In step i, the base is potassium carbonate and the ethyl haloacetate is ethyl bromide; In step ii, the acid is glacial acetic acid; In step iii, the base is sodium hydroxide, and the acid is selected from at least one of acetic acid and citric acid.

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