Preparation method of itramod

Abstract

The invention provides a preparation method of itramod, and relates to the technical field of pharmaceutical chemicals. The method comprises a coupling-oxidative hydroxylation reaction, a mitsunobo reaction, a hydrolysis reaction and a salt forming process. According to the preparation method of the itramod, provided by the invention, the itramod arginine salt is prepared, the process route is novel, the total molar yield is high, and the preparation method has the characteristics of more controllable quality, high chiral purity, high atom economy and stable process.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of etrasimod. Background Art

[0002] Etrasimod is an orally administered once-daily 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. Through an oral, once-daily treatment regimen, it can take effect quickly and achieve steroid-free remission and mucosal healing, providing a new treatment option for adult patients with moderate to severe active ulcerative colitis. The structural formula of etrasimod is (R)-2-(7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, as shown below:

[0003]

[0004] Currently, the published preparation processes are as follows:

[0005] As shown in Chinese Patent CN103221391A:

[0006]

[0007] This route uses 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (Formula 1) and ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3(4H)-ylidene)acetate (Formula 2) as materials. First, a docking reaction is carried out to prepare etrasimod ethyl ester, and then etrasimod is obtained by enzymatic hydrolysis resolution. However, its yield is too low.

[0008] As shown in Chinese Patent CN108558740A:

[0009]

[0010] However, the above route has the following drawbacks: (1) The stability of the intermediates obtained in the first and second steps is poor; (2) The total yield is low, and the yields of the first three steps are all lower than 50%; (3) The atom economy is poor. The chiral construction is placed in the hydrolysis step (the sixth step), and the S configuration is removed by enzymatic catalysis resolution, resulting in a large amount of intermediate waste.

[0011] In summary, based on the insurmountable disadvantages of the existing technical solutions, such as poor stability of some intermediates, low total yield, and poor atom economy, it is of great significance for researchers in this field to provide a new preparation method of etrasimod. Summary of the Invention

[0012] In view of the above problems, the present invention provides a preparation method of itraconazole. By optimizing the preparation method, the obtained product has the characteristics of high yield, high purity and high enantiomeric purity.

[0013] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0014] On the one hand, the present invention provides a preparation method of itraconazole, and its reaction route is as follows:

[0015]

[0016] It includes the following specific steps:

[0017] S1: The compound of formula VII undergoes a borylation reaction and then an oxidation reaction in the presence of an oxidant to obtain the compound of formula VIII;

[0018] S2: The compound of formula VIII is mixed with a phosphine reagent, an azo reagent, and (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol, and undergoes a Mitsunobo reaction in a non-polar solvent to obtain the compound of formula IX;

[0019] S3: The compound of formula IX is hydrolyzed with a base to obtain the compound of formula X;

[0020] S4: The compound of formula X is salted to obtain the compound of formula XI.

[0021] Preferably, the borylation reaction described in S1 includes two options, namely Option 1 or Option 2, specifically:

[0022] Option 1 is that the compound of formula VII, a boron-containing compound, a Lewis base, and a metal catalyst undergo a borylation reaction in a solvent, and the metal catalyst is selected from at least one of palladium-based catalysts, nickel-based catalysts, and copper-based catalysts;

[0023] Option 2 is that the compound of formula VII, a boron-containing compound, and butyllithium undergo a borylation reaction in an organic solvent.

[0024] Preferably, the boron-containing compound described in Option 1 or Option 2 is selected from at least one of tetrahydroxy diboron, trimethyl borate, triisopropyl borate, bis(pinacolato)diboron, pinacol borane, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, and 1H-naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-ylboronic acid pinacol ester;

[0025] More preferably, the boron-containing compound described in Option 1 or Option 2 is tetrahydroxy diboron.

[0026] Preferably, the Lewis base described in Option 1 is selected from at least one of potassium acetate, potassium phenoxide, and N,N,N′,N′-tetramethylethylenediamine;

[0027] The metal catalyst described in Scheme 1 is at least one selected from tetrakis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, triacetylacetonate palladium, palladium carbon, bis(diphenylphosphino)ferrocenepalladium dichloride and di-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) dichloride;

[0028] The butyl lithium described in Scheme 2 is n-butyl lithium.

[0029] Preferably, in S1, the oxidant is hydrogen peroxide;

[0030] Preferably, in S2, the non-polar solvent is toluene;

[0031] Preferably, in S2, the phosphine reagent is selected from at least one of triphenylphosphine, tri-tert-butylphosphine and tripyridylphosphine; further preferably, the phosphine reagent is triphenylphosphine.

[0032] Preferably, in S2, the azo reagent is selected from at least one of di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dibenzyl azodicarboxylate, dicyclohexyl azodicarboxylate and dipyridinium azodicarboxylate; further preferably, in S2, the azo reagent is selected from di-tert-butyl azodicarboxylate.

[0033] Preferably, in S3, the base is selected from at least one of sodium hydroxide, lithium hydroxide and potassium hydroxide; further preferably, in S3, the base is selected from sodium hydroxide.

[0034] Preferably, the compound of formula XI is istramod arginine salt, and the structure is shown below:

[0035]

[0036] Preferably, the compound of formula VII is prepared by the following method:

[0037]

[0038] Step a: reacting a compound of formula IV with a carboxylic acid activator and a chiral auxiliary group in the presence of a base to obtain a compound of formula V; the chiral auxiliary group is selected from at least one of a chiral amine compound and a chiral alcohol compound;

[0039] R of the compound of formula V is selected from a chiral amino group corresponding to a chiral amine compound or a chiral hydroxyl group corresponding to a chiral alcohol compound;

[0040] Step b: removing the chiral auxiliary group from the compound of formula V in the presence of hydrogen peroxide and a base at a reaction temperature of -10-5°C to obtain a compound of formula VI;

[0041] Step c: The compound of formula VI reacts with an ethylating agent in the presence of a base and a solvent to obtain a compound of formula VII.

[0042] Preferably,

[0043] 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 pivaloyl chloride;

[0044] More preferably, in step a, the base is selected from triethylamine; the carboxylic acid activator is selected from pivaloyl chloride;

[0045] Preferably, in step b, the reaction temperature is -10 to 0 °C, and more preferably, the reaction temperature is -5 to 0 °C;

[0046] Preferably, in step b, the mass ratio of hydrogen peroxide to the compound of formula V is 1.5 - 2.5:1; more preferably, the mass ratio of hydrogen peroxide to the compound of formula V is 2:1.

[0047] Preferably, in step b, the base is selected from at least one of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium ethoxide and sodium methoxide; more preferably, in step b, the base is selected from lithium hydroxide.

[0048] Preferably, in step c, the base is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate and sodium ethoxide; more preferably, the base is potassium carbonate.

[0049] 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.

[0050] Preferably, in step c, the ethylating agent is selected from at least one of haloethane and ethyl sulfonate. More preferably, in step c, the ethylating agent is selected from haloethane. Even more preferably, in step c, the ethylating agent is bromoethane.

[0051] Preferably, in step a, the chiral auxiliary is a substituted chiral oxazolin-2-one compound, and R of the compound of formula V is a chiral amino group corresponding to the substituted chiral oxazolin-2-one compound.

[0052] More preferably, in step a, the chiral auxiliary is (S)-4-methyl-2-oxazolidinone, (S)-4-isopropyl-2-oxazolidinone or (S)-4-phenyl-2-oxazolidinone, and R of the compound of formula V correspondingly is

[0053]

[0054] Preferably, the compound of formula IV is prepared by the following method:

[0055]

[0056] Step i: The compound of formula I reacts with ethyl haloacetate in the presence of a base to obtain the compound of formula II;

[0057] Step ii: The compound of formula II reacts with 4-bromophenylhydrazine hydrochloride in the presence of an acid to obtain the compound of formula III;

[0058] Step iii: The compound of formula III is hydrolyzed by adding a base and then decarboxylated by adding an acid to obtain the compound of formula IV.

[0059] Preferably, in step i, the base is selected from at least one of potassium carbonate, sodium carbonate, potassium phosphate, sodium phosphate, potassium bicarbonate, and potassium tert-butoxide; more preferably, the base is selected from potassium carbonate.

[0060] 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.

[0061] Preferably, in step iii, the base is selected from at least one of sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate, and potassium carbonate; more preferably, in step iii, the base is selected from potassium carbonate.

[0062] 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.

[0063] Compared with the prior art, the present invention has the following beneficial effects:

[0064] The present invention provides a new preparation method of itraconazole, for preparing itraconazole arginine salt, with a novel process route, high total molar yield, characteristics of more controllable quality, high chiral purity, high atom economy, and stable process. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 It is the 1H NMR spectrum of compound II.

[0066] Figure 2 It is the 1H NMR spectrum of compound V.

[0067] Figure 3 It is the 1H NMR spectrum of compound VI.

[0068] Figure 4 It is the 1H NMR spectrum of compound VIII.

[0069] Figure 5 It is the 1H NMR spectrum of compound IX.

[0070] Figure 6 1H NMR spectrum of compound XI. Detailed implementation manners

[0071] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the present invention will be further illustrated below in conjunction with specific embodiments. However, the following embodiments are only the preferred embodiments of the present invention, not all of them. Based on the embodiments in the implementation manners, other embodiments obtained by those skilled in the art without creative efforts all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is made on their sources. The technical and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0072] Example 1

[0073]

[0074] Step i: Condensation reaction (preparing compound of formula II):

[0075] Acetone (7.11 kg), 2-methoxycarbonylcyclopentanone (0.90 kg), and K2CO3 (1.75 kg) were successively added to a reaction kettle. Ethyl bromoacetate (1.10 kg) was added dropwise at 25 - 55 °C. After the addition was complete, the mixture was reacted at 50 - 60 °C for 1 h. Sampling was performed to detect that the raw material 2-methoxycarbonylcyclopentanone was less than 1%. It was concentrated under reduced pressure until no distillate was collected, and 1.37 kg of a light yellow oily substance, i.e., the compound of formula II, was obtained with a yield of 95%. (m / z +1: 229).

[0076] 1 H NMR (400 MHz, Chloroform-d) δ4.06 (q, J = 7.1 Hz, 2H), 3.65 (s, 3H), 2.91 (d, J = 17.2 Hz, 1H), 2.75 (d, J = 17.3 Hz, 1H), 2.57 - 2.50 (m, 1H), 2.46 - 2.33 (m, 2H), 2.10 - 1.93 (m, 3H), 1.19 (t, J = 7.2 Hz, 3H).

[0077] Step ii: Fischer indole cyclization (preparing compound of formula III):

[0078] Add acetic acid (6.83 kg), Compound of Formula II (1.30 kg), p-bromophenylhydrazine hydrochloride (1.27 kg), and citric acid monohydrate (0.24 kg) to the reaction kettle. Heat up to 75 - 85 °C and react for 6 h. After the reaction is completed, add MTBE (4.81 kg) and water (19.50 kg), stir for 15 min, let it stand for phase separation, collect the organic phase. Adjust the pH of the organic phase to 6 - 7 with 5% aqueous sodium bicarbonate solution, then wash it once with water (6.50 kg). Dry the organic phase with anhydrous sodium sulfate and concentrate it under reduced pressure at 45 - 55 °C until no distillate is obtained, to obtain 1.56 kg of Compound of Formula III, with a yield of 72%. (m / z + 1: 380, 382).

[0079] Step iii: Decarboxylation (preparation of Compound of Formula IV):

[0080] Dissolve the above Compound of Formula III in ethanol (6.15 kg), control the temperature below 45 °C and dropwise add an aqueous sodium hydroxide solution (0.91 kg of sodium hydroxide dissolved in 3.25 kg of water). Keep the temperature at 40 - 50 °C and react for 1 h. After the reaction is completed, cool down to 20 - 30 °C, add water (19.5 kg) and MTBE (4.81 kg) to remove impurities, then add MTBE (7.69 kg), adjust the pH of the aqueous phase to 1 - 2 with hydrochloric acid, separate the layers. Wash the organic phase twice with water (6.50 kg * 2), concentrate the organic phase at 50 - 60 °C until no distillate is obtained. Then add acetic acid (6.83 kg) to the concentrated dry product, heat up to 70 - 80 °C and react for 2 h. After the reaction is completed, cool down to 20 - 30 °C, add MTBE (7.69 kg), and wash it again with water (13.0 kg * 2). Purify the organic phase by column chromatography and concentrate it until no distillate is obtained to obtain 700 g of Compound of Formula IV, with a purity of 98.13% and a yield of 70%. (m / z + 1: 294, 296).

[0081] Step a: Acid-amide condensation and resolution (preparation of Compound of Formula V):

[0082]

[0083] Add DCM (39.7 kg), Compound of Formula IV (5 kg), (S)-4-phenyl-2-oxazolidinone (2.91 kg), TEA (6.02 kg), and DMAP (0.21 kg) into the reaction kettle in sequence. Replace the air with nitrogen for three times. Dropwise add pivaloyl chloride (4.30 kg) at 25 - 35 °C. After the addition is completed, keep the temperature at 25 - 35 °C and stir for 1 h. After the reaction is completed, wash the reaction solution with 3N hydrochloric acid twice, 10% sodium bicarbonate aqueous solution once, and 15% sodium chloride aqueous solution once. Concentrate the organic phase under reduced pressure until no distillate is obtained. Crystallize twice with ethyl acetate (18.04 kg) / n-heptane (6.84 kg), filter, and dry the filter cake to obtain 3 kg of white solid, which is the Compound of Formula V, with a purity of 99.88%, a chiral purity of 100%, and a yield of 40%. (m / z +1: 439, 441).

[0084] 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 5.0, 2.0 Hz, 3H), 7.32 - 7.28 (m, 2H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 5.53 (dd, J = 8.8, 4.2 Hz, 1H), 4.76 (t, J = 8.9 Hz, 1H), 4.31 (dd, J = 9.0, 4.2 Hz, 1H), 3.68 - 3.60 (m, 1H), 3.45 (dd, J = 18.3, 4.0 Hz, 1H), 3.13 (dd, J = 18.3, 11.1 Hz, 1H), 2.88 - 2.73 (m, 3H), 2.30 - 2.17 (m, 1H).

[0085] Step b: Removal of chiral auxiliary group (preparation of Compound of Formula VI):

[0086] Add tetrahydrofuran (21.7 L) into the reaction kettle, then add the Compound of Formula V (1.55 kg). Add 30% hydrogen peroxide (0.80 kg, 2 eq.). Cool down to -5 °C. Dropwise add an aqueous solution of lithium hydroxide (0.44 kg of lithium hydroxide dissolved in 3.72 kg of water) into the system, and control the temperature at -10 ~ -3 °C during the dropping. After the addition is completed, keep the temperature at -10 ~ -3 °C and react for 1 h.

[0087] After the reaction was completed, water (16 kg) was added dropwise to the system, and the temperature was controlled at 0 - 15 °C. Then, n-heptane (8 L) was used to extract impurities twice. 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. After stirring evenly, the phases were separated, and the upper organic phase was collected. The organic phase was washed once with a sodium bisulfite solution (0.18 kg, 4 kg of water). The organic phase was collected. n-Heptane (30 L) was added to the organic phase and stirred evenly. The mixture was added to a filtration cylinder and silica gel (4 kg) was brushed. The filtrate was collected. The silica gel was eluted with a mixed solution of methyl tert-butyl ether and n-heptane (1V:2V). It was concentrated under reduced pressure until no distillate was obtained, and 0.78 kg of the compound of formula VI was obtained, with a purity of 97.62%, a chiral purity of 99.97%, and a yield of 75%. (m / z + 1: 294, 296).

[0088] 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 10.87 (s, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.09 (dd, J = 8.6, 2.0 Hz, 1H), 3.52 (dq, J = 8.8, 6.3, 5.8 Hz, 1H), 2.78 - 2.64 (m, 4H), 2.41 (dd, J = 16.1, 8.7 Hz, 1H), 2.15 - 2.07 (m, 1H).

[0089] Step c: Ethylation reaction (preparation of the compound of formula VII):

[0090] DMF (3.40 kg), the compound of formula VI (0.72 kg), and K2CO3 (0.85 kg) were successively added to a reaction flask. The temperature was raised to 50 - 60 °C, and bromoethane (0.27 kg) was added dropwise. After addition, it was stirred at 50 - 60 °C for 1 h. After the reaction was completed, the temperature was lowered to 20 - 30 °C. Methyl tert-butyl ether (5.33 kg) and water (7.2 kg) were added to the system and stirred evenly. The phases were separated, and the upper organic phase was collected. The organic phase was washed once with water and once with saturated brine. The supernatant was concentrated until no distillate was obtained, and 0.75 kg of the compound of formula VII was obtained, with a purity of 97.63% and a yield of 95%. (m / z + 1: 322, 324).

[0091] S1: Coupling-oxidative hydroxylation reaction (preparation of the compound of formula VIII):

[0092] Add tetrahydrofuran (3.36 kg), methanol (2.39 kg), Compound VIII (0.75 kg), potassium acetate (0.68 kg), tetrahydroxy diboron (0.31 kg), dichloro di-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (1.7 g) into the reaction kettle in sequence. Heat up to 40 - 45 °C and react for 2 h. After the reaction is completed, cool down to make the internal temperature reach 0 - 10 °C. Dropwise add 30% hydrogen peroxide (0.53 kg) into the system. After dropping, keep the temperature at 0 - 10 °C and react for 2 h. After the reaction is completed, dropwise add sodium thiosulfate solution to quench the reaction. Extract with methyl tert-butyl ether. Wash the organic phase with brine once. Concentrate under reduced pressure until there is no distillate, and obtain 0.54 kg of Compound VIII with a purity of 98.65% and a yield of 90%. (m / z +1: 260).

[0093] 1 H NMR (400 MHz, Chloroform-d) δ 7.15 (d, J = 8.6 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 8.6, 2.5 Hz, 1H), 4.21 (qd, J = 7.1, 2.2 Hz, 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, 3.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H).

[0094] S2: Mitsunobu reaction (preparing Compound IX):

[0095] Add toluene (3.3 kg), Compound VIII (0.54 kg), (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (0.61 kg), triphenylphosphine (1.64 kg) into the reaction flask in sequence. After adding, heat up to 30 - 40 °C. Dropwise add the toluene solution of DBAD (diethyl azodicarboxylate) (0.96 kg DBAD dissolved in 2.36 kg toluene) into the system. After adding, keep the temperature at 30 - 40 °C and react for 1 h. After the reaction is completed, add 5.4 kg of water to quench the reaction. Separate the phases. Wash the organic phase with methanol / water (4V:2V) 3 times. Concentrate the organic phase under reduced pressure until there is no distillate. Add 2.13 kg of ethanol, heat up to 60 °C to dissolve, and then slowly cool down to crystallize. Filter and dry to obtain 0.71 kg of Compound IX with a purity of 98.9% and a yield of 70%. (m / z +1: 486).

[0096] 11H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.73 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.74 (dd, J = 8.8, 2.4 Hz, 1H), 5.11 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.51 (p, J = 7.7, 6.4 Hz, 1H), 3.26 (p, J = 8.3, 7.5 Hz, 1H), 2.83 - 2.60 (m, 4H), 2.52 - 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 = 7.1 Hz, 3H).

[0097] S3: Hydrolysis reaction (preparation of Compound Ⅹ):

[0098] Add ethanol (2.21 kg) and Compound Ⅸ (0.71 kg) into the reaction flask. Dropwise add an aqueous lithium hydroxide solution (0.12 kg dissolved in 2.13 kg of water) into the system at 20 - 30 °C. After dropping, react at 20 - 30 °C for 2 h. After the reaction is completed, add methyl tert-butyl ether (2.62 kg) and stir. Separate the phases, collect the lower aqueous phase. Adjust the pH of the aqueous phase to 2 - 3 with 1N HCl, add ethyl acetate (0.32 kg) for extraction. Concentrate the organic phase under reduced pressure to 1 L, dropwise add n-heptane (1.94 kg), cool down to 0 - 5 °C and stir for 1 h, filter, and dry the filter cake to obtain 0.60 kg of Compound Ⅹ with a purity of 99.96% and a yield of 90% (m / z + 1: 458).

[0099] S4: Salt formation (preparation of Compound Ⅺ):

[0100] Add isopropanol (7.56 kg) and Compound Ⅹ (600 g) into the reaction flask, heat up to 55 - 60 °C, add appropriate amount of seeds, and dropwise add an aqueous L-arginine solution (228 g of L-arginine dissolved in 600 g of water) into the system. After dropping, stir at 55 - 60 °C for 1 h, then cool down to 25 °C and stir for 10 h, filter, wash the filter cake with isopropanol and ethyl acetate to obtain the wet product, and dry the wet product to obtain 700 g of Compound Ⅺ with a purity of 99.92% and a chiral purity of 99.96% and a yield of 85%. (m / z - 2: 173 + 456).

[0101] 11H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 7.72 - 7.65 (m, 2H), 7.59 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 8.7, 2.4 Hz, 1H), 5.09 (s, 2H), 3.50 - 3.30 (m, 2H), 3.25 (q, J = 8.4 Hz, 1H), 3.10 (s, 2H), 2.65 (dt, J = 29.4, 8.2 Hz, 3H), 2.45 (d, J = 6.3 Hz, 1H), 2.16 (dd, J = 15.0, 8.3 Hz, 1H), 2.08 - 1.93 (m, 3H), 1.88 - 1.76 (m, 3H), 1.75 - 1.44 (m, 7H).

[0102] Example 2

[0103] S1: Coupling - oxidative hydroxylation reaction (preparation of compound of formula VIII):

[0104] Add the compound of formula VII prepared in Example 1 (321 mg) and tetrahydrofuran (5 mL) to the reaction kettle, cool down to -78 °C, dropwise add n-butyllithium (77 mg), then dropwise add trimethyl borate (125 mg), keep the temperature for reaction for 1 h, pour the reaction solution into saturated ammonium chloride solution for quenching, separate the layers, cool the organic layer to 0 - 5 °C, dropwise add 30% hydrogen peroxide (227 mg), keep the temperature for reaction for 1 h, add aqueous sodium thiosulfate solution for quenching, separate the layers, concentrate the organic layer under reduced pressure to obtain 228 mg of the compound of formula VIII, with a purity of 98.33% and a yield of 88%.

[0105] Example 3

[0106] S2: Mitsunobo reaction (preparation of compound of formula IX):

[0107] Add toluene (3.3 g), the compound of formula VIII prepared in Example 1 (0.54 g), (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (0.61 g), and triphenylphosphine (1.64 g) into the reaction flask in sequence. After adding, heat up to 30 - 40 °C, and dropwise add a toluene solution of di(piperidin-1-yl)azodicarboxylate (1.05 g of di(piperidin-1-yl)azodicarboxylate dissolved in 2.36 g of toluene) into the system. After adding, keep the temperature at 30 - 40 °C for reaction for 1 h. After the reaction is completed, add 5.4 g of water to quench the reaction, separate the phases, wash the organic phase with methanol / water (4V:2V) for 3 times, concentrate the organic phase under reduced pressure until there is no distillate, add 2.13 g of ethanol, heat up to 60 °C for dissolution, then slowly cool down for crystallization, filter, and dry to obtain 0.67 g of the compound of formula IX, with a purity of 98.9% and a yield of 66%.

[0108] Example 4

[0109] Step a: Acid amide condensation and resolution (preparation of Compound of Formula V):

[0110]

[0111] Add DCM (39.7 g), the Compound of Formula IV prepared in Example 1 (5 g), (S)-4-methyl-2-oxazolidinone (1.80 g), TEA (6.02 g), and DMAP (0.21 g) into the reaction kettle in sequence. Replace the air with nitrogen for 3 times. Dropwise add pivaloyl chloride (4.30 g) at 25 - 35°C. After addition, keep the temperature at 25 - 35°C and stir for 1 h. After the reaction is completed, wash the reaction solution twice with 3N hydrochloric acid, once with 10% aqueous sodium bicarbonate solution, and once with 15% aqueous sodium chloride solution. Concentrate the organic phase under reduced pressure until no distillate is obtained. Crystallize twice with ethyl acetate (18.04 g) / n-heptane (6.84 g), filter, and dry the filter cake to obtain 2.56 g of white solid, which is the Compound of Formula V, with a purity of 99.89%, a chiral purity of 100%, and a yield of 40%.

[0112] Example 5

[0113] Step a: Acid amide condensation and resolution (preparation of Compound of Formula V):

[0114]

[0115] Add DCM (39.7 g), the Compound of Formula IV prepared in Example 1 (5 g), (S)-4-isopropyl-2-oxazolidinone (2.31 g), TEA (6.02 g), and DMAP (0.21 g) into the reaction kettle in sequence. Replace the air with nitrogen for 3 times. Dropwise add pivaloyl chloride (4.30 g) at 25 - 35°C. After addition, keep the temperature at 25 - 35°C and stir for 1 h. After the reaction is completed, wash the reaction solution twice with 3N hydrochloric acid, once with 10% aqueous sodium bicarbonate solution, and once with 15% aqueous sodium chloride solution. Concentrate the organic phase under reduced pressure until no distillate is obtained. Crystallize twice with ethyl acetate (18.04 g) / n-heptane (6.84 g), filter, and dry the filter cake to obtain 2.68 g of white solid, which is the Compound of Formula V, with a purity of 99.79%, a chiral purity of 100%, and a yield of 39%.

[0116] Example 6

[0117] Step a: Acid amide condensation and resolution (preparation of Compound of Formula V):

[0118]

[0119] In a reaction kettle, DCM (39.7 g), the compound of formula 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 successively. After purging with nitrogen three times, pivaloyl chloride (4.30 g) was added dropwise at 25 - 35°C. After addition, the mixture was stirred at 25 - 35°C for 1 h. After the reaction was completed, the reaction solution was washed twice with 3N hydrochloric acid, once with 10% aqueous sodium bicarbonate solution, and once with 15% aqueous sodium chloride solution. The organic phase was concentrated under reduced pressure until no distillate was obtained. Crystallization was carried out twice using ethyl acetate (18.04 g) / n-heptane (6.84 g). After filtration, the filter cake was dried to obtain 2.61 g of a white solid, which is the compound of formula V, with a purity of 99.68%, a chiral purity of 100%, and a yield of 35%.

[0120] Example 7

[0121] Step b: Removal of chiral auxiliary (preparation of the compound of formula VI):

[0122] In a reaction kettle, tetrahydrofuran (21.7 mL) was added, and then the compound of formula V prepared in Example 1 (1.55 g) was added. 30% hydrogen peroxide (0.80 g, 2.0 eq.) was added, and the temperature was lowered to 0°C. An aqueous solution of lithium hydroxide (0.44 g of lithium hydroxide dissolved in 3.72 g of water) was added dropwise to the system, and the dropping temperature was controlled at -5 to 0°C. After addition, the mixture was stirred at 0 - 5°C for 1 h. After the reaction was completed, an aqueous solution of sodium bisulfite (0.18 g, 4 g of water) was added dropwise to quench the reaction, and then methyl tert-butyl ether (11.10 g) was added. The pH was adjusted to 2 - 3 with 3N hydrochloric acid, and the mixture was stirred evenly. After phase separation, the upper organic phase was collected. The organic phase was concentrated to dryness to obtain 0.72 g of the compound of formula VI, with a purity of 97.62% and a yield of 69%.

[0123] Comparative Example 1

[0124] S2: Mitsunobo reaction (preparation of the compound of formula IX):

[0125] In a reaction flask, DMF (4 mL), the compound of formula VIII prepared in Example 1 (0.54 g), (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol (0.6 g), and triphenylphosphine (1.7 g) were added successively. After addition, the temperature was raised to 30 - 40°C. A toluene solution of di(piperidin-1-yl)azodicarboxylate (1.0 g of di(piperidin-1-yl)azodicarboxylate dissolved in 2.4 g of toluene) was added dropwise to the system. After addition, the mixture was stirred at 30 - 40°C for 1 h. After the reaction was completed, 5.4 g of water was added to quench the reaction. After phase separation, the organic phase was washed 3 times with methanol / water (4V:2V). The organic phase was concentrated under reduced pressure until no distillate was obtained. 2.1 g of ethanol was added, and the temperature was raised to 60°C to dissolve. Then, the temperature was slowly lowered for crystallization. After filtration and drying, 0.26 g of the compound of formula IX was obtained, with a purity of 98.9% and a yield of 26%.

[0126] Comparative Example 2

[0127] Step b: Removable protecting group (preparing Compound of Formula VI):

[0128] Add tetrahydrofuran (9.63 g) into a reaction kettle, then add the Compound of Formula V prepared in Example 1 (1.55 g), add 30% hydrogen peroxide (0.80 g, 2 eq.), cool down to 0 °C, and dropwise add an aqueous solution of lithium hydroxide (0.44 g of lithium hydroxide dissolved in 3.72 g of water) into the system. The temperature of the system rises sharply during the dropping process, and the temperature rises to 15 °C. After the dropping is completed, cool down to 5 °C and react for 1 h. The purity detected by in-process control is only 53.2%, and 32% of impurities are generated.

[0129] Comparative Example 3

[0130] Step b: Removable protecting group (preparing Compound of Formula VI):

[0131] Add tetrahydrofuran (14 mL) into a reaction kettle, then add the Compound of Formula V prepared in Example 1 (2 g, 1.0 eq.), add 30% hydrogen peroxide (0.52 g, 1.0 eq.), cool down to 0 °C, and dropwise add an aqueous solution of lithium hydroxide (0.38 g of lithium hydroxide dissolved in 3.2 g of water) into the system. Control the temperature at 0 - 5 °C during the dropping process. After the dropping is completed, keep the temperature at 0 - 5 °C and react for 1 h. The in-process control test results show that ring-opening impurities are generated.

[0132] Comparative Example 4

[0133] Step b: Removable protecting group (preparing Compound of Formula VI):

[0134] Add tetrahydrofuran (1.4 mL) into a reaction kettle, then add the Compound of Formula V prepared in Example 1 (0.2 g, 1.0 eq.), add 30% hydrogen peroxide (1.6 g, 3.0 eq.), cool down to 0 °C, and dropwise add an aqueous solution of lithium hydroxide (0.38 g of lithium hydroxide dissolved in 3.2 g of water) into the system. Control the temperature at 0 - 5 °C during the dropping process. After the dropping is completed, keep the temperature at 0 - 5 °C and react for 1 h. The in-process control test results show that the amount of peroxide impurities increases significantly.

[0135] Comparative Example 5

[0136] Step b: Removable protecting group (preparing Compound of Formula VI):

[0137] Add tetrahydrofuran (1.4 mL) to the reaction kettle, then add the compound of formula V prepared in Example 1 (0.2 g, 1.0 eq.), add 30% hydrogen peroxide (2.1 g, 4.0 eq.), cool down to 0 °C, and dropwise add an aqueous solution of lithium hydroxide (0.38 g of lithium hydroxide dissolved in 3.2 g of water) to the system. Control the temperature at 0-5 °C during the dropping process. After the dropping is completed, keep the temperature at 0-5 °C and react for 1 h. The in-process detection results show that the content of peroxide impurities increases compared with Example 4.

[0138] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Any simple modification or equivalent replacement made by those of ordinary skill in the art to the technical solution of the present invention shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing istramod and its salt, characterized in that: The reaction route is as follows: The following specific steps are included: S1: The compound of formula VII is subjected to boron esterification reaction and then subjected to oxidation reaction in the presence of an oxidant to obtain a compound of formula VIII; S2: The compound of formula VIII is mixed with a phosphine reagent, an azo reagent, and (4-cyclopentyl-3-(trifluoromethyl)phenyl)methanol, and subjected to a Mitsunobo reaction in a non-polar solvent to obtain a compound of formula IX; S3: hydrolyzing the compound of formula IX with base to obtain the compound of formula X; S4: The compound of formula X is salified to obtain the compound of formula XI.

2. The preparation method according to claim 1, characterized in that: The boron esterification reaction described in S1 includes two schemes, Scheme 1 and Scheme 2, specifically: Scheme 1 is a boroesterification 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 a palladium catalyst, a nickel catalyst, and a copper catalyst; Scheme 2 is a boroesterification reaction of the compound of formula VII, a boron-containing compound and butyl lithium in an organic solvent.

3. The preparation method according to claim 2, characterized in that: The boron-containing compound in Scheme 1 or Scheme 2 is at least one selected from tetrahydroxydiboron, trimethyl borate, triisopropyl borate, bispinacoldiboron, pinacol borane, sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate and 1H-naphtho[1,8-de][1,3,2]diazaborane-2(3H)-boronic acid pinacol ester; The Lewis base in Scheme 1 is selected from at least one of potassium acetate, potassium phenoxide and N,N,N′,N′-tetramethylethylenediamine; The metal catalyst described in Scheme 1 is at least one selected from tetrakis(triphenylphosphine)palladium, tetrakis(triphenylphosphine)palladium, triacetylacetonate palladium, palladium carbon, bis(diphenylphosphino)ferrocenepalladium dichloride and di-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) dichloride; The butyl lithium described in Scheme 2 is n-butyl lithium.

4. The preparation method according to claim 1, characterized in that: In S1, the oxidant is hydrogen peroxide; In S2, the non-polar solvent is toluene; The phosphine reagent is selected from at least one of triphenylphosphine, tri-tert-butylphosphine and tripyridylphosphine; The azo reagent is selected from at least one of di-tert-butyl azodicarboxylate, diisopropyl azodicarboxylate, diethyl azodicarboxylate, dibenzyl azodicarboxylate, dicyclohexyl azodicarboxylate and dipiperidine azodicarboxylate; In S3, the base 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 istramod arginine salt, and its structure is shown below:

6. The preparation method according to claim 1, characterized in that: The compound of formula VII is prepared by the following method: Step a: reacting a compound of formula IV with a carboxylic acid activator and a chiral auxiliary group in the presence of a base to obtain a compound of formula V; the chiral auxiliary group is selected from at least one of a chiral amine compound and a chiral alcohol compound; R of the compound of formula V is selected from a chiral amino group corresponding to a chiral amine compound or a chiral hydroxyl group corresponding to a chiral alcohol compound; Step b: removing the chiral auxiliary group from the compound of formula V in the presence of hydrogen peroxide and a base at a reaction temperature of -10 to 5°C to obtain a compound of formula VI; Step c: The compound of formula VI reacts with an ethylating agent in the presence of a base and a solvent to obtain a 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 pivaloyl chloride; In step b, the reaction temperature is -10 to 0°C, the mass ratio of the hydrogen peroxide to the compound of formula V is 1.5-2.5:1, and the base 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 ethane halides and ethyl sulfonates.

8. The preparation method according to claim 6, characterized in that: In step a, the chiral auxiliary group is a substituted chiral oxazoline-2-one compound, and R of 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 auxiliary group is (S)-4-methyl-2-oxazolidinone, (S)-4-isopropyl-2-oxazolidinone or (S)-4-phenyl-2-oxazolidinone, and R of 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 activating agent is pivaloyl chloride; In step b, the reaction temperature is -5-0°C, the mass ratio of hydrogen peroxide to the compound of formula V is 2:1, and the base is lithium hydroxide; In step c, the base is potassium carbonate; the solvent is N,N-dimethylformamide; and the ethylating agent is ethyl bromide.

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

12. The preparation method according to claim 11, characterized in that: In step i, the base 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 base 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 halide is ethyl bromoacetate; 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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