Synthesis method of itramod and intermediate thereof

Abstract

The invention provides a synthesis method of itramod, which comprises the following steps: carrying out condensation reaction on a new compound 7 and a compound 8 under the action of alkali to obtain an intermediate compound 9; and finally salifying to obtain a final product compound 10 of istratimod. The istratimod synthesis method is short in synthesis route, simple to operate, high in yield, high in product purity and suitable for industrial production, and the reaction route is # imgabs0 #.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a synthesis method of etrasimod and its series of intermediate compounds. Background Art

[0002] Etrasimod is an oral, once-daily selective sphingosine-1-phosphate (S1P) receptor modulator developed by Pfizer Inc., USA. It can partially and reversibly block the ability of lymphocytes to flow out of lymphoid organs, thereby reducing the number of lymphocytes in peripheral blood, and is used for adult patients with moderate to severe active ulcerative colitis (UC). Etrasimod was approved by the US Food and Drug Administration (FDA) in October 2023 for the treatment of adult patients with moderate to severe active ulcerative colitis, and was approved in the European Union in February 2024 for the treatment of adult patients with moderate to severe active ulcerative colitis who are insufficiently responsive, have lost response, or are intolerant to conventional therapies or advanced treatment regimens.

[0003] The finished product of etrasimod is formulated and applied in the form of a complex salt with L-arginine. The chemical name of etrasimod arginine salt is: L-arginine salt of (S)-1-carboxy-4-guanidinobutyl-1-amine (R)-2-(7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, and its structural formula is as follows:

[0004]

[0005] The PCT patent WO2011094008A1 reported the synthesis route of etrasimod: Ethyl 2-oxocyclopentanecarboxylate was condensed with ethyl 2-bromoacetate under the action of potassium carbonate, then an elimination decarboxylation reaction was carried out under the action of concentrated hydrochloric acid, and then it was esterified with ethanol under the action of sulfuric acid to obtain ethyl 2-(2-oxocyclopentyl)acetate; Then it was cyclized with 2-iodo-4-methoxyaniline under the catalysis of palladium acetate under the action of PPTS and tetraethoxysilane, and then the methoxy group was removed by boron tribromide to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate, and then it was condensed with 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene under the action of cesium carbonate, and then hydrolyzed by lipase catalysis to obtain the free acid of etrasimod: (R)-2-(7-((4-cyclopentyl-3-(trifluoromethyl)benzyl)oxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid, and finally it was salted with L-arginine to obtain the target product etrasimod arginine salt. This method has more steps, the yield of indole ring synthesis is lower, chiral resolution needs to be carried out by enzyme-catalyzed hydrolysis, the atom economy is not high, the synthesis efficiency is low, and the total yield is low.

[0006]

[0007] WO2011094008A1 reported another synthetic method of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. Cyclopentanone was enaminated with morpholine and then reacted with ethyl glyoxylate to obtain the intermediate ethyl 2-(2-morpholinocyclopent-2-enylidene)acetate. Then it was cyclized with (4-(benzyloxy)phenyl)hydrazine hydrochloride under the action of an acid to form an indole ring to obtain ethyl 2-(7-(benzyloxy)-1,2-dihydrocyclopenta[b]indol-3(4H)-ylidene)acetate. Then, under the catalysis of palladium on carbon, the olefin double bond was reduced by formic acid and debenzylated in one pot to obtain ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate. Although this method reduces the steps, the yield of indole ring synthesis is relatively low, and the double bond reduction has no selectivity. To obtain chiral products for subsequent reactions, methods such as enzymatic catalytic hydrolysis resolution or preparative separation are still needed, and the atom economy is relatively low, and the total yield is still relatively low.

[0008]

[0009] Generally speaking, the total yields of these two synthetic methods of itramod are low and the costs are too high. There is still a need to find a method with a simple process route, low cost and suitable for industrial production. Summary of the Invention

[0010] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a synthetic method of itramod with a short synthetic route, simple operation, high yield, high product purity and suitable for industrial production.

[0011] To achieve the purpose of the invention, the following technical solutions are adopted:

[0012] One of the purposes of the present invention is to provide a series of intermediates 4, 5, 6 and 7a for the synthesis of itramod, and the structural formulas are as follows:

[0013]

[0014] Wherein R 2 is selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl.

[0015] A synthetic method of itramod provided by the present invention adopts the following technical solutions:

[0016] A synthetic method of itramod includes the following steps:

[0017] (1) Condensing compound 7 with compound 8 under the action of a base to obtain intermediate compound 9;

[0018]

[0019] (2) Hydrolyze compound 9 with a base hydrolysis reagent and form a salt with L-arginine to obtain the target product 10;

[0020]

[0021] wherein LG is chlorine, bromine, iodine, hydroxyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, and R 2 is selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl.

[0022] Preferably, in the condensation reaction of step (1), the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, pyridine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or 1,4-dioxane; the reaction temperature is -15 to 110 °C.

[0023] Preferably, in the hydrolysis reaction of step (2), the base hydrolysis reagent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide or a combination formed by lithium bromide and one of diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol, n-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, tetrahydrofuran, isopropyl acetate, ethyl acetate, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, any one or two combined solvents thereof or a mixed solvent system formed by them and water; the reaction temperature is -20 to 90 °C.

[0024] The present invention also relates to a method for synthesizing itraconazole intermediate compound 7, adopting the following technical solution:

[0025] A method for synthesizing itraconazole intermediate compound 7, comprising the following steps:

[0026] (1) Carry out an esterification reaction on compound 5 with an alkylating reagent to obtain compound 6;

[0027]

[0028] (2) Remove the benzyl protecting group from compound 6 under the action of a palladium catalyst and a reducing agent to obtain compound 7;

[0029]

[0030] wherein R 2 is selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl.

[0031] Preferably, in the esterification reaction of step (1), it is reacted with an alkylating agent under the action of a base to complete the esterification reaction, wherein the alkylating agent is selected from haloalkanes R 2 I, R 2 Br, alkoxysulfonates R 2 OMs, R 2 OTs, R 2 OTf or dialkyl sulfates (R 2 2SO4), wherein R 2 is methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl; the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO, DMAP or N-methylmorpholine; the reaction temperature is -30 to 130 °C; alternatively, in the esterification reaction of step (1), it is reacted with an alkylating agent alcohol R 2 OH under the action of a condensing agent to complete the esterification reaction, wherein the condensing agent is selected from any one or any two combinations of hydrogen chloride, concentrated sulfuric acid, boric acid, p-toluenesulfonic acid, thionyl chloride, phosphorus oxychloride, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, pivaloyl chloride, DCC, DIC, HATU, HBTU, CMPU, CDI, EDCI, HOPO, HOBT; no base is added or the base added is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO, DMAP, N-methylmorpholine or any two combinations thereof; the alcohol R 2 OH is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol or benzyl alcohol; no reaction solvent is added or the reaction solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran; the reaction temperature is -20 to 60 °C.

[0032] Preferably, in the deprotection reaction of step (2), the catalyst is selected from palladium on carbon or palladium hydroxide; the reducing agent is selected from hydrogen, formic acid or ammonium formate; the catalyst is selected from palladium on carbon or palladium hydroxide; the reducing agent is selected from hydrogen, formic acid or ammonium formate; the reaction solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetic acid, ethyl acetate, isopropyl acetate, triethylamine, diisopropylethylamine or a mixed solvent formed by any two of these solvents; the reaction temperature is 0 to 100 °C.

[0033] The present invention also relates to a method for synthesizing the intermediate compound 5 of itraconazole, adopting the following technical solution:

[0034] A method for synthesizing the intermediate compound 5 of itraconazole, comprising the following steps:

[0035] (1) Diazotize the compound 1 with a nitrosating reagent, then complete the condensation with the compound 2 under the action of a base, and then complete the cyclization and decarboxylation reaction under acidolysis to obtain the intermediate compound 3 in one pot;

[0036]

[0037] (2) Condense the compound 3 with malonic acid or its derivative or a wig reagent and hydrolyze to obtain the intermediate compound 4;

[0038]

[0039] (3) Asymmetric double bond reduction of the compound 4 under the action of a catalyst and hydrogen to obtain the intermediate compound 5;

[0040]

[0041] Wherein, R 1 is methyl or ethyl.

[0042] Preferably, the reaction in the step (1) includes a nitrosation reaction, a condensation reaction, and a cyclization and decarboxylation reaction. The reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-pentanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetic acid, water or a mixed solution formed by any two of these solvents; in the nitration reaction, the nitrating reagent is selected from sodium nitrite, isoamyl nitrite, tert-butyl nitrite, and the reaction temperature is -20 to 50 °C; for the condensation reaction, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or potassium acetate, and the reaction temperature is -20 to 60 °C; for the cyclization and decarboxylation, the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or trifluoromethanesulfonic acid; the reaction temperature is -20 to 130 °C.

[0043] Preferably, the reaction in step (2) includes a condensation reaction and a hydrolysis reaction. For the condensation reaction, dimethyl malonate, diethyl malonate, di-tert-butyl malonate, malonic acid, (ethoxycarbonylmethyl)triphenylphosphonium chloride, (ethoxycarbonylmethyl)triphenylphosphonium bromide, methoxyformylmethylene triphenylphosphine, ethoxyformylmethylene triphenylphosphine, or triethyl phosphonoacetate is selected; no base is added or a base is added, and the base is selected from n-butyllithium, LDA, LiHMDS, NaHMDS, KHMDS, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, diisopropylethylamine, triethylamine, DBU, DABCO, piperidine, morpholine, or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP, or acetonitrile; the hydrolysis reagent can be selected to add a base or a strong acid for hydrolysis, where the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, and the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or trifluoromethanesulfonic acid; the reaction temperature is -30 to 130 °C.

[0044] Preferably, in the asymmetric double bond reduction reaction in step (3), the catalyst is selected from (1,2-bis((2R,5R)-2,5-diethylphospholano-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene(1,5-cyclooctadiene)rhodium tetrafluoroborate, 1,2-bis[(2R,5R)-2,5-diethylphospholanyl]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, 1,2-bis((2R,5R)-2,5-diphenylphospholano-1-yl)ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, 1,2-bis[(2R,5R)-2,5-dimethylphospholyl]benzene(cyclooctadiene)rhodium(I) tetrafluoroborate, or (R,R)-(+)-1,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, Ru(R-MonoPhos)(p-cymene)Cl2, Rh(R-MonoPhos)(p-cymene)Cl2, Ru(R-SepPhos)(p-cymene)Cl2, Rh(R-SepPhos)(p-cymene)Cl2, Ru(R-SunPhos)(η 6 -benzene)Cl2, Rh(R-SunPhos)(η 6-benzene)Cl2, Ru(R-Binap)(p-cymene)Cl2 or Rh(R-Binap)(p-cymene)Cl2; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, n-pentanol, tert-pentanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or isopropyl acetate; the reaction temperature is -20 to 90 °C.

[0045] Specifically, a method for synthesizing itramod provided by the present invention adopts the following technical solution:

[0046] A method for synthesizing itramod, comprising using alkoxyaniline compound 1 as the starting material, first carrying out a nitrosation reaction and then condensing with compound 2 under the action of a base and acidolysis in one pot to obtain compound 2, then carrying out a condensation reaction with a malonic acid derivative or a Wittig reagent and a hydrolysis reaction to obtain compound 4, and compound 4 can be subjected to asymmetric reduction of the double bond to obtain an optically pure compound 5, then through esterification and reduction to remove the benzyl protection to obtain compound 7, and finally condensing with compound 8 to obtain itramod free acid compound 9, and finally salifying to obtain the final product compound 10 of itramod, the route is:

[0047]

[0048] wherein R 1 is methyl or ethyl; R 2 is selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl; LG is chlorine, bromine, iodine, hydroxyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy.

[0049] The synthesis method of itramod according to the present invention adopts inexpensive starting materials, optimizes the experimental method of cyclization decarboxylation reaction, obtains the main skeleton structure of the mother ring in one step, reduces the synthesis steps, and has a simple route. The chiral center is generated by asymmetric reduction, and the overall yield of the route is also provided, reducing the process cost. The present invention makes full use of asymmetric reduction to improve the selectivity of the route, improve the atom economy and the purity of the final product. This route is simple to operate, not only has a relatively high overall yield, but also the obtained product has a relatively high purity, and is suitable for large-scale production. Detailed Embodiments

[0050] The following describes the embodiments of the present invention in detail. The embodiments are implemented on the premise of the technical solution of the present invention, and the detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following embodiments.

[0051] Example 1

[0052]

[0053] Compound 1a (23.91 g, 120 mmol) was added to a three-necked flask, and 15% hydrochloric acid (71.1 mL) was added and stirred until dissolved. It was cooled to 0 - 10 °C, and sodium nitrite (8.28 g, 120 mmol) was added. Stirring was carried out at 0 - 10 °C for 2 - 3 hours. After the reaction ended and the mixture was allowed to stand, the supernatant was carefully withdrawn and discarded. Another 71.1 mL of water was added to the lower layer and stirred evenly to obtain a mixture of diazonium salt and water for later use. In another three-necked flask, compound 2a (14.22 g, 100 mmol) was added, 71.1 mL of methanol was added, and sodium hydroxide solution (12.00 g, 300 mmol, dissolved in 71.1 mL of water) was added, and stirring was carried out for 3 - 4 hours. The prepared mixture of diazonium salt and water was slowly added to the reaction flask, and stirring was carried out at room temperature for 5 - 8 hours. 36% concentrated hydrochloric acid (71.1 mL) was added, and the mixture was heated to reflux for 1 - 2 hours. After the reaction ended, filtration was carried out to filter out the crude product. 42.7 mL of methanol was added, and the mixture was heated to 50 - 55 °C. Water (99.5 mL) was slowly added, and the mixture was cooled to 0 - 10 °C and slurried. After filtration and drying, intermediate formula 3a (23.79 g, yield 85.8%) was obtained.

[0054] In Example 1, methanol can be replaced by ethanol, isopropanol, n-butanol, tert-butanol, tert-pentanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetic acid, water or a mixed solution formed by any two of these solvents; sodium nitrite can be replaced by isoamyl nitrite or tert-butyl nitrite; sodium hydroxide can be replaced by potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate or potassium acetate; 36% concentrated hydrochloric acid can be replaced by hydrobromic acid, sulfuric acid, phosphoric acid or trifluoromethanesulfonic acid.

[0055] Example 2

[0056]

[0057] Compound 3a (27.73 g, 100 mmol) was added to a three-necked flask, and dichloromethane (148 mL) was added and stirred until dissolved. Potassium carbonate (13.82 g, 100 mmol) was added. After stirring evenly, triethyl phosphonoacetate (24.66 g, 110 mmol) was added, and the reaction was carried out at 20 - 30 °C for 5 - 6 hours while maintaining the temperature. After the reaction ended, it was cooled to room temperature, 120 mL of 20% aqueous sodium hydroxide solution (600 mol) was added, and stirring was carried out at room temperature for 2 hours. Then, the aqueous phase was separated and collected. The organic phase was washed once with 50 mL of 5% sodium hydroxide solution. The aqueous phases were combined, and concentrated hydrochloric acid was added to adjust the pH to 3 - 4. It was slowly cooled to 0 - 10 °C and slurried. After filtration and drying, intermediate formula 4a (29.54 g, yield 92.5%) was obtained.

[0058] MS(ESI-) m / z = 318.1

[0059] 1 1H NMR (500 MHz, DMSO) δ 11.73 (br, 1H), 11.26 (s, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.28 - 7.35 (m, 2H), 7.13 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 9.0, 2.0 Hz, 1H), 5.94 (t, J = 2.0 Hz, 1H), 5.10 (s, 2H), 3.43 - 3.46 (m, 2H), 2.86 - 2.90 (m, 2H).

[0060] In Example 2, dichloromethane can be replaced by methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP or acetonitrile; triethyl phosphonoacetate can be replaced by dimethyl malonate, diethyl malonate, di-tert-butyl malonate, malonic acid, (ethoxycarbonylmethyl)triphenylphosphonium chloride, (ethoxycarbonylmethyl)triphenylphosphonium bromide, methoxyformylmethylene triphenylphosphine or ethoxyformylmethylene triphenylphosphine; potassium carbonate can be not added, or can also be replaced by n-butyllithium, LDA, LiHMDS, NaHMDS, KHMDS, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, diisopropylethylamine, triethylamine, DBU, DABCO, piperidine, morpholine or N-methylmorpholine; the hydrolysis reagent sodium hydroxide can be replaced by lithium hydroxide, potassium hydroxide, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or trifluoromethanesulfonic acid.

[0061] Example 3

[0062]

[0063] Compound 4a (31.94 g, 100 mmol) was added to a hydrogenation bottle, and methanol (160 mL) was added and stirred until dissolved. After the water pump was switched to nitrogen 3 times, (1,2-bis((2R,5R)-2,5-diethylphospholano-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (36.1 mg, 0.05 mmol) was quickly added. After addition, hydrogen was switched 3 times and then pressurized to 3.8 - 4.0 Mpa and heated to 45 - 50 °C for reaction for 18 - 24 hours. After the reaction was completed, it was filtered through diatomaceous earth, and part of the methanol was evaporated. Then it was heated to 50 - 55 °C, and water (240 mL) was slowly added. It was slowly cooled to 0 - 5 °C for pulping, and then filtered and dried to obtain intermediate formula 5a (29.96 g, yield 93.2%).

[0064] MS (ESI-) m / z = 320.2

[0065] 11H NMR (500 MHz, DMSO) δ 12.22 (br, 1H), 10.47 (s, 1H), 7.43 - 7.47 (m, 2H), 7.35 - 7.40 (m, 2H), 7.28 - 7.33 (m, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 8.5, 2.5 Hz, 1H), 5.06 (s, 2H), 3.42 - 3.50 (m, 1H), 2.60 - 2.76 (m, 4H), 2.33 - 2.39 (m, 1H), 2.04 - 2.12 (m, 1H).

[0066] In Example 3, (1,2-bis((2R,5R)-2,5-diethylphospholane-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate can be replaced with R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene(1,5-cyclooctadiene)rhodium tetrafluoroborate, 1,2-bis[(2R,5R)-2,5-diethylphospholanyl]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, 1,2-bis[(2R,5R)-2,5-dimethylphospholyl]benzene(cyclooctadiene)rhodium(I) tetrafluoroborate or (R,R)-(+)-1,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, Ru(R-MonoPhos)(p-cymene)Cl2, Rh(R-MonoPhos)(p-cymene)Cl2, Ru(R-SepPhos)(p-cymene)Cl2, Rh(R-SepPhos)(p-cymene)Cl2, Ru(R-SunPhos)(η 6 -benzene)Cl2, Rh(R-SunPhos)(η 6 -benzene)Cl2, Ru(R-Binap)(p-cymene)Cl2 or Rh(R-Binap)(p-cymene)Cl2; methanol can be replaced with ethanol, isopropanol, n-butanol, tert-butanol, n-pentanol, tert-pentanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or isopropyl acetate.

[0067] Example 4

[0068]

[0069] Compound 5a (32.14 g, 100 mmol) and methanol (160 mL) were added to a three-necked flask. Thionyl chloride (14.28 g, 120 mmol) was slowly added. After stirring evenly, the mixture was heated under reflux. After the reaction was completed, most of the methanol was removed by rotary evaporation. Then n-heptane (240 mL) was added, and the mixture was slowly cooled to 0 - 10 °C. A solid precipitated, which was filtered and dried to obtain compound 6a (31.59 g, 94.2%).

[0070] MS(ESI+) m / z = 336.2

[0071] 1 1H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 7.46 (d, J = 7.0 Hz, 2H), 7.38 (t, J = 8.0 Hz, 2H), 7.29 - 7.32 (m, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.73 (dd, J = 9.0, 2.5 Hz, 1H), 5.04 (s, 2H), 3.74 (s, 3H), 3.40 - 3.53 (m, 1H), 2.58 - 2.77 (m, 4H), 2.42 - 2.49 (m, 1H), 2.03 - 2.13 (m, 1H).

[0072] In Example 4, the condensing agent thionyl chloride can be replaced by hydrogen chloride, concentrated sulfuric acid, boric acid, p-toluenesulfonic acid, phosphorus oxychloride, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate or pivaloyl chloride; methanol can be replaced by ethanol, isopropanol, n-butanol, tert-butanol or benzyl alcohol.

[0073] Example 5

[0074]

[0075] Compound 5a (32.14 g, 100 mmol), DMAP (24.43 g, 200 mmol) and ethanol (160 mL) were added to a three-necked flask. EDCI (23.00 g, 120 mmol) was slowly added. After stirring evenly, the reaction was carried out at room temperature for 10 - 16 hours. After the reaction was completed, water (320 mL) was added, and the mixture was extracted twice with ethyl acetate (160 mL). The organic phases were combined, washed with water, concentrated to a small volume, heated to 55 - 60 °C, and n-heptane (240 mL) was slowly added. The mixture was slowly cooled to 0 - 10 °C. A solid precipitated, which was filtered and dried to obtain compound 6b (31.27 g, 89.5%).

[0076] MS(ESI+) m / z = 350.2

[0077] 11H NMR (500 MHz, DMSO) δ 10.47 (s, 1H), 7.45 (d, J = 7.0 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.28 - 7.33 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.71 (dd, J = 9.0, 2.5 Hz, 1H), 5.06 (s, 2H), 4.11 (q, J = 7.0 Hz, 2H), 3.44 - 3.52 (m, 1H), 2.60 - 2.80 (m, 4H), 2.41 - 2.47 (m, 1H), 2.05 - 2.12 (m, 1H) 1.20 (t, J = 7.0 Hz, 3H).

[0078] Example 6

[0079]

[0080] Compound 6a (33.54 g, 100 mmol) was added to a hydrogenation flask, and methanol (167.7 mL) was added and stirred until dissolved. After evacuating the water pump and replacing with nitrogen three times, 5% palladium on carbon (66 mg) was quickly added. After addition, hydrogen was replaced three times and then the pressure was increased to 0.20 - 0.25 Mpa, and the mixture was heated to 35 - 40 °C and reacted for 10 - 16 hours. After the reaction was completed, it was filtered through diatomaceous earth, and part of the methanol was removed by rotary evaporation. Then it was heated to 50 - 55 °C, water (201 mL) was slowly added, and it was slowly cooled to 0 - 10 °C for pulping, and then filtered and dried to obtain intermediate formula 7a (22.74 g, yield 92.7%).

[0081] MS (ESI+) m / z = 246.1

[0082] 1 1H NMR (500 MHz, DMSO) δ 10.28 (s, 1H), 8.52 (br, 1H) 7.08 (d, J = 9.5 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 8.5, 2.0 Hz, 1H), 3.70 (s, 3H) 3.41 - 3.50 (m, 1H), 2.73 - 2.79 (m, 1H), 2.55 - 2.72 (m, 3H), 2.39 - 2.45 (m, 1H), 2.03 - 2.10 (m, 1H).

[0083] In Example 6, palladium on carbon can be replaced by palladium hydroxide; methanol can be replaced by ethanol, isopropanol, tetrahydrofuran, acetic acid, ethyl acetate, isopropyl acetate or a mixed solvent formed by any two of these solvents.

[0084] Example 7

[0085]

[0086] Compound 6b (33.94 g, 100 mmol) was added to a hydrogenation flask, and ethyl acetate (170 mL) was added and stirred until dissolved. Triethylamine (20.23 g, 200 mmol) was added. After evacuating with a water pump and replacing the air with nitrogen three times, 5% palladium on carbon (68 mg) was quickly added. Formic acid (9.21 g, 200 mmol) was added, and the reaction was carried out at room temperature for 20 hours under nitrogen protection. After the reaction was completed, it was filtered through diatomaceous earth, washed with water, concentrated, heated to 50 - 55 °C, and n-heptane (203 mL) was slowly added. It was slowly cooled to 0 - 10 °C and slurried, then filtered and dried to obtain intermediate formula 7b (24.11 g, yield 93.0%).

[0087] In Example 7, palladium on carbon can be replaced by palladium hydroxide; triethylamine can be replaced by methanol, ethanol, isopropanol, tetrahydrofuran, acetic acid, ethyl acetate, isopropyl acetate or diisopropylethylamine; ethyl acetate can be replaced by methanol, ethanol, isopropanol, tetrahydrofuran, acetic acid, isopropyl acetate or diisopropylethylamine.

[0088] Example 8

[0089]

[0090] Compound 7a (24.53 g, 100 mmol), compound 8a (28.90 g, 110 mmol) and N,N-dimethylacetamide (123 mL) were added to a three-necked flask. After stirring evenly, potassium carbonate (20.73 g, 150 mmol) was added, and the reaction was carried out at an internal temperature of 20 - 30 °C for 10 - 12 hours. After the reaction was completed, water (245 mL) was added to quench the reaction, and it was slowly cooled to crystallize, then filtered, washed with water and dried to obtain product 9a (43.05 g, yield 91.3%).

[0091] In Example 8, potassium carbonate can be replaced by potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, pyridine, DBU, DABCO or N-methylmorpholine; the reaction solvent N,N-dimethylacetamide can be replaced by N,N-dimethylformamide, N-methylpyrrolidone, DMSO, dichloromethane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or 1,4-dioxane.

[0092] Example 9

[0093]

[0094] Compound 7b (25.93 g, 100 mmol), compound 8b (33.79 g, 110 mmol) and N,N-dimethylacetamide (130 mL) were added to a three-necked flask. After stirring evenly, potassium carbonate (20.73 g, 150 mmol) was added, and the reaction was carried out at an internal temperature of 20 - 30 °C for 10 - 12 hours. After the reaction was completed, water (259 mL) was added to quench the reaction, and the mixture was slowly cooled for crystallization, filtered, washed with water, and dried to obtain product 9b (44.82 g, yield 92.3%).

[0095] In Example 9, the reaction solvent N,N-dimethylacetamide can be replaced by N,N-dimethylformamide, N-methylpyrrolidone, DMSO, dichloromethane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or 1,4-dioxane; potassium carbonate can be replaced by potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, pyridine, DBU, DABCO or N-methylmorpholine.

[0096] Example 10

[0097]

[0098] Compound 9a (47.15 g, 100 mmol) and tetrahydrofuran (235 mL) were added to a three-necked flask. After stirring evenly, sodium hydroxide solution (12.00 g dissolved in 117 mL of water, 300 mmol) was added, and the reaction was carried out at 25 - 35 °C for 4 - 5 hours. After the reaction was completed, it was slowly cooled to 0 - 5 °C, ethyl acetate (235 mL) was added, 5% dilute hydrochloric acid (235 mL) was added, and the mixture was stirred and separated to collect the organic phase. The aqueous phase was extracted with ethyl acetate (235 mL) once again. The combined organic phases were dried over sodium sulfate, filtered, the filtrate was collected and concentrated, ethanol (377 mL) was added, and the mixture was heated to 50 - 55 °C. L-arginine (17.42 g, 100 mmol) was added, and after stirring for 1 hour, it was slowly cooled to 0 - 5 °C, filtered, and dried to obtain the final product 10. (56.98 g, yield 90.2%, purity ≥99.8%, chiral purity ≥99.8%).

[0099] In Example 10, sodium hydroxide can be replaced by potassium hydroxide, lithium hydroxide or by using lithium bromide and diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; tetrahydrofuran can be replaced by methanol, ethanol, isopropanol, tert-butanol, n-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, isopropyl acetate, ethyl acetate, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, any one or a combination of two solvents, or a mixed solvent system formed by them and water.

[0100] Example 11

[0101]

[0102] Compound 9b (48.55 g, 100 mmol), tetrahydrofuran (121 mL), and ethanol (121 mL) were added to a three-necked flask. After stirring evenly, sodium hydroxide solution (12.00 g dissolved in 121 mL of water, 300 mmol) was added. The reaction was carried out at 25 - 35 °C for 4 - 5 hours. After the reaction was completed, it was slowly cooled to 0 - 5 °C. Ethyl acetate (242 mL) was added, and 5% dilute hydrochloric acid (242 mL) was added. After stirring and separating the liquid, the organic phase was collected. The aqueous phase was extracted once more with ethyl acetate (242 mL). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was collected and concentrated. Isopropanol (485 mL) was added, and it was heated to 5 - 55 °C. L-arginine (17.42 g, 100 mmol) was added. After stirring for 1 hour, it was slowly cooled to 50 - 55 °C, filtered, and dried to obtain the final product 10. (58.12 g, yield 92.0%, purity ≥99.8%, chiral purity ≥99.9%).

[0103] In Example 11, sodium hydroxide can be replaced by potassium hydroxide, lithium hydroxide, or by using lithium bromide and diisopropyl ethylamine, triethylamine, DBU, DABCO, or N-methylmorpholine; the mixed solvent of tetrahydrofuran and ethanol can be replaced by any one or a combination of two solvents such as methanol, isopropanol, tert-butanol, n-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, isopropyl acetate, ethyl acetate, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, or a mixed solvent system formed by them and water.

[0104] Example 12

[0105]

[0106] Compound 9b (48.55 g, 100 mmol) and acetonitrile (243 mL) were added to a three-necked flask. After stirring evenly, lithium bromide (17.37 g, 200 mmol) was added, and then diisopropylethylamine (19.39 g, 150 mmol) was added. The temperature was raised to 55 - 60 °C and the reaction was carried out for 4 - 5 hours. After the reaction was completed, it was slowly cooled to 0 - 5 °C. The filter cake was collected by filtration and transferred to another reaction flask. Ethyl acetate (243 mL) and 5% dilute hydrochloric acid (243 mL) were added. After stirring, the organic phase was collected by liquid separation. The aqueous phase was extracted once more with ethyl acetate (243 mL). The combined organic phases were dried over sodium sulfate, filtered, and the filtrate was collected and concentrated. Isopropanol (388 mL) was added, and the temperature was raised to 50 - 55 °C. L-arginine (17.42 g, 100 mmol) was added. After stirring for 1 hour, it was slowly cooled to 0 - 5 °C. The product was collected by filtration and dried to obtain the final product 10. (58.62 g, yield 92.8%, purity ≥ 99.8%, chiral purity ≥ 99.9%).

[0107] In Example 12, the combination of lithium bromide and diisopropylethylamine can be replaced by potassium hydroxide, sodium hydroxide or lithium hydroxide; diisopropylethylamine can be replaced by triethylamine, DBU, DABCO or N-methylmorpholine; acetonitrile can be replaced by methanol, ethanol, isopropanol, tert-butanol, n-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, isopropyl acetate, ethyl acetate, toluene, 1,4-dioxane or a mixed solvent system formed by them and water.

Claims

1. Intermediate compounds 4, 5, 6 and 7a for the synthesis of itraconazole, with the structural formulas shown below: wherein R 2 is selected from methyl or ethyl.

2. A synthetic method of itraconazole, characterized in that The steps include the following: (1) Condensing compound 7 with compound 8 under the action of a base to obtain intermediate compound 9; (2) Hydrolyzing compound 9 under the action of a base hydrolysis reagent and salifying with L-arginine to obtain the target product 10; wherein LG is bromine, iodine, hydroxyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, and R 2 is selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl.

3. A method for synthesizing itraconazole according to claim 1, characterized in that, In the condensation reaction of step (1), the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, pyridine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or 1,4-dioxane; in the hydrolysis reaction of step (2), the base hydrolysis reagent is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide or a combination formed by lithium bromide and one of diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol, n-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, DMSO, dichloromethane, tetrahydrofuran, isopropyl acetate, ethyl acetate, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, any one or two combined solvents thereof or a mixed solvent system formed by them and water.

4. A method for synthesizing the intermediate compound 7 of itraconazole, characterized in that, The steps include the following: (1) Completing the esterification reaction of compound 5 with an alkylating reagent to obtain compound 6; (2) Removing the benzyl protecting group from compound 6 under the action of a palladium catalyst and a reducing agent to obtain compound 7; wherein R 2 is selected from methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl.

5. The synthesis method of an itraconazole intermediate compound 7 according to claim 4, characterized in that, In the esterification reaction of step (1), it is selected to react with an alkylating agent under the action of a base to complete the esterification reaction, wherein the alkylating agent is selected from haloalkanes R 2 I, R 2 Br, alkoxysulfonates R 2 OMs, R 2 OTs, R 2 OTf or dialkyl sulfates (R 2 2SO4), wherein R 2 is methyl, ethyl, isopropyl, n-butyl, tert-butyl or benzyl; the base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO or N-methylmorpholine; alternatively, in the esterification reaction of step (1), it is selected to react with the alkylating agent alcohol R 2 OH under the action of a condensing agent to complete the esterification reaction, wherein the condensing agent is selected from any one or any two combinations of hydrogen chloride, concentrated sulfuric acid, boric acid, p-toluenesulfonic acid, thionyl chloride, phosphorus oxychloride, methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, tert-butyl chloroformate, pivaloyl chloride, DCC, DIC, HATU, HBTU, CMPU, CDI, EDCI, HOPO, HOBT; no base is added or the added base is selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, cesium carbonate, lithium tert-butoxide, potassium tert-butoxide, sodium tert-butoxide, diisopropylethylamine, triethylamine, DBU, DABCO, DMAP, N-methylmorpholine or any two combinations thereof; the alcohol R 2 OH is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol or benzyl alcohol; no reaction solvent is added or the reaction solvent is selected from dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran or 2-methyltetrahydrofuran.

6. The synthesis method of an itraconazole intermediate compound 7 according to claim 4, characterized in that, In the reduction deprotection reaction of step (2), the catalyst is selected from palladium on carbon or palladium hydroxide; the reducing agent is selected from hydrogen, formic acid, sodium formate, potassium formate or ammonium formate; the reaction solvent is selected from methanol, ethanol, isopropanol, tetrahydrofuran, acetic acid, ethyl acetate, isopropyl acetate, triethylamine, diisopropylethylamine or a mixed solvent formed by any two of these solvents.

7. A method for synthesizing itraconazole intermediate compound 5, which is characterized in that it includes the following steps: (1) Performing a diazotization reaction of compound 1 with a nitrosating reagent, then completing the condensation with compound 2 under the action of a base, and then completing the cyclodecarboxylation reaction under acidolysis in one pot to obtain intermediate compound 3; (2) Condensing and hydrolyzing compound 3 with malonic acid or its derivative or a wig reagent to obtain intermediate compound 4; (3) Asymmetrically reducing the double bond of compound 4 under the action of a catalyst and hydrogen to obtain intermediate compound 5; Among them, R 1 is methyl or ethyl.

8. The synthesis method of an itraconazole intermediate compound 5 according to claim 7 is characterized in that, The reaction in step (1) includes nitrosation reaction, condensation reaction, and cyclization decarboxylation reaction. The reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, acetic acid, water, or a mixed solution formed by any two of these solvents; in the nitrosation reaction, the nitrating reagent is selected from sodium nitrite, isoamyl nitrite, tert-butyl nitrite; in the condensation reaction, the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, or potassium acetate; in the cyclization decarboxylation, the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or trifluoromethanesulfonic acid; the reaction in step (2) includes a condensation reaction and a hydrolysis reaction. The condensation reaction uses dimethyl malonate, diethyl malonate, di-tert-butyl malonate, malonic acid, (ethoxycarbonylmethyl)triphenylphosphonium chloride, (ethoxycarbonylmethyl)triphenylphosphonium bromide, methoxyformylmethylene triphenylphosphine, ethoxyformylmethylene triphenylphosphine, or triethyl phosphonoacetate; no base is added or the added base is selected from n-butyllithium, LDA, LiHMDS, NaHMDS, KHMDS, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, diisopropylethylamine, triethylamine, DBU, DABCO, piperidine, morpholine, or N-methylmorpholine; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, toluene, dichloromethane, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, DMF, DMAC, NMP, or acetonitrile; the hydrolysis reagent is selected to carry out hydrolysis by adding a base or a strong acid, where the base is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide, and the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or trifluoromethanesulfonic acid.

9. The synthesis method of an itraconazole intermediate compound 5 according to claim 7 is characterized in that, In the asymmetric double bond reduction reaction of step (3), the catalyst is selected from (1,2-bis((2R,5R)-2,5-diethylphospholano-1-yl)benzene)(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, R-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene(1,5-cyclooctadiene)rhodium tetrafluoroborate, 1,2-bis[(2R,5R)-2,5-diethylphospholanyl]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, 1,2-bis((2R,5R)-2,5-diphenylphospholano-1-yl)ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, 1,2-bis[(2R,5R)-2,5-dimethylphospholyl]benzene(cyclooctadiene)rhodium(I) tetrafluoroborate or (R,R)-(+)-1,2-bis[(2-methoxyphenyl)(phenyl)phosphino]ethane(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate, Ru(R-MonoPhos)(p-cymene)Cl2, Rh(R-MonoPhos)(p-cymene)Cl2, Ru(R-SepPhos)(p-cymene)Cl2, Rh(R-SepPhos)(p-cymene)Cl2, Ru(R-SunPhos)(η 6 -benzene)Cl2, Rh(R-SunPhos)(η 6 -benzene)Cl2, Ru(R-Binap)(p-cymene)Cl2 or Rh(R-Binap)(p-cymene)Cl2; the reaction solvent is selected from methanol, ethanol, isopropanol, n-butanol, tert-butanol, n-pentanol, tert-pentanol, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate or isopropyl acetate.

10. A method for synthesizing itraconazole, which includes using alkoxyaniline compound 1 as the starting material, first carrying out nitrosation reaction and then condensing with compound 2 under the action of a base and acidolysis in one pot to obtain compound 2, then carrying out a condensation reaction with a malonic acid derivative or a Wittig reagent and a hydrolysis reaction to obtain compound 4, and compound 4 can be subjected to asymmetric reduction of the double bond to obtain optically pure compound 5, then through esterification and reduction debenzylation protection to obtain compound 7, and finally condensing with compound 8 to obtain itraconazole free acid compound 9, and finally salifying to obtain the final itraconazole finished product compound 10, and the route is as follows: wherein R 1 is methyl or ethyl; R 2 is selected from methyl, ethyl, isopropyl, n-butyl, t-butyl or benzyl; LG is bromine, iodine, hydroxyl, methanesulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy.

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