Method for preparing key intermediate of drug maralixibat chloride and use thereof

Abstract

The present invention relates to a method for preparing a compound of formula I, which is a key intermediate of maralixibat chloride, and a use thereof. The compound of formula I can be synthesised by using a compound of formula IV or a compound of formula IX as a starting substrate, wherein the compound of formula IX undergoes a Mitsunobu reaction with a compound of formula VIII and sulfhydryl deprotection and substitution reactions to obtain the compound of formula IV, and the compound of formula IV then undergoes in sequence a reduction reaction and two oxidation reactions to obtain the compound of formula I, wherein R1, R4, and R5 are as defined in the description. The present invention provides a new method for synthesising a compound of formula I as a key intermediate of maralixibat chloride from different starting substrates; the method of the present invention has the advantages of simple steps, inexpensive raw materials, mild reaction conditions, high total yield, and high product purity, and is suitable for industrial production.

Description

Process for the preparation of a key intermediate for the drug maralixibat and its use

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese Patent Application No. 202411282928.3, filed on September 13, 2024, to the China Patent Office, which is incorporated herein by reference. TECHNICAL FIELD

[0003] The present application belongs to the field of pharmaceutical chemistry, and specifically relates to a preparation method of a key intermediate compound of formula I for the drug maralixibat and its use. BACKGROUND

[0004] Maralixibat chloride is a sodium-bile acid cotransporting polypeptide and ileal bile acid transporter (IBAT) inhibitor. It can interrupt the enterohepatic circulation of bile acids by inhibiting IBAT, prevent the intestinal reabsorption of bile acids, direct more bile acids to the colon to stimulate colon motility, increase the excretion of bile acids, and thus reduce cholestasis and improve liver function. It can be used for treating cholestatic pruritus in patients with Alagille Syndrome (ALGS) at the age of 1 and above. Its structural formula is shown in the following figure:

[0005] At present, the reported preparation methods of the related key intermediate of maralixibat include:

[0006] Patent CN1284953A reports a method for preparing the intermediate compound of formula Ia for the drug maralixibat. The method is to use p-fluorophenol as a raw material, and to obtain it through substitution, isomerization, and oxidation reaction:

[0007] In the method, the dangerous chemical reagent sodium hydride (NaH) is needed for multiple reaction steps, and at least one step needs a reaction temperature as high as 270°C, which is harsh in reaction condition; at the same time, the step of converting benzene thiol to a chiral sulfoxide compound needs an expensive chiral ligand Davis Oxaziridine, and the multi-step reaction needs column chromatography purification, making the preparation process complex and high in cost, so the method is not suitable for industrial production.

[0008] WO2001068637A2 reports two methods for preparing the intermediate compound of formula Ib for the drug maralixibat, and the reaction schemes are as follows:

[0009] Scheme 1:

[0010] Scheme 2:

[0011] Both the above-mentioned Scheme 1 and Scheme 2 need to use the expensive raw material hydrogen bromide, and also need to perform hydroxyl protection and deprotection, and the subsequent steps also need to perform aldehyde group protection and deprotection, so the method has long steps and high cost, and is not conducive to industrial production.

[0012] Therefore, there is a need in the art to develop and design a new method for preparing the key intermediate compound of the drug Clomaxibat. SUMMARY

[0013] In order to overcome the deficiencies in the prior art, the present application provides an improved preparation method of the key intermediate compound of Formula I of Clomaxibat. The method has simple steps, cheap raw materials, mild reaction conditions and high total yield, and is suitable for industrial production.

[0014] To this end, in one aspect, the present application provides a method for preparing a compound of Formula I, comprising:

[0015] Step 1: reducing the carbonyl group in the compound of Formula IV to a methylene group in the presence of a reducing agent and a solvent to obtain a compound of Formula III;

[0016] Step 2: oxidizing the sulfide group in the compound of Formula III to a sulfone group in the presence of an oxidizing agent and a solvent to obtain a compound of Formula II;

[0017] Step 3: oxidizing the hydroxyl group in the compound of Formula II to an aldehyde group in the presence of an oxidizing agent and a solvent, thereby obtaining a compound of Formula I,

[0018] wherein Me represents a methyl group, R 1 is selected from NO2, NR 2 R 3 , F, Cl, Br or I, and wherein R 2 and R 3 are independently selected from hydrogen, a methyl group or an amino protecting group, and are not simultaneously an amino protecting group selected from benzyl, 4-methoxybenzyl, benzylformyl, tert-butyloxycarbonyl, formyl, acetyl, trifluoroacetyl or 9-fluorenylmethyloxycarbonyl.

[0019] In a preferred embodiment, in Step 1, the reducing agent used is one or more selected from tetramethyldisilazane, sodium borohydride, triethylsilane, lithium aluminum hydride, hydrazine hydrate, red aluminum, zinc and sodium cyanoborohydride, and the solvent used is one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane and 2-methyltetrahydrofuran.

[0020] In preferred embodiments, in step 2, the oxidizing agent used is one or more selected from the group consisting of hydrogen peroxide, sodium hypochlorite, benzenediazonium dichloride, chromium trioxide, potassium permanganate, oxone, potassium monopersulfate, meta-chloroperoxybenzoic acid, meta-chloroperoxybenzoic acid, oxygen, iodosylbenzene, peroxyacetic acid, peroxytrifluoroacetic acid, peroxydodecanoic acid, sodium periodate, iodosylbenzene diacetate, sodium periodate, periodic acid, potassium manganate, zinc manganate, potassium cuprate, N-methyloxymorpholine, and dimethyldioxirane, and the solvent used is one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, and 2-methyltetrahydrofuran.

[0021] In preferred embodiments, in step 3, the oxidizing agent used is one or more selected from the group consisting of iodic acid, molybdic acid, oxygen, hydrogen peroxide, chromic acid, potassium permanganate, potassium dichromate, dimethyl sulfoxide, pyridinium chlorochromate, pyridinium dichromate, Jones reagent, manganese dioxide, 2,2,6,6-tetramethylpiperidine oxide, and 2-iodoxybenzoic acid, and the solvent used is one or more selected from the group consisting of toluene, tetrahydrofuran, acetonitrile, dichloromethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, and 2-methyltetrahydrofuran.

[0022] In preferred embodiments, the compound of formula IV is prepared by a method comprising the steps of:

[0023] Step 4: subjecting the compound of formula IX to a Mitsunobu reaction with the compound of formula VIII in the presence of a phosphine reagent, an azo reagent, and a solvent to obtain the compound of formula VII;

[0024] Step 5: deprotecting the thiol group of the compound of formula VII in the presence of a solvent to obtain the compound of formula VI;

[0025] Step 6: subjecting the compound of formula VI to a substitution reaction with the compound of formula V in the presence of a base and a solvent to obtain the compound of formula IV,

[0026] wherein R 1 R 4 is selected from O or S, R 5 is selected from C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 heteroaryl, or C 3-10 heterocyclyl, R 6selected from F, CI, Br, or I, and the heteroaryl is a monocyclic or fused polycyclic aryl group containing one or more ring heteroatoms selected from N, O, S, and P, and the heterocyclyl is a monocyclic or polycyclic hydrocarbon group containing one or more ring heteroatoms selected from N, O, S, and P.

[0027] In preferred embodiments, in step 4, the phosphine reagent used is one or more selected from triphenylphosphine, tributylphosphine, and tri-tert-butylphosphine, and the azo reagent used is one or more selected from N,N,N',N'-tetramethylazodicarbonamide, diethyl azodicarboxylate, and diisopropyl azodicarboxylate, and the solvent used is one or more selected from tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, toluene, and 2-methyltetrahydrofuran.

[0028] In preferred embodiments, in step 5, the reagent used for thiol deprotection is one or more selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, aqueous ammonia, triethylamine, ethylenediamine, hydrazine hydrate, methylhydrazine, sulfuric acid, nitric acid, phosphoric acid, hypophosphorous acid, phosphorous acid, thionyl chloride, hydrogen chloride, formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, and 2,2-dimethylbutyryl chloride, and the solvent used is one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, and 2-methyltetrahydrofuran.

[0029] In preferred embodiments, in step 6, the base used is one or more selected from trimethylamine, ethylenediamine, tetramethylethylenediamine, triethylamine, N,N-diisopropylethylamine, pyridine, piperidine, piperazine, 1,8-diazabicyclo[5.4.0]undec-7-ene, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, aqueous ammonia, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, and rubidium bicarbonate, and the solvent used is one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, and 2-methyltetrahydrofuran.

[0030] In another aspect, the present application provides a compound of formula IV and a compound of formula VII:

[0031] wherein R 1 , R 4 , and R 5 are as defined above.

[0032] In another aspect, the present application provides the following intermediate compounds for use in the preparation of the drug Clomaxibat:

[0033] In another aspect, the present application provides the use of the above-mentioned compound of formula I or the above-mentioned intermediate compound in the preparation of the drug Clomaxibat. DETAILED DESCRIPTION

[0034] DEFINITIONS

[0035] For the purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural; and vice versa. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0036] As used herein, the terms "alkyl", "alkenyl" and "alkynyl" refer to straight chain, branched chain or cyclic hydrocarbon groups of from 1 to 20 carbon atoms (i.e. C 1-20 alkyl, preferably C 1-10 alkyl, more preferably C 1-6 alkyl), or 2 to 20 carbon atoms (i.e. C 2-20 alkenyl, preferably C 2-10 alkenyl, more preferably C 2-6 alkenyl), or 2 to 20 carbon atoms (i.e. C 2-20 alkynyl, preferably C 2-10 alkynyl, more preferably C 2-6 alkynyl). Thus, for example, C 1-20 alkyl includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, methylpentyl and their isomers. C 2-20 alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl and their isomers. C 2-20 alkynyl includes, but is not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl and their isomers. The above alkyl, alkenyl or alkynyl groups can be optionally substituted with one or more substituents which can include, but are not limited to, cycloalkyl, aryl, heteroaryl, halo, alkoxy, hydroxy, aryloxy, -NO2, amino or alkylamino.

[0037] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic cyclic hydrocarbon group, wherein each ring contains from 3 to 10 carbon atoms (i.e. C 3-10 cycloalkyl, preferably C 3-6 cycloalkyl), and wherein any ring can contain one or more double or triple bonds, but is not fully unsaturated.

[0038] As used herein, the term "aryl" refers to a monocyclic or fused polycyclic aromatic hydrocarbon radical containing 6 to 10 ring carbon atoms (i.e., C 6-10 Examples include, but are not limited to, substituted or unsubstituted phenyl, naphthyl, or anthryl groups.

[0039] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic radical containing one or more ring heteroatoms selected from N, O, S, and P.

[0040] As used herein, the term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic radical containing one or more ring heteroatoms selected from N, O, S, and P.

[0041] As used herein, other related scientific and technical terms not specifically defined have meanings as commonly understood by one of ordinary skill in the art.

[0042] The present application provides a method for preparing a compound of Formula I, comprising the following steps:

[0043] wherein Me represents a methyl group, R 1 selected from NO2, NR 2 R 3 , F, CI, Br, or I, and wherein R 2 and R 3 are independently selected from hydrogen, methyl, or an amino protecting group, and are not simultaneously an amino protecting group selected from benzyl, 4-methoxybenzyl, benzylformyl, tert-butoxycarbonyl, formyl, acetyl, trifluoroacetyl, or 9-fluorenylmethoxycarbonyl.

[0044] Step 1

[0045] The carbonyl group in the compound of Formula IV is reduced to methylene in the presence of a reducing agent and a solvent to obtain the compound of Formula III.

[0046] Preferably, in Step 1, the reducing agent used can be one or more selected from tetramethyldisilazane, sodium borohydride, triethylsilane, lithium aluminum hydride, hydrazine hydrate, red aluminum, zinc, and sodium cyanoborohydride.

[0047] Preferably, in Step 1, the solvent used can be one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, and 2-methyltetrahydrofuran.

[0048] Preferably, in Step 1, the reaction temperature can be about -10 to 35°C.

[0049] Preferably, in Step 1, the reaction time can be about 4 to 24 hours.

[0050] Step 2

[0051] The thioether group in the compound of formula III is oxidized to a sulfone group in the presence of an oxidizing agent and a solvent to obtain the compound of formula II.

[0052] Preferably, in step 2, the oxidizing agent used can be one or more selected from the group consisting of hydrogen peroxide, sodium hypochlorite, iodobenzene dichloride, chromium trioxide, potassium permanganate, oxone, m-chloroperbenzoic acid, oxygen, iodosylbenzene, peroxyacetic acid, peroxytrifluoroacetic acid, peroxydodecanoic acid, sodium periodate, iodosylbenzene diacetate, sodium periodate, periodic acid, potassium manganate, zinc manganate, potassium cuprate, N-methyloxymorpholine, and dimethyldioxirane.

[0053] Preferably, in step 2, the solvent used can be one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, and 2-methyltetrahydrofuran.

[0054] Preferably, in step 2, the reaction temperature can be about -10 to 50°C.

[0055] Preferably, in step 2, the reaction time can be about 1 to 10 hours.

[0056] Step 3

[0057] The hydroxyl group in the compound of formula II is oxidized to an aldehyde group in the presence of an oxidizing agent and a solvent to thereby obtain the compound of formula I.

[0058] Preferably, in step 3, the oxidizing agent used can be one or more selected from the group consisting of iodic acid, molybdic acid, oxygen, hydrogen peroxide, chromic acid, potassium permanganate, potassium dichromate, dimethyl sulfoxide, pyridinium chlorochromate, pyridinium dichromate, Jones reagent, manganese dioxide, 2,2,6,6-tetramethylpiperidine oxide, and 2-iodoxybenzoic acid.

[0059] Preferably, in step 3, the solvent used can be one or more selected from the group consisting of toluene, tetrahydrofuran, acetonitrile, dichloromethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, and 2-methyltetrahydrofuran.

[0060] Preferably, in step 3, the reaction temperature can be about -10 to 60°C.

[0061] Preferably, in step 3, the reaction time can be about 1 to 10 hours.

[0062] In the process of the present application, preferably, the compound of formula IV used can be prepared by a process comprising the steps of:

[0063] wherein R 1 R 4 is selected from O or S, R 5 is selected from C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 heteroaryl or C 3-10 heterocyclyl, R 6 is selected from F, Cl, Br or I, and said heteroaryl is a monocyclic or a fused polycyclic aryl group containing one or more ring heteroatoms selected from N, O, S and P, and said heterocyclyl is a monocyclic or a polycyclic hydrocarbyl group containing one or more ring heteroatoms selected from N, O, S and P.

[0064] Step 4

[0065] The compound of formula IX (2,2-di-n-butyl-1,3-propanediol, commercially available) is subjected to Mitsunobu reaction with the compound of formula VIII in the presence of a phosphine reagent, an azo reagent and a solvent to obtain the compound of formula VII.

[0066] Preferably, in step 4, the phosphine reagent used can be one or more selected from triphenylphosphine, tributylphosphine and tri-tert-butylphosphine.

[0067] Preferably, in step 4, the azo reagent used can be one or more selected from N,N,N',N'-tetramethylazodicarbonamide, diethyl azodicarboxylate and diisopropyl azodicarboxylate.

[0068] Preferably, in step 4, the solvent used can be one or more selected from tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, toluene and 2-methyltetrahydrofuran.

[0069] Preferably, in step 4, the reaction temperature can be about -10 to 55°C;

[0070] Preferably, in step 4, the reaction time can be about 1 to 10 hours.

[0071] Step 5

[0072] The thiol group of the compound of formula VII is deprotected in the presence of a solvent to obtain the compound of formula VI.

[0073] Preferably, in step 5, the reagent for thiol deprotection can be one or more selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, aqueous ammonia, triethylamine, ethylenediamine, hydrazine hydrate, methylhydrazine, sulfuric acid, nitric acid, phosphoric acid, hypophosphorous acid, phosphorous acid, thionyl chloride, hydrogen chloride, formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride and 2,2-dimethylbutyryl chloride.

[0074] Preferably, in step 5, the solvent used can be one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane and 2-methyltetrahydrofuran.

[0075] Preferably, in step 5, the reaction temperature can be about -10-60°C.

[0076] Preferably, in step 5, the reaction time can be about 1-10 hours.

[0077] Step 6

[0078] In the presence of a base and a solvent, a substitution reaction of a compound of formula VI with a compound of formula V is carried out to obtain a compound of formula IV.

[0079] Preferably, in step 6, the base used can be one or more selected from trimethylamine, ethylenediamine, tetramethylethylenediamine, triethylamine, N,N-diisopropylethylamine, pyridine, piperidine, piperazine, 1,8-diazabicyclo[5.4.0]undec-7-ene, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, aqueous ammonia, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and rubidium bicarbonate.

[0080] Preferably, in step 6, the solvent used can be one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane and 2-methyltetrahydrofuran.

[0081] Preferably, in step 6, the reaction temperature can be about 10-120°C.

[0082] Preferably, in step 6, the reaction time can be about 2-8 hours.

[0083] In the method of the present application, the above reactions can all be carried out under relatively mild reaction conditions (such as in a reaction bottle or a reaction kettle at normal temperature and pressure), and the reaction process is completed by conventional post-treatment operations such as rotary evaporation, suction filtration, vacuum concentration, etc.

[0084] The method of the present application is further illustrated by the following examples. It should be understood that the examples are provided solely for the purpose of enabling better understanding of the present application and are not intended to limit the scope of the present application in any way.

[0085] Unless otherwise indicated, the various starting compounds, solvents, and other reagents used in the following examples were commercially available from market. The starting materials used were either commercially available or were prepared by further processing through conventional reactions well known in the art.

[0086] In addition, it is to be understood that, for the purpose of more closely reflecting actual reaction operation and for the purpose of more facilitating reaction control, some reaction condition parameters in the following examples are expressed in the form of a range of values rather than a specific value. Those skilled in the art can understand that such a range indicates that the corresponding reaction result can be achieved as long as the corresponding reaction condition is controlled within the corresponding range (without the need for a specific value). If a specific value is indeed needed, any specific value within the corresponding range can be used, for example, the middle value of the range.

[0087] Example 1

[0088] Under nitrogen atmosphere, 150 mL of 1,4-dioxane and 16.6 g of triphenylphosphine were added to a 250 mL reaction flask, and incubated at 50-55 °C for 1 hour, then 12.8 g of diisopropyl azodicarboxylate was added, and incubated for 2 hours. Subsequently, 10 g of 2,2-di-n-butyl-1,3-propanediol and 4.2 g of thioacetic acid were added in sequence, and incubated at 50-60 °C for 1 hour, then the temperature was raised to 80 °C for 4 hours. After the reaction was completed, the temperature was lowered to room temperature, and 25 g of calcium bromide was added, and stirred at room temperature for 4 hours. After incubation, the filtrate was obtained by filtration. The filtrate was concentrated to dryness under reduced pressure, and was subjected to azeotropic distillation with 20 mL of methanol to obtain 12.7 g of the product, with a yield of 97%. 1 H NMR (500 MHz, Chloroform-d) δ 3.20 (s, 2H), 2.89 (s, 2H), 2.80 (br s, 1H), 2.38 (s, 3H), 1.43 - 1.06 (m, 12H), 0.91 (t, J = 7.2 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 199.09, 65.21, 41.15, 34.34, 32.09, 30.63, 25.18, 23.40, 14.05. ESI-MS: [C 13 H 26 O2S+H] + Theoretical value: 247.1726, Experimental value: 247.1726.

[0089] Example 2

[0090] Into a 250 mL reaction flask, 150 mL of 1,4-dioxane and 16.6 g of triphenylphosphine were added under a nitrogen atmosphere, and the mixture was kept at 50-55°C for 1 hour. Then, 12.8 g of diisopropyl azodicarboxylate was added, and the mixture was kept at 50-60°C for 2 hours. Subsequently, 10 g of 2,2-di-n-butyl-1,3-propanediol and 5.1 g of dithioacetic acid were added in this order, and the mixture was kept at 50-60°C for 1 hour, and then the temperature was raised to 80°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, and 25 g of calcium bromide was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was filtered to obtain a filtrate. The filtrate was concentrated under reduced pressure to dryness, and then distilled with 20 mL of methanol to obtain 12.7 g of the product, with a yield of 97%.

[0091] Example 3

[0092] Into a 250 mL reaction flask, 40 mL of isopropyl alcohol was added under a nitrogen atmosphere, and 15.8 g of acetyl chloride was added, followed by the addition of 20 g of 2,2-di-n-butyl-3-acetylthio-1-propanol, and the mixture was kept at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, and then 100 mL of ethyl acetate was added to dissolve the crude product, and then the mixture was washed with 100 mL of water to separate an organic phase. The organic phase was dried with anhydrous sodium sulfate, and then the organic phase was concentrated under reduced pressure to obtain 15.9 g of the product, with a yield of 96%. 1 H NMR (500 MHz, Chloroform-d) δ 3.48 (s, 2H), 2.52 (d, J = 8.4 Hz, 2H), 1.50 (s, 1H), 1.38 - 1.09 (m, 12H), 0.91 (t, J = 7.3 Hz, 6H). 13 C NMR (126 MHz, CDCl3) δ 65.97, 40.63, 32.10, 30.06, 25.21, 23.49, 14.10. ESI-MS: [C 25 H 33 NO5S-H] - Theoretical value: 203.1475, Experimental value: 203.1475.

[0093] Example 4

[0094] Into a reaction flask, 50 mL of acetonitrile, 7.5 g of (2-chloro-5-nitrophenyl) (4-methoxyphenyl) methanone, 3.8 g of potassium carbonate and 6.3 g of 2,2-di-n-butyl-3-mercapto-1-propanol were added under a nitrogen atmosphere, and the temperature was raised to 70-75 °C, and the reaction was carried out for 3-5 hours. After the reaction was completed, the reaction system was cooled to 40-45 °C, 150 g of water was added dropwise to the reaction system, and the dropping was continued for 3-4 hours, after the dropping was completed, the temperature was maintained for 1 hour. Then, the temperature was lowered to 20-30 °C, and the temperature was maintained for 1 hour. Subsequently, filtration was performed, the filter cake was washed with 50 g of water, and then the filter cake was transferred to a reaction flask, 50 g of ethyl acetate was added, and the mixture was stirred to dissolve, and then the mixture was washed with 50 g of drinking water, and the stirring was continued for 30 minutes. After the mixture was allowed to stand, the organic layer was separated, and the aqueous layer was extracted once more with 50 g of ethyl acetate. The organic layers were combined, and then the organic layer was washed with 30 g of 5% sodium chloride solution and 30 g of drinking water in this order, and then the organic layer was dried with 10 g of anhydrous sodium sulfate. Subsequently, the mixture was filtered, and the filter cake was washed with 30 g of ethyl acetate, and then the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 11 g of ethyl acetate, and the internal temperature was controlled at 40-50 °C, and the mixture was stirred to dissolve, and then the temperature was maintained for 1 hour. Subsequently, 40 g of n-hexane was added dropwise, and the dropping was continued for 2 hours, and after the dropping was completed, the internal temperature was controlled at 40-45 °C, and the temperature was maintained for 1 hour, and then the temperature was lowered to 10-20 °C, and the temperature was maintained for 2 hours, and then the mixture was centrifuged, and the filter cake was washed with 10 g of ethyl acetate and 40 g of n-hexane. The solid was collected to obtain a wet product, and the wet product was placed in a vacuum oven, and the temperature was maintained at 50 °C for 15 hours to obtain 11.5 g of the product at a yield of 97%. 1 H NMR (500 MHz, DMSO-d6) δ 8.29 (m, 1H), 8.09 (d, J = 2.6 Hz, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.72 (m, 2H), 7.08 (m, 2H), 4.60 (t, J = 4.9 Hz, 1H), 3.86 (s, 3H), 3.15 (d, J = 4.9 Hz, 2H), 3.00 (s, 2H), 1.14 (m, 12H), 0.79 (t, J = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 192.97, 164.47, 147.20, 144.41, 139.16, 132.68, 128.95, 128.67, 125.15, 122.83, 114.75, 64.43, 56.15, 41.39, 39.04, 33.09, 25.01, 23.36, 14.32. ESI-MS: [C 25 H 33 NO5S+H] + Theoretical value: 460.2152, Experimental value: 460.2152.

[0095] Example 5

[0096] Under nitrogen atmosphere, 50 mL of acetonitrile, 6.7 g of (2-chloro-5- aminophenyl) (4-methoxyphenyl) methanone, 3.8 g of potassium carbonate and 6.3 g of 2,2-di-n-butyl-3-mercapto-1-propanol were added into a reaction flask, and the temperature was raised to 70-75 °C, and the reaction was carried out for 3-5 hours. After the reaction was completed, the reaction system was cooled to 40-45 °C, 150 g of water was added dropwise into the reaction system, and the dropping was continued for 3-4 hours, and after the dropping was completed, the temperature was maintained for 1 hour. Then, the temperature was cooled to 20-30 °C, and the temperature was maintained for 1 hour. Subsequently, filtration was carried out, the filter cake was washed with 50 g of water, and then the filter cake was transferred into a reaction flask, 50 g of ethyl acetate was added, and the mixture was stirred to dissolve, and then 50 g of drinking water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand to separate into layers, and the organic layer was used as it was; the water layer was extracted with 50 g of ethyl acetate once more, and the mixture was allowed to stand to separate into layers. The organic layers were combined, and then the organic layer was washed with 30 g of 5% sodium chloride solution and 30 g of drinking water in this order, and then the organic layer was dried with 10 g of anhydrous sodium sulfate. Subsequently, the mixture was suction filtered, and the filter cake was washed with 30 g of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was added into 11 g of ethyl acetate, and the internal temperature was controlled to be 40-50 °C, and the mixture was stirred to dissolve, and the temperature was maintained for 1 hour. Subsequently, 40 g of n-hexane was added dropwise, and the dropping was continued for 2 hours, and after the dropping was completed, the internal temperature was controlled to be 40-45 °C, and the temperature was maintained for 1 hour, and the temperature was cooled to 10-20 °C, and the temperature was maintained for 2 hours, and then centrifugation was carried out, and the filter cake was washed with 10 g of ethyl acetate and 40 g of n-hexane, and the solid was collected to obtain a wet product. The wet product was placed in a vacuum oven, and the temperature was controlled to be 50 °C, and the product was dried for 15 hours to obtain 10 g of a product, and the yield was 91%.

[0097] Example 6

[0098] Into a reaction flask, 50 mL of acetonitrile, 7.5 g of (2-chloro-5-dimethylaminophenyl) (4-methoxyphenyl) methanone, 3.8 g of potassium carbonate and 6.3 g of 2,2-di-n-butyl-3-mercapto-1-propanol were added under a nitrogen atmosphere, and the temperature was raised to 70-75°C, and the reaction was allowed to proceed for 3-5 hours. After the reaction was completed, the reaction system was cooled to 40-45°C, 150 g of water was added dropwise to the reaction system over a period of 3-4 hours, and after the dropping was completed, the system was maintained at the temperature for 1 hour. Then, the temperature was lowered to 20-30°C, and the system was maintained at the temperature for 1 hour. Subsequently, the system was filtered, the filter cake was washed with 50 g of water, and then the filter cake was transferred to a reaction flask, 50 g of ethyl acetate was added, and the system was stirred until the solution became clear, and then 50 g of drinking water was added, and the system was stirred for 30 minutes. The system was allowed to stand until it was separated into layers, and the organic layer was reserved; 50 g of ethyl acetate was added to the water layer, and the extraction was continued for one more time, and the system was allowed to stand until it was separated into layers. The organic layers were combined, and then the organic layer was washed with 30 g of 5% sodium chloride solution and 30 g of drinking water in this order, and then the organic layer was dried with 10 g of anhydrous sodium sulfate. Subsequently, the system was suction filtered, and the filter cake was washed with 30 g of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 11 g of ethyl acetate, and the internal temperature was controlled at 40-50°C, and the system was stirred until the solution became clear, and then the system was maintained at the temperature for 1 hour. Subsequently, 40 g of n-hexane was added dropwise, and the dropping was continued for 2 hours, and after the dropping was completed, the internal temperature was controlled at 40-45°C, and the system was maintained at the temperature for 1 hour, and then the temperature was lowered to 10-20°C, and the system was maintained at the temperature for 2 hours, and then the system was centrifuged. The filter cake was washed with 10 g of ethyl acetate and 40 g of n-hexane, and the solid was collected to obtain a wet product. The wet product was placed in a vacuum oven, and the system was dried at 50°C for 15 hours to obtain 10 g of the product at a yield of 85%.

[0099] Example 7

[0100] Into a reaction flask, 50 mL of acetonitrile, 6.8 g of (2-chloro-5-fluorophenyl)(4-methoxyphenyl)methanone, 3.8 g of potassium carbonate and 6.3 g of 2,2-di-n-butyl-3-mercapto-1-propanol were added under a nitrogen atmosphere, and the temperature was raised to 70-75°C, and the reaction was allowed to proceed for 3-5 hours. After the reaction was completed, the reaction system was cooled to 40-45°C, 150 g of water was added dropwise to the reaction system over a period of 3-4 hours, and after the dropwise addition was completed, the system was maintained at the same temperature for 1 hour. Then, the temperature was lowered to 20-30°C, and the system was maintained at the same temperature for 1 hour. Subsequently, the mixture was filtered, the filter cake was washed with 50 g of water, and then the filter cake was transferred to a reaction flask, 50 g of ethyl acetate was added, and the mixture was stirred until it dissolved, 50 g of drinking water was added, and the mixture was stirred for 30 minutes. The mixture was allowed to stand until it separated into layers, and the organic layer was used as is; the aqueous layer was extracted with 50 g of ethyl acetate once more, and the mixture was allowed to stand until it separated into layers. The organic layers were combined, and then the organic layer was washed sequentially with 30 g of a 5% sodium chloride solution and 30 g of drinking water, and then the organic layer was dried over 10 g of anhydrous sodium sulfate. Subsequently, the mixture was filtered, and the filter cake was washed with 30 g of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 11 g of ethyl acetate, and the internal temperature was controlled at 40-50°C, and the mixture was stirred until it dissolved, and the system was maintained at the same temperature for 1 hour. Subsequently, 40 g of n-hexane was added dropwise over a period of 2 hours, and after the dropwise addition was completed, the internal temperature was controlled at 40-45°C, and the system was maintained at the same temperature for 1 hour, the temperature was lowered to 10-20°C, and the system was maintained at the same temperature for 2 hours, and then the mixture was centrifuged. The filter cake was washed with 10 g of ethyl acetate and 40 g of n-hexane, and the solid was collected to obtain a wet product. The wet product was placed in a vacuum oven, and the system was dried at 50°C for 15 hours to obtain 10.8 g of the product, and the yield was 97%.

[0101] Example 8

[0102] Into a reaction flask, 50 mL of acetonitrile, 7.2 g of (2-chloro-5-chlorophenyl) (4-methoxyphenyl) methanone, 3.8 g of potassium carbonate and 6.3 g of 2,2-di-n-butyl-3-mercapto-1-propanol were added under a nitrogen atmosphere, and the temperature was raised to 70-75°C, and the reaction was allowed to proceed for 3-5 hours. After the reaction was completed, the reaction system was cooled to 40-45°C, 150 g of water was added dropwise to the reaction system over a period of 3-4 hours, and after the dropping was completed, the system was allowed to stand for 1 hour. Then, the temperature was lowered to 20-30°C, and the system was allowed to stand for 1 hour. Subsequently, the system was filtered, the filter cake was washed with 50 g of water, and then the filter cake was transferred to a reaction flask, 50 g of ethyl acetate was added, and the system was stirred until the solution became clear, and then 50 g of drinking water was added, and the system was stirred for 30 minutes. The system was allowed to stand until it was separated into two layers, and the organic layer was used as it was; the water layer was extracted with 50 g of ethyl acetate once more, and the system was allowed to stand until it was separated into two layers. The organic layers were combined, and then the organic layer was washed with 30 g of 5% sodium chloride solution and 30 g of drinking water in this order, and then the organic layer was dried with 10 g of anhydrous sodium sulfate. Subsequently, the system was suction filtered, and the filter cake was washed with 30 g of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 11 g of ethyl acetate, and the internal temperature was controlled at 40-50°C, and the system was stirred until it became clear, and then the system was allowed to stand for 1 hour. Subsequently, 40 g of n-hexane was added dropwise over a period of 2 hours, and after the dropping was completed, the internal temperature was controlled at 40-45°C, and the system was allowed to stand for 1 hour, and then the temperature was lowered to 10-20°C, and the system was allowed to stand for 2 hours, and then the system was centrifuged. The filter cake was washed with 10 g of ethyl acetate and 40 g of n-hexane, and the solid was collected to obtain a wet product. The wet product was placed in a vacuum oven, and the system was dried at 50°C for 15 hours to obtain 10.8 g of the product at a yield of 94%.

[0103] Example 9

[0104] Into a reaction flask, 50 mL of acetonitrile, 8.4 g of (2-chloro-5-bromophenyl) (4-methoxyphenyl) methanone, 3.8 g of potassium carbonate and 6.3 g of 2,2-di-n-butyl-3-mercapto-1-propanol were added under nitrogen atmosphere, and the temperature was raised to 70-75 °C, and the reaction was carried out for 3-5 hours. After the reaction was completed, the reaction system was cooled to 40-45 °C, 150 g of water was added dropwise to the reaction system, and the dropping was continued for 3-4 hours, and after the dropping was completed, the temperature was maintained for 1 hour. Then, the temperature was lowered to 20-30 °C, and the temperature was maintained for 1 hour. Subsequently, filtration was performed, the filter cake was washed with 50 g of water, and then the filter cake was transferred to a reaction flask, 50 g of ethyl acetate was added, and the mixture was stirred to dissolve the solid, and then 50 g of drinking water was added, and the mixture was stirred for 30 minutes. After the mixture was allowed to stand, the layers were separated, and the organic layer was used as it was; the water layer was further extracted with 50 g of ethyl acetate once, and the layers were separated. The organic layers were combined, and then the organic layer was washed with 30 g of 5% sodium chloride solution and 30 g of drinking water in this order, and then the organic layer was dried with 10 g of anhydrous sodium sulfate. Subsequently, the mixture was suction-filtered, and the filter cake was washed with 30 g of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 11 g of ethyl acetate, and the internal temperature was controlled at 40-50 °C, and the mixture was stirred to dissolve the solid, and then the temperature was maintained for 1 hour. Subsequently, 40 g of n-hexane was added dropwise, and the dropping was continued for 2 hours, and after the dropping was completed, the internal temperature was controlled at 40-45 °C, and the temperature was maintained for 1 hour, and then the temperature was lowered to 10-20 °C, and the temperature was maintained for 2 hours, and then centrifugation was performed. The filter cake was washed with 10 g of ethyl acetate and 40 g of n-hexane, and the solid was collected to obtain a wet product. The wet product was placed in a vacuum oven, and the temperature was controlled at 50 °C, and the product was dried for 15 hours to obtain 12 g of the product at a yield of 95%.

[0105] Example 10

[0106] Under nitrogen atmosphere, 50 mL of acetonitrile, 9.6 g of (2-chloro-5-iodophenyl)(4-methoxyphenyl)methanone, 3.8 g of potassium carbonate and 6.3 g of 2,2-di-n-butyl-3-mercapto-1-propanol were added into a reaction flask, and the temperature was raised to 70-75 °C, and reacted for 3-5 hours. After the reaction was completed, the reaction system was cooled to 40-45 °C, 150 g of water was added dropwise into the reaction system for 3-4 hours, and after the dropping was completed, the temperature was maintained for 1 hour. Then, the temperature was lowered to 20-30 °C, and maintained for 1 hour. Subsequently, filtration was performed, and the filter cake was washed with 50 g of water. Then, the filter cake was transferred into a reaction flask, 50 g of ethyl acetate was added, stirred to dissolve, and then 50 g of drinking water was added, and stirred for 30 minutes. After the mixture was allowed to stand, the organic layer was separated and used as is. The water layer was further extracted with 50 g of ethyl acetate once, and the mixture was allowed to stand to separate the layers. The organic layers were combined, and then the organic layer was washed with 30 g of 5% sodium chloride solution and 30 g of drinking water in this order, and then dried with 10 g of anhydrous sodium sulfate. Subsequently, filtration was performed, and the filter cake was washed with 30 g of ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in 11 g of ethyl acetate, and the internal temperature was controlled at 40-50 °C, and stirred to dissolve, and then maintained for 1 hour. Subsequently, 40 g of n-hexane was added dropwise, and the dropping was continued for 2 hours. After the dropping was completed, the internal temperature was controlled at 40-45 °C, and maintained for 1 hour, and then the temperature was lowered to 10-20 °C, and maintained for 2 hours. Then, centrifugation was performed. The filter cake was washed with 10 g of ethyl acetate and 40 g of n-hexane mixed solvent, and the solid was collected to obtain a wet product. The wet product was placed in a vacuum oven, and dried at 50 °C for 15 hours to obtain 12.6 g of the product at a yield of 91%.

[0107] Example 11

[0108] Under nitrogen atmosphere, 250 g of dichloromethane and 25 g of (2-(2-butyl-2-(hydroxymethyl)hexyl)thio)-5-nitrophenyl)(4-methoxyphenyl)methanone were added into a reaction flask, and the temperature was lowered to 5-10 °C, and then 33 g of trifluoromethanesulfonic acid was added dropwise, followed by the dropwise addition of 20 g of triethylsilane. After the dropping was completed, the temperature was controlled at 15-20 °C, and maintained for 8 hours. The liquid in the reaction flask was added dropwise into water which was previously cooled to 0-10 °C, and after the dropping was completed, the temperature was maintained for 1 hour. The organic layer was separated, and then the organic layer was washed with 123 g of 5% sodium bicarbonate solution, and then the organic layer was washed with 100 g of water. The organic layer was separated, and then 30 g of anhydrous sodium sulfate was added into the organic layer to perform drying, and then filtration was performed. The filter cake was washed with 30 g of dichloromethane, and the filtrate was concentrated to obtain 22.5 g of the product at a yield of 93%.

[0109] Example 12

[0110] Under nitrogen atmosphere, 10 g of compound 2-butyl-2-(((2-(4- methoxybenzyl)-4-nitrophenyl)thio)methyl)hexan-1-ol and 100 mL of dichloromethane were added into a reaction bottle. Then, the reaction system was cooled to 0-5 °C, and 16.6 g of meta-chloroperoxybenzoic acid was added in batches. After the addition was completed, the temperature was raised to 20-30 °C, and the reaction was carried out for 4-6 hours. After the reaction was completed, the reaction was quenched with 100 mL of saturated sodium sulfite solution, followed by washing with 100 mL of saturated sodium bicarbonate solution and 100 mL of saturated brine. The organic phase was separated, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain 9.8 g of product, with a yield of 92%.

[0111] Example 13

[0112] Under nitrogen atmosphere, 9.5 g of compound 2-butyl-2-((2-(4- methoxybenzyl)-4-nitrophenyl)sulfonyl)methyl)hexan-1-ol, 6.4 g of pyridine chlorochromate, 100 g of diatomite, and 200 mL of dichloromethane were added into a reaction bottle, and the reaction was carried out at 20-30 °C for 4-5 hours. After the reaction was completed, 400 mL of methyl tert-butyl ether was added, and the mixture was stirred at room temperature for 1 hour. Then, the filtrate was obtained by filtering through diatomite, and the filtrate was concentrated to obtain 8.8 g of product, with a yield of 93%.

[0113] The above only describes the preferred embodiments and / or examples of the present application, and it should be noted that for those skilled in the art, several improvements and changes can be made without departing from the principles of the present application, and these improvements and changes are also within the scope of protection of the present application.

Claims

1. A process for preparing a compound of formula I, comprising: Step 1 : Reducing the carbonyl group in the compound of formula IV to methylene group in the presence of a reducing agent and a solvent to obtain the compound of formula III; Step 2: Oxidizing the thioether group in the compound of formula III to sulfone group in the presence of an oxidizing agent and a solvent to obtain the compound of formula II; Step 3: Oxidizing the hydroxyl group in the compound of formula II to aldehyde group in the presence of an oxidizing agent and a solvent to obtain the compound of formula I, wherein Me represents a methyl group, R 1 is selected from NO2, NR 2 R 3 , F, CI, Br or I, and wherein R 2 and R 3 are independently selected from hydrogen, a methyl group or an amino protecting group, and are not simultaneously an amino protecting group selected from benzyl, 4-methoxybenzyl, benzylformyl, tert-butyloxycarbonyl, formyl, acetyl, trifluoroacetyl or 9-fluorenylmethyloxycarbonyl.

2. The method of claim 1, wherein, In step 1, the reducing agent used is one or more selected from tetramethyldisilazane, sodium borohydride, triethylsilane, lithium aluminum hydride, hydrazine hydrate, red aluminum, zinc and sodium cyanoborohydride, and the solvent used is one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane and 2-methyltetrahydrofuran.

3. The method of claim 1, wherein, In step 2, the oxidizing agent used is one or more selected from hydrogen peroxide, sodium hypochlorite, iodobenzene dichloride, chromium trioxide, potassium permanganate, potassium peroxomonosulfate, m-chloroperbenzoic acid, oxygen, iodosyldiazomethane, peroxyacetic acid, peroxytrifluoroacetic acid, peroxydodecanoic acid, sodium periodate, iodosobenzoic acid, sodium periodate, periodate, potassium manganate, zinc manganate, potassium cuprate, N-methylmorpholine oxide and dimethyldioxirane, and the solvent used is one or more selected from methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane and 2-methyltetrahydrofuran.

4. The method of claim 1, wherein, In step 3, the oxidizing agent used is one or more selected from iodic acid, molybdic acid, oxygen, hydrogen peroxide, chromic acid, potassium permanganate, potassium dichromate, dimethyl sulfoxide, pyridine chlorochromate, pyridine dichromate, Jones reagent, manganese dioxide, 2,2,6,6-tetramethylpiperidine oxide and 2-iodoxybenzoic acid, and the solvent used is one or more selected from toluene, tetrahydrofuran, acetonitrile, dichloromethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether and 2-methyltetrahydrofuran.

5. The method of claim 1, wherein, The compound of formula IV is prepared by a process comprising the following steps: Step 4: Mitsunobu reaction of the compound of formula IX with the compound of formula VIII in the presence of a phosphine reagent, an azo reagent and a solvent to obtain the compound of formula VII; Step 5: Deprotection of the mercapto group of the compound of formula VII in the presence of a solvent to obtain the compound of formula VI; Step 6: Substitution reaction of the compound of formula VI with the compound of formula V in the presence of a base and a solvent to obtain the compound of formula IV, wherein R 1 As defined above, R 4 is selected from O or S, R 5 is selected from C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-10 heteroaryl or C 3-10 heterocyclyl, R 6 is selected from F, Cl, Br or I, and said heteroaryl is a monocyclic or a fused polycyclic aryl group containing one or more ring heteroatoms selected from N, O, S and P, and said heterocyclyl is a monocyclic or a polycyclic hydrocarbyl group containing one or more ring heteroatoms selected from N, O, S and P.

6. The method of claim 5, wherein, In step 4, the phosphine reagent used is one or more selected from the group consisting of triphenylphosphine, tributylphosphine and tri-tert-butylphosphine, and the azo reagent used is one or more selected from the group consisting of N,N,N',N'-tetramethylazodicarbonamide, diethyl azodicarboxylate and diisopropyl azodicarboxylate, and the solvent used is one or more selected from the group consisting of tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane, toluene and 2-methyltetrahydrofuran.

7. The method of claim 5, wherein, In step 5, the reagent for thiol deprotection is one or more selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, aqueous ammonia, triethylamine, ethylenediamine, hydrazine hydrate, methylhydrazine, sulfuric acid, nitric acid, phosphoric acid, hypophosphorous acid, phosphorous acid, phosphorus oxychloride, hydrogen chloride, formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride and 2,2-dimethylbutyryl chloride, and the solvent used is one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane and 2-methyltetrahydrofuran.

8. The method of claim 5, wherein, In step 6, the base used is one or more selected from the group consisting of trimethylamine, ethylenediamine, tetramethylethylenediamine, triethylamine, N,N-diisopropylethylamine, pyridine, piperidine, piperazine, 1,8-diazabicyclo[5.4.0]undec-7-ene, lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, aqueous ammonia, potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, rubidium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and rubidium bicarbonate, and the solvent used is one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, toluene, tetrahydrofuran, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, benzene, diethyl ether, dichloromethane and 2-methyltetrahydrofuran.

9. The compound of formula IV and the compound of formula VII for use in the manufacture of the drug Clomacalcic acid: wherein R 1 , R 4 and R 5 are as defined above.

10. The following intermediate compounds for the preparation of the drug Clomacabate:

11. Use of a compound of formula I according to any one of claims 1 to 8 or of an intermediate compound according to claim 9 or 10 for the manufacture of the medicament Clomacabt.

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