Process for the preparation of intermediate compounds for the drug maralixibat and use thereof

Abstract

The present application relates to a preparation method and application of an important intermediate compound of formula I of a drug Maralixibat. The compound of formula (I) can be synthesized by taking compound (5) or compound (2) as a starting substrate, wherein compound (2) is reacted with compound (S5), compound 5 is obtained after two reductions, compound 5 is sequentially subjected to amino protection, chiral catalytic sulfoxidation, terminal hydroxyl oxidation, cyclization, again sulfoxidation and reductive amination to obtain the compound of formula (I), wherein R 1 and R 2 as defined herein. The present application provides a new method for synthesizing the compound of formula (I) as an important intermediate of the drug Maralixibat by using different starting substrates, and the method of the present application has the advantages of simple steps, mild reaction conditions, high yield and purity, and is suitable for industrial production. In addition, the obtained compound of formula I and the intermediate compounds involved in the synthesis process can be applied to the preparation of the drug Maralixibat.

Description

Method for preparing intermediate compound of drug Maralixibat and application thereof

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to Chinese invention patent application No. 202311737549.4 filed with the Patent Office of China on December 18, 2023, which is incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of medicinal chemistry, and in particular to a method for preparing an intermediate compound of Maralixibat, a drug for treating cholestatic pruritus in patients with Alageri syndrome, and application thereof. Background Art

[0004] Alagille syndrome (ALGS) is a rare genetic disorder characterized by abnormal narrowing, malformation, and decreased number of bile ducts. Bile accumulates in the liver, leading to progressive liver disease. In patients with Alagille syndrome, multiple organ systems may be affected by gene mutations, including the liver, heart, kidneys, and central nervous system.

[0005] The accumulation of bile acids prevents the liver from working properly and removing waste products from the blood. Reportedly, 60% to 75% of people with Alagille syndrome undergo a liver transplant before adulthood. Signs and symptoms of liver damage in Alagille syndrome include jaundice, xanthomas, and itching. The itching experienced by people with Alagille syndrome is the most severe of any chronic liver disease, and most affected children develop symptoms before the age of 3.

[0006] In September 2021, Maralixibat oral solution was approved for marketing in the United States, becoming the first and only FDA-approved drug for Alagille syndrome to treat cholestatic pruritus in children one year of age and older. In June 2023, Maralixibat oral solution became the first drug approved in China for the treatment of cholestatic pruritus in patients with Alagille syndrome. The structure of the drug Maralixibat is as follows:

[0007] CN1284953A reports a method for preparing the intermediate compound of formula Ia of the drug Maralixibat. The method uses p-fluorophenol as a raw material and sequentially undergoes four steps of substitution reaction, two steps of oxidation reaction, cyclization and oxidation reaction to obtain:

[0008] However, multiple reaction steps in this method require the use of the hazardous chemical reagent sodium hydride (NaH), and at least one step requires a reaction temperature of up to 270°C, resulting in harsh reaction conditions. Furthermore, the step of converting thiophenol to a chiral sulfoxide compound requires the expensive chiral ligand Davis Oxiziricine, and multiple reaction steps require column chromatography purification, making the preparation process complex and costly, making it unsuitable for industrial production.

[0009] WO2001068637A2 reports a method for preparing a compound of formula Ib, an intermediate of the drug Maralixibat, and the reaction scheme is as follows:

[0010] However, this method requires redundant steps of adding and removing protecting groups on the aldehyde group, as well as post-processing steps of obtaining the target compound through chiral column separation, which are not conducive to industrial production.

[0011] Therefore, there is a need in the art to develop and design new methods for preparing key intermediate compounds as the drug Maralixibat. Summary of the Invention

[0012] In order to overcome the above-mentioned deficiencies in the prior art, the present invention develops and designs a new method for preparing a compound of formula I, which is an important intermediate of the drug Maralixibat. By reducing or eliminating the use of the expensive specific chiral ligand Davis Oxiziricine, reducing the column chromatography treatment steps and eliminating the chiral column separation step, the present invention can industrially produce the compound of formula I, which is an important intermediate of the drug Maralixibat, in a cheaper, simpler and cost-effective manner.

[0013] To this end, in one aspect, the present invention provides a method for preparing a compound of formula I, comprising:

[0014] Step 1: Compound 5 is reacted with an amino protecting group R 3 and R 4 The protective reagent was reacted to obtain compound 6;

[0015] Step 2: In the presence of a chiral ligand and a metal catalyst, the obtained compound 6 is subjected to an oxidation reaction with a first oxidant to obtain compound 7;

[0016] Step 3: reacting the obtained compound 7 with a second oxidant to obtain compound 8;

[0017] Step 4: Under alkaline conditions, the obtained compound 8 undergoes a cyclization reaction to obtain compound 9;

[0018] Step 5: reacting the obtained compound 9 with a third oxidizing agent to obtain compound 10; and

[0019] Step 6: In the presence of a first reducing agent, react the obtained compound 10 with a methylating agent to obtain a compound of formula I.

[0020] Among them, R 1 and R 2 Independently selected from H and C 1-10 Alkyl, R 3 and R 4 is an amino protecting group independently selected from H, benzyl, 4-methoxybenzyl, benzylformyl, tert-butoxycarbonyl, formyl, acetyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl, provided that R 3 and R 4 Not H at the same time.

[0021] In a preferred embodiment, R 1 and R 2 independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

[0022] In a preferred embodiment, R 1 and R 2 are independently selected from H, methyl, ethyl, n-propyl and n-butyl.

[0023] In a preferred embodiment, the chiral ligand used in step 2 is selected from One or more of .

[0024] In a preferred embodiment, the metal catalyst used in step 2 is one or more selected from PdCl2, NiCl2, Pd(OH)2, Ni(acac)2, RhCl2 and CrCl2.

[0025] In a preferred embodiment, the first oxidizing agent used in step 2 is one or more selected from the group consisting of H2O2, 3-phenyl-2-phenylsulfonyl-1,2-oxaziridine and benzoyl peroxide.

[0026] In a preferred embodiment, the second oxidant used in step 3 is one or more selected from potassium permanganate, manganese dioxide, and sodium hypochlorite.

[0027] In a preferred embodiment, the base used in step 4 is one or more selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, NaH, KH, lithium diisopropylamide, lithium hexamethyldisilazide and sodium hexamethyldisilazide.

[0028] In a preferred embodiment, the third oxidizing agent used in step 5 is one or more selected from peracetic acid, sodium periodate and m-chloroperbenzoic acid.

[0029] In a preferred embodiment, the first reducing agent used in step 6 is one or more selected from Pd / C and H2, Raney nickel and H2, or zinc powder and H2.

[0030] In a preferred embodiment, the methylamination reagent used in step 6 is one or more selected from formaldehyde, triformaldehyde and paraformaldehyde.

[0031] In a preferred embodiment, the compound 5 used is prepared by a process comprising the following steps:

[0032] Step 7: Compound 2 reacts with compound S5 under alkaline conditions to obtain compound 3;

[0033] Step 8: Compound 3 is reacted with a second reducing agent to obtain compound 4; and

[0034] Step 9: Compound 4 is reacted with a third reducing agent to obtain compound 5;

[0035] Among them, R 1 and R 2 As mentioned above.

[0036] In a preferred embodiment, the base used in step 7 is one or more selected from potassium carbonate, sodium carbonate, potassium phosphate, potassium bicarbonate and sodium bicarbonate.

[0037] In a preferred embodiment, the second reducing agent used in step 8 is one or more selected from sodium borohydride, potassium borohydride, borane, trimethylsilane, triethylsilane and tripropylsilane.

[0038] In a preferred embodiment, the third reducing agent used in step 9 is one or more selected from Pd / C / H2, Raney nickel / H2, iron / hydrochloric acid or zinc / hydrochloric acid.

[0039] In another aspect, the present invention provides the following intermediate compound for preparing the drug Maralixibat:

[0040] Among them, R 1 、R2 、R 3 and R 4 As defined above.

[0041] In a preferred embodiment, the intermediate compound is selected from:

[0042] In these, Me represents a methyl group, Et represents an ethyl group, Bu represents a butyl group, and CBz represents a benzyloxycarbonyl group.

[0043] In another aspect, the present invention provides use of the compound of formula I or the intermediate compound in the preparation of the drug Maralixibat.

[0044] The present invention provides a novel method for synthesizing compounds of Formula I, important intermediates of the drug maralixibat, from different starting substrates. The method has the advantages of simple steps, mild reaction conditions, high yield and purity, and is suitable for industrial production. Furthermore, the resulting compounds of Formula I and the intermediates involved in the synthesis process can be used in the preparation of the drug maralixibat. DETAILED DESCRIPTION

[0045] The following detailed description is provided to help those skilled in the art to implement and realize the present invention, but it should be understood that these descriptions should not be interpreted as unduly limiting the present invention. In addition, the content of each document mentioned in this article is also incorporated herein by reference for all purposes.

[0046] The method of the present invention uses a 3-((4-amino-2-(4-methoxy)benzyl)-phenylthio)propan-1-ol derivative (i.e., Compound 5) as a starting substrate for synthesis, wherein Compound 5 undergoes amino protection, chiral catalytic sulfur (S) oxidation, oxidation of the terminal hydroxyl group, cyclization, further sulfur (S) oxidation, and reductive amination to obtain a compound of Formula I, which is an important intermediate of the drug Maralixibat. Preferably, Compound 5 can be synthesized using 1-chloro-2-(4-methoxybenzyl)-4-nitrobenzene (i.e., Compound 2) as a starting substrate, wherein Compound 2 reacts with a 3-mercapto-propan-1-ol derivative (i.e., Compound S5) and undergoes two reductions to obtain Compound 5.

[0047] Specifically, the method of the present invention can be shown by the following reaction schemes 1 and 2:

[0048] Reaction Scheme 1

[0049] Preferably, the compound 5 used is prepared by the following reaction scheme 2:

[0050] Reaction Scheme 2

[0051] More preferably, the compound of formula I can be synthesized using compound 2 as a starting substrate via the following reaction scheme 3:

[0052] Reaction Scheme 3

[0053] As shown above, Reaction Scheme 1 includes the following steps 1 to 6 in sequence, and Reaction Scheme 2 includes steps 7 to 9 in sequence, while Reaction Scheme 3 includes steps 7 to 9 and then steps 1 to 6 in sequence.

[0054] Step 1

[0055] Compound 5 is reacted with an amino protecting group R 3 and R 4 The protective reagent was reacted to obtain compound 6.

[0056] Preferably, step 1 can be carried out as follows: in an organic solvent, in the presence of a base, compound 5 is reacted with a 3 and R 4 The protective reagent is reacted at -5-25 ° C to react the two H groups on the amino group of compound 5 with amino protecting groups R 3 and R 4 Replacement to obtain compound 6.

[0057] In the present invention, the group R in compound 5 1 and R 2 Can be independently selected from H and C 1-10 Alkyl. For example, R 1 and R 2 R can be independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. 1 and R 2 may be independently selected from H, methyl, ethyl, n-propyl and n-butyl.

[0058] In the present invention, the amino protecting group R 3 and R 4 may be an amino protecting group independently selected from H, benzyl, 4-methoxybenzyl, benzylformyl, tert-butoxycarbonyl, formyl, acetyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl, provided that R 3 and R 4 Different from H, that is, group R 3 and R 4 At least one of them is not H. The present inventors have found that by introducing such an amino protecting group R to the amino group in compound 5 through step 1 3 and R4 It not only protects the amino group in the subsequent reactions, but also introduces at least one relatively large sterically hindered group or carbonyl-containing group such as benzyloxycarbonyl into the amino group, making the protected compound more conducive to subsequent selective oxidation and cyclization reactions.

[0059] In step 1, preferably, the base used can be one or more selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, etc.;

[0060] In step 1, preferably, the organic solvent used can be one or more independently selected from tetrahydrofuran, acetonitrile, isopropanol, methanol, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylaniline, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetone, etc.

[0061] In the present invention, more specifically, for example, step 1 can be carried out as follows: Compound 5 is dissolved in an organic solvent, an inorganic base is added, stirring is started, the temperature is lowered to -5-15°C, the protective reagent is added dropwise, and the reaction is incubated for 2-6 hours. After the reaction is complete, water is added, the layers are separated, the organic phase is washed with water, and the organic phase is concentrated to dryness to obtain Compound 6 as an oil.

[0062] Step 2

[0063] In the presence of a chiral ligand and a metal catalyst, the obtained compound 6 is subjected to an oxidation reaction with a first oxidizing agent to obtain compound 7.

[0064] Preferably, step 2 can be carried out as follows: in an organic solvent, in the presence of a chiral ligand and a metal catalyst, oxidize the obtained compound 6 with a first oxidizing agent at -5-20° C. to obtain compound 7.

[0065] In step 2, preferably, the chiral ligand used can be selected from

[0066] One or more of .

[0067] In step 2, preferably, the metal catalyst used may be one or more selected from PdCl2, NiCl2, Pd(OH)2, Ni(acac)2, RhCl2, and CrCl2. Such metal catalysts are commercially available and not only promote the reaction but also do not affect the chirality of the sulfur center of compound 7. In step 2, preferably, the first oxidant used may be one or more selected from H2O2, 3-phenyl-2-phenylsulfonyl-1,2-oxaziridine, and benzoyl peroxide. Such first oxidants are known in the art and are commercially available.

[0068] In step 2, preferably, in the presence of the chiral ligand and metal catalyst, by using the first oxidizing agent, sulfur (S) in compound 6 can be oxidized only once to obtain a sulfur-centered chiral compound 7 with high enantioselectivity.

[0069] In the present invention, preferably, the organic solvent used in step 2 may be an organic solvent independently selected from those described above for step 1.

[0070] In the present invention, more specifically, for example, step 2 can be carried out as follows: a metal catalyst and a chiral ligand are added to an organic solvent, stirred for 10-30 minutes, and then compound 6 is added. The temperature is lowered to -5-10°C, and an organic solution of the first oxidant is slowly added dropwise. After the reaction is completed, a sodium thiosulfate solution is added to terminate the reaction. The reaction solution is spin-dried, and an organic solvent and water are added. The layers are separated, and the organic phase is washed with brine. The organic phase is concentrated to dryness to obtain compound 7 as a solid.

[0071] Step 3

[0072] The resulting compound 7 is reacted with a second oxidizing agent to give compound 8.

[0073] Preferably, step 3 can be carried out as follows: oxidizing the obtained compound 7 with a second oxidizing agent at 0-25° C. in an organic solvent to obtain compound 8.

[0074] In step 3, preferably, the second oxidant used can be selected from one or more of potassium permanganate, manganese dioxide, and sodium hypochlorite. Such second oxidants are known in the art and can be commercially obtained. In this step 3, by utilizing such a second oxidant, only the terminal hydroxyl group (OH) in compound 7 can be oxidized to an aldehyde group to obtain compound 8.

[0075] In the present invention, preferably, the inorganic base used in step 3 can be one or more selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, etc.

[0076] In the present invention, preferably, the organic solvent used in step 3 may be an organic solvent independently selected from those described above for step 1.

[0077] In the present invention, more specifically, for example, step 3 can be carried out as follows: dissolve compound 7 in an organic solvent, start stirring, cool to 0-15 ° C, add the second oxidant in batches, naturally warm to room temperature, and stir for 1-4 hours. After the reaction is complete, add diatomaceous earth for filtration, and the filtrate is spin-dried to obtain a concentrate. The concentrate is dissolved in an organic solvent, an inorganic base is added to adjust the pH to 7-10, and stirred at room temperature for 3-6 hours. Filter by suction to obtain a filtrate, wash the filtrate with saturated brine, separate the layers to obtain an organic phase, spin-dry the filtrate, and concentrate the organic phase to obtain compound 8 as a solid.

[0078] Step 4

[0079] The resulting compound 8 undergoes a cyclization reaction under basic conditions to give compound 9.

[0080] Preferably, step 4 can be carried out as follows: in an organic solvent, in the presence of a base, subjecting the obtained compound 8 to a cyclization reaction at 25-60° C. to obtain compound 9.

[0081] In the present invention, preferably, the inorganic base used in step 4 can be one or more selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydride, potassium hydride, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, etc.

[0082] In the present invention, preferably, the inorganic acid used in step 4 can be one or more selected from hydrochloric acid, sulfuric acid, phosphoric acid, glacial acetic acid, citric acid and the like.

[0083] In the present invention, preferably, the organic solvent used in step 4 may be an organic solvent independently selected from those described above for step 1.

[0084] In the present invention, more specifically, for example, step 4 can be carried out as follows: under an inert atmosphere such as a nitrogen atmosphere, compound 8 is dissolved in an organic solvent, stirring is started, and then an inorganic base solution is slowly added, the temperature is raised to 35-45°C, and the temperature is kept stirred for 10-14 hours. After the reaction is complete, the temperature is lowered to -15-0°C, water is added to quench the reaction, and then an inorganic acid is added dropwise to adjust the pH to 3-6. After adjustment, the layers are separated, and the organic layer is washed once with a saturated sodium bicarbonate solution and once with saturated brine. The organic layer is then spin-dried to obtain compound 9 as a solid.

[0085] Step 5

[0086] The resulting compound 9 is reacted with a third oxidizing agent to give compound 10.

[0087] Preferably, step 5 can be carried out as follows: oxidizing the obtained compound 9 with a third oxidizing agent at 0-25° C. in an organic solvent to obtain compound 10.

[0088] In step 5, preferably, the third oxidant used can be one or more selected from peracetic acid, sodium periodate and m-chloroperbenzoic acid. Such third oxidants are known in the art and can be commercially obtained. In this step 5, by utilizing such a third oxidant, reoxidation can occur on the sulfhydryl (S) in compound 9 to obtain compound 10.

[0089] In the present invention, preferably, the organic solvent used in step 5 may be an organic solvent independently selected from those described above for step 1.

[0090] In the present invention, more specifically, for example, step 5 can be performed as follows: Compound 9 is dissolved in an organic solvent, stirred, cooled to 0-10°C, and an organic solution of a third oxidant is added. After the addition is complete, the temperature is raised to room temperature and incubated for 1 hour. After the reaction is complete, a quencher such as a saturated aqueous NaHCO₃ solution is added to terminate the reaction. The organic phase is dried by spin drying, an organic solvent such as ethyl acetate is added, and the layers are extracted and separated. The organic layer is washed with saturated brine to obtain an organic phase, which is then dried by spin drying and purified by column chromatography to yield Compound 10.

[0091] Step 6

[0092] The obtained compound 10 is reacted with a methylating agent in the presence of a first reducing agent to obtain a compound of formula I.

[0093] Preferably, step 6 can be carried out as follows: in an organic solvent, in the presence of a first reducing agent and a methyl amination reagent, the obtained compound 10 is subjected to reductive amination at 0-25° C. to remove the amino protecting group R 3 and R 4 are replaced by methyl groups, thereby obtaining compounds of formula I.

[0094] In step 6, preferably, the first reducing agent used can be a combination of one or more selected from Pd / C and H2, Raney nickel and H2, or zinc powder and H2. Such a first reducing agent is known in the art and can be commercially obtained or conventionally prepared by those skilled in the art.

[0095] In step 6, preferably, the methylamination reagent used can be one or more selected from aqueous formaldehyde, trioxymethylene and paraformaldehyde. Such methylamination reagents are known in the art and can be commercially obtained or conventionally prepared by those skilled in the art.

[0096] In the present invention, preferably, the reductive amination in step 6 is actually a one-pot reaction of deprotection reaction and reductive methylation. In step 6, by using such a first reducing agent and a methylation agent, the protecting group R on the amino group of compound 10 can be simultaneously achieved. 3 and R 4 removal and reductive dimethylation.

[0097] In step 6, preferably, the organic solvent used may be an organic solvent independently selected from those described above for step 1.

[0098] In the present invention, more specifically, for example, step 6 can be carried out as follows: compound 10 is dissolved in an organic solvent, stirring is started, a methylating agent and a first reducing agent are added in sequence, and the reaction is carried out at room temperature for a period of time, for example, 6 hours. Preferably, after the reductive amination reaction is completed, the resulting reaction mixture is subjected to post-treatment including extraction, washing, drying and column chromatography to obtain a compound of formula I. Specifically, for example, after the reductive amination reaction is completed, the resulting reaction mixture is filtered, the organic phase is spin-dried, an organic solvent and an aqueous solution such as NaHCO3 solution are added, the organic layer is separated, and the organic layer is washed once with a saturated saline solution, dried over anhydrous sodium sulfate, filtered, the filtrate is spin-dried, and column chromatography is performed to obtain the desired compound of formula I.

[0099] In the present invention, compound 5 used as a reaction substrate can be prepared using commercially available compound 2 as a starting material.

[0100] Step 7

[0101] Under basic conditions, compound 2 is reacted with compound S5 to give compound 3.

[0102] Preferably, step 7 can be carried out as follows: Compound 2 as a starting substrate is reacted with compound S5 at 40-90° C. in an organic solvent in the presence of a base to obtain compound 3.

[0103] In the present invention, compounds 2 and S5 used as starting substrates are commercially available or synthesized or prepared according to methods in existing literature.

[0104] In the present invention, the group R in compound S5 1 and R 2 are as defined above for compound 5, and they may be independently selected from H and C 1-10 alkyl.

[0105] In step 7, preferably, the base used can be one or more selected from potassium carbonate, sodium carbonate, potassium phosphate, potassium bicarbonate, sodium bicarbonate, etc.

[0106] In step 7, preferably, the organic solvent used may be an organic solvent independently selected from those described above for step 1.

[0107] In the present invention, more specifically, for example, step 7 can be performed as follows: Compound 2, Compound S5, and an inorganic base are dissolved in an organic solvent, stirred, and heated in a water bath to 60-80°C and incubated overnight. Water is then added to terminate the reaction, the temperature is reduced to 0-10°C and incubated for 30 minutes, filtered, and the organic phase is spin-dried to obtain a concentrate. The temperature is then raised to 40-60°C, and the concentrate is crystallized in a crystallization solvent. The temperature is then reduced to 0°C and incubated for 30 minutes, filtered, and the solid is dried to obtain Compound 3.

[0108] In step 7, preferably, the crystallization solvent used can be a combination solvent such as ethyl acetate / n-hexane, dichloromethane / n-hexane, etc.

[0109] Step 8

[0110] Compound 3 is reacted with a second reducing agent to obtain compound 4.

[0111] Preferably, step 8 can be carried out as follows: in an organic solvent, in the presence of a second reducing agent, subjecting the obtained compound 3 to a reduction reaction at 0-20° C. to obtain compound 4.

[0112] In step 8, preferably, the second reducing agent used can be one or more selected from sodium borohydride, potassium borohydride, borane, trimethylsilane, triethylsilane and tripropylsilane. Such second reducing agents are known in the art and can be commercially obtained or conventionally prepared by those skilled in the art. By utilizing such a second reducing agent, only the connecting carbonyl group between the two phenyl rings of compound 3 can be reduced to a methylene group (-CH2) in step 8.

[0113] In step 8, preferably, the organic solvent used may be an organic solvent independently selected from those described above for step 1.

[0114] In the present invention, more specifically, for example, step 8 can be performed as follows: Compound 3 is dissolved in an organic solvent, stirred, cooled to 0-10°C, a second reducing agent is added, and the temperature is kept overnight. Water is then added to terminate the reaction, the layers are separated, and the mixture is washed twice with saturated sodium bicarbonate and twice with water. The organic phase is concentrated to dryness and then filtered through a column to obtain Compound 4.

[0115] Step 9

[0116] Compound 4 is reacted with a third reducing agent to obtain compound 5.

[0117] Preferably, step 9 can be carried out as follows: in an organic solvent, in the presence of a third reducing agent, subjecting the obtained compound 4 to a reduction reaction at 0-25° C. to obtain compound 5.

[0118] In step 9, preferably, the third reducing agent used can be a combination reducing agent selected from one or more of Pd / C / H2, Raney nickel / H2, iron / hydrochloric acid, or zinc / hydrochloric acid. Such third reducing agents are known in the art and can be commercially obtained or conventionally prepared by those skilled in the art. By utilizing such a third reducing agent, the nitro group (-NO2) of compound 4 can be reduced to an amino group (-NH2) in step 9.

[0119] In step 9, preferably, the organic solvent used may be an organic solvent independently selected from those described above for step 1.

[0120] In the present invention, more specifically, for example, step 9 can be performed as follows: dissolve compound 4 in an organic solvent, start stirring, add a third reducing agent, and keep warm for 5-9 hours. Filter with suction, and evaporate the filtrate to dryness to obtain compound 5.

[0121] The present invention also provides the following intermediate compounds 3 to 10 obtained by the method of the present invention:

[0122] Among them, R 1 、R 2 、R 3 and R 4 As defined above. More specifically, in the method of the present invention, the following intermediate compound is provided:

[0123] The compound of formula I obtained by the method of the present invention and the intermediate compound can be used to prepare the drug Maralixibat. For example, the specific process can be shown in the following reaction scheme 4:

[0124] Reaction Scheme 4

[0125] For example, the specific reaction process for preparing the drug Maralixibat from Compound I of Formula I can refer to the content disclosed in CN1284953A.

[0126] The starting materials used in the preparation method of the present invention are known or commercially available, or can be prepared by conventional methods known to those skilled in the art or by methods in the prior art, or can be readily prepared by methods similar to methods known in the art. For example, the chiral ligands that can be used in the present invention can be purchased from Daicel Pharmaceutical Chiral Technology (Shanghai) Co., Ltd., and the starting material compound S5 can be prepared, for example, according to the contents described in the prior art document (Bioorg. Med. Chem. Lett. 24 (2014) 386–389).

[0127] The organic solvents, acids, bases, catalysts, protecting groups, etc. used in the present invention are all commercial products and are not particularly limited in their use.

[0128] The abbreviations used in the foregoing description and the following examples are as follows:

[0129] Cbz: benzyloxycarbonyl.

[0130] CbzCl: benzyl chloroformate.

[0131] DMP: dimethyl phthalate.

[0132] NaHCO3: sodium bicarbonate.

[0133] H2O2: Hydrogen peroxide.

[0134] (Boc)2O: Di-tert-butyl dicarbonate

[0135] NaH: sodium hydride

[0136] KH: Potassium hydride

[0137] The following examples are used to specifically illustrate certain preferred or specific compounds and reaction conditions that can be used in the present invention, but the scope of protection of the present invention is not limited thereto.

[0138] In addition, it should be noted that, in order to be more in line with actual reaction operation and to be more convenient for reaction control, some reaction condition parameters in the following examples use numerical ranges rather than specific values. It will be understood by those skilled in the art that such ranges represent that corresponding reaction results can be achieved as long as corresponding reaction conditions are controlled within corresponding ranges (without the need for an accurate specific value) in the reaction.

[0139] Example 1

[0140] At room temperature, a reaction flask was added with 70g of compound 2 (B&K), 36.1g of potassium carbonate, 55.1g of compound S5 (2-butyl-2-(mercaptomethyl)hexan-1-ol, obtained according to the method described in Bioorg. Med. Chem. Lett. 24 (2014) 386–389), and 300ml of N,N-dimethylformamide. The mixture was heated to approximately 70-75°C and stirred overnight. After the reaction was complete, 900ml of water was added dropwise, causing solid precipitation. The temperature was cooled to room temperature and then to 0°C for 30 minutes. The filtrate was filtered and concentrated to dryness to obtain a concentrate. 105ml of ethyl acetate was added to the concentrate, and the temperature was heated to 50-55°C with stirring to dissolve the mixture. Hexane was added dropwise until solid precipitation occurred. The temperature was then cooled to 0°C for 30 minutes. The solid was filtered and dried to obtain 94.8g of compound 3, with a yield of 88%. 1 H NMR (400MHz, chloroform-d) δ8.23(dd,J=8.77,2.53Hz,1H),8.13(d,J=2.51Hz,1H),7.76(d,J=8.88Hz,2H),7.62(d,J=8.83Hz,1H ), 6.95 (d, J = 8.87Hz, 2H), 3.88 (s, 3H), 3.41 (d, J = 5.48Hz, 2H), 2.99 (s, 2H), 1.30 ~ 1.12 (m, 12H), 0.85 (t, J = 7.07Hz, 6H). 13 C NMR (101 MHz, chloroform-d) δ 193.2, 164.4, 147.5, 144.3, 139.3, 132.6, 128.9, 128.3, 124.7, 123.3, 114.1, 65.8, 55.6, 41.4, 39.7, 32.8, 25.1, 23.3, 14.0.

[0141] Example 2

[0142] At room temperature, 70g of compound 2, 54.6g of potassium phosphate, 55.1g of compound S5, and 280ml of tetrahydrofuran were added to a reaction flask, heated to 70°C, and stirred overnight. After the reaction was complete, the mixture was evaporated to dryness, and the concentrate was added with 1000ml of water and slurried for 1-2 hours. The filtrate was then filtered and concentrated to dryness. 105ml of ethyl acetate was added to the concentrate, and the temperature was raised to 50-55°C and stirred to dissolve. N-hexane was added dropwise until solid precipitated. The mixture was then cooled to room temperature and then to 0°C for 30 minutes. The solid was filtered and dried to obtain 92.9g of compound 3, with a yield of 85%.

[0143] Example 3

[0144] At room temperature, add 70g of compound 2, 27.7g of sodium carbonate, 55.1g of compound S5, and 350ml of methanol to a reaction flask, raise the temperature to 65-70°C, and keep warm overnight. After the reaction is complete, evaporate to dryness, add 850ml of water to the concentrate, beat for 0.5-1h, cool to 0°C, keep warm for 1-2 hours, filter with suction, and concentrate the filtrate to obtain a concentrate. Add 120ml of dichloromethane to the concentrate, heat to 40°C, stir to dissolve, add n-heptane dropwise until solid precipitates, cool to 0°C, keep warm for 60 minutes, filter with suction, and dry the solid to obtain 94.0g of compound 3, with a yield of 86%.

[0145] Example 4

[0146] At room temperature, 140 g of compound 3 and 900 g of dichloromethane were added to a reaction flask. The temperature was lowered to 0°C, and 195.2 g of trifluoromethanesulfonic acid and 114.2 g of triethylsilane were added sequentially. The mixture was stirred overnight. After the reaction was complete, ice water was slowly added to terminate the reaction. The layers were separated and washed twice with saturated sodium bicarbonate and twice with water. The organic phase was concentrated, dried, and filtered through a column to yield 115.5 g of compound 4, with a yield of 85%. 1 H NMR (400MHz, chloroform-d) δ8.02(dd,J=8.74,2.58Hz,1H),7.86(d,J=2.54Hz,1H),7.38(d,J=8.78Hz,1H),7.10(m,J=8.61Hz,2H),6.8 5(d,J=8.66Hz,2H),4.03(s,1H),3.79(s,2H),3.51(d,J=4.17Hz,1H),3.00(s,1H),1.43~1.18(m,14H),0.91(t,J=7.13Hz,6H).

[0147] Example 5

[0148] At room temperature, 140 g of compound 3 and 1000 ml of 1,2-dichloroethane were added to a reaction flask. The temperature was lowered to 0°C, followed by the addition of 180.0 g of hydrochloric acid and 114.2 g of triethylsilane. The reaction was stirred overnight. After the reaction was complete, saturated sodium bicarbonate was slowly added to terminate the reaction. The layers were separated and washed twice with brine and twice with water. The organic phase was concentrated to dryness and filtered through a column to yield 111.3 g of compound 4, with a yield of 83%.

[0149] Example 6

[0150] At room temperature, 140 g of compound 3 and 940 ml of ethyl acetate were added to a reaction flask. The temperature was lowered to 0°C, followed by the addition of 240 g of glacial acetic acid and 114.2 g of triethylsilane. The reaction was stirred overnight. Water was added, the layers separated, and the mixture was washed twice with water. The organic phase was concentrated, dried, and filtered through a column to yield 114.0 g of compound 4, with a yield of 84%.

[0151] Example 7

[0152] At room temperature, 50 g of compound 4, 500 ml of methanol, and 5.0 g of Raney nickel were added to an autoclave, replaced with hydrogen, and sealed and kept at room temperature for 6 hours. After the reaction was complete, the filtrate was filtered and evaporated to dryness to obtain 86 g of compound 5, with a crude yield of 100%.

[0153] Next, 86 g of compound 5, 750 ml of tetrahydrofuran, and 42.5 g of finely powdered potassium carbonate were added to the reaction flask, stirring was started, the temperature was lowered to 5 ° C, and 38.6 g of CbzCl was slowly added dropwise. After the dropwise addition, the mixture was kept warm for 3-4 hours. After the reaction was complete, the solvent was evaporated, 500 g of water and 500 g of ethyl acetate were added, and the mixture was stirred thoroughly and separated. The aqueous phase was washed with ethyl acetate, the organic phases were combined, washed with 500 g of water, and the organic phase was concentrated under reduced pressure to obtain 160 g of oily compound 6, with a crude yield of 100%.

[0154] Example 8

[0155] At room temperature, a reaction flask was charged with 60 g of compound 4, 360 ml of ethanol, 240 ml of water, and 4.8 g of Pd / C. The atmosphere was replaced with hydrogen and the mixture was kept at room temperature for 6 hours. After the reaction was complete, the mixture was filtered, evaporated to dryness, and jacketed twice with 150 ml of ethanol to yield 103.2 g of compound 5, a crude yield of 100%.

[0156] Next, 103.2 g of compound 5, 900 ml of acetonitrile, and 39.1 g of finely powdered sodium carbonate were added to the reaction flask. Stirring was initiated, the temperature was lowered to 0-10°C, and 45.4 g of CbzCl was slowly added dropwise. After completion of the addition, the mixture was incubated for 3 hours. After the reaction was complete, 500 g of water was added. The layers were separated, and the organic phase was washed with 500 g of water. The organic phase was evaporated to dryness to obtain 192 g of compound 6 as an oil, with a crude yield of 100%.

[0157] Example 9

[0158] At room temperature, under H2 protection, 40g of compound 4, 400ml of methanol, and 4.0g of Raney nickel were added to the reaction flask and kept warm for 6-7 hours. After the reaction was complete, the filtrate was filtered and evaporated to dryness to obtain 68.9g of compound 5, with a crude yield of 100%.

[0159] Next, 68.8 g of compound 5, 600 ml of tetrahydrofuran, and 33.5 g of finely powdered potassium carbonate were added to the reaction flask. Stirring was initiated, the temperature was lowered to 5°C, and 39.5 g of (Boc)2O was slowly added dropwise. After completion of the addition, the mixture was incubated for 3 hours. After the reaction was complete, the mixture was evaporated to dryness, 400 g of water and 400 g of dichloromethane were added, and the layers were separated. The organic phase was washed once with 350 g of water and evaporated to dryness to obtain 136.4 g of compound 6 as an oil, with a crude yield of 100%.

[0160] Example 11

[0161] At room temperature, 26.5 mg (1 mol%) of acetylacetonatovanadium and 40 mL of acetone were added to dissolve the mixture. 31.9 mg (1.04 mol%) of the chiral ligand (as shown in the chemical formula to the right of the dotted line in the above reaction formula) was then added. After stirring for 10 minutes, a solution of 5.5 g (10 mmol) of compound 6 in acetone (40 mL) was added. The mixture was cooled to -10°C and a 30% hydrogen peroxide solution (1 mL) in acetone (30 mL) was slowly added dropwise to the reaction mixture at a flow rate of 3.1 mL / h using a syringe pump. The addition was completed over 10 hours. After the reaction was complete, a dilute sodium thiosulfate solution was added and stirred to quench the mixture for 10 minutes. The reaction mixture was spin-dried, and about 200 mL of EA was added to dissolve the solid. The mixture was washed with saturated brine. The EA phase was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the mixture was spin-dried to obtain 5.65 g of solid, with a crude yield of 99.9%. A sample was taken for chiral HPLC detection, and the ee value was 89.1%. Add 15 mL of isopropanol and 0.75 mL of water to the crude product and heat to 80°C until the solid completely dissolves. Slowly cool to 40°C and maintain for 1–2 h. After this, turn off the heat and cool to room temperature. Solids gradually precipitate and are filtered to yield 5.6 g of compound 7, a 99% yield with an ee value of 99.5%. 1 H NMR (400MHz, chloroform-d) δ7.96 (d, J=8.60Hz, 1H), 7.55 (dd, J=8.62, 2.25Hz, 1H), 7.44~7.36 (m, 6H), 7 .02(d,J=8.20Hz,2H),6.84(d,J=8.54Hz,2H),5.24(s,2H),4.04(s,2H),3.80(s,3H),3.69(d,J =12.21Hz,1H),3.46(d,J=12.22Hz,1H),2.78(d,J=13.81Hz,1H),2.24(d,J=13.83Hz,1H),1.61 (dd, J=12.81, 9.70Hz, 1H), 1.38~1.09 (m, 11H), 0.95 (t, J=7.20Hz, 3H), 0.87 (t, J=7.30Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ 158.4, 153.1, 140.9, 139.0, 136.7, 135.8, 130.8, 129.6, 128.7, 128.6, 128.4, 126.0, 120.3, 118.1, 114.3, 68.0, 67.4, 55.3, 42.2, 37.1, 35.6, 32.5, 25.1, 25.0, 23.5, 23.3, 14.2, 14.0.

[0162] Example 12

[0163] At room temperature, 25.6 mg (1 mol%) of nickel acetylacetonate Ni(acac) 2, 33.3 mg (1.04 mol%) of a chiral ligand (as shown in the chemical formula to the right of the dotted line in the above reaction formula), 5.5 g (10 mmol) of compound 6, and 40 mL of acetonitrile were added to dissolve the mixture. The mixture was cooled to -10 ° C and slowly added with a solution of 0.76 g of peracetic acid in 30 mL of acetonitrile and kept warm for 3 hours. After the reaction was completed, the mixture was filtered, the mother liquor was dried, 200 mL of ethyl acetate was added to dissolve the solid, the mixture was washed with saturated salt water, and the organic phase was dried to give 5.65 g of solid, with a crude yield of 99.9%. The chiral HPLC analysis showed an ee value of 89.1%. 50 mL of methanol and 60 mL of water were added to the crude product, the mixture was heated to 50 ° C, the solid was completely dissolved, the temperature was slowly lowered to room temperature, and the mixture was kept warm for 2 h. After the insulation was completed, the heat was turned off and the mixture was cooled to room temperature. The solid gradually precipitated and filtered to give 5.6 g of compound 7, with a yield of 99% and an ee value of 98.9%.

[0164] Example 13

[0165] At room temperature, add 17.7 mg (1 mol%) of palladium dichloride and 40 mL of isopropanol to dissolve the mixture. Then add 36.7 mg (1.04 mol%) of the chiral ligand (as shown in the chemical formula to the right of the dotted line in the above reaction equation) and stir for 10 minutes. Then add a solution of 5.5 g (10 mmol) of compound 6 in isopropanol (10 mL). Cool to -10°C and slowly add a solution of 1.72 g of m-chloroperbenzoic acid in isopropanol (10 mL). Keep warm for 2-3 hours. Filter with suction, concentrate and dry, add 15 mL of isopropanol and 0.75 mL of water, heat to 80°C, and completely dissolve the solid. Slowly cool to 40°C and keep warm for 2 hours. After the insulation is completed, turn off the heat and cool to room temperature. The solid gradually precipitates and is filtered to obtain 5.6 g of compound 7 with a yield of 99% and an ee value of 99.8%.

[0166] Example 14

[0167] At room temperature, add 26.5 mg (1 mol%) of acetylacetonatovanadium and 40 mL of acetone, dissolve it, then add 31.9 mg (1.04 mol%) of the chiral ligand (specifically, as shown in the chemical formula to the right of the dotted line in the above reaction equation), stir for 10 minutes, and then add a solution of 5.15 g (10 mmol) of compound 6 in acetone (40 mL). Cool the temperature to -10°C, slowly add a solution of 1.72 g of m-chloroperbenzoic acid in acetone (10 mL), and keep the reaction warm for 3 hours. Filter with suction, concentrate and dry to obtain a crude product. Add 12 mL of isopropanol and 1.1 mL of water to the crude product, heat to 80°C, and completely dissolve the solid. Slowly cool to 40°C and keep warm for 2 hours. After the insulation is completed, turn off the heat, cool to room temperature, and the solid gradually precipitates. Filter with suction to obtain 5.2 g of compound 7, with a yield of 98% and an ee value of 99.1%.

[0168] Example 15

[0169] At room temperature, 2.43g of compound 7 (4.3mmol) and 25mL of dichloromethane were added, cooled to 15°C, and 2.19g (11.3mmol) of dimethyl phthalate were added in batches, and the temperature was naturally raised and stirred for 1h. After the reaction was complete, diatomaceous earth was added and the filtrate was spin-dried, 75mL of methyl tert-butyl ether was added, and 25mL of saturated sodium bicarbonate solution was added to adjust the pH to 7. The mixture was stirred at room temperature for 3 hours until a solid precipitated. The filter cake was washed several times with methyl tert-butyl ether, the filtrate was combined, and saturated brine was added to wash the mixture. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give the product compound 8, 2.43g, with a yield of 100%, which was directly used in the next step. 1 H NMR (400MHz, chloroform-d) δ9.46 (s, 1H), 7.92 (d, J = 8.66Hz, 1H), 7.51 (dd, J = 8.61, 2.24Hz, 1H), 7.37 (dd, J = 3.59 ,1.29Hz,4H),7.25(d,J=4.15Hz,1H),6.99(d,J=8.41Hz,3H),6.80(d,J=8.63Hz,2H),5.18(s,2H),4.01( q,J=15.74Hz,2H),3.75(s,3H),2.90(d,J=13.96Hz,1H),2.46(d,J=14.02Hz,1H),1.88(td,J=13.23,12. 14,3.99Hz,1H),1.67~1.56(m,4H),1.36~1.18(m,5H),1.10~1.01(m,3H),0.87(dt,J=20.31,7.19Hz,6H). 13C NMR (101 MHz, chloroform-d) δ 204.0, 158.4, 153.0, 140.8, 139.2, 137.7, 135.7, 131.0, 129.7, 128.6, 128.4, 128.3, 125.9, 120.1, 118.0, 114.2, 67.3, 60.9, 55.2, 51.9, 36.9, 33.0, 32.0, 25.7, 25.5, 23.1, 23.1, 13.8, 13.7.

[0170] Next, under nitrogen, 1.13 g of compound 8 (2 mmol) and 30 mL of anhydrous tetrahydrofuran were added, and 5.0 mL of a 1 mol / L potassium tert-butoxide solution was added dropwise at room temperature. After completion of the addition, the temperature was raised to 40°C and stirring was continued for 10 h. After the reaction, the temperature was lowered to -15°C, 20 mL of water was added dropwise to quench the reaction, and 0.5 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 3. After adjustment, the layers were separated, the aqueous layer was extracted with EA, and the organic layers were combined and washed sequentially with saturated NaHCO3 and saturated brine. The organic layers were spin-dried to obtain 91.14 g of crude compound (100% yield), which was used directly in the next reaction. 1 H NMR (400 MHz, chloroform-d) δ 7.72 (s, 2H), 7.36 (d, J = 8.61 Hz, 2H), 7.30 (s, 5H), 6.90 (d, J = 8.74 Hz, 2H), 6.57 (s, 1H), 5.10 (s, 2H), 4.44 (s, 1H), 4.10 (q, J = 7.15 Hz, 1H), 3.94 (s, 1H), 3.79 (s ,3H),2.95(d,J=12.95Hz,1H),2.83(dd,J=12.97,2.63Hz,1H),2.02(s,2H),1.87(td,J=1 3.20, 3.68Hz, 1H), 1.64 ~ 1.57 (m, 1H), 1.47 ~ 1.30 (m, 7H), 0.90 (dt, J = 17.29, 7.12Hz, 6H). 13 C NMR (101 MHz, chloroform-d) δ 158.7, 153.0, 139.9, 136.2, 135.8, 134.0, 129.8, 128.5, 128.3, 128.2, 123.8, 121.0, 117.8, 114.3, 74.5, 67.1, 60.3, 59.6, 55.2, 46.7, 44.9, 35.4, 31.8, 25.0, 24.3, 23.3, 23.2, 13.9.

[0171] Example 16

[0172] At room temperature, 2.69g of compound 7 (5.0mmol) and 25mL of dichloromethane were added, cooled to 10°C, and 2.41g (12.5mmol) of dimethyl phthalate were added in batches. The temperature was naturally raised and stirred for 1h. After the reaction was complete, celite was added and filtered. The filtrate was spin-dried, 45mL of dichloromethane was added, and 25mL of saturated sodium bicarbonate solution was added to adjust the pH to 8. The mixture was stirred at room temperature for 5 hours until a solid precipitated. The filtrate was filtered and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was spin-dried to give the product compound 8, 2.67g, with a yield of 100%, which was directly used in the next step.

[0173] Next, under nitrogen, 1.07 g of compound 8 (2 mmol) and 25 mL of anhydrous acetonitrile were added, and 5.0 mL of a 1 mol / L potassium tert-butoxide solution was added dropwise at room temperature. After completion, the temperature was raised to 45°C and stirring continued for 12 h. After the reaction, the temperature was lowered to -15°C, quenched by the addition of 20 mL of water, and the pH was adjusted to 5 by the addition of glacial acetic acid. After adjustment, the layers were separated, the aqueous layer was extracted with EA, and the organic layers were combined and washed sequentially with saturated NaHCO3 and saturated brine. The organic layers were then spin-dried to obtain 1.07 g of crude compound 9 (a crude yield of 100%), which was used directly in the next reaction.

[0174] Example 17

[0175] At room temperature, add 2.89 g of compound 7 (5.0 mmol) and 30 mL of dichloromethane. Cool to 10°C, then add 10 mL of aqueous hydrogen peroxide in portions. Heat naturally and stir for 1 hour. After the reaction is complete, wash the organic phase twice with saturated brine, combine the filtrates, and spin-dry to obtain 82.89 g of the product compound (100% yield), which is used directly in the next reaction.

[0176] Next, under nitrogen, 1.15 g of compound 8 (2 mmol) and 30 mL of anhydrous dichloromethane were added, and 5.0 mL (2.5 mmol) of a 1 mol / L sodium tert-butoxide solution was added dropwise at room temperature. After completion, the temperature was raised to 60°C and stirring continued for 12 hours. After the reaction was complete, the temperature was lowered to 0°C, and methanesulfonic acid was added dropwise to adjust the pH to 3. The layers were separated, and the organic layer was washed twice with saturated NaHCO₃ and then dried to dryness, yielding 1.16 g of crude compound 9 (100% yield), which was used directly in the next reaction.

[0177] Example 18

[0178] At room temperature, 2.28 g of compound 7 (4.3 mmol) and 20 mL of acetone were added. The mixture was cooled to 15°C, and 2.54 g of dimethyl phthalate (6.0 mmol) was added portionwise. The mixture was naturally heated and stirred for 1 h. After the reaction was complete, celite was added and filtered to obtain a filtrate. The filtrate was adjusted to pH 7 with saturated NaHCO₃ solution and stirred at room temperature for 3 hours until a solid precipitated. The mixture was filtered and the filter cake was washed several times with acetone. The filtrates were combined and washed with saturated brine. The layers were separated and the organic phase was spin-dried to obtain 2.43 g of the product, compound 8, with a yield of 100%, which was used directly in the next reaction.

[0179] Next, under nitrogen, 1.06 g of compound 8 (2 mmol) and 30 mL of acetone were added, and 5.0 mL (2.5 mmol) of a 1 mol / L potassium tert-butoxide solution was added dropwise at room temperature. After completion of the addition, the temperature was raised to 40°C and stirring was continued for 10 h. After the reaction was complete, the temperature was lowered to 0°C, and aqueous citric acid was added dropwise to adjust the pH to 4. The layers were separated, the aqueous layer was extracted with EA, and the organic layers were combined, washed with saturated brine, and dried to give 1.06 g of crude compound 9 (a crude yield of 100%), which was used directly in the next reaction.

[0180] Example 19

[0181] At room temperature, add 2.43 g of compound 7 (4.3 mmol) and 25 mL of acetonitrile, cool to 15°C, and add 10 mL of aqueous hydrogen peroxide in portions. Heat naturally and stir for 1 hour. After the reaction is complete, concentrate to dryness, add ethyl acetate to dissolve the clear phase, and wash the organic phase twice with saturated brine. The combined filtrates are then spin-dried to give 2.43 g of compound 8 (100% yield), which is used directly in the next reaction.

[0182] Next, under nitrogen, 1.13 g of compound 8 (2 mmol) and 30 mL of acetonitrile were added, and 5.0 mL (2.5 mmol) of 1 mol / L potassium tert-butoxide solution was added dropwise at room temperature. After completion of the addition, the temperature was raised to 40°C and stirring was continued for 10 h. After the reaction was completed, the temperature was lowered to -15°C, 20 mL of water was added dropwise to quench the reaction, and 0.5 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 3. After adjustment, the layers were separated, the aqueous layer was extracted with EA, and the organic layers were combined and washed sequentially with saturated NaHCO3 and saturated brine. The organic layers were spin-dried to obtain 1.14 g of crude compound 9, with a crude yield of 100%, which was used directly in the next reaction.

[0183] Example 20

[0184] At room temperature, 1.14 g of compound 9 and 20 mL of methanol were added. After dissolution, the temperature was lowered to 0°C and 508 mg of chloroperbenzoic acid was added. After addition, the mixture was warmed to room temperature and incubated for 1 hour. After the reaction was complete, the methanol was evaporated, 20 mL of ethyl acetate was added, and the pH was adjusted to 7 with saturated NaHCO₃. The layers were separated by extraction and the organic layer was washed with saturated brine. The organic phase was evaporated and purified by column chromatography to yield 1.06 g of compound 10. The three-step yield was 92.1%, the ee value was 99.9%, and the dr value was >20:1.

[0185] 647 mg (1.12 mmol) of compound 10 and 10 mL of acetonitrile were added, stirred, and dissolved. 453 mg of 37% formaldehyde solution, 64 mg of Pd / C, and 26 mg of concentrated sulfuric acid were then added sequentially. The system was hydrogenated to 5 atm and reacted at room temperature for 6 hours. The Pd / C was recovered by filtration, and 60 mL of ethyl acetate and NaHCO3 solution were added. The layers were separated, and the organic layer was washed once with saturated NaCl solution. The filtrate was spin-dried and purified by column chromatography to obtain 725.6 mg of the compound of formula I in a yield of 98.5%, an ee value of 99.9%, and a dr value >20:1. 1 H NMR (400 MHz, chloroform-d) δ 7.93 (d, J = 8.83 Hz, 1H), 7.46 (d, J = 8.15 Hz, 2H), 6.97 (d, J = 8.59 Hz, 2H), 6.55 (dd, J = 8.89, 2.61 Hz, 1H), 6.02 (d, J = 2.57 Hz, 1H), 5.52 (s, 1H), 4.15 (d, J = 6.07 Hz, 1H), 3.88 (s, 3H), 3.1 8(d,J=15.18Hz,1H),3.03(d,J=15.12Hz,1H),2.85(s,6H),2.25(td,J=14.45,13.71,3.69Hz,1H),1 .66(td,J=13.57,12.86,4.06Hz,2H),1.54~1.38(m,2H),1.33~1.11(m,7H),0.94(q,J=6.88Hz,6H). 13 C NMR (101 MHz, chloroform- d ) δ 158.5, 153.1, 139.8, 135.1, 130.1, 129.3, 126.0, 114.6, 108.7, 57.5, 55.4, 46.3, 44.2, 39.8, 35.4, 29.8, 25.0, 24.5, 23.3, 14.2, 14.1.

[0186] Example 21

[0187] At room temperature, compound 9 (1.14 g) and 1,2-dichloroethane (20 mL) were added. After dissolution, the mixture was cooled to 0°C and sodium periodate (486 mg) was added. After addition, the mixture was warmed to room temperature and incubated for 1 hour. After the reaction was complete, the concentrate was filtered and evaporated to dryness. Column chromatography afforded compound 10 (1.15 g) with a three-step yield of 90%, an ee value of 99.7%, and a dr value >20:1.

[0188] Next, 647 mg (1.12 mmol) of compound 10 and 10 mL of ethanol were added. After stirring and dissolving, 410 mg of paraformaldehyde, 64 mg of Pd / C, and 45 mg of concentrated hydrochloric acid were added in sequence. The system was hydrogenated to 5 atm and reacted at room temperature for 6 hours. The Pd / C was recovered by filtration, the ethanol was dried, and EA and NaHCO3 solutions were added. The layers were separated, and the organic layer was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried. After column chromatography, 722 mg of the compound of formula I was obtained with a yield of 98%, an ee value of 99.7%, and a dr value of >20:1.

[0189] Example 22

[0190] At room temperature, under nitrogen, a reaction flask was added with 13 g of the compound of Formula I, 5.9 g of L-methionine, and 76 mL of methanesulfonic acid. The temperature was raised to 75°C and the reaction was maintained for 8 hours. After the reaction was complete, 100 g of water and 180 g of ethyl acetate were added for extraction. The organic phase was washed sequentially with 100 mL of saturated sodium bicarbonate solution and 100 g of water twice, and the organic phase was concentrated under reduced pressure to obtain a concentrate. The concentrate was filtered through a column to obtain 12.1 g of white compound 11 with a yield of 96%, an ee value of 99.9%, and a dr value of >20:1.

[0191] Next, under nitrogen, 12 g of compound 11, 2.0 g of 50% NaOH solution, and 80 g of N,N-dimethylacetamide were added to a reaction flask, stirred, and heated to 50°C for 30 minutes. A mixed solution containing 4 g of 4-(chloromethyl)-benzyl alcohol and 10 mL of N,N-dimethylacetamide was then added, and the mixture was allowed to react at 50°C for 24 hours. After completion of the reaction, 120 g of toluene and 70 g of water were added, and the mixture was stirred at 50°C for 10 minutes. The layers were separated, and the organic phase was washed with 100 g x 2 saturated NaCl solution, concentrated, and filtered to obtain 15 g of white compound 12 with a yield of 99.0%, an ee value of 99.9%, and a dr value >20:1.

[0192] Example 23

[0193] At room temperature, under nitrogen, 15 g of compound 12 and 80 g of toluene were added to a reaction flask. After stirring to dissolve, 3.3 g of thionyl chloride was added dropwise and the reaction was allowed to proceed at 35°C for 30 minutes. After the reaction was complete, 250 mL of 0.25 mol / L aqueous NaOH was added. The layers were separated, and the organic phase was washed twice with 100 mL x 2 saturated NaCl solution. The organic phase was evaporated to dryness to obtain a concentrate, which was then filtered through a column to obtain 14.78 g of white compound 13 with a yield of 95%, an ee value of 99.9%, and a dr value >20:1.

[0194] Next, under nitrogen protection, 13g of compound 13, 2.68g of triethylenediamine, and 280mL of acetonitrile were added to the reaction flask and the temperature was raised to 35°C for 2 hours. After the reaction was complete, filtration was performed to obtain 16.1g of a white solid. Recrystallization from methanol / diethyl ether gave 14.1g of the white solid pharmaceutical compound Maralixibat with a yield of 84%, an ee value of 99.9%, and a dr value of >20:1 (the characterization data of the pharmaceutical compound Maralixibat can be found in Example 10 of CN1284953A).

[0195] The above descriptions are merely preferred embodiments and / or examples of the present invention. It should be noted that a person skilled in the art may make several improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also within the scope of protection of the present invention.

Claims

1. A method for preparing a compound of formula I, comprising: Step 1: Compound 5 is reacted with an amino protecting group R 3 and R 4 The protective reagent was reacted to obtain compound 6; Step 2: In the presence of a chiral ligand and a metal catalyst, compound 6 is subjected to an oxidation reaction with a first oxidant to obtain compound 7; Step 3: reacting compound 7 with a second oxidant to obtain compound 8; Step 4: Under alkaline conditions, compound 8 undergoes a cyclization reaction to obtain compound 9; Step 5: reacting compound 9 with a third oxidant to obtain compound 10; and Step 6: In the presence of a first reducing agent, compound 10 is reacted with a methyl amination reagent to obtain a compound of formula I, Among them, R 1 and R 2 Independently selected from H and C 1-10 Alkyl, R 3 and R 4 is an amino protecting group independently selected from H, benzyl, 4-methoxybenzyl, benzylformyl, tert-butoxycarbonyl, formyl, acetyl, trifluoroacetyl and 9-fluorenylmethoxycarbonyl, and R 3 and R 4 Not H at the same time.

2. The method according to claim 1, characterized in that R 1 and R 2 independently selected from H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl.

3. The method according to claim 1, characterized in that R 1 and R 2 are independently selected from H, methyl, ethyl, n-propyl and n-butyl.

4. The method according to claim 1, characterized in that: The chiral ligand used in step 2 is selected from One or more of .

5. The method according to claim 1, characterized in that The metal catalyst used in step 2 is one or more selected from PdCl2, NiCl2, Pd(OH)2, Ni(acac)2, RhCl2 and CrCl2.

6. The method according to claim 1, characterized in that The first oxidant used in step 2 is one or more selected from H2O2, 3-phenyl-2-phenylsulfonyl-1,2-oxaziridine and benzoyl peroxide.

7. The method according to claim 1, characterized in that The second oxidant used in step 3 is one or more selected from potassium permanganate, manganese dioxide, and sodium hypochlorite.

8. The method according to claim 1, characterized in that The base used in step 4 is one or more selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, NaH, KH, lithium diisopropylamide, lithium hexamethyldisilazide and sodium hexamethyldisilazide.

9. The method according to claim 1, characterized in that: The third oxidant used in step 5 is one or more selected from peracetic acid, sodium periodate and meta-chloroperbenzoic acid.

10. The method according to claim 1, characterized in that The first reducing agent used in step 6 is one or more selected from Pd / C and H2, Raney nickel and H2, or zinc powder and H2.

11. The method according to claim 1, characterized in that: The methylamination reagent used in step 6 is one or more selected from formaldehyde, trioxymethylene and polyformaldehyde.

12. The method according to claim 1, characterized in that The compound 5 used was prepared by a method comprising the following steps: Step 7: Compound 2 reacts with compound S5 under alkaline conditions to obtain compound 3; Step 8: Compound 3 is reacted with a second reducing agent to obtain compound 4; and Step 9: Compound 4 is treated with a third reducing agent to obtain compound 5; Among them, R 1 and R 2 As mentioned above.

13. The method according to claim 12, characterized in that The base used in step 7 is one or more selected from potassium carbonate, sodium carbonate, potassium phosphate, potassium bicarbonate and sodium bicarbonate.

14. The method according to claim 12, characterized in that The second reducing agent used in step 8 is one or more selected from sodium borohydride, potassium borohydride, borane, trimethylsilane, triethylsilane and tripropylsilane.

15. The method according to claim 12, characterized in that The third reducing agent used in step 9 is one or more selected from Pd / C / H2, Raney nickel / H2, iron / hydrochloric acid or zinc / hydrochloric acid.

16. The following intermediate compounds used to prepare the drug Maralixibat: in, R 1 , R 2 , R 3 and R 4 As defined above.

17. The intermediate compound according to claim 16, characterized in that The intermediate compound is selected from: In these, Me represents a methyl group, Et represents an ethyl group, Bu represents a butyl group, and CBz represents a benzyloxycarbonyl group.

18. Use of a compound of formula I according to any one of claims 1 to 15 or an intermediate compound according to claim 16 or 17 in the preparation of the drug Maralixibat.

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