7-Ketolithocholic acid intermediates and their synthesis and application

Abstract

The present invention provides a method for synthesizing 7-ketolithocholic acid or its intermediates produced from a novel intermediate I-1. In the method, bisnoralcohol, a decomposition product of phytosterol, is used as a starting material, and 7-ketolithocholic acid or its intermediates can be obtained through oxidation, Knoevenagel reaction (or Wittig reaction), hydrogenation, esterification, ketal protection, allylic oxidation, ketal deprotection, and hydrogenation. The method of the present invention allows easy availability of raw materials, high yields, simple and mild reaction conditions, and is suitable for industrial production.

Description

[Technical field]

[0001] The present invention claims priority to the Chinese patent application filed with the State Intellectual Property Office of China on March 25, 2022, bearing patent application number 202210321891.5 and titled "7-ketolithocholic acid intermediate and its synthesis method and application", and the Chinese patent application filed with the State Intellectual Property Office of China on June 7, 2022, bearing patent application number 202210641979.5 and titled "7-ketolithocholic acid intermediate and its synthesis method and application", the entire contents of which are incorporated by reference into this application.

[0002] The present invention relates to the field of pharmaceutical synthesis, in particular to a 7-ketolithocholic acid intermediate and its synthesis method and application. [Background technology]

[0003] 7-ketolithocholic acid has a CAS number of 4651-67-6 and a molecular formula of C 24 H 38 O4, molecular weight 390.56, and structural formula: [ka]

[0004] 7-Ketotricholic acid is an important pharmaceutical intermediate. Chenodeoxycholic acid (Tetrahedron Letters Volume 24, Issue 24, 1983, Pages 2487-2490), ursodeoxycholic acid (J. Org. Chem. 1993, 58, Pages 499-501), obeticholic acid (J. Med. Chem. 2002, 45, 17, Pages 3569-3572), etc. can be synthesized using 7-ketotricholic acid as an intermediate as shown below. [ka]

[0005] Currently, most of the production processes for ursodeoxycholic acid and obeticholic acid are based on methods that use 7-ketolithocholic acid as a raw material, so it is extremely important to efficiently obtain 7-ketolithocholic acid.

[0006] According to the current literature and patent research situation, the synthesis of 7-ketolithocholic acid can be mainly classified into the following methods:

[0007] 1. Method using cholic acid as raw material WO2014020024A1 reports that cholic acid is used as a raw material, the acid in the side chain is esterified with a hydrochloric acid methanol solution, the hydroxyl groups (hydroxyl groups) at the 3- and 7-positions are doubly protected with acetic anhydride, the hydroxyl group at the 12-position is oxidized with sodium hypochlorite to form a ketone, and the ketone at the 12-position is reduced by performing a HuangMinglong reduction reaction, and finally, the hydroxyl group at the 7-position is selectively oxidized with sodium hypobromite to form a ketone, thereby obtaining the target compound 7-ketocholic acid. In the entire process, a high-temperature HuangMinglong reduction reaction is used. This reaction has relatively high requirements for equipment due to the relatively high temperature, high toxicity of hydrazine hydrate, and easy explosion. [ka]

[0008] 2. Method using chenodeoxycholic acid as raw material CN106046095 reports a method for oxidizing chenodeoxycholic acid with NBS (N-bromosuccinimide) in acetone and water to obtain 7-ketolithocholic acid. Chenodeoxycholic acid has a relatively high price, which limits its applications. [ka]

[0009] 3. Method using hyocholic acid as raw material Patent document CN110423261A reports a preparation method using hyocholic acid as raw material. The shortcomings of this solution are: 1) Chromium-based reagents such as Jones reagent are used, so there is a lot of pollution and environmental protection pressure; 2) Some reagents such as lithium iodide, TBSCl, etc. are expensive, so the cost of the whole route is high; 3) In the third step, pyridine is used as a solvent, so it has a strong odor and is relatively toxic. [ka]

[0010] In addition to the various shortcomings listed in the above three methods, another major reason is that all of these methods use cholic acid derived from animals. Animals generally contain various animal viruses, such as hog cholera, avian influenza, prion, and other various biologically active substances. These substances have a certain degree of toxicity to the human body. Therefore, it is necessary to find a new, safe and effective 7-ketolithocholic acid intermediate and its synthesis method. Summary of the Invention

[0011] In order to solve the above problems, the present invention aims to provide a method for producing 7-ketolithocholic acid or an intermediate thereof. The method is simple, has a high yield, and is safe and effective because it is produced by using a novel intermediate I-1. Another object of the present invention is to provide a novel intermediate I-1 and a method for producing the same.

[0012] The object of the present invention can be achieved by the following technical solutions: A method for producing a compound of formula I, comprising the step of hydrogenating a compound I-1 under the action of a catalyst to obtain a compound of formula I. [ka] (wherein R1 is a hydrogen atom (H) or an alkyl group; the alkyl group is, for example, 1~6 C is an alkyl group; 1~6 The alkyl groups are methyl, ethyl, propyl, and tert-butyl.

[0013] In one embodiment of the present invention, in the reaction, the catalyst is selected from the group consisting of Raney-Ni catalyst, Pd / C catalyst, Pt / C catalyst, and Ru / C catalyst.

[0014] In one embodiment of the present invention, in the reaction, the mass ratio of the compound I-1 to the catalyst is (2-20):1, for example, (5-15):1, and for example, 10:1.

[0015] In one embodiment of the present invention, the reaction is carried out in the presence of a solvent. The solvent is an amide-based solvent. The amide-based solvent is, for example, at least one selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide, and N,N-dimethylpropyleneurea.

[0016] In the present invention, in the above-mentioned method, when R1 in the compound of formula I is an alkyl group, the method further comprises the following step: hydrolyzing the compound of formula I in which R1 is an alkyl group to obtain the compound of formula I in which R1 is H, i.e., 7-ketolithocholic acid (7-KLCA). [ka]

[0017] According to the present invention, the hydrolysis reaction is carried out under alkaline conditions, for example, in the presence of sodium hydroxide, potassium hydroxide, or the like.

[0018] The present invention also provides intermediate compounds I-1 and I-2 shown below. [ka] (wherein R1 has the above definition and R2 is an alkyl group).

[0019] The present invention also provides a method for producing a pharmaceutical composition comprising the steps of: [ka] The present invention provides a method for producing compound I-1, comprising: (wherein R1 has the above definition and R2 is an alkyl group; h) performing an allylic oxidation reaction on compound I-3 to obtain compound I-2; i) A step of subjecting compound I-2 to a deprotection reaction with ethylene glycol to obtain compound I-1 in which R1 is an alkyl group; or a step of subjecting compound I-2 to a deprotection reaction with ethylene glycol and a hydrolysis reaction to obtain compound I-1 in which R1 is H.

[0020] In one embodiment of the present invention, in step h), compound I-3 undergoes an allylic oxidation reaction in the presence of an oxidizing agent and a catalyst to give compound I-2.

[0021] In one embodiment of the present invention, step h) is carried out in the following reaction sequence h1 or h2: h1: a reaction system in which the oxidant is oxygen gas or air, and the catalyst is N-hydroxyphthalimide (NHPI) and cobalt acetate; the reaction system may further include a radical initiator such as benzoyl peroxide; in an embodiment of the present invention, the molar ratio of compound I-3, catalyst, initiator and cobalt acetate is (1-20):1:1:(0.01-0.5), for example, (5-15):1:1:(0.02-0.1), for example, 10:1:1:0.05; h2: A reaction system in which the oxidant is tert-butyl hydroperoxide (TBHP) and the catalyst is manganese (III) acetate, manganese (III) acetate dihydrate, or copper iodide (CuI). In an embodiment of the present invention, the molar ratio of compound I-3, the oxidant, and the catalyst is 1:(1-20):(0.5-10), for example, 1:(2-10):(1-5), and for example, 1:5:2.74.

[0022] In one embodiment of the present invention, in step i), the deprotection reaction of ethylene glycol is carried out in the presence of an acid. The acid is, for example, at least one selected from the group consisting of concentrated sulfuric acid, p-toluenesulfonic acid, and hydrochloric acid. The hydrolysis reaction is carried out under alkaline conditions, for example, in the presence of sodium hydroxide or potassium hydroxide.

[0023] In one embodiment of the present invention, the method for preparing compound I-3 includes the following Scheme 1 or Scheme 2:

[0024] [ka] (wherein R2 has the above definition; b) Compound I-8 and malonic acid monoalkyl ester ( [ka] ) to obtain compound I-7 by Knoevenagel condensation reaction, or [ka] ) etc. [ka] (However, R3 and R4 are, for example, C such as ethyl.1~6 an alkyl group) to obtain compound I-7; d) performing a protection reaction of compound I-7 with ethylene glycol to obtain compound I-5; f) A step of subjecting compound I-5 to a reduction reaction to obtain compound I-3.

[0025] In one embodiment of the present invention, in step b), the molar ratio of compound 1-8 to malonic acid monoalkyl ester is 1:(0.5-10), for example, 1:(1-5), for example, 1:1.5.

[0026] In one embodiment of the present invention, step b) is carried out in the presence of a catalyst, said catalyst being DMAP (4-dimethylaminopyridine).

[0027] According to one embodiment of the present invention, step d) is carried out under the action of a catalyst. The catalyst is selected from catalyst A and / or catalyst B. The catalyst A is selected from p-toluenesulfonic acid or concentrated sulfuric acid. The catalyst B is selected from trimethyl orthoformate, triethyl orthoformate, or trimethyl orthoacetate. In one embodiment, when the catalyst is selected from catalyst A and catalyst B, the mass ratio of catalyst A to catalyst B may be 1:(0-100), for example, 1:(40-80), for example, 1:56.

[0028] In one embodiment of the present invention, in step d), the mass ratio of compound I-7, ethylene glycol, and the catalyst is 1:(0.2-5):(0.1-5), for example, 1:(0.5-3):(0.2-2), and one example is 1:1:0.57.

[0029] In one embodiment of the invention, step f) is carried out under the action of a catalyst, said catalyst being Pd / C.

[0030] In one embodiment of the present invention, in step f), the mass ratio of compound I-5 to the catalyst is (2-30):1, for example, (10-25):1, for example, 20:1.

[0031] [ka] (wherein R2 has the above definition; c) Compound I-8 and Meldrum's acid compounds ( [ka] , where R5 and R6 are C 1~6 an alkyl group (e.g., methyl), or R5, R6 together with the carbon atom to which they are attached are C 3~8 forming a cycloalkyl group) to obtain compound I-6; e) reacting compound I-6 with ROH to obtain compound I-4; g) Compound I-4 is subjected to a protection reaction with ethylene glycol to obtain compound I-3.

[0032] In one embodiment of the present invention, in step c), the molar ratio of compound I-8 to the Meldrum's acid compound is 1:(0.1-10), for example, 1:(0.5-5), for example, 1:1.2.

[0033] In one embodiment of the present invention, step e) is carried out under the action of a catalyst, said catalyst being at least one selected from the group consisting of concentrated sulfuric acid, p-toluenesulfonic acid and hydrochloric acid.

[0034] According to one embodiment of the present invention, step g) is carried out under the action of a catalyst. The catalyst is selected from catalyst A and / or catalyst B. The catalyst A is selected from p-toluenesulfonic acid or concentrated sulfuric acid. The catalyst B is selected from trimethyl orthoformate, triethyl orthoformate, or trimethyl orthoacetate. In one embodiment, when the catalyst is selected from catalyst A and catalyst B, the mass ratio of catalyst A to catalyst B may be 1:(0-100), for example, 1:(20-80), for example, 1:0, 1:29, 1:73.

[0035] In one embodiment of the present invention, in step g), the molar ratio of compound I-4, ethylene glycol, and the catalyst is 1:(1-50):(1-20), for example, 1:(5-25):(1-10), for example, 1:6.5:1.5, 1:21.6:6.2.

[0036] In one embodiment of the present invention, the method for preparing compound I-8 comprises the steps of: A step of oxidizing compound BA to obtain compound I-8. [ka] Effect of the Invention

[0037] The present invention provides a novel method for synthesizing 7-ketolithocholic acid or its intermediates produced from a novel intermediate I-1. The method of the present invention uses a novel intermediate I-1 to carry out the reaction, which can further promote the production of the compound of formula I, reduce isomers, and increase the yield. In addition, an amide solvent having a weak base is used in this reaction, which promotes the conversion of tautomers to the compound of formula I. The production method of the present invention has mild and simple reaction conditions, a high yield, and is suitable for industrial production. In the present invention, 7-ketolithocholic acid can be obtained by using bisnoralcohol (BA), a biodegradable substance of phytosterol, as the starting material through oxidation, Knoevenagel condensation (or Wittig) reaction, hydrogenation, esterification, ketal protection, allylic oxidation, ketal deprotection, hydrogenation, and hydrolysis. This method is suitable for industrial production because the raw materials are easily available, the yield is high, and the reaction conditions are simple and mild.

[0038] <Terminology definitions and explanations> Unless otherwise specified, the definitions of groups and terms described in the specification and claims of this application can be combined with each other in any combination, including exemplary definitions, exemplary definitions, preferred definitions, definitions listed in the tables, definitions of specific compounds in the examples, etc. Such combined and combined group definitions and compound structures should be understood to be within the scope described in the specification and / or claims of this application.

[0039] The term “C 1~6 The term "alkyl group" refers to a saturated monovalent hydrocarbon group of a straight or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of the alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, and the like, and isomers thereof.

[0040] The term “C 3~8A "cycloalkyl group" should be understood to represent a saturated monovalent monocyclic cyclic hydrocarbon ring of 3, 4, 5, 6, 7, or 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] The technical solution of the present invention will be described in more detail below based on specific examples. However, it should be understood that the following examples are merely illustrative and specific to the present invention and should not be regarded as limiting the scope of protection of the present invention. Any technology realized based on the above content of the present invention is within the intended scope of protection of the present invention.

[0042] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products or can be produced by known methods.

[0043] Example 1: Synthesis of A8 [ka] To a mixture of BA (100 g, 303 mmol) in DCM (600 mL) and water (100 mL), NaBr (3.2 g, 31.06 mmol), TEMPO (1 g, 6.4 mmol), and NaHCO3 (30.6 g, 364 mmol) were added, cooled to 0-5°C, and 10% NaClO solution (115 g, 155 mmol) was added dropwise while stirring. After the addition was completed, the mixture was stirred for 30 minutes. After quenching with the addition of 5 g of Na2SO3, the mixture was stirred for 30 minutes. After leaving the mixture to stand, the lower layer was washed once with saturated NaHCO3, dried, and concentrated under reduced pressure to obtain 90 g of white solid A8 (yield: 90.5%, HPLC purity: 90%).

[0044] Example 2: Synthesis of A8 [ka] To a reaction flask, BA (33 g, 100 mmol) was added, followed by DCM (100 mL). After dissolving under stirring, hydrochloric acid (3.7%, 2 mmol, 2 g), TEMPO (0.31 g, 2 mmol), and sodium bromate (5 g, 35 mmol) were added. The mixture was reacted at 25° C. for 16 h under stirring. After adding water (100 mL) and separating the liquid, the organic phase was washed with an aqueous solution of saturated sodium bicarbonate (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated to remove the solvent, and purified by silica gel column chromatography (n-hexane:EtOAc (ethyl acetate) = 10:1) to give 28.2 g of A8 (yield: 86%, HPLC purity: 96%).

[0045] Example 3: Synthesis of A7 [ka] In a 1L three-neck flask containing 500mL of DMF, A8 (65.6g, 200.00mmol) prepared in Example 2 and monoethyl malonate (39.6g, 300.00mmol) were added, stirred uniformly, and DMAP (2.44g, 20mmol) was added at 25°C, and the reaction was allowed to proceed with stirring for 16 hours. After monitoring by TLC showed the completion of the reaction of A8, 500mL of tert-butyl methyl ether was added, and the organic phase was washed successively with saturated aqueous NaHCO3 solution (500mL) and saturated saline solution (500mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 90g of white solid A7 (yield: 90.5%, HPLC purity: 98%).

[0046] Example 4: Synthesis of A7 [ka] In a 1L three-neck flask, 40.9g of triethyl phosphonoacetate and 400mL of THF were added. The temperature was controlled at 0-5°C, and 6.7g of 60% NaH was added in portions with stirring, releasing a large amount of gas. After stirring for 1 hour, 300mL of a THF solution containing 49.8g of A8 produced in Example 2, which had been prepared in advance, was added dropwise to the reaction system via a 500mL constant pressure funnel. After the dropwise addition was completed, the reaction was stirred for 2 hours. The reaction was quenched by adding 200mL of an aqueous solution containing 20g of ammonium chloride. After stirring for 1 hour, the liquids were separated. The aqueous phase was extracted once with 200mL of EA, and the organic phases were combined, dried, and concentrated under reduced pressure to obtain 55g of crude product. The crude product was slurried with 80mL of petroleum ether and filtered to obtain 55g of off-white solid A7 (yield: 91%, HPLC purity: 95%).

[0047] Example 5: Synthesis of A5 [ka] Under the protection of nitrogen gas (N2), 50g of A7 prepared in Example 3, 50g of ethylene glycol, 600mL of DCM, 28g of triethyl orthoformate, and 0.5g of p-toluenesulfonic acid were added to a 1L three-neck flask and stirred at 25°C for 10 hours. After TLC showed the reaction was completed, 1mL of triethylamine was added and stirred for 30 minutes. 100mL of water was added to wash, the liquid was separated, dried and concentrated to obtain 55g of crude product A5. 150mL of petroleum ether was added to the crude product, and the mixture was refluxed to form a slurry, and 48.5g of A5 (yield: 87.3%, HPLC purity: 97%) was obtained.

[0048] Example 6: Synthesis of A3 [ka] 2.01 g of A5 prepared in Example 5 and 0.1 g of 5% palladium on carbon (Pd / C) catalyst were added to 20 mL of ethyl acetate and stirred at 0.2 MPa hydrogen gas pressure for 1 hour at 25° C. Filtration and concentration under reduced pressure gave 1.95 g of white solid A3 (yield: 97%, HPLC purity: 97%).

[0049] Example 7: Synthesis of A6 [ka] A reaction flask was charged with A8 (258 g, 789 mmol, 1.0 eq.) prepared in Example 2, Meldrum's acid (136 g, 947 mmol, 1.2 eq.), and a mixed solution of formic acid / triethylamine (formic acid / triethylamine=5:2, 1000 mL). The reaction mixture was heated at 110° C. for 16 h. After monitoring by TLC showed the completion of the reaction of A8, the reaction was poured into ice water (1000 mL), then adjusted to pH=10 with 1N NaOH and washed with ethyl acetate (200 mL×2). The aqueous phase was adjusted to pH=2 with 1N HCl, and then further extracted with ethyl acetate (200 mL×3), and the organic phases were combined to obtain 288 g of crude product. The crude product was purified with acetone to obtain 270 g of A6 (yield: 91.8%, HPLC purity: 96%).

[0050] Example 8: Synthesis of A4 [ka] A reaction flask was charged with A6 (100 g, 270 mmol) prepared in Example 7, ethanol (300 mL) and hydrochloric acid (20 mL, 37.5%) and stirred at 25° C. for 16 h. After monitoring by TLC showed the completion of the reaction of A6, the reaction was concentrated under reduced pressure to remove excess ethanol and diluted by adding ethyl acetate (300 mL). The organic phase was washed successively with water (300 mL), saturated aqueous sodium bicarbonate solution (300 mL), saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 100 g of A4 (yield: 93%, HPLC purity: 96%). ESI-MS: [M+H] + :445.33.

[0051] Example 9: Synthesis of A4 [ka] A reaction flask was charged with A6 (74.4 g, 200 mmol), ethanol (200 mL) and concentrated sulfuric acid (5 mL) prepared in Example 7, and reacted with stirring at reflux for 24 hours. After monitoring by TLC showed the completion of the reaction of A6, the reaction was concentrated under reduced pressure to remove excess ethanol and diluted with dichloromethane (200 mL). The organic phase was washed successively with water (200 mL), aqueous saturated sodium bicarbonate solution (200 mL), aqueous saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 73.6 g of A4 (yield: 92%, HPLC purity: 97%). ESI-MS: [M+H] + :445.33.

[0052] Example 10: Synthesis of A3 [ka] Under the protection of nitrogen gas (N2), A4 (50g, 125mmol) prepared in Example 9, ethylene glycol (50g, 806mmol), DCM (600mL), triethyl orthoformate (28g, 189mmol), and p-toluenesulfonic acid (0.5g, 2.6mmol) were added to a 1L three-neck flask and stirred at 25°C for 10 hours. After TLC showed the completion of the reaction, 1mL of triethylamine was added and stirred for 30 minutes. 100mL of water was added to wash and the liquid was separated. The organic phase was dried with anhydrous sodium sulfate and concentrated to obtain 58g of crude product A3. 150mL of petroleum ether was added to the crude product and refluxed to form a slurry, and 51.8g of A3 (yield: 95%, HPLC purity: 95%) was obtained. ESI-MS: [M+H] + :444.35. 1 H-NMR(CDCl3, 400MHz) δ(ppm):5.36-5.34(m, 1H), 4.12(q, J=7.2Hz, 2H), 3.98-3.91(m, 4H), 2.58-2.54(m, 1H), 2.38-2.30(m, 1H), 2.13-2.09(m, 1H), 2.00-1.92(m, 2H), 1.89-1.73(m, 4H), 1.67-1.60(m, 3H), 1.49-1.40(m, 4H), 1.36-1.30(m, 2H), 1.25(t, J=7.2Hz, 3H), 1.20-1.06(m, 4H), 1.02(s, 3H), 0.92(d, J=6.4Hz, 3H), 0.68(s, 3H).

[0053] Example 11: Synthesis of A3 [ka] Under the protection of inert gas, A4 (50 g, 125 mmol) prepared in Example 9, ethylene glycol (150 mL, 2702 mmol), 90 g of trimethyl orthoacetate (90 g, 750 mmol), and p-toluenesulfonic acid (5 g, 26 mmol) were added to a reaction flask, and reacted at 25 ° C for 2 hours to precipitate a large amount of solid, which was dispersed by adding methanol (100 mL), adjusted to pH 7-8 with triethylamine, filtered, and dried in an oven to obtain 50.2 g of compound A3 (yield: 92%, HPLC purity: 98%). ESI-MS: [M+H] + :444.35.

[0054] Example 12: Synthesis of A3 [ka] Under the protection of inert gas, A4 (50 g, 125 mmol) prepared in Example 9, ethylene glycol (39 g, 625 mmol), p-toluenesulfonic acid (5 g, 26 mmol), and toluene (200 mL) were added to a reaction flask, and the reaction mixture was heated to reflux and subjected to a water separation reaction for 24 hours. The reaction mixture was cooled to 25° C., washed with water (200 mL), saturated aqueous sodium bicarbonate solution (200 mL), and saturated saline solution (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 57 g of crude product A3. The crude product was added with 150 mL of petroleum ether, and the mixture was refluxed to form a slurry, and 46.3 g of A3 (yield: 85%, HPLC purity: 90%) was obtained. ESI-MS: [M+H] + :444.35.

[0055] Example 13: Synthesis of A2 [ka] Compound A3 (44.4 g, 100 mmol) prepared in Example 11, N-hydroxyphthalimide (NHPI) (1.63 g, 10 mmol), and benzoyl peroxide (2.4 g, 10 mmol), cobalt acetate (88 mg, 0.5 mmol), and cyclohexanone (200 mL) were added to a reaction flask. The reaction mixture was stirred at 25° C. for 10 minutes, heated to 60° C., and reacted by blowing air into the mixture. After the reaction was completed, the mixture was concentrated to remove cyclohexanone, dichloromethane was added, the mixture was filtered to remove the catalyst, triethylamine (10 g, 100 mmol) and acetic anhydride (10 g, 100 mmol) were added, and the mixture was reacted at 25° C. for 10 hours. After the reaction was completed, the mixture was quenched by adding ethanol, concentrated, drained by adding ethanol, and dried in an oven to obtain 30 g of compound A2 (yield: 65.8%, HPLC purity: 95%). ESI-MS: [M+H] + :459.35. 1 H-NMR(CDCl3, 400MHz) δ(ppm):5.67(s, 1H), 4.12(brs, 2H), 3.97(brs, 4H), 2.70-2.66(m, 1H), 2.45-2.22(m, 5H), 2.00-1.75(m, 6H), 1.59-1.11(m, 17H), 0.94(s, 3H), 0.69(s, 3H).

[0056] Example 14: Synthesis of A2 [ka] A reaction flask was charged with A3 (100 g, 270 mmol) prepared in Example 11, ethyl acetate (200 mL), TBHP (270 mL, 1350 mmol, 5.0 M solution in n-decane), 3A molecular sieves (20 g), and manganese(III) acetate dihydrate (740 mg, 27 mmol). The reaction was allowed to react at 25° C. for 48 hours. The reaction was diluted with tert-butyl methyl ether (200 mL) and filtered through diatomaceous earth. The solvent was removed from the filtrate under reduced pressure and purified by column chromatography (n-hexane:EtOAc=5:1) to give 110 g of product (yield: 90%, HPLC purity: 98%). ESI-MS: [M+H] + :459.35.

[0057] Example 15: Synthesis of A2 [ka] A reaction flask was charged with A3 (44 g, 100 mmol) prepared in Example 11, TBHP (120 mL, 600 mmol, 5.0 M solution in n-decane), copper iodide (0.19 g, 1 mmol), and acetonitrile (200 mL). The reaction was allowed to react at 50° C. for 20 hours. The reaction was filtered through diatomaceous earth. The solvent was removed from the filtrate under reduced pressure and purified by column chromatography (n-hexane: EtOAc = 5: 1) to give 38 g of product (yield: 83%, HPLC purity: 96%). ESI-MS: [M+H] + :459.35.

[0058] Example 16: Synthesis of A1 [ka] In a 1L one-neck flask, add water (40mL) and THF (100mL), add concentrated sulfuric acid (4g, 40.8mmol) while stirring at 0℃, and stir for 10 minutes. Then, add A2 (12g, 26.2mmol) prepared in Example 14, remove the ice-cold water bath, and stir at 25℃ overnight. After adding 100mL of water, add NaHCO3 (10g, 119mmol) in portions to control the pH to 7-8. Then, add 200mL of EtOAc to extract twice, combine the organic phases, and concentrate under reduced pressure to obtain a crude product as a yellow oil. The crude product was purified by column chromatography (n-hexane: EtOAc = 3:1) to obtain 9.97g of solid A1 (yield: 92%, HPLC purity: 95%). ESI-MS: [M+H] + :415.30.

[0059] Example 17: Synthesis of A1 [ka] A 1L reaction flask containing 200 mL of toluene and 50 mL of water was charged with A2 (54 g, 118 mmol) prepared in Example 14, p-toluenesulfonic acid monohydrate (5.2 g, 27.4 mmol). The reaction was stirred at 50° C. for 1 h, then the temperature was lowered to 25° C. and quenched by adding NaHCO3 (10 g, 119 mmol). After settling and separating the liquid, the aqueous phase was extracted once with toluene (100 mL). The organic phases were combined and concentrated under reduced pressure to give the crude product as a yellow oil. The crude product was purified by column chromatography (n-hexane: EtOAc = 3: 1) to give 46.8 g of pale yellow solid A1 (yield: 96%, HPLC purity: 98%). ESI-MS: [M+H] + :415.30. 1H-NMR(DMSO-d6, 400MHz) δ(ppm):10.25(brs, 1H), 5.29-5.28(m, 2H), 4.03(q, J=7.2Hz, 2H), 2.41-2.12(m, 6H), 1.98-1.66(m, 4H), 1.11-1.53(m, 10H), 1.17(t, J=7.2Hz, 3H), 1.05(s, 3H), 0.91(d, J=6Hz, 3H), 0.66(s, 3H).

[0060] Example 18: Synthesis of A [ka] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylformamide (DMF) (32 mL), and 0.32 g of Raney-Ni catalyst was added. The reaction mixture was hydrogenated for 12 hours at 25° C. and 0.1 MPa hydrogen gas pressure. After the hydrogenation reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain 3.3 g of crude product A. The crude product was purified with acetone to obtain 2.84 g of white solid A (yield: 88%, HPLC purity: 98%). ESI-MS: [M+H] + :419.30. 1H-NMR (DMSO-d6, 400MHz) δ(ppm): 4.48(d, J=4.8Hz, 1H), 4.04(q, J=6.8Hz, 2H), 2.90(dd, J=6Hz, 12Hz, 1H), 2.47-2.41(m, 1H), 2.36-2.27(m, 1H), 2.22-2.15(m, 1H), 2.09-2.02(m, 1H), 1.94-1.90(m, 1H), 1.85-1.76(m, 2H), 1.73-1.64(m, 4H), 1.50-1.45(m, 2H), 1.39-1.30(m, 4H), 1.27-1.21(m, 2H), 1.17(t, J=6.8Hz, 3H), 1.14(s, 3H), 1.11-1.01(m, 5H), 0.96-0.77(m, 2H), 0.88(d, J=6.4Hz, 3H), 0.61(s, 3H).

[0061] Example 19: Synthesis of A [ka] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylacetamide (32 mL), and 0.32 g of Raney-Ni catalyst was added. The reaction mixture was hydrogenated for 12 hours at 25° C. and 0.1 MPa hydrogen gas pressure. After the hydrogenation reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain 3.4 g of crude product A. The crude product was purified with acetone to obtain 2.74 g of white solid A (yield: 85%, HPLC purity: 98%). ESI-MS: [M+H] + :419.30.

[0062] Example 20: Synthesis of A [ka] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N-methylpyrrolidone (32 mL), and 0.32 g of Raney-Ni catalyst was added. The reaction mixture was hydrogenated for 12 hours at a temperature of 25° C. and a hydrogen gas pressure of 0.1 MPa. After the hydrogenation reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain 3.0 g of crude product A. The crude product was purified with acetone to obtain 2.52 g of white solid A (yield: 78.3%, HPLC purity: 95%). ESI-MS: [M+H] + :419.30.

[0063] Example 21: Synthesis of A [ka] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylformamide (32 mL), and 0.32 g of 5% palladium on carbon (Pd / C) catalyst was added. The reaction mixture was hydrogenated for 12 hours at 25° C. and 0.1 MPa hydrogen gas pressure. After the hydrogenation reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (n-hexane: EtOAc (ethyl acetate) = 3:1) to obtain 2.09 g of a white solid A (yield: 65%, HPLC purity: 91%). ESI-MS: [M+H] + :419.30.

[0064] Example 22: Synthesis of A [ka] A1 (3.2 g, 7.73 mmol) prepared in Example 17 was dissolved in N,N-dimethylformamide (32 mL), and 0.32 g of 5% platinum on carbon (Pt / C) catalyst was added. The reaction mixture was hydrogenated for 12 hours at 25° C. and 0.1 MPa hydrogen gas pressure. After the hydrogenation reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (n-hexane: EtOAc (ethyl acetate) = 3:1) to obtain 1.70 g of a white solid A (yield: 53%, HPLC purity: 92%). ESI-MS: [M+H] + :419.30.

[0065] Example 23: Synthesis of A1-1 [ka] A1 (5 g, 12.08 mmol) prepared in Example 17 was dissolved in a mixture of THF (20 mL) and water (10 mL), and 3N NaOH aqueous solution (6 mL, 18 mmol) was added. The reaction mixture was reacted at 25° C. for 1 hour. After monitoring by TLC showed that the raw material reaction was completed, the reaction mixture was cooled to an internal temperature of 0° C., 3N HCl aqueous solution (8 mL, 24 mmol) was added dropwise, and extracted with ethyl acetate (30 mL×2). The organic phases were combined, washed with water (30 mL), washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified with acetone to obtain 4.38 g of white solid A1-1 (yield: 94%, HPLC purity: 98%). ESI-MS: [M+H] + :387.30. 1 H-NMR(CDCl, 400MHz) δ(ppm): 5.72-5.68(m, 1H), 3.49-3.41(m, 1H), 3.10-3.02(m, 1H), 2.61-2.11(m, 7H),2.10-1.63(m, 9H), 1.49-1.22(m, 5H), 1.23-1.02(m, 3H), 0.72-0.71(m, 3H).

[0066] Example 24: Synthesis of 7-LCA [ka] A1-1 (3 g, 7.77 mmol) prepared in Example 23 was dissolved in N,N-dimethylformamide (DMF) (30 mL), and 0.3 g of Raney-Ni catalyst was added. The reaction mixture was hydrogenated for 12 hours under conditions of a temperature of 25° C. and a hydrogen gas pressure of 0.1 MPa. After the hydrogenation reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified with acetone to obtain 2.5 g of white solid 7-LCA (yield: 82%, HPLC purity: 92%). ESI-MS: [M+H] + :391.30.

[0067] The above is an illustrative description of the embodiments of the present invention. However, it should be understood that the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent changes, improvements, etc. made without departing from the spirit and principle of the present disclosure should be included in the scope of protection of the claims of this application.

Claims

1. A method for producing a compound of formula I, comprising the step of hydrogenating compound I-1 under the action of a catalyst to obtain a compound of formula I. 【Chemistry 1】 (However, R １ is H or an alkyl group, and the alkyl group is, for example, C １～６ is an alkyl group, １～６ The alkyl group is, for example, methyl, ethyl, propyl, or tert-butyl.

2. the catalyst is selected from a Raney-Ni catalyst, a Pd / C catalyst, a Pt / C catalyst, or a Ru / C catalyst; The method according to claim 1, characterized in that the reaction is preferably carried out in the presence of a solvent, and the solvent is selected from an amide solvent, for example, at least one selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide, and N,N-dimethylpropyleneurea.

3. R in the compound of formula I １ When is an alkyl group, R １ is an alkyl group to give a compound of formula I, １ 3. The method according to claim 1 or 2, characterized in that it comprises a step of obtaining a compound of formula I, wherein 【Chemistry 2】

4. The intermediate compounds I-1 or I-2 shown below. 【Chemistry 3】 (However, R １ has the definition defined in claim 1; R ２ is an alkyl group.

5. A method for producing compound I-1, comprising the steps of: 【Chemistry 4】 (However, R １ has the definition defined in claim 1; R ２ is an alkyl group; h) subjecting compound I-3 to an allylic oxidation reaction to obtain compound I-2; i) Compound I-2 is subjected to a deprotection reaction of ethylene glycol to obtain R １ or a step of subjecting compound I-2 to a deprotection reaction of ethylene glycol and a hydrolysis reaction to obtain compound I-3, wherein R １ obtaining compound I-1, wherein is H.

6. The method according to claim 5, characterized in that in step h), the reaction is carried out in the presence of an oxidizing agent and a catalyst; preferably, step h) is carried out in the following reaction system h1 or h2. h1: A reaction system in which the oxidant is oxygen gas or air, and the catalyst is N-hydroxyphthalimide (NHPI) and cobalt acetate; the reaction system may further include a radical initiator, such as benzoyl peroxide; h2: A reaction system in which the oxidant is tert-butyl hydroperoxide (TBHP) and the catalyst is manganese (III) acetate, manganese (III) acetate dihydrate, or copper iodide (CuI).

7. In step i), the deprotection reaction of ethylene glycol is carried out under the action of an acid, and the acid is at least one selected from the group consisting of concentrated sulfuric acid, concentrated hydrochloric acid, and p-toluenesulfonic acid; 6. The method according to claim 5, wherein the hydrolysis reaction is carried out under alkaline conditions, for example in the presence of sodium hydroxide, potassium hydroxide.

8. The method according to claim 5, wherein the method for producing compound I-3 includes the following scheme 1 or scheme 2. 【Chemistry 5】 (However, R ２ has the definition defined in claim 3; b) Compound I-8 and a monoalkyl malonate ( 【Chemistry 6】 ) by Knoevenagel condensation reaction to obtain compound I-7, or compound I-8 and 【Chemistry 7】 (However, R ３ and R ４ is C １～６ an alkyl group) to obtain compound I-7; d) subjecting compound I-7 to a protection reaction with ethylene glycol to obtain compound I-5; f) A step of subjecting compound I-5 to a reduction reaction to obtain compound I-3. 【Chemistry 8】 (However, R ２ has the definition defined in claim 3; c) compound I-8, 【Chemistry 9】 (However, R ５ and R ６ is C １～６ is an alkyl group, or R ５ , R ６ are C together with the carbon atoms connected to them. ３～８ forming a cycloalkyl group) to obtain compound I-6; e) Reconstituting compound I-6 by R ２ OH to obtain compound I-4; g) Compound I-4 is subjected to a protection reaction with ethylene glycol to obtain compound I-3.

9. In step b), the Knoevenagel condensation reaction is carried out in the presence of a catalyst, the catalyst being DMAP (4-dimethylaminopyridine); step d) is carried out under the action of a catalyst, said catalyst being selected from catalyst A and / or catalyst B, said catalyst A being selected from p-toluenesulfonic acid or concentrated sulfuric acid, said catalyst B being selected from trimethyl orthoformate, triethyl orthoformate or trimethyl orthoacetate, 9. The process according to claim 8, characterized in that step f) is carried out under the action of a catalyst, said catalyst being Pd / C.

10. Step e) is carried out under the action of a catalyst, said catalyst being at least one selected from the group consisting of concentrated sulfuric acid, p-toluenesulfonic acid, and hydrochloric acid; 9. The process according to claim 8, characterized in that step g) is carried out under the action of a catalyst, said catalyst being selected from catalyst A and / or catalyst B, said catalyst A being selected from p-toluenesulfonic acid or concentrated sulfuric acid, and said catalyst B being selected from trimethyl orthoformate, triethyl orthoformate, or trimethyl orthoacetate.

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