7-Ketritochole intermediate, its synthesis method, and applications

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】 This invention claims priority based on a Chinese patent application filed with the China National Intellectual Property Administration on March 25, 2022, with patent application number 202210321891.5, titled "7-Ketritocholic Acid Intermediate and Method of Synthesis Thereof and its Application," and a Chinese patent application filed with the China National Intellectual Property Administration on June 7, 2022, with patent application number 202210641979.5, titled "7-Ketritocholic Acid Intermediate and Method of Synthesis Thereof and its Application," all of which are incorporated herein by reference. 【0002】 This invention relates to the field of pharmaceutical synthesis, and more particularly to 7-ketritocholic acid intermediates, their synthesis methods, and applications. [Background technology] 【0003】 7-Ketolithocholic acid has a CAS number of 4651-67-6 and a molecular formula of C 24 H 38 O4 has a molecular weight of 390.56, and its structural formula is as follows. [ka] 【0004】 7-Ketothicolic acid is an important pharmaceutical intermediate. As described below, 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), and others can be synthesized using 7-ketothicolic acid as an intermediate. [ka] 【0005】 Currently, the majority of the manufacturing processes for ursodeoxycholic acid and obeticholic acid are based on methods that use 7-ketritocholic acid as a raw material, so efficiently obtaining 7-ketritocholic acid is extremely important. 【0006】 Based on current literature and patent searches, the synthesis of 7-ketritocholic acid can be broadly classified into the following methods. 【0007】 1. A method using cholic acid as a raw material. WO2014020024A1 reports that cholic acid is used as a starting material, the acid in the side chain is esterified with a methanol hydrochloric acid solution, the hydroxyl groups at positions 3 and 7 are double-protected with acetic anhydride, the hydroxyl group at position 12 is oxidized with sodium hypochlorite to form a ketone, the ketone at position 12 is reduced by the HuangMinglong reduction reaction, and finally, the hydroxyl group at position 7 is selectively oxidized with sodium hypobromite to form a ketone, thereby obtaining the target compound, 7-ketritocholic acid. The HuangMinglong reduction reaction, which involves high temperatures, is used throughout the entire process. This reaction requires relatively high equipment because it involves relatively high temperatures, the hydrazine hydrate is highly toxic, and it is easily explosive. [ka] 【0008】 2. A method using chenodeoxycholic acid as a raw material. CN106046095 reports a method for obtaining 7-ketritocholic acid by oxidizing chenodeoxycholic acid with NBS (N-bromosuccinimide) in acetone and water. Chenodeoxycholic acid is relatively expensive, which limits its applications. [ka] 【0009】 III. Method Using Hyocholic Acid as Raw Material Patent Document CN110423261A reports a manufacturing method using hyocholic acid as a raw material. The disadvantages of this solution are as follows: 1) Since chromium-based reagents such as Jones reagent are used, there is a lot of pollution and great environmental protection pressure; 2) Some reagents such as lithium iodide and TBSCl are expensive, so the cost of the whole route is high; 3) In the third step, pyridine is used as a solvent, so the odor is strong and the toxicity is relatively high. 【Chemical formula】 【0010】 In addition to the various disadvantages listed in the above three methods, another major reason is that cholic acid derived from animals is used in all of these methods. Generally, the bodies of animals contain various animal viruses such as swine cholera, avian influenza, and prions, as well as other various bioactive 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, an object of the present invention is to provide a method for producing 7-ketolithocholic acid or its intermediate. Since the method is produced by using a novel intermediate I-1, it is simple, has a high yield, and is safe and effective. In addition, an object of the present invention is to provide a novel intermediate I-1 and its production method. 【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 subjecting compound I-1 to a hydrogenation reaction under the action of a catalyst to obtain a compound of formula I. 【Chemical formula】 (However, R1 is a hydrogen atom (H) or an alkyl group; an alkyl group is, for example, C 1~6 C is an alkyl group; 1~6 Alkyl alkyl groups are methyl, ethyl, propyl, and tert-butyl. 【0013】 In one embodiment of the present invention, the catalyst in the reaction is selected from the group consisting of Raney-Ni (Raney nickel) 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 compound I-1 to the catalyst is (2-20):1, for example (5-15):1, and as an 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 solvent. The amide 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, if R1 in the compound of formula I is an alkyl group, the method further comprises the following steps: hydrolyzing the compound of formula I in which R1 is an alkyl group to obtain a compound of formula I in which R1 is H, i.e., 7-ketritocholic acid (7-KLCA). [ka] 【0017】 According to the present invention, the hydrolysis reaction can be carried out under alkaline conditions, for example, in the presence of sodium hydroxide, potassium hydroxide, or the like. 【0018】 Furthermore, the present invention provides compound I-1 or I-2, which are intermediates as shown below. [ka] (However, R1 has the definition described above, and R2 is an alkyl group.) 【0019】 Furthermore, the present invention involves the following steps: [ka] The present invention provides a method for producing compound I-1, which includes the compound I-1. (However, R1 has the above definition, and R2 is an alkyl group; h) A step in which compound I-3 is subjected to an allyl oxidation reaction to obtain compound I-2; i) A step of performing a deprotection reaction of compound I-2 with ethylene glycol to obtain compound I-1 in which R1 is an alkyl group; or a step of performing a deprotection reaction of compound I-2 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 is subjected to an allyl oxidation reaction in the presence of an oxidizing agent and a catalyst to obtain compound I-2. 【0021】 In one embodiment of the present invention, step h) is carried out in the following reaction system h1 or h2: h1: A reaction system in which the oxidizing agent is oxygen gas or air, and the catalysts are N-hydroxyphthalimide (NHPI) and cobalt acetate; a radical initiator, such as benzoyl peroxide, may be further added to the reaction system; in embodiments 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), and as an example, 10:1:1:0.05; h2: This is a reaction system in which the oxidizing agent is tert-butyl hydroperoxide (TBHP) and the catalyst is manganese(III) acetate, manganese(III) acetate dihydrate, or copper iodide (CuI). In embodiments of the present invention, the molar ratio of compound I-3 to the oxidizing agent to the catalyst is 1:(1~20):(0.5~10), for example, 1:(2~10):(1~5), and as an 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 producing compound I-3 includes the following scheme 1 or scheme 2: 【0024】 [ka] (However, R2 has the above definition; b) Compound I-8 and monoalkyl malonate ( [ka] ) and a Knoevenagel condensation reaction to obtain compound I-7, or compound I-8 and, for example, triethyl phosphonoacetate ( [ka] ) etc. [ka] (However, R3 and R4 are C such as ethyl, for example.)1~6 A step to obtain compound I-7 by subjecting it to a Wittig reaction with an alkyl group; d) A step in which compound I-7 is subjected to a protection reaction with ethylene glycol to obtain compound I-5; f) The step of reducing compound I-5 to obtain compound I-3. 【0025】 In one embodiment of the present invention, in step b), the molar ratio of compound 1-8 to monoalkyl malonate is 1:(0.5~10), for example, 1:(1~5), and as an example, 1:1.5. 【0026】 In one embodiment of the present invention, step b) is carried out in the presence of a catalyst. The catalyst is 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. Catalyst A is selected from p-toluenesulfonic acid or concentrated sulfuric acid. 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), and as an example, 1:56. 【0028】 In one embodiment of the present invention, in step d), the mass ratio of compound I-7, ethylene glycol, and catalyst is 1:(0.2~5):(0.1~5), for example, 1:(0.5~3):(0.2~2), and as an example, 1:1:0.57. 【0029】 In one embodiment of the present invention, step f) is carried out under the action of a catalyst. The catalyst is Pd / C. 【0030】 In one embodiment of the present invention, in step f), the mass ratio of compound I-5 to catalyst is (2-30):1, for example (10-25):1, and as an example 20:1. 【0031】 [ka] (However, R2 has the above definition; c) Compound I-8 and Meldrum acid-based compounds ( [ka] However, R5 and R6 are C 1~6 It is an alkyl group (e.g., methyl), or R5, R6 together with the carbon atom linked to them is C 3~8 A step to obtain compound I-6 by performing a Knoevenagel condensation reaction with (which forms a cycloalkyl group); e) A step of reacting compound I-6 with R2OH to obtain compound I-4; g) Compound I-4 is subjected to a protection reaction with ethylene glycol, and compound I-3 is added to the next step. 【0032】 In one embodiment of the present invention, in step c), the molar ratio of compound I-8 to the meldrum acid compound is 1:(0.1~10), for example, 1:(0.5~5), and as an example, 1:1.2. 【0033】 In one embodiment of the present invention, step e) is carried out under the action of a catalyst. The catalyst is 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. Catalyst A is selected from p-toluenesulfonic acid or concentrated sulfuric acid. 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 catalyst is 1:(1~50):(1~20), for example, 1:(5~25):(1~10), for example, 1:6.5:1.5 and 1:21.6:6.2. 【0036】 In one embodiment of the present invention, the method for producing compound I-8 includes the following steps: A step in which compound BA is oxidized to obtain compound I-8. [ka] [Effects of the Invention] 【0037】 This invention provides a novel method for synthesizing 7-ketritocholic acid or its intermediates, produced from a novel intermediate I-1. Because the method uses the novel intermediate I-1, it can further promote the formation of the compound of formula I, reduce isomers, and increase yield. Furthermore, since a weakly basic amide solvent is used in this reaction, the conversion of tautomers to the compound of formula I is promoted. The production method of this invention has mild and simple reaction conditions, high yields, and is suitable for industrial production. In the present invention, bisnoralcohol (BA), a biodegradable substance of phytosterol, is used as a starting material, and 7-ketolithocholic acid can also be obtained through an oxidation reaction, a Knoevenagel condensation reaction (or Wittig reaction), a hydrogenation reaction, an esterification reaction, a ketal protection reaction, an allylic oxidation reaction, a ketal deprotection, a hydrogenation reaction, and a hydrolysis reaction. This method has easily available raw materials, a high yield, simple and mild reaction conditions, and is suitable for industrial production. 【0038】 <Definition and Explanation of Terms> Unless otherwise specified, the definitions of groups and terms described in the specification and claims of the present application can be arbitrarily combined and joined with each other, including, for example, definitions, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in the examples, etc. The definitions of groups and the structures of compounds combined and joined in this way should be understood to be within the scope described in the specification and / or claims of the present application. 【0039】 The term "C" 1~6 "alkyl group" represents a saturated monovalent hydrocarbon group of a linear 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, etc., or isomers thereof. 【0040】 The term "C" 3~8A "cycloalkyl group" should be understood as representing a saturated monovalent monocyclic hydrocarbon ring with 3, 4, 5, 6, 7, or 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. [Modes for carrying out the invention] 【0041】 The technical aspects 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 examples of the present invention and should not be considered as limiting the scope of protection of the present invention. All technologies realized based on the above-described aspects of the present invention fall within the intended scope of protection of the present invention. 【0042】 Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be manufactured by known methods. 【0043】 Example 1: Synthesis of A8 [ka] To a mixture of DCM (600 mL) containing BA (100 g, 303 mmol) 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. The temperature was cooled to 0-5°C, and 10% NaClO solution (115 g, 155 mmol) was added dropwise while stirring. After the addition was complete, the mixture was stirred for 30 minutes. 5 g of Na2SO3 was added to quench the mixture, and the mixture was stirred for 30 minutes. After standing and separating the liquid, 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] In a reaction flask, BA (33 g, 100 mmol) was added, followed by DCM (100 mL). After dissolving with 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 hours with stirring. After adding water (100 mL) and separating the liquid, the organic phase was washed with 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:ethyl ethyl acetate = 10:1) to obtain 28.2 g of A8 (yield: 86%, HPLC purity: 96%). 【0045】 Example 3: Synthesis of A7 [ka] In a 1 L three-necked flask containing 500 mL of DMF, A8 (65.6 g, 200.00 mmol) prepared in Example 2 and monoethyl malonate (39.6 g, 300.00 mmol) were added and mixed uniformly. DMAP (2.44 g, 20 mmol) was added at 25°C and the mixture was reacted with stirring for 16 hours. After monitoring by TLC to indicate the completion of the A8 reaction, 500 mL of tert-butyl methyl ether was added, and the organic phase was sequentially washed with saturated NaHCO3 aqueous solution (500 mL) and saturated brine (500 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 90 g of white solid A7 (yield: 90.5%, HPLC purity: 98%). 【0046】 Example 4: Synthesis of A7 [ka] 40.9 g of triethyl phosphonoacetate and 400 mL of THF were added to a 1 L three-necked flask. The temperature was controlled to 0-5°C, and 6.7 g of 60% NaH was added in installments while stirring, releasing a large amount of gas. After stirring for 1 hour, 300 mL of THF solution containing 49.8 g of A8 prepared in Example 2 was added dropwise to the reaction system via a 500 mL constant-pressure funnel. After the addition was complete, the mixture was stirred for 2 hours. Quenched by adding 200 mL of aqueous solution containing 20 g of ammonium chloride. After stirring for 1 hour, the mixture was separated. The aqueous phase was extracted once with 200 mL of EA, the organic phase was combined, dried, and concentrated under reduced pressure to obtain 55 g of crude product. The crude product was slurryed with 80 mL of petroleum ether, filtered, and obtained 55 g of off-white solid A7 (yield: 91%, HPLC purity: 95%). 【0047】 Example 5: Synthesis of A5 [ka] Under the protection of nitrogen gas (N2), 50 g of A7 prepared in Example 3, 50 g of ethylene glycol, 600 mL of DCM, 28 g of triethyl orthoformate, and 0.5 g of p-toluenesulfonic acid were added to a 1 L three-necked flask and stirred at 25°C for 10 hours. After the reaction was complete as indicated by TLC, 1 mL of triethylamine was added and stirred for 30 minutes. 100 mL of water was added to wash the mixture, the liquid was separated, dried, and concentrated to obtain 55 g of crude product A5. 150 mL of petroleum ether was added to the crude product, refluxed to form a slurry, and 48.5 g 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-carbon (Pd / C) catalyst were added to 20 mL of ethyl acetate and stirred at 25°C for 1 hour under a hydrogen gas pressure of 0.2 MPa. The mixture was filtered and concentrated under reduced pressure to obtain 1.95 g of white solid A3 (yield: 97%, HPLC purity: 97%). 【0049】 Example 7: Synthesis of A6 [ka] 258 g, 789 mmol, 1.0 equivalent of A8 prepared in Example 2, 136 g, 947 mmol, 1.2 equivalents of meldramic acid, and a mixed solution of formic acid / triethylamine (formic acid / triethylamine = 5:2, 1000 mL) were added to the reaction flask. The reaction mixture was heated at 110°C for 16 hours. After monitoring by TLC to indicate the completion of the reaction of A8, the reaction product was poured into ice water (1000 mL), then the pH was adjusted to 10 with 1 N NaOH, and washed with ethyl acetate (200 mL x 2). The aqueous phase was adjusted to 2 pH with 1 N HCl, and then extracted with ethyl acetate (200 mL x 3). The organic phase was 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] In a reaction flask, 100 g (270 mmol) of A6 prepared in Example 7, 300 mL of ethanol, and 20 mL (37.5%) of hydrochloric acid were added and the mixture was stirred at 25°C for 16 hours. After monitoring by TLC to indicate the completion of the reaction of A6, the reaction product was concentrated under reduced pressure to remove excess ethanol, and diluted with ethyl acetate (300 mL). The organic phase was sequentially washed with water (300 mL), aqueous solution of saturated sodium bicarbonate (300 mL), and aqueous solution of saturated sodium chloride (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 100 g of A4 (yield: 93%, HPLC purity: 96%). ESI-MS: [M+H] + :445.33. 【0051】 Example 9: Synthesis of A4 [ka] In a reaction flask, 74.4 g (200 mmol) of A6 prepared in Example 7, 200 mL of ethanol, and 5 mL of concentrated sulfuric acid were added and the mixture was reacted under reflux and stirring for 24 hours. After monitoring by TLC to indicate the completion of the reaction of A6, the reaction product was concentrated under reduced pressure to remove excess ethanol, and diluted with 200 mL of dichloromethane. The organic phase was sequentially washed with 200 mL of water, 200 mL of saturated sodium bicarbonate aqueous solution, and 200 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 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), 50 g, 125 mmol of A4 prepared in Example 9, 50 g, 806 mmol of ethylene glycol, 600 mL of DCM, 28 g, 189 mmol of triethyl orthoformate, and 0.5 g, 2.6 mmol of p-toluenesulfonic acid were added to a 1 L three-necked flask and stirred at 25°C for 10 hours. After TLC indicated the end of the reaction, 1 mL of triethylamine was added and stirred for 30 minutes. Washed with 100 mL of water, the liquid was separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain 58 g of crude product A3. 150 mL of petroleum ether was added to the crude product, refluxed to form a slurry, and 51.8 g 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 an inert gas, 50 g (125 mmol) of A4 prepared in Example 9, 150 mL (2702 mmol), 90 g (90 g (750 mmol)) of trimethyl orthoacetate, and 5 g (26 mmol) of p-toluenesulfonic acid were added to a reaction flask. The mixture was reacted at 25°C for 2 hours to precipitate a large amount of solid. 100 mL of methanol was added to disperse the solid, the pH was adjusted to 7-8 with triethylamine, the mixture was filtered, and the mixture was 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 an 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 subjected to a heated reflux water separation reaction for 24 hours. The reaction mixture was cooled to 25°C, washed sequentially with water (200 mL), aqueous solution of saturated sodium bicarbonate (200 mL), and saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated to obtain 57 g of crude product A3. 150 mL of petroleum ether was added to the crude product, and after reflux to form a slurry, 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), benzoyl peroxide (2.4 g, 10 mmol), cobalt acetate (88 mg, 0.5 mmol), and cyclohexanone (200 mL) were added to the reaction flask. The reaction mixture was stirred at 25°C for 10 minutes, heated to 60°C, and blown in air to continue the reaction. After the reaction was complete, the mixture was concentrated to remove cyclohexanone, dichloromethane was added, the catalyst was removed by filtration, 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 complete, ethanol was added to quench the mixture, it was concentrated, ethanol was added to drain the mixture, and the mixture was 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] In a reaction flask, A3 (100 g, 270 mmol) prepared in Example 11, ethyl acetate (200 mL), TBHP (270 mL, 1350 mmol, 5.0 M n-decane solution), 3A molecular sieve (20 g), and manganese(III) acetate dihydrate (740 mg, 27 mmol) were added. The reaction mixture was allowed to react at 25°C for 48 hours. This reaction system 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 the mixture was purified by column chromatography (n-hexane:siRNA = 5:1) to obtain 110 g of product (yield: 90%, HPLC purity: 98%). ESI-MS: [M+H] + :459.35. 【0057】 Example 15: Synthesis of A2 [ka] In a reaction flask, A3 (44 g, 100 mmol) prepared in Example 11, TBHP (120 mL, 600 mmol, 5.0 M n-decane solution), copper iodide (0.19 g, 1 mmol), and acetonitrile (200 mL) were added. The reaction mixture was allowed to react at 50°C for 20 hours. The reaction system was filtered through diatomaceous earth. The solvent was removed from the filtrate under reduced pressure, and the mixture was purified by column chromatography (n-hexane:siRNA = 5:1) to obtain 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 necked flask, water (40mL) and THF (100mL) were added. Concentrated sulfuric acid (4g, 40.8 mmol) was added while stirring at 0°C, and the mixture was stirred for 10 minutes. Then, A2 (12g, 26.2 mmol) prepared in Example 14 was added, the ice bath was removed, and the mixture was stirred overnight at 25°C. After adding 100mL of water, NaHCO3 (10g, 119 mmol) was added in installments to control the pH to 7-8. Next, 200mL of siRNA was added and the mixture was extracted twice. The organic phases were combined and concentrated under reduced pressure to obtain a crude product, which was a yellow oily substance. The crude product was purified by column chromatography (n-hexane:siRNA = 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] To a 1 L reaction flask containing 200 mL of toluene and 50 mL of water, A2 (54 g, 118 mmol) prepared in Example 14 and p-toluenesulfonic acid monohydrate (5.2 g, 27.4 mmol) were added. The reaction mixture was stirred at 50°C for 1 hour, then the temperature was lowered to 25°C and NaHCO3 (10 g, 119 mmol) was added to quench the reaction. After standing 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 obtain a crude product, which was a yellow oily substance. The crude product was purified by column chromatography (n-hexane:siRNA = 3:1) to obtain 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 (Raney nickel) catalyst was added. The reaction mixture was hydrogenated for 12 hours under conditions of 25°C and a hydrogen gas pressure of 0.1 MPa. After the hydrogenation reaction was complete, 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 (Raney nickel) catalyst was added. The reaction mixture was hydrogenated for 12 hours under conditions of 25°C and a hydrogen gas pressure of 0.1 MPa. After the hydrogenation reaction was complete, 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 (Raney nickel) catalyst was added. The reaction mixture was hydrogenated for 12 hours under conditions of 25°C and a hydrogen gas pressure of 0.1 MPa. After the hydrogenation reaction was complete, 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-carbon (Pd / C) 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 complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (n-hexane:ethyl acetate = 3:1) to obtain 2.09 g of 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-carbon (Pt / C) 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 complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (n-hexane:ethyl acetate = 3:1) to obtain 1.70 g of 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 mixed solution of THF (20 mL) and water (10 mL), and then 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 to indicate that the reaction of the starting materials was complete, the reaction mixture was cooled to an internal temperature of 0°C, 3N HCl aqueous solution (8 mL, 24 mmol) was added dropwise, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the 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 (Raney nickel) catalyst was added. The reaction mixture was hydrogenated for 12 hours under conditions of 25°C and a hydrogen gas pressure of 0.1 MPa. After the hydrogenation reaction was complete, the mixture was filtered and concentrated under reduced pressure to obtain the 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 has provided illustrative examples of embodiments of the present invention. However, it should be understood that the scope of protection of the present invention is not limited to the embodiments described above. Any modifications, equivalent changes, improvements, etc., made without departing from the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

[Claim 1] The process includes a step of hydrogenating compound I-1 under the action of a catalyst to obtain the compound of formula I. A method for producing a compound of formula I, characterized by the features described above. 【Chemistry 1】 (However, R １ (This is H or an alkyl group.) [Claim 2] R １ C １ ~ ６ The method according to claim 1, characterized in that it is an alkyl group. [Claim 3] R １ The method according to claim 1, characterized in that is methyl, ethyl, propyl, or tert-butyl. [Claim 4] The method according to claim 1, characterized in that the catalyst is selected from a Raney-Ni catalyst, a Pd / C catalyst, a Pt / C catalyst, or a Ru / C catalyst. [Claim 5] The method according to claim 1, characterized in that the reaction is carried out in the presence of a solvent, and the solvent is selected from amide solvents. [Claim 6] The method according to claim 5, characterized in that the amide solvent is 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. [Claim 7] R in the compound of formula I １ If is an alkyl group, then R1 is as shown below. When the alkyl compound of formula I is hydrolyzed, R １ Steps to obtain a compound of formula I in which is H. The method according to claim 1, characterized by including the following: 【Chemistry 2】 [Claim 8] The method according to claim 1, characterized in that the method for producing compound I-1 includes the following steps. 【Transformation 3】 (However, R １ has the definition specified in claim 1, and R ２ is an alkyl group; h) A step of performing an allyl oxidation reaction on compound I-3 to obtain compound I-2; i) Deprotection reaction of compound I-2 with ethylene glycol, R １ A step to obtain compound I-1 in which is an alkyl group; or, a deprotection reaction and hydrolysis reaction of ethylene glycol are performed on compound I-2, １ A step to obtain compound I-1 in which is H. [Claim 9] The method according to 8, characterized in that in step h), the reaction is carried out in the presence of an oxidizing agent and a catalyst. [Claim 10] The method according to 9, characterized in that step h) is carried out in the reaction system of h1 or h2 below. h1: A reaction system in which the oxidizing agent is oxygen gas or air, and the catalysts are N-hydroxyphthalimide and cobalt acetate; h2: A reaction system in which the oxidizing agent is tert-butyl hydroperoxide (TBHP) and the catalyst is manganese(III) acetate, manganese(III) acetate dihydrate, or copper iodide (CuI). [Claim 11] The method according to 10, characterized in that a radical initiator is further added to h1. [Claim 12] The method according to 11, characterized in that the radical initiator is benzoyl peroxide. [Claim 13] In step i), the deprotection reaction of ethylene glycol is carried out under the action of an acid, the acid being at least one selected from the group consisting of concentrated sulfuric acid, concentrated hydrochloric acid, and p-toluenesulfonic acid. The method according to 8, characterized in that the hydrolysis reaction is carried out under alkaline conditions. [Claim 14] The method according to 13, characterized in that the hydrolysis reaction is carried out in the presence of sodium hydroxide and potassium hydroxide. [Claim 15] The method according to 8, characterized in that the method for producing compound I-3 comprises the following scheme 1 or scheme 2. 【Chemistry 4】 (However, R ２ has the definition set forth in claim 8; b) Compound I-8 and, 【Transformation 5】 A step to obtain compound I-7 by subjecting it to a Knoevenagel condensation reaction, or compound I-8 and 【Transformation 6】 The process involves a Wittig reaction between and to obtain compound I-7; however, R ３ and R ４ C １～６ It is an alkyl group; d) A step of performing a protective reaction with ethylene glycol on compound I-7 to obtain compound I-5; f) A step in which compound I-5 is reduced to obtain compound I-3. 【Transformation 7】 (However, R ２ has the definition set forth in claim 8; c) Compound I-8 and, 【Transformation 8】 A step of obtaining compound I-6 by subjecting it to a Knoevenagel condensation reaction; however, R ５ and R ６ C １～６ It is an alkyl group, or R ５ , R ６ C ３～８ Forms a cycloalkyl group; e) Compound I-6 to R ２ A step to obtain compound I-4 by reacting with OH; g) Compound I-4 is subjected to a protective reaction with ethylene glycol, and compound I-3 is added to the process. [Claim 16] 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, the catalyst being selected from catalyst A and / or catalyst B, catalyst A being selected from p-toluenesulfonic acid or concentrated sulfuric acid, and catalyst B being selected from trimethyl orthoformate, triethyl orthoformate, or trimethyl orthoacetate. The method according to 15, characterized in that step f) is carried out under the action of a catalyst, the catalyst being Pd / C. [Claim 17] Step e) is carried out under the action of a catalyst, the catalyst being at least one selected from the group consisting of concentrated sulfuric acid, p-toluenesulfonic acid, and hydrochloric acid; The method according to 15, characterized in that step g) is carried out under the action of a catalyst, the catalyst being selected from catalyst A and / or catalyst B, catalyst A being selected from p-toluenesulfonic acid or concentrated sulfuric acid, and catalyst B being selected from trimethyl orthoformate, triethyl orthoformate, or trimethyl orthoacetate.

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