Synthetic methods and applications of 7-ketolithocholic acid intermediates

Abstract

The present invention provides a method for synthesizing 7-ketolithocholic acid intermediate, which comprises the step of obtaining 7-ketolithocholic acid intermediate OB from compound OB-1 in an amide solvent. The method of the present invention has easy availability of raw materials, high yield, simple and mild reaction conditions, and is suitable for industrial production.

Description

[Technical field]

[0001] The present invention claims priority based on a Chinese patent application filed with the State Intellectual Property Office of the People's Republic of China on March 25, 2022, bearing patent application number 202210321879.4 and entitled "Synthetic Method and Application of 7-Ketolithocholic Acid Intermediate", the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to the field of pharmaceutical synthesis, in particular to the synthesis method and application of 7-ketolithocholic acid intermediates. [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 has the 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] Currently, 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 at the 3- and 7-positions are doubly protected with acetic anhydride, the hydroxyl group at the 12-position is oxidized to a ketone with sodium hypochlorite, 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 manufacturing method using hyocholic acid as raw material. The disadvantages 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 and TBSCl are expensive, so the cost of the entire 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, prions, 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 method for the synthesis of 7-ketolithocholic acid intermediates. Summary of the Invention

[0011] In order to solve the above problems, the present invention provides The present invention provides a method for synthesizing a 7-ketolithocholic acid intermediate OB, comprising the step of subjecting a compound OB-1 to a hydrogenation reaction in an amide solvent to obtain the 7-ketolithocholic acid intermediate OB. [ka] where R1 is, for example, C such as methyl, ethyl, propyl, and tert-butyl. 1~6 The alkyl group is an alkyl group such as an alkyl group.

[0012] In one embodiment of the invention, the reaction is carried out in the presence of a catalyst, for example, selected from the group consisting of Raney-Ni catalyst, Pd / C catalyst, Pt / C catalyst, and Ru / C catalyst;

[0013] In one embodiment of the present invention, the mass ratio of the compound OB1 to the catalyst is (2-20):1, for example, (5-15):1, and in one example, is 10:1.

[0014] In one embodiment of the present invention, the amide solvent in the reaction 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;

[0015] In one embodiment of the present invention, the ratio (g:mL) of the mass of the compound OB1 to the volume of the solvent is 1:(1 to 20), for example, 1:(1 to 10), and as an example, 1:6.

[0016] As a result of investigation, the present inventors have found that OB1 has the following tautomer 1. [ka]

[0017] The amide solvent used in the present invention has a weak alkaline property, so that the tautomer conversion to OB1 is favorably promoted in the presence of the amide solvent, and the product OB is mainly obtained under the conditions of the present invention.

[0018] In one embodiment of the present invention, a method for preparing compound OB-1 comprises the steps of: [ka] Includes. wherein R1 has the above definition. a) subjecting compound BA to an oxidation reaction to obtain compound OB-5; b) Compound OB-5 and, for example, triethyl phosphonoacetate ( [ka] ) etc. [ka] (However, R2 and R3 are, for example, C such as ethyl. 1~6 a step of reacting compound OB-5 with a compound: [ka] and subjecting the compound to a Knoevenagel condensation reaction to obtain compound OB-4; c) performing a protection reaction of compound OB-4 with ethylene glycol to obtain compound OB-3; d) subjecting compound OB-3 to an oxidation reaction to obtain compound OB-2; e) A step of subjecting compound OB-2 to a deprotection reaction with ethylene glycol to obtain compound OB-1.

[0019] The present invention also provides a method for producing 7-ketolithocholic acid (7-KLCA), comprising the steps of producing compound OB by the above steps and then hydrolyzing compound OB to obtain 7-ketolithocholic acid (7-KLCA). [ka] wherein R1 has the above definition. Effect of the Invention

[0020] According to the present invention, a novel method for synthesizing 7-ketolithocholic acid intermediate OB can be provided. In this synthesis method, the structure of raw material OB-1 can be stabilized by using a specific amide solvent to produce intermediate OB.

[0021] In the present invention, bisnoralcohol (BA), a biodegradable material of phytosterol, can be used as the starting material. Bisnoralcohol has a wide supply source, low cost, and no risk factor of animal viruses. The raw material undergoes oxidation reaction, Wittig reaction, ketal protection reaction, allylic oxidation reaction, ketal deprotection and hydrogenation reaction to obtain 7-ketolithocholic acid intermediate OB. The method of the present invention has easy availability of raw materials, high yield, simple and mild reaction conditions, and is suitable for industrialized production.

[0022] <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.

[0023] The term “C 1~6"Alkyl" refers to a saturated monovalent hydrocarbon radical of a straight or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl groups 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, or isomers thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] 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 considered as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included in the intended scope of the claims of the present invention.

[0025] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products or can be produced by known methods.

[0026] Patent document: CN1137800A, BA is oxidized with sodium hypochlorite to prepare compound 5; reference: Heletica Chimica Acta, 2002 vol.85,4,p.1096-1101, compound 5 is subjected to Wittig reaction to prepare compound 4.

[0027] Example 1: Synthesis of Compound 3 [ka] Under the protection of nitrogen gas (N2), compound 4 (50 g, 126 mmol), ethylene glycol (50 g, 806 mmol), DCM (600 mL), triethyl orthoformate (28 g, 189 mmol), and p-methylbenzenesulfonic acid (0.5 g, 2.6 mmol) were added to a 1 L three-neck flask and stirred at 25 °C for 10 hours. After TLC showed the completion of the reaction, 1 mL of triethylamine was added and stirred for 30 minutes. 100 mL of water was added and washed with water. After drying with anhydrous sodium sulfate, the mixture was concentrated to remove the solvent, and a crude product was obtained. The crude product was separated and purified by column chromatography (n-hexane: EtOAc = 10: 1) to obtain 51.1 g of compound 3 (yield: 92%, HPLC purity: 95%). ESI-MS: [M + H] + :443.35.

[0028] Example 2: Synthesis of Compound 2 [ka] Compound 3 (44.2 g, 100 mmol), TBHP (120 mL, 600 mmol, 5.0 M in n-decane), copper(I) iodide (0.19 g, 1 mmol), and acetonitrile (300 mL) were added to a reaction flask, and the mixture was reacted at 50° C. for 20 hours, cooled to 25° C., and saturated aqueous sodium sulfite solution (300 mL) was added to quench the reaction. The mixture was filtered through Celite. The filtrate was extracted with ethyl acetate (200 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure, and purified by column chromatography (n-hexane:EtOAc=6:1) to give 36.9 g of product (yield: 81%, HPLC purity: 97%). ESI-MS: [M+H] + :457.29.

[0029] Example 3: Synthesis of Compound 1 [ka] In a 1L one-neck flask, water (40mL) and THF (100mL) were added, followed by adding concentrated sulfuric acid (4g, 40.8mmol) with stirring at 0°C, stirring for 10 minutes, and then adding compound 2 (12g, 26.2mmol), removing the cold bath, and stirring at 25°C for 6 hours. Water (100mL) was added to this, followed by adding NaHCO3 (10g, 119mmol) in batches to adjust the pH to 7-8. Then, EtOAc (100mL x 2) was added for extraction, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a yellow oil as a crude product. The crude product was purified by column chromatography (n-hexane: EtOAc = 3:1) to obtain 9.4g of solid compound 1 (yield: 87%, HPLC purity: 94%). ESI-MS: [M+H] + :413.37.

[0030] Example 4: Synthesis of Compound A [ka] 0.5 g of Raney-Ni catalyst was added to a solution of compound 1 (5.0 g, 12.13 mmol) in N,N-dimethylformamide (DMF) (30 mL). The reaction mixture was hydrogenated at 25° C. and 0.1 MPa hydrogen gas for 12 hours. After the hydrogenation reaction was completed, the mixture was filtered and concentrated under reduced pressure to obtain 5.10 g of crude compound A. The crude product was purified with acetone to obtain 4.57 g of white solid A (yield: 76%, HPLC purity: 92%). 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).

[0031] Example 5: Synthesis of Compound A Compound 1 (5.0 g, 12.13 mmol) was added to a solution of N,N-dimethylformamide DMF (30 mL) with 0.5 g of 5% palladium carbon catalyst. The reaction mixture was hydrogenated at 25° C. and 0.1 MPa hydrogen gas for 12 hours. 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 = 3:1) to obtain 3.8 g of white solid A (yield: 65%, HPLC purity: 90%). ESI-MS: [M+H] + :419.30.

[0032] Example 6: Synthesis of Compound A Compound 1 (5.0 g, 12.13 mmol) was added to a solution of N,N-dimethylformamide DMF (30 mL) with 0.5 g of 5% platinum-on-carbon catalyst. The reaction mixture was hydrogenated at 25° C. and 0.1 MPa hydrogen gas for 12 hours. 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 = 3:1) to obtain 3.19 g of white solid A (yield: 68%, HPLC purity: 91%). ESI-MS: [M+H] +:419.30.

[0033] Example 7: Synthesis of Compound A Compound 1 (5.0 g, 12.13 mmol) was added to a solution of N,N-dimethylformamide DMF (30 mL) with 0.5 g of 5% ruthenium carbon catalyst. The reaction mixture was hydrogenated at 25° C. and 0.1 MPa hydrogen gas for 12 hours. 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 = 3:1) to obtain 3.45 g of white solid A (yield: 58%, HPLC purity: 91%). ESI-MS: [M+H] + :419.30.

[0034] Example 8: Synthesis of Compound A To a solution of compound 1 (5.0 g, 12.13 mmol) in N,N-dimethylacetamide (30 mL), 0.5 g of Raney nickel catalyst was added. The reaction mixture was hydrogenated at 25° C. and 0.1 MPa of hydrogen gas for 12 hours. 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 = 3:1) to obtain 4.46 g of white solid A (yield: 71%, HPLC purity: 92%). ESI-MS: [M+H] + :419.30.

[0035] Example 9: Synthesis of Compound A To a solution of compound 1 (5.0 g, 12.13 mmol) in formamide (30 mL), 0.5 g of Raney nickel catalyst was added. The reaction mixture was hydrogenated at 25° C. and 0.1 MPa of hydrogen gas for 12 hours. 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 = 3:1) to obtain 4.46 g of white solid A (yield: 67%, HPLC purity: 92%). ESI-MS: [M+H] + :419.30.

[0036] Example 10: Synthesis of Compound A To a solution of compound 1 (5.0 g, 12.13 mmol) in N-methylpyrrolidone (30 mL), 0.5 g of Raney nickel catalyst was added. The reaction mixture was hydrogenated at 25° C. and 0.1 MPa of hydrogen gas for 12 hours. 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 = 3: 1) to obtain 4.31 g of white solid A (yield: 62%, HPLC purity: 91%). ESI-MS: [M+H] + :419.30.

[0037] The above is an illustrative description of the embodiments of the present invention. However, it should be understood that the scope 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 the claims of this application.

Claims

1. A method for synthesizing a 7-ketolithocholic acid intermediate OB, comprising the step of hydrogenating a compound OB-1 in an amide solvent to obtain a 7-ketolithocholic acid intermediate OB. 【Chemistry 1】 However, R １ is an alkyl group.

2. R １ But, C １～６ 2. The method of claim 1, wherein the alkyl group is an alkyl group, for example, methyl, ethyl, propyl, or tert-butyl.

3. 3. The method of claim 1 or 2, wherein the reaction is carried out in the presence of a catalyst, the catalyst being selected from the group consisting of, for example, a Raney-Ni catalyst, a Pd / C catalyst, a Pt / C catalyst, and a Ru / C catalyst.

4. The method according to claim 3, characterized in that the mass ratio of the OB1 to the catalyst is (2-20):

1.

5. The method according to any one of claims 1 to 4, wherein the amide solvent in the reaction is at least one selected from the group consisting of, for example, N,N-dimethylformamide, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, N-methylformamide, N-methylacetamide, and N,N-dimethylpropyleneurea.

6. The method according to any one of claims 1 to 5, characterized in that the ratio (g:mL) of the mass of OB1 to the volume of the solvent is 1:(1 to 20).

7. The method for producing the compound OB-1 includes the following steps: a) a step of oxidizing compound BA to obtain compound OB-5; b) Compound OB-5 and, for example, triethyl phosphonoacetate ( 【Chemistry 2】 ) etc. 【Chemistry 3】 (However, R ２ and R ３ is C １～６ a step of subjecting compound OB-5 and compound OB-6 to a Wittig reaction to obtain compound OB-7; 【Chemistry 4】 and subjecting the resulting compound to a Knoevenagel condensation reaction to obtain compound OB-4; c) performing a protection reaction of compound OB-4 with ethylene glycol to obtain compound OB-3; d) subjecting compound OB-3 to an oxidation reaction to obtain compound OB-2; e) performing a deprotection reaction of compound OB-2 with ethylene glycol to obtain compound OB-1. 【Chemistry 5】 However, R １ has the definition set forth in claim 1.

8. A method for producing 7-ketolithocholic acid, comprising the steps of producing compound OB by the method according to any one of claims 1 to 7, and then hydrolyzing compound OB to obtain 7-ketolithocholic acid (7-KLCA). 【Chemistry 6】 However, R １ has the definition set forth in claim 1.

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