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CN-119707905-B - Process for preparing dihydroisoflavone derivatives

CN119707905BCN 119707905 BCN119707905 BCN 119707905BCN-119707905-B

Abstract

The application discloses a preparation method of a dihydroisoflavone derivative. The preparation method of the compound 16 comprises the following steps of carrying out Suzuki-Miyaura reaction on the compound 12 and the compound 15 in an organic solvent in the presence of alkoxide, a catalyst and a ligand to obtain the compound 16, wherein the catalyst is Pd (OAc) 2 , and the ligand is PPh 3 . The application designs and synthesizes the target natural product (compound 1) by a total synthesis method, and the research provides a basis for the total synthesis of the dihydroisoflavone alcohol compound containing chiral centers.

Inventors

  • SUN QINGYAN
  • Du Zhiteng
  • ZHAO ZENG

Assignees

  • 上海医药工业研究院有限公司
  • 中国医药工业研究总院有限公司

Dates

Publication Date
20260505
Application Date
20230928

Claims (16)

  1. 1. A preparation method of the compound 16 is characterized by comprising the following steps of carrying out Suzuki-Miyaura reaction on a compound 12 and a compound 15 in an organic solvent in the presence of alkoxide, a catalyst and a ligand to obtain the compound 16, wherein the catalyst is Pd (OAc) 2 , and the ligand is PPh 3 ; 。
  2. 2. The method of claim 1, wherein one or more of the following conditions are satisfied: (1) The organic solvent is an amide solvent; (2) The volume-mass ratio of the organic solvent to the compound 12 is (5-100): 1 mL/g; (3) The molar ratio of the compound 15 to the compound 12 is (1-5): 1; (4) The molar ratio of the catalyst to the compound 12 is (0.01-0.1): 1; (5) The molar ratio of the ligand to the compound 12 is (0.01-0.1): 1; (6) The molar ratio of the catalyst to the ligand is (1-5): 1; (7) The alkoxide is lithium salt, sodium salt or potassium salt; (8) The molar ratio of the alkoxide to the compound 12 is (1-6): 1; (9) The reaction temperature of the Suzuki-Miyaura reaction is 50-120 ℃; and (10) the Suzuki-Miyaura reaction has a reaction time of 3-10 h.
  3. 3. The method of claim 2, wherein one or more of the following conditions are satisfied: (1) The amide solvent is N, N-dimethylformamide; (2) The volume-mass ratio of the organic solvent to the compound 12 is 25.5:1 mL/g; (3) The molar ratio of the compound 15 to the compound 12 is 2:1; (4) The molar ratio of the catalyst to the compound 12 is 0.04:1; (5) The molar ratio of the ligand to the compound 12 is 0.04:1; (6) The molar ratio of the catalyst to the ligand is 1:1; (7) The alkoxide is t-BuOLi; (8) The molar ratio of the alkoxide to the compound 12 is 2:1; (9) The reaction temperature of the Suzuki-Miyaura reaction is 90 ℃; and (10) the reaction time of the Suzuki-Miyaura reaction is 4 h.
  4. 4. The process of claim 3, wherein the amide solvent is anhydrous DMF.
  5. 5. The preparation method of the compound 16, as set forth in claim 1, further comprising the step of carrying out a hydroxyl protection reaction between the compound 14 and the pinacol diboronate in an organic solvent in the presence of a catalyst to obtain a compound 15; 。
  6. 6. the method of claim 5, wherein the method of preparing compound 15 satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent and/or a sulfoxide solvent; (2) The mass volume ratio of the compound 14 to the organic solvent is (0.5-0.05) 1 g/ml; (3) The mole ratio of the pinacol ester of diboron to the compound 14 is (1-6): 1; (4) The catalyst is bivalent palladium; (5) The molar ratio of the catalyst to the compound 14 is (0.01-0.2): 1; and (6) the reaction temperature of the hydroxyl group protection reaction is 0-50 ℃.
  7. 7. The method of claim 6, wherein the method of preparing compound 15 satisfies one or more of the following conditions: (1) The organic solvent is an alcohol solvent and a sulfoxide solvent; (2) The mass volume ratio of the compound 14 to the organic solvent is 0.116:1 g/ml; (3) The molar ratio of the pinacol ester of diboron to the compound 14 is 1.5:1; (4) The catalyst is palladium (II) tetrafluoroborate tetra (acetonitrile); (5) The molar ratio of the catalyst to the compound 14 is 0.05:1; and (6) the reaction temperature of the hydroxyl group protection reaction is 0 ℃.
  8. 8. The method of claim 7, wherein the method of preparing compound 15 satisfies one or more of the following conditions: (1) The alcohol solvent is one or more of methanol, ethanol and isopropanol; (2) The sulfoxide solvent is dimethyl sulfoxide; and (3) when the organic solvent is an alcohol solvent and a sulfoxide solvent, the volume ratio of the alcohol solvent to the sulfoxide solvent is (1-5): 1.
  9. 9. The method of claim 8, wherein the method of preparing compound 15 satisfies one or more of the following conditions: (1) The alcohol solvent is methanol; (2) The organic solvent is methanol and dimethyl sulfoxide; And (3) when the organic solvent is an alcohol solvent and a sulfoxide solvent, the volume ratio of the alcohol solvent to the sulfoxide solvent is 1:1.
  10. 10. The preparation process of compound 15 includes the steps of hydroxyl protecting reaction between compound 14 and pinacol diboronate in organic solvent in the presence of catalyst to obtain compound 15; 。
  11. 11. The process according to claim 10, wherein the reaction conditions of the hydroxy-protecting reaction are as defined in any one of claims 6 to 9.
  12. 12. The preparation process of compound 1 includes the steps of debenzylating compound 16 in solvent in the presence of hydrogen donor and catalyst to obtain compound 1; 。
  13. 13. the method of claim 12, wherein one or more of the following conditions are satisfied: (1) The solvent is an alcohol solvent; (2) The mass volume ratio of the compound 16 to the solvent is (2-8): 1 mg/ml; (3) The hydrogen donor is ammonium formate and/or 1, 4-cyclohexadiene; (4) The mass volume ratio of the compound 16 to the hydrogen donor is 1 (1-5) mg/mu L; (5) The catalyst is Pd/C and/or Pd (OH) 2 ; (6) The reaction temperature of the debenzylation reaction is 50-120 ℃; And (7) the debenzylation reaction time is 1-5 h.
  14. 14. The method of claim 13, wherein one or more of the following conditions are satisfied: (1) The alcohol solvent is one or more of methanol, ethanol and isopropanol; (2) The mass volume ratio of the compound 16 to the solvent is 3.75:1 mg/ml; (3) The hydrogen donor is 1, 4-cyclohexadiene; (4) The mass-volume ratio of the compound 16 to the hydrogen donor is 1:2 mg/mu L; (5) The catalyst is 10% Pd/C and Pd (OH) 2 ; (6) When the catalyst is Pd/C and Pd (OH) 2 , the mass ratio of Pd/C to Pd (OH) 2 is (2-6): 1; (7) The reaction temperature of the debenzylation reaction is 80 ℃; and (8) the debenzylation reaction time was 2 h.
  15. 15. The method of claim 14, wherein one or both of the following conditions are satisfied: (1) The alcohol solvent is isopropanol; (2) When the catalyst is Pd/C and Pd (OH) 2 , the mass ratio of Pd/C to Pd (OH) 2 is 4:1.
  16. 16. A compound which is compound 15 or compound 16, , 。

Description

Process for preparing dihydroisoflavone derivatives Technical Field The invention belongs to the field of medicines. In particular, the invention relates to a preparation method of a dihydroisoflavone derivative. Background (S, E) -3- (2, 4-dihydroxy-3- (7-hydroxy-3, 7-dimethyloct-2-en-1-yl) phenyl) -3,5, 7-trihydroxybenzopyran-4-one (Compound 1) was derived from Mao Hangzi points. Mao Hangzi tip is a plant distributed in subtropical region of China, and its root has medicinal value, and can be used for treating menoxenia, dysmenorrhea, hemorrhage, gastric ulcer, etc. The flavonoids isolated from their roots have immunosuppressive effects. Compound 1 is a class of flavonoids containing chiral tertiary alcohols, which are usually isolated from natural products, and synthesis reports thereof are not yet seen. Disclosure of Invention The technical problem to be solved by the invention is to overcome the defect of lack of synthesis of the compound 1 in the prior art, thereby providing a preparation method of the dihydroisoflavone derivative. The invention can obtain a large amount of natural products by designing a synthetic route, solves the problem that the content of the natural products is small and is difficult to obtain again, and meets the requirement of further research. The invention provides a preparation method of a compound 16, which comprises the following steps of carrying out Suzuki-Miyaura reaction on a compound 12 and a compound 15 in an organic solvent in the presence of alkoxide, a catalyst and a ligand to obtain the compound 16, wherein the catalyst is Pd (OAc) 2, and the ligand is PPh 3; In one embodiment, the organic solvent may be an amide solvent, and the amide solvent may be N, N-Dimethylformamide (DMF), preferably anhydrous DMF. In one embodiment, the ratio of the organic solvent to the compound 12 may be (5-100): 1mL/g, e.g., 25.5:1mL/g. In one embodiment, the molar ratio of compound 15 to compound 12 can be (1-5): 1, e.g., 2:1. In one embodiment, the molar ratio of the catalyst to the compound 12 may be (0.01-0.1): 1, e.g., 0.04:1. In one embodiment, the molar ratio of the ligand to the compound 12 may be (0.01-0.1): 1, e.g., 0.04:1. In one embodiment, the molar ratio of the catalyst to the ligand may be (1-5): 1, e.g., 1:1. In one embodiment, the alkoxide may be a lithium, sodium or potassium salt, such as t-BuOLi. In one embodiment, the molar ratio of alkoxide to compound 12 may be (1-6): 1, e.g., 2:1. The reaction temperature of the Suzuki-Miyaura reaction is a temperature conventional in the art for such reactions, e.g., 50-120 ℃, preferably 90 ℃. The progress of the Suzuki-Miyaura reaction is detected using methods conventional in the art (e.g., TLC, HPLC, LCMS or NMR), typically with the endpoint of the reaction when compound 12 is lost or no longer reacted. The reaction time of the Suzuki-Miyaura reaction is a conventional reaction time of this type of reaction in the art, for example 3-10h, preferably 4h. The process for the preparation of compound 16 may further comprise a post-treatment, which is conventional in the art of such preparation. For example, the preparation method further comprises the steps of extraction, drying, concentration and purification after the Suzuki-Miyaura reaction is finished. The quenching is preferably performed by ethyl acetate and water. The drying is preferably anhydrous sodium sulfate drying. The purification is preferably column chromatography, and the eluent of the column chromatography can be PE: EA=4:1. The preparation method of the compound 16 further comprises the following steps that in an organic solvent, in the presence of a catalyst, the compound 14 and the pinacol diboronate undergo a hydroxyl protection reaction to obtain a compound 15; in a certain scheme, the organic solvent can be an alcohol solvent and/or a sulfoxide solvent, the alcohol solvent can be one or more of methanol, ethanol and isopropanol, preferably methanol, the sulfoxide solvent can be dimethyl sulfoxide, the organic solvent is preferably an alcohol solvent and a sulfoxide solvent, such as methanol and dimethyl sulfoxide, and when the organic solvent is an alcohol solvent and a sulfoxide solvent, the volume ratio of the alcohol solvent to the sulfoxide solvent is (1-5): 1, such as 1:1. In one embodiment, the mass to volume ratio of the compound 14 to the organic solvent may be (0.5-0.05): 1g/ml, e.g., 0.116:1g/ml. In one embodiment, the mole ratio of the pinacol ester of diboronic acid to the compound 14 may be (1-6): 1, for example 1.5:1. In one embodiment, the catalyst may be a divalent palladium, such as palladium (II) tetra (acetonitrile) tetrafluoroborate (Pd (BF 4)2(MeCN)4. In one embodiment, the molar ratio of the catalyst to the compound 14 may be (0.01-0.2): 1, e.g., 0.05:1. The reaction temperature of the hydroxyl-protecting reaction is a temperature conventional in this type of reaction in the art, for example, 0 to 50 ℃, preferably 0 ℃. The progress