Method for preparing burenolone precursor through photocatalytic configuration inversion

Abstract

The invention discloses a method for preparing a burenolone precursor through photocatalytic configuration inversion. The invention provides a preparation method of a burenolone precursor, which comprises the following steps of: in a solution containing titanium tetrachloride and alkali, placing pregnenolone (formula I) under a 380nm LED (light-emitting diode) lamp under an open illumination condition, and carrying out reaction as shown in the following formula to obtain the burenolone precursor (formula II), the method has the advantages of high yield, simple synthesis method, greenness and safety.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for preparing a brenoside precursor by photocatalytic configuration inversion. Background Art

[0002] Brenolone is an innovative allosteric modulator of GABAA (gamma-Aminobutyric acid) receptors developed by SAGE. It can regulate the function of GABAA receptors located inside and outside synapses. GABAA receptors and NMDA (N-methyl-D-aspartate) receptors play the role of inhibiting and stimulating brain neurons to produce nerve impulses, respectively. The imbalance between the activity of these two receptors is the cause of a variety of mental illnesses, including depression. Brenolone can effectively and safely restore the balance between the activity of GABAA receptors and NMDA receptors. At the same time, it has obtained the FDA's breakthrough therapy designation and the European Medicines Agency's priority drug designation [CK010358] for the treatment of postpartum depression (PPD). SAGE submitted an application for Brenolone to the FDA on April 24, 2018, and it was approved for marketing on March 19, 2019. The trade name of the intravenous solution is It became the first drug approved by the FDA for the treatment of postpartum depression.

[0003] Patents WO2009 / 108804, WO 93 / 03732, WO 2012 / 127176, and CN 103396467 respectively report that allopregnanolone (Formula III) is used as a raw material, and intermediates with different substituents are synthesized by Mitsunobu reaction, and then hydrolyzed to achieve the flipping of the 3β-hydroxyl group, and the yield of preparing brenosone (Formula IV) is 50-90%. Under these reaction conditions, it is necessary to obtain an intermediate containing a protective group and then hydrolyze it, which has low atom economy, complex reaction conditions, high reagent cost and high risk.

[0004] Summary of the invention

[0005] The technical problem to be solved by the present invention is that the reagents used in the method for preparing brenosone (Formula IV) using allopregnanolone (Formula III) as a raw material in the prior art are relatively dangerous, and the atom economy is poor, and there are more three wastes. To this end, the present invention provides a method for efficiently preparing brenosone precursor (Formula II) through a photocatalytic configuration reversal strategy. The method has the advantages of high yield and greenness.

[0006] The present invention provides a method for preparing a brenosone precursor (Formula II), comprising the following steps: in a solution containing titanium tetrachloride and an alkali, the solution is exposed to light at a wavelength of 380 nm under an LED lamp, and pregnenolone (Formula I) is subjected to a reaction as shown in the following formula to obtain a brenosone precursor (Formula II).

[0007]

[0008] Preferably, the solvent is one or a mixture of n-hexane, dichloromethane, acetonitrile and trifluorotoluene.

[0009] Preferably, the base is one of potassium carbonate, sodium carbonate, lithium carbonate, triethylamine, N,N-diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0010] Preferably, the chiral ligand is one of L1-L6.

[0011]

[0012] Preferably, the molar volume ratio of the pregnenolone to the solvent is 1 mol:5L.

[0013] Preferably, the molar ratio of titanium tetrachloride to pregnenolone is 1:10.

[0014] Preferably, the molar ratio of the base to pregnenolone is 1:1.

[0015] Preferably, the molar ratio of the chiral ligand to pregnenolone is 1:5-10.

[0016] Preferably, the reaction temperature is -20-30°C, the reaction time is 2-8 hours, and the stirring speed is 50-60 rpm.

[0017] Preferably, the lighting condition is a 380nm LED light.

[0018] Preferably, the reaction system of the reaction consists of the solvent, pregnenolone, titanium tetrachloride, a base and a chiral ligand.

[0019] Preferably, after the reaction is completed, a post-treatment step is further included, and the post-treatment step is selected from one or more of concentration, extraction, drying and purification.

[0020] Preferably, the concentration is vacuum distillation, the purification is silica gel plate or silica gel column purification, and the eluent for the purification is a mixed solvent of dichloromethane and methanol.

[0021] Preferably, the method for preparing a brucerolide precursor by photocatalytic reconfiguration comprises the following steps (a) and (b):

[0022] (a) mixing the base, chiral ligand, titanium tetrachloride and solvent in a nitrogen atmosphere to obtain a mixed solution;

[0023] (b) adding pregnenolone to the mixed solution obtained in step (a), mixing thoroughly, and then leaving the mixture open under corresponding light conditions to react, thereby obtaining the brenoside precursor.

[0024] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0025] The reagents and raw materials used in the present invention are commercially available.

[0026] Beneficial effects of the present invention: The preparation method of the brenosaurolone precursor provided by the present invention has the advantages of high yield, greenness and safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is the preparation process of the precursor of brenosaurus. DETAILED DESCRIPTION

[0028] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0029] In the following examples, those skilled in the art will know that diastereomeric excess, which stands for diastereoisomer excess, is an important concept in describing chiral molecular chemistry, and refers to the excess of one diastereomer over another diastereomer. The dr value is measured using a nuclear magnetic resonance spectrometer (400 MHz or 500 MHz).

[0030] Example 1

[0031] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L4 (12.6 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded on the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 55.0 mg of the product with a yield of 87.0% and a dr value of 1:1.

[0032] Example 2

[0033] Sodium carbonate (21.2 mg, 0.2 mmol, 1.0 equiv) and L4 (12.6 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 53.1 mg of the product with a yield of 84.1% and a dr value of 1:1.4.

[0034] Example 3

[0035] Lithium carbonate (14.8 mg, 0.2 mmol, 1.0 equiv) and L4 (12.6 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 45.9 mg of the product with a yield of 72.6% and a dr value of 1:1.1.

[0036] Example 4

[0037] 1,8-diazabicyclo[5.4.0]undec-7-ene (30.4 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen atmosphere was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25°C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 59.6 mg of the product with a yield of 94.3% and a dr value of 1:40.

[0038] Example 5

[0039] Triethylamine (20.2 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 58.9 mg of the product with a yield of 93.2% and a dr value of 1:30.

[0040] Example 6

[0041] N,N-diisopropylethylamine (25.8 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded on the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 58.2 mg of the product with a yield of 92.1% and a dr value of 1:15.

[0042] Example 7

[0043] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of n-hexane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded on the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 60.4 mg of the product with a yield of 95.6% and a dr value of 1:28.

[0044] Example 8

[0045] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of acetonitrile were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded on the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 54.2 mg of the product with a yield of 85.8% and a dr value of 1:2.

[0046] Example 9

[0047] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of trifluorotoluene were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded on the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 58.1 mg of the product with a yield of 91.9% and a dr value of 1:8.

[0048] Example 10

[0049] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv), 0.5 mL of n-hexane and 0.5 mL of acetonitrile were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded on the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 53.7 mg of the product with a yield of 85.0% and a dr value of 1:2.

[0050] Embodiment 11

[0051] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 0°C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 57.6 mg of the product with a yield of 91.2% and a dr value of 3:1.

[0052] Example 12

[0053] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L4 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at -20 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 44.9 mg of the product with a yield of 71.0% and a dr value of 6:1.

[0054] Comparative Example 1

[0055] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L2 (25.2 mg, 0.08 mmol, 0.4 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 53.7 mg of the product with a yield of 85.0% and a dr value of 1:2.

[0056] Comparative Example 2

[0057] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L3 (11.5 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 51.2 mg of the product with a yield of 81.0% and a dr value of 1:3.

[0058] Comparative Example 3

[0059] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L1 (11.5 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded on the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 52.0 mg of the product with a yield of 82.3% and a dr value of 1:4.

[0060] Comparative Example 4

[0061] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L5 (13.2 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 52.0 mg of the product with a yield of 82.3% and a dr value of 1:1.2.

[0062] Comparative Example 5

[0063] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L5 (13.2 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 52.0 mg of the product with a yield of 82.3% and a dr value of 1:1.2.

[0064] Comparative Example 6

[0065] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) and L6 (13.2 mg, 0.04 mmol, 0.2 equiv) were added to the reaction tube, and the nitrogen was replaced by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, and pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added after stirring for 5 min. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 50.6 mg of the product with a yield of 80.1% and a dr value of 1:1.

[0066] Comparative Example 7

[0067] Potassium carbonate (27.6 mg, 0.2 mmol, 1.0 equiv) was replaced with nitrogen by vacuum for 3 times. Titanium tetrachloride (3.8 mg, 0.02 mmol, 0.1 equiv) and 1 mL of dichloromethane were added in a nitrogen atmosphere, stirred for 5 min, and then pregnenolone (63.2 mg, 0.2 mmol, 1.0 equiv) was added. The mixture was placed under a 380 nm LED lamp, stirred at 25 ° C for 5 hours, and the stirring speed was 50 rpm. The mixture was monitored by TLC. After the reaction was completed, the solvent was removed by vacuum distillation, the sample was mixed with silica gel and loaded onto the column, and the sample was separated using a dichloromethane / methanol system. The eluents were combined and concentrated to obtain 50.6 mg of the product with a yield of 80.1% and a dr value of 1:1.

Claims

1. A method for preparing a brenoside precursor by photocatalytic configuration inversion, comprising the following steps: In a solution containing titanium tetrachloride and alkali, the solution is exposed to light at 380 nm under an LED lamp, and pregnenolone (Formula I) is subjected to the reaction shown in the following formula to obtain a brexanolone precursor (Formula II).

2. The method for preparing a brenoside precursor by photocatalytic configuration inversion according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The solvent is one or a mixture of two of n-hexane, dichloromethane, acetonitrile and trifluorotoluene. (2) The base is one of potassium carbonate, sodium carbonate, lithium carbonate, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene. (3) Preferably, the chiral ligand is one of L1-L6. (4) The molar volume ratio of the pregnenolone to the solvent is 1 mol:5 L. (5) The molar ratio of titanium tetrachloride to pregnenolone is 1:

10. (6) The molar ratio of the base to pregnenolone is 1:

1. (7) The molar ratio of the chiral ligand to pregnenolone is 1:5-10. (8) The reaction temperature is -20-30°C, the reaction time is 2-8 hours, and the stirring speed is 50-60 rpm. (9) The lighting condition is a 380nm LED light. (10) The reaction system of the reaction consists of the solvent, pregnenolone, titanium tetrachloride, a base and a chiral ligand. (11) After the reaction is completed, a post-treatment step is further included, and the post-treatment step is selected from one or more of concentration, extraction, drying and purification.

3. The method for preparing a brenoside precursor by photocatalytic configuration inversion as claimed in claim 2, characterized in that: It meets one or more of the following conditions: (1) The concentration is performed by vacuum distillation, the purification is performed by silica gel plate or silica gel column purification, and the eluent for the purification is a mixed solvent of dichloromethane and methanol. (2) The method for preparing a brucerolide precursor by photocatalytic reconfiguration comprises the following steps (a) and (b): (a) mixing the base, chiral ligand, titanium tetrachloride and solvent in a nitrogen atmosphere to obtain a mixed solution; (b) adding pregnenolone to the mixed solution obtained in step (a), mixing thoroughly, and then leaving the mixture open under corresponding light conditions to react, thereby obtaining the brenoside precursor.

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