Highly syn / anti isomer ratio oxime ether derivatives, raltegravir intermediates and methods of preparation

Abstract

The application provides an oxime ether derivative with high cis / trans isomer ratio, a raltegravir intermediate and a preparation method. A first compound shown in formula 1 and a second compound shown in formula 2 are subjected to an addition reaction in a first solvent under the action of a vitamin B2 compound-containing catalyst to obtain an oxime ether derivative with high cis / trans isomer ratio. The application can effectively improve the cis / trans isomer ratio of the oxime ether derivative, and then significantly improve the purity and yield of the raltegravir intermediate.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical synthesis technology, specifically involving high cis / trans isomeric oxime ether derivatives, retegvir intermediates, and their preparation methods. Background Technology

[0002] Rettigvir is a commonly used integrase inhibitor anti-HIV drug in clinical practice. The quality of its active pharmaceutical ingredient (API) synthesis is highly dependent on the purity, isomer ratio, and yield of key intermediates. Therefore, a highly selective, high-yield, and low-energy-consumption intermediate synthesis process is crucial for the industrial production of retegvir API. Currently, the mainstream industrial process for preparing retegvir intermediates mainly utilizes a tandem route of precursor compound addition reaction, rearrangement reaction, and solvent crystallization purification, which can meet the basic requirements for the large-scale preparation of retegvir intermediates and subsequent API synthesis.

[0003] However, the existing addition reaction process lacks sufficient control over the cis / trans isomer ratio, resulting in low conversion efficiency of subsequent rearrangement reactions, limited product purity and yield, and the need to compensate for process defects through high-temperature reactions and complex solvent systems, ultimately increasing energy consumption, safety hazards and environmental burden.

[0004] Therefore, how to improve the cis / trans isomer ratio of oxime ether derivatives, thereby significantly improving the purity and yield of retegvir intermediate, is an urgent technical problem to be solved. Summary of the Invention

[0005] This application provides a high cis / trans isomer ratio oxime ether derivative, a retegvir intermediate, and a method for its preparation. This application can effectively increase the cis / trans isomer ratio of the oxime ether derivative, thereby significantly improving the purity and yield of the retegvir intermediate.

[0006] This application provides a method for preparing an oxime ether derivative with a high cis / trans isomer ratio, comprising the following steps: in a first solvent, a first compound represented by Formula 1 and a second compound represented by Formula 2 are subjected to an addition reaction under the action of a catalyst to obtain an oxime ether derivative with a high cis / trans isomer ratio; wherein, the catalyst comprises a vitamin B2-like compound;

[0007] Formula 1,

[0008] Equation 2,

[0009] R3 and R4 are each independently selected from C1-C4 straight-chain alkyl groups and C1-C4 branched alkyl groups; the first solvent includes one or more of acetonitrile, acetone, and dichloromethane.

[0010] According to one embodiment of this application, the vitamin B2 compound includes riboflavin.

[0011] According to one embodiment of this application, the mass ratio of the first compound shown in Formula 1 to the second compound shown in Formula 2 is (0.7~1.0):1.

[0012] According to one embodiment of this application, the mass ratio of the catalyst to the first compound represented by Formula 1 is (0.001~0.05):1.

[0013] According to one embodiment of this application, the addition reaction of the first compound represented by Formula 1 and the second compound represented by Formula 2 in the first solvent under the action of a catalyst specifically includes: mixing the first compound represented by Formula 1, the catalyst, and the first solvent to obtain a first mixture; adjusting the temperature of the first mixture to the temperature of the addition reaction, adding the second compound represented by Formula 2 to the first mixture, and then carrying out the addition reaction under the condition of maintaining the temperature of the addition reaction to obtain the oxime ether derivative with a high cis / trans isomer ratio.

[0014] According to one embodiment of this application, the temperature of the addition reaction is 5~40°C, and the time of the addition reaction is 4~8h.

[0015] This application also provides a method for preparing a retegvir intermediate, comprising the following steps: subjecting the oxime ether derivative with a high cis / trans isomer ratio obtained by the above preparation method to a rearrangement reaction in a second solvent to obtain the retegvir intermediate shown in Formula 5;

[0016] Formula 5.

[0017] According to one embodiment of this application, the rearrangement reaction is carried out at a temperature of 110-125°C for a time of 4-6 hours.

[0018] According to one embodiment of this application, the second solvent includes one or more of xylene, ethylbenzene, and cumene.

[0019] According to one embodiment of this application, the rearrangement reaction further includes: after the rearrangement reaction is completed, the obtained reaction solution is heated to 60-100°C, a third solvent is added, the temperature is further lowered to -10-20°C for crystallization, and the solid product is collected by filtration to obtain the Retegwei intermediate; the third solvent includes one or more of methanol, ethanol, isopropanol, and tert-butanol.

[0020] This application provides a high cis / trans isomer ratio oxime ether derivative, a retegvir intermediate, and a method for its preparation. In the preparation of the oxime ether derivative, the stereoselectivity of the addition reaction is controlled by introducing a vitamin B2-like compound catalyst. The vitamin B2-like compound preferentially stabilizes the cis-configuration transition state by forming a diastereomeric intermediate with the reactants, reducing the probability of trans-configuration formation. This significantly increases the proportion of the cis-configuration in the addition reaction, thereby significantly improving the purity and yield of the retegvir intermediate. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only a part of the embodiments of this application, and not all of the embodiments. Based on the embodiments in this application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of this application.

[0022] In existing industrial routes, the first compound shown in Formula 1 and the second compound shown in Formula 2 are typically reacted in an organic solvent to form an oxime ether intermediate, which is then purified by subsequent rearrangement and crystallization to obtain the target intermediate. The core of this route lies in the composition of the isomers generated in the initial addition reaction, as different configurations directly affect subsequent conversion efficiency, separation difficulty, and the quality of the final product. However, in actual production, the cis-trans isomer selectivity of the addition step is insufficient, resulting in significant fluctuations in the configuration ratio of the obtained intermediate. This leads to a low proportion of effective reactants in the subsequent rearrangement reaction, limiting the overall yield and process stability.

[0023] In view of this, this application provides a method for preparing an oxime ether derivative with a high cis / trans isomer ratio, comprising the following steps: in a first solvent, a first compound shown in Formula 1 and a second compound shown in Formula 2 are subjected to an addition reaction under the action of a catalyst to obtain an oxime ether derivative with a high cis / trans isomer ratio; wherein the catalyst includes a vitamin B2-like compound;

[0024] Formula 1,

[0025] Equation 2,

[0026] R3 and R4 are each independently selected from C1-C4 straight-chain alkyl groups and C1-C4 branched alkyl groups; the first solvent includes one or more of acetonitrile, acetone, and dichloromethane.

[0027] This application discloses a method for preparing high cis / trans isomer ratio oxime ether derivatives. A vitamin B2-based compound is used as a catalyst in the addition reaction to achieve stereoselectivity. The vitamin B2-based compound combines with the reactants to form a diastereomeric intermediate, preferentially stabilizing the cis-configuration transition state and reducing the probability of trans-configuration formation. Through the synergistic effect of steric hindrance and electronic effects, the proportion of the cis-configuration in the addition reaction is significantly increased, thereby improving the purity and yield of the retegvir intermediate. By carrying the addition reaction in the aforementioned first solvent system, the first compound shown in Formula 1 and the second compound shown in Formula 2 can maintain a relatively stable reaction pathway under the catalysis of the vitamin B2-based compound, further effectively increasing the cis / trans isomer ratio of the oxime ether derivative, and ultimately significantly improving the purity and yield of the retegvir intermediate.

[0028] In some embodiments, the first compound has the structure shown in Formula 1-1:

[0029] Equation 1-1.

[0030] In some embodiments, the second compound has the structure shown in Formula 2-1:

[0031] Equation 2-1.

[0032] In the embodiments of this application, the oxime ether derivatives with a high cis / trans isomer ratio include the cis oxime ether derivative shown in Formula 3 and the trans oxime ether derivative shown in Formula 4:

[0033] Formula 3,

[0034] Formula 4.

[0035] In some embodiments, the cis-oxime ether derivative has the structure shown in Formula 3-1:

[0036] Equation 3-1.

[0037] In some embodiments, the trans-oxime ether derivative has the structure shown in Formula 4-1: Equation 4-1.

[0038] The cis-trans ratio of oxime ether derivatives can be determined using conventional methods in the art, such as high performance liquid chromatography (HPLC, area normalization method).

[0039] In some embodiments, vitamin B2 compounds include riboflavin. These vitamin B2 compounds possess a large conjugated molecular structure, enabling them to form stable diastereomeric intermediates with reactants and preferentially inducing cis configuration formation. Such catalysts effectively suppress side reactions under mild reaction conditions and significantly enhance the cis configuration ratio by modulating transition state stability through electronic effects. Compared to traditional catalysts such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-diisopropylethylamine (DIPEA), vitamin B2 compounds exhibit stronger configuration selectivity and milder reaction conditions, resulting in better yields of oxime ether derivatives with high cis / trans isomer ratios.

[0040] In some embodiments, the mass ratio of the first compound shown in Formula 1 to the second compound shown in Formula 2 is (0.7~1.0):1. When the mass ratio of the first compound shown in Formula 1 to the second compound shown in Formula 2 is within this range, the conversion of the reaction substrate during the addition reaction is more balanced, the unreacted raw material residue and the configuration shift caused by excessively high local concentrations are reduced, thereby further promoting the formation of high cis / trans isomer ratio oxime ether derivatives.

[0041] For example, the mass ratio of the first compound shown in Formula 1 to the second compound shown in Formula 2 can be 0.7:1, 0.8:1, 0.9:1, 1:1, or any combination of the two above.

[0042] In some embodiments, the mass ratio of the catalyst to the first compound shown in Formula 1 is (0.001~0.05):1. Limiting the amount of catalyst to the above-mentioned range is beneficial to improving the stereoselectivity of the addition reaction, increasing the proportion of the target isomer in the product, and reducing the generation of side reaction impurities. Furthermore, this ratio reduces the loss of catalytic activity caused by insufficient catalyst amount while avoiding the residual impurities in the system caused by excessive catalyst amount.

[0043] For example, the mass ratio of the catalyst to the first compound shown in Formula 1 can be 0.001:1, 0.005:1, 0.007:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, or any value between the two.

[0044] In this embodiment, the first compound shown in Formula 1 and the second compound shown in Formula 2 undergo an addition reaction in a first solvent under the action of a catalyst. Specifically, this includes: mixing the first compound shown in Formula 1, the catalyst, and the first solvent to obtain a first mixture; adjusting the temperature of the first mixture to the temperature of the addition reaction; adding the second compound shown in Formula 2 to the first mixture; and then carrying out the addition reaction while maintaining the temperature of the addition reaction to obtain an oxime ether derivative with a high cis / trans isomer ratio. In specific implementation, the first compound shown in Formula 1, the catalyst, and the first solvent are first added to a reaction vessel and stirred thoroughly to form a homogeneous first mixture; then the mixture is adjusted to the temperature of the addition reaction, and the second compound shown in Formula 2 is added in batches or continuously, allowing it to participate in the reaction under conditions where the system temperature has stabilized. By establishing the system first and then adding the second compound shown in Formula 2, it is possible to avoid the reaction of the substrate being too fast at local high concentrations, which could cause fluctuations in the isomer ratio, and to allow the reaction to proceed at a controlled rate. The stepwise addition method also allows the second compound shown in Formula 2 to maintain a relatively stable effective concentration throughout the reaction, increasing the proportion of the target configuration formed. This further increases the cis / trans isomer ratio of the oxime ether derivative, thereby improving the purity and yield of the Rettgvir intermediate.

[0045] In some embodiments, the addition reaction temperature is 5~40°C, which allows the addition reaction to proceed fully and efficiently, thereby suppressing side reactions and isomer imbalance that may accompany the addition reaction under high temperature conditions; the addition reaction time is 4~8h, which allows the raw materials to fully contact and complete the conversion under the catalysis of vitamin B2 compounds, further improving the purity and yield of the retegvir intermediate.

[0046] For example, the temperature of the addition reaction can be 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, or any value between two of the above.

[0047] For example, the addition reaction time can be 4h, 5h, 6h, 7h, 8h, or any value between two of these.

[0048] This application embodiment also provides a method for preparing a retegvir intermediate, comprising the following steps: subjecting the oxime ether derivative with a high cis / trans isomer ratio obtained by the above preparation method to a rearrangement reaction in a second solvent to obtain the retegvir intermediate shown in Formula 5;

[0049] Formula 5.

[0050] This application prepares retegvir intermediates from the aforementioned oxime ether substrates with high cis / trans isomer ratios, which can avoid a large number of trans isomer impurities from the source, reduce the generation of by-products in the rearrangement process, improve the conversion efficiency of the rearrangement reaction, and significantly increase the purity and yield of the retegvir intermediates. The highly selective substrate can reduce the temperature required for the rearrangement reaction, reduce the risk of material degradation and production energy consumption caused by high temperature, and improve the safety of process operation. At the same time, the total amount of impurities in the reaction system is lower, simplifying the subsequent crystallization and purification process, reducing the use and recovery costs of mixed organic solvents, and reducing the complexity of industrial production.

[0051] In this embodiment, the rearrangement reaction uses the oxime ether derivative with a high cis / trans isomer ratio obtained in the above addition step as the reaction substrate. In the reaction system composed of the second solvent, the skeleton or substituent positions are reconstructed, thereby converting it into the Rettgwe intermediate shown in Formula 5. Because the aforementioned oxime ether derivative has a high cis / trans isomer ratio, the proportion of substrate with the effective configuration increases during the rearrangement step, making the components capable of participating in the target transformation more concentrated, thus reducing the influence of isomer entrainment on the reaction selectivity. The second solvent is used to provide a suitable reaction medium environment for the rearrangement reaction.

[0052] In some embodiments, the rearrangement reaction is carried out at a temperature of 110-125°C for 4-6 hours, which is beneficial to further improve the yield and batch stability of the Rettgwe intermediate shown in Formula 5.

[0053] In some embodiments, the second solvent includes one or more of xylene, ethylbenzene, and cumene. These solvents exhibit excellent thermal stability and good solubility for oxime ether derivative substrates, enabling the formation of a homogeneous reaction system and promoting sufficient skeletal rearrangement of the substrate molecules. Furthermore, these solvents are inert aprotic aromatic media, preventing side reactions with the substrate and product, reducing impurity formation, and further improving the yield of the Rettgwij intermediate and the purity of the product.

[0054] In some embodiments, the rearrangement reaction is followed by: heating the resulting reaction solution to 60-100°C, adding a third solvent, and then cooling to -10-20°C for crystallization. The solid product is then collected by filtration to obtain the Rettgvir intermediate. The reaction solution after the rearrangement reaction refers to a system that still contains the target intermediate, solvent, and a small amount of byproducts after the aforementioned rearrangement transformation. Heating to 60-100°C maintains good fluidity and facilitates subsequent solvent replacement and crystallization control. Adding the third solvent and then cooling the system to -10-20°C for crystallization significantly reduces the solubility of the target component in the mixed solvent system, thereby inducing the directional precipitation of the Rettgvir intermediate and the formation of a filterable solid. After filtration and collection of the solid product, the Rettgvir intermediate is obtained.

[0055] In some embodiments, the third solvent includes one or more of methanol, ethanol, isopropanol, and tert-butanol. Xylene serves as a highly hydrophobic crystallization medium, methanol adjusts the system polarity, and methyl tert-butyl ether helps reduce the solubility of the target product and promotes complete crystallization. This results in more stable crystal precipitation, better filtration performance, and reduced residue of the target product in the mother liquor, thereby obtaining a higher purity Retegwert intermediate.

[0056] The technical solution of this application will be further described below with reference to specific embodiments.

[0057] In the addition reaction of this application, there is no strict limitation on the dropping rate of the second compound shown in Formula 2-1 added to the first mixture; it is only necessary to maintain the system temperature stable at 0~40℃ during the dropping process. The same reaction effect can be achieved with a total dropping time of 2~16h.

[0058] Example 1

[0059] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0060] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetonitrile to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 87:13. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. Add 200 mL of xylene, heat to 120 °C for rearrangement reaction for 5 hours, then distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. Add 200 mL of methanol, heat to 60 °C and hold for 2 hours, then cool to 0 °C for crystallization for 4 hours. Filter to obtain an off-white solid, dry in a forced-air environment at 40 °C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 62.4%, and the purity was 99.3% as determined by HPLC.

[0061] Example 2

[0062] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0063] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetonitrile to a 500mL four-necked reaction flask and mix to obtain a first mixture. Cool the system to 30℃ and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 30℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 80:20. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. Add 200 mL of xylene, heat to 120 °C for rearrangement reaction for 5 hours, then distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. Add 200 mL of methanol, heat to 60 °C and hold for 2 hours, then cool to 0 °C for crystallization for 4 hours. Filter to obtain an off-white solid, dry at 40 °C with forced air to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 56%, and the purity was 99.1% as determined by HPLC.

[0064] Example 3

[0065] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0066] Add 50g of the first compound shown in Formula 1-1, 2.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetonitrile to a 500mL four-necked reaction flask and mix to obtain a first mixture. Cool the system to 10℃ and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 87:13. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. Add 200 mL of xylene, heat to 120 °C for rearrangement reaction for 5 hours, then distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. Add 200 mL of methanol, heat to 60 °C and hold for 2 hours, then cool to 0 °C for crystallization for 4 hours. Filter to obtain an off-white solid, dry at 40 °C with forced air to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 62%, and the purity was 99.0% as determined by HPLC.

[0067] Example 4

[0068] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0069] Add 50g of the first compound shown in Formula 1-1, 0.05g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetonitrile to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 83:27. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. Add 200 mL of xylene, heat to 120 °C for rearrangement reaction for 5 hours, then distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. Add 200 mL of methanol, heat to 60 °C and hold for 2 hours, then cool to 0 °C for crystallization for 4 hours. Filter to obtain an off-white solid, dry in a forced-air environment at 40 °C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 59%, and the purity was 99.2% as determined by HPLC.

[0070] Example 5

[0071] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0072] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetonitrile to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 87:13. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, acetonitrile was recovered from the system. 200 mL of xylene was added, and the mixture was heated to 120 °C for a rearrangement reaction for 5 hours. Distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, xylene was recovered. 200 mL of methanol was added, and the mixture was heated to 60 °C and held at that temperature for 2 hours. Then, the mixture was cooled to 10 °C and crystallized for 4 hours. The resulting off-white solid was filtered and dried under blast at 40 °C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 55%, and the purity was 99.4% as determined by HPLC.

[0073] Example 6

[0074] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0075] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetonitrile to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 87:13. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. Add 200 mL of xylene, heat to 120 °C for rearrangement reaction for 5 hours, then distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. Add 200 mL of ethanol, heat to 60 °C and hold for 2 hours, then cool to 0 °C for crystallization for 4 hours. Filter to obtain an off-white solid, dry in a forced-air environment at 40 °C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 50%, and the purity was 96.1% as determined by HPLC.

[0076] Example 7

[0077] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0078] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetonitrile to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 87:13. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. Added 200 mL of xylene, heated to 120 °C for rearrangement reaction for 5 hours. Distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. Added 200 mL of isopropanol, heated to 60 °C and held for 2 hours, then cooled to 0 °C for crystallization for 4 hours. Filtered to obtain an off-white solid, dried at 40 °C by forced air to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 58%, and the purity was 94.6% as determined by HPLC.

[0079] Example 8

[0080] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0081] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of acetone to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 74:26. The acetone in the system was recovered by vacuum distillation at -0.09 MPa and 60 °C until no fraction was produced. 200 mL of xylene was added, and the mixture was heated to 120 °C for a rearrangement reaction for 5 hours. Xylene was recovered by vacuum distillation at -0.08 MPa and 100 °C. 200 mL of methanol was added, and the mixture was heated to 60 °C and held at that temperature for 2 hours. The mixture was then cooled to 0 °C and crystallized for 4 hours. The resulting off-white solid was filtered and dried at 40 °C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 50%, and the purity was 98.9% as determined by HPLC.

[0082] Example 9

[0083] The preparation method of the Rettgwe intermediate in this embodiment includes the following steps:

[0084] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of dichloromethane to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 87:13. Distilled under reduced pressure at -0.09 MPa and 20°C until no distillate was produced, recovering dichloromethane from the system. 200 mL of xylene was added, and the mixture was heated to 120°C for a rearrangement reaction for 5 hours. Distilled under reduced pressure at -0.08 MPa and 100°C until no distillate was produced, recovering xylene. 200 mL of methanol was added, and the mixture was heated to 60°C and held at that temperature for 2 hours. Then, the mixture was cooled to 0°C and crystallized for 4 hours. The resulting off-white solid was filtered and dried under blast at 40°C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 46%, and the purity was 98.1% as determined by HPLC.

[0085] Note: Dichloromethane has low polarity, which weakens the stabilizing effect of vitamin B2 compounds on the cis-configuration transition state, leading to a decrease in the cis-trans ratio. This example demonstrates that solvent selection affects the stereoselectivity of the reaction, and the solvent system needs to be optimized according to the target configuration.

[0086] Comparative Example 1

[0087] The preparation method of the comparative example Rettgwe intermediate includes the following steps:

[0088] 50 g of the first compound shown in Formula 1-1, 0.5 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 300 mL of acetonitrile were added to a 500 mL four-necked reaction flask to obtain a first mixture. The system was cooled to 10 °C, and the second compound shown in Formula 2-1 was added dropwise to the first mixture. After the addition was complete, the mixture was kept at 10 °C for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 76:24. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. Add 200 mL of xylene, heat to 120 °C for rearrangement reaction for 5 hours, then distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. Add 200 mL of methanol, heat to 60 °C and hold for 2 hours, then cool to 0 °C for crystallization for 4 hours. Filter to obtain an off-white solid, dry at 40 °C with forced air to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 51%, and the purity was 97.8% as determined by HPLC.

[0089] Comparative Example 2

[0090] The preparation method of the comparative example Rettgwe intermediate includes the following steps:

[0091] 50 g of the first compound shown in Formula 1-1, 0.5 g of N,N-diisopropylethylamine (DIPEA), and 300 mL of acetonitrile were added to a 500 mL four-necked reaction flask to obtain a first mixture. The system was cooled to 10 °C, and the second compound shown in Formula 2-1 was added dropwise to the first mixture. After the addition was complete, the mixture was kept at 10 °C for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 24:76. Distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, recovering acetonitrile from the system. 200 mL of xylene was added, and the mixture was heated to 120 °C for a rearrangement reaction for 5 hours. Distilled under reduced pressure at -0.08 MPa and 100 °C until no fraction was produced, recovering xylene. 200 mL of methanol was added, and the mixture was heated to 60 °C and held at that temperature for 2 hours. Then, the mixture was cooled to 0 °C for crystallization for 4 hours. The resulting off-white solid was filtered and dried under blast heat at 40 °C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of the retegvir intermediate was 28%, and the purity was 92.3% as determined by HPLC. Note: DIPEA, as a non-chiral base, did not exhibit significant selectivity for the cis configuration, indicating that its mechanism of action differs from that of riboflavin. This example verifies the crucial role of chiral catalysts in stereoselectivity, further highlighting the necessity of riboflavin in this application.

[0092] Comparative Example 3

[0093] The preparation method of the comparative example Rettgwe intermediate includes the following steps:

[0094] Add 50g of the first compound shown in Formula 1-1 and 175 mL of methanol to a 1000mL four-necked reaction flask and mix to obtain a first mixture. Cool the system to 10°C and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10°C for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 65:35. The system was distilled under reduced pressure at -0.09 MPa and 60 °C until no fraction was produced, and methanol was recovered. 135 mL of xylene was added, and the temperature was raised to 125 °C for a rearrangement reaction for 2 hours. The temperature was then raised to 135 °C for 5 hours. The temperature was lowered to 60 °C, and 175 mL of methanol was added. The temperature was lowered to 35 °C, and 525 mL of methyl tert-butyl ether was added dropwise. The temperature was lowered to -10 °C, and the system was crystallized for 4 hours. The solid was filtered to obtain an off-white solid, which was dried under blast at 40 °C to obtain 39.3 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 54.0%, and the purity was 97.6% as determined by HPLC.

[0095] Comparative Example 4

[0096] The preparation method of the comparative example Rettgwe intermediate includes the following steps:

[0097] Add 50g of the first compound shown in Formula 1-1 and 300mL of methanol to a 1000mL four-necked reaction flask and mix to obtain a first mixture. Cool the system to 10℃ and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 65:35. The system was distilled under reduced pressure at -0.09 MPa and 40 °C until no fraction was produced, and methanol was recovered. 200 mL of xylene was added, and the temperature was raised to 120 °C for a rearrangement reaction for 5 hours. 200 mL of methanol was added, and the temperature was lowered to 60 °C and held for 2 hours. The temperature was then lowered to 0 °C and crystallized for 4 hours. The resulting off-white solid was filtered and dried under blast at 40 °C to obtain 31.9 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 44.3%, and the purity was 99.2% as determined by HPLC.

[0098] Comparative Example 5

[0099] The preparation method of the comparative example Rettgwe intermediate includes the following steps:

[0100] Add 50g of the first compound shown in Formula 1-1, 0.5g of levorotatory riboflavin ((-)-riboflavin), and 300 mL of N,N-dimethylformamide to a 500mL four-necked reaction flask to obtain a first mixture. Cool the system to 10℃, and add the second compound shown in Formula 2-1 dropwise to the first mixture. After the addition is complete, maintain the temperature at 10℃ for 6 hours to obtain a reaction solution containing a cis-oxime ether derivative (structure as shown in Formula 3-1) and a trans-oxime ether derivative (structure as shown in Formula 4-1) with a cis-trans isomer ratio of 14:86. The N,N-dimethylformamide in the system was recovered by vacuum distillation at -0.09 MPa and 80 °C until no distillate was produced. 200 mL of xylene was added, and the mixture was heated to 120 °C for a rearrangement reaction for 5 hours. The mixture was then distilled under reduced pressure at -0.08 MPa and 100 °C until no distillate was produced, and the xylene was recovered. 200 mL of methanol was added, and the mixture was heated to 60 °C and held at that temperature for 2 hours. The mixture was then cooled to 0 °C and crystallized for 4 hours. The resulting off-white solid was filtered and dried at 40 °C to obtain 44.6 g of retegvir intermediate (structure shown in Formula 5-1). The yield of retegvir intermediate was 19%, and the purity was 72% as determined by HPLC.

[0101] The yield and purity of the Rettgwei intermediate in the above embodiments and comparative examples were tested using the following methods:

[0102] 1) Purity of Rettgvir intermediate: Take the dried Rettgvir intermediate, dissolve and dilute it in solvent, filter it through an organic filter membrane, and then inject it. Record the liquid chromatogram by high performance liquid chromatography. The purity of the main peak of the intermediate is obtained by the percentage of the peak area of ​​each chromatographic peak to the total peak area. This is the purity of the Rettgvir intermediate.

[0103] 2) Yield of Rettgwer intermediate: Yield of Rettgwer intermediate = (M1 × purity of Rettgwer intermediate) / M2, where M1 is the mass of the Rettgwer intermediate obtained and M2 is the mass of the reaction raw materials (i.e. the sum of the masses of the first compound shown in Formula 1 and the second compound shown in Formula 2).

[0104] Table 1 summarizes the types and mass percentages of catalysts, addition reaction temperatures, first solvents, cis-trans isomer ratios of oxime ether derivatives, types of third solvents, crystallization temperatures, purity of Rettgwei intermediates, and yields of Rettgwei intermediates in each of the above embodiments and comparative examples.

[0105] Table 1

[0106]

[0107]

[0108] Analysis of Table 1 shows that, compared with Comparative Examples 1-5, the oxime ether derivatives in Examples 1-9 have a higher cis / trans isomer ratio, which significantly improves the purity and yield of the Rettgwe intermediate.

[0109] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for preparing an oxime ether derivative with a high cis / trans isomer ratio, characterized in that, Includes the following steps: In a first solvent, the first compound shown in Formula 1 and the second compound shown in Formula 2 are subjected to an addition reaction in the presence of a catalyst to obtain an oxime ether derivative with a high cis / trans isomer ratio; wherein the catalyst includes vitamin B2 compounds. Formula 1, Equation 2, R3 and R4 are each independently selected from C1-C4 straight-chain alkyl groups and C1-C4 branched alkyl groups; The first solvent includes one or more of acetonitrile, acetone, and dichloromethane.

2. The method for preparing the oxime ether derivative with a high cis / trans isomer ratio according to claim 1, characterized in that, The vitamin B2 compounds include riboflavin.

3. The method for preparing the oxime ether derivative with a high cis / trans isomer ratio according to claim 1 or 2, characterized in that, The mass ratio of the first compound shown in Formula 1 to the second compound shown in Formula 2 is (0.7~1.0):

1.

4. The method for preparing the oxime ether derivative with a high cis / trans isomer ratio according to claim 1 or 2, characterized in that, The mass ratio of the catalyst to the first compound shown in Formula 1 is (0.001~0.05):

1.

5. The method for preparing the oxime ether derivative with a high cis / trans isomer ratio according to claim 1, characterized in that, The addition reaction of the first compound of Formula 1 and the second compound of Formula 2 in the first solvent under the action of a catalyst specifically includes: mixing the first compound of Formula 1, the catalyst and the first solvent to obtain a first mixture; adjusting the temperature of the first mixture to the temperature of the addition reaction, adding the second compound of Formula 2 to the first mixture, and then carrying out the addition reaction under the condition of maintaining the temperature of the addition reaction to obtain the oxime ether derivative with a high cis / trans isomer ratio.

6. The method for preparing the oxime ether derivative with a high cis / trans isomer ratio according to claim 1 or 5, characterized in that, The addition reaction is carried out at a temperature of 5~40℃ for 4~8 hours.

7. A method for preparing a Retegwei intermediate, characterized in that, The process includes the following steps: subjecting the oxime ether derivative with a high cis / trans isomer ratio obtained by the preparation method according to any one of claims 1-6 to a rearrangement reaction in a second solvent to obtain the Rettgwe intermediate shown in Formula 5; Formula 5.

8. The method for preparing the Rettgwe intermediate according to claim 7, characterized in that, The rearrangement reaction is carried out at a temperature of 110-125℃ for 4-6 hours.

9. The method for preparing the Rettgwe intermediate according to claim 7 or 8, characterized in that, The second solvent includes one or more of xylene, ethylbenzene, and cumene.

10. The method for preparing the Rettgwe intermediate according to claim 7 or 8, characterized in that, The rearrangement reaction further includes: after the rearrangement reaction is completed, the resulting reaction solution is heated to 60-100°C, a third solvent is added, and the temperature is further lowered to -10-20°C for crystallization. The solid product is then collected by filtration to obtain the Retegwei intermediate. The third solvent includes one or more of methanol, ethanol, isopropanol, and tert-butanol.

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