A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-ones

Abstract

The application discloses a kind of 3-alkyl bicyclo [3.2.0] hept-3-en-6-ketone resolution method, belong to the field of medicinal chemistry. Including the following steps: (1) the racemic mixture of 3-alkyl bicyclo [3.2.0] hept-3-en-6-ketone and aprotic polar solvent are added to reaction bottle, and the mixture is obtained;(2) under stirring, (1) mixture is added to the resolution reagent in step, and the reaction product is obtained after reaction, and the optical purity ee. After post-treatment of reaction product, (1R,5S) -3-alkyl bicyclo [3.2.0] hept-3-en-6-ketone with 98% is obtained. The method of the application is simple in operation steps, low in material cost, and high in optical purity of product.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one. Background Technology

[0002] Diastereomers are stereoisomers of molecules that have two or more chiral centers and are not mirror images of each other. Although they have the same molecular formula and connection mode, they may have different chemical and biological activities due to their different spatial arrangements.

[0003] In drug development, there is often a pharmacological requirement for enantioselectivity, meaning that only one isomer has the desired therapeutic effect, while the other may have side effects or be ineffective. Therefore, by resolving and separating diastereomers, highly pure single isomers can be obtained, allowing each isomer to be independently studied and tested for subsequent efficacy evaluation and clinical trials. Furthermore, the resolution of diastereomers also helps in studying the reaction mechanisms and steric effects in fields such as optically active substances and catalysts. The resolved single isomers can be used to further study their optical rotation properties, symmetry, chiral induction, and other characteristics to gain a deeper understanding of the relationship between molecular structure and properties.

[0004] The resolution of diastereomers is a challenging task in the scientific field, facing several difficulties: First, because diastereomers are chemically very similar, achieving high selectivity during resolution is often difficult, thus reducing resolution efficiency and purity. Second, the resolution of many diastereomers requires sophisticated synthetic techniques, advanced analytical methods, and stringent experimental conditions, which also makes the resolution operation difficult. Third, some resolution methods may use reagents or reaction conditions that have adverse environmental impacts, such as generating toxic waste or using large amounts of organic solvents. Therefore, developing sustainable diastereomer resolution methods is an urgent problem to be solved. Fourth, different diastereomers may have significant structural and property differences, which may limit the applicability of resolution methods.

[0005] Patent CN107667097 discloses a method for separating enantiomers of 3-ethylbicyclo[3.2.0]hept-3-en-6-one. This method involves reacting a mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one with a basic heterocyclic aldehyde compound and an optically active amine under alkaline conditions. The reaction product is then extracted to obtain (1R,5S)3-ethylbicyclo[3.2.0]hept-3-en-6-one. This preparation method is complex and not conducive to industrial production. Patent CN103987687 discloses an optical resolution method for bicyclic compounds using an asymmetric catalyst. This method uses an optically active amine to effectively produce optically active bicyclic compounds through optical resolution. In this method, the optically active amine is used as a catalyst; other optically active amines cannot achieve effective resolution.

[0006] Therefore, developing new, efficient, selective, and sustainable methods for diastereomer resolution is a research task of great significance. Summary of the Invention

[0007] This invention provides a method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one. This method uses (R)-(+)-α,α-diphenylprolyl or its derivatives as the resolving agent, requiring no other reaction reagents or catalysts; the method is simple, the obtained product has an optical purity of ee.% ≥ 98%, the material cost is low, and it is environmentally friendly.

[0008] The synthetic route of this invention is as follows:

[0009]

[0010] in,

[0011] R1 is H or a C1-C6 alkyl group;

[0012] R2 is selected from H or a leaving group, wherein the leaving group is trimethylsilyl or tert-butyldimethylsilyl;

[0013] R3 and R4 are each independently selected from H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl or OR5;

[0014] R5 is a C1-C3 alkyl group.

[0015] The present invention provides a method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one, comprising the following steps:

[0016] A racemic mixture of 3-alkylbicyclo[3.2.0]hept-3-en-6-one, an aprotic polar solvent, and a resolving agent were added to a reaction flask. After the reaction, the reaction product was obtained. After post-treatment of the reaction product, (1R,5S)-3-alkylbicyclo[3.2.0]hept-3-en-6-one was obtained.

[0017] The 3-alkylbicyclo[3.2.0]hept-3-en-6-one is one of 3-ethylbicyclo[3.2.0]hept-3-en-6-one, 3-methylbicyclo[3.2.0]hept-3-en-6-one, or 3-propylbicyclo[3.2.0]hept-3-en-6-one.

[0018] The aprotic polar solvent is one or more of acetonitrile (CH3CN), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and hexamethylphosphoric triamine (HMPA);

[0019] Preferably, the aprotic polar solvent is one or more of N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), or dimethyl sulfoxide (DMSO).

[0020] The structure of the resolving reagent is shown in formula (1):

[0021]

[0022] in:

[0023] R2 is selected from H or a leaving group, wherein the leaving group is trimethylsilyl or tert-butyldimethylsilyl;

[0024] R3 and R4 are each independently selected from H, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, or OR5; R5 is a C1-C3 alkyl.

[0025] Preferably, the resolving agent has one of the following structures:

[0026]

[0027]

[0028] Wherein: R2 is selected from H or a leaving group, wherein the leaving group is trimethylsilyl or tert-butyldimethylsilyl.

[0029] More preferably, the resolving agent is (R)-(+)-α,α-diphenylprolyl, (R)-(+)-α,α-diphenylprolyl trimethylsilyl ether, or (R)-(+)-α,α-bis(4-fluorophenyl)prolyl.

[0030] The molar ratio of the resolving reagent to the racemic mixture of 3-alkylbicyclo[3.2.0]hept-3-en-6-one is 0.5-2.5:1.

[0031] The reaction is carried out at a temperature of 0℃-60℃ and for a time of ≥12h.

[0032] The post-processing steps include extraction, washing, drying, filtration, concentration, and vacuum distillation.

[0033] The post-processing steps are as follows:

[0034] (1) After cooling the reaction product to room temperature, add an organic solvent, and then wash with acid solution, saturated saline solution and water respectively to separate the organic phase and obtain the crude compound.

[0035] (2) After drying, filtering, concentrating and distilling under reduced pressure, the crude compound was obtained as (1R,5S)-3-alkylbicyclo[3.2.0]hept-3-en-6-one.

[0036] The organic solvent mentioned in step (1) is one or more of n-heptane, diethyl ether, methyl ether or n-hexane.

[0037] Preferably, the organic solvent is n-heptane.

[0038] The acid solution mentioned in step (1) is an aqueous solution of HCl with a concentration of 1 mol / L.

[0039] The acid solution washing in step (1) is performed twice, the saturated saline solution washing is performed twice, and the water washing is performed once.

[0040] The drying agent used in step (2) is anhydrous magnesium sulfate.

[0041] The beneficial effects of this application include, but are not limited to:

[0042] 1. According to the resolution method of this application, (R)-(+)-α,α-diphenylprolyl and its derivatives are used as resolving agents, without the need for other reaction reagents or catalysts.

[0043] 2. The splitting method described in this application reduces material costs, is environmentally friendly, has simple operation steps, and high splitting efficiency. Attached image description:

[0044] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below. In the drawings:

[0045] Figure 1 This is a diagram showing the optical purity of a racemic mixture.

[0046] Figure 2 This is a chemical purity diagram for Example 1.

[0047] Figure 3 This is the optical purity diagram for Example 1.

[0048] Figure 4 Comparative Example 1: Chemical Purity Diagram

[0049] Figure 5 Comparative Example 1: Optical Purity Diagram

[0050] Figure 6 Comparative Example 2: Chemical Purity Diagram

[0051] Figure 7 Comparative Example 2: Optical Purity Diagram Detailed implementation method:

[0052] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. The specific embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0053] Example 1: A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one

[0054] Includes the following steps:

[0055] (1) 0.2 mol (27.3 g) of a racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 200 mL of N-methylpyrrolidone (NMP) were added sequentially to a reaction flask to obtain a mixture.

[0056] (2) Under stirring conditions, 0.15 mol (37.9 g) of chiral resolving reagent (R)-(+)-α,α-diphenylprolyl was added to the mixture in step (1), and the mixture was reacted at 40 °C for 16 h to obtain the reaction product.

[0057] (3) Cool the reaction product obtained in step (2) to room temperature, add 350 mL of n-heptane, wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0058] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.9 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 39.9%, chemical purity of 96.55% and optical purity of ee.% ≥98%.

[0059] Example 2: A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one

[0060] Includes the following steps:

[0061] (1) 0.2 mol (27.3 g) of a racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 150 mL of N-methylpyrrolidone (NMP) were added sequentially to a reaction flask to obtain a mixture.

[0062] (2) Under stirring conditions, 0.1 mol (32.5 g) of chiral resolving reagent (R)-(+)-α,α-diphenylprolyl trimethylsilyl ether was added to the mixture in step (1), and the mixture was reacted at 40 °C for 16 h to obtain the reaction product.

[0063] (3) Cool the reaction product obtained in step (2) to room temperature, add 350 mL of n-heptane, wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0064] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.6 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 38.8%, chemical purity >96%, and optical purity ee.% ≥98%.

[0065] Example 3: A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one

[0066] Includes the following steps:

[0067] (1) 0.2 mol (27.3 g) of a racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 300 mL of N-methylpyrrolidone (NMP) were added sequentially to the reaction flask.

[0068] (2) Under stirring conditions, 0.1 mol (28.9 g) of chiral resolving reagent (R)-(+)-α,α-bis(4-fluorophenyl)prolyl was added to the reaction flask of the mixture in step (2), and the mixture was stirred at 40 °C for 16 h to obtain the reaction product.

[0069] (3) Cool the reaction product obtained in step (2) to room temperature, add 350 mL of n-heptane, wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0070] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.6 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 38.8%, chemical purity >96%, and optical purity ee.% ≥98%.

[0071] Example 4: A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one

[0072] Includes the following steps:

[0073] (1) 0.2 mol (27.3 g) of racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 200 mL of N,N-dimethylformamide (DMF) were added sequentially to the reaction flask.

[0074] (2) Under stirring conditions, 0.15 mol (37.9 g) of chiral resolving reagent (R)-(+)-α,α-diphenylprolyl was added to the mixture in step (1), and the mixture was stirred at 60 °C for 12 h to obtain the reaction product.

[0075] (3) Cool the reaction product obtained in step (2) to room temperature, add 350 mL of n-heptane, wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0076] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.3 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 37.7%, chemical purity >96% and optical purity ee.% ≥98%.

[0077] Example 5: A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one

[0078] Includes the following steps:

[0079] (1) 0.2 mol (27.3 g) of a racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 200 mL of N-methylpyrrolidone (NMP) were added sequentially to the reaction flask.

[0080] (2) Under stirring conditions, 0.5 mol (126.3 g) of chiral resolving reagent (R)-(+)-α,α-diphenylprolyl was added to the mixture in step (1), and the mixture was stirred at 40 °C for 16 h to obtain the reaction product.

[0081] (3) Cool the reaction product obtained in step (2) to room temperature, add 350 mL of n-heptane, wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0082] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.7 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 39.2%, chemical purity >96% and optical purity ee.% ≥98%.

[0083] Example 6: A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one

[0084] Includes the following steps:

[0085] (1) 0.2 mol (27.3 g) of a racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 200 mL of N-methylpyrrolidone (NMP) were added sequentially to the reaction flask.

[0086] (2) Under stirring conditions, 0.15 mol (37.9 g) of chiral resolving reagent (R)-(+)-α,α-diphenylprolyl was added to the mixture in step (1), and the mixture was stirred at 20 °C for 30 h to obtain the reaction product.

[0087] (3) Add 350 mL of n-heptane to the reaction product obtained in step (2), wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0088] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.6 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 38.8%, chemical purity >96%, and optical purity ee.% ≥98%.

[0089] Example 7: A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one

[0090] Includes the following steps:

[0091] (1) 0.2 mol (27.3 g) of a racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 200 mL of N-methylpyrrolidone (NMP) were added sequentially to the reaction flask.

[0092] (2) Under stirring conditions, 0.15 mol (37.9 g) of chiral resolving reagent (R)-(+)-α,α-diphenylprolyl was added to the mixture in step (1), and the mixture was stirred at 0 °C for 66 h to obtain the reaction product.

[0093] (3) Add 350 mL of n-heptane to the reaction product obtained in step (2), wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0094] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.2 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 37.4%, chemical purity >96% and optical purity ee.% ≥98%.

[0095] Comparative Example 1

[0096] The difference from Example 1 is that the chiral resolving agent used in step (2) is (R)-diphenylmethylpyrrolidine.

[0097] The method for resolving the 3-alkylbicyclo[3.2.0]hept-3-en-6-one includes the following steps:

[0098] (1) 0.2 mol (27.3 g) of a racemic mixture of 3-ethylbicyclo[3.2.0]hepten-3-en-6-one and 200 mL of N-methylpyrrolidone (NMP) were added sequentially to the reaction flask.

[0099] (2) Under stirring conditions, 0.15 mol (35.5 g) of chiral resolving reagent (R)-diphenylmethylpyrrolidine was added to the mixture in step (1), and the mixture was stirred at 20 °C for 16 h to obtain the reaction product.

[0100] (3) Add 350 mL of n-heptane to the reaction product obtained in step (2), wash twice with 1 mol / L HCl aqueous solution, each time with a washing volume of 300 mL; then wash twice with saturated saline solution, each time with a washing volume of 100 mL; finally wash once with water, with a washing volume of 100 mL; then separate the organic phase to obtain the crude compound.

[0101] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.7 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 39.2%, chemical purity of 96.35% and optical purity of ee.% < 50%.

[0102] Comparative Example 2

[0103] Referring to the separation method disclosed in CN107667097, a mixture of 3-ethylbicyclo[3.2.0]hept-3-en-6-one is reacted with a basic heterocyclic aldehyde compound and an optically active amine under basic conditions. This method involves many reactants and complex operating procedures.

[0104] The method for resolving the 3-alkylbicyclo[3.2.0]hept-3-en-6-one includes the following steps:

[0105] (1) Dissolve 0.2 mol of p-aldehyde benzoic acid (30.1 g) and 0.22 mol of N-methylmorpholine (22.2 g) in 80 mL of N-methyl-2-pyrrolidone to obtain a mixture.

[0106] (2) Add 0.2 mol (27.3 g) of 3-ethylbicyclo[3.2.0]hept-3-en-6-one racemic mixture and 0.02 mol (5.35 g) (R)-diphenylmethoxymethylpyrrolidine to the mixture obtained in step (1), heat to 40 °C, stir for 20 h, and then cool to room temperature to obtain the reaction product.

[0107] (3) Add 130 mL of methyl tert-butyl ether and 180 mL of 1 mol / L hydrochloric acid aqueous solution to the reaction product obtained in step (2), stir, separate the organic layer, extract the aqueous phase with 130 mL of methyl tert-butyl ether, combine the organic phases, wash twice with 260 mL of water, separate the organic phase, and obtain the crude compound.

[0108] (4) The crude compound was dried with anhydrous magnesium sulfate, then filtered, concentrated and distilled under reduced pressure to obtain 10.4 g of (1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-one, which was a colorless oil with a yield of 38.1%, chemical purity of 96.41% and optical purity of ee.% ≥98%.

[0109] As can be seen from the examples and comparative results, the method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one described in this invention has the advantages of simple process steps, low material cost, environmental friendliness and high optical purity of product.

[0110] The above description is merely an embodiment of this application, and the scope of protection of this application is not limited to these specific embodiments, but is determined by the claims of this application. Various modifications and variations can be made to this application by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the technical concept and principles of this application should be included within the scope of protection of this application.

Claims

1. A method for resolving 3-alkylbicyclo[3.2.0]hept-3-en-6-one, characterized in that: Includes the following steps: A racemic mixture of 3-alkylbicyclo[3.2.0]hept-3-en-6-one, an aprotic polar solvent, and a resolving agent were added to a reaction flask. After the reaction, the reaction product was obtained. After post-treatment of the reaction product, (1R,5S)-3-alkylbicyclo[3.2.0]hept-3-en-6-one was obtained. The aprotic polar solvent is one or more of acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, and hexamethylphosphoric triamine; The structure of the resolving reagent is shown in the following formula (1): （1） in: R2 is selected from H or a leaving group, wherein the leaving group is trimethylsilyl or tert-butyldimethylsilyl; R3 and R4 are each independently selected from H, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, or OR5; R5 is a C1-C3 alkyl. The reaction is carried out at a temperature of 0℃-60℃ and for a time of 12-66 h.

2. The method according to claim 1, characterized in that: The 3-alkylbicyclo[3.2.0]hept-3-en-6-one is one of 3-ethylbicyclo[3.2.0]hept-3-en-6-one, 3-methylbicyclo[3.2.0]hept-3-en-6-one, or 3-propylbicyclo[3.2.0]hept-3-en-6-one.

3. The method according to claim 1, characterized in that: The aprotic polar solvent is one or more of N,N-dimethylformamide, N-methylpyrrolidone, or dimethyl sulfoxide.

4. The method according to claim 1, characterized in that: The resolving agent has one of the following structures: Wherein: R2 is selected from H or a leaving group, wherein the leaving group is trimethylsilyl or tert-butyldimethylsilyl.

5. The method according to claim 4, characterized in that: The resolving reagents are (R)-(+)-α,α-diphenylprolyl, (R)-(+)-α,α-diphenylprolyl trimethylsilyl ether, or (R)-(+)-α,α-bis(4-fluorophenyl)prolyl.

6. The method according to claim 1, characterized in that: The molar ratio of the resolving agent to the racemic mixture of 3-alkylbicyclo[3.2.0]hept-3-en-6-one is 0.5-2.5:

1.

7. The method according to claim 1, characterized in that: The post-processing steps include extraction, washing, drying, filtration, concentration, and vacuum distillation.

8. The method according to claim 7, characterized in that: The post-processing steps are as follows: (1) After cooling the obtained reaction product to room temperature, add an organic solvent, and then wash with acid solution, saturated saline solution and water respectively to separate the organic phase and obtain crude compound; (2) After drying, filtering, concentrating and distilling under reduced pressure, the crude compound was obtained as (1R,5S)-3-alkylbicyclo[3.2.0]hept-3-en-6-one; The organic solvent mentioned in step (1) is one or more of n-heptane, diethyl ether, methyl ether or n-hexane.

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