Synthesis method of azabicyclo [3.2. 1] octyl-2-ene derivative
By using addition, dehydration, and chiral salt formation resolution methods, the synthesis problem of optically pure nitrogen-containing bicyclic [3.2.1]oct-2-ene in the prior art has been solved, providing a simple and efficient synthetic route suitable for industrial production. The absolute configuration was confirmed by mandelic acid resolution.
Patent Information
- Application Number
- CN202511815913.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-04
- Publication Date
- 2026-02-03
AI Technical Summary
Existing technologies make it difficult to synthesize optically pure (1S,5R)- and (1R,5S)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene efficiently and simply. Moreover, the synthetic routes are cumbersome and the conditions are harsh, making them unsuitable for industrial production. There is also a lack of effective chiral resolution methods.
An addition reaction was used to generate an aryllithium reagent, which was then reacted with N-Boc-nortropinone. After dehydration and deprotection, the product was separated by chiral salt formation using mandelic acid as the resolving agent. The crystallization solvent system was optimized to achieve efficient separation of the optically pure product.
A simple and efficient method for synthesizing optically pure (1S,5R)- and (1R,5S)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene was achieved. The operation was simple and the conditions were mild, making it suitable for industrial production. The absolute configuration was confirmed by single-crystal X-ray diffraction.
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Figure CN121449601A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology and relates to a method for synthesizing a nitrogen-based bicyclic [3.2.1]oct-2-ene derivative. Background Technology
[0002] Azabicyclo[3.2.1]octene derivatives are an important class of pharmacologically active molecules. As inhibitors of monoamine neurotransmitter reuptake, they have shown great potential in the treatment of mental illnesses such as depression and anxiety. Among them, 3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene, especially its optically pure enantiomers—(1S,5R)- and (1R,5S)-configurations—have attracted much attention due to their specific pharmacological activities.
[0003] However, there are very few reports on the synthesis of these two optically pure enantiomers in the existing technology. The known synthetic routes generally have the following limitations: First, they cannot efficiently and specifically construct the specific chiral center, resulting in racemic products; second, there is a lack of effective chiral resolution and purification methods, making it difficult to obtain target products with high optical purity; third, the reported synthetic routes are cumbersome, have harsh reaction conditions, or use expensive chiral catalysts, making them unsuitable for industrial-scale production. In addition, the existing technology has not provided clear data to confirm the absolute configuration of the compound through authoritative means such as single-crystal X-ray diffraction, which poses an obstacle to its subsequent development and regulatory application as a pharmaceutical active ingredient. Therefore, there is an urgent need in the field to develop a simple, mild, high-yield, and easily scalable method for the synthesis and resolution of optically pure (1S,5R)-(+)- and (1R,5S)-(-)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene, and to clarify their absolute configuration. Summary of the Invention
[0004] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for synthesizing azabicyclic [3.2.1]oct-2-ene derivative, which has the characteristics of simple operation of each step of the reaction, mild conditions, high yield, good reproducibility, and suitability for industrial scale-up production.
[0005] The objective of this invention can be achieved through the following technical solutions: A method for synthesizing a aziridine bicyclic [3.2.1]oct-2-ene derivative, the specific steps of which are as follows: S1. Addition reaction: Under inert gas protection and low temperature conditions, the haloaromatic hydrocarbon reacts with the alkyl lithium reagent to generate the aryl lithium reagent, which then reacts with N-Boc-nortropinone. After quenching, extraction and purification, the intermediate IM1 is obtained. S2, Dehydration / Deprotection: The Boc protecting group of intermediate IM1 is removed and dehydrated in an organic solvent using acid. After alkalization, extraction and purification, intermediate IM2 is obtained. S3. Chiral salt formation and resolution: The intermediate IM2 is salted with the resolving agent in the first solvent, and then the diastereomeric salts are separated in the second solvent by stepwise crystallization. After alkali release, (1S,5R)-(+)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene and (1R,5S)-(-)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene are obtained. The synthetic route is as follows. ; The structural formula of (1S,5R)-(+)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene is: ; The structural formula of (1R,5S)-(-)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene is: .
[0006] As a preferred embodiment of the present invention, the halogenated aromatic hydrocarbon in S1 is one or two of bromobenzene and azirbenzene compounds, iodobenzene and azirbenzene compounds; the alkyl lithium reagent is one or more of n-butyllithium, sec-butyllithium and tert-butyllithium; the reaction solvent is one or two of tetrahydrofuran and methyltetrahydrofuran; and the low temperature environment is -80~-70℃.
[0007] As a preferred embodiment of the present invention, the reaction solvent in S2 is one or more of tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, and dichloromethane; the acid used is one or more of hydrochloric acid, acetic acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.
[0008] As a preferred embodiment of the present invention, the reaction temperature in S2 is 0~80℃.
[0009] As a preferred embodiment of the present invention, the resolving agent in S3 is one of tartaric acid, cysteine, mandelic acid, malic acid, and camphor sulfonic acid.
[0010] In a preferred embodiment of the present invention, the resolving agent in S3 is mandelic acid.
[0011] As a preferred embodiment of the present invention, the first solvent in S3 is one or more of isopropanol, ethyl acetate, acetonitrile, dichloromethane, acetone, methanol, ethanol and water.
[0012] In a preferred embodiment of the present invention, the first solvent in step S3 is methanol.
[0013] As a preferred embodiment of the present invention, the second solvent in S3 is one or more of isopropanol, acetonitrile, acetone, methanol, ethanol, tetrahydrofuran, and water.
[0014] As a preferred embodiment of the present invention, the second solvent in S3 is a mixed solution of isopropanol and water.
[0015] The beneficial effects of this invention are as follows: This invention provides a simple, efficient, and easily scalable synthetic route. Optically pure (1S,5R)- and (1R,5S)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene can be obtained in high yield from readily available N-Boc-nortropinone through a three-step reaction involving addition, dehydration / deprotection, and chiral salt formation. This invention successfully achieves efficient separation of the key racemic intermediate by using mandelic acid as the resolving agent and optimizing the crystallization solvent system. This process is simple to operate, has mild conditions, and excellent reproducibility. In summary, the reaction yields of each step in this invention are good, the purification operation is simple, and the overall process is robust and reliable, making it suitable for industrial-scale production. Attached Figure Description
[0016] To facilitate understanding by those skilled in the art, the present invention will be further described below with reference to the accompanying drawings.
[0017] Figure 1 The image shows the X-ray single-crystal diffraction results of the compound (1S,5R)-(+)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene obtained in Example 1 of this invention. Detailed Implementation
[0018] To further illustrate the technical means and effects of the present invention in achieving its intended purpose, the following detailed description of the specific implementation methods, structures, features, and effects of the present invention, in conjunction with the accompanying drawings and preferred embodiments, is provided.
[0019] In this embodiment of the invention: N-Boc-nortropinone: purchased from Chengdu Jingzhihuacheng Biotechnology Co., Ltd., CAS: 185099-67-6, purity: 100.0%.
[0020] Example 1 S1: Add 1500 mL of tetrahydrofuran and 230 g of 4-bromochlorobenzene, cool to -75°C under nitrogen protection, add 500 mL of 2.5 M n-butyllithium dropwise, stir at -80 to -70°C for 0.5 h after the addition is complete; at -80 to -70°C, add a tetrahydrofuran solution of N-Boc-nortropinone (225 g of N-Boc-nortropinone dissolved in 1500 mL of tetrahydrofuran), allow to rise naturally to room temperature, and stir overnight.
[0021] The reaction was quenched by adding 2000 mL of saturated ammonium chloride solution, stirred for 1 h, allowed to stand and separate into layers, extracted three times with 500 mL of ethyl acetate in the aqueous phase, concentrated to dryness, washed with 1000 mL of ethyl acetate and 500 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and subjected to column chromatography to obtain 280 g of pale yellow liquid IM1, with a separation yield of 83%.
[0022] S2: Dissolve the 280g IM1 obtained above in 2000mL of dichloromethane, stir until homogeneous, adjust the temperature to 20-30℃, add 550g trifluoroacetic acid dropwise (to release gas), and stir at 20-30℃ for 1-2 hours.
[0023] After the reaction was completed, the reaction solution was concentrated to dryness, and 1000 mL of 2N sodium hydroxide solution and 500 mL of dichloromethane were added for extraction three times. The solution was washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 180 g of low-melting solid IM2, with a separation yield of 98%.
[0024] 1 H-NMR (400MHz, CDCl3): δ =7.26 (4H, m), δ = 6.42 (1H, dt, J=1.6,5.6Hz), δ = 3.86 (1H, t, J=5.6Hz), δ = 3.80 (1H, t, J=5.6Hz), δ = 2.82 (1H,dd, J=4.8, 16.8Hz), δ = 2.18 (1H, d, J=16.8Hz), δ = 1.80-2.15 (3H, m), δ =1.63 (1H, m) S3: Dissolve 24g of IM2 in 100mL of methanol by stirring. Adjust the temperature to 20-30℃, add S-mandelic acid, heat to 55℃, stir until clear, cool to 25℃, concentrate to dryness, add a small amount of 90% isopropanol aqueous solution, heat to reflux, continue adding 90% isopropanol aqueous solution until dissolved under slight reflux (approximately 70℃), maintain at 70-80℃ for 1 hour, cool naturally to 20℃, maintain at 70℃ for 1 hour, filter, and wash with a small amount of isopropanol. Repeat recrystallization until 2g of mandelic acid salt with acceptable chiral purity is obtained (configuration determined by single crystal diffraction of S-mandelic acid salt).
[0025] The filtered mother liquor was combined and concentrated to dryness. 0.5N sodium hydroxide was added to adjust the alkali and release the free liquor. After extraction with dichloromethane, the liquor was concentrated, dissolved in methanol, and R-mandelic acid was added to form a salt. The solution was recrystallized to obtain 1g of R-mandelic acid salt with qualified chirality.
[0026] S-mandelate free: 1.0 g of qualified S-mandelate was dissolved in 20 mL of 0.5 N sodium hydroxide, extracted three times with 10 mL of dichloromethane, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated at low temperature, and dried at 30-40 °C to obtain 0.5 g of white solid (1S,5R)-(+)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene.
[0027] 1 H-NMR (400MHz, CDCl3): δ=7.26(4H, m), δ=6.42(1H, dd, J=5.6Hz), δ=3.86(1H, t, J=5.6Hz), δ= 3.79 (1H, t, J=5.6Hz), δ=2.82(1H, dd, J=4.0, 16.8Hz), δ=2.18 (1H, d, J=16.8Hz), δ=1.87-2.08 (3H, m), δ= 1.63 (1H, m) R-mandelate free: 1.0 g of qualified R-mandelate was dissolved in 20 mL of 0.5 N sodium hydroxide, extracted three times with 10 mL of dichloromethane, washed with saturated brine, dried with anhydrous sodium sulfate, concentrated at low temperature, and dried at 30-40 °C to obtain 0.5 g of white solid (1R,5S)-(-)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene.
[0028] 1 H-NMR(400MHz, CDCl3):=7.26(4H, m), δ=6.42(1H, dd, J=5.6Hz), δ=3.87(1H, t, J=5.6Hz), δ=3.82(1H, t, J=5.6Hz), δ=2.86(1H, dd, J=4.8, 17.2Hz), δ=2.19 (1H,d, J=17.2Hz), δ=1.90-2.11 (3H, m), δ=1.65(1H, m).
[0029] Example 2 S1: Add 5000 mL of tetrahydrofuran and 480 g of 4-bromochlorobenzene, cool to -75°C under nitrogen protection, add 1000 mL of 2.5 M n-butyllithium dropwise, stir at -80 to -70°C for 0.5 h after the addition is complete; at -80 to -70°C, add a tetrahydrofuran solution of N-Boc-nortropinone (450 g of N-Boc-nortropinone dissolved in 2000 mL of tetrahydrofuran), allow to rise naturally to room temperature, and stir overnight.
[0030] The reaction was quenched by adding 3000 mL of saturated ammonium chloride solution, stirred for 1 h, allowed to stand and separate into layers, extracted three times with 1000 mL of ethyl acetate in the aqueous phase, concentrated to dryness, washed with 3000 mL of ethyl acetate and 1000 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness, and subjected to column chromatography to obtain 600 g of pale yellow liquid IM1, with a separation yield of 89%.
[0031] S2: Dissolve 600g of the obtained IM1 in 3000mL of dichloromethane, stir until homogeneous, adjust the temperature to 20-30℃, add trifluoroacetic acid dropwise (to release gas), and stir at 20-30℃ for 1-2 hours. After the reaction was completed, the reaction solution was concentrated to dryness, and extracted three times with 1500 mL of 2N sodium hydroxide solution and 1000 mL of dichloromethane. The solution was washed with 1000 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness, yielding 350 g of low-melting-point solid IM2 with a separation yield of 90%.
[0032] S3: Dissolve 800g of IM2 in 4000mL of methanol by stirring. Adjust the temperature to 20-30℃, add S-mandelic acid, raise the temperature to 55℃, stir until clear, lower the temperature by 25℃, concentrate to dryness, add a small amount of 90% isopropanol aqueous solution, raise the temperature to reflux, continue adding 90% isopropanol aqueous solution until dissolved under slight reflux (approximately 70℃), maintain the temperature at 70-80℃ for 1 hour, allow to cool naturally to 20℃, maintain the temperature for 1 hour, filter, and wash with a small amount of isopropanol. Repeat recrystallization until 240g of S-mandelic acid salt with acceptable chiral purity is obtained.
[0033] The filtered mother liquor was combined and concentrated to dryness. 0.5N sodium hydroxide was added to adjust the alkali and release the free liquor. After extraction with dichloromethane, the liquor was concentrated, dissolved in methanol, and R-mandelic acid was added to form a salt. The solution was recrystallized to obtain 250g of R-mandelic acid salt with qualified chirality.
[0034] S-mandelate free: 240g of qualified S-mandelate was dissolved in 1000mL of 0.5N sodium hydroxide solution, extracted three times with 500mL of dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated at low temperature, and dried at 30-40℃ to obtain 114g of white solid (1S,5R)-(+)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene, with a separation yield of 28.6%.
[0035] R-mandelic acid salt free: 250g of qualified R-mandelic acid salt was dissolved in 1000ml of 0.5N sodium hydroxide solution and extracted three times with 500mL of dichloromethane. The solution was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated at low temperature, and dried at 30-40℃ to obtain 127g of a white solid (1R,5S)-(-)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene, with a separation yield of 31.8%. The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.
Claims
1. A method for synthesizing a aziridine bicyclic [3.2.1]oct-2-ene derivative, characterized in that, The specific steps of the synthesis method are as follows. S1. Addition reaction: Under inert gas protection and low temperature conditions, the haloaromatic hydrocarbon reacts with the alkyl lithium reagent to generate the aryl lithium reagent, which then reacts with N-Boc-nortropinone. After quenching, extraction and purification, the intermediate IM1 is obtained. S2, Dehydration / Deprotection: The Boc protecting group of intermediate IM1 is removed and dehydrated in an organic solvent using acid. After alkalization, extraction and purification, intermediate IM2 is obtained. S3. Chiral salt formation and resolution: The intermediate IM2 is salted with the resolving agent in the first solvent, and then the diastereomeric salts are separated in the second solvent by stepwise crystallization. After alkali release, (1S,5R)-(+)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene and (1R,5S)-(-)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]oct-2-ene are obtained. The synthetic route is as follows. 。 2. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The halogenated aromatic hydrocarbon in S1 is one or two of bromobenzene and azirbenzene compounds, iodobenzene and azirbenzene compounds; the alkyl lithium reagent is one or more of n-butyllithium, sec-butyllithium and tert-butyllithium; the reaction solvent is one or two of tetrahydrofuran and methyltetrahydrofuran, and the low temperature environment is -80~-70℃.
3. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The reaction solvent in S2 is one or more of tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, and dichloromethane; the acid used is one or more of hydrochloric acid, acetic acid, sulfuric acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid.
4. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The reaction temperature in S2 is 0~80℃.
5. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The resolving agent in S3 is one of tartaric acid, cysteine, mandelic acid, malic acid, and camphor sulfonic acid.
6. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The resolving agent in S3 is mandelic acid.
7. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The first solvent in S3 is one or more of isopropanol, ethyl acetate, acetonitrile, dichloromethane, acetone, methanol, ethanol, and water.
8. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The first solvent in S3 is methanol.
9. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The second solvent in S3 is one or more of isopropanol, acetonitrile, acetone, methanol, ethanol, tetrahydrofuran, and water.
10. The method for synthesizing a azirmonobicyclic [3.2.1]oct-2-ene derivative according to claim 1, characterized in that, The second solvent in S3 is a mixture of isopropanol and water.