A method for preparing high-optical-purity trans-2-aminocyclopentanol

Abstract

The present invention discloses a method for preparing high-optical-purity trans-2-aminocyclopentanol. The method mainly comprises the following steps: first, ring-opening cyclopentane in ammonia water to obtain a trans-2-aminocyclopentanol racemate; second, using optically pure N-Boc-proline as a resolving agent, resolving the racemic trans-2-aminocyclopentanol in an alcohol solvent to obtain (1R, 2R)-2-aminocyclopentanol resolvate or (1S, 2S)-2-aminocyclopentanol resolvate, and then hydrolyzing the mixture with alkaline solution to obtain optically pure trans-2-aminocyclopentanol. The preparation method has readily available raw materials, a short process, a high yield, and is suitable for process-based production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a method for preparing trans-2-aminocyclopentanol with high optical purity. Background Art

[0002] The 1,2-amino alcohol backbone is widely present in a variety of natural products and bioactive molecules. Chiral cyclic 1,2-amino alcohols, in particular, are important structural components of numerous drugs and peptide nucleic acids, providing a wealth of research material for pharmaceutical development. They are also used as potent chiral ligands and chiral auxiliaries in asymmetric syntheses. For example, (1R,2R)-trans-2-aminocyclopentanol is a key intermediate in the synthesis of ITI-214 (lenrispodun), a PDE inhibitor currently under Phase 2 clinical development as a potential treatment for Parkinson's disease.

[0003] There are three main methods for preparing optically pure trans-2-aminocyclopentanol reported in the literature:

[0004] The first method involves separating diastereomers by ring-opening cyclopentane with a chiral amine. The Journal of Organic Chemistry, 1985, vol. 50, #21, pp. 4154-4155, reported the reaction of cyclopentane with (R)-α-methylbenzylamine in the presence of trimethylaluminum to produce diastereomers. Column chromatography separation and palladium-carbon debenzylation yielded optically pure trans-2-aminocyclopentanol. This method utilizes trimethylaluminum, which is prone to spontaneous combustion, and carries high safety risks. The separation using column chromatography is not easily scalable.

[0005] The second method is asymmetric synthesis. Epoxides are enantioselectively opened using a suitable nucleophilic reagent. Patent EP1398310 discloses a method using methyl 2-oxocyclopentylcarboxylate as the starting material. This method involves hydrogenation in the presence of a chiral ruthenium catalyst to obtain chirality. This is followed by a four-step reaction of hydrazinolysis, rearrangement, and hydrolysis to yield optically pure trans-2-aminocyclopentanol. Organic Letters, 2013, vol. 15, #12, pp. 2895-2897 reports on the chirality of cyclopentane oxide and phenyl carbamate in the presence of a macromolecular chiral compound (salen) Co-OTf catalyst. This method, however, has low atom utilization and results in high production costs.

[0006] The third method is the resolution of racemates or related precursors. <4> 53, p.864, reports the resolution of the racemic form of trans-2-aminocyclopentanol using chiral tartaric acid. However, this method yields unsatisfactory resolution, resulting in a salt with poor optical purity and an ee value of approximately 70%. Journal of Organic Chemistry, 2006, vol. 71, #6, pp. 2320-2331 reports the resolution of the racemic form of trans-N-benzyl-2-aminocyclopentanol using chiral mandelic acid, followed by dissociation and palladium-on-carbon debenzylation to obtain optically pure trans-2-aminocyclopentanol. This method yields a salt with high optical purity, but requires a palladium-on-carbon hydrogenation debenzylation step. Tetrahedron: Asymmetry 22 (2011) 2134–2143 reports a method for resolving precursors of trans-2-aminocyclopentanol using Arthrobacter lipase. Although this method yields a product with high optical purity, the enzyme is difficult to obtain, sources are limited, and the process is high in cost and involves multiple steps, making industrial production difficult.

[0007] Existing synthesis methods lack direct and effective technical means. Therefore, it is necessary to develop a route with fewer steps, higher yield and higher optical purity. Summary of the Invention

[0008] To overcome the above problems, the present invention discloses a method for preparing high-optically pure trans-2-aminocyclopentanol. The method comprises the following steps: first, ring-opening cyclopentane in aqueous ammonia to obtain a racemic trans-2-aminocyclopentanol; second, resolving the racemic trans-2-aminocyclopentanol in an alcohol solvent using optically pure N-Boc-proline as a resolving agent to obtain a single enantiomer, trans-(1R,2R)-2-aminocyclopentanol resolved acid salt or trans-(1S,2S)-2-aminocyclopentanol resolved acid salt; and then hydrolyzing the product with alkaline solution to obtain optically pure trans-2-aminocyclopentanol. This method utilizes readily available raw materials, requires only a short number of steps, offers high yield, high optical purity, and is suitable for industrial production.

[0009] The present invention provides a method for preparing trans-2-aminocyclopentanol with high optical purity, comprising the following steps:

[0010]

[0011] In the first step, cyclopentene oxide undergoes a ring-opening reaction in aqueous ammonia. After the reaction is completed, the insoluble matter is filtered out, and the filtrate is concentrated under reduced pressure to obtain trans-2-aminocyclopentanol racemate 1;

[0012] In the second step, the trans-2-aminocyclopentanol racemate 1 and optically pure N-Boc-proline are resolved into salts in alcohol and filtered to obtain compound 2-LN-Boc-proline or ent-2-DN-Boc-proline;

[0013] In the third step, the compound 2-LN-Boc-proline or ent-2-DN-Boc-proline is adjusted to alkaline pH with an alkaline aqueous solution, extracted with an organic solvent, and the organic layer is concentrated and slurried to obtain trans-2-aminocyclopentanol with high optical purity.

[0014] Furthermore, in the first step, the molar ratio of cyclopentane oxide to ammonia water is 1.0:5.0-12.0.

[0015] Furthermore, in the first step, the ring-opening reaction temperature is 20-60°C.

[0016] Furthermore, in the second step, the reaction solvent alcohol is selected from anhydrous ethanol or isopropanol.

[0017] Furthermore, in the second step, the molar ratio of the trans-2-aminocyclopentanol racemate to the optically pure N-Boc-proline is 1:0.5-1.0, preferably 1:0.5.

[0018] Furthermore, in the second step, the reaction temperature is 0-90°C.

[0019] Furthermore, in the third step, the base is selected from KOH or NaOH.

[0020] Furthermore, in the third step, the organic solvent is selected from 2-methyltetrahydrofuran.

[0021] The present invention has the following advantages:

[0022] 1. Using optically pure N-Boc-proline as a resolving agent, trans-2-aminocyclopentanol is directly resolved. After alkaline hydrolysis, a single enantiomer with high optical purity is obtained, with an ee value of >99%.

[0023] 2. The method has cheap and easily available raw materials, short steps, simple operation, high yield, good optical purity, and is suitable for process production. Specific embodiments

[0024] Example 1

[0025] Synthesis of compound 1

[0026] To the reaction flask, add cyclopentene oxide (84.1 g, 1.0 mol) and aqueous ammonia (concentration 25%, 408.0 g, 6.0 mol), stir at 20-30 ° C for 16 hours, control the raw material cyclopentene oxide to <1% in GC, filter, and concentrate the filtrate under reduced pressure to obtain a light yellow oil. Let it stand at low temperature overnight and solidify to obtain 97.1 g of light yellow solid compound 1, GC: 95.7%, yield 96.2%.

[0027] Synthesis of compound 2

[0028] Compound 1 (GC95.7%, 97.1 g, 0.96 mol) and 200 mL of anhydrous ethanol were added to the reaction flask and stirred until completely dissolved. The mixture was heated to 60-70 ° C and a solution of N-Boc-L-proline (103.3 g, 0.48 mol) in 280 mL of anhydrous ethanol was added dropwise. After the addition was completed, heating and reflux were continued for 2 hours until the system was completely dissolved. The temperature was slowly lowered to 0-5 ° C and kept warm for 3 hours. The mixture was filtered and the filter cake was washed with 50 mL of cold anhydrous ethanol to give 107.3 g of white solid compound, HPLC: 99.5%, ee value 99.2%, and yield 35.3%.

[0029] Synthesis of (1S,2S)-2-aminocyclopentanol

[0030] Under nitrogen protection, 100 mL of water and compound 2 (100.0 g, 0.316 mol) were added to the reaction flask and stirred. At 10-20°C, 55 mL of 30% NaOH solution was added dropwise, and 2-methyltetrahydrofuran (150 mL × 3) was added for extraction. The organic layers were combined and washed with saturated brine. The organic layer was concentrated under reduced pressure. After the organic layer was concentrated under reduced pressure, 30 mL of n-heptane was added and slurried for 1 hour. The mixture was filtered to obtain 28.0 g of (1S,2S)-2-aminocyclopentanol as a white solid. GC: 99.8%, 99.4% ee, yield 87.7%; HNMR (CDCl3, 400 MHz) was consistent with standard NMR.

[0031] Example 2

[0032] The operation of this example refers to the preparation method of compound 1 in Example 1.

[0033] Synthesis of compound 2-LN-Boc-proline

[0034] Compound 1 (GC95.0%, 92.0 g, 0.80 mol) and 200 mL of isopropyl alcohol were added to the reaction flask and stirred until completely dissolved. The mixture was heated to 60-70 ° C and a solution of N-Boc-L-proline (172.2 g, 0.80 mol) in 720 mL of isopropyl alcohol was added dropwise. After the addition was completed, heating and reflux were continued for 2 hours until the system was completely dissolved. The temperature was slowly lowered to 0-5 ° C and kept warm for 3 hours. The mixture was filtered and the filter cake was washed with 100 mL of cold isopropyl alcohol to give 186.7 g of white solid compound, HPLC: 99.3%, 98.2% ee, and a yield of 73.8%.

[0035] Synthesis of (1S,2S)-2-aminocyclopentanol

[0036] Under nitrogen protection, 100 mL of water and compound 2-LN-Boc-proline (100.0 g, 0.316 mol) were added to the reaction flask and stirred. At 10-20°C, 75 mL of 30% KOH solution was added dropwise, and 2-methyltetrahydrofuran (150 mL × 3) was added for extraction. The organic layers were combined and washed with saturated brine. The organic layer was concentrated under reduced pressure. After the organic layer was concentrated under reduced pressure, 30 mL of n-heptane was added and slurried for 1 hour. The mixture was filtered to obtain 27.4 g of (1S,2S)-2-aminocyclopentanol as a white solid, GC: 99.8%, 98.5% ee, and a yield of 85.8%; HNMR (CDCl3, 400 MHz) was consistent with standard NMR.

[0037] Example 3

[0038] The operation of this example refers to the preparation method of compound 1 in Example 1.

[0039] Synthesis of the compound ent-2-DN-Boc-proline

[0040] Compound 1 (GC 95.2%, 101.0 g, 1.00 mol) and 200 mL of anhydrous ethanol were added to a reaction flask and stirred until completely dissolved. A solution of N-Boc-D-proline (107.6 g, 0.50 mol) in 300 mL of anhydrous ethanol was added dropwise at 60-70°C. After addition, the mixture was heated under reflux for 2 hours until the mixture was completely dissolved. The temperature was then slowly lowered to 0-5°C and kept warm for 3 hours. The mixture was filtered and the filter cake was rinsed with 50 mL of cold ethanol to obtain 114.2 g of a white solid compound. HPLC analysis indicated a 99.6% yield, 99.3% ee, and a yield of 36.1%. Synthesis of (1R,2R)-2-aminocyclopentanol

[0041] Under nitrogen protection, 100 mL of water and compound ent-2-DN-Boc-proline (100.0 g, 0.316 mol) were added to the reaction flask and stirred. At 10-20°C, 55 mL of 30% NaOH solution was added dropwise, and 2-methyltetrahydrofuran (150 mL × 3) was added for extraction. The organic layers were combined and washed with saturated brine. The organic layer was concentrated under reduced pressure. After the organic layer was concentrated under reduced pressure, 30 mL of n-heptane was added and slurried for 1 hour. The mixture was filtered to obtain 28.2 g of white solid (1R, 2R)-2-aminocyclopentanol, GC: 99.9%, 99.5% ee, and a yield of 88.3%; HNMR (CDCl3, 400 MHz) was consistent with standard NMR.

[0042] The operation of this example refers to the preparation method of compound 1 in Example 1. 23g of compound 1 (0.2mol, 1.0eq) was used, and different resolution conditions were used. The results obtained are as follows:

[0043]

[0044]

[0045] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing trans-2-aminocyclopentanol with high optical purity, characterized in that: The steps include: ； In the first step, cyclopentane oxide undergoes a ring-opening reaction in aqueous ammonia. After the reaction is completed, the insoluble matter is filtered out and the filtrate is concentrated under reduced pressure to obtain trans-2-aminocyclopentanol racemate 1. The ring-opening reaction temperature is 20-30°C. In the second step, the trans-2-aminocyclopentanol racemate 1 and optically pure N-Boc-proline are resolved into salts in ethanol and filtered to obtain compound 2-LN-Boc-proline or ent-2-DN-Boc-proline; the molar ratio of the trans-2-aminocyclopentanol racemate to optically pure N-Boc-proline is 1:0.5; In the third step, the compound 2-LN-Boc-proline or ent-2-DN-Boc-proline is adjusted to alkaline pH with an alkaline aqueous solution, extracted with 2-methyltetrahydrofuran, and the organic layer is concentrated and beaten to obtain high optical purity trans-2-aminocyclopentanol.

2. The method for preparing trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein: In the first step, the molar ratio of cyclopentane oxide to ammonia water is 1.0: 5.0-12.

0.

3. The method for preparing trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein: In the second step, the reaction temperature is 0-90°C.

4. The method for preparing trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein: In the third step, the base is selected from KOH or NaOH.

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