Absolute chiral 3-hydroxy-4-fluoropiperidine compound as well as synthesis method and application thereof
Through a multi-step reaction method under the protection of inert gas, including hydrofluorate reaction, Mitsunobu reaction and chiral resolution, the existing 3-hydroxy-4-fluoroperidine compounds have been successfully solved, and an efficient and stable synthesis method has been achieved.
Patent Information
- Application Number
- CN202411743542.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-30
- Publication Date
- 2025-02-25
AI Technical Summary
The existing synthesis methods of 3-hydroxy-4-haloperidine compounds are complex and costly, and lack efficient chemical resolution methods.
A multi-step reaction method under the protection of inert gas is adopted, including reaction of compound 1 with hydrofluorate, reversal of Mitsunobu reaction configuration, reaction with phthalic anhydride, and finally disassembled by chiral resolving agent to obtain an absolutely chiral 3-hydroxy-4-fluoroperidine compound.
The synthesis of 3-hydroxy-4-haloperidine compounds with simple operation, stable product structure and high yield was achieved.
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Figure CN119504564A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of piperidine structure preparation, and in particular to an absolutely chiral 3-hydroxy-4-fluoropiperidine compound, a synthesis method and application thereof. Background Art
[0002] The core structure of 3-hydroxy-4-fluoropiperidine compounds is a piperidine ring, in which carbon atom No. 3 carries a hydroxyl group (-OH) and carbon atom No. 4 carries a fluorine atom (-F). With the continuous development of drug research and development and chemical synthesis technology, the application prospects of 3-hydroxy-4-fluoropiperidine compounds are becoming more and more broad, and they play an important role in drug research and development. They can be used as part of drug molecules to play a therapeutic role by affecting the activity of biological macromolecules such as receptors and enzymes in organisms. They can be used to synthesize a variety of high-value-added drugs, such as anti-diabetic drugs, antiviral drugs, etc. In addition, this type of compound can also be used as an intermediate in chemical synthesis to synthesize other biologically active compounds.
[0003] The synthesis method of 3-hydroxy-4-fluoropiperidine compounds usually involves multi-step reactions. During the synthesis process, the reaction conditions, such as temperature, pressure, catalyst, etc., need to be strictly controlled to ensure the purity and yield of the product. In "NOVARTIS-WO2022 / 254362, 2022, A1", it was found that a chiral chromatographic column (Column: 250 mm x 30 mm, 5 um DAICEL CHIRALPAK AD-H; CO2 Co-solvent 30% MeOH + 0.1% NH3*H2O; at 60 g / min at 100 bar) can be used for chiral separation in the synthesis of compound (3S,4R)-1-Boc-3-hydroxy-4-fluoropiperidine, but its cost is high, and it requires a professional organization and is more complicated to prepare. At present, no reports on the chemical separation method of compound (3S,4R)-1-Boc-3-hydroxy-4-fluoropiperidine and corresponding patents have been found.
[0004] Therefore, a simple synthesis process for 3-hydroxy-4-fluoropiperidine compounds is urgently needed. Summary of the invention
[0005] The purpose of the present invention is to provide an absolutely chiral 3-hydroxy-4-fluoropiperidine compound, a synthesis method and application thereof. The method is simple to operate, the obtained product has a stable structure and a high yield.
[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions: The present invention provides a method for synthesizing an absolutely chiral 3-hydroxy-4-fluoropiperidine compound, comprising the following steps: (1) Under the protection of inert gas, compound 1 is used as a starting material and reacted with hydrofluoric acid to obtain compound 2; (2) Under the protection of inert gas, compound 2 undergoes Mitsunobu reaction to reverse the configuration and obtain compound 4; (3) Under the protection of inert gas, compound 4 reacts with phthalic anhydride to obtain compound 5; (4) Compound 5 is resolved by a chiral resolving agent to obtain absolutely chiral 3-hydroxy-4-fluoropiperidine compounds.
[0007] Preferably, in step (1), the molar ratio of compound 1 to hydrofluoric acid salt is 1:1; the reaction temperature is 80-100° C., and the reaction time is 2-4 h; and the hydrofluoric acid salt is triethylamine trihydrofluoric acid salt or pyridine hydrofluoric acid salt.
[0008] Preferably, the Mitsunobu reaction in step (2) comprises: S1. Compound 2 is mixed with p-nitrobenzoic acid and triphenylphosphine, cooled to 0°C under the protection of an inert gas, and DIAD is added to react to obtain compound 3; S2. Compound 3 was dissolved in THF, and 2N lithium hydroxide solution was added under ice bath conditions to react to obtain compound 4.
[0009] Preferably, in step S1, the molar ratio of compound 2: p-nitrobenzoic acid: triphenylphosphine: DIAD is 0.8~1:1~2:1~2:1~2, the reaction temperature is 25~28°C, and the reaction time is 15~20h; in step S2, the molar ratio of compound 3 to lithium hydroxide is 0.2~0.3:0.6~1, the reaction temperature is 25~28°C, and the reaction time is 1~5h.
[0010] Preferably, in step (3), the molar ratio of the compound 4 to phthalic anhydride is 1-2:1-2, the reaction temperature is 85-95° C., and the reaction time is 2-6 h.
[0011] Preferably, in step (4), the splitting step includes: A. Compound 5 reacts with a chiral resolving agent, and then is filtered and extracted to obtain compound 6; B. Collect the filtrate of step A, extract and combine the organic phases, dry and concentrate to obtain a crude product, react the crude product with a chiral resolving agent, filter and extract to obtain compound 7; C. Compound 6 was dissolved in THF, and 2N lithium hydroxide solution was added under ice bath conditions. After reaction, compound 8 was obtained by extraction; D. Compound 7 was dissolved in THF, and 2N lithium hydroxide solution was added under ice bath conditions. After reaction, compound 9 was obtained by extraction.
[0012] Preferably, in step A, the molar ratio of compound 5 to the chiral resolving agent is 0.15-0.2:0.12-0.16; the reaction time is 0.5-2 h; in step B, the concentration of the crude product is 0.27 mol / L; the molar ratio of the crude product to the chiral resolving agent is 0.15-0.2:0.10-0.15; the reaction time is 0.5-2 h.
[0013] Preferably, the chiral resolving agent in steps A and B includes one of (R)-(+)-alpha-phenylethylamine, S-1-phenylethylamine, (S)-1-(2-naphthyl)ethylamine, and (R)-1-(2-naphthyl)ethylamine.
[0014] Preferably, in step C, the molar volume ratio of compound 6, 2N lithium hydroxide, and THF is 30-35 mmol: 0.10-0.15 mol: 90-110 mL; in step D, the molar volume ratio of compound 7, 2N lithium hydroxide, and THF is 20-25 mmol: 85-90 mmol: 75-90 mL.
[0015] The present invention also provides an absolutely chiral 3-hydroxy-4-fluoropiperidine compound prepared by the synthesis method of the absolutely chiral 3-hydroxy-4-fluoropiperidine compound.
[0016] The present invention also provides an application of an absolutely chiral 3-hydroxy-4-fluoropiperidine compound in the preparation of a drug intermediate.
[0017] The beneficial effects of the present invention compared with the prior art are: The preparation method of the present invention uses N-Boc-7-oxa-3-azabicyclo[4.1.0]heptane as a raw material, reacts with triethylamine trihydrofluoride to obtain trans-1-Boc-3-hydroxy-4-fluoropiperidine (compound 2), then undergoes Mitsunobu reaction configuration inversion, reacts with phthalic anhydride, and then uses a chiral resolving agent for resolving to obtain an absolutely chiral 3-hydroxy-4-fluoropiperidine compound. The synthesis method of the present invention is simple to operate, the product is stable, and the yield is high. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.
[0019] Figure 1 is the structural formula of compounds 1 to 9 in Example 1 of the present invention. DETAILED DESCRIPTION
[0020] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.
[0021] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that each intermediate value between the upper and lower limits of the scope is also specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.
[0022] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials associated with the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.
[0023] It will be apparent to those skilled in the art that various modifications and variations may be made to the specific embodiments of the present invention description without departing from the scope or spirit of the present invention. Other embodiments derived from the present invention description will be apparent to the skilled artisan. The present invention description and examples are exemplary only.
[0024] The words “include,” “including,” “have,” “contain,” etc. used in this document are open-ended terms, meaning including but not limited to.
[0025] The present invention provides a method for synthesizing an absolutely chiral 3-hydroxy-4-fluoropiperidine compound, comprising the following steps: (1) Under the protection of inert gas, compound 1 is used as a starting material and reacted with hydrofluoric acid to obtain compound 2; (2) Under the protection of inert gas, compound 2 undergoes Mitsunobu reaction to reverse the configuration and obtain compound 4; (3) Under the protection of inert gas, compound 4 reacts with phthalic anhydride to obtain compound 5; (4) Compound 5 is resolved by a chiral resolving agent to obtain absolutely chiral 3-hydroxy-4-fluoropiperidine compounds.
[0026] Example 1 Example 1 of the present invention provides a simple synthesis process of absolutely chiral 3-hydroxy-4-fluoropiperidine compounds, which specifically comprises the following steps: (1) Synthesis of compound 2: Add 200g (1.0mol, 1.0eq) of compound 1 (structure as shown in Figure 1 1), 161.8g (1.0mol, 1.0eq) triethylamine trihydrofluoride, reacted at 90°C for 3h under nitrogen protection. TLC detection showed that the raw material was completely reacted. Cooled, 1L sodium bicarbonate solution and 1L DCM were added and stirred, separated, extracted with DCM twice, the organic phases were combined, dried, concentrated, and PE slurried (solid precipitated after stirring) to obtain 133g white solid, namely compound 2 (structure as shown in Figure 1 (as shown in Figure 2), Y=60.7%.
[0027] Hydrogen spectrum of compound 2: 1H-NMR (400MHz, CDCl3): δ 4.54 - 4.41 (m, 1H), 3.95 -3.75 (m, 3H), 3.11 (br s, 2H), 2.69 - 2.38 (m, 1H), 2.11 - 2.02 (m, 1H), 1.72(br s, 1H), 1.46 (s, 9H).
[0028] (2) Synthesis of compound 3: In a 2L three-necked flask, 83.6g (0.381mol, 1.0eq) of compound 2 prepared in step (1), 1000mL of THF, 79.6g (0.476mol, 1.25eq) of p-nitrobenzoic acid, and 124.8g (0.476mol, 1.25eq) of triphenylphosphine were added. Under nitrogen protection, the temperature was lowered to 0°C, and 96.3g (0.476mol, 1.25eq) of DIAD was added dropwise. After the addition, the mixture was reacted at room temperature for 18h. According to TLC detection, the reaction of the raw materials was complete.
[0029] 500 mL of sodium bicarbonate solution was added dropwise, and 500 mL of water was added. The mixture was stirred and separated. EA was extracted once. The organic phases were combined, dried, concentrated, and subjected to column chromatography (PE\EA=10:1). PE slurry was used to obtain 77 g of solid, namely compound 3 (structure as shown in FIG. Figure 1 (as shown in Figure 3), Y=55%.
[0030] Hydrogen spectrum of compound 3: 1H-NMR (400MHz, CDCl3): δ 8.30 - 8.28 (d, 2H), 8.21-8.19 (d, 2H), 5.13 (br s, 1H), 4.91 - 4.76 (m, 1H), 3.84 - 3.71 (m, 2H), 3.63 (br s, 1H), 3.55-3.48 (m, 1H), 2.09-2.06 (m, 1H), 1.93 (br s, 1H), 1.49-1.44 (m,9H). (3) Synthesis of compound 4: In a 1L three-necked flask, add 77g (0.209mol, 1.0eq) of compound 3 prepared in step (2) and 500mL of THF, and add 313mL (0.627mol, 3.0eq) of 2N lithium hydroxide solution dropwise under ice bath. After addition, react at room temperature for 2h. TLC detection shows that the raw material reacts completely. Add 200mL of water, extract 3 times with EA, wash with Brine, dry, and concentrate to obtain 44.9g of viscous liquid, i.e., compound 4 (structure as Figure 1 (as shown in Figure 4), Y=98%.
[0031] Hydrogen spectrum of compound 4: 1H-NMR (400MHz, CDCl3): δ 4.87 - 4.74 (m, 1H), 3.78 -3.75 (m, 2H), 3.56 (br s, 1H), 2.25 - 2.31 (m, 2H), 2.05 - 2.15 (m, 1H), 1.79-1.70 (m, 1H), 1.46 (s, 9H). (4) Synthesis of compound 5: 44.9 g (0.205 mol, 1.0 eq) of compound 4 prepared in step (3), 225 mL of pyridine, 2.64 g of DMAP (0.02 mol, 0.1 eq), and 33.3 g of phthalic anhydride (0.225 mol, 1.1 eq) were added to a 500 mL three-necked flask. After the addition was completed, the mixture was reacted at 90 °C for 5 h under nitrogen protection. TLC detection showed that the raw materials were completely reacted. The pyridine was removed by rotation, EA was added to dissolve, the mixture was washed with 1 M hydrochloric acid and Brine, dried, concentrated, and PE slurried to obtain 72.7 g of white solid, namely compound 5 (structure as shown in Figure 1 (5) Y=96%.
[0032] Hydrogen spectrum of compound 5: 1H-NMR (400MHz, CDCl3): δ 7.79 - 7.75 (m, 2H), 7.58-7.56 (m, 2H), 6.31 (br s, 1H), 4.98 - 4.78 (m, 1H), 4.11 - 3.61 (m, 2H), 3.41-3.13 (m, 2H), 2.64-2.04 (m, 1H), 1.90-1.81 (m, 1H), 1.47 (s, 9H). (5) Synthesis of compound 6: In a 1000mL three-necked flask, add 72.7g (0.197mol, 1.0eq) of compound 5 prepared in step (4) and 720mL of EA, heat to 70°C, add dropwise 19.15g (0.158mol, 0.8eq) of (R)-(+)-alpha-phenylethylamine, react for 1h after addition, cool naturally to RT, filter, collect the filtrate, recrystallize the filter cake EA (10V) 3 times, filter, collect the filtrate, and obtain ee = 100%.
[0033] The filter cake was suspended in water, stirred with 1M hydrochloric acid for 10 min, extracted with EA three times, and the organic phases were combined, dried, and concentrated to obtain 12.3 g of solid, namely compound 6 (structure as Figure 1 (as shown in Figure 6), Y=16.9%.
[0034] Hydrogen spectrum of compound 6: 1H-NMR (400MHz, CDCl3): δ 7.79 - 7.75 (m, 2H), 7.58-7.56 (m, 2H), 6.31 (br s, 1H), 4.98 - 4.78 (m, 1H), 4.11 - 3.61 (m, 2H), 3.41-3.13 (m, 2H), 2.64-2.04 (m, 1H), 1.90-1.81 (m, 1H), 1.47 (s, 9H). (6) Synthesis of Compound 7: Combine all filtered filtrates in step (5), concentrate, stir with 1M hydrochloric acid for 10 min, extract with EA 3 times, combine the organic phases, dry, and concentrate to obtain 55 g (0.15 mol, 1.0 eq) of crude product. Add the crude product to a 1000 mL three-necked flask, add 550 mL of EA, heat to 70 ° C, add 14.5 g (0.12 mol, 0.8 eq) of S-1-phenylethylamine dropwise, react for 1 h after addition, cool naturally to RT, filter, and recrystallize the filter cake with EA (10V) 2 times to obtain ee = 98.5%. Suspend the filter cake in water, stir with 1M hydrochloric acid for 10 min, extract with EA 3 times, combine the organic phases, dry, and concentrate to obtain 8.0 g of solid, i.e., compound 7 (structure as Figure 1 (as shown in Figure 7) Y=14.5%.
[0035] Hydrogen spectrum of compound 7: 1H-NMR (400MHz, CDCl3): δ 7.79 - 7.75 (m, 2H), 7.58-7.56 (m, 2H), 6.31 (br s, 1H), 4.98 - 4.78 (m, 1H), 4.11 - 3.61 (m, 2H), 3.41-3.13 (m, 2H), 2.64-2.04 (m, 1H), 1.90-1.81 (m, 1H), 1.47 (s, 9H). (7) Synthesis of compound 8: 12.3 g (33.4 mmol, 1.0 eq) of compound 6 and 100 mL of THF were added to a 250 mL three-necked flask, and 66.9 mL (0.13 mol, 4.0 eq) of 2N lithium hydroxide solution was added dropwise under an ice bath. After addition, the mixture was reacted at room temperature for 18 h. TLC detection showed that the raw material was completely reacted. MTBE was extracted twice, washed with Brine, dried, concentrated, and the solvent was drained to precipitate the solid. PE pulping was performed to obtain 6.3 g of solid, i.e., compound 8 (structure as shown in FIG. 1 ). Figure 1 (8 in the figure). Y=86.3%.
[0036] Hydrogen spectrum of compound 8: 1H-NMR (400MHz, CDCl3): δ 4.87 - 4.74 (m, 1H), 3.78 -3.75 (m, 2H), 3.56 (br s, 1H), 2.25 - 2.31 (m, 2H), 2.05 - 2.15 (m, 1H), 1.79-1.70 (m, 1H), 1.46 (s, 9H). (8) Synthesis of compound 9: 8.0 g (21.7 mmol, 1.0 eq) of compound 7 and 80 mL of THF were added to a 250 mL three-necked flask, and 43 mL (87.1 mmol, 4.0 eq) of 2N lithium hydroxide solution was added dropwise under an ice bath. After addition, the mixture was reacted at room temperature for 18 h. TLC detection showed that the raw material was completely reacted. MTBE was extracted twice, washed with Brine, dried, concentrated, and the solvent was drained to precipitate a solid. PE pulping was performed to obtain 3.9 g of a solid, namely compound 9 (structure as shown in FIG. Figure 1 (as shown in Figure 9), Y=83%.
[0037] Hydrogen spectrum of compound 9: 1H-NMR (400MHz, CDCl3): δ 4.87 - 4.74 (m, 1H), 3.78 -3.75 (m, 2H), 3.56 (br s, 1H), 2.25 - 2.31 (m, 2H), 2.05 - 2.15 (m, 1H), 1.79-1.70 (m, 1H), 1.46 (s, 9H). The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A method for synthesizing an absolutely chiral 3-hydroxy-4-fluoropiperidine compound, characterized in that: The steps include: (1) Under the protection of inert gas, compound 1 is used as a starting material and reacted with hydrofluoric acid to obtain compound 2; (2) Under the protection of inert gas, compound 2 undergoes Mitsunobu reaction to reverse the configuration and obtain compound 4; (3) Under the protection of inert gas, compound 4 reacts with phthalic anhydride to obtain compound 5; (4) Compound 5 is resolved by a chiral resolving agent to obtain absolutely chiral 3-hydroxy-4-fluoropiperidine compounds.
2. The method for synthesizing the absolutely chiral 3-hydroxy-4-fluoropiperidine compound according to claim 1, characterized in that: In step (1), the molar ratio of compound 1 to hydrofluoric acid salt is 1:1; the reaction temperature is 80-100° C., and the reaction time is 2-4 hours; and the hydrofluoric acid salt is triethylamine trihydrofluoric acid salt or pyridine hydrofluoric acid salt.
3. The method for synthesizing absolutely chiral 3-hydroxy-4-fluoropiperidine compounds according to claim 1, characterized in that: The steps of the Mitsunobu reaction in step (2) include: S1. Compound 2 is mixed with p-nitrobenzoic acid and triphenylphosphine, cooled to 0°C under the protection of an inert gas, and DIAD is added to react to obtain compound 3; S2. Compound 3 was dissolved in THF, and 2N lithium hydroxide solution was added under ice bath conditions to react to obtain compound 4.
4. The method for synthesizing absolutely chiral 3-hydroxy-4-fluoropiperidine compounds according to claim 3, characterized in that: In step S1, the molar ratio of compound 2: p-nitrobenzoic acid: triphenylphosphine: DIAD is 0.8~1:1~2:1~2:1~2, the reaction temperature is 25~28°C, and the reaction time is 15~20h; in step S2, the molar ratio of compound 3 to lithium hydroxide is 0.2~0.3:0.6~1, the reaction temperature is 25~28°C, and the reaction time is 1~5h.
5. The method for synthesizing absolutely chiral 3-hydroxy-4-fluoropiperidine compounds according to claim 1, characterized in that: In step (3), the molar ratio of compound 4 to phthalic anhydride is 1-2:1-2, the reaction temperature is 85-95° C., and the reaction time is 2-6 h.
6. The method for synthesizing absolutely chiral 3-hydroxy-4-fluoropiperidine compounds according to claim 1, characterized in that: In step (4), the splitting step includes: A. Compound 5 reacts with a chiral resolving agent, and then is filtered and extracted to obtain compound 6; B. Collect the filtrate of step A, extract and combine the organic phases, dry and concentrate to obtain a crude product, react the crude product with a chiral resolving agent, filter and extract to obtain compound 7; C. Compound 6 was dissolved in THF, and 2N lithium hydroxide solution was added under ice bath conditions. After reaction, compound 8 was obtained by extraction; D. Compound 7 was dissolved in THF, and 2N lithium hydroxide solution was added under ice bath conditions. After reaction, compound 9 was obtained by extraction.
7. The method for synthesizing absolutely chiral 3-hydroxy-4-fluoropiperidine compounds according to claim 6, characterized in that: In step A, the molar ratio of compound 5 to the chiral resolving agent is 0.15-0.2:0.12-0.16; the reaction time is 0.5-2 h; in step B, the concentration of the crude product is 0.27 mol / L; the molar ratio of the crude product to the chiral resolving agent is 0.15-0.2:0.10-0.15; the reaction time is 0.5-2 h; the chiral resolving agent in steps A and B includes one of (R)-(+)-alpha-phenylethylamine, S-1-phenylethylamine, (S)-1-(2-naphthyl)ethylamine, and (R)-1-(2-naphthyl)ethylamine.
8. The method for synthesizing absolutely chiral 3-hydroxy-4-fluoropiperidine compounds according to claim 6, characterized in that: In step C, the molar volume ratio of compound 6, 2N lithium hydroxide, and THF is 30-35 mmol: 0.10-0.15 mol: 90-110 mL; in step D, the molar volume ratio of compound 7, 2N lithium hydroxide, and THF is 20-25 mmol: 85-90 mmol: 75-90 mL.
9. An absolutely chiral 3-hydroxy-4-fluoropiperidine compound prepared by the method for synthesizing absolutely chiral 3-hydroxy-4-fluoropiperidine compounds according to any one of claims 1 to 8.
10. Use of the absolutely chiral 3-hydroxy-4-fluoropiperidine compound according to claim 9 in the preparation of a pharmaceutical intermediate.