Vorcerotropine derivative and preparation method thereof
By preparing voxelotor derivatives 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde or 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde, the problems of limited types of existing SCD treatment drugs and adverse reactions of voxelotor were solved, achieving a highly effective and low-toxicity treatment effect.
Patent Information
- Application Number
- CN202510862181.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-25
- Publication Date
- 2025-10-31
AI Technical Summary
There are few existing SCD treatment options, and Voxelotor has adverse reactions, making it difficult to meet patients' needs for choice.
We developed vocerotrox derivatives 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde or 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde, which were prepared by hydrogenation and photoelectrophoresis. The structures are novel and have low toxicity and side effects.
It provides a highly effective drug for treating sickle cell disease with low toxicity and side effects, and its preparation method is simple and suitable for large-scale production.
Smart Images
Figure BDA0005467676620000021 
Figure BDA0005467676620000031 
Figure BDA0005467676620000041
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a vorselotto derivative and its preparation method. Background Technology
[0002] Sickle cell disease (SCD) is a hereditary disorder caused by a dysfunction of hemoglobin molecules. When hemoglobin molecules are exposed to various environments, they aggregate and twist into sickle-shaped structures (HbS) in red blood cells, leading to nutritional impairment in downstream tissues. SCD is characterized by abnormal blood rheology, hemolytic anemia, and vascular obstruction. After deoxygenation, HbS polymerizes, causing permanent damage to the cell membrane.
[0003] Voxelotor, also known as GBT440, is an orally administered first-line drug approved by the U.S. Food and Drug Administration (FDA) in 2019 for the treatment of sickle cell disease (SCD). It is used to treat SCD in adolescents aged 12 years and older and adults. Voxelotor increases the affinity of hemoglobin for oxygen, stabilizing red blood cells in an oxidized state and inhibiting hemoglobin sickling. As an inhibitor of HbS polymerization, Voxelotor has a very broad clinical application prospect.
[0004] However, the number of available SCD treatments is currently limited, making it difficult to meet the needs of SCD patients. Furthermore, Voxelotor also has some adverse reactions, such as insomnia, fatigue, abdominal pain, vomiting, diarrhea, rash, elevated liver enzyme levels, limb pain, and lower back pain. Therefore, developing more SCD drugs with novel structures, significant efficacy, and low toxicity is of great research importance. Summary of the Invention
[0005] To address the aforementioned problems in the prior art, this invention provides a vocerotrope derivative and its preparation method. The technical problem to be solved by this invention is achieved through the following technical solution:
[0006] This invention provides a vocerotropin derivative, wherein the vocerotropin derivative is 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a) or 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b), with the following structural formula:
[0007]
[0008] Another embodiment of the present invention provides a method for preparing a vocerotropin derivative, comprising the steps of:
[0009] Using 2-[(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl]methanol (2a) as the reactant, the reaction first undergoes a hydrogenation reaction to obtain intermediate (3a). Then, intermediate (3a) is reacted with 2,6-dihydroxybenzaldehyde (4) via photo-tracing to obtain the vocerotropin derivative 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a); or,
[0010] Using 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (2b) as the reactant, the intermediate (3b) was first obtained by hydrogenation. Then, the intermediate (3b) was reacted with 2,6-dihydroxybenzaldehyde (4) by photo-extending reaction to obtain the Voselotto derivative 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b).
[0011] In one embodiment of the present invention, the hydrogenation reaction process is as follows:
[0012] Under nitrogen protection, the reactants are dissolved in the first solvent and stirred until homogeneous. Then, a palladium / carbon catalyst is added, and the mixture is stirred for a first preset time at a first preset temperature in a hydrogen atmosphere. After the reaction is completed, the mixture is filtered under reduced pressure and the filtrate is concentrated under reduced pressure to obtain the intermediate.
[0013] In one embodiment of the present invention, the amount of the palladium / carbon catalyst is 5% to 20% of the mass of the 2-[(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl]methanol (2a) or 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (2b).
[0014] In one embodiment of the present invention, the first solvent includes one or more of methanol and ethanol.
[0015] In one embodiment of the present invention, the first preset temperature is 0 to 50°C, and the first preset time is 2 to 10 hours.
[0016] In one embodiment of the present invention, the process of the photoelongation reaction is as follows:
[0017] The intermediate, 2,6-dihydroxybenzaldehyde (4), and triphenylphosphine were added to the second solvent in sequence. After stirring evenly, a tetrahydrofuran solution of diisopropyl azodicarbonate was added at 0°C. The mixture was then reacted at a second preset temperature for a second preset time. After the reaction was completed, the mixture was concentrated under reduced pressure and the concentrated crude product was separated and purified to obtain the Voselotto derivative.
[0018] In one embodiment of the present invention, the molar ratio of 2,6-dihydroxybenzaldehyde (4) to the intermediate is 1.0:1 to 1.4:1.
[0019] In one embodiment of the present invention, the second solvent includes one or more of the following four solvents: ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.
[0020] In one embodiment of the present invention, the second preset temperature is 0 to 25°C, and the second preset time is 6 to 14 hours.
[0021] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0022] 1. The vocerotrop derivative of the present invention has a novel structure, providing a new compound for the development of highly effective and low-toxicity drugs against sickle cell disease;
[0023] 2. The method for preparing the Voselotto derivative of the present invention is simple, mild, and has high synthesis efficiency, making it suitable for large-scale preparation. Detailed Implementation
[0024] The present invention will be further described in detail below with reference to specific embodiments, but the implementation of the present invention is not limited thereto.
[0025] Drug development based on structural adjustment or modification of active molecules is an important approach in current drug development. This invention synthesizes a novel vorselotor derivative based on the structural design of vorselotor. This vorselotor derivative is 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a) or 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b), with the following structural formula:
[0026]
[0027] Specifically, the structural formula of 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a) is:
[0028]
[0029] The structural formula of 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b) is:
[0030]
[0031] This embodiment also provides a method for preparing a vocerotrop derivative, comprising the following steps: using 2-[(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl]methanol (2a) as a reactant, first undergoing a hydrogenation reaction to obtain an intermediate (3a), then reacting the intermediate (3a) with 2,6-dihydroxybenzaldehyde (4) via a Mitsunobu reaction (photocatalytic reaction) to obtain the vocerotrop derivative 2-hydroxy-6-{[2-(1- Isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a); or, using 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (2b) as the reactant, the intermediate (3b) is first hydrogenated to obtain intermediate (3b), and then intermediate (3b) is photo-extended with 2,6-dihydroxybenzaldehyde (4) to obtain the Voselotto derivative 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b). The synthetic route is as follows:
[0032]
[0033] In one specific embodiment, the hydrogenation reaction process is as follows: under nitrogen protection, the reactants are dissolved in a first solvent, stirred evenly, and then a palladium / carbon catalyst is added. The mixture is then stirred for a first preset time at a first preset temperature in a hydrogen environment. After the reaction is completed, the mixture is filtered under reduced pressure and the filtrate is concentrated under reduced pressure to obtain an intermediate.
[0034] Specifically, the amount of palladium / carbon catalyst used is 5% to 20% of the mass of 2-[(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl]methanol (2a) or 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (2b).
[0035] Specifically, the first solvent includes one or more of methanol and ethanol.
[0036] Specifically, the first preset temperature is 0 to 50°C, and the first preset time is 2 to 10 hours.
[0037] In one specific embodiment, the photo-extending reaction process is as follows: the intermediate, 2,6-dihydroxybenzaldehyde (4), and triphenylphosphine are added sequentially to the second solvent, stirred evenly, and then a tetrahydrofuran solution of diisopropyl azodicarbonate is added at 0°C. The reaction is then carried out at a second preset temperature for a second preset time. After the reaction is completed, the product is concentrated under reduced pressure and the concentrated crude product is separated and purified to obtain the Voselotto derivative.
[0038] Specifically, the molar ratio of 2,6-dihydroxybenzaldehyde (4) to the intermediate is: n(4):n(3) = 1.0:1 to 1.4:1.
[0039] Specifically, the second solvent includes one, two, or a mixture of two or more of the following four solvents: ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.
[0040] Specifically, the second preset temperature is 0–25°C, and the second preset time is 6–14 hours.
[0041] To facilitate understanding of the present invention, the following embodiments are provided. Those skilled in the art should understand that these embodiments are merely illustrative and should not be construed as limiting the scope of the invention.
[0042] Example 1
[0043] A method for preparing the voseloto derivative 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a) includes the following steps:
[0044] Step 1: Synthesis of [2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methanol (3a)
[0045] Under nitrogen protection, 2.06 g (10.0 mmol) of compound 2a was dissolved in 20 mL of methanol and stirred until homogeneous. Then, 188 mg of palladium / carbon was added, followed by three purgings with hydrogen. The reaction was carried out in a hydrogen atmosphere at 25 °C for 5 h with stirring. After the reaction was complete as monitored by TLC (thin-layer chromatography), the mixture was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to give 2.01 g of a pale yellow oily liquid, with a yield of 96.8% (based on compound 2a). ESI-MS [M+1]+m / z 329.1.
[0046] Step 2: Synthesis of 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a)
[0047] 624 mg (3.0 mmol) of compound 3a, 497 mg (3.6 mmol) of compound 4, and 1.2 g (4.5 mmol) of triphenylphosphine PPh3 were sequentially added to tetrahydrofuran (THF) (20 mL). After stirring until homogeneous, 910 mg (4.5 mmol) of a tetrahydrofuran solution of diisopropyl azodicarbonate (DIAD) (3 mL) was slowly added at 0 °C. The reaction was then carried out at 25 °C for 6 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). PE :V EA =2:1), yielding 554 mg of a grayish-white solid, with a yield of 56.3% (based on compound 3a). 1H NMR (400MHz, DMSO-d6, ppm) δ10.05 (s, 1H), 7.45 (t, J = 8.4Hz, 1H), 7.32 (s, 1H) ,6.47(d,J=8.4Hz,1H),6.35(d,J=8.4Hz,1H),6.04(s,1H),4.67-4.63(m,1H), 3.77-3.73(m,1H),3.64-3.60(m,1H),3.52-3.46(m,1H),2.71-2.66(m,1H),2. 06-1.98(m,2H),1.93-1.86(m,2H),1.75-1.68(m,2H),1.33(d,,J=6.8Hz,6H). ESI-MS[M+1] + m / z 329.1.
[0048] Example 2
[0049] A method for synthesizing the voseloto derivative 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b) includes the following steps:
[0050] Step 1: Synthesis of (2-phenylcyclohexyl)methanol (3b)
[0051] Under nitrogen protection, 1.88 g (10.0 mmol) of compound 2b was dissolved in 20 mL of methanol and stirred until homogeneous. Then, 188 mg of Pd / C was added, followed by three purgings with hydrogen. The reaction was carried out in a hydrogen atmosphere at 25 °C for 5 h with stirring. After the reaction was complete as monitored by TLC (thin-layer chromatography), the mixture was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to give 1.87 g of a pale yellow oily liquid, with a yield of 98.2% (based on compound 2). ESI-MS (m / z) 191.2 [M+1]+.
[0052] Step 2: Synthesis of 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b)
[0053] 570 mg (3.0 mmol) of compound 3b, 497 mg (3.6 mmol) of compound 4, and 1.2 g (4.5 mmol) of PPh3 were sequentially added to THF (50 mL). After stirring until homogeneous, 910 mg (4.5 mmol) of DIAD in THF solution (5 mL) was slowly added at 0 °C. The reaction was then carried out at 25 °C for 10 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: V). PE :V EA =8:1), yielding 574 mg of a pale yellow oily liquid, with a yield of 61.7% (based on compound 3b). 1H NMR (300MHz, CDCl3) δ9.91(s,1H),7.32-7.17(m,6H),6.43(d,J=8.4Hz,1H),6.09(d,J=8.4Hz,1H),4.03-3.90(m,1H),3.80-3.75(m,1H ),3.05-2.99(m,1H),2.53-2.48(m,1H),2.07-2.02(m,1H),1.96-1.93(m,1H),1.86-1.84(m,2H),1.77-1.62(m,2H),1.55-1.44(m,2H). ESI-MS(m / z)311.3[M+1] + .
[0054] Example 3
[0055] A method for preparing the voseloto derivative 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a) includes the following steps:
[0056] Step 1: Synthesis of [2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methanol (3a)
[0057] Under nitrogen protection, 2.06 g (10.0 mmol) of compound 2a was dissolved in 20 mL of methanol and stirred until homogeneous. Then, 103 mg of palladium / carbon was added, and the mixture was purged three times with hydrogen. The reaction was carried out in a hydrogen atmosphere at 50 °C for 2 h with stirring. After the reaction of the starting material was complete, it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure to obtain a pale yellow oily liquid.
[0058] Step 2: Synthesis of 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a)
[0059] 748.8 mg (3.6 mmol) of compound 3a, 497 mg (3.6 mmol) of compound 4 and 1.2 g (4.5 mmol) of triphenylphosphine PPh3 were added sequentially to tetrahydrofuran (THF) (20 mL). After stirring until homogeneous, 910 mg (4.5 mmol) of a tetrahydrofuran solution of diisopropyl azodicarbonate (DIAD) (3 mL) was slowly added at 0 °C. The mixture was then reacted at 15 °C for 10 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a grayish-white solid.
[0060] Example 4
[0061] A method for synthesizing the voseloto derivative 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b) includes the following steps:
[0062] Step 1: Synthesis of (2-phenylcyclohexyl)methanol (3b)
[0063] Under nitrogen protection, 1.88 g (10.0 mmol) of compound 2b was dissolved in 20 mL of methanol and stirred until homogeneous. Then, 376 mg of Pd / C was added, and the mixture was purged with hydrogen three times. The reaction was carried out in a hydrogen environment at 0 °C for 10 h. After the reaction of the starting material was complete, it was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily liquid.
[0064] Step 2: Synthesis of 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b)
[0065] 488.43 mg (2.57 mmol) of compound 3b, 497 mg (3.6 mmol) of compound 4 and 1.2 g (4.5 mmol) of PPh3 were added sequentially to THF (50 mL). After stirring until homogeneous, 910 mg (4.5 mmol) of DIAD in THF solution (5 mL) was slowly added at 0 °C. The mixture was then reacted at 0 °C for 14 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain a pale yellow oily liquid.
[0066] The vocerotroto derivatives of this invention have novel structures, providing a new compound for developing highly active, highly effective, and low-toxicity drugs against sickle cell disease, and can be used for subsequent activity screening studies. The preparation method of the vocerotroto derivatives of this invention is simple, mild, and highly efficient, suitable for large-scale preparation, and provides a conceptual approach and feasible process for the derivatization of this type of compound.
[0067] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.
Claims
1. A vocerotroto derivative, characterized in that, The vocerotrox derivative is 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a) or 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b), with the following structural formula:
2. A method for preparing a vocerotrope derivative, characterized in that, Including the following steps: Using 2-[(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl]methanol (2a) as the reactant, the reaction first undergoes a hydrogenation reaction to obtain intermediate (3a). Then, intermediate (3a) is reacted with 2,6-dihydroxybenzaldehyde (4) via photo-tracing to obtain the vocerotropin derivative 2-hydroxy-6-{[2-(1-isopropyl-1H-pyrazol-5-yl)cyclopentyl]methyl}benzaldehyde (1a); or, Using 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (2b) as the reactant, the intermediate (3b) was first obtained by hydrogenation. Then, the intermediate (3b) was reacted with 2,6-dihydroxybenzaldehyde (4) by photo-extending reaction to obtain the Voselotto derivative 2-hydroxy-6-[(2-phenylcyclohexyl)methoxy]benzaldehyde (1b).
3. The method for preparing the vocerotroto derivative according to claim 2, characterized in that, The hydrogenation reaction process is as follows: Under nitrogen protection, the reactants are dissolved in the first solvent and stirred until homogeneous. Then, a palladium / carbon catalyst is added, and the mixture is stirred for a first preset time at a first preset temperature in a hydrogen atmosphere. After the reaction is completed, the mixture is filtered under reduced pressure and the filtrate is concentrated under reduced pressure to obtain the intermediate.
4. The method for preparing the vocerotroto derivative according to claim 3, characterized in that, The amount of the palladium / carbon catalyst is 5% to 20% of the mass of the 2-[(1-isopropyl-1H-pyrazol-5-yl)cyclopent-1-en-1-yl]methanol (2a) or 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methanol (2b).
5. The method for preparing the vocerotroto derivative according to claim 3, characterized in that, The first solvent includes one or more of methanol and ethanol.
6. The method for preparing the vocerotroto derivative according to claim 3, characterized in that, The first preset temperature is 0 to 50°C, and the first preset time is 2 to 10 hours.
7. The method for preparing the vocerotroto derivative according to claim 2, characterized in that, The process of the photoelongation reaction is as follows: The intermediate, 2,6-dihydroxybenzaldehyde (4), and triphenylphosphine were added to the second solvent in sequence. After stirring evenly, a tetrahydrofuran solution of diisopropyl azodicarbonate was added at 0°C. The mixture was then reacted at a second preset temperature for a second preset time. After the reaction was completed, the mixture was concentrated under reduced pressure and the concentrated crude product was separated and purified to obtain the Voselotto derivative.
8. The method for preparing the Voselotto derivative according to claim 7, characterized in that, The molar ratio of 2,6-dihydroxybenzaldehyde (4) to the intermediate is 1.0:1 to 1.4:
1.
9. The method for preparing the vocerotroto derivative according to claim 7, characterized in that, The second solvent includes one or more of the following four solvents: ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetonitrile.
10. The method for preparing the vocerotroto derivative according to claim 7, characterized in that, The second preset temperature is 0 to 25°C, and the second preset time is 6 to 14 hours.