A method for introducing a c-14 labeled ethanolic group at the 3-position of a pyridine ring
By cyclizing and hydrogenating C-14-labeled 3-carbonylpyridine compounds with lithium reagents, the problem of low yield introducing ethanol groups onto the pyridine ring was solved, and efficient synthesis of C-14-labeled ethanol groups was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- WUXI BEITA PHARMATECH CO LTD
- Filing Date
- 2022-10-25
- Publication Date
- 2026-07-14
AI Technical Summary
Existing techniques for introducing C-14-labeled ethanol groups onto the pyridine ring result in low yields, especially due to side reactions between the N atom of the pyridine ring and the Ylide reagent, leading to low efficiency.
A cyclization reaction was carried out with a C-14-labeled 3-carbonylpyridine compound using a lithium reagent, followed by a ring-opening reaction under the action of a hydrogenation catalyst and hydrogen gas to form a C-14-labeled 3-hydroxyethylpyridine compound.
This significantly improved the yield of introducing C-14-labeled ethanol groups at the 3-position of the pyridine ring, avoided the generation of byproducts, and reduced the amount of C-14 raw material used.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of isotope labeling, specifically relating to a method for introducing a C-14 labeled ethanol group at the 3-position of a pyridine ring. Background Technology
[0002] A common C-12 ethanol group is introduced at the meta position of pyridine, typically starting with a brominated derivative, to directly introduce an aldehyde group, yielding a 3-ethanolpyridine compound (the target product). The reaction route is as follows:
[0003]
[0004] In the above-mentioned routes, the preparation of 3-ethanolpyridine compounds from 3-aldehyde pyridine compounds generally involves an epoxide intermediate. There are two ways to obtain epoxide intermediates from 3-aldehyde pyridine compounds: the first method is to use a Wittig reagent to first form an olefin, and then perform an epoxidation reaction; the second method is to use an aldehyde to react with a Wittig reagent to directly form an epoxide product, thereby introducing a carbon atom at the 2-position. The second method is more commonly used.
[0005] For the introduction of ethanol groups on benzene ring compounds, the method of introducing carbon atoms at the 2-position using ylide reagents (such as sulfur and phosphine ylides) can achieve good substitution results and generally has a high yield. However, for pyridine ring compounds, since the N atom of the pyridine ring is also prone to side reaction with ylide reagents to introduce methyl groups, the yield is generally low (usually below 20%).
[0006] Therefore, it would be of great significance to develop a method that can introduce an ethanol group at the 3-position of pyridine, especially an ethanol group labeled C-14. Summary of the Invention
[0007] This invention provides a method for introducing a C-14-labeled ethanol group at the 3-position of the pyridine ring, which significantly improves the yield of C-14-labeled 2-(3-pyridyl)ethanol.
[0008] The technical solution of the present invention is as follows:
[0009] A method for introducing a C-14 labeled ethanol group at the 3-position of a pyridine ring, comprising the following steps:
[0010] (1) Under the action of lithium reagent, the C-14 labeled 3-carbonylpyridine compound undergoes a cyclization reaction with CH2I2, and after the reaction is completed, the C-14 labeled 3-(1,2-oxoethyl)carbonylpyridine compound is obtained.
[0011] (2) The C-14 labeled 3-(1,2-oxoethyl)carbonylpyridine compound from step (1) undergoes a ring-opening reaction under the action of a hydrogenation catalyst and hydrogen to obtain the C-14 labeled 3-hydroxyethylpyridine compound.
[0012] The reaction formula is as follows:
[0013]
[0014] R1 and R2 are independently selected from C1-C4 alkyl, C1-C4 alkoxy, or trifluoromethyl; preferably methyl, methoxy, or trifluoromethyl.
[0015] Preferably, in step (1), the lithium reagent is one or more of LiMe.LiBr, n-BuLi, and t-BuLi.
[0016] Preferably, in step (1), the reaction is carried out in tetrahydrofuran, dichloromethane or diethyl ether.
[0017] Preferably, in step (1), the reaction temperature is 0–30°C.
[0018] Preferably, in step (2), the hydrogenation catalyst is Pd / C.
[0019] Preferably, in step (2), the solvent for the reaction is one or more of methanol, ethanol, and propanol.
[0020] Preferably, in step (2), the reaction temperature is 0–30°C.
[0021] Compared with the prior art, the beneficial effects of the present invention are reflected in:
[0022] This invention introduces a C-14-labeled ethanol group at the 3-position of the pyridine ring, which avoids the generation of byproducts due to the methyl group attacking the N atom of pyridine in the ylide, greatly improves the yield, and reduces the amount of C-14 raw material used. Detailed Implementation
[0023] Example 1
[0024] The reaction formula is as follows:
[0025]
[0026] Cu 14CN (205 mg, 2.235 mmol, 1.0 eq) and compound 7A (667 mg, 1 eq) were miscible in 6.1 mL of anhydrous DMF. Under nitrogen protection, the mixture was stirred overnight (22 hrs) at 120 °C. TLC (PE / EA 10:1) showed that the reaction was complete. The reaction was stopped, and the reaction solution was cooled in an ice-water bath. 10 g of crushed ice was added to quench the reaction. EtOAc (50 mL x 3) was added. The organic phase was washed with water and saturated brine. The solution was dried under reduced pressure and purified by column chromatography to give 400 mg of pale yellow solid (8A).
[0027] 300 mg of 8A (1.453 mmol, 1 eq) was dissolved in 3 ml of dry THF, cooled in an ice-water bath, and CH2I2 (428 mg, 1.1 eq, dissolved in 3 ml of anhydrous THF) was added dropwise by injection. The mixture was stirred at 0°C for 1 hr, then at 25°C for 2.5 hr. TLC (PE / EA 10:1) showed that 8A disappeared / no obvious new spot / no obvious peak on HPLC. The reaction was stopped, and 10 g of crushed ice was added to quench the reaction mixture. The mixture was extracted with EA (25 ml x 3, as there was no effective monitoring method to determine whether there was product residue in the aqueous phase). The EA extracts were combined, washed with saturated brine, dried under reduced pressure, and evaporated to obtain 353 mg of pale yellow viscous 9A, which was used directly in the next step.
[0028] 80 mg 9A (0.39 mmol, 1.0 eq) was dissolved in 1.6 mL of anhydrous THF under nitrogen protection. 110 mg CH2I2 (1.05 eq) was added, and the mixture was cooled in an ice-water bath. LiMe·LiBr (1.5 M in ether, 0.53 mL, 2.0 eq, added dropwise over 5 min) was added, and the system changed from a pale yellow to a pale brown solution. The mixture was stirred at 0 °C for 1 hr, then at 25 °C for 2 hr. TLC (PE / EA 10:1, developed twice, UV / I2 colorimetric analysis) showed that the reaction was complete. The reaction was stopped, and 5 g of crushed ice was added to quench the reaction. The mixture was extracted with EtOAc (20 mL x 2, until no product was found on TLC of the aqueous phase). The organic phases were combined, washed with saturated brine (5 mL), dried over Na2SO4 / MgSO4, and evaporated to dryness under reduced pressure using a water pump at 30 °C to obtain 97 mg of crude 10A, which was used directly in the next step.
[0029] 97 mg of crude 10A was dissolved in 4 ml of MeOH, and 45 mg of 10% Pd / C was added. The mixture was then purged three times with a H2 balloon, followed by stirring at room temperature for 2 hours. TLC (DCM / MeOH 10:1, UV / I2 colorimetric analysis) showed the reaction was complete. The reaction solution was directly filtered through silica gel, washed with MeOH until no product was found, and evaporated to dryness under reduced pressure to obtain 72 mg of 11. TLC showed acceptable purity (M+H). + 224.10, 83.4% yield. (Used for the next reaction with 100% yield; compound 11 is of acceptable quality.)
[0030] Example 2
[0031] The reaction formula is as follows:
[0032]
[0033] 25mg(CH3)3S + I - (0.122 mmol, 1.0 eq) was dissolved in 2 mL of t-BuOH under nitrogen protection. t-BuOK (1 M in THF, 0.122 mL, 1.0 eq) was added dropwise at room temperature, followed by stirring for 30 min. 12 (25 mg, dissolved in 0.1 mL of anhydrous THF) was then added dropwise, and the reaction was stirred for another 30 min. TLC (PE / EA 10:1) showed significant residual starting material. Stirring was continued for 5 hrs, and TLC still showed residual starting material with no obvious new spots. The reaction was stopped, and 3 g of crushed ice was added to quench the reaction. Extraction was performed using Et2O (20 mL x 2). The organic phases were combined, washed with saturated brine (5 mL), dried over Na2SO4 / MgSO4, and evaporated to dryness under reduced pressure using a water pump at 0 °C to obtain 35 mg of crude product 13. HPLC showed low content and impurities, which was directly used in the next step.
[0034] 35 mg of crude product 13 was dissolved in 2 ml of anhydrous EtOH, and 10 mg of 10% Pd / C, H2 was added and replaced three times by a balloon. The mixture was then stirred at room temperature for 2 to 12 hours. TLC (DCM / MeOH 10:1) showed a very mixed composition with very little product.
Claims
1. A method for introducing a C-14 labeled ethanol group at the 3-position of a pyridine ring, characterized in that, The reaction formula is as follows: ； Includes the following steps: (1) Under the action of lithium reagent, the C-14 labeled 3-carbonylpyridine compound undergoes a cyclization reaction with CH2I2, and after the reaction is completed, the C-14 labeled 3-(1,2-oxoethyl)carbonylpyridine compound is obtained; (2) The C-14 labeled 3-(1,2-oxoethyl)carbonylpyridine compound from step (1) undergoes a ring-opening reaction under the action of a hydrogenation catalyst and hydrogen to obtain the C-14 labeled 3-hydroxyethylpyridine compound. In step (1), the lithium reagent is LiMe.LiBr; In step (2), the hydrogenation catalyst is Pd / C; In step (2), the solvent for the reaction is methanol.
2. The method for introducing a C-14-labeled ethanol group at the 3-position of the pyridine ring according to claim 1, characterized in that, In step (1), the reaction is carried out in tetrahydrofuran, dichloromethane or diethyl ether.
3. The method for introducing a C-14-labeled ethanol group at the 3-position of the pyridine ring according to claim 1, characterized in that, In step (1), the reaction temperature is 0~30℃.
4. The method for introducing a C-14-labeled ethanol group at the 3-position of the pyridine ring according to claim 1, characterized in that, In step (2), the reaction temperature is 0~30℃.