A method for the lipase-catalyzed resolution of (R,S)-2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol

Abstract

This invention relates to a lipase-catalyzed resolution ( R , S )-2-(1 H A method for 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol. This method includes: adding a certain amount of organic solvent, a catalyst (lipase), an acylation reagent, and a substrate (...) to a reactor. R , S Stereoselective catalytic transesterification was carried out by controlling the reaction temperature and time, and the reaction was monitored to produce 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol. S Configurational transesterification products and R The mixture of unreacted substrates was subsequently separated and purified by simple filtration. This method features mild reaction conditions, high stereoselectivity, and simple operation. Furthermore, the lipase is easily recovered and reused multiple times, significantly reducing production costs. It is suitable for the synthesis of chiral SKF 96365 and its analogues.

Description

Technical Field

[0001] This invention belongs to the technical field of biological resolution for the preparation of chiral compounds, and is a method for catalytic resolution using lipase. R , S )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethanol was given a single configuration ( R )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethanol and ( S )-2-(1 H Method for 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate. Background Technology

[0002] ( R , S )-2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol (as shown in structural formula 1) is an important intermediate for the Transient Receptor Potential Channel (TRPC) antagonist SKF 96365. As shown in structural formula 1, it can be prepared by subsequent etherification reaction with 1-(3-bromopropyl)-4-methoxybenzene under reflux in dimethyl sulfoxide solvent to generate SKF96365 (Dago, CD; et al.). Molbank 2016, 2016 SKF 96365, as a calcium ion inhibitor, can inhibit intracellular calcium (M909). 2+ The expression of compounds is an important tool in pharmacological research (Singh, A.; et al.). British Journal of Pharmacology 2010, 160 (1464–1475), but current literature reports only describe the synthesis and application of this compound as a racemic mixture. Enantiomers of chiral drugs often exhibit different pharmacodynamics, drug transport, metabolism, and toxicity; therefore, exploring efficient and economical methods to obtain high enantiomeric excesses ( R )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethanol and ( S )-2-(1 H The chiral synthesis of chiral SKF 96365 and its analogues, as well as the in-depth study of the effects of different configurations on their biological activities, are of great significance.

[0003]

[0004] ( R ,S )-2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol is more challenging to resolve than 1-phenylethanol, 2-chloro-1-phenylethanol, and 2-bromo-1-phenylethanol due to the presence of an imidazole group in its structure. This was the focus of the Gotor V research group (Mangas-Sanchez, J.; et al.). Journal of Organic Chemistry 2011, 76 (2115–2122) using lipase to resolve similar structural compounds 1-(2,4-dichlorophenyl)-2-(1 H When using 1-imidazolium-1-yl)ethanol (as shown in structural formula II), no reaction was observed with vinyl acetate as the acyl donor at either 30°C or 60°C, and with different organic solvents (tetrahydrofuran, 1,4-dioxane, or vinyl acetate itself) and representative biocatalysts (such as Candida antarcticis lipase B (CAL-B), Pseudomonas cepacia lipase (PSL-CI), Candida antarcticis lipase A (CAL-A), porcine pancreatic lipase (PPL), Candida columnaris lipase (CCL), or Serratia marcescens lipase (CVL)). Subsequent studies using the lipase CAL-B to catalyze the resolution of 2-bromo-1-(2,4-dichlorophenyl)ethanol from 2-chloro-1-(2,4-dichlorophenyl)ethanol showed no activity; however, when using tert-butyl methyl ether (TBME) and vinyl acetate itself as solvents at 30°C, the kinetic resolution of 2-bromo-1-(2,4-dichlorophenyl)ethanol catalyzed by PSL showed low conversion (2-3%), but excellent enantioselectivity (>99% ee). The PSL catalyzed racemic 2-chloro-1-(2,4-dichlorophenyl)ethanol showed extremely low reactivity, yielding (…). S 2-Chloro-1-(2,4-dichlorophenyl)ethanol is almost in racemic form. Summary of the Invention

[0005] The purpose of this invention is to achieve ( R , S )-2-(1 H The resolution of the enantiomers of 2-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol belongs to the technical field of biological resolution for the preparation of chiral compounds. H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol is a key intermediate in the transient receptor potential channel antagonist SKF 96365, and currently reported synthesis and applications of this compound are all racemic. This invention utilizes the stereoselectivity of lipases and the... S )-2-(1 HHighly efficient catalytic catalysis of 2-(1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol for transesterification. H -imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric synthesis of the corresponding ( S )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate (96%) ee The conversion rate was 50.6%; the remaining unreacted substrate was of high optical purity (…). R )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethanol (93%) ee After the reaction is complete, it can be achieved through simple filtration. S )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate and ( R )-2-(1 H Separation of (-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, S )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate can be obtained by subsequent hydrolysis. S )-2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol. This method features mild reaction conditions, high stereoselectivity, and simple operation. Furthermore, the lipase is easily recovered and reused multiple times, significantly reducing production costs. It provides a green, economical, and efficient method for the large-scale preparation of high-optical-purity target chiral intermediates, and is suitable for the synthesis of chiral SKF 96365 and its analogues.

[0006] The technical solution adopted by this invention to solve this technical problem is: A lipase-catalyzed resolution ( R , S )-2-(1 H The method includes: adding a certain organic solvent, a catalyst (lipase), an acylation reagent, and a substrate (-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol to a reactor. R , S )-2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, stereoselectively catalytically catalyzed transesterification reaction was carried out by controlling the reaction temperature and reaction time, and the reaction was monitored; to produce ( S )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate (96%) ee The conversion rate was 50.6%, and the remaining unreacted substrate was of high optical purity (…).R )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethanol (93%) ee Subsequently, it was separated and purified through simple filtration. in, The lipase is one or more of the following: Novozym 435 (immobilized Candida antarcticis lipase B), PPL (porcine pancreatic lipase), CRL (Candida lipolyticis lipase), Amano PS (Burkholderia cepacia lipase), and CAL-A (Candida antarcticis lipase A). The organic solvent is one or more selected from ethylene glycol dimethyl ether, tert-butanol, isooctane, n-hexane, cyclohexane, toluene, and methyl tert-butyl ether; The acylation reagent is one or more of vinyl acetate, ethyl acetate, and isopropyl acetate; The transesterification reaction time is 24~96 hours; The transesterification reaction temperature is 30~70 ℃; by( R , S )-2-(1 H The amount of lipase used is 1-150 wt% based on the mass of the 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol substrate; The amount of organic solvent used is per mole ( R , S )-2-(1 H The substrate (-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol is used in organic solvents ranging from 0.1 L to 20 L. The ( R , S )-2-(1 H The molar ratio of 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol to the acylation reagent is 1:1 to 1:5.

[0007] Compared with the prior art, the present invention has the following outstanding substantive features and significant progress: (1) Compared with the method of preparing chiral 2-aza-1-phenylethanol by catalytic asymmetric reduction of 2-aza-1-phenylethyl-1-one using ruthenium metal catalysis (Vyas, VK; et al.). Tetrahedron:Asymmetry 2017, 28 , 974–982; Barrios-Rivera,J.; et al. Tetrahedron 2022, 103(132562.), the method of the present invention can obtain two configurations of the product, without the need for expensive metal catalysts, and the purification operation is simple.

[0008] (2) With the Gotor V research group (Mangas-Sanchez, J.; et al.). Journal of Organic Chemistry 2011, 76 (2115–2122) reported the use of lipase to resolve a similar compound 1-(2,4-dichlorophenyl)-2-(1 H Compared to 1-imidazol-1-yl)ethanol, the yield of transesterification products by the method of the present invention can be significantly increased to about 50%. Attached Figure Description

[0009] Figure 1 for( R , S )- 2-(1 H High performance liquid chromatography chromatogram of (-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol; Figure 2 for( R , S )- 2-(1 H High performance liquid chromatography chromatogram of imidazole-1-yl)-1-(4-methoxyphenyl)ethyl acetate; Figure 3 After splitting ( S )- 2-(1 H High performance liquid chromatography chromatogram of imidazole-1-yl)-1-(4-methoxyphenyl)ethyl acetate; Figure 4 After splitting ( R )- 2-(1 H High performance liquid chromatography chromatogram of 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol. Detailed Implementation

[0010] Example 1: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 100 mg immobilized lipase Novozym 435, 1.5 mmol isopropyl acetate, and 5 mL anhydrous methyl tert-butyl ether were added to a 25 mL reactor and heated at 50 °C for 24 h; the reaction was detected by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 32.99%, with an enantiomeric excess of 98%. R )-2-(1H The enantiomeric excess of 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol was 45%. R )-2-(1 H 1H NMR data of imidazole-1-yl)-1-(4-methoxyphenyl)ethanol: 1 H NMR (400 MHz, DMSO- d 6) δ 7.53 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H),7.11 (s, 1H), 6.87 (d, J = 8.2 Hz, 2H), 6.83 (s, 1H), 4.75 (m, J = 7.9, 4.2 Hz,1H), 4.11–3.98 (m, 2H), 3.72 (s, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ 158.5, 137.6, 134.6, 127.2, 120.2, 113.5, 71.6, 55.0, 53.7; the product was determined to be (…) by 1H magnetic resonance spectroscopy analysis. R )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethanol. S )-2-(1 H 1H NMR spectrum of imidazole-1-yl)-1-(4-methoxyphenyl)ethyl acetate: 1 H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H),7.15 (d, J = 8.6 Hz, 2H), 7.03 (s, 1H), 6.86 (d, J = 8.6 Hz, 2H), 6.82 (s, 1H), 5.92–5.85 (t, 1H), 4.33–4.15 (m, 2H), 3.79 (s, 3H), 2.05 (s, 3H).; 13 C10 NMR (101MHz, CDCl3) δ 174.5, 169.6, 159.9, 137.5, 128.5, 128.4, 127.7, 119.6, 114.2, 74.7, 55.2, 51.6, 21.4, 21.0), and the product was determined to be (…) by 1H NMR spectroscopy. S )-2-(1 H-Imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate.

[0011] Example 2: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 10 mg porcine pancreatic lipase, 1.2 mmol isopropyl acetate, and 10 mL anhydrous methyl tert-butyl ether were added to a 25 mL reactor and heated at 45 °C for 48 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 23%, with an enantiomeric excess of 96%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value is 45%.

[0012] Example 3: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 10 mg of Candida albicans lipase, 2 mmol of isopropyl acetate, and 10 mL of anhydrous methyl tert-butyl ether were added to a 25 mL reactor and heated at 45 °C for 48 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 27%, with an enantiomeric excess of 95%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value is 60%.

[0013] Example 4: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 10 mg Burkholderia cepacia lipase, 2 mmol isopropyl acetate, and 10 mL anhydrous methyl tert-butyl ether were added to a 25 mL reactor and heated at 45 °C for 48 h; the reaction was detected by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethylacetic acid was 33%, with an enantiomeric excess of 98%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value was 78%.

[0014] Example 5: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 10 mg of Candida antarctica lipase A, 2 mmol of isopropyl acetate, and 10 mL of anhydrous methyl tert-butyl ether were added to a 25 mL reactor and heated at 45 °C for 48 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 3%, with an enantiomeric excess of 99%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value is 2%.

[0015] Example 6: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 150 mg immobilized lipase Novozym 435, 1.5 mmol vinyl acetate, and 10 mL n-hexane were added to a 25 mL reactor and heated at 40 °C for 24 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 20%, with an enantiomeric excess of 97%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value was 78%.

[0016] Example 7: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 150 mg immobilized lipase Novozym 435, 1.5 mmol vinyl acetate, and 10 mL n-hexane were added to a 25 mL reactor and heated at 60 °C for 24 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 30%, with an enantiomeric excess of 95%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value was 88%.

[0017] Example 8: Add 0.5 mmol of racemic 2-(1 H(-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 150 mg immobilized lipase Novozym 435, 1.5 mmol isopropyl acetate, and 5 mL methyl tert-butyl ether were added to a 25 mL reactor and heated at 60 °C for 48 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 50.6%, with an enantiomeric excess of 96%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value was 93%.

[0018] Example 9: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 50 mg immobilized lipase Novozym 435, 2 mmol of isopropyl acetate, and 5 mL of toluene were added to a 25 mL reactor and heated at 60 °C for 48 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 45%, with an enantiomeric excess of 98%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value was 93%.

[0019] Example 10: Add 0.5 mmol of racemic 2-(1 H (-Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, 100 mg immobilized lipase Novozym 435, 1.5 mmol isopropyl acetate, and 5 mL methyl tert-butyl ether were added to a 25 mL reactor and heated at 60 °C for 96 h. The reaction was then analyzed by high performance liquid chromatography (HPLC). S The yield of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate was 53%, with an enantiomeric excess of 94%. R )-2-(1 H -Imidazol-1-yl)-1-(4-methoxyphenyl)ethanol enantiomeric excess value was 88%.

[0020] The examples described above are merely illustrative of several embodiments of the present invention, and while the descriptions are relatively specific and detailed, the technical scope is not limited to these embodiments. For those skilled in the art, various improvements and implementations can be made without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this patent should be determined by the appended claims. The raw materials and reagents involved in the above embodiments are all commercially available, and the chemical reaction processes are mastered by those skilled in the art.

[0021] Matters not covered in this invention are common knowledge.

Claims

1. A lipase-catalyzed resolution ( R , S )-2-(1 H The method of 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, characterized in that, The method includes: adding a certain amount of organic solvent, catalyst lipase, acylation reagent, and substrate to the reactor. R , S )-2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol, stereoselectively catalytically catalyzed transesterification reaction was carried out by controlling the reaction temperature and reaction time, and the reaction was monitored to produce ( S )-2-(1 H -imidazol-1-yl)-1-(4-methoxyphenyl)ethyl acetate and ( R )-2-(1 H The mixture of 1-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol was subsequently separated and purified by simple filtration.

2. The method according to claim 1, characterized in that, The lipase is one or more of the following: Novozym 435 (immobilized Candida antarcticis lipase B), PPL (porcine pancreatic lipase), CRL (Candida rubra lipase), Amano PS (Burkholderia cepacia lipase), and CAL-A (Candida antarcticis lipase A).

3. The method according to claim 1, characterized in that, The organic solvent is one or more of ethylene glycol dimethyl ether, tert-butanol, isooctane, n-hexane, cyclohexane, toluene, and methyl tert-butyl ether.

4. The method according to claim 1, characterized in that, The acylation reagent is one or more of vinyl acetate, ethyl acetate, and isopropyl acetate.

5. The method according to claim 1, characterized in that, The transesterification reaction time is 24~96 hours.

6. The method according to claim 1, characterized in that, The transesterification reaction temperature is 30~70 ℃.

7. The method according to claims 1 and 2, characterized in that, by( R , S The amount of lipase used is 1-150 wt%, based on the mass of the 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol substrate.

8. The method according to claims 1 and 3, characterized in that, The amount of organic solvent used is per mole ( R , S )-2-(1 H The substrate (-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol is used in organic solvents ranging from 0.1 L to 20 L.

9. The method according to claims 1 and 4, characterized in that, The ( R , S The molar ratio of 2-(1H-imidazol-1-yl)-1-(4-methoxyphenyl)ethanol to the acylation reagent is 1:1 to 1:5.

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