Preparation method of 2-(4-(cyclopropylformyl) phenyl)-2-tert-butyl methyl propionate 13C
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-18
- Publication Date
- 2026-03-31
AI Technical Summary
2-(4-(环丙甲酰基)苯基)-2-甲基丙酸叔丁酯其在医药、生物方面代谢示踪具有非常大的应用前景，但目前合成2-(4-(环丙甲酰基)苯基)-2-甲基丙酸叔丁酯-13C未见报导
该路线合成2-(4-(环丙甲酰基)苯基)-2-甲基丙酸叔丁酯未有文献报导，反应原料存在不易挥发，容易得到且容易化学合成，反应条件温和，反应装置简单，便于操作，产品提纯方便，收率高，填补了国内同位素标记2-(4-(环丙甲酰基)苯基)-2-甲基丙酸叔丁酯合成的空白。
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis technology, specifically to a method for preparing tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C by isotope labeling. Background Technology
[0002] The description of the background art in this invention pertains to related technologies and is used merely for illustration and to facilitate understanding of the invention. It should not be construed as the applicant explicitly believing or presuming that the invention was prior art on the filing date of the first application.
[0003] 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate tert-butyl ester is a high-value compound containing tert-butyl ester, cyclopropanoyl group, and quaternary carbon center. This structural unit is widely found in various pharmaceutically active molecules, particularly as a key intermediate for protein kinase inhibitors, anti-inflammatory agents, and antitumor drugs, and is widely used to treat allergic dermatitis, urticaria, and other skin diseases. Third-generation antihistamines, compared to the first two generations, have no central sedative effects, no cardiotoxicity risk, no anticholinergic side effects, and offer higher safety, efficacy, and better tolerability. 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate tert-butyl ester is a key intermediate in the preparation of third-generation antihistamines. Fexofenadine tablets are a very effective prescription anti-allergy drug. Fexofenadine is a highly selective and potent antagonist of peripheral H1 receptors. It can rapidly and effectively block the effects of histamine, thus significantly relieving the symptoms of allergic rhinitis (such as sneezing, runny nose, and itchy nose) and skin itching and wheals of chronic urticaria. It has active metabolites, but it is highly polar and extremely difficult to cross the blood-brain barrier. 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate tert-butyl ester is an important pharmaceutical intermediate for the preparation of fexofenadine. Currently, there are few reports on the synthesis of this compound. Existing synthetic routes suffer from problems such as lengthy steps, use of expensive catalysts, harsh reaction conditions, low overall yield, or being unsuitable for industrial production. For example, some methods may attempt to construct this molecule through palladium-catalyzed reactions such as Suzuki coupling, but this significantly increases production costs and the risk of metal residue. CN106380441 uses phenylacetonitrile as a starting material, involving methylation, alkaline hydrolysis, Weinreb amide reaction, Friedel-Crafts reaction, acid hydrolysis, and esterification steps, but the reaction is overly complex and has low yield. CN114539131 uses α,α... Using methyl dimethylphenylacetate as a starting material, 2-[4-[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]-2,2-dimethylacetate (intermediate III) is obtained through Friedel-Crafts acylation, ring-opening, and condensation with cyclopropionic acid chloride. This reaction has drawbacks, including the need for Friedel-Crafts acylation and the formation of an acyl chloride, resulting in a long route and low yield. Existing synthetic routes suffer from lengthy steps, the use of expensive catalysts, harsh reaction conditions, low overall yield, or are unsuitable for industrial production. Some methods may attempt to construct this molecule through palladium-catalyzed reactions such as Suzuki coupling, but this significantly increases production costs and the risk of metal residue. Therefore, developing a synthetic route with readily available starting materials, simple operation, high yield, and suitability for large-scale production is of great significance for technological advancement in this field. 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate tert-butyl ester has great potential for metabolic tracing in medicine and biology, but the synthesis of 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate tert-butyl ester-13C has not been reported.
[0004] The existing methods for synthesizing tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate mainly include: 1. CN106380441 uses phenylacetonitrile as raw material and involves steps such as methylation, alkaline hydrolysis, Weinreb amide reaction, Friedel-Crafts reaction, acid hydrolysis, and esterification. However, the reaction is too complex and has a low yield.
[0005] 2. CN114539131 uses methyl α,α-dimethylphenylacetate as a raw material, and obtains 2-[4-[4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]phenyl]-2,2-dimethylacetate (intermediate III) by Friedel-Crafts acylation, ring opening and condensation with cyclopropionyl chloride. This reaction has the disadvantages of requiring Friedel-Crafts acylation and the formation of acyl chloride, resulting in a long route and low yield.
[0006] 3. Existing synthetic routes suffer from problems such as lengthy steps, use of expensive catalysts, harsh reaction conditions, low overall yield, or being unfavorable for industrial production. Some methods may attempt to construct the molecule through palladium-catalyzed reactions such as Suzuki coupling, but this would significantly increase production costs and the risk of metal residue. Summary of the Invention
[0007] The purpose of this invention is to provide a method for preparing tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate that is rational in its route, low in cost, high in yield, and easy to industrialize.
[0008] A method for preparing tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C includes the following steps: Cyclopropylformic acid-13C is synthesized from tetrahydrofuran and reagent A by passing carbon dioxide (-13C) through at -80 degrees Celsius. Reagent A is cyclopropylmagnesium bromide or cyclopropylmagnesium iodide. N-methoxy-N-methylcyclopropaneformamide-13C was synthesized by adding triethylamine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to cyclopropaneformamide-13C at room temperature, along with chloromethane, dimethylhydroxylamine hydrochloride, and 4-dimethylaminopyridine. 2-(4-bromophenyl)-2-methylpropionate tert-butyl ester, tetrahydrofuran, alkaline solution added dropwise at -40℃, followed by the addition of N-methoxy-N-methylcyclopropaneformamide-13C 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate tert-butyl ester-13C.
[0009]
[0010] Furthermore, the alkaline solution is a n-butyllithium solution or a diisopropylaminolithium solution.
[0011] Furthermore, it is characterized by, The synthesis of cyclopropionic acid-13C specifically includes the following steps: In a 100ml two-necked flask, under nitrogen protection, add 15ml of tetrahydrofuran and 4.8ml of cyclopropylmagnesium bromide (1.2eq, 1.0mol / L in THF). Purge with carbon dioxide-13C at -80℃ and slowly raise the temperature to room temperature for 1h. After the reaction is complete, quench the reaction with water, extract three times with ethyl acetate, wash once with saturated brine, dry with sodium sulfate, filter, and evaporate to dryness to obtain the compound cyclopropionic acid-13C. The synthesis of N-methoxy-N-methylcyclopropaneformamide-13C specifically includes the following steps: In a 50 ml two-necked flask, cyclopropaneformic acid-13C (313 mg, 1.0 eq), dichloromethane (10 ml), dimethylhydroxylamine hydrochloride (386 mg, 1.1 eq), and 4-dimethylaminopyridine (74 mg, 0.2 eq) were added. At room temperature, triethylamine (410 mg, 1.0 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (759 mg, 1.1 eq) were added. The mixture was reacted at room temperature for 3 h under nitrogen protection. After the reaction was complete, the mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain N-methoxy-N-methylcyclopropaneformamide-13C. The synthesis of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C specifically includes the following steps: Under nitrogen protection, tert-butyl 2-(4-bromophenyl)-2-methylpropionate (936 mg, 1.1 eq) and tetrahydrofuran (10 ml) were added to a 50 ml two-necked flask. A solution of n-butyllithium (1.25 ml, 1.1 eq, 2.5 mol / L in THF) was added dropwise at -40 °C. The reaction was carried out at -30 °C for 1 h. Then, N-methoxy-N-methylcyclopropaneformamide-13C (370 mg, 1.0 eq) was added dropwise, and the reaction was carried out at -30 °C for 1 h. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid. The reaction was extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, and purified by column chromatography to obtain tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C.
[0012] Furthermore, the carbon dioxide-13C is obtained by adding 5 ml of concentrated sulfuric acid to 793 mg of barium carbonate-13C.
[0013] Further, the synthesis of cyclopropionic acid-13C specifically includes the following steps: In a 100ml two-necked flask, under nitrogen protection, 15ml of tetrahydrofuran was added, followed by cyclopropylmagnesium bromide (2.6ml, 1.3eq, 1.0mol / L in THF). Carbon dioxide-13C was bubbled through at -80℃, and the mixture was slowly heated to room temperature for 1.5h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain the compound cyclopropionic acid-13C. The synthesis of N-methoxy-N-methylcyclopropaneformamide-13C specifically includes the following steps: In a 50 ml two-necked flask, cyclopropaneformic acid-13C (167 mg, 1.0 eq), dichloromethane (6 ml), dimethylhydroxylamine hydrochloride (204 mg, 1.1 eq), and 4-dimethylaminopyridine (23 mg, 0.1 eq) were added. At room temperature, triethylamine (192 mg, 1.0 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (401 mg, 1.1 eq) were added. Under nitrogen protection, the reaction was carried out at room temperature for 3 h. After the reaction was complete, the mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain N-methoxy-N-methylcyclopropaneformamide-13C. The synthesis of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C specifically includes the following steps: In a 50 ml two-necked flask under nitrogen protection, ethyl 2-(4-bromophenyl)-2-methylpropionate (482 mg, 1.1 eq) and tetrahydrofuran (5 ml) were added. A solution of n-butyllithium (0.7 ml, 1.1 eq, 2.5 mol / L in THF) was added dropwise at -40 °C. The reaction was carried out at -30 °C for 1.5 h. Then, N-methoxy-N-methylcyclopropaneformamide-13C (210 mg, 1.0 eq) was added dropwise, and the reaction was carried out at -30 °C for 1 h. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid. The reaction was extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, and purified by column chromatography to obtain ethyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C.
[0014] Furthermore, carbon dioxide-13C is obtained by adding 3 ml of concentrated sulfuric acid to 396.5 mg of barium carbonate-13C.
[0015] Further, the synthesis of cyclopropionic acid-13C specifically includes the following steps: In a 100ml two-necked flask, under nitrogen protection, 15ml of tetrahydrofuran was added, followed by cyclopropylmagnesium bromide (2.6ml, 1.3eq, 1.0mol / L in THF). Carbon dioxide-13C was bubbled through at -80℃, and the mixture was slowly heated to room temperature for 1.5h. After the reaction was complete, water was added to quench the reaction. The mixture was extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain the compound cyclopropionic acid-13C. The synthesis of N-methoxy-N-methylcyclopropaneformamide-13C specifically includes the following steps: In a 50 ml two-necked flask, cyclopropaneformic acid-13C (162 mg, 1.0 eq), dichloromethane (4 ml), dimethylhydroxylamine hydrochloride (201 mg, 1.1 eq), and 4-dimethylaminopyridine (22 mg, 0.1 eq) were added. At room temperature, triethylamine (190 mg, 1.0 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (399 mg, 1.1 eq) were added. Under nitrogen protection, the reaction was carried out at 30 °C for 2 h. After the reaction was complete, the mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain N-methoxy-N-methylcyclopropaneformamide-13C. The synthesis of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C specifically includes the following steps: Under nitrogen protection, 2-(4-bromophenyl)-2-methylpropionate benzyl ester (532 mg, 1.1 eq) and tetrahydrofuran (5 ml) were added to a 50 ml two-necked flask. A solution of n-butyllithium (0.64 ml, 1.1 eq, 2.5 mol / L in THF) was added dropwise at -40 °C. The reaction was carried out at -30 °C for 1.5 h. Then, N-methoxy-N-methylcyclopropaneformamide-13C (189 mg, 1.0 eq) was added dropwise, and the reaction was carried out at -30 °C for 1 h. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid. The reaction was extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, and purified by column chromatography to obtain 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C.
[0016] Furthermore, carbon dioxide-13C is obtained by adding 3 ml of concentrated sulfuric acid to 396.5 mg of barium carbonate-13C.
[0017] The embodiments of the present invention have the following beneficial effects: This route for the synthesis of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate has not been reported in the literature. The reactants are non-volatile, readily available, and easily synthesized chemically. The reaction conditions are mild, the reaction apparatus is simple and easy to operate, the product is easy to purify, and the yield is high. This method fills the gap in the domestic synthesis of isotopically labeled tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate.
[0018] This invention avoids using complex or hard-to-find labeled compounds as starting materials, and directly uses commercially available labeled barium carbonate-13C as a starting material to produce cyclopropionic acid-13C, thus simplifying the synthesis process of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C. 2. The tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C synthesized in this invention can not only fill the domestic gap, but also help meet the huge needs of the domestic and international markets; 3. The reaction conditions of this invention are mild and the reaction apparatus is simple, which can achieve high yield of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate, which can be widely used in pharmaceuticals and biological labeling metabolism. Detailed Implementation
[0019] The present application will be further described below with reference to the embodiments.
[0020] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, in the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Different embodiments can be substituted or combined, and for those skilled in the art, other implementation methods can be obtained based on these embodiments without creative effort.
[0021] A method for preparing tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C includes the following steps: Cyclopropylformic acid-13C is synthesized from tetrahydrofuran and reagent A by passing carbon dioxide (-13C) through at -80 degrees Celsius. Reagent A is cyclopropylmagnesium bromide or cyclopropylmagnesium iodide. N-methoxy-N-methylcyclopropaneformamide-13C was synthesized by adding triethylamine and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride to cyclopropaneformamide-13C at room temperature, along with chloromethane, dimethylhydroxylamine hydrochloride, and 4-dimethylaminopyridine. 2-(4-bromophenyl)-2-methylpropionate tert-butyl ester and tetrahydrofuran were added dropwise with an alkaline solution at -40°C, and then N-methoxy-N-methylcyclopropaneformamide-13C was added dropwise to synthesize 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate tert-butyl ester-13C.
[0022]
[0023] Example 1 Synthesis of cyclopropionic acid-13C (intermediate I): In a 100 ml two-necked flask under nitrogen protection, 15 ml of tetrahydrofuran was added, followed by cyclopropylmagnesium bromide (4.8 ml, 1.2 eq, 1.0 mol / L in THF). Carbon dioxide-13C (obtained by adding 5 ml of concentrated sulfuric acid to 793 mg of barium carbonate-13C) was bubbled through at -80 °C. The mixture was slowly brought to room temperature and reacted for 1 h. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain the compound cyclopropionic acid-13C (313 mg, 90% yield).
[0024] Synthesis of N-methoxy-N-methylcyclopropaneformamide-13C (Intermediate II): In a 50 mL two-necked flask, cyclopropionic acid-13C (313 mg, 1.0 eq), dichloromethane (10 mL), dimethylhydroxylamine hydrochloride (386 mg, 1.1 eq), and 4-dimethylaminopyridine (74 mg, 0.2 eq) were added. At room temperature, triethylamine (410 mg, 1.0 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (759 mg, 1.1 eq) were added. The reaction was carried out at room temperature for 3 h under nitrogen protection. After the reaction was complete, the mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain N-methoxy-N-methylcyclopropaneformamide-13C (370 mg, yield 79%).
[0025] Synthesis of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C (TM): In a 50 mL two-necked flask under nitrogen protection, tert-butyl 2-(4-bromophenyl)-2-methylpropionate (936 mg, 1.1 eq) and tetrahydrofuran (10 mL) were added. A solution of n-butyllithium (1.25 mL, 1.1 eq, 2.5 mol / L in THF) was added dropwise at -40 °C. The reaction was carried out at -30 °C for 1 h. Then, N-methoxy-N-methylcyclopropaneformamide-13C (370 mg, 1.0 eq) was added dropwise, and the reaction was carried out at -30 °C for 1 h. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid, extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, and purified by column chromatography to obtain tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C (658 mg, 80% yield). Example 2
[0026] Synthesis of cyclopropionic acid-13C (intermediate I): In a 100 mL two-necked flask under nitrogen protection, 15 mL of tetrahydrofuran was added, followed by 2.6 mL of cyclopropylmagnesium bromide (1.3 eq, 1.0 mol / L in THF). Carbon dioxide-13C (obtained by adding 3 mL of concentrated sulfuric acid to 396.5 mg of barium carbonate-13C) was bubbled through at -80 °C. The mixture was slowly brought to room temperature and reacted for 1.5 h. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain the compound cyclopropionic acid-13C (167 mg, 95% yield).
[0027] Synthesis of N-methoxy-N-methylcyclopropaneformamide-13C (Intermediate II): In a 50 mL two-necked flask, cyclopropionic acid-13C (167 mg, 1.0 eq), dichloromethane (6 mL), dimethylhydroxylamine hydrochloride (204 mg, 1.1 eq), and 4-dimethylaminopyridine (23 mg, 0.1 eq) were added. At room temperature, triethylamine (192 mg, 1.0 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (401 mg, 1.1 eq) were added. The reaction was carried out at room temperature for 3 h under nitrogen protection. After the reaction was complete, the mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain N-methoxy-N-methylcyclopropaneformamide-13C (210 mg, yield 85%).
[0028] Synthesis of ethyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C (TM): In a 50 mL two-necked flask under nitrogen protection, ethyl 2-(4-bromophenyl)-2-methylpropionate (482 mg, 1.1 eq) and tetrahydrofuran (5 mL) were added. A solution of n-butyllithium (0.7 mL, 1.1 eq, 2.5 mol / L in THF) was added dropwise at -40 °C. The reaction was carried out at -30 °C for 1.5 h. Then, N-methoxy-N-methylcyclopropaneformamide-13C (210 mg, 1.0 eq) was added dropwise, and the reaction was carried out at -30 °C for 1 h. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid, extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, and purified by column chromatography to obtain ethyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C (316 mg, 75% yield). Example 3
[0029] Synthesis of cyclopropionic acid-13C (intermediate I): In a 100 mL two-necked flask under nitrogen protection, 15 mL of tetrahydrofuran was added, followed by 2.6 mL of cyclopropylmagnesium bromide (1.3 eq, 1.0 mol / L in THF). Carbon dioxide-13C (obtained by adding 3 mL of concentrated sulfuric acid to 396.5 mg of barium carbonate-13C) was bubbled through at -80 °C. The mixture was slowly brought to room temperature and reacted for 1.5 h. After the reaction was complete, the reaction was quenched with water, extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain the compound cyclopropionic acid-13C (162 mg, 93% yield).
[0030] Synthesis of N-methoxy-N-methylcyclopropaneformamide-13C (Intermediate II): In a 50 mL two-necked flask, cyclopropionic acid-13C (162 mg, 1.0 eq), dichloromethane (4 mL), dimethylhydroxylamine hydrochloride (201 mg, 1.1 eq), and 4-dimethylaminopyridine (22 mg, 0.1 eq) were added. Triethylamine (190 mg, 1.0 eq) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (399 mg, 1.1 eq) were added at room temperature. The reaction was carried out at 30 °C for 2 h under nitrogen protection. After the reaction was completed, the mixture was extracted three times with dichloromethane, washed once with saturated brine, dried over sodium sulfate, filtered, and evaporated to dryness to obtain N-methoxy-N-methylcyclopropaneformamide-13C (189 mg, yield 78%).
[0031] Synthesis of 2-(4-(cyclopropanoyl)phenyl)-2-methylpropanoate benzyl ester-13C (TM): In a 50 mL two-necked flask under nitrogen protection, 2-(4-bromophenyl)-2-methylpropanoate benzyl ester (532 mg, 1.1 eq) and tetrahydrofuran (5 mL) were added. A solution of n-butyllithium (0.64 mL, 1.1 eq, 2.5 mol / L in THF) was added dropwise at -40 °C. The reaction was carried out at -30 °C for 1.5 h. Then, N-methoxy-N-methylcyclopropaneformamide-13C (189 mg, 1.0 eq) was added dropwise, and the reaction was carried out at -30 °C for 1 h. After the reaction was complete, the reaction was quenched with dilute hydrochloric acid, extracted three times with ethyl acetate, washed once with saturated brine, dried over sodium sulfate, and purified by column chromatography to obtain 2-(4-(cyclopropanoyl)phenyl)-2-methylpropanoate benzyl ester-13C (57 mg, yield 76%). This route for the synthesis of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate has not been reported in the literature. The reactants are non-volatile, readily available, and easily synthesized chemically. The reaction conditions are mild, the reaction apparatus is simple and easy to operate, the product is easy to purify, and the yield is high. This method fills the gap in the domestic synthesis of isotopically labeled tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate.
[0032] This invention avoids using complex or hard-to-find labeled compounds as starting materials, and directly uses commercially available labeled barium carbonate-13C as a starting material to produce cyclopropionic acid-13C, thus simplifying the synthesis process of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C. 2. The tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate-13C synthesized in this invention can not only fill the domestic gap, but also help meet the huge needs of the domestic and international markets; 3. The reaction conditions of this invention are mild and the reaction apparatus is simple, which can achieve high yield of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate, which can be widely used in pharmaceuticals and biological labeling metabolism.
[0033] This invention is also applicable to the isotope labeling synthesis of tert-butyl 2-(4-(cyclopropanoyl)phenyl)-2-methylpropionate. 14 Synthesis of C.
[0034] It should be noted that the above embodiments can be freely combined as needed. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various modifications and variations. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A process for the preparation of tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2- methylpropanoate- 13C, characterized in that, It comprises the following steps: Synthesizing cyclopropanecarboxylic acid-13C from tetrahydrofuran and reagent A under-80 degrees Celsius, wherein the reagent A is cyclopropyl magnesium bromide or cyclopropyl magnesium iodide: Synthesizing N-methoxy-N-methylcyclopropanecarboxamide-13C from cyclopropanecarboxylic acid-13C, dichloromethane, dimethylhydroxylamine hydrochloride, 4-dimethylaminopyridine, triethylamine added at room temperature, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; Synthesizing 2-(4-(cyclopropanecarbonyl)phenyl)-2-methylpropionic acid tert-butyl ester-13C from 2-(4-bromophenyl)-2-methylpropionic acid tert-butyl ester, tetrahydrofuran, and dropping the alkali solution at-40 degrees Celsius, and dropping N-methoxy-N-methylcyclopropanecarboxamide-13C.
2. A process for the synthesis of tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2- methylpropanoate-13C according to claim 1, characterized in that, The alkali solution is n-butyllithium solution or diisopropylaminolithium.
3. The method for synthesizing 2-(4-(cyclopropanecarbonyl)phenyl)-2-methylpropionic acid tert-butyl ester-13C according to claim 1, wherein the synthesis of cyclopropanecarboxylic acid-13C comprises the following steps: 100ml two-necked flask, under nitrogen protection, adding tetrahydrofuran 15ml, adding cyclopropyl magnesium bromide (4.8ml, 1.2eq, 1.0mol / l in THF), and passing carbon dioxide-13C at-80 degrees Celsius, slowly rising to room temperature for 1h, adding water to quench the reaction after the reaction is completed, extracting with ethyl acetate for 3 times, washing the organic phase with saturated brine for 1 time, drying with sodium sulfate, filtering, and rotary evaporation to obtain the compound cyclopropanecarboxylic acid-13C; The synthesis of N-methoxy-N-methylcyclopropanecarboxamide-13C comprises the following steps: 50ml two-necked flask, adding cyclopropanecarboxylic acid-13C (313mg, 1.0eq), dichloromethane (10ml), dimethylhydroxylamine hydrochloride (386mg, 1.1eq), 4-dimethylaminopyridine (74mg, 0.2eq), adding triethylamine (410mg, 1.0eq) at room temperature, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (759mg, 1.1eq), under nitrogen protection, and reacting at room temperature for 3h, extracting with dichloromethane for 3 times, washing with saturated brine for 1 time, drying with sodium sulfate, filtering, and rotary evaporation to obtain N-methoxy-N-methylcyclopropanecarboxamide-13C. The synthesis of tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropanoate-13C specifically includes the following steps: 50 ml two-necked flask, under nitrogen protection, add tert-butyl 2-(4-bromophenyl)-2-methylpropanoate (936 mg, 1.1 eq), tetrahydrofuran (10 ml), drop 1.25 ml of n-butyllithium solution (1.1 eq, 2.5 mol / l in THF) at -40 °C, react for 1 h at -30 °C, then drop add N-methoxy-N-methylcyclopropanecarboxamide-13C (370 mg, 1.0 eq), react for 1 h at -30 °C, after the reaction is completed, quench the reaction with dilute hydrochloric acid, extract the reaction with ethyl acetate three times, wash the organic phase with saturated brine once, dry with sodium sulfate, and pass through a column to obtain tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropanoate-13C.
4. The process of claim 3 for the synthesis of tert-butyl 2-(4- (cyclopropylcarbonyl)phenyl)-2-methylpropanoate-13C, characterized in that, The carbon dioxide-13C is obtained by drop 5 ml of concentrated sulfuric acid from 793 mg of barium carbonate-13C.
5. The method for synthesizing tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropanoate-13C according to claim 1, characterized in that, The synthesis of cyclopropanecarboxylic acid-13C specifically includes the following steps: 100 ml two-necked flask, under nitrogen protection, add tetrahydrofuran 15 ml, add cyclopropyl magnesium bromide (2.6 ml, 1.3 eq, 1.0 mol / l in THF), and pass in carbon dioxide-13C at -80 °C, slowly warm to room temperature and react for 1.5 h, after the reaction is completed, quench the reaction with water, extract with ethyl acetate three times, wash the organic phase with saturated brine once, dry with sodium sulfate, filter, and spin dry to obtain the compound cyclopropanecarboxylic acid-13C; The synthesis of N-methoxy-N-methylcyclopropanecarboxamide-13C specifically includes the following steps: 50 ml two-necked flask, add cyclopropanecarboxylic acid-13C (167 mg, 1.0 eq), dichloromethane (6 ml), dimethylhydroxylamine hydrochloride (204 mg, 1.1 eq), 4-dimethylaminopyridine (23 mg, 0.1 eq), add triethylamine (192 mg, 1.0 eq) at room temperature, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (401 mg, 1.1 eq), under nitrogen protection, react for 3 h at room temperature, after the reaction is completed, extract with dichloromethane three times, wash with saturated brine once, dry with sodium sulfate, filter, and spin dry to obtain N-methoxy-N-methylcyclopropanecarboxamide-13C; The synthesis of tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropanoate-13C specifically includes the following steps: 50 ml two-necked flask, under nitrogen protection, add 2-(4-bromophenyl)-2-methylpropanoic acid ethyl ester (482 mg, 1.1 eq), tetrahydrofuran (5 ml), drop 0.7 ml of n-butyllithium solution (1.1 eq, 2.5 mol / l in THF) at -40 ℃, react for 1.5 h at -30 ℃, then drop add N-methoxy-N-methylcyclopropanecarboxamide-13C (210 mg, 1.0 eq), react for 1 h at -30 ℃, after the reaction is completed, quench the reaction with dilute hydrochloric acid, extract the reaction with ethyl acetate for 3 times, wash the organic phase with saturated brine for 1 time, dry with sodium sulfate, and pass through a column to obtain 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropanoic acid ethyl ester-13C.
6. The process for the preparation of tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2- methylpropanoate-13C according to claim 5, characterized in that, Carbon dioxide-13C is obtained by drop 3 ml of concentrated sulfuric acid from 396.5 mg of barium carbonate-13C.
7. The method for preparing tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropanoate-13C according to claim 1, characterized in that, The synthesis of cyclopropanecarboxylic acid-13C specifically includes the following steps: 100 ml two-necked flask, under nitrogen protection, add tetrahydrofuran 15 ml, add cyclopropyl magnesium bromide (2.6 ml, 1.3 eq, 1.0 mol / l in THF), and pass in carbon dioxide-13C at -80 ℃, slowly rise to room temperature and react for 1.5 h, after the reaction is completed, quench the reaction with water, extract with ethyl acetate for 3 times, wash the organic phase with saturated brine for 1 time, dry with sodium sulfate, filter, and spin dry to obtain compound cyclopropanecarboxylic acid-13C; The synthesis of N-methoxy-N-methylcyclopropanecarboxamide-13C specifically includes the following steps: 50 ml two-necked flask, add cyclopropanecarboxylic acid-13C (162 mg, 1.0 eq), dichloromethane (4 ml), dimethylhydroxylamine hydrochloride (201 mg, 1.1 eq), 4-dimethylaminopyridine (22 mg, 0.1 eq), add triethylamine (190 mg, 1.0 eq) at room temperature, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (399 mg, 1.1 eq), under nitrogen protection, react for 2 h at 30 ℃, after the reaction is completed, extract with dichloromethane for 3 times, wash with saturated brine for 1 time, dry with sodium sulfate, filter, and spin dry to obtain N-methoxy-N-methylcyclopropanecarboxamide-13C; The synthesis of 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropionic acid tert-butyl ester-13C specifically includes the following steps: 50 ml two-necked flask, under nitrogen protection, add 2-(4-bromophenyl)-2-methylpropionic acid benzyl ester (532 mg, 1.1 eq), tetrahydrofuran (5 ml), drop in n-butyllithium solution (0.64 ml, 1.1 eq, 2.5 mol / l in THF) at -40°C, react for 1.5 h at -30°C, then drop in N-methoxy-N-methylcyclopropanecarboxamide-13C (189 mg, 1.0 eq), react for 1 h at -30°C, after the reaction is complete, quench the reaction with dilute hydrochloric acid, extract the reaction with ethyl acetate 3 times, wash the organic phase with saturated brine once, dry over sodium sulfate, and pass through a chromatography column to obtain 2-(4-(cyclopropylcarbonyl)phenyl)-2-methylpropionic acid benzyl ester-13C.
8. The process for the preparation of tert-butyl 2-(4-(cyclopropylcarbonyl)phenyl)-2- methylpropanoate-13C according to claim 7, characterized in that, Carbon dioxide-13C is obtained by dropwise adding 3 ml of concentrated sulfuric acid to 396.5 mg of barium carbonate-13C.