Preparation method of pentafluorocarbonyl oxomethyl carboxylate

Abstract

This invention discloses a method for preparing pentafluorocarbonyl oxomethyl carboxylate. Specifically, this invention discloses a method for preparing a compound as shown in formula (I), comprising the following steps: Step S1: In a solvent, under the action of an organic base, compound 1 and compound 2 undergo a substitution reaction as shown below to prepare compound 3; Step S2: In a solvent, in the presence of a base and an iodide salt, compound 3 and compound 4 undergo a condensation reaction as shown below to prepare the compound as shown in formula (I).

Description

Technical Field

[0001] This invention relates to a method for preparing pentafluorocarbonyl oxymethyl carboxylate. Background Technology

[0002] The carbonyl oxomethyl carboxylate structure is a common structural fragment in drug molecules and appears in many drugs. It is generally introduced by reacting phenoxy carbonyl oxomethyl carboxylate with an amino group.

[0003] The presence of electron-withdrawing groups on the benzene ring facilitates nucleophilic substitution reactions between amines and carbonates. In recent years, pentafluorophenyl has received widespread attention due to its excellent leaving properties.

[0004] Patent CN117003673 discloses a conventional method for preparing pentafluorocarbonyl oxymethyl carboxylic acid esters. The method uses chloromethyl chloroformate as a raw material, reacts it with sodium methanethiol to obtain chloromethyl methylthiocarbonate, then reacts it with a carboxylic acid to obtain a carboxylic acid ester, and finally reacts it with pentafluorophenol to obtain the target product. The products of the first two steps do not exhibit UV absorption, making reaction monitoring inconvenient. Furthermore, the use of strongly odorous sodium methanethiol is environmentally unfriendly and detrimental to operators. The reaction formula is as follows:

[0005] . Summary of the Invention

[0006] The technical problem this invention aims to solve is to address the shortcomings of existing methods for preparing pentafluorocarbonyl oxomethyl carboxylate, which suffer from low yield, environmental unfriendliness, and inconvenient monitoring. This invention provides a novel method for preparing pentafluorocarbonyl oxomethyl carboxylate. The method of this invention offers high yield, environmental friendliness, convenient monitoring, and simple post-processing, avoiding silica gel column chromatography and making it suitable for industrial scale-up.

[0007] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0008] This invention provides a method for preparing a compound as shown in formula (I), comprising the following steps:

[0009] Step S1: In a solvent, under the action of an organic base, compound 1 and compound 2 undergo the substitution reaction shown below to prepare compound 3;

[0010]

[0011] Step S2: In a solvent, in the presence of a base and an iodide salt, compound 3 and compound 4 undergo the condensation reaction shown below to prepare the compound shown in formula (I).

[0012]

[0013] R is C1-C 20 alkyl;

[0014] In step S1, the solvent is a cyclic ether solvent and / or a haloalkane solvent; the organic base is N(R) 1 )3 and / or pyridine, R 1 It is independently a C1-C6 alkyl group; the molar ratio of compound 1 to compound 2 is (1~2):1; the molar ratio of organic base to compound 2 is (1~2):1; the reaction temperature of the substitution reaction is 20~30℃;

[0015] In step S2, the solvent is N,N-dimethylformamide and / or dimethyl sulfoxide; the base is an alkali metal carbonate; the iodide salt is tetrabutylammonium iodide; the molar ratio of compound 3 to compound 4 is 1:(1~2); the molar ratio of the base to compound 3 is (0.7~0.9):1; the molar ratio of the iodide salt to compound 3 is (1~2):1; and the reaction temperature of the condensation reaction is 20~30℃.

[0016] In certain preferred embodiments of the present invention, certain features of the preparation method are defined as follows, and features not mentioned are the same as those described in any embodiment of the present invention (hereinafter referred to as "in a certain embodiment of the present invention").

[0017] In one embodiment of the present invention, R is C2-C 15 Alkyl groups, such as C2-C 15 Straight-chain alkyl groups.

[0018] In one aspect of the present invention, the R 1 It can be methyl, ethyl, isopropyl or n-propyl independently.

[0019] In one embodiment of the present invention, in step S1, the cyclic ether solvent is tetrahydrofuran.

[0020] In one embodiment of the present invention, in step S1, the haloalkane solvent is dichloromethane.

[0021] In one embodiment of the present invention, in step S1, the solvent is tetrahydrofuran and / or dichloromethane.

[0022] In one embodiment of the present invention, in step S1, the organic base is selected from one or more of triethylamine, pyridine, and diisopropylethylamine, for example, triethylamine and / or pyridine.

[0023] In one embodiment of the present invention, in step S1, the solvent is tetrahydrofuran and the organic base is triethylamine.

[0024] In one embodiment of the present invention, in step S1, the solvent is dichloromethane and the organic base is pyridine.

[0025] In one embodiment of the present invention, in step S1, the molar ratio of compound 1 to compound 2 is (1.1~1.5):1.

[0026] In one embodiment of the present invention, in step S1, the molar ratio of the organic base to compound 2 is (1.1~1.5):1.

[0027] In one embodiment of the present invention, in step S1, the volume-to-mass ratio of the solvent to the compound 2 is 10-20 mL / g, for example, 10-17 mL / g.

[0028] In one embodiment of the present invention, in step S1, the reaction temperature of the substitution reaction is 25°C.

[0029] In step S1, the reaction time of the substitution reaction is the conventional reaction time for such reactions in the art, until a certain raw material reacts completely or no longer reacts.

[0030] In one embodiment of the present invention, in step S1, the reaction time of the substitution reaction is 0.8 to 10 hours, for example, 1 to 8 hours.

[0031] In one embodiment of the present invention, after the substitution reaction in step S1 is completed, post-processing is performed through the following steps, which include: filtration; concentration of the filtrate; washing the mixture of the concentrate and a water-insoluble organic solvent (e.g., an ester solvent, preferably ethyl acetate) sequentially with an aqueous solution of sodium bicarbonate (e.g., an 8wt%~12wt% aqueous solution of sodium bicarbonate, preferably a 10wt% aqueous solution of sodium bicarbonate), an aqueous solution of hydrochloric acid (e.g., a 1mol / L aqueous solution of hydrochloric acid), and an aqueous solution of saturated sodium chloride; drying; and concentration.

[0032] In one embodiment of the present invention, in step S2, the alkali is potassium carbonate.

[0033] In one embodiment of the present invention, in step S2, the molar ratio of compound 3 to compound 4 is 1:(1~1.3).

[0034] In one embodiment of the present invention, in step S2, the molar ratio of the alkali to the compound 3 is 0.8:1.

[0035] In one embodiment of the present invention, in step S2, the molar ratio of the iodized salt to compound 3 is 1.2:1.

[0036] In one embodiment of the present invention, in step S2, the reaction temperature of the condensation reaction is 25°C.

[0037] In step S2, the reaction time of the condensation reaction is the conventional reaction time for such reactions in the art, until a certain raw material reacts completely or no longer reacts.

[0038] In one embodiment of the present invention, in step S2, the reaction time of the condensation reaction is 15-20 hours, for example 16-17 hours.

[0039] In one embodiment of the present invention, after the condensation reaction in step S2 is completed, the following post-processing steps are performed, which include: filtration, filtrate concentration, and recrystallization. Preferably, the recrystallization solvent is ethanol or methanol.

[0040] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0041] The reagents and raw materials used in this invention are all commercially available.

[0042] The positive and progressive effects of this invention are as follows: the preparation method of pentafluorocarbonyl oxymethyl carboxylate provided by this invention has a short route, high yield, is environmentally friendly, easy to monitor, and has simple post-processing suitable for industrial scale-up. Detailed Implementation

[0043] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0044] Example 1

[0045] Step 1: Chloromethyl pentafluorophenyl carbonate

[0046]

[0047] In a 250 mL reaction flask, tetrahydrofuran (100 mL), pentafluorophenol (6.0 g, 32.6 mmol, 1.0 eq), triethylamine (4.0 g, 39.1 mmol, 1.2 eq), and chloromethyl chloroformate (4.6 g, 35.8 mmol, 1.1 eq) were added sequentially, and the mixture was stirred at 25 °C for 1 hour. Thin-layer chromatography with silica gel plate monitoring showed the reaction was complete. The mixture was filtered, the filtrate was concentrated, and the residue was diluted with ethyl acetate. The residue was washed successively with 10 wt% sodium bicarbonate solution, 1 N hydrochloric acid solution, and saturated brine, and dried over anhydrous sodium sulfate. The mixture was filtered again, and the filtrate was concentrated to give chloromethyl pentafluorophenyl carbonate (8.7 g, yield: 96.5%), a pale yellow oil.

[0048] Step 2: (((pentafluorophenoxy)carbonyl)oxo)methyl acetate

[0049]

[0050] In a 50 mL reaction flask, DMF (10 mL), chloromethyl pentafluorophenyl carbonate (1.0 g, 3.62 mmol, 1.0 eq), acetic acid (280 mg, 4.7 mmol, 1.3 eq), tetrabutylammonium iodide (1.6 g, 4.3 mmol, 1.2 eq), and potassium carbonate (0.4 g, 2.9 mmol, 0.8 eq) were added sequentially. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored for completion using a silica gel plate for thin-layer chromatography. The mixture was filtered, the filtrate was concentrated, and recrystallized from ethanol to give (((pentafluorophenoxy)carbonyl)oxo)methyl acetate (760 mg, yield: 70.0%), a white solid.

[0051] HNMR (400 MHz, CDCl3): δ5.90(s, 2H), 2.41(s, 3H).

[0052] Example 2

[0053] Step 1: Chloromethyl pentafluorophenyl carbonate

[0054]

[0055] In a 1000 mL reaction flask, dichloromethane (500 mL), pentafluorophenol (50.0 g, 271.6 mmol, 1.0 eq), pyridine (25 mL), and chloromethyl chloroformate (38.5 g, 298.8 mmol, 1.1 eq) were added sequentially, and the mixture was stirred at 25 °C for 8 hours. Thin-layer chromatography with silica gel plate monitoring showed the reaction was complete. The mixture was filtered, the filtrate was concentrated, and the residue was diluted with ethyl acetate. It was washed sequentially with 10 wt% sodium bicarbonate solution, 1 N hydrochloric acid solution, and saturated brine, and dried over anhydrous sodium sulfate. The filtrate was filtered again and concentrated to give chloromethyl pentafluorophenyl carbonate (73.3 g, yield: 97.6%), a pale yellow oil.

[0056] Step 2: (((pentafluorophenoxy)carbonyl)oxo)methylpalmitate

[0057]

[0058] In a 50 mL reaction flask, DMF (30 mL), chloromethyl pentafluorophenyl carbonate (2.0 g, 7.2 mmol, 1.0 eq), palmitic acid (1.8 g, 7.2 mmol, 1.0 eq), tetrabutylammonium iodide (3.2 g, 8.7 mmol, 1.2 eq), and potassium carbonate (0.8 g, 5.8 mmol, 0.8 eq) were added sequentially. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored for completion using a silica gel plate for thin-layer chromatography. The mixture was filtered, the filtrate was concentrated, and recrystallized from ethanol to give (((pentafluorophenoxy)carbonyl)oxo)methyl palmitate (2.6 g, yield: 72.4%), as a white solid.

[0059] HNMR (400 MHz, CDCl3): δ5.88(s, 2H), 2.42(t, J=7.4Hz, 2H), 1.63-1.70(m, 2H), 1.27-1.25 (m, 24H), 0.88(t, J=6.8Hz, 3H).

[0060] Comparative Example 1: Step two in Example 2 does not use an iodine reagent.

[0061] In a 50 mL reaction flask, DMF (30 mL), chloromethyl pentafluorophenyl carbonate (2.0 g, 7.2 mmol, 1.0 eq), palmitic acid (1.8 g, 7.2 mmol, 1.0 eq), and potassium carbonate (0.8 g, 5.8 mmol, 0.8 eq) were added sequentially, and the mixture was stirred at 60 °C for 16 hours. The reaction was monitored for completion by thin-layer chromatography using a silica gel plate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (V ethyl acetate / V petroleum ether = 1 / 10) to give (((pentafluorophenoxy)carbonyl)oxo)methyl palmitate (1.2 g, yield: 33.4%) as a white solid.

[0062] Comparative Example 2: Sodium iodide reagent was used for step two in Example 2.

[0063] In a 50 mL reaction flask, DMF (30 mL), chloromethyl pentafluorophenyl carbonate (2.0 g, 7.2 mmol, 1.0 eq), palmitic acid (1.8 g, 7.2 mmol, 1.0 eq), sodium iodide (1.3 g, 8.7 mmol, 1.2 eq), and potassium carbonate (0.8 g, 5.8 mmol, 0.8 eq) were added sequentially. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored for completion using a silica gel plate for thin-layer chromatography. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (V... 乙酸乙酯 / V 石油醚 =1 / 10), yielding (((pentafluorophenoxy)carbonyl)oxo)methyl palmitate (1.6 g, yield: 44.6%), a white solid.

[0064] Comparative Example 3: Reducing the amount of potassium carbonate used in step two of Example 2

[0065] In a 50 mL reaction flask, DMF (30 mL), chloromethyl pentafluorophenyl carbonate (2.0 g, 7.2 mmol, 1.0 eq), palmitic acid (1.8 g, 7.2 mmol, 1.0 eq), tetrabutylammonium iodide (3.2 g, 8.7 mmol, 1.2 eq), and potassium carbonate (0.5 g, 3.6 mmol, 0.5 eq) were added sequentially. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored for completion using a silica gel plate for thin-layer chromatography. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (V... 乙酸乙酯 / V 石油醚 =1 / 10), yielding (((pentafluorophenoxy)carbonyl)oxo)methyl palmitate (1.9 g, yield: 52.9%), a white solid.

[0066] Comparative Example 4: Acetonitrile was used as a solvent in step two of Example 2.

[0067] In a 50 mL reaction flask, acetonitrile (30 mL), chloromethyl pentafluorophenyl carbonate (2.0 g, 7.2 mmol, 1.0 eq), palmitic acid (1.8 g, 7.2 mmol, 1.0 eq), tetrabutylammonium iodide (3.2 g, 8.7 mmol, 1.2 eq), and potassium carbonate (0.8 g, 5.8 mmol, 0.8 eq) were added sequentially. The mixture was stirred at 25 °C for 16 hours. The reaction was monitored for completion using a silica gel plate for thin-layer chromatography. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (V... 乙酸乙酯 / V 石油醚 =1 / 10), yielding (((pentafluorophenoxy)carbonyl)oxo)methyl palmitate (1.7 g, yield: 47.3%), a white solid.

[0068] Based on the comparative examples above, it is evident that in the second condensation reaction, the yield without iodination reagent is significantly lower than the yield achieved with iodination reagent. Furthermore, even with iodination reagent, high yields are not achievable under all conditions. For instance, using sodium iodide as the iodination reagent, reducing the sodium carbonate content, or using other solvents all fail to achieve high yields. Moreover, the applicant also discovered during the research that a reaction temperature of around 25°C (e.g., 20-30°C) is generally optimal, and that increasing the reaction temperature leads to a corresponding increase in the content of reaction impurities.

[0069] Furthermore, during the experiment, it was found that under the reaction conditions of the comparative ratio, there were many byproducts and the reaction yield was low. Under recrystallization conditions, the purity of the product was not high, and it could only be purified by silica gel column chromatography.

Claims

1. A method for preparing a compound as shown in formula (I), comprising the following steps: Step S1: In a solvent, under the action of an organic base, compound 1 and compound 2 undergo the substitution reaction shown below to prepare compound 3; ； Step S2: In a solvent, in the presence of a base and an iodide salt, compound 3 and compound 4 undergo the condensation reaction shown below to prepare the compound shown in formula (I). ； R is C1-C 20 alkyl; In step S1, the solvent is a cyclic ether solvent and / or a haloalkane solvent; the organic base is N(R) 1 )3 and / or pyridine, R 1 It is independently a C1-C6 alkyl group; the molar ratio of compound 1 to compound 2 is (1~2):1; the molar ratio of organic base to compound 2 is (1~2):1; the reaction temperature of the substitution reaction is 20~30℃; In step S2, the solvent is N,N-dimethylformamide and / or dimethyl sulfoxide; the base is an alkali metal carbonate; the iodide salt is tetrabutylammonium iodide; the molar ratio of compound 3 to compound 4 is 1:(1~2); the molar ratio of the base to compound 3 is (0.7~0.9):1; the molar ratio of the iodide salt to compound 3 is (1~2):1; and the reaction temperature of the condensation reaction is 20~30℃.

2. The method for preparing the compound as shown in formula (I) according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The R mentioned is C2-C 15 alkyl; (2) The R mentioned above 1 It can be methyl, ethyl, isopropyl or n-propyl independently.

3. The method for preparing the compound as shown in formula (I) according to claim 1, characterized in that, R is C2-C 15 Straight-chain alkyl groups.

4. The method for preparing the compound as shown in formula (I) according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In step S1, the organic base is selected from one or more of triethylamine, pyridine and diisopropylethylamine; (2) In step S1, the cyclic ether solvent is tetrahydrofuran; (3) In step S1, the haloalkane solvent is dichloromethane; (4) In step S1, the molar ratio of compound 1 to compound 2 is (1.1~1.5):1; (5) In step S1, the molar ratio of organic base to compound 2 is (1.1~1.5):1; (6) In step S1, the volume-to-mass ratio of the solvent to compound 2 is 10-20 mL / g; (7) In step S1, the reaction temperature of the substitution reaction is 25°C; (8) In step S1, the reaction time of the substitution reaction is 0.8~10h; (9) In step S1, after the substitution reaction is completed, the following post-processing steps are performed, which include: filtration, concentration of the filtrate; washing of the mixture of the concentrate and water-insoluble organic solvent with sodium bicarbonate aqueous solution, hydrochloric acid aqueous solution and saturated sodium chloride aqueous solution in sequence; drying; concentration; (10) In step S2, the alkali is potassium carbonate; (11) In step S2, the molar ratio of compound 3 to compound 4 is 1: (1~1.3); (12) In step S2, the molar ratio of the alkali to the compound 3 is 0.8:1; (13) In step S2, the molar ratio of the iodized salt to compound 3 is 1.2:1; (14) In step S2, the reaction temperature of the condensation reaction is 25°C; (15) In step S2, the reaction time of the condensation reaction is 15~20h; (16) In step S2, after the condensation reaction is completed, the following post-processing steps are performed, including: filtration, filtrate concentration, and recrystallization.

5. The method for preparing the compound as shown in formula (I) according to claim 4, characterized in that, It meets one or more of the following conditions: (1) In step S1, the solvent is tetrahydrofuran and / or dichloromethane; (2) In step S1, the organic base is triethylamine and / or pyridine; (3) In step S1, the volume-to-mass ratio of the solvent to compound 2 is 10-17 mL / g; (4) In step S1, the reaction time of the substitution reaction is 1 to 8 hours; (5) In step S1, the water-insoluble organic solvent in the post-processing step is an ester solvent; (6) In step S1, the sodium bicarbonate aqueous solution in the post-processing step is an 8wt%~12wt% sodium bicarbonate aqueous solution. (7) In step S1, the hydrochloric acid aqueous solution in the post-processing step is a 1 mol / L hydrochloric acid aqueous solution; (8) In step S2, the reaction time of the condensation reaction is 16-17 hours; (9) In step S2, the solvent for recrystallization in the post-processing step is methanol or ethanol.

6. The method for preparing the compound as shown in formula (I) according to claim 5, characterized in that, It meets one or more of the following conditions: (1) In step S1, the solvent is tetrahydrofuran and the organic base is triethylamine; Alternatively, the solvent may be dichloromethane, and the organic base may be pyridine; (2) In step S1, the water-insoluble organic solvent in the post-processing step is ethyl acetate; (3) In step S1, the sodium bicarbonate aqueous solution in the post-processing step is a 10wt% sodium bicarbonate aqueous solution.

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