Preparation method of pentafluorocarbonyl oxomethyl carboxylate

Abstract

The invention discloses a preparation method of pentafluorocarbonyl oxomethyl carboxylate. Specifically, the invention discloses a preparation method of a compound as shown in a formula (I), which comprises the following steps: step S1, in a solvent, under the action of organic alkali, a compound 1 and a compound 2 are subjected to a substitution reaction as shown in the specification, and a compound 3 is prepared; s2, in a solvent, in the presence of alkali and iodized salt, the compound 3 and a compound 4 are subjected to a condensation reaction as shown in the specification, and the compound as shown in the formula (I) is prepared.

Description

Technical Field

[0001] The present invention relates to a preparation method of pentafluorocarbonyloxymethyl carboxylate. Background Art

[0002] The carbonyloxymethylcarboxylate structure is a common drug molecular structure fragment that appears in many drugs. It is generally introduced through the reaction of phenoxycarbonyloxymethylcarboxylate with an amine group.

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

[0004] Patent CN117003673 reports a conventional method for preparing pentafluorocarbonyloxymethyl carboxylate. Chloromethyl chloroformate is reacted with sodium methyl mercaptide to produce chloromethyl methylthiocarbonate, which is then reacted with a carboxylic acid to produce a carboxylate ester. Finally, the target product is reacted with pentafluorophenol. The products of the first two steps of this method lack UV absorption, making reaction monitoring inconvenient. Furthermore, the use of sodium methyl mercaptide, which has a strong odor, is unfriendly to the environment and operators. The reaction formula is as follows:

[0005] . Summary of the Invention

[0006] The present invention aims to address the shortcomings of existing methods for preparing pentafluorocarbonyloxymethyl carboxylate, which suffer from low yields, environmental unfriendliness, and inconvenient monitoring. The present method for preparing pentafluorocarbonyloxymethyl carboxylate offers high yields, is environmentally friendly, facilitates monitoring, and simplifies post-processing, avoiding silica gel column chromatography and making it suitable for industrial scale-up.

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

[0008] The present invention provides a method for preparing a compound represented by 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 a substitution reaction as shown below to prepare compound 3;

[0010]

[0011] Step S2: In a solvent, in the presence of a base and an iodine salt, compound 3 and compound 4 undergo a condensation reaction as shown below to prepare a compound represented by 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 are independently C1-C6 alkyl; the molar ratio of compound 1 to compound 2 is (1-2): 1; the molar ratio of the organic base to compound 2 is (1-2): 1; the reaction temperature of the substitution reaction is 20-30°C;

[0015] In step S2, the solvent is N, N-dimethylamide and / or dimethyl sulfoxide; the base is an alkali metal carbonate; the iodine 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 iodine salt to compound 3 is (1-2):1; and the reaction temperature of the condensation reaction is 20-30°C.

[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 (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.

[0018] In a certain embodiment of the present invention, the R 1 is independently methyl, ethyl, isopropyl or n-propyl.

[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 alkyl halide 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, such as 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 the compound 2 is (1.1-1.5):1.

[0027] In one embodiment of the present invention, in step S1, the volume 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 of this type of reaction in the art, and is continued until a certain raw material is completely reacted 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, in step S1, after the substitution reaction is completed, post-treatment is performed by the following steps, which include: filtering and concentrating the filtrate; washing the mixture of the concentrate and a water-insoluble organic solvent (e.g., an ester solvent, preferably ethyl acetate) with an aqueous sodium bicarbonate solution (e.g., an 8wt% to 12wt% sodium bicarbonate solution, preferably a 10wt% sodium bicarbonate solution), an aqueous hydrochloric acid solution (e.g., a 1mol / L hydrochloric acid solution), and a saturated sodium chloride solution in sequence; drying; and concentrating.

[0032] In one embodiment of the present invention, in step S2, the base 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 base to the compound 3 is 0.8:1.

[0035] In one embodiment of the present invention, in step S2, the molar ratio of the iodine 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 of this type of reaction in the art, and is 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 to 20 hours, for example, 16 to 17 hours.

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

[0040] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0041] The reagents and raw materials used in the present invention are commercially available.

[0042] The positive progress of the present invention is that the preparation method of pentafluorocarbonyloxymethylcarboxylate provided by the present invention has a short route, high yield, is environmentally friendly, easy to monitor, and has simple post-processing and is suitable for industrial scale-up. DETAILED DESCRIPTION

[0043] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0044] Example 1

[0045] Step 1: Chloromethyl pentafluorophenyl carbonate

[0046]

[0047] To 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 stirred at 25°C for 1 hour. Thin-layer chromatography on silica gel indicated completion of the reaction. The mixture was filtered, the filtrate concentrated, and the residue diluted with ethyl acetate. The mixture was washed sequentially with 10 wt% sodium bicarbonate solution, 1N hydrochloric acid solution, and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to afford chloromethyl pentafluorophenyl carbonate (8.7 g, 96.5% yield) as a light yellow oil.

[0048] Step 2: (((Pentafluorophenoxy)carbonyl)oxy)methyl acetate

[0049]

[0050] To 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 and stirred at 25°C for 16 hours. Completion of the reaction was monitored by thin-layer chromatography on silica gel. The mixture was filtered, the filtrate was concentrated, and recrystallized from ethanol to afford (((pentafluorophenoxy)carbonyl)oxy)methyl acetate (760 mg, 70.0% yield) as 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] To 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 stirred at 25°C for 8 hours. Thin-layer chromatography on silica gel indicated completion of the reaction. The mixture was filtered, the filtrate concentrated, and the residue diluted with ethyl acetate. The residue was washed sequentially with 10 wt% sodium bicarbonate solution, 1N hydrochloric acid solution, and saturated brine, and then dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated to yield chloromethyl pentafluorophenyl carbonate (73.3 g, 97.6% yield) as a light yellow oil.

[0056] Step 2: (((Pentafluorophenoxy)carbonyl)oxy)methyl palmitate

[0057]

[0058] To 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 and stirred at 25°C for 16 hours. Completion of the reaction was monitored by thin-layer chromatography on silica gel. The mixture was filtered, the filtrate was concentrated, and recrystallized from ethanol to obtain (((pentafluorophenoxy)carbonyl)oxy)methyl palmitate (2.6 g, 72.4% yield) 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: No iodination reagent is used in step 2 of Example 2

[0061] To 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 stirred at 60°C for 16 hours. Completion of the reaction was monitored by thin-layer chromatography on silica gel. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (v / v ethyl acetate / v / petroleum ether = 1 / 10) to afford (((pentafluorophenoxy)carbonyl)oxy)methyl palmitate (1.2 g, 33.4% yield) as a white solid.

[0062] Comparative Example 2: Using sodium iodide reagent for step 2 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 in sequence and stirred at 25°C for 16 hours. The reaction was monitored by thin layer chromatography on silica gel. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (V 乙酸乙酯 / V 石油醚 =1 / 10) to give (((pentafluorophenoxy)carbonyl)oxy)methyl palmitate (1.6 g, yield: 44.6%) as a white solid.

[0064] Comparative Example 3: Reducing the amount of potassium carbonate in step 2 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 in sequence and stirred at 25°C for 16 hours. The reaction was monitored by thin layer chromatography on silica gel. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (V 乙酸乙酯 / V 石油醚 =1 / 10) to give (((pentafluorophenoxy)carbonyl)oxy)methyl palmitate (1.9 g, yield: 52.9%) as a white solid.

[0066] Comparative Example 4: Using acetonitrile as solvent for step 2 in 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 in sequence and stirred at 25°C for 16 hours. The reaction was monitored by thin layer chromatography on silica gel. The mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel chromatography (V 乙酸乙酯 / V 石油醚 =1 / 10) to give (((pentafluorophenoxy)carbonyl)oxy)methyl palmitate (1.7 g, yield: 47.3%) as a white solid.

[0068] Based on the above comparative examples, it can be seen that when performing the second-step condensation reaction without using an iodination reagent, the yield is much lower than the yield achieved when using an iodination reagent. Even when using an iodination reagent, high yields are not achieved under all conditions. For example, when sodium iodide is used as the iodination reagent, or when the sodium carbonate content is reduced, or when other solvents are used, high yields cannot be achieved. In addition, during the research process, the applicant also found that the reaction temperature is generally preferably around 25°C (e.g., 20-30°C), and when the reaction temperature is increased, the reaction impurity content will increase accordingly.

[0069] Moreover, during the experiment, it was found that under the reaction conditions of the comparative example, many by-products were produced, the reaction yield was low, and the purity of the product obtained under the recrystallization conditions was not high and could only be purified by silica gel column chromatography.

Claims

1. A method for preparing a compound represented by 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 iodine salt, compound 3 and compound 4 undergo a condensation reaction as shown below to prepare a compound represented by 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 are independently C1-C6 alkyl; the molar ratio of compound 1 to compound 2 is (1-2): 1; the molar ratio of the organic base to compound 2 is (1-2): 1; the reaction temperature of the substitution reaction is 20-30°C; In step S2, the solvent is N, N-dimethylamide and / or dimethyl sulfoxide; the base is an alkali metal carbonate; the iodine 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 iodine salt to compound 3 is (1-2): 1; and the reaction temperature of the condensation reaction is 20-30°C.

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

3. The method for preparing the compound of formula (I) according to claim 1, wherein: R is C2-C 15 Straight chain alkyl.

4. The method for preparing the compound of formula (I) according to claim 1, wherein: 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 halogenated alkane 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 the organic base to the compound 2 is (1.1-1.5):1; (6) In step S1, the volume mass ratio of the solvent to the 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 to 10 hours; (9) In step S1, after the substitution reaction is completed, post-treatment is performed by the following steps, which include: filtering, concentrating the filtrate; washing the mixture of the concentrate and the water-insoluble organic solvent with a sodium bicarbonate aqueous solution, a hydrochloric acid aqueous solution, and a saturated sodium chloride aqueous solution in sequence; drying; and concentrating. (10) In step S2, the base 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 base to the compound 3 is 0.8:1; (13) In step S2, the molar ratio of the iodine 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 to 20 hours; (16) In step S2, after the condensation reaction is completed, post-treatment is performed by the following steps, which include: filtration, filtrate concentration, and recrystallization.

5. The method for preparing the compound of formula (I) according to claim 4, wherein: 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 mass ratio of the solvent to the 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, in the post-treatment step, the water-insoluble organic solvent is an ester solvent; (6) In step S1, in the post-treatment step, the sodium bicarbonate aqueous solution is an 8 wt% to 12 wt% sodium bicarbonate aqueous solution; (7) In step S1, in the post-treatment step, the hydrochloric acid aqueous solution is a 1 mol / L hydrochloric acid aqueous solution; (8) In step S2, the reaction time of the condensation reaction is 16 to 17 hours; (9) In step S2, in the post-treatment step, the recrystallization solvent is methanol or ethanol.

6. The method for preparing the compound of formula (I) according to claim 5, wherein: 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 is dichloromethane and the organic base is pyridine; (2) In step S1, in the post-treatment step, the water-insoluble organic solvent is ethyl acetate; (3) In step S1, in the post-treatment step, the sodium bicarbonate aqueous solution is a 10 wt% sodium bicarbonate aqueous solution.

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