Patent Application
20240270675
The present invention relates to the field of carboxylic acid ester synthesis technology, in particular to a method for synthesizing carboxylic acid methyl ester compounds.
The currently known methods for synthesizing esters mostly have the following disadvantages: the pre-activation is required for the raw materials, the reaction conditions are strict, the substrates used are harmful to the environment, the catalysts used are precious metals or heavy metals, which are expensive, the range of substrates is narrow, and atomic economy is poor; more importantly, due to the fact that general drug molecules have multiple functional groups, including sensory functional groups, while traditional esterification methods have poor tolerance to functional groups, the traditional esterification methods are generally not suitable for the esterification of drug molecules. For example, (1) The esterification of carboxylic acids and alcohols catalyzed by acids is a classic method for synthesizing esters. However, acids can cause damage to equipment and are harmful to the environment. At the same time, this method is not applicable when there are components sensitive to acids. (Reference: E. Emmet Reid; Ind. Eng. Chem; 1948, 40, 1596-1601; Junzo Otera; Chem. Rev. 1993, 93. 1449-1470).
Based on the above, it is particularly important to develop an esterification method that includes but is not limited to the carboxylic acid of drug molecules.
To solve the above technical problems, the purpose of the present invention is to provide a method for preparing carboxylic acid ester compounds, and it has mild reaction conditions; rich sources of raw materials; wide universality of reaction substrates; and the advantages of simple operation to modify a series of carboxylic acids with drug properties and fatty carboxylic acid esters such as biologically active amino acids.
The present invention discloses a method for preparing carboxylic acid ester compounds. In the presence of nitrous acid ester, carboxylic acid compound and alcohol are used as raw materials to react and prepare carboxylic acid ester compounds; and the alcohol is ethanol, propanol, or trifluoroethanol.
The present invention discloses the application of nitrous acid ester in catalyzing the reaction of carboxylic acid compound and alcohol to prepare carboxylic acid ester compounds; and the alcohol is ethanol, propanol, or trifluoroethanol.
The method for preparing carboxylic acid ester compounds of the present invention is as follows: the nitrous acid ester, carboxylic acid compound and alcohol are added into a reaction tube in sequence in the air; then the reaction is carried out under the condition of 60-80° C. for 30-60 hours to obtain the carboxylate ester compounds.
The general formula of the carboxylic acid compound is:
The general formula of the carboxylic acid compound is:
In the above formula, R1 is selected from one of hydrogen, C1-C12 alkyl, alkoxy, phenyl, benzyl, substituent phenyl, thienyl, indolyl, phenolic group, naphthyl, biphenyl, or amide groups; R2 is selected from one of hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl, or phenyl; R3 is selected from one of hydrogen, methyl, methylene, ethyl, isopropyl, propyl, butyl, or phenyl; the substituents on the substituent phenyl are selected from one or more of hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetylamino, fluorine, chlorine, bromine, iodine, etc.; the nitrous acid ester is one or more of isopropyl nitrite, butyl nitrite, isobutyl nitrite, and tert-butyl nitrite, preferably tert-butyl nitrite (tBuONO).
Furthermore, the molar ratio of the carboxylic acid compound to the nitrous acid ester is 10:5-20; preferably, the molar ratio of carboxylic acid compound to nitrous acid ester is 1:1.
Furthermore, the dosage ratio of carboxylic acid compound and alcohol is 0.5 mmol:2 mL.
Furthermore, the reaction time is 30-60 hours, preferably 48 hours; the reaction temperature is 60-80° C., preferably 80° C.
Furthermore, the reaction is carried out in the air.
Furthermore, after the reaction is completed, the quenching reaction is carried out with sodium thiosulfate to routinely separate carboxylic ester compound. For example, after the quenching reaction, the product is extracted with ethyl acetate, removed from the solvent and adsorbed on silica gel, and then subject to column chromatography to obtain the carboxylic ester compound.
The above description is only an overview of the technical solution of the present invention. In order to have a clearer understanding of the technical means of the present invention and to implement it according to the content of the specification, the following are preferred embodiments of the present invention and detailed explanations.
The raw materials of the present invention are all existing commercially available products, and the specific preparation and testing methods are conventional methods. The present invention only uses nitrous acid ester, carboxylic acid compound, and alcohol as raw materials for reaction without the addition of other substances to prepare carboxylic acid esters in the air under mild conditions, solving the problem of metal or metal compound catalytic reaction in the present invention, and overcoming the problem that traditional esterification methods are not suitable for esterification of drug molecules; the following is the detailed description of the specific embodiments of the present invention with embodiments. The following embodiments are used to illustrate the present invention, but are not intended to limit its scope.
The drug molecule 1a (Naproxen) (0.5 mmol, 115.2 mg) and ethanol containing 1 equiv tert-butyl nitrite (2 mL ethanol, 0.5 mmol tert-butyl nitrite, the same meaning for the following embodiments) were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3a, with a yield of 74% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 7.75-7.68 (m, 3H), 7.45-7.43 (m, 1H), 7.19-7.12 (m, 2H), 4.22-4.09 (m, 2H), 3.91 (s, 3H), 3.86 (q, J=7.2 Hz, 1H), 1.60 (d, J=7.2 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.5, 157.5, 135.7, 133.6, 129.1, 128.8, 127.0, 126.1, 125.8, 118.8, 105.5, 60.6, 55.1, 45.4, 18.5, 14.1; HRMS (ESI-TOF): Anal. Calcd. For C16H18O3+Na+: 281.1148, Found: 281.1149; IR (neat, cm−1): ν 3060, 2981, 2939, 1728, 1590, 1456, 1372, 1264, 1173, 1027, 856.
When the tert-butyl nitrite was replaced with the same molar amount of tert-butyl hydrogen peroxide, and the remaining kept unchanged, the product yield was less than 5%.
The drug molecule 1a (Naproxen) (0.5 mmol, 115.2 mg) and ethanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 60° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3a, with a yield of 60% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
The drug molecule 1b (Naproxen) (0.5 mmol, 115.2 mg) and propanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3b, with a yield of 72% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 7.74-7.66 (m, 3H), 7.44-7.41 (m, 1H), 7.17-7.10 (m, 2H), 4.04 (t, J=6.7 Hz, 2H), 3.91 (s, 3H), 3.86 (q, J=7.2 Hz, 1H), 1.63-1.58 (m, 5H), 0.86 (t, J=7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.7, 157.6, 135.9, 133.6, 129.3, 128.9, 127.0, 126.3, 125.9, 118.9, 105.6, 66.3, 55.3, 45.5, 21.9, 18.5, 10.3; HRMS (ESI-TOF): Anal. Calcd. For C17H20O3+Na+: 295.1305, Found: 295.1323; IR (neat, cm−1): ν 2967, 2935, 1724, 1605, 1461, 1262, 1181, 858, 813.
The drug molecule 1b (Naproxen) (0.5 mmol, 115.2 mg) and propanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 60° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3b, with a yield of 37% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
The drug molecule 1c (Indomethacin) (0.5 mmol, 178.9 mg) and ethanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3c, with a yield of 60% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 7.69-7.62 (m, 2H), 7.50-7.42 (m, 2H), 6.97 (d, J=2.5 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 6.68-6.65 (m, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.65 (s, 2H), 2.38 (s, 3H), 1.26 (t, J=7.1 Hz, 3H); 13C NMR (100 MHZ, CDCl3) δ 170.8, 168.2, 156.0, 139.1, 135.8, 133.9, 131.1, 130.7, 130.6, 129.0, 114.9, 112.6, 111.6, 101.2, 60.9, 55.6, 30.3, 14.2, 13.3; HRMS (ESI-TOF): Anal. Calcd. For C21H2035ClNO4+Na+: 408.0973, Found: 408.0950. Anal. Calcd. For C21H2037ClNO4+Na+: 410.0944, Found: 410.0947; IR (neat, cm−1): ν 2978, 2929, 1727, 1673, 1602, 1466, 1358, 1321, 1173, 1035, 912, 802.
The drug molecule 1d (Bendazac) (0.5 mmol, 178.9 mg) and ethanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3d, with a yield of 71% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 7.73 (d, J=8.1 Hz, 1H), 7.32-7.19 (m, 4H), 7.17-7.09 (m, 3H), 7.05-7.01 (m, 1H), 5.33 (s, 2H), 4.98-4.92 (m, 2H), 4.21 (q, J=7.1 Hz, 2H), 1.22 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.8, 154.8, 141.7, 137.3, 128.5, 127.4, 126.9, 120.1, 119.3, 112.4, 108.8, 65.5, 61.0, 52.2, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C18H18N2O3+Na+: 333.1210, Found: 333.1225; IR (neat, cm−1): ν 2977, 2932, 1752, 1684, 1615, 1530, 1495, 1452, 1198, 1145, 1063, 737.
The drug molecule 1e (Nateglinide) (0.5 mmol, 158.8 mg) and ethanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3e, with a yield of 94% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 7.32-7.18 (m, 3H), 7.13-7.06 (m, 2H), 6.03 (d, J=7.7 Hz, 1H), 4.88-4.83 (m, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.15 (dd, J=13.8, 5.9 Hz, 1H), 3.08 (dd, J=13.8, 5.8 Hz, 1H), 2.05-1.97 (m, 1H), 1.91-1.82 (m, 2H), 1.81-1.72 (m, 2H), 1.46-1.33 (m, 3H), 1.24 (t, J=7.2 Hz, 3H), 1.10-0.90 (m, 3H), 0.85 (d, J=8.8 Hz, 6H); 13C NMR (100 MHZ, CDCl3) δ 175.4, 171.6, 135.9, 129.2, 128.3, 126.8, 61.3, 52.6, 45.3, 43.1, 37.7, 32.6, 29.6, 29.3, 28.84, 28.75, 19.6, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C21H31NO3+Na+: 368.2196, Found: 368.2187; IR (neat, cm−1): ν 3310, 2976, 2931, 2868, 1724, 1641, 1539, 1445, 1279, 1180, 697.
The drug molecule If (Isoxepac) (0.5 mmol, 134.2 mg) and ethanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3f, with a yield of 98% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 8.10 (d, J=2.3 Hz, 1H), 7.87-7.84 (m, 1H), 7.52-7.48 (m, 1H), 7.45-7.38 (m, 2H), 7.33-7.28 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.13 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.60 (s, 2H), 1.24 (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 190.6, 171.2, 160.3, 140.3, 136.2, 135.4, 132.6, 132.3, 129.3, 129.1, 127.8, 127.6, 125.0, 120.9, 73.4, 60.8, 40.1, 14.0; HRMS (ESI-TOF): Anal. Calcd. For C18H16O4+Na+: 319.0941, Found: 319.0947; IR (neat, cm−1): ν 3059, 2981, 2957, 2924, 1733, 1654, 1612, 1490, 1300, 1176, 1008, 769.
The drug molecule 1g (Nateglinide) (0.5 mmol, 158.8 mg) and propanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3g, with a yield of 90% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 7.30-7.20 (m, 3H), 7.12-7.06 (m, 2H), 6.01 (d, J=7.8 Hz, 1H), 4.90-4.85 (m, 1H), 4.12-4.06 (m, 1H), 4.06-4.01 (m, 2H), 3.15 (dd, J=13.8, 6.0 Hz, 1H), 3.08 (dd, J=13.8, 5.8 Hz, 1H), 2.04-1.97 (m, 1H), 1.91-1.83 (m, 2H), 1.78-1.75 (m, 2H), 1.69-1.58 (m, 2H), 1.47-1.33 (m, 3H), 1.10-0.94 (m, 3H), 0.91 (t, J=7.4 Hz, 3H), 0.85 (d, J=6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 175.5, 171.8, 135.9, 129.2, 128.3, 126.9, 66.9, 52.6, 45.3, 43.1, 37.8, 32.6, 29.6, 29.4, 28.86, 28.78, 21.7, 19.6, 10.2; HRMS (ESI-TOF): Anal. Calcd. For C22H33NO3+H+: 360.2533, Found: 360.2530; IR (neat, cm−1): ν 3301, 2975, 2927, 2858, 1724, 1638, 1548, 1444, 1286, 1182, 696.
The drug molecule 1 h (Isoxepac) (0.5 mmol, 134.2 mg) and propanol containing 1 equiv tert-butyl nitrite were added into the reaction tube in sequence; the reaction was carried out at 80° C. for 48 hours in the air; after the reaction was completed, sodium thiosulfate was added and stirred for quenching. The solvent was then removed by a rotary evaporator and adsorbed on silica gel. Finally, a mixed solvent of ethyl acetate and petroleum ether was used for column chromatography to obtain product 3 h, with a yield of 97% and separation yield. The main test data of the prepared product are as follows. Through analysis, it can be seen that the actual synthesized product is consistent with theoretical analysis.
1H NMR (400 MHZ, CDCl3) δ 8.10 (d, J=2.3 Hz, 1H), 7.87-7.84 (m, 1H), 7.53-7.49 (m, 1H), 7.46-7.38 (m, 2H), 7.32-7.30 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 5.13 (s, 2H), 4.04 (t, J=6.7 Hz, 2H), 3.62 (s, 2H), 1.68-1.58 (m, 2H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (100 MHZ, CDCl3) δ 190.6, 171.3, 160.3, 140.3, 136.2, 135.4, 132.6, 132.3, 129.3, 129.1, 127.83, 127.65, 125.0, 120.8, 73.4, 66.4, 40.1, 21.8, 10.2; HRMS (ESI-TOF): Anal. Calcd. For C19H18O4+H+: 333.1097, Found: 333.1111; IR (neat, cm−1): ν 3060, 2976, 2879, 1730, 1648, 1599, 1489, 1298, 1171, 1139, 766.
The foregoing is only a preferred Example of the present invention and is not intended to limit the present invention, and it should be noted that for a person of ordinary skill in the art, several improvements and variations can be made without departing from the technical principles of the present invention, which should also be regarded as the scope of protection of the present invention. The method of the present invention has the advantages of abundant source of raw materials, easy operation, strong compatibility of functional groups, good universality of substrates, green and safe, and can modify a series of known drug molecules by methyl esterification, which is also a shortcut to develop and discover new drug molecules or physiologically active molecules.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202011566880.0 | Dec 2020 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/075896 | 2/7/2021 | WO |
