METHOD FOR PREPARING CARBOXYLIC ACID ESTER COMPOUND

Abstract

The present invention relates to a method for preparing a carboxylic acid ester compound. Under the catalysis of nitrite, a carboxylic acid reacts with an alcohol in air so as to obtain an ester compound; and the alcohol is ethanol, propanol or trifluoroethanol. The present invention has the advantages such as mild reaction conditions, rich source of raw materials, wide universality of reaction substrates, and simple operation, and can modify a series of carboxylic acids having medicinal properties and aliphatic carboxylic acids such as biologically active amino acids.

Claims

1. A method for preparing a carboxylic acid ester compound, wherein in the presence of a nitrous acid ester, a carboxylic acid compound and an alcohol are used as starting materials to react and prepare the carboxylic acid ester compound; and the alcohol is ethanol, propanol, or trifluoroethanol.

2. The method for preparing the carboxylic acid ester compound according to claim 1, wherein a general formula of the carboxylic acid compound is: ##STR00012## R.sup.1 is selected from group consisting of hydrogen, C.sub.1-C.sub.12 alkyl, alkoxy, phenyl, benzyl, substituent phenyl, thienyl, indolyl, phenolic group, naphthyl, biphenyl, and an amide group; R.sup.2 is selected from the group consisting of hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl, and phenyl; R.sup.3 is selected from the group consisting of hydrogen, methyl, methylene, ethyl, isopropyl, propyl, butyl, and phenyl; substituents on the substituent phenyl are selected from one or more selected from the group consisting of hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetylamino, fluorine, chlorine, bromine, and iodine.

3. The method for preparing the carboxylic acid ester compound according to claim 1, wherein the nitrous acid ester is selected from the group consisting of isopropyl nitrite, butyl nitrite, isobutyl nitrite and tert-butyl nitrite.

4. The method for preparing the carboxylic acid ester compound according to claim 1, wherein a molar ratio of the carboxylic acid compound to the nitrous acid ester is 10:5-20.

5. The method for preparing the carboxylic acid ester compound according to claim 1, wherein a molar ratio of the carboxylic acid compound to the nitrous acid ester is 1:1.

6. The method for preparing the carboxylic acid ester compound according to claim 1, wherein a reaction time is 30-60 hours; a reaction temperature is 60-80? C.

7. The method for preparing the carboxylic acid ester compound according to claim 1, wherein the reaction is carried out in air.

8. A carboxylic acid ester compound prepared by the method for preparing carboxylic acid ester compounds according to claim 1.

9. An application of nitrous acid ester in catalyzing a reaction of carboxylic acid compound and an alcohol to prepare a carboxylic acid ester compound; and the alcohol is ethanol, propanol, or trifluoroethanol.

10. The application according to claim 9, wherein the reaction is free of a metals or a metal compound.

Description

EXAMPLES OF THE PRESENT INVENTION

[0026] 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.

Example 1

[0027] ##STR00002##

[0028] 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.

[0029] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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, CDCl.sub.3) ? 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 C.sub.16H.sub.18O.sub.3+Na.sup.+: 281.1148, Found: 281.1149; IR (neat, cm.sup.?1): ? 3060, 2981, 2939, 1728, 1590, 1456, 1372, 1264, 1173, 1027, 856.

[0030] 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%.

Example 2

[0031] ##STR00003##

[0032] 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.

Example 3

[0033] ##STR00004##

[0034] 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.

[0035] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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, CDCl.sub.3) ? 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 C.sub.17H.sub.20O.sub.3+Na.sup.+: 295.1305, Found: 295.1323; IR (neat, cm.sup.?1): ? 2967, 2935, 1724, 1605, 1461, 1262, 1181, 858, 813.

Example 4

[0036] ##STR00005##

[0037] 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.

Example 5

[0038] ##STR00006##

[0039] 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.

[0040] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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, CDCl.sub.3) ? 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 C.sub.21H.sub.20.sup.35ClNO.sub.4+Na.sup.+: 408.0973, Found: 408.0950. Anal. Calcd. For C.sub.21H.sub.20.sup.37ClNO.sub.4+Na.sup.+: 410.0944, Found: 410.0947; IR (neat, cm.sup.?1): ? 2978, 2929, 1727, 1673, 1602, 1466, 1358, 1321, 1173, 1035, 912, 802.

Example 6

[0041] ##STR00007##

[0042] 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.

[0043] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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, CDCl.sub.3) ? 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 C.sub.18H.sub.18N.sub.2O.sub.3+Na.sup.+: 333.1210, Found: 333.1225; IR (neat, cm.sup.?1): ? 2977, 2932, 1752, 1684, 1615, 1530, 1495, 1452, 1198, 1145, 1063, 737.

Example 7

[0044] ##STR00008##

[0045] 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.

[0046] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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); .sup.13C NMR (100 MHZ, CDCl.sub.3) ? 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 C.sub.21H.sub.31NO.sub.3+Na.sup.+: 368.2196, Found: 368.2187; IR (neat, cm.sup.?1): ? 3310, 2976, 2931, 2868, 1724, 1641, 1539, 1445, 1279, 1180, 697.

Example 8

[0047] ##STR00009##

[0048] 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.

[0049] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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, CDCl.sub.3) ? 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 C.sub.18H.sub.16O.sub.4+Na.sup.+: 319.0941, Found: 319.0947; IR (neat, cm.sup.?1): ? 3059, 2981, 2957, 2924, 1733, 1654, 1612, 1490, 1300, 1176, 1008, 769.

Example 9

[0050] ##STR00010##

[0051] 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.

[0052] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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, CDCl.sub.3) ? 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 C.sub.22H.sub.33NO.sub.3+H.sup.+: 360.2533, Found: 360.2530; IR (neat, cm.sup.?1): ? 3301, 2975, 2927, 2858, 1724, 1638, 1548, 1444, 1286, 1182, 696.

Example 10

[0053] ##STR00011##

[0054] 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.

[0055] .sup.1H NMR (400 MHZ, CDCl.sub.3) ? 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, CDCl.sub.3) ? 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 C.sub.19H.sub.18O.sub.4+H.sup.+: 333.1097, Found: 333.1111; IR (neat, cm.sup.?1): ? 3060, 2976, 2879, 1730, 1648, 1599, 1489, 1298, 1171, 1139, 766.

[0056] 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.