The synthetic method of 3-methylene isoindolone compound

Abstract

The invention relates to a synthetic method of 3-methylene isoindolone compounds. The synthetic method comprises the following step: in a reaction solvent, under argon shield, carrying out reaction under the catalytic action of a Pd compound to obtain the 3-methylene isoindolone compounds by taking benzamide compounds and anhydride or carboxylic acid compounds. The raw materials used in the method provided by the invention are simple and easily available and are industrial commodities which are wide in source, low in price, stable in property and unharsh in storage condition. In addition, the synthetic method is short in route, and the 3-methylene isoindolone compounds are constructed in one step by virtue of C-H bond activation and C-N bond formation. The synthetic method is high in atom economy and excellent in efficiency, and the reaction yield reaches 99%, so that the breakthrough of chemical synthesis of the system is realized, and deep extension of chemical researches of related drugs in the system is promoted.

Description

technical field

[0001] The invention belongs to the field of organic compound synthesis, in particular to a method for synthesizing 3-methylene isoindolinone compounds. Background technique

[0002] 3-Methyleneisoindolinone is a compound containing a γ-lactam ring, which is the core skeleton of many natural products and drug molecules, and has unique biological activities. At present, many anti-degenerative neurological disease drugs, receptor antagonists or agonists, and enzyme inhibitors contain the structure of 3-methyleneisoindolinone. For example, the newly developed anti-anxiety drugs Pazinaclone and Pagoclone, as well as the diuretic and antihypertensive drug Fumaridine, all contain such skeletons. In addition, isoindolinone compounds are also the core skeleton of many potentially active alkaloids and clinical drug molecules. Among these compounds, substituted 3-methylene isoindolinone derivatives are particularly effective, and are widely used in the development an...

Examples

Embodiment 1

[0028]

[0029] Take a 20mL reaction tube, add the weighed benzamide compound 1a (0.1mmol), acetic anhydride 2a (0.2mmol), palladium trifluoroacetate (0.005mmol), and then add After toluene (1 mL), the reaction tube was sealed with a Teflon stopper. Place the reaction tube in an oil bath at 130°C and stir for 12 hours. After the reaction is complete, cool down to room temperature, filter with diatomaceous earth, and then rinse with 20 mL of ethyl acetate until the filtrate is colorless. Combine the organic phases and spin to remove the solvent to obtain The mixture containing 3-methylene-2-(quinolin-8-yl)isoindolin-1-one(3aa) was subjected to flash column chromatography to obtain the product 3aa in a yield of 99%.

[0030] 1 H NMR (600MHz, CDCl 3 )δ9.00–8.81(m,1H),8.24(d,J=8.3Hz,1H),7.97(t,J=8.6Hz,2H),7.79(dd,J=17.3,7.4Hz,2H), 7.71–7.63(m, 2H), 7.58(t, J=7.5Hz, 1H), 7.44(dd, J=8.3, 4.1Hz, 1H), 5.19(d, J=1.8Hz, 1H), 4.41(d ,J=1.8Hz,1H). 13 C NMR (150MHz, CDCl 3 )δ167.4...

Embodiment 2

[0032]

[0033] Operation steps are with embodiment 1, obtain product

[0034] 3-methylene-2-(quinolin-8-yl)-5-(trifluoromethyl)isoindolin-1-one(3ba), the yield is 80%.

[0035] 1 H NMR (600MHz, CDCl 3)δ8.89(dd, J=4.1,1.5Hz,1H),8.26(dd,J=8.3,1.3Hz,1H),8.10(d,J=7.9Hz,1H),8.06(s,1H), 7.99(dd, J=8.2,0.8Hz,1H),7.85(d,J=7.9Hz,1H),7.82–7.76(m,1H),7.70(t,J=7.7Hz,1H),7.46(dd ,J=8.3,4.1Hz,1H),5.29(d,J=2.4Hz,1H),4.53(d,J=2.4Hz,1H). 13 C NMR (150MHz, CDCl 3 )δ166.1, 151.2, 144.5, 143.0, 136.9, 136.3, 134.2 (q, 2 J C-F =32.4Hz), 132.2, 132.0, 130.8, 129.6, 129.5, 126.5 (q, 3 J C-F =3.6Hz), 126.2, 124.7(q, 1 J C-F =271.2Hz), 124.3, 121.9, 117.7(q, 3 J C-F =3.9Hz), 92.0; (ESI) calculated value C 19 h 11 f 3 N 2 O[M+Na] + 363.0721, actual value 363.0721.

Embodiment 3

[0037]

[0038] Operation steps are with embodiment 1, obtain product

[0039] 5-methyl-3-methylene-2-(quinolin-8-yl)isoindolin-1-one(3ca), yield 99%.

[0040] 1 H NMR (600MHz, CDCl 3 )δ8.89(dd, J=4.0,1.5Hz,1H),8.23(dd,J=8.3,1.4Hz,1H),7.95(dd,J=8.2,0.9Hz,1H),7.86(d,J =7.7Hz,1H),7.76(dd,J=7.2,1.0Hz,1H),7.67(t,J=7.7Hz,1H),7.59(s,1H),7.43(dd,J=8.3,4.1Hz ,1H),7.39(d,J=7.7Hz,1H),5.14(d,J=2.0Hz,1H),4.36(d,J=1.9Hz,1H),2.53(s,3H). 13 C NMR (150MHz, CDCl 3 C 19 h 14 N 2 O[M+H] + 287.1184, actual value 287.1185.

technical field

[0001] The invention belongs to the field of organic compound synthesis, in particular to a method for synthesizing 3-methylene isoindolinone compounds. Background technique

[0002] 3-Methyleneisoindolinone is a compound containing a γ-lactam ring, which is the core skeleton of many natural products and drug molecules, and has unique biological activities. At present, many anti-degenerative neurological disease drugs, receptor antagonists or agonists, and enzyme inhibitors contain the structure of 3-methyleneisoindolinone. For example, the newly developed anti-anxiety drugs Pazinaclone and Pagoclone, as well as the diuretic and antihypertensive drug Fumaridine, all contain such skeletons. In addition, isoindolinone compounds are also the core skeleton of many potentially active alkaloids and clinical drug molecules. Among these compounds, substituted 3-methylene isoindolinone derivatives are particularly effective, and are widely used in the development an...

Examples

Embodiment 1

[0028]

[0029] Take a 20mL reaction tube, add the weighed benzamide compound 1a (0.1mmol), acetic anhydride 2a (0.2mmol), palladium trifluoroacetate (0.005mmol), and then add After toluene (1 mL), the reaction tube was sealed with a Teflon stopper. Place the reaction tube in an oil bath at 130°C and stir for 12 hours. After the reaction is complete, cool down to room temperature, filter with diatomaceous earth, and then rinse with 20 mL of ethyl acetate until the filtrate is colorless. Combine the organic phases and spin to remove the solvent to obtain The mixture containing 3-methylene-2-(quinolin-8-yl)isoindolin-1-one(3aa) was subjected to flash column chromatography to obtain the product 3aa in a yield of 99%.

[0030] 1 H NMR (600MHz, CDCl 3 )δ9.00–8.81(m,1H),8.24(d,J=8.3Hz,1H),7.97(t,J=8.6Hz,2H),7.79(dd,J=17.3,7.4Hz,2H), 7.71–7.63(m, 2H), 7.58(t, J=7.5Hz, 1H), 7.44(dd, J=8.3, 4.1Hz, 1H), 5.19(d, J=1.8Hz, 1H), 4.41(d ,J=1.8Hz,1H). 13 C NMR (150MHz, CDCl 3 )δ167.4...

Embodiment 2

[0032]

[0033] Operation steps are with embodiment 1, obtain product

[0034] 3-methylene-2-(quinolin-8-yl)-5-(trifluoromethyl)isoindolin-1-one(3ba), the yield is 80%.

[0035] 1 H NMR (600MHz, CDCl 3)δ8.89(dd, J=4.1,1.5Hz,1H),8.26(dd,J=8.3,1.3Hz,1H),8.10(d,J=7.9Hz,1H),8.06(s,1H), 7.99(dd, J=8.2,0.8Hz,1H),7.85(d,J=7.9Hz,1H),7.82–7.76(m,1H),7.70(t,J=7.7Hz,1H),7.46(dd ,J=8.3,4.1Hz,1H),5.29(d,J=2.4Hz,1H),4.53(d,J=2.4Hz,1H). 13 C NMR (150MHz, CDCl 3 )δ166.1, 151.2, 144.5, 143.0, 136.9, 136.3, 134.2 (q, 2 J C-F =32.4Hz), 132.2, 132.0, 130.8, 129.6, 129.5, 126.5 (q, 3 J C-F =3.6Hz), 126.2, 124.7(q, 1 J C-F =271.2Hz), 124.3, 121.9, 117.7(q, 3 J C-F =3.9Hz), 92.0; (ESI) calculated value C 19 h 11 f 3 N 2 O[M+Na] + 363.0721, actual value 363.0721.

Embodiment 3

[0037]

[0038] Operation steps are with embodiment 1, obtain product

[0039] 5-methyl-3-methylene-2-(quinolin-8-yl)isoindolin-1-one(3ca), yield 99%.

[0040] 1 H NMR (600MHz, CDCl 3 )δ8.89(dd, J=4.0,1.5Hz,1H),8.23(dd,J=8.3,1.4Hz,1H),7.95(dd,J=8.2,0.9Hz,1H),7.86(d,J =7.7Hz,1H),7.76(dd,J=7.2,1.0Hz,1H),7.67(t,J=7.7Hz,1H),7.59(s,1H),7.43(dd,J=8.3,4.1Hz ,1H),7.39(d,J=7.7Hz,1H),5.14(d,J=2.0Hz,1H),4.36(d,J=1.9Hz,1H),2.53(s,3H). 13 C NMR (150MHz, CDCl 3 C 19 h 14 N 2 O[M+H] + 287.1184, actual value 287.1185.

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