1‑n‑substituted benzyl‑6‑n'‑substituent‑2,3,6,9‑tetrahydro‑1h‑[1,4]oxazino[3,2‑g]quinolin‑9‑one ‑8‑Formic acid compound and its preparation method and application

Abstract

The invention belongs to the technical field of medicine compounds, and discloses a 1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetralin-1H-[1,4] benzoxazine [3,2-g] quinolone-9-ketone-8-formic acid compound and a preparation method and application thereof. According to the formula (I) of the 1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetralin-1H-[1,4] benzoxazine [3,2-g] quinolone-9-ketone-8-formic acid compound, R1 represents a benzyl or a substituted benzyl, and R2 represents hydrogen or an alkyl or a hydroxyalkyl or a substituted benzyl or a carboxyalkyl. The method comprises the steps that firstly, 2-amino-5-nitrophenol is used as a raw material, acetylation protection, affinity substitute ring closure and deprotection are performed, affinity substitute is introduced into substituted benzyl, nitro reduction is performed through stannous chloride, condensation is performed, Gould-Jacobs reaction ring closure is performed, affinity substitute is introduced into different substituent groups, and finally hydrolysis is performed to obtain the compound of the formula (I). The compound has the inhibiting effect on the HIV-1 integrase.

Description

technical field

[0001] The present invention relates to 1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinoline- The 9-keto-8-formic acid compound, its preparation method and its application as an HIV-1 integrase inhibitor belong to the technical field of pharmaceutical compounds. Background technique

[0002] HIV-1 (human immunodeficiency virus-type I), which belongs to the retroviruses, is the virus that causes AIDS. The HIV-1 virus cell invasion of host cells can be roughly divided into the following four stages: In the first stage, the gp120 protein on the outer membrane of HIV-1 specifically recognizes the CD4 molecule on the T cell membrane and binds to it with high affinity, thereby making Target cells are in intimate contact with viral particles. Then gp41 mediates the fusion between the HIV-1 outer lipid membrane and the target cell, and releases the viral core particle into the cytoplasm of the target cell. In the second stage,...

Examples

Embodiment 1

[0046] 1-N-Benzyl 6-N'-methyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8 - Preparation of formic acid

[0047] (a) Preparation of 2-acetamido-5-nitrophenol

[0048]

[0049] Add 2-amino-5-nitrophenol (20g, 0.130mol) and 50mL of acetic acid into 250mL of toluene, add 15mL of acetic anhydride dropwise after the system rises to 80°C, after the addition is completed, react at 80°C for 3 to 4 hours, and collect the insoluble matter by filtration The insoluble matter was washed with 100mL×3 petroleum ether, and dried to obtain 2-acetamido-5-nitrophenol.

[0050] The pure product is khaki solid 24.7g, the yield is 97%

[0051] 1 H NMR(400MHz,DMSO)δ11.01(s,1H),9.55(s,1H),8.31(d,J=9.0Hz,1H),7.82–7.59(m,2H),2.19(s,3H) .

[0052] (b) Preparation of N-acetyl-7-nitrobenzo[1,4]oxazine

[0053]

[0054] Dissolve 2-acetamido-5-nitrophenol (24.7g, 0.126mol) in 200mL N,N-dimethylformamide, add potassium carbonate (52g, 0.378mol), and add dropwise after the system rise...

Embodiment 2

[0090] Preparation of 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylic acid

[0091] Step (a) (b) (c) (d) (e) (f) (g) is the same as embodiment 1

[0092] (h) Preparation of 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylic acid

[0093]

[0094] Ethyl 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylate (182mg , 0.5mmol) was added to 10mL ethanol and 10mL 20% potassium hydroxide solution, heated to reflux for 4h. Cool, add 1M hydrochloric acid to adjust to pH=1~2, filter, wash the insoluble matter with water and 50% ethanol aqueous solution successively, and dry to obtain 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1 ,4]oxazino[3,2-g]quinolin-9-one-8-carboxylic acid.

[0095] The pure product is light yellow solid 134mg, the yield is 80%

[0096] 1 H NMR(400MHz,DMSO)δ15.89(s,1H),13.02(s,1H),8.63(d,J=6.6Hz,1H),7.38–7.27(m,5H),7.21(s,1H) ,7.12(s,1H),4.65(s,2H),4.43(d,J=3.8Hz,2H),3.59(d,J=4.1...

Embodiment 3

[0099] 1-N-Benzyl-6-N'-ethyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one- Preparation of 8-formic acid

[0100] Steps (a) (b) (c) (d) (e) (f) (g) are the same as in Example 1.

[0101] (h) 1-N-Benzyl-6-N'-ethyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinoline-9 - Preparation of ethyl ketone-8-carboxylate

[0102]

[0103] Ethyl 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylate (364mg ,1mmol) was dissolved in 15mL N,N-dimethylformamide, potassium carbonate (1.3g, 9.5mmol) was added and the system was heated to 70°C, bromoethane (218mg, 2mmol) was added dropwise, and the reaction was completed at 70°C for 4h , TLC monitors that the raw material point disappears, suction filtration, the filtrate is poured into 50mL ice water, and the insoluble matter is collected by filtration after the ice completely melts, the insoluble matter is washed with 10mL×3 water, column chromatography (neutral alumina, dichloromethane / methanol =100:1~...

technical field

[0001] The present invention relates to 1-N-substituted benzyl-6-N'-substituent-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinoline- The 9-keto-8-formic acid compound, its preparation method and its application as an HIV-1 integrase inhibitor belong to the technical field of pharmaceutical compounds. Background technique

[0002] HIV-1 (human immunodeficiency virus-type I), which belongs to the retroviruses, is the virus that causes AIDS. The HIV-1 virus cell invasion of host cells can be roughly divided into the following four stages: In the first stage, the gp120 protein on the outer membrane of HIV-1 specifically recognizes the CD4 molecule on the T cell membrane and binds to it with high affinity, thereby making Target cells are in intimate contact with viral particles. Then gp41 mediates the fusion between the HIV-1 outer lipid membrane and the target cell, and releases the viral core particle into the cytoplasm of the target cell. In the second stage,...

Examples

Embodiment 1

[0046] 1-N-Benzyl 6-N'-methyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8 - Preparation of formic acid

[0047] (a) Preparation of 2-acetamido-5-nitrophenol

[0048]

[0049] Add 2-amino-5-nitrophenol (20g, 0.130mol) and 50mL of acetic acid into 250mL of toluene, add 15mL of acetic anhydride dropwise after the system rises to 80°C, after the addition is completed, react at 80°C for 3 to 4 hours, and collect the insoluble matter by filtration The insoluble matter was washed with 100mL×3 petroleum ether, and dried to obtain 2-acetamido-5-nitrophenol.

[0050] The pure product is khaki solid 24.7g, the yield is 97%

[0051] 1 H NMR(400MHz,DMSO)δ11.01(s,1H),9.55(s,1H),8.31(d,J=9.0Hz,1H),7.82–7.59(m,2H),2.19(s,3H) .

[0052] (b) Preparation of N-acetyl-7-nitrobenzo[1,4]oxazine

[0053]

[0054] Dissolve 2-acetamido-5-nitrophenol (24.7g, 0.126mol) in 200mL N,N-dimethylformamide, add potassium carbonate (52g, 0.378mol), and add dropwise after the system rise...

Embodiment 2

[0090] Preparation of 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylic acid

[0091] Step (a) (b) (c) (d) (e) (f) (g) is the same as embodiment 1

[0092] (h) Preparation of 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylic acid

[0093]

[0094] Ethyl 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylate (182mg , 0.5mmol) was added to 10mL ethanol and 10mL 20% potassium hydroxide solution, heated to reflux for 4h. Cool, add 1M hydrochloric acid to adjust to pH=1~2, filter, wash the insoluble matter with water and 50% ethanol aqueous solution successively, and dry to obtain 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1 ,4]oxazino[3,2-g]quinolin-9-one-8-carboxylic acid.

[0095] The pure product is light yellow solid 134mg, the yield is 80%

[0096] 1 H NMR(400MHz,DMSO)δ15.89(s,1H),13.02(s,1H),8.63(d,J=6.6Hz,1H),7.38–7.27(m,5H),7.21(s,1H) ,7.12(s,1H),4.65(s,2H),4.43(d,J=3.8Hz,2H),3.59(d,J=4.1...

Embodiment 3

[0099] 1-N-Benzyl-6-N'-ethyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one- Preparation of 8-formic acid

[0100] Steps (a) (b) (c) (d) (e) (f) (g) are the same as in Example 1.

[0101] (h) 1-N-Benzyl-6-N'-ethyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinoline-9 - Preparation of ethyl ketone-8-carboxylate

[0102]

[0103] Ethyl 1-N-benzyl-2,3,6,9-tetrahydro-1H-[1,4]oxazino[3,2-g]quinolin-9-one-8-carboxylate (364mg ,1mmol) was dissolved in 15mL N,N-dimethylformamide, potassium carbonate (1.3g, 9.5mmol) was added and the system was heated to 70°C, bromoethane (218mg, 2mmol) was added dropwise, and the reaction was completed at 70°C for 4h , TLC monitors that the raw material point disappears, suction filtration, the filtrate is poured into 50mL ice water, and the insoluble matter is collected by filtration after the ice completely melts, the insoluble matter is washed with 10mL×3 water, column chromatography (neutral alumina, dichloromethane / methanol =100:1~...

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