CN102702098A

CN102702098A - Synthesis of 6-methoxyl-1, 2, 3, 4 tetrahydroquinoline-5 methyl ester carboxylate

Info

Publication number: CN102702098A
Application number: CN2012101638896A
Authority: CN
Inventors: 张福治; 丁炬平; 张仁延; 余强
Original assignee: Cgenetech Suzhou China Co Ltd
Current assignee: Cgenetech Suzhou China Co Ltd
Priority date: 2012-05-24
Filing date: 2012-05-24
Publication date: 2012-10-03

Abstract

Aiming at the shortages of complex post-process, high cost and relatively low yield in the existing synthetic methods of 6-methoxyl-1, 2, 3, 4 tetrahydroquinoline-5 methyl ester carboxylate, the invention discloses a synthesis of 6-methoxyl-1, 2, 3, 4 tetrahydroquinoline-5 methyl ester carboxylate. With the adoption of the method to obtain the 6-methoxyl-1, 2, 3, 4 tetrahydroquinoline-5 methyl ester carboxylate by using p-methoxyaniline as a starting material, substituting the p-methoxyaniline by ethoxy methylene, closing a loop at high temperature, hydrolyzing, performing de-carboxylation, halogenating, removing hydrogen and adding carboxylic acid ester by LDA, and finally hydrogenating, de-bromizing, and reducing aryl ring, the whole process is easy to control, the post-process is simple, and the yield is greatly increased.

Description

6-methoxyl group-1,2,3,4 tetrahydroquinolines-5 carboxylate methyl ester synthetic

Technical field

The present invention relates to 6-methoxyl group-1,2, synthesizing of 3,4 tetrahydroquinolines-5 carboxylate methyl ester belongs to medicine, chemical technology field.

Background technology

6-methoxyl group-1,2,3; 4 tetrahydroquinolines-5 carboxylate methyl ester is important chemical intermediate, the phenolic hydroxyl group on its female ring, amino; Reach carboxylicesters and be widely used in medicine and pesticide field with different functional group reactions products, especially in the new drug development field, this compounds bibliographical information seldom at present; Only several pieces also exist cost high, and yield is low, is difficult for many deficiencies such as purifying.

Summary of the invention

The present invention is directed to 6-methoxyl group-1,2, the compound method aftertreatment in the past of 3,4 tetrahydroquinolines-5 carboxylate methyl ester compounds is loaded down with trivial details; Cost is high, and yield is on the low side to wait deficiency, and having invented described is that starting raw material and oxyethyl group methene replace with the P-nethoxyaniline, and high temperature closes ring; Hydrolysis, decarboxylation, halo, LDA pull out the method that the last hydrodebromination of carboxylicesters and aromatic ring reduction on the hydrogen obtains product; Make whole process easy handling, aftertreatment is simple, and yield improves greatly.

Described 6-methoxyl group-1,2,3,4 tetrahydroquinolines-5 carboxylate methyl ester synthetic; Being reacted to (7) used alkali by (6) comprises but is not limited to LDA, n-Butyl Lithium, s-butyl lithium, phenyl lithium etc.; Last carboxylicesters reagent comprises but is not limited to methyl-chloroformate, Vinyl chloroformate, methylcarbonate, chloroformic acid benzyl ester etc.; Solvent for use comprises but is not limited to THF, methyltetrahydrofuran, dioxane, MTBE etc.

Described 6-methoxyl group-1,2,3,4 tetrahydroquinolines-5 carboxylate methyl ester synthetic; Be reacted to (8) temperature of reaction by (7) and comprise but be not limited only to 25 degrees centigrade to 100 degrees centigrade, reaction solvent comprises but is not limited to methyl alcohol, ethanol; THF, dioxane etc., used hydrogenation catalyst comprise but are not limited to palladium carbon; Palladium hydroxide carbon, platinum dioxides etc., used neutralizing agent comprise but are not limited to triethylamine; Diisopropyl ethyl amine, Trimethylamine 99 etc., hydrogenation pressure are not limited to 1 atmosphere and are pressed onto 250 normal atmosphere.

Above-mentioned is that the chemical reaction route of starting raw material is following with the P-nethoxyaniline:

Embodiment

Preparation compound (2) and (3):

Starting raw material (1) 246 gram (2 moles) and oxyethyl group methene 432 grams (2 moles) mix, and are warmed up to 100 degree stirrings and obtain compound (2) in 2 hours, cooling; Be warmed up to 250 degree behind the ethanol that removes generation that reduces pressure and refluxed 2 hours, cooling, residual solution is poured in 1 liter of ETHYLE ACETATE; Even after-filtration is treated in stirring; ETHYLE ACETATE is washed, and oven dry obtains khaki color solid 371 grams (yield 75%).

Preparation compound (4):

Freshly prepd compound (3) 247 grams (1 mole) are dissolved in 2 liters of methyl alcohol, add 2 liters of 2N sodium hydroxide solutions, and the hydrochloric acid of 24 hours 6N of stirring at room is transferred PH to 2, and solid is separated out, filter, and washing, oven dry obtains off-white color solid 191g (yield 88%).

Preparation compound (5):

Oily matter (4) 110 grams (0.5 mole) after the reduction are dissolved in 500 milliliters of quinoline, reflux 8 hours, boil off most of solvent; Residual solution is poured in 1 liter of frozen water, ETHYLE ACETATE (500 milliliters of * 3) layering extraction, and saturated brine (500 milliliters) is washed; Anhydrous sodium sulfate drying; Filter, revolve driedly, obtain reddish-brown solid 68 grams (yield 78%).

Preparation compound (6):

Raw material (5) 52.5 grams (0.3 mole) and 103 gram tribromo oxygen phosphorus mix to heat up spends reaction 24 hours 120, cooling, and reaction solution is poured in 200 milliliters of frozen water; 5N sodium hydroxide is transferred PH to 10, ETHYLE ACETATE (200 milliliters of * 3) layering extraction, and saturated brine (200 milliliters) is washed; Anhydrous sodium sulfate drying; Filter, revolve driedly, obtain reddish-brown oily matter 61 grams (yield 85%).

Preparation compound (7):

Oily matter (6) 47.6 grams (0.2 mole) of reddish-brown are dissolved in 500 milliliters of anhydrous tetrahydro furans, and dry ice/acetone is cooled to subzero 70 degree, 220 milliliters of the LDA solution of the 1N that the dropping prepared beforehand is good under the nitrogen protection; Temperature control subzero 60 is to subzero 70 degree, react to drip methyl-chloroformate 21 grams (0.22 mole) after 2 hours again and continue temperature controls and react after 3 hours and rise to room temperature gradually, and reaction solution is poured in 1 liter of frozen water; ETHYLE ACETATE (500 milliliters of * 3) layering extraction; Saturated brine (500 milliliters) is washed, and anhydrous sodium sulfate drying filters; Revolve dried, the oily matter column chromatography purification that obtains get 38 the gram solids (yield 64%).

Preparation compound (8):

Raw material (7) 29.6 gram (0.1 mole) is dissolved in 300 ml methanol, adds triethylamine 11.1 grams (0.11 mole), in autoclave, is warmed up to the stirring 24 hours down of 60 normal atmosphere of 100 degree behind palladium carbon 3 gram (catalytic amount) hydrogen exchanges of 10% three times; Cooling, methyl alcohol is removed in decompression, and residual solution is poured ETHYLE ACETATE in 500 water (200 milliliters of * 3) layering extraction into; Saturated brine (200 milliliters) is washed, and anhydrous sodium sulfate drying filters; Revolve driedly, obtain oily matter 16.8 gram (yield 76%).

Claims

1. to have invented with the P-nethoxyaniline be that starting raw material and oxyethyl group methene replace to this patent, and high temperature closes ring, hydrolysis; Decarboxylation, halo, LDA pull out that the reduction of the last hydrodebromination of carboxylicesters and aromatic ring obtains 6-methoxyl group-1 on the hydrogen; The method of 2,3,4 tetrahydroquinoline-5 carboxylate methyl esters; Make whole process easy handling, aftertreatment is simple, and yield improves greatly.

2. described 6-methoxyl group-1,2,3,4 tetrahydroquinolines-5 carboxylate methyl ester synthetic; Being reacted to (7) used alkali by (6) comprises but is not limited to LDA, n-Butyl Lithium, s-butyl lithium, phenyl lithium etc.; Last carboxylicesters reagent comprises but is not limited to methyl-chloroformate, Vinyl chloroformate, methylcarbonate, chloroformic acid benzyl ester etc.; Solvent for use comprises but is not limited to THF, methyltetrahydrofuran, dioxane, MTBE etc.

3. described 6-methoxyl group-1,2,3,4 tetrahydroquinolines-5 carboxylate methyl ester synthetic; Be reacted to (8) temperature of reaction by (7) and comprise but be not limited only to 25 degrees centigrade to 100 degrees centigrade, reaction solvent comprises but is not limited to methyl alcohol, ethanol; THF, dioxane etc., used hydrogenation catalyst comprise but are not limited to palladium carbon; Palladium hydroxide carbon, platinum dioxides etc., used neutralizing agent comprise but are not limited to triethylamine; Diisopropyl ethyl amine, Trimethylamine 99 etc., hydrogenation pressure are not limited to 1 atmosphere and are pressed onto 250 normal atmosphere.