CN102746209A

CN102746209A - A synthetic method for 3-(2-(4-chlorophenoxy)phenyl )-1-methyl-2,4-dione

Info

Publication number: CN102746209A
Application number: CN2012102039670A
Authority: CN
Inventors: 李春雷; 丁炬平; 张仁延; 余强
Original assignee: Cgenetech Suzhou China Co Ltd
Current assignee: Cgenetech Suzhou China Co Ltd
Priority date: 2012-06-20
Filing date: 2012-06-20
Publication date: 2012-10-24

Abstract

The invention discloses a synthetic method for 3-(2-(4-chlorophenoxy)phenyl )-1-methyl-2,4-dione which is an important intermediate for the synthesis of asenapine. Under current technology conditions, according to the method, 3-(2-(4-chlorophenoxy)phenyl)-1-methyl-2,4-dione is obtained through two simple reaction using 2-(2-(4-chlorophenyl)phenyl) acetate as a starting material. The method explores and optimizes the synthetic route of 3-(2-(4-chlorophenoxy)phenyl )-1-methyl-2,4-dione. The method is advantaged by simple and safe operation, low material cost, and suitability for mass production in factories.

Description

A kind of 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the compound method of 4-diketone

Technical field

The present invention relates to a kind of 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the synthesis technology of 4-diketone improves, and belongs to medicine, chemical technology field.

Background technology

3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the 4-diketone is a kind of white solid, is the flat important intermediate raw material of synthetic Arsenal.

Summary of the invention

The present invention is being under the prerequisite of raw material with 2-(2-(4-chloro-phenyl-) phenyl) acetate, attempted three condition circuits after, finally confirmed the technology circuit of this patent.Article one, attempting circuit is; 2-(2-(4-chloro-phenyl-) phenyl) acetate obtains 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min. under the condition that sulfur oxychloride refluxes, and then through N; Dinethylformamide; The processing of triethylamine and hydrochloride methyl sarcosnate obtain methyl-2-(2-(2-(4-chlorophenoxy) phenyl)-N-methylacetamido) acetic acid, the processing through toluene and potassium tert.-butoxide just can obtain 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2,4-diketone then; The consumption of this method sulfur oxychloride is too big; Environmental pollution is more serious, and the removal of the sulfur oxychloride that cost is high and excessive is also very complicated, and effect is bad on the whole.Second is attempted route and is to use oxalyl chloride to replace sulfur oxychloride; Make solvent with methylene dichloride; 2-(2-(4-chloro-phenyl-) phenyl) acetate is made 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min., and the back is operated identical, and the reaction of this method generation 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min. is relatively poor; Its result has caused 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, and the productive rate of 4-diketone declines to a great extent.The third method is; Make 2-(2-(4-chloro-phenyl-) phenyl) acetate change into 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min. with oxalyl chloride and THF processing; The result shows that reaction is fine, has not only reduced production cost, and has greatly reduced the pollution to environment.

3-according to the invention (2-(4-chlorophenoxy) phenyl)-1-methyl-2, the compound method of 4-diketone is to be raw material with 2-(2-(4-chloro-phenyl-) phenyl) acetate; Handle at normal temperatures with oxalyl chloride and THF, obtain 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min., 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min. of gained is added drop-wise to the N that contains hydrochloride methyl sarcosnate and triethylamine under the condition below 10 degree; In the dinethylformamide solution; Stirred overnight at room temperature reacts completely, and reaction solution is poured in the water; Ethyl acetate extraction; Washing ETHYLE ACETATE, anhydrous sodium sulfate drying selects dried methyl-2-(2-(2-(4-chlorophenoxy) phenyl)-N-methylacetamido) bullion of acetic acid that obtains.(2-(2-(4-chlorophenoxy) phenyl)-N-methylacetamido) bullion of acetic acid is dissolved in and slowly is added drop-wise in the toluene in the toluene that contains potassium tert.-butoxide, and mechanical stirring 30 minutes reacts completely with methyl-2-.To react and also pour in the water, separatory, water with concentrated hydrochloric acid acid adjustment degree to about the neutrality; Have the tawny solid to separate out, filter, the tawny solid is washed with the mixing solutions of ETHYLE ACETATE and toluene; Solid becomes white; Filter, obtaining white solid is 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the pure article of 4-diketone.

Above-mentioned 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the compound method of 4-diketone is characterized in that: the consumption of said oxalyl chloride is the twice of the amount of substance of 2-(2-(4-chloro-phenyl-) phenyl) acetate.

Above-mentioned 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2; 4-diketone compound method; It is characterized in that: the said THF that uses is the dry THF of crossing of sodium silk, and consumption is the THF of five milliliters of each gram 2-(2-(4-chloro-phenyl-) phenyl) acetate.

Above-mentioned 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the compound method of 4-diketone is characterized in that the gained midbody does not need purifying, can directly carry out next step reaction.

Above-mentioned is the synthetic 3-(2-(4-chlorophenoxy) phenyl) of raw material-1-methyl-2 with 2-(2-(4-chloro-phenyl-) phenyl) acetate, and the chemical reaction and the reaction formula of 4-diketone are following:

(1) reaction equation of Synthetic 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min. is:

(2) reaction is accomplished, and revolves the reaction equation of doing the back direct reaction to be:

(3) reaction is accomplished, and the gained bullion continues the reactionization reaction equation and is:

(4) react completely after, pour in the water, separatory, water is transferred to neutrality with concentrated hydrochloric acid, separates out solid, solid is washed 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the pure article of 4-diketone of obtaining with the mixing solutions of ETHYLE ACETATE and sherwood oil.

Embodiment

Embodiment:

Said 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2; The compound method of 4-diketone makes: in 10 liters there-necked flask, add 948 gram 2-(2-(4-chloro-phenyl-) phenyl) acetate; 4740 milliliters THF, room temperature condition slowly drip the oxalyl chloride of 910 grams (2 equivalent) down, after the dropping fully; The N of slow Dropwise 5 milliliter; Dinethylformamide (reacting very violent), room temperature continue to stir one hour, revolved the bullion of dried 1320 gram 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min.s.1500 milliliters of N, dinethylformamide dissolve away 1320 gram 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min.s, and under the condition below 10 degree, slowly are added drop-wise to and contain 526 (1.2 equivalents) and restrain hydrochloride methyl sarcosnate; 3500 milliliters of N, dinethylformamide is in the there-necked flask of 1161 grams (3.2 equivalent); In the dropping process, keep temperature to be lower than 10 degree, after the dropping fully; Stirred overnight at room temperature reacts completely.Reaction solution is poured in 8 premium on currency, used 5000 milliliters respectively, 3000 milliliters 2000 milliliters ethyl acetate extraction once merges organic phase.2000 milliliters of washings 2 times, anhydrous sodium sulfate drying revolves dried methyl-2-(bullion 931 grams of 2-(2-(4-chlorophenoxy) phenyl)-N-methylacetamido) acetic acid.Purifying does not directly carry out next step reaction.In 10 liters there-necked flask, drop into the potassium tert.-butoxide of 600 grams (2 equivalent), 5000 milliliters toluene, mechanical stirring; ((2-(4-chlorophenoxy) phenyl)-N-methylacetamido) bullion of acetic acid (being untreated) is dissolved in 1500 milliliters of toluene 2-, is added drop-wise in the reaction flask, drips fully in 30 minutes with 931 gram methyl-2-; After dripping fully, stirring at room 30 minutes, TLC point plate; React completely (thermopositive reaction), reaction solution is poured in 8000 ml waters, mechanical stirring 30 minutes; Separatory, water is jumped about acidity to 2 with concentrated hydrochloric acid, has a large amount of off-white color solids to separate out; Filter, solid filters with 1000 milliliters of washings 2 times; (ETHYLE ACETATE: wash, and filters 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the pure article of 4-diketone of obtaining by the mixing solutions of sherwood oil=1:2) with 1500 milliliters of ETHYLE ACETATE and sherwood oil for solid.

Claims

(1.3-2-(4-chlorophenoxy) phenyl)-1-methyl-2, the compound method of 4-diketone is that employing 2-(2-(4-chloro-phenyl-) phenyl) acetate is raw material; Handle at normal temperatures with oxalyl chloride and THF, obtain 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min., 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min. of gained is added drop-wise to the N that contains hydrochloride methyl sarcosnate and triethylamine under the condition below 10 degree; In the dinethylformamide solution, stirred overnight at room temperature reacts completely; Reaction solution is poured in the water into ethyl acetate extraction, washing ETHYLE ACETATE; Anhydrous sodium sulfate drying, revolve dried obtain methyl-2-(2-(2-(4-chlorophenoxy) phenyl)-N-methylacetamido) bullion of acetic acid, ((2-(4-chlorophenoxy) phenyl)-N-methylacetamido) bullion of acetic acid is dissolved in and slowly is added drop-wise in the toluene that contains potassium tert.-butoxide in the toluene 2-with methyl-2-; Mechanical stirring 30 minutes reacts completely, and will react and also pour in the water; Separatory, water to about the neutrality, has the tawny solid to separate out with concentrated hydrochloric acid acid adjustment degree; Filter, the tawny solid is washed with the mixing solutions of ETHYLE ACETATE and toluene, and solid becomes white; Filter, obtain pure 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2, the 4-diketone.
2. as claimed in claim 3,4-dihydro-2H-pyrans is the compound method of [3,2-b] pyridine also, it is characterized in that: described initial feed is meant that with 2-(2-(4-chloro-phenyl-) phenyl) acetate be raw material.
3. 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2 as claimed in claim, the compound method of 4-diketone is characterized in that: use oxalyl chloride to replace sulfur oxychloride.
4. 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2 as claimed in claim, the compound method of 4-diketone is characterized in that: to be that the sodium silk is dry cross employed THF.
5. 3-(2-(4-chlorophenoxy) phenyl)-1-methyl-2 as claimed in claim, the compound method of 4-diketone is characterized in that: the temperature when dripping 2-(2-(4-chlorophenoxy) phenyl) Acetyl Chloride 98Min. is 10 to spend.