CN103420823B

CN103420823B - The synthetic method of ��-chloro-4 fluorophenyl benzyl ketones

Info

Publication number: CN103420823B
Application number: CN201310304842.1A
Authority: CN
Inventors: 陈本顺; 周长岳; 徐秋斌
Original assignee: NANJING OCEAN PHARMACEUTICAL TECHNOLOGY Co Ltd
Current assignee: NANJING OCEAN PHARMACEUTICAL TECHNOLOGY Co Ltd
Priority date: 2013-07-19
Filing date: 2013-07-19
Publication date: 2016-06-08
Anticipated expiration: 2033-07-19
Also published as: CN103420823A

Abstract

The present invention relates to chemical field, more particularly relate to medicinal chemistry art, more particularly relate to the synthetic method of ��-chloro-4 fluorophenyl benzyl ketones. High for phenylacetic acid synthesis compound (4) cost in conventional preparation techniques, complex process, the problem being not suitable for industrialized production, the invention provides a kind of brand-new synthetic method synthesizing ��-chloro-4 fluorophenyl benzyl ketones with mandelic acid. The chloro of �� position is reacted as the first step, and coordinate corresponding synthetic parameters, so that with mandelic acid for initiation material, the total yield of synthesis compound (4) three step synthesis has reached 67.8%, and the by-product produced in reacting is few, the purity of target product is high, purification is easy, is adapted to industrialized production.

Description

The synthetic method of ��-chloro-4 fluorophenyl benzyl ketones

Technical field

The present invention relates to chemical field, more particularly relate to medicinal chemistry art, more particularly relate to the synthetic method of ��-chloro-4 fluorophenyl benzyl ketones.

Background technology

Compound (4) is a kind of important pharmaceutical intermediate. Having the synthetic method of multiple compounds (4) in current industry, with phenylacetic acid for initiation material, synthesis compound (4) is one of them, and its synthetic route is as follows:

��

It was found that under this synthetic route, the difficulty of �� position chlorination is high, and by-product is many, has chlorine two substitution product; In turn resulting in target product yield low, the purifying process of target product requires height, has high input, and therefore application industrially is restricted.

The synthesis of mandelic acid is relatively easy to, and it is less costly, and therefore the emphasis that the preparation technology of compound (4) is current pharmaceutical field one research prepared by improvement mandelic acid.

Our purpose is in that: by the improvement of synthetic route, improves yield and the purity of compound (4), simplifies subsequent purification technique. Make to synthesize compound (4) with mandelic acid for initiation material and meet the demand of industrialized production.

Summary of the invention

High for phenylacetic acid synthesis compound (4) cost in conventional preparation techniques, complex process, the problem being not suitable for industrialized production, the invention provides a kind of brand-new synthetic method synthesizing ��-chloro-4 fluorophenyl benzyl ketones with mandelic acid.

Technical scheme is as follows:

1, the synthetic method of ��-chloro-4 fluorophenyl benzyl ketones, the synthetic route of described ��-chloro-4 fluorophenyl benzyl ketones as shown in Equation 1:

(formula 1)

2, the synthetic route of described compound (3) is as shown in Equation 2:

(formula 2)

3, the synthetic route of described compound (2) is as shown in Equation 3:

(formula 3).

4, further, we disclosing ��-chlorophenylacetyl chloride and occur friedel-crafts acylation to generate ��-chloro-4 fluorophenyl benzyl ketones in a solvent with fluorobenzene, concrete synthesis step is, is dissolved in organic solvent by ��-chlorophenylacetyl chloride; Under the temperature conditions of-10 ~ 0 DEG C, instill fluorobenzene, keep reaction temperature at 50 ~ 90 DEG C; The mixing mol ratio of ��-chlorophenylacetyl chloride and fluorobenzene is 1:1.2-1:10, ��-chlorophenylacetyl chloride is 1:0.5-1:2 with aluminum chloride mol ratio.

5, simultaneously, we also disclosed described alpha chlorophenylacetic acid and ��-chlorophenylacetyl chloride is synthesized with chloride reagent; Described reaction temperature is 20 ~ 80 DEG C, and the mixing mol ratio of described alpha chlorophenylacetic acid and chloride reagent is 1:1.1 ~ 1:5.

6, simultaneously we further disclose the step of mandelic acid synthesis ��-chlorophenylacetyl chloride and are:

(1) mandelic acid and alcohol synthesis mandelate under the catalysis of acid; Here alcohol can be methanol, ethanol, isopropanol etc., it is particularly preferred to for ethanol. Acid can be hydrogen chloride, concentrated sulphuric acid, p-methyl benzenesulfonic acid, it is preferable that hydrogen chloride. Reaction temperature is 30 ~ 80 DEG C. The mixing quality ratio of mandelic acid and alcohol is: 1:2 ~ 1:10. The mol ratio of mandelic acid and acid is: 1:0.1 ~ 1:0.3.

(2) mandelate synthesizes alpha chlorophenylacetic acid ethyl ester under thionyl chloride effect; The temperature of this reaction is preferably 30 ~ 80 DEG C. Reaction completes preferably in thionyl chloride, toluene or dichloromethane solvent. The mol ratio of mandelate and thionyl chloride is: 1:1.1 ~ 1:2.

(3) alpha chlorophenylacetic acid ethyl ester acidic hydrolysis becomes alpha chlorophenylacetic acid. Here acidic hydrolysis refers to and completes in acetic acid, hydrochloric acid or dilute sulfuric acid aqueous solution.

7, in the 4th technical scheme we it is preferred that, described solvent is fluorobenzene, halogenated hydrocarbons or Nitrobenzol.

8, in the 5th technical scheme, we limit chloride reagent further as thionyl chloride or oxalyl chloride.

9, simultaneously, in the 5th group or the 8th group of technical scheme, we prefer that described reaction dissolvent is thionyl chloride, oxalyl chloride, chlorohydrocarbon or toluene.

Adopt technical scheme disclosed in this invention, the chloro of �� position is reacted as the first step, and coordinate corresponding synthetic parameters, so that with mandelic acid for initiation material, the total yield of synthesis compound (4) three step synthesis has reached 67.8%, and the by-product produced in reacting is few, the purity of target product is high, purification is easy, is adapted to industrialized production.

Detailed description of the invention

Embodiment 1

(formula 3)

Synthetic method is specifically described as: adding 152g mandelic acid and 300mL dehydrated alcohol in the there-necked flask of 1L, pass into 10g hydrogen chloride, system heats to 78 DEG C, fully reacts, and after reacting completely, reactant liquor concentration is obtained 174g ethyl mandelate. Adding 131g thionyl chloride in concentrated solution, heating, to 78 DEG C, is reacted 2h, after abundant reaction, is added acetic acid 250ml, concentrated hydrochloric acid 150ml, after continuing 100 DEG C of reaction 2h of heating maintenance, and decompression distillation, obtain 143g alpha-chloro phenylacetic acid, yield 84%.

Embodiment 2

(formula 2)

Synthetic method is specifically described as: compound (2) 85g obtained in Example 1, joins in 500ml there-necked flask, after dissolving with 100mL toluene solution, adds thionyl chloride 62g, fully dissolves mixing, 2h is stirred at room temperature, then heat, back flow reaction 0.5h. Gained solution decompression is concentrated into no longer has liquid to be distilled out of, and obtains 90g alpha-chloro phenyllacetyl chloride, yield 95%.

Embodiment 3

(formula 1)

Synthetic method is specifically described as: be separately added into 150g fluorobenzene in 500ml there-necked flask, 33g aluminum chloride, it is cooled to 0 DEG C, compound (3) 47g obtained in dropping embodiment 2, rate of addition is 47g/h, after dropwising, system is warming up to 80 DEG C, insulation reaction 4h, is down to 0 DEG C by reaction system, pours in the 2mol/L hydrochloric acid of 0 DEG C of 100mL. Stand, be layered, take organic solution layer, regulate pH to neutral with saturated sodium bicarbonate. Stand, be layered, take organic layer and water layer respectively; Wherein water layer 20g fluorobenzene extracts, and takes organic layer, is merged by the organic layer of twice acquisition, be concentrated into and no longer have liquid to steam, obtain the chloro-1-(4-fluorophenyl of 2-after stratification)-1-Phenylethanone., it is weighed as 52g, yield 85%.

Embodiment 4

Successively according to embodiment 1 to embodiment 3, by the mandelic acid preparation synthesis chloro-1-(4-fluorophenyl of 2-)-1-Phenylethanone..

Meanwhile, according to following traditional preparation method, the chloro-1-(4-fluorophenyl of 2-is carried out) synthesis of-1-Phenylethanone..

(1) preparation of phenyllacetyl chloride: take phenylacetic acid 136g, joins in 1000ml there-necked flask, after dissolving with 200mL toluene solution, adds thionyl chloride 120g, fully dissolves mixing, 2h is stirred at room temperature, then heat, back flow reaction 0.5h. Gained solution decompression is concentrated into no longer has liquid to be distilled out of, and obtains 143g phenyllacetyl chloride, yield 95%.

(2) preparation of fluorophenyl 1-Phenylethanone.: add aluminum chloride 15g, fluorobenzene 62g in reaction bulb, under ice-water bath, drips phenyllacetyl chloride 21g, and temperature controls at 40 DEG C; It is warming up to 80 DEG C; Insulated and stirred 5 hours, it is complete that TLC analyzes raw material reaction, is down to room temperature, obtains dark green solution; It is poured into 55g trash ice and in the mixture of the hydrochloric acid of 35ml2mol/L, controls temperature below 60 DEG C, layering; Organic layer adds 120mL saturated sodium bicarbonate and regulates pH, layering; Water layer carries with appropriate fluorobenzene is counter, merges organic layer, is concentrated into dry, adds appropriate petroleum ether recrystallization, obtain 20g4-fluorophenyl 1-Phenylethanone., yield 69%;

(3) the chloro-1-(4-fluorophenyl of 2-) preparation of-1-Phenylethanone.: in reaction bulb, add 4-fluorophenyl 1-Phenylethanone. 13g, dichloromethane 120mL, chlorine 6g is passed under room temperature, when 4-fluorophenyl 1-Phenylethanone. has reacted, in reaction bulb, add the sodium sulfite solution of 150mL15%, add 150mL saturated sodium bicarbonate and regulate pH; Layering, organic layer adds suitable quantity of water washing, concentrates to obtain the chloro-1-(4-fluorophenyl of grease 9g2-)-1-Phenylethanone., yield 60%;

The total recovery of traditional approach is 39.33%, and the total recovery prepared by technical scheme disclosed by the invention is 67.8%.

Claims

1. the synthetic method of ��-chloro-4 fluorophenyl benzyl ketones, is characterized in that the synthetic route of described ��-chloro-4 fluorophenyl benzyl ketones as shown in Equation 1:

(formula 1);

��-chlorophenylacetyl chloride and fluorobenzene occur friedel-crafts acylation to generate ��-chloro-4 fluorophenyl benzyl ketones in a solvent, and concrete synthesis step is, is dissolved in organic solvent by ��-chlorophenylacetyl chloride; Under the temperature conditions of-10 ~ 0 DEG C, instill fluorobenzene, keep reaction temperature at 50 ~ 90 DEG C; The mixing mol ratio of ��-chlorophenylacetyl chloride and fluorobenzene is 1:1.2-1:10, ��-chlorophenylacetyl chloride is 1:0.5-1:2 with aluminum chloride mol ratio;

The synthetic route of described compound (3) is as shown in Equation 2:

(formula 2);

The synthetic route of described compound (2) is as shown in Equation 3:

(formula 3);

Adding 152g mandelic acid and 300mL dehydrated alcohol in the there-necked flask of 1L, pass into 10g hydrogen chloride, system heats to 78 DEG C, fully reacts, and after reacting completely, reactant liquor concentration is obtained 174g ethyl mandelate,

Adding 131g thionyl chloride in concentrated solution, heating, to 78 DEG C, is reacted 2h, after abundant reaction, is added acetic acid 250mL, concentrated hydrochloric acid 150mL, after continuing 100 DEG C of reaction 2h of heating maintenance, and decompression distillation, obtain 143g alpha-chloro phenylacetic acid, yield 84%.

2. the synthetic method of �� according to claim 1-chloro-4 fluorophenyl benzyl ketones, is characterized in that: alpha chlorophenylacetic acid and chloride reagent are synthesized ��-chlorophenylacetyl chloride; Described reaction temperature is 20 ~ 80 DEG C, and the mixing mol ratio of described alpha chlorophenylacetic acid and chloride reagent is 1:1.1 ~ 1:5.

3. the synthetic method of �� according to claim 1-chloro-4 fluorophenyl benzyl ketones; it is characterized in that: described ��-chlorophenylacetyl chloride and fluorobenzene occur friedel-crafts acylation to generate in the step of ��-chloro-4 fluorophenyl benzyl ketones in a solvent, and described solvent is halogenated hydrocarbons or Nitrobenzol.

4. the synthetic method of �� according to claim 3-chloro-4 fluorophenyl benzyl ketones, is characterized in that: described halogenated hydrocarbons is fluorobenzene.

5. the synthetic method of �� according to claim 2-chloro-4 fluorophenyl benzyl ketones, is characterized in that: chloride reagent is thionyl chloride or oxalyl chloride.

6. the synthetic method of the �� according to claim 2 or 5-chloro-4 fluorophenyl benzyl ketones, it is characterized in that: described alpha chlorophenylacetic acid and chloride reagent are synthesized in the step of ��-chlorophenylacetyl chloride, and the reaction dissolvent adopted is thionyl chloride, oxalyl chloride, chlorohydrocarbon or toluene.