A process for the preparation of 3'-acetamido-2'-hydroxyacetophenone

Abstract

The application belongs to the technical field of pharmaceutical intermediate synthesis, and discloses a preparation method of 3'-acetamino-2'-hydroxyacetophenone, which comprises the following steps: S1, under weak acid conditions, cyclization condensation reaction of o-amino phenol and original acetic acid trimethyl ester is carried out to obtain 2-methylbenzoxazole; S2, under the action of a catalyst, 2-methylbenzoxazole and acetic anhydride are subjected to Friedel-Crafts acylation reaction to obtain 1-(2-methyl-1,3-benzoxazol-7-yl)-1-ethanone; S3, the 1-(2-methyl-1,3-benzoxazol-7-yl-1-ethanone is subjected to ring-opening reaction under the condition of an acid to generate 3'-acetamino-2'-hydroxyacetophenone. The method is simple in operation, high in yield, low in material cost, and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for preparing 3'-acetamido-2'-hydroxyacetophenone. Background Technology

[0002] Pranlukast, a novel anti-asthma drug launched in the mid-1990s, is one of the three leukotriene receptor antagonists currently receiving widespread international attention. Developed by Ono Pharmaceutical Co., Ltd. of Japan, Pranlukast is characterized by extremely low toxicity and significant inhibitory efficacy. Clinically, this compound is effective not only for atopic asthma but also for infectious, mixed, chronic, episodic, and non-seasonal bronchial asthma, with no serious adverse reactions, no impact on the cytochrome P450 enzyme system, and no significant drug interactions. Currently, there are reports on the preparation processes of Pranlukast and its intermediates; however, existing processes generally suffer from drawbacks such as high production costs, low overall yields, and significant toxicity.

[0003] The synthetic route for prensil is as follows: ; Among them, 3'-acetamido-2'-hydroxyacetophenone is a key intermediate in the synthesis of pranstar, and its cost greatly affects the material cost of pranstar.

[0004] Currently, there are many reported methods for synthesizing 3'-acetamido-2'-hydroxyacetophenone: Synthetic circuit 1: ; The literature *Applied and Environmental Microbiology*, 69(11):6520-6526, reports a method for preparing 3'-acetamido-2'-hydroxyacetophenone using a bio-enzymatic approach. This method uses m-nitroacetophenone to synthesize 3'-acetamido-2'-hydroxyacetophenone by lysing *Escherichia coli* cells to release a bio-enzyme, which then introduces a hydroxyl group at the ortho-position of m-nitroacetophenone. Although this method has simple post-processing, mild conditions, and low pollution, further research is needed before it can be applied to large-scale industrial production, and the bio-enzyme used in this method is relatively expensive.

[0005] Synthetic circuit 2: ; Chinese patent CN102060731A reports this relatively mature process. Using 4-chloro-2-aminophenol as a raw material, the process involves acylation, Fries rearrangement, and finally dechlorination to produce the target compound 3'-acetamido-2'-hydroxyacetophenone. This route offers high yields at each step, but the starting materials need to be prepared in-house, and the reduction / dechlorination steps utilize hydrogenation, requiring expensive catalysts. Therefore, the overall cost of this route is high.

[0006] Synthetic circuit three: ; Chinese patent CN114394908B reports a method for obtaining 3'-amino-2'-hydroxyacetophenone from o-hydroxyacetophenone via sulfonation, mixed acid nitration, hydrolysis to remove sulfonate groups, and iron powder reduction. This compound requires selective acylation to obtain the target product. While this method does not require noble metal-catalyzed hydrogenation, sulfonation, nitration, and iron powder reduction are all highly polluting steps, posing a significant environmental burden. Furthermore, practical repetition of this process reveals that the nitration product is essentially unextractable in water, hindering purification.

[0007] Synthesis Route 4: ; Chinese patent CN106995366A reports a method using o-aminophenol as a raw material, which, after acylation, yields 2-acetamidophenol acetate, which is then rearranged to obtain 3'-amino-2'-hydroxyacetophenone. This compound requires further selective acylation to obtain the target product. However, when titanium tetrachloride is added to N-methylpyrrolidone, the system experiences violent exothermic reactions, producing a large amount of white fumes, posing a safety hazard to production.

[0008] Therefore, developing a preparation method that is simple to operate, low in cost, and has a high yield is of great research significance and practical application value. Summary of the Invention

[0009] In view of the above-mentioned problems in the prior art, this application provides a method for preparing 3'-acetamido-2'-hydroxyacetophenone, which is simple to operate, has a high yield, low material cost, and is suitable for industrial production.

[0010] To address the above problems, the present invention provides the following technical solution: A method for preparing 3'-acetamido-2'-hydroxyacetophenone, the synthetic route of which is as follows: .

[0011] In one embodiment of this application, a method for preparing 3'-acetamido-2'-hydroxyacetophenone includes the following steps: S1. Under weakly acidic conditions, o-aminophenol and trimethyl orthoacetate undergo a cyclization condensation reaction to give 2-methylbenzoxazole; S2. Under the action of a catalyst, 2-methylbenzoxazole and acetic anhydride undergo a Friedel-Crafts acylation reaction to give 1-(2-methyl-1,3-benzoxazole-7-yl)-1-ethyl ketone. S3, 1-(2-methyl-1,3-benzoxazol-7-yl)-1-ethyl ketone undergoes a ring-opening reaction under acidic conditions to produce 3'-acetamido-2'-hydroxyacetophenone.

[0012] In one embodiment of this application, in step S1, the weak acid condition is selected from acetic acid, formic acid, ammonium chloride, trimethylamine hydrochloride, triethylamine hydrochloride, and pyridine hydrochloride.

[0013] In one embodiment of this application, in step S1, the weakly acidic condition is selected from ammonium chloride.

[0014] In one embodiment of this application, in step S1, the equivalent ratio of o-aminophenol, trimethyl orthoacetate, and ammonium chloride is 1.0:1.0~1.50:0.10~0.20.

[0015] In one embodiment of this application, in step S1, the equivalent ratio of o-aminophenol, trimethyl orthoacetate, and ammonium chloride is 1.0:1.05:0.15.

[0016] In one embodiment of this application, the reaction temperature in step S1 is 20~50°C.

[0017] In one embodiment of this application, the reaction time in step S1 is 2-4 hours.

[0018] In one embodiment of this application, in step S2, the catalyst is selected from one of anhydrous aluminum trichloride, concentrated sulfuric acid, anhydrous ferric chloride, anhydrous zinc chloride, boron trifluoride ether, and titanium tetrachloride.

[0019] In one embodiment of this application, in step S2, the solvent is selected from one of dichloromethane, dichloroethane, chlorobenzene, o-dichlorobenzene, and 1,1,2,2-tetrachloroethane.

[0020] In one embodiment of this application, in step S2, the catalyst is selected from anhydrous aluminum trichloride.

[0021] In one embodiment of this application, in step S2, the equivalent ratio of 2-methylbenzoxazole to acetic anhydride is 1.0:1.0~1.5.

[0022] In one embodiment of this application, in step S2, the equivalent ratio of acetic anhydride to anhydrous aluminum trichloride is 1.0:2.0.

[0023] In one embodiment of this application, in step S2, the reaction temperature of the Friedel-Crafts acylation reaction is 100~150°C.

[0024] In one embodiment of this application, in step S2, the reaction temperature of the Friedel-Crafts acylation reaction is 120~130°C.

[0025] In one embodiment of this application, in step S2, the reaction time of the Friedel-Crafts acylation reaction is 2-4 h.

[0026] In one embodiment of this application, in step S3, the acid is selected from trifluoroacetic acid, concentrated sulfuric acid, hydrogen chloride gas, and anhydrous aluminum chloride.

[0027] In one embodiment of this application, in step S3, the acid is selected from trifluoroacetic acid.

[0028] In one embodiment of this application, in step S3, the equivalent ratio of 1-(2-methyl-1,3-benzoxazol-7-yl)-1-ethyl ketone to trifluoroacetic acid is 1.0:1.0~1.50.

[0029] In one embodiment of this application, in step S3, the equivalent ratio of 1-(2-methyl-1,3-benzoxazol-7-yl)-1-ethyl ketone to trifluoroacetic acid is 1.0:1.05.

[0030] In one embodiment of this application, in step S3, 1-(2-methyl-1,3-benzoxazol-7-yl)-1-ethyl ketone and trifluoroacetic acid are reacted overnight at -20~30°C.

[0031] Compared with the prior art, the beneficial effects of this application are as follows: This application uses o-aminophenol and trimethyl orthoacetate as raw materials to prepare 3'-acetamido-2'-hydroxyacetophenone via cyclization condensation, Friedel-Crafts acylation, and ring-opening reactions. The method described in this application is simple to operate, has a high yield, and low material costs, making it suitable for industrial production. Attached Figure Description

[0032] Figure 1 The NMR spectrum of target compound 1 obtained in Example 3; Figure 2 The chromatogram is of target compound 1 obtained in Example 3. Detailed Implementation

[0033] The technical solutions in the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments.

[0034] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of the particular range. The range defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range.

[0035] Unless otherwise stated, when this invention relates to percentages between liquids, it is volume / volume percentage; when this invention relates to percentages between liquids and solids, it is volume / weight percentage; when this invention relates to percentages between solids and liquids, it is weight / volume percentage; the rest are weight / weight percentage.

[0036] Example 1: Preparation of Intermediate 2 In a 500 mL flask, 100 mL of water, 10.0 g (110.11, 0.091 mol, 1.0 eq) of o-aminophenol, 0.72 g (53.49, 0.0136 mol, 0.15 eq) of ammonium chloride, and 11.48 g (120.15, 0.096 mol, 1.05 eq) of trimethyl orthoacetate were added. The mixture was heated to 40 °C and reacted for 3 h. The temperature was lowered to 20 °C, and ethyl acetate (3 × 50 mL) was added for extraction. The extracts were combined. The mixture was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oily substance. Heptane was added and the mixture was stirred for 2 h. The mixture was filtered and dried to obtain 11.07 g of an off-white solid, with a yield of 91.4%.

[0037] Example 2 Preparation of Intermediate 3 In a 250 mL flask, add 55 mL of o-dichlorobenzene and 19.2 g (0.14 mol, 2.6 eq) of aluminum trichloride, stir and cool to 5 °C. Slowly add 7.35 g (0.072 mol, 1.3 eq) of acetic anhydride, stir at 5-10 °C for 0.5 h, and then slowly raise the temperature to 120 °C. Dissolve 7.38 g (0.055 mol, 1.0 eq) of intermediate 2 (CAS No.: 95-21-6) in 30 mL of o-dichlorobenzene, and add it dropwise to the above mixture. Maintain the temperature at 120-130 °C and react at this temperature for 2.5 h. Cool to 10 °C, pour the black liquid into 200 g of crushed ice, and stir to dissolve. Filter, wash with plenty of water to obtain a brown solid, and dry. Add the dried solid to 75 mL of dichloroethane, heat to dissolve, decolorize with activated carbon, and filter hot. The filtrate was concentrated to about 1 / 3 of its volume, cooled to 5°C, filtered, and dried to give 7.64 g of a light brown solid, with a yield of 79.3%.

[0038] Example 3 Preparation of target compound 1 In a 250 mL flask, add 60 mL of tetrahydrofuran and 11.39 g (0.065 mol, 1.0 eq) of intermediate 3 (CAS No.: 952182-98-8), cool to 5 °C, and slowly add 7.78 g (0.068 mol, 1.05 eq) of trifluoroacetic acid. After the addition is complete, stir overnight at room temperature. Cool to 0-5 °C, and slowly add saturated sodium bicarbonate solution, keeping the temperature below 20 °C, while stirring for 1 h. Extract twice with ethyl acetate, combine the ethyl acetate extracts, wash with water, and dry. Concentrate under reduced pressure to obtain the crude product. Recrystallize from acetonitrile to obtain 10.82 g of an off-white solid, yield 86.2%, purity greater than 99%.

[0039] The present application has been described in detail above with reference to specific embodiments and exemplary examples. However, these descriptions should not be construed as limiting the present application. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and implementation methods of the present application without departing from the spirit and scope of the present application, and all such modifications and improvements fall within the scope of the present application.

Claims

1. A method for preparing 3'-acetamido-2'-hydroxyacetophenone, characterized in that, Includes the following steps: S1. Under weakly acidic conditions, o-aminophenol and trimethyl orthoacetate undergo a cyclization condensation reaction to give 2-methylbenzoxazole; S2. Under the action of a catalyst, 2-methylbenzoxazole and acetic anhydride undergo a Friedel-Crafts acylation reaction to give 1-(2-methyl-1,3-benzoxazole-7-yl)-1-ethyl ketone. S3, 1-(2-methyl-1,3-benzoxazol-7-yl)-1-ethyl ketone undergoes a ring-opening reaction under acidic conditions to produce 3'-acetamido-2'-hydroxyacetophenone.

2. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 1, characterized in that, In step S1, the weakly acidic condition is selected from one of acetic acid, formic acid, ammonium chloride, trimethylamine hydrochloride, triethylamine hydrochloride, and pyridine hydrochloride.

3. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 2, characterized in that, In step S1, the weakly acidic condition is selected from ammonium chloride; the equivalent ratio of o-aminophenol, trimethyl orthoacetate and ammonium chloride is 1.0:1.0~1.50:0.10~0.

20.

4. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 1, characterized in that, In step S1, the reaction temperature is 20~50℃.

5. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 1, characterized in that, In step S2, the catalyst is selected from one of anhydrous aluminum trichloride, concentrated sulfuric acid, anhydrous ferric chloride, anhydrous zinc chloride, boron trifluoride diethyl ether, and titanium tetrachloride; The solvent used is selected from one of dichloromethane, dichloroethane, chlorobenzene, o-dichlorobenzene, and 1,1,2,2-tetrachloroethane.

6. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 5, characterized in that, In step S2, the catalyst is selected from anhydrous aluminum trichloride; the equivalent ratio of 2-methylbenzoxazole to acetic anhydride is 1.0:1.0~1.5; and the equivalent ratio of acetic anhydride to anhydrous aluminum trichloride is 1.0:2.

0.

7. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 1, characterized in that, In step S2, the Friedel-Crafts acylation reaction is carried out at a temperature of 100-150°C for 2-4 hours.

8. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 1, characterized in that, In step S3, the acid is selected from one of trifluoroacetic acid, concentrated sulfuric acid, hydrogen chloride gas, and anhydrous aluminum chloride.

9. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 8, characterized in that, In step S3, the acid is selected from trifluoroacetic acid; the equivalent ratio of 1-(2-methyl-1,3-benzoxazol-7-yl)-1-ethyl ketone to trifluoroacetic acid is 1.0:1.0~1.

50.

10. The method for preparing 3'-acetamido-2'-hydroxyacetophenone according to claim 1, characterized in that, In step S3, the reaction temperature of the ring-opening reaction is -20~30℃.

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