Synthesis method of (4-chlorphenyl) (4-hydroxy-3, 5-dimethoxyphenyl) ketone

Abstract

The invention relates to a synthesis method of (4-chlorphenyl) (4-hydroxy-3, 5-dimethoxyphenyl) ketone, belongs to the field of organic chemical synthesis, and provides a method for solving the problems of high cost, low yield and more byproducts in the existing preparation method, and the method comprises the following steps: 1) reacting a compound shown as a formula I with an acyl chloride substance under the protection of nitrogen to obtain a compound II; 2) mixing the compound shown in the formula II with alkali, dropwise adding a Grignard reagent, and carrying out Grignard reaction to obtain a compound shown in a formula III; and 3) demethylating the compound in the formula III under the action of Lewis acid to obtain a compound in a formula IV. The technical scheme provided by the invention has the beneficial effects that the method for synthesizing (4-chlorphenyl) (4-hydroxy-3, 5-dimethoxyphenyl) ketone is novel in process route, the total yield is greater than 50%, and the method has the characteristics of short route, high chemical purity, easiness in production and the like.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone. Background Art

[0002] (4-Chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone is a key intermediate in the formation of ethers with antitussive (anti-cough) activity.

[0003] Currently, there is one main synthetic route for this intermediate, as shown in the figure below. This route first prepares the Grignard reagent, which then undergoes a Grignard reaction with the corresponding benzaldehyde compound; then it is oxidized under the action of oxygen to generate the corresponding benzophenone compound, which is then demethylated under the action of sulfuric acid, and finally reacts with the corresponding morpholine compound to form ethers with antitussive (anti-cough) activity.

[0004]

[0005] The starting material trialkylbenzaldehyde used in the first step of this route is relatively expensive, which will lead to high product costs; in the third step of oxidation, O2 is used as an oxidant, which poses a great safety hazard and is not conducive to industrialization. At the same time, oxidation generates a large number of by-products, resulting in a low yield; in addition, in the fourth step of demethylation, a strong acidic reagent sulfuric acid is used, which has poor selectivity, resulting in a large number of by-products, difficult purification, low yield and affected product quality;

[0006] In summary, the development of the pharmaceutical industry requires pharmaceutical intermediates such as (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone, but its current synthesis method still has much room for improvement. Summary of the invention

[0007] The present invention aims to improve the problems of low safety, low yield and difficulty in obtaining high-purity products in the existing route, and provides a new method for synthesizing (4-chlorophenyl) (4-hydroxy-3,5-dimethoxyphenyl) ketone. Specifically, the method comprises the following reaction steps:

[0008] 1) reacting the compound of formula I with an acyl chloride substance under nitrogen protection, keeping the temperature at 70-90° C. to generate a compound of formula II, in a molar ratio of compound of formula I: acyl chloride substance = 1:1.5-9; removing the unreacted acyl chloride substance, washing, and drying to obtain compound II;

[0009] The acyl chloride compound can be selected from oxalyl chloride, thionyl chloride, etc., preferably thionyl chloride.

[0010] Step 1) After the reaction is completed, unreacted thionyl chloride is removed by distillation under reduced pressure, and then n-heptane is added for pulping and filtration. The filter cake is washed with n-heptane and dried to obtain compound II, which can improve the purity of compound II.

[0011] 2) Mixing the compound of formula II and a base, controlling the temperature to -10-15°C, adding a Grignard reagent dropwise for a Grignard reaction, stirring, and obtaining a compound of formula III, in which the molar ratio of compound of formula II: Grignard reagent: base is 1:0.8-1.2:1-2;

[0012] The Grignard reagent is 4-chlorophenylmagnesium chloride, 4-chlorophenylmagnesium bromide, 4-chlorophenylmagnesium iodide and lithium chloride complex thereof, preferably 4-chlorophenylmagnesium bromide and complex thereof; the base is ethylenediamine, tetramethylethylenediamine, NMP (N-methylpyrrolidone) and the like, preferably tetramethylethylenediamine;

[0013] Step 2) After the reaction is completed, the reaction solution is poured into an ammonium chloride solution to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, crystallized with ethyl acetate / n-heptane, and dried to obtain a compound of formula III.

[0014] 3) The compound of formula III is demethylated under the action of Lewis acid, and the reaction is carried out under nitrogen protection at 10-30° C. with stirring to obtain the compound of formula IV, in which the molar ratio of compound of formula III to Lewis acid is 1:1-4;

[0015] The Lewis acid is aluminum chloride, zinc chloride and / or ferric chloride, preferably aluminum chloride.

[0016] Step 3) After the reaction is completed, the reaction solution is poured into a 2N hydrochloric acid solution to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated, MTBE (methyl tert-butyl ether) is added to the solid, pulped and filtered, and dried to obtain compound IV.

[0017]

[0018] The specific technical solutions are as follows:

[0019] 1) Add thionyl chloride (9 eq) and compound of formula I (1 eq) to a reaction kettle; then heat to 75° C. under nitrogen protection, keep warm for 5 hours, and then remove unreacted thionyl chloride by distillation under reduced pressure; then add n-heptane (2 vol), beat and filter, wash the filter cake with n-heptane (1 vol), and dry to obtain compound II;

[0020] 2) Add the compound of formula II (1 eq), tetrahydrofuran (6 vol), and tetramethylethylenediamine (1.3 eq) to the reaction kettle, control the temperature to -10-0°C, add 4-chlorophenylmagnesium bromide (0.8 eq) dropwise, and stir for 2 hours after the addition is complete; pour the reaction solution into an ammonium chloride solution to quench, extract with ethyl acetate, and then dry over anhydrous sodium sulfate and concentrate, crystallize with ethyl acetate / n-heptane, and dry to obtain the compound of formula III;

[0021] 3) Add the compound of formula III (1 eq) to the reaction kettle, add dichloromethane (10 vol), then drop the temperature to 10-20°C under nitrogen protection, add aluminum chloride (3 eq) in batches, and stir for 5 h after the addition. Pour the reaction solution into 2N hydrochloric acid solution to quench, extract with dichloromethane (5 vol), dry over anhydrous sodium sulfate and concentrate, add MTBE (3 vol) to the solid, slurry and filter, and dry to obtain compound IV.

[0022] The synthesis method of the invention is used to synthesize (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone, the process route is novel, the total yield is greater than 50%, and the method has the characteristics of short route, high chemical purity and easy production.

[0023] The beneficial effects brought by the technical solution of the present invention are as follows: a method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone of the present invention has a novel process route, a total yield of more than 50%, and has the characteristics of a short route, high chemical purity, and easy production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the HPLC spectrum of Example 1;

[0025] Figure 2 is the H-NMR spectrum of Example 1;

[0026] Figure 3 It is the HPLC spectrum of Example 2;

[0027] Figure 4 is the H-NMR spectrum of Example 2;

[0028] Figure 5 The HPLC spectrum of Example 3 is shown below:

[0029] Figure 6 is the H-NMR spectrum of Example 3; DETAILED DESCRIPTION

[0030] Example 1

[0031] S1: Preparation of Compound II

[0032] Add 400 mL of thionyl chloride and 100 g of the compound of formula I to the reactor, heat to 75° C. under nitrogen protection, keep warm for 5 hours, concentrate the excess thionyl chloride under reduced pressure, slurry the crude product with 200 mL of n-heptane, filter, and dry to obtain 106.5 g of compound II with a yield of 98%.

[0033] S2: Preparation of Compound III

[0034] In a three-necked flask, add 106.5g of compound II and 745mL of THF, cool to -10-0℃, add 70g of tetramethylethylenediamine, stir for 10min after adding, control the temperature at -10-0℃ and add 416mL of 4-chlorophenylmagnesium bromide solution, stir for 2h after adding, pour the reaction solution into ammonium chloride solution, separate the liquids, extract with EA, dry and concentrate with sodium sulfate, and crystallize with ethyl acetate / n-heptane to obtain 92g of compound III with a yield of 65%.

[0035] S3: Preparation of Compound IV

[0036] In a three-necked flask, add 80g of compound III, add 800mL of dichloromethane, cool down 10-20℃, add 104g of aluminum chloride in batches, stir at 20-30℃ for 3h after addition, pour the reaction solution into pre-cooled 2N hydrochloric acid, extract the aqueous phase with 400mL of dichloromethane, wash with 400mL of saturated brine, dry with anhydrous sodium sulfate, filter and concentrate the organic phase to form a solid, and slurry with 240mL of methyl tert-butyl ether to obtain 64.9g of compound IV, with a yield of 86.5% and a total yield of 55%.

[0037] Figure 1-Figure 2 They are HPLC spectrum and H-NMR spectrum respectively. It can be seen from the figures that the HPLC purity is 99.53%, the maximum unknown single impurity is ≤0.10%, and the structure is correct as identified by NMR.

[0038] Example 2

[0039] S1: Preparation of Compound II

[0040] Add 400 mL of oxalyl chloride and 100 g of compound I to the reactor, raise the temperature to 75°C under nitrogen protection, and react for 5 hours. Concentrate the excess oxalyl chloride under reduced pressure, slurry the crude product with 200 mL of n-heptane, filter, and dry to obtain 106 g of compound II with a yield of 98%.

[0041] S2: Preparation of Compound III

[0042] In a three-necked flask, add 104g of compound II and 745mL of THF, cool to -10-0℃, add 68g of tetramethylethylenediamine, stir for 10min after adding, control the temperature at -10-0℃ and add 406mL of 4-chlorophenylmagnesium chloride solution, stir for 2h after adding, pour the reaction solution into ammonium chloride solution, separate the liquids, extract with EA, dry and concentrate with sodium sulfate, and crystallize with ethyl acetate / n-heptane to obtain 87g of compound III with a yield of 62%.

[0043] S3: Preparation of Compound IV

[0044] In a three-necked flask, add 80g of compound III and 800mL of dichloromethane, cool down by 10-20℃, add 127g of ferric chloride in batches, stir at 20-30℃ for 3h after the addition, pour the reaction solution into pre-cooled 2N hydrochloric acid, extract the aqueous phase with 400mL of dichloromethane, wash with 400mL of saturated brine, dry with anhydrous sodium sulfate, filter and concentrate the organic phase to form a solid, and slurry with 240mL of methyl tert-butyl ether to obtain 64g of compound IV with a yield of 85.7% and a total yield of 52%.

[0045] Figure 3-Figure 4 They are HPLC spectrum and H-NMR spectrum respectively. It can be seen from the figures that the HPLC purity is 99.51%, the maximum unknown single impurity is ≤0.10%, and the structure is correct as identified by NMR.

[0046] Example 3

[0047] S1: Preparation of Compound II

[0048] Add 400 mL of thionyl chloride and 100 g of the compound of formula I to the reactor, raise the temperature to 75°C under nitrogen protection, and react for 5 hours. Concentrate the excess thionyl chloride under reduced pressure, slurry the crude product with 200 mL of n-heptane, filter, and dry to obtain 107 g of compound II.

[0049] S2: Preparation of Compound III

[0050] In a three-necked flask, add 107g of compound II and 745mL of THF, cool to -10-0℃, add 61g of ethylenediamine, stir for 10min after adding, control the temperature at -10-0℃ and add 416mL of 4-chlorophenylmagnesium bromide solution, stir for 2h after adding, pour the reaction solution into ammonium chloride solution, separate the liquids, extract with EA, dry and concentrate with sodium sulfate, and crystallize with ethyl acetate / n-heptane to obtain 86.4g of compound III with a yield of 61%.

[0051] S3: Preparation of Compound IV

[0052] In a three-necked flask, add 70g of compound III and 800mL of dichloromethane, cool down by 10-20℃, add 93g of zinc chloride in batches, stir at 20-30℃ for 3h after the addition, pour the reaction solution into pre-cooled 2N hydrochloric acid, extract the aqueous phase with 400mL of dichloromethane, wash with 400mL of saturated brine, dry with anhydrous sodium sulfate, filter and concentrate the organic phase to form a solid, and slurry with 240mL of methyl tert-butyl ether to obtain 56g of compound IV with a yield of 85% and a total yield of 50.8%.

[0053] Figure 5-Figure 6 They are HPLC spectrum and H-NMR spectrum respectively. It can be seen from the figures that the HPLC purity is 99.52%, the maximum unknown single impurity is ≤0.24%, and the structure is correct as identified by NMR.

Claims

1. A method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)ketone, characterized in that: The synthetic method comprises the following steps: 1) reacting the compound of formula I with an acyl chloride substance under nitrogen protection, keeping the temperature at 70-90° C. to generate a compound of formula II, wherein the molar ratio of the compound of formula I to the acyl chloride substance is 1:1.5-9; removing the unreacted acyl chloride substance, washing, and drying to obtain compound II; 2) Mixing the compound of formula II and a base, controlling the temperature to -10-15°C, adding a Grignard reagent dropwise for a Grignard reaction, stirring, and obtaining a compound of formula III, wherein the molar ratio of the compound of formula II: the Grignard reagent: the base is 1:0.8-1.2:1-2; 3) The compound of formula III is demethylated under the action of Lewis acid, and the reaction is carried out under nitrogen protection at 10-30°C with stirring to obtain the compound of formula IV, wherein the molar ratio of the compound of formula III to the Lewis acid is 1:1-4.

2. The method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone according to claim 1, characterized in that: The acyl chloride compound in step 1) is oxalyl chloride and / or thionyl chloride.

3. The method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone according to claim 1, characterized in that: Step 1) After the reaction is completed, unreacted acyl chloride substances are removed by distillation under reduced pressure, and then n-heptane is added for pulping and filtration. The filter cake is washed with n-heptane and dried to obtain the compound of formula II.

4. The method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone according to claim 1, characterized in that: The Grignard reagent in step 2) is 4-chlorophenylmagnesium chloride, 4-chlorophenylmagnesium bromide, 4-chlorophenylmagnesium iodide and / or lithium chloride complex.

5. The method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone according to claim 1, characterized in that: Step 2) After the reaction is completed, the reaction solution is poured into an ammonium chloride solution to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, crystallized with ethyl acetate / n-heptane, and dried to obtain a compound of formula III.

6. The method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone according to claim 1, characterized in that: The base in step 2) is ethylenediamine, tetramethylethylenediamine and / or NMP.

7. The method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone according to claim 1, characterized in that: The Lewis acid in step 3) is aluminum chloride, zinc chloride and / or ferric chloride.

8. The method for synthesizing (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone according to claim 1, characterized in that: Step 3) After the reaction is completed, the reaction solution is poured into a 2N hydrochloric acid solution to quench, extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated, MTBE is added to the solid to pulp and filter, and dried to obtain compound IV.

9. A (4-chlorophenyl) (4-hydroxy-3,5-dimethoxyphenyl) ketone, characterized in that The (4-chlorophenyl)(4-hydroxy-3,5-dimethoxyphenyl)methanone is synthesized by the method described in any one of claims 1 to 8.

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