Synthetic method of fenoprofen

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a synthesis method of fenoprofen. The method comprises the following steps: taking 3-hydroxyacetophenone and boric acid as raw materials, and carrying out Chan-Lam coupling reaction under the catalysis of copper acetate to generate 3-phenoxyacetophenone; the preparation method comprises the following steps: carrying out a Corey-Chaykovsky epoxidation reaction on 3-phenoxyacetophenone and a sulfur salt under an alkaline condition to obtain 2-methyl-2-(3-phenoxyphenyl) cyclohexane; the preparation method comprises the following steps: carrying out a Meinwald rearrangement reaction on ethylene oxide and Lewis acid or protonic acid to obtain 2-(3-phenoxy phenyl) propionaldehyde; the 2-(3-phenoxy phenyl) propionaldehyde is subjected to Pinnick oxidation under the condition of sodium hypochlorite, and finally the raceme fenoprofen is obtained. The fenoprofen is integrally prepared through four procedures, the process steps are simple, raw materials adopted in all the procedures are low in price and easy to obtain, the process is simple, products are easy to purify, the total yield is high, and industrial production is easy to achieve.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a synthesis method of fenoprofen. Background Art

[0002] Fenoprofen calcium tablets (FC) are phenylpropionic acid nonsteroidal anti-inflammatory analgesics developed by Lilly Company of the United States and approved for marketing by the US FDA in 1976. Its chemical name is 2-(3-phenoxyphenyl)propionic acid, and its structural formula is shown in Formula I below.

[0003]

[0004] Fenoprofen is clinically used to relieve acute and chronic rheumatoid arthritis, osteoarthritis, and mild to moderate pain. Animal experiments have shown that its anti-inflammatory effect is 50 times stronger than that of aspirin, and it has good oral absorption and little gastrointestinal irritation. It has been widely used abroad. At present, there are few reports on the synthesis of fenoprofen (Arkivoc (XV), 2005, 53-58; Rasayan J. Chem, 2021, 14, 1035-1040; CN106748726A), and there are some problems, such as the need to use highly toxic reagent sodium cyanide, harsh reaction conditions, and cumbersome reaction steps. Therefore, it is of great significance to study efficient, environmentally friendly, and simple new asymmetric synthesis methods. Summary of the invention

[0005] The technical problem to be solved by the present invention is to provide a new method for synthesizing the fenoprofen racemate in view of the deficiencies of the prior art.

[0006] In order to solve the above technical problems, the present invention discloses a synthesis method of fenoprofen, which comprises the following specific steps:

[0007] S1. 3-hydroxyacetophenone (Formula II) and boric acid (Formula III) are subjected to a Chan-Lam coupling reaction under the catalysis of copper acetate to generate 3-phenoxyacetophenone (Formula IV);

[0008] S2. subjecting 3-phenoxyacetophenone to a Corey-Chaykovsky epoxidation reaction with a sulfur salt under alkaline conditions to obtain 2-methyl-2-(3-phenoxyphenyl)cyclohexane (Formula V);

[0009] S3. subjecting 2-methyl-2-(3-phenoxyphenyl)cyclohexane to a Meinwald rearrangement reaction under acidic conditions to obtain 2-(3-phenoxyphenyl)propanal (Formula VI);

[0010] S4. 2-(3-phenoxyphenyl)propanal is subjected to Pinnick oxidation reaction under sodium hypochlorite conditions to obtain fenoprofen.

[0011] Preferably, the synthetic route of the fenoprofen is

[0012]

[0013] In S1, the molar ratio of the 3-hydroxyacetophenone to the boric acid is 1:(1-4); the molar ratio of the 3-hydroxyacetophenone to the copper acetate is 1:(1-4);

[0014] Preferably, the molar ratio of the 3-hydroxyacetophenone to boric acid is 1:2; the molar ratio of the 3-hydroxyacetophenone to copper acetate is 1:2;

[0015] More preferably, the boric acid is phenylboric acid.

[0016] In S1, the substrate in the Chan-Lam coupling reaction is pyridine; the molar ratio of 3-hydroxyacetophenone to pyridine is 1:(1-4);

[0017] Preferably, the molar ratio of 3-hydroxyacetophenone to pyridine is 1:2.

[0018] In S2, the molar ratio of the 3-phenoxyacetophenone to the sulfur salt is 1:(1-4); the sulfur salt includes trimethylsulfur iodide, trimethylsulfur bromide and trimethylsulfoxide bromide;

[0019] Preferably, the molar ratio of the 3-phenoxyacetophenone to the sulfur salt is 1:1.5; and the sulfur salt is trimethylsulfur bromide.

[0020] In S2, the base providing alkaline conditions in the Corey-Chaykovsky epoxidation reaction includes potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride and potassium tert-butoxide; the molar ratio of the 3-phenoxyacetophenone to the base is 1:(1-10);

[0021] Preferably, the base providing alkaline conditions in the Corey-Chaykovsky epoxidation reaction is sodium hydroxide; and the molar ratio of the 3-phenoxyacetophenone to the base is 1:3.

[0022] In S2, the temperature in the Corey-Chaykovsky epoxidation reaction is 0 to 80°C;

[0023] Preferably, in S2, the temperature in the Corey-Chaykovsky epoxidation reaction is 60°C.

[0024] In S3, the acid providing acidic conditions in the Meinwald rearrangement reaction is a Lewis acid or a protonic acid; the molar ratio of the 2-methyl-2-(3-phenoxyphenyl)cyclohexane to the acid is 1:(0.1-1);

[0025] Preferably, in S3, the molar ratio of the 2-methyl-2-(3-phenoxyphenyl)cyclohexane to the acid is 1:0.2; the acid comprises boron trifluoride ethyl etherate, cation exchange resin, p-toluenesulfonic acid monohydrate, pyridine p-toluenesulfonate, anhydrous p-toluenesulfonic acid and camphorsulfonic acid;

[0026] More preferably, the acid is boron trifluoride etherate.

[0027] In S4, the molar ratio of 2-(3-phenoxyphenyl)propanal to sodium hypochlorite is 1:(1-3);

[0028] Preferably, in S4, the molar ratio of 2-(3-phenoxyphenyl)propanal to sodium hypochlorite is 1:1.5.

[0029] In S4, the reactants of the Pinnick oxidation reaction also include potassium dihydrogen phosphate and isopentene; the molar ratio of the 2-(3-phenoxyphenyl)propanal to potassium dihydrogen phosphate is 1:(1-3); the molar ratio of the 2-(3-phenoxyphenyl)propanal to isopentene is 1:(1-4);

[0030] Preferably, in S4, the molar ratio of the 2-(3-phenoxyphenyl)propanal to potassium dihydrogen phosphate is 1:1.5; the molar ratio of the 2-(3-phenoxyphenyl)propanal to isopentene is 1:2.

[0031] In S4, the temperature of the Pinnick oxidation reaction is 0°C or room temperature;

[0032] Preferably, in S4, the temperature of the Pinnick oxidation reaction is 0°C.

[0033] Beneficial effects: The present invention prepares fenoprofen through a four-step process as a whole, the process steps are simple, and the raw materials used in each step are cheap and easily available. The process is simple, the product is easy to purify, the total yield is high, and industrial production is easy to achieve. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0035] Figure 1 This is the H NMR spectrum of fenoprofen prepared in the example of the present invention. DETAILED DESCRIPTION

[0036] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0037] Example 1: Synthesis of Fenoprofen

[0038] (1) Preparation of 3-phenoxyacetophenone (Compound IV)

[0039] The synthetic route is as follows:

[0040]

[0041] 200 ml of dichloromethane was added to a 500 ml round-bottom flask, and 10 g of 3-hydroxyacetophenone (Compound II), 17.7 g of phenylboric acid (Compound III), 26.9 g of copper acetate and 11.8 ml of pyridine were added in sequence. The mixture was reacted at room temperature for 72 hours. After the reaction was completed, the mixture was concentrated by vacuum distillation, dried, concentrated, and purified by silica gel column to obtain 13.9 g of Compound IV with a yield of 90%.

[0042] The NMR data of compound IV are as follows: 1 H NMR (400MHz, CDCl3) δ7.70–7.66(m,1H),7.58(dd,J=2.5,1.6Hz,1H),7.43(t,J=7.9Hz,1H),7.36(dd,J =8.7,7.4Hz,2H),7.21(ddd,J=8.2,2.6,1.1Hz,2H),7.17–7.12(m,1H),7.02(dd,J=8.7,1.1Hz,2H),and 2.58(s,3H).

[0043] (2) Preparation of 2-methyl-2-(3-phenoxyphenyl)cyclohexane (Compound V)

[0044] The synthetic route is as follows:

[0045]

[0046] In a 1-liter round-bottom flask, 100 ml of dimethyl sulfoxide and 100 ml of tetrahydrofuran were added, followed by 3.4 g of sodium hydride and 29 g of trimethylsulfide iodide. The mixture was reacted at room temperature for 10 minutes. 12 g of compound IV was dissolved in a mixed solution of 50 ml of dimethyl sulfoxide and 50 ml of tetrahydrofuran, added to the reaction flask, and reacted at room temperature for 23 hours. After the reaction was completed, 200 ml of water was added to quench the mixture, and the mixture was extracted three times with 300 ml of dichloromethane, dried, concentrated, and purified by silica gel column to obtain 11 g of compound V with a yield of 86%.

[0047] (3) Preparation of 2-(3-phenoxyphenyl)propanal (Compound VI)

[0048] The synthetic route is as follows:

[0049]

[0050] 100 ml of tetrahydrofuran and 10 g of compound V were added to a 500 ml round-bottom flask, and 13.6 ml of boron trifluoride ether was added under nitrogen protection. The reaction was allowed to react at room temperature for 40 minutes. After the reaction was completed, 100 ml of saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted three times with 450 ml of dichloromethane, dried, concentrated, and purified by silica gel column to obtain 8.6 g of compound VI with a yield of 85%.

[0051] The NMR data of compound VI are as follows: 1 H NMR(400MHz, CDCl3)δ9.68(d,J=1.4Hz,1H),7.39–7.33(m,3H),7.16–7.10(m,1H),7.0 6–6.99(m,2H),6.97–6.91(m,2H),6.90–6.88(m,1H),3.61(qd,J=7.1,1.6Hz,1H),and 1.43(d,J=7.1Hz,3H).

[0052] (4) Preparation of Fenoprofen (Compound I)

[0053] The synthetic route is as follows:

[0054]

[0055] 1 g of compound VI was added to a 100 ml round-bottom flask, 15 ml of tert-butanol and 5 ml of water were added as a reaction mixed solvent, 0.98 ml of isopentene, 0.90 g of potassium dihydrogen phosphate and 0.60 g of sodium chlorite were added in sequence at room temperature, and the reaction was carried out at room temperature for 1.5 hours. After the reaction was completed, 30 ml of water was added to quench, and the mixture was extracted three times with 30 ml of ethyl acetate, dried, concentrated, and separated and purified by silica gel column to obtain 0.89 g of fenoprofen (compound I) with a yield of 84%.

[0056] The NMR data of fenoprofen (Compound I) are as follows: 1 H NMR (400MHz, CDCl3) δ7.34 (dd, J=8.6, 7.4Hz, 2H), 7.28 (t, J=7.9Hz, 1H), 7.14–7.09 (m, 1H), 7.06(dt,J=7.7,1.3Hz,1H),7.03–7.01(m,2H),7.01–7.00(m,1H),3.72(q,J=7.2Hz,1H),and 1.50(d,J=7.2Hz,3H).

[0057] Example 2: Synthesis of Fenoprofen

[0058] Compared with Example 1, the preparation method of compound V in Example 2 is different, and the other steps are the same, wherein the specific preparation method of compound V is:

[0059] The synthetic route is as follows:

[0060]

[0061] In a 500 ml round-bottom flask, add 100 ml of acetonitrile, and then add 7.5 g of sodium hydroxide, 14.7 g of trimethylsulfur bromide and 0.3 ml of water. React at room temperature for 10 minutes. Dissolve 13.2 g of compound IV in 100 ml of acetonitrile and add to the reaction flask. React at 60°C for 3 hours. After the reaction is completed, add 200 ml of ethyl acetate to dilute, filter, dry, concentrate, and separate and purify by silica gel column to obtain 12.5 g of compound V with a yield of 89%.

[0062] The NMR data of compound V are as follows: 1 H NMR(400MHz, CDCl3)δ7.35(dd,J=8.7,7.4Hz,2H),7.30(t,J=7.9Hz,1H),7.14–7.11(m,1H),7.07– 7.05(m,2H),7.01(dd,J=8.7,1.1Hz,1H),6.91(ddd,J=8.1,2.5,1.1Hz,1H),3.03–2.70(m,2H),and 1.71(s,3H).

[0063] Example 3: Synthesis of Fenoprofen

[0064] Compared with Example 1, the preparation method of Compound I in Example 3 is different, and the other steps are the same, wherein the specific method for preparing Compound I is:

[0065] 8.6 g of compound VI was added to a 500 ml round-bottom flask, 150 ml of tert-butanol and 50 ml of water were added as a reaction mixed solvent, 8.5 ml of isopentene, 7.8 g of potassium dihydrogen phosphate and 5.2 g of sodium chlorite were added in turn under ice bath conditions, and the reaction was carried out at room temperature for 1.5 hours. After the reaction was completed, 150 ml of water was added to quench, and the mixture was extracted three times with 45 ml of ethyl acetate, dried, concentrated, and separated and purified by silica gel column to obtain 8.8 g of fenoprofen (compound I) with a yield of 96%.

[0066] The present invention provides a method for synthesizing fenoprofen. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. A method for synthesizing fenoprofen, characterized in that: The specific steps are: S1. 3-hydroxyacetophenone and boric acid are subjected to a Chan-Lam coupling reaction catalyzed by copper acetate to generate 3-phenoxyacetophenone; S2. subjecting 3-phenoxyacetophenone to a Corey-Chaykovsky epoxidation reaction with a sulfur salt under alkaline conditions to obtain 2-methyl-2-(3-phenoxyphenyl)cyclohexane; S3. subjecting 2-methyl-2-(3-phenoxyphenyl)cyclohexane to a Meinwald rearrangement reaction under acidic conditions to obtain 2-(3-phenoxyphenyl)propanal; S4. 2-(3-phenoxyphenyl)propanal is subjected to Pinnick oxidation reaction under sodium hypochlorite conditions to obtain fenoprofen.

2. The synthesis method according to claim 1, characterized in that In S1, the molar ratio of the 3-hydroxyacetophenone to boric acid is 1:(1-4); the molar ratio of the 3-hydroxyacetophenone to copper acetate is 1:(1-4).

3. The synthesis method according to claim 1, characterized in that In S1, the substrate in the Chan-Lam coupling reaction is pyridine; the molar ratio of 3-hydroxyacetophenone to pyridine is 1:(1-4).

4. The synthesis method according to claim 1, characterized in that In S2, the molar ratio of the 3-phenoxyacetophenone to the sulfur salt is 1:(1-4); the sulfur salt includes trimethylsulfur iodide, trimethylsulfur bromide and trimethylsulfoxide bromide.

5. The synthesis method according to claim 1, characterized in that In S2, the base providing alkaline conditions in the Corey-Chaykovsky epoxidation reaction includes potassium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride and potassium tert-butoxide; the molar ratio of the 3-phenoxyacetophenone to the base is 1:(1-10).

6. The synthesis method according to claim 5, characterized in that In S2, the temperature in the Corey-Chaykovsky epoxidation reaction is 0 to 80°C.

7. The synthesis method according to claim 1, characterized in that In S3, the acid providing acidic conditions in the Meinwald rearrangement reaction is a Lewis acid or a protonic acid; and the molar ratio of the 2-methyl-2-(3-phenoxyphenyl)cyclohexane to the acid is 1:(0.1-1).

8. The synthesis method according to claim 1, characterized in that In S4, the molar ratio of 2-(3-phenoxyphenyl)propanal to sodium hypochlorite is 1:(1-3).

9. The synthesis method according to claim 1, characterized in that In S4, the reactants of the Pinnick oxidation reaction also include potassium dihydrogen phosphate and isopentene; the molar ratio of the 2-(3-phenoxyphenyl)propanal to potassium dihydrogen phosphate is 1:(1-3); the molar ratio of the 2-(3-phenoxyphenyl)propanal to isopentene is 1:(1-4).

10. The synthesis method according to claim 9, characterized in that In S4, the temperature of the Pinnick oxidation reaction is 0°C or room temperature.

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