Method for preparing clopidogrel by using sulfur hexafluoride

Abstract

The invention discloses a method for preparing clopidogrel by using sulfur hexafluoride, which comprises the following steps: taking methanol and (S)-(2-chlorphenyl)-6, 7-dihydrothiophene [3, 2-C] pyridine-5 (4H)-acetic acid as raw materials, taking an alkaline substance as an additive, and reacting in a solvent in the presence of sulfur hexafluoride, a photocatalyst and illumination to obtain the clopidogrel. According to the method disclosed by the invention, SF6 is activated under a photocatalytic condition, and an esterification reaction of carboxylic acid is realized by utilizing an SF6 decomposition product to prepare clopidogrel; wherein the decomposition product of SF6 is used as a condensation reagent, the greenhouse gas SF6 is effectively activated by the method, carboxylic acid esterification is realized by fully utilizing the decomposition product of SF6, clopidogrel is prepared, and the SF6 is turned into wealth from waste; the raw materials required by the method are simple and easy to obtain, the reaction conditions are simple and convenient, and the method is green and energy-saving and has higher application value.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing clopidogrel by using sulfur hexafluoride. Background Art

[0002] As a common group, ester group is widely present in many drug molecules. It can not only increase the lipophilicity of drugs, but also is a necessary structure-effect group in many drug molecules. Ester compounds are also an important class of chemical products in the chemical industry and indispensable in our lives. Ester compounds are also an important class of solvents. They play a very obvious role in dissolving cellulose and also play a very important role in the field of food additives and spices. Therefore, promoting the condensation esterification reaction of alcohol and carboxylic acid has important use value. At present, the methods of esterification are:

[0003] Method 1: Fischer-Speier esterification reaction is the most classic esterification reaction. Under the action of acidic catalysts (sulfuric acid, sulfonic acid, phosphoric acid, hydrochloric acid, etc.), carboxylic acid and alcohol undergo a reversible reaction to generate ester compounds. Because it is a reversible reaction, it is often necessary to add an excess of one of the raw materials, or use a Dean-Stark device to remove water.

[0004]

[0005] This method uses an acidic catalyst, which has the characteristics of high catalytic activity, low price and easy preparation. However, the disadvantage is that the yield in the esterification of secondary and tertiary alcohols is low and the raw materials are wasted (or additional equipment is required to remove water).

[0006] Method 2: Esterification reaction catalyzed by N,N-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine

[0007]

[0008] This method has the advantages of mild reaction conditions, high yield, good selectivity, etc., but it produces dicyclohexylurea as a by-product and the post-processing is cumbersome.

[0009] Method 3: Use elemental iodine alone to catalyze the esterification reaction of carboxylic acid and alcohol.

[0010]

[0011] The advantages of this reaction system are simple operation, non-toxicity, strong applicability, relatively mild conditions and high yield; however, the post-processing is complicated and the reactant alcohol is in excess, resulting in great waste.

[0012] Therefore, there is still a need to develop a carboxylic acid esterification method that has simple and readily available raw materials, simple operation, high reaction yield, good functional group tolerance, environmental friendliness, and is easy to promote in industrial production.

[0013] And for the following reasons: SF6 gas is a colorless, odorless, non-toxic, non-combustible, non-corrosive gas at room temperature and pressure. It is an inert gas with high stability. It does not decompose at high temperatures of 500-600°C, and does not react with acids, alkalis, water, etc. It is also an insulating gas with excellent insulating properties. The gas can adsorb free discrete electrons in the electric field, effectively reducing ionization collisions in the gas, which actually has an insulating effect and can be used to eliminate high-voltage arcs. Therefore, SF6 is widely used in the power sector, but SF6 has a strong greenhouse effect, and its climate warming power is 23,900 times that of CO2. Secondly, because SF6 is an artificially synthesized gas with quite stable chemical properties, SF6 is extremely difficult to decompose, and its natural lifespan in the atmosphere can be as long as more than 3,000 years. With continuous accumulation in the atmosphere, the greenhouse effect it brings is also continuously increasing. SF6 is currently subject to strict emission restrictions, and the treatment of large amounts of SF6 stored in the power sector faces difficulties.

[0014] SF6 itself has a high potential for utilization. One SF6 molecule contains one sulfur atom and six fluorine atoms. The decomposition products of SF6 contain high-valent sulfur-fluorine intermediates, which can be used as condensation reagents in the field of organic synthesis.

[0015] Clopidogrel is an original drug developed by Sanofi, France, and is usually used as an antithrombotic drug. Mechanistically, clopidogrel is an adenosine diphosphate inhibitor that can bind to the P2Y12 receptor on platelets and inhibit the release of the first messenger ADP, thereby reducing platelet aggregation and preventing thrombosis. It is a chiral drug molecule that can be prepared by preparing racemic clopidogrel and splitting it to obtain a pure product, or by chiral splitting the raw materials and then synthesizing clopidogrel in steps.

[0016] The Chinese patent application document with publication number CN117865981A discloses a high-purity clopidogrel hydrogen sulfate and its preparation method. Specifically comprising: step S1: reacting (+)-α-(2-thienylethylamino)-2-(2-chlorobenzene) acetic acid methyl ester hydrochloride and formaldehyde in an acidic organic solvent; after the reaction is completed, adding an extraction solvent and a sodium carbonate solution for extraction, collecting the organic phase for washing, drying, and concentrating to obtain clopidogrel base; step S2: adding a dissolving solvent to the clopidogrel base, stirring and dissolving, dripping concentrated sulfuric acid, heating and refluxing after solid precipitation, cooling and crystallizing, filtering, collecting the filter cake and drying to obtain clopidogrel hydrogen sulfate. The synthetic method provided by it has the beneficial effects of mild reaction conditions, low energy consumption, high reaction efficiency, low cost, etc., and is particularly suitable for industrial production of clopidogrel hydrogen sulfate products. And the intermediate product clopidogrel base and the product clopidogrel hydrogen sulfate obtained have the characteristics of high yield and high purity, which can meet the high quality requirements of pharmaceutical products, but its steps are complicated, which limits its application. Summary of the invention

[0017] The technical problem to be solved by the present invention is how to synthesize clopidogrel simply and safely.

[0018] The present invention solves the above technical problems through the following technical means:

[0019] A method for preparing clopidogrel using sulfur hexafluoride, which uses (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid and methanol as raw materials, uses an alkaline substance as an additive, and reacts in a solvent in the presence of sulfur hexafluoride, a photocatalyst and light to obtain the clopidogrel.

[0020] Preferably, the method for preparing clopidogrel using sulfur hexafluoride comprises the following steps: adding (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid and a photocatalyst into a reaction device, adding a solvent after evacuation, adding methanol and an alkaline substance after sulfur hexafluoride is introduced, placing the reaction system under light conditions for reaction, and obtaining the clopidogrel after post-treatment after the reaction is completed.

[0021] Preferably, the photocatalyst is an organic photocatalyst or a transition metal photocatalyst, or a mixture of both; and the alkaline substance is an organic base.

[0022] Preferably, the organic base is a tertiary amine, preferably N,N-diisopropylethylamine. When the base is N,N-diisopropylethylamine, the product yield is the highest.

[0023] Preferably, the photocatalyst is 4CZIPN, Mes-Acr + ClO4 —(9-mesityl-10-methylacridine perchlorate), Ir[dF(CF3)ppy]2(dtbbpy)PF6, a mixture of one or more of Ir(dtbbpy)ppy2PF6.

[0024] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0025] Preferably, the solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

[0026] Preferably, the solvent is tetrahydrofuran.

[0027] The present invention is carried out in a system with a single organic solvent; if necessary, other organic solvents may also be present in the system, but from the perspective of reaction yield and simplicity of operation, it is preferred not to add other organic solvents, that is, to use a single organic solvent as the reaction solvent.

[0028] Preferably, the molar ratio of methanol to (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 1:1 to 20:1.

[0029] Preferably, the molar ratio of methanol to (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 10:1.

[0030] Preferably, the molar ratio of the alkaline substance and (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 1:1 to 10:1; the molar ratio of the photocatalyst and (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 0.010:1 to 0.002:1; the dosage ratio of the (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid to the solvent is 0.5 to 0.1 mmol:1 mL.

[0031] Preferably, the molar ratio of the alkaline substance and (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 5:1; the molar ratio of the photocatalyst and (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 0.005:1; the dosage ratio of the (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid to the solvent is 0.17 mmol:1 mL, and the clopidogrel yield is the highest.

[0032] Preferably, the light source is blue light with a wavelength of 450 to 480 nm; the pressure of sulfur hexafluoride gas is 1 atm, the reaction temperature is 0 to 50° C., and the reaction time is 5 to 48 hours.

[0033] Preferably, the light source power of the illumination is 15W.

[0034] Preferably, the reaction temperature is room temperature and the reaction time is 20 hours.

[0035] Preferably, during the reaction, the sulfur hexafluoride gas pressure is 1 atm. When the pressure is 1 atm, the yield of clopidogrel is the highest.

[0036] The advantages of the present invention are:

[0037] The present invention uses methanol and (S)-(2-chlorophenyl)-6,7-dihydrothieno[3,2-C]pyridin-5(4H)-acetic acid ((S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetic acid) which are easily available as reaction substrates, uses commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 and the like as photocatalysts, uses cheap and easily available alkaline substances such as N,N-diisopropylethylamine as additives, uses 15W blue light as a light source under SF6 gas at room temperature, and simply and efficiently synthesizes clopidogrel. The present invention has mild reaction conditions, the reaction raw materials used are all cheap and easily available, and it has the characteristics of cost saving, environmental friendliness, and industrial promotion. The method effectively activates and utilizes SF6, a greenhouse gas, and fully utilizes the decomposition products of SF6 to realize the esterification reaction of carboxylic acid to prepare clopidogrel, thereby turning SF6 into treasure. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the H NMR spectrum of (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)acetate described in Example 1 of the present invention;

[0039] Figure 2 This is the carbon NMR spectrum of methyl (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)acetate described in Example 1 of the present invention. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0041] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0042] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.

[0043] The raw materials used in the following specific examples are all commercially available, and each reagent is purified by means known in the art before use when necessary.

[0044] 1 H NMR and 13 C NMR was measured using a Bruker Avance 400 spectrometer. The test temperature was room temperature, the solvent was deuterated chloroform, and the reference was selected: 1 H NMR: CHCl3 7.260 ppm; 13 C NMR: CHCl3: 77.000 ppm.

[0045] In the following examples, irradiation and stirring were performed at room temperature under SF6 gas at one atmosphere pressure.

[0046] Example 1

[0047] Synthesis of (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)acetate (Clopidogrel)

[0048] (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid (154 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, evacuated, and an SF6 balloon was inserted, 3.0 mL of anhydrous tetrahydrofuran was added, and bubbled for 3 minutes. Methanol (202.5 μL) and diisopropylethylamine (434.6 μL) were then added, and the reaction system was placed under a 15 W 465 nm blue LED light source and stirred for 20 hours. After the reaction, the organic solvent was removed under vacuum, and (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)acetic acid methyl ester, i.e., clopidogrel 64.2 mg, was obtained by silica gel column chromatography (petroleum ether:ethyl acetate volume ratio = 20:1), with a yield of 40%.

[0049] Product (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)acetic acid methyl ester The H-NMR and C-NMR spectra are as follows Figure 1-2 The specific data are as follows: 1 H NMR(400MHz, CDCl3)δ7.72–7.69(m,1H),7.42–7.40(m,1H),7.32–7.25(m,2H),7.0 7–7.05(m,1H),6.68–6.67(m,1H),4.92(s,1H),3.79–3.61(m,5H),2.88(s,4H)ppm. 13 C NMR (101MHz, CDCl3) δ171.3,134.6,133.7,133.2,133.2,129.9,129.7,129.4,127.1,125.2,122.7,67.8,52.2,50.7,48.3,25.5ppm.

[0050] As can be seen from Example 1, the present invention uses easily available methanol and (S)-(2-chlorophenyl)-6,7-dihydrothiophene [3,2-C] pyridine-5 (4H)-acetic acid as reaction substrates, commercially available Ir [dF (CF3) ppy] 2 (dtbbpy) PF6 as a photocatalyst, and cheap and easily available N, N-diisopropylethylamine as a base. Under an atmospheric pressure of SF6 gas, at room temperature, 15W of 465nm blue light is used as a light source to simply and efficiently synthesize clopidogrel. This method is a method for synthesizing clopidogrel with mild conditions, simple operation, and easy industrial promotion. And this method effectively activates and utilizes SF6, a greenhouse gas, turning SF6 into treasure.

[0051] Example 2

[0052] Synthesis of (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)acetate (Clopidogrel)

[0053] (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-acetic acid (154 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, evacuated, and an SF6 balloon was inserted, 5.0 mL of anhydrous tetrahydrofuran was added, and bubbled for 3 minutes. Methanol (20.3 μL) and diisopropylethylamine (869.2 μL) were then added, and the reaction system was placed under a 15W 450 nm blue LED light source for irradiation and stirred for 48 hours. After the reaction was completed, the organic solvent was removed under vacuum, and (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)yl)acetic acid methyl ester was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 20:1).

[0054] Example 3

[0055] Synthesis of (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)yl)acetate (Clopidogrel)

[0056] (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-c]pyridine-5(4H)-acetic acid (154 mg) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (5.6 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, evacuated, and an SF6 balloon was inserted, 3.0 mL of anhydrous tetrahydrofuran was added, and bubbled for 3 minutes. Methanol (404 μL) and diisopropylethylamine (88 μL) were then added, and the reaction system was placed under a 15W 480 nm blue LED light source for irradiation and stirred for 5 hours. After the reaction was completed, the organic solvent was removed under vacuum, and (S)-2-(2-chlorophenyl)-2-(6,7-dihydrothiophene[3,2-c]pyridine-5(4H)yl)acetic acid methyl ester was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 20:1).

[0057] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing clopidogrel using sulfur hexafluoride, characterized in that: The method uses (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid and methanol as raw materials, uses alkaline substances as additives, and reacts in a solvent under the conditions of sulfur hexafluoride, a photocatalyst and light to obtain the clopidogrel.

2. The method for preparing clopidogrel using sulfur hexafluoride according to claim 1, characterized in that: The following steps are involved: (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid and a photocatalyst are added to a reaction device, and a solvent is added after vacuuming. After sulfur hexafluoride is introduced, methanol and an alkaline substance are added, and the reaction system is placed under light conditions for reaction. After the reaction is completed, the clopidogrel is obtained through post-treatment.

3. The method for preparing clopidogrel using sulfur hexafluoride according to claim 1, characterized in that: The alkaline substance is N,N-diisopropylethylamine.

4. The method for preparing clopidogrel using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is a mixture of one or more of 4CZIPN, 9-mesityl-10-methylacridine perchlorate, Ir[dF(CF3)ppy]2(dtbbpy)PF6, and Ir(dtbbpy)ppy2PF6.

5. The method for preparing clopidogrel using sulfur hexafluoride according to claim 4, characterized in that: The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

6. The method for preparing clopidogrel using sulfur hexafluoride according to claim 1, characterized in that: The solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

7. The method for preparing clopidogrel using sulfur hexafluoride according to claim 1, characterized in that: The solvent is tetrahydrofuran.

8. The method for preparing clopidogrel using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of methanol to (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 1:1 to 20:

1.

9. The method for preparing clopidogrel using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the alkaline substance and (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 1:1 to 10:1; the molar ratio of the photocatalyst and (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid is 0.010:1 to 0.002:1; the dosage ratio of the (S)-(2-chlorophenyl)-6,7-dihydrothiophene[3,2-C]pyridine-5(4H)-acetic acid to the solvent is 0.5 to 0.1 mmol:1 mL.

10. The method for preparing clopidogrel using sulfur hexafluoride according to any one of claims 1 to 9, characterized in that: The light source is blue light with a wavelength of 450-480nm; the pressure of sulfur hexafluoride gas is 1atm, the reaction temperature is 0-50°C, and the reaction time is 5-48h.

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