Method for preparing olaparib from sulfur hexafluoride

Abstract

The invention discloses a method for preparing olaparib by adopting sulfur hexafluoride, which comprises the following steps: by taking 1-cyclopropyl formyl piperazine and 2-fluoro-5-((4-oxo-3, 4-dihydrophthalazine-1-yl) methyl) benzoic acid as raw materials, carrying out illumination reaction in an organic solvent under the conditions of a photocatalyst, alkali, sulfur hexafluoride and illumination to obtain the olaparib. The reaction conditions are mild, the used reaction raw materials are cheap and easy to obtain, and the method has the characteristics of cost saving, environment friendliness and industrial popularization. According to the method, the greenhouse gas SF6 is effectively activated and utilized, the decomposition product SF6 is fully utilized to realize the amidation reaction of carboxylic acid to prepare olaparib, the SF6 is turned into wealth, the required raw materials are simple and easy to obtain, the reaction conditions are simple and convenient, the method is green and energy-saving, and the method has relatively high application value.

Description

Technical Field

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

[0002] Amidation reaction is the most commonly used organic synthesis reaction. A study on drug synthesis shows that 65% of drug synthesis processes use amidation reactions. In addition, amidation products play an important role in the biomedical, pharmaceutical and food industries, and are also widely used in industrial products. For example, sulfamide can modify peptide units and proteins, and sulfamide modification can significantly improve the stability and activity of peptide drugs; tyramine-derived hydroxycinnamamide in plant-based foods can be used as a food preservative due to its natural antioxidant effect; amide greases are often used in nuclear power and aerospace fields due to their excellent properties such as strong thermal stability, radiation resistance and mechanical stability. At present, the synthesis of amide compounds includes:

[0003] Method 1: Use 3,4,5-trifluorophenylboronic acid to catalyze the amidation reaction between carboxylic acid and amine.

[0004]

[0005] This method is not only applicable to the reaction of primary and tertiary amines with carboxylic acids, but is also applicable to some special substrates with large steric hindrance and olefin groups. However, it requires high temperature (>100°C) and anhydrous conditions, and has the problem of low atom economy.

[0006] Method 2: Using two zirconium catalysts (ZrCp2Cl2 / ZrCl4) in toluene solvent and heating reflux at 110°C, the amidation reaction of carboxylic acid and amine can be efficiently catalyzed.

[0007]

[0008] This method has a high yield and can achieve the synthesis of two drug molecules, acetaminophen and moclobemide, with a relatively high yield, but this method introduces metal compounds and requires high temperature conditions.

[0009] Method 3: Using active ester as acyl source and zinc powder as catalyst, the synthesis of secondary amide was achieved under the conditions of microwave heating in DMF solvent or heating in THF solvent.

[0010]

[0011] The reaction has the following characteristics: simple, efficient, environmentally friendly and the catalyst can be reused. However, the substrate has a narrow scope of application and alcohol is also generated, which makes it very difficult to separate the subsequent products.

[0012] According to the above analysis, there is still a need to develop a carboxylic acid amidation 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] 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 insulation properties and can be used to extinguish high-voltage arcs. Therefore, SF6 is widely used in the power sector. However, 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. As it continues to accumulate in the atmosphere, the greenhouse effect it brings is also continuously increasing. Therefore, the emission of SF6 is strictly restricted, and the large amount of SF6 stored in the power sector faces tremendous pressure in treatment.

[0014] Olaparib is a poly ADP-ribose polymerase (PARP) inhibitor developed by AstraZeneca, an international pharmaceutical company. The first approved indication for Olaparib was ovarian cancer (2014). In July 2017, the FDA approved a new indication for the drug, approving it for second-line maintenance treatment of patients with recurrent ovarian epithelial cancer, fallopian tube cancer, and primary peritoneal cancer who have been effectively treated with platinum-based drugs. As a PARP inhibitor, Olaparib can kill cancer cells by inhibiting PARP, reducing or even preventing cancer cells carrying damaged BRCA genes from repairing their DNA. Therefore, Olaparib is an effective targeted drug for BRCA gene-mutated tumors.

[0015] The Chinese patent application document with publication number CN110078671A discloses a method for preparing Olaparib, which includes chemically reacting 2-(2-(4-fluoro-3-carboxyphenyl)acetyl)benzoate and a hydrazine reagent to obtain a 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid compound, and then condensing 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid and 1-cyclopropylformylpiperazine to prepare Olaparib. However, the condensation reagents used include HOBT, EDCI, DCC, HBTU, and TBTU, and heating is required during the reaction. There are many by-products, and the economic cost is high. Summary of the invention

[0016] The technical problem to be solved by the present invention is how to prepare Olaparib simply, safely and greenly.

[0017] The present invention solves the above technical problems through the following technical means:

[0018] A method for preparing olaparib by using sulfur hexafluoride, wherein 1-cyclopropylformylpiperazine and 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid are used as raw materials, and a reaction is carried out in an organic solvent under the conditions of a photocatalyst, a base, sulfur hexafluoride and light to obtain the olaparib.

[0019] Preferably, the method for preparing Olaparib using sulfur hexafluoride comprises the following steps: adding 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid and a photocatalyst into a reaction device, adding an organic solvent after evacuation, introducing sulfur hexafluoride gas, and then adding 1-cyclopropylformylpiperazine and a base, and placing the reaction system under a light source to react to obtain the Olaparib.

[0020] Preferably, the photocatalyst is an organic photocatalyst or a mixture of one or more transition metal photocatalysts.

[0021] Preferably, the organic photocatalyst is 4CZIPN, Mes-Acr + ClO4 — (9-mesityl-10-methylacridinium perchlorate) or a mixture of two thereof.

[0022] Preferably, the transition metal photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6, Ir(dtbbpy)ppy2PF6 or a mixture of the two.

[0023] Preferably, the photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

[0024] Preferably, the organic solvent is a mixture of one or more of tetrahydrofuran, acetonitrile and dichloromethane.

[0025] Preferably, the organic solvent is acetonitrile.

[0026] 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.

[0027] Preferably, the base is an organic base.

[0028] Preferably, the organic base is a tertiary amine.

[0029] Preferably, the base is N,N-diisopropylethylamine. When the base is N,N-diisopropylethylamine, the product yield is the highest.

[0030] Preferably, the molar ratio of 1-cyclopropylformylpiperazine to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid is 1:1 to 20:1.

[0031] Preferably, the molar ratio of 1-cyclopropylformylpiperazine to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid is 3:1.

[0032] Preferably, the molar ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid to the photocatalyst is 100:0.2-1; the molar ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid to the base is 1:1-1:10.

[0033] Preferably, the molar ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid to the base is 1:5.

[0034] Preferably, the molar ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid to the photocatalyst is 100:0.5.

[0035] Preferably, the light source is blue light of 450-480nm.

[0036] Preferably, 465 nm blue light is used as the light source.

[0037] Preferably, during the reaction process, the SF6 gas pressure is 1 atm, the reaction temperature is 0-50°C, and the reaction time is 5-48 hours.

[0038] Preferably, the yield of the product is highest when the gas pressure is 1 atm.

[0039] Preferably, the reaction temperature is room temperature and the reaction time is 20 hours.

[0040] Preferably, the usage ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid and the organic solvent is 0.5-0.1 mmol:3 mL.

[0041] Preferably, during the reaction, the decomposition products of SF6 serve as condensation agents.

[0042] The advantages of the present invention are:

[0043] In the present invention, 1-cyclopropylformylpiperazine and 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid which are easily available are used as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 and the like are used as photocatalysts, and cheap and easily available N,N-diisopropylethylamine and the like are used as bases, and olaparib is simply and efficiently synthesized under SF6 gas. The reaction conditions of the present invention are mild, the reaction raw materials used are cheap and easily available, and the method 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 prepare olaparib, turning SF6 into treasure. The required raw materials are simple and easily available, the reaction conditions are simple, and the method is green and energy-saving, and has a high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 This is the H NMR spectrum of Olaparib described in Example 1 of the present invention;

[0045] Figure 2 This is the NMR carbon spectrum of Olaparib described in Example 1 of the present invention. DETAILED DESCRIPTION

[0046] 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.

[0047] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.

[0048] 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.

[0049] 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.

[0050] 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 references were: 1 H NMR: CHCl3 7.260 ppm; 13C NMR: CHCl3: 77.000 ppm.

[0051] Example 1

[0052] Synthesis of Olaparib

[0053] 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (149.13 mg, 0.5 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and an SF6 balloon was inserted after evacuation, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, 1-cyclopropylformylpiperazine (1.5 mmol, 231.3 mg) and N,N-diisopropylethylamine (434.6 μL) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source, irradiated and stirred at room temperature for 20 hours, wherein the reaction was carried out under an atmospheric pressure of SF6 gas. After the reaction was completed, the organic solvent was removed under vacuum, and olaparib was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 1:4) 126.0 mg, yield 58%.

[0054] The NMR spectrum of the product Olaparib is as follows Figure 1 and 2 As shown, the NMR data are as follows: 1 H NMR(400MHz, CDCl3)δ10.9(s,1H),8.48–8.46(m,1H),7.78–7.72(m,3H),7.34–7.31(m,2H),7.06–7.02(m ,1H),4.29(s,2H),3.77–3.60(m,6H),3.35–3.29(m,2H),1.77(s,1H),1.02–0.98(m,2H),0.80(s,2H)ppm. 13 C NMR (101MHz, CDCl3) δ172.3,165.2,160.7,156.9(d,J C-F =248.6Hz),145.5,134.4(d,J C-F =3.5Hz),133.7,131.7(d,J C-F =8.1Hz),131.6,129.5,129.2(bs),128.3,127.1,125.0,123.6(d,J C-F =16.5Hz),116.2(d,J C-F=22.1Hz),46.8,45.1,42.2(bs,2C),37.6,11.0,7.7(2C)ppm.

[0055] As can be seen from Example 1, the present invention uses easily available 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid and 1-cyclopropylformylpiperazine as reaction substrates, commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst, and cheap and readily 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 olaparib. This method is a method for synthesizing olaparib with mild conditions, simple operation, and easy industrial promotion. In addition, this method effectively activates and utilizes SF6, a greenhouse gas, and makes full use of SF6 decomposition products to prepare olaparib, turning SF6 into treasure.

[0056] Example 2

[0057] Synthesis of Olaparib

[0058] 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (149.13 mg, 0.5 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1.2 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and an SF6 balloon was inserted after vacuuming, and then 3.0 mL of anhydrous tetrahydrofuran was added and bubbled for 3 minutes. Subsequently, 1-cyclopropylformylpiperazine (0.5 mmol, 77.2 mg) and N,N-diisopropylethylamine (434.6 μL) were added, and the reaction system was placed under a 15 W, 450 nm blue LED light source, irradiated and stirred at room temperature for 48 hours, wherein the reaction was carried out under an atmospheric pressure of SF6 gas. After the reaction was completed, the organic solvent was removed under vacuum, and olaparib was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 1:4).

[0059] Example 3

[0060] Synthesis of Olaparib

[0061] 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (149.13 mg, 0.5 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.8 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and an SF6 balloon was inserted after vacuuming, and then 3.0 mL of dichloromethane was added and bubbled for 3 minutes. Subsequently, 1-cyclopropylformylpiperazine (1.5 mmol, 231.3 mg) and N,N-diisopropylethylamine (87.5 μL) were added, and the reaction system was placed under a 15 W, 480 nm blue LED light source, irradiated and stirred at room temperature for 5 hours, wherein the reaction was carried out under an atmospheric pressure of SF6 gas. After the reaction was completed, the organic solvent was removed under vacuum, and olaparib was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 1:4).

[0062] Example 4

[0063] Synthesis of Olaparib

[0064] 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (149.13 mg, 0.5 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (5.6 mg) were added to a 12 mL headspace glass vial with a PTFE gasket, and an SF6 balloon was inserted after vacuuming, and then 3.0 mL of anhydrous acetonitrile was added and bubbled for 3 minutes. Subsequently, 1-cyclopropylformylpiperazine (10 mmol, 1542 mg) and N,N-diisopropylethylamine (869.2 μL) were added, and the reaction system was placed under a 15 W, 465 nm blue LED light source, irradiated and stirred at room temperature for 20 hours, wherein the reaction was carried out under an atmospheric pressure of SF6 gas. After the reaction was completed, the organic solvent was removed under vacuum, and olaparib was obtained by silica gel column chromatography (petroleum ether: ethyl acetate volume ratio = 1:4).

[0065] 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 Olaparib using sulfur hexafluoride, characterized in that: The method uses 1-cyclopropylformylpiperazine and 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid as raw materials, and reacts in an organic solvent under the conditions of a photocatalyst, a base, sulfur hexafluoride and light to obtain the olaparib.

2. The method for preparing Olaparib using sulfur hexafluoride according to claim 1, characterized in that: The following steps are involved: 2-Fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid and a photocatalyst are added to a reaction device, and an organic solvent is added after vacuuming, sulfur hexafluoride gas is introduced, and then 1-cyclopropylformylpiperazine and a base are added, and the reaction system is placed under a light source to react to obtain the olaparib.

3. The method for preparing Olaparib using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is Ir[dF(CF3)ppy]2(dtbbpy)PF6.

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

5. The method for preparing Olaparib using sulfur hexafluoride according to claim 1, characterized in that: The base is N,N-diisopropylethylamine.

6. The method for preparing Olaparib using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the 1-cyclopropylformylpiperazine to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid is 1:1 to 20:

1.

7. The method for preparing Olaparib using sulfur hexafluoride according to claim 1, characterized in that: The molar ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid to the photocatalyst is 100:0.2-1; the molar ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid to the base is 1:1-1:

10.

8. The method for preparing Olaparib using sulfur hexafluoride according to claim 1, characterized in that: The light source is blue light of 450-480nm.

9. The method for preparing Olaparib using sulfur hexafluoride according to claim 1, characterized in that: During the reaction process, the SF6 gas pressure is 1 atm, the reaction temperature is 0-50°C, and the reaction time is 5-48 hours.

10. The method for preparing Olaparib using sulfur hexafluoride according to any one of claims 1 to 9, characterized in that: The usage ratio of the 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid and the organic solvent is 0.5-0.1 mmol:3 mL.

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