A method of synthesizing olaparib

Abstract

The present application relates to the field of organic synthesis, in particular to a synthesis method of olaparib. The synthesis method of olaparib provided by the present application comprises the following steps: 4-(4-fluoro-3-iodobenzyl) phthalazine-1(2H)-one, carbon monoxide and 1-cyclopropylformylpiperazine are reacted under the action of a Pd monatomic catalyst and an alkaline substance to generate olaparib; wherein the Pd monatomic catalyst comprises a carrier and Pd monatomic atoms loaded on the carrier. The present application provides a method for efficiently synthesizing olaparib directly from simple phthalazine raw materials, which uses a Pd monatomic catalyst, not only realizes high yield and selectivity, but also can directly filter the solid catalyst after the reaction to avoid the pollution of heavy metal Pd to the product, and does not need to go through complex column chromatography separation.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and in particular to a method for synthesizing olaparib. Background Technology

[0002] Olaparib is a off-white solid that is sensitive to light and air. Common formulations include tablets and capsules. It is a chemotherapy drug used to treat ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer.

[0003] Olaparib is a PARP (poly(ADP-ribose) polymerase) inhibitor used to treat ovarian, breast, prostate, and pancreatic cancers associated with BRCA1 / 2 gene mutations. It works by blocking DNA repair in cancer cells, leading to cancer cell death, while simultaneously reducing damage to normal cells.

[0004] The existing methods for synthesizing olaparib are as follows:

[0005] 1. Synthesis method using piperazine and cyclopropane carbonyl chloride as raw materials: First, piperazine and cyclopropane carbonyl chloride are added to AcOH and reacted at 40℃ to generate cyclopropyl(piperazin-1-yl) methyl ketone. Using cyclopropyl(piperazin-1-yl) methyl ketone and 5-bromo-2-fluorobenzoic acid as raw materials, HBTU and DIPEA as condensing agents, and DMF as solvent, the reaction was carried out overnight at room temperature to generate (4-(5-bromo-2-fluorobenzoyl)piperazin-1-yl)(cyclopropyl) methyl ketone. Then, (4-(5-bromo-2-fluorobenzoyl)piperazin-1-yl)(cyclopropyl) methyl ketone, 2-acetylbenzoic acid, and sodium tert-butoxide (NaOtBu) were added to DMF. The reaction was carried out at 120°C for 36 hours to generate 2-(2-(3-(4-(cyclopropanecarbonyl)piperazin-1-carbonyl)-4-fluorophenyl)acetyl)benzoic acid. This product was reacted with hydrazine hydrate as a cyclizing agent and ethanol as a solvent, and refluxed overnight to finally generate olaparib.

[0006] 2. Two-step synthesis of olaparib from piperazine: First, 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid and N,N-carbonyldiimidazole (CDI) are added to the solvent N,N-dimethylacetamide (DMA) and reacted in a microreactor at a temperature of 70°C for a residence time of 12 minutes. The molar ratio of CDI to 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid is 1.2:1. Then, the imidazole generated in the first step, 4-(4-fluoro-3-(piperazin-1-carbonyl)benzyl)benzothiazol-1(2H)-one, and cyclopropaneformyl chloride are added to DMA and reacted in a cascade microreactor (continuous with the first step) at a temperature of 70°C for a residence time of 10 minutes, finally producing olaparib.

[0007] Existing synthetic routes suffer from high raw material costs, with some routes requiring expensive intermediates or multiple reaction steps to prepare raw materials, increasing production costs. Furthermore, reagents such as cyclopropionyl chloride are toxic and corrosive, necessitating strict safety control and posing high operational risks. Traditional routes, with their low atom economy, are lengthy, produce numerous byproducts, and have insufficient atom utilization, failing to align with green chemistry principles. Additionally, these routes involve harsh reaction conditions, complex processes, and high costs. Summary of the Invention

[0008] In view of this, the present invention provides a method for synthesizing olaparib. The synthesis method of the present invention does not require the use of toxic reagents such as cyclopropionyl chloride, and the process is simple, enabling the one-step synthesis of olaparib while ensuring high yield and high selectivity.

[0009] This invention provides a method for synthesizing olaparib, comprising the following steps:

[0010] Under the action of a Pd single-atom catalyst and alkaline substances, 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, carbon monoxide and 1-cyclopropylformylpiperazine react to generate olaparib.

[0011] in,

[0012] The Pd single-atom catalyst includes a support and Pd single atoms supported on the support.

[0013] Preferably, the carrier is at least one of activated carbon, iron oxide, aluminum oxide, cerium oxide, zirconium oxide, titanium oxide, manganese oxide, and silicon dioxide.

[0014] Preferably, the mass fraction of Pd single atoms in the Pd single-atom catalyst is 2% to 10%.

[0015] Preferably, the Pd single-atom catalyst is prepared by the following method:

[0016] S1. Mix Pd salt, EDTA salt and solvent to obtain an EDTA solution containing Pd ions;

[0017] S2. The Pa-containing EDTA solution is mixed with the support and the solvent is removed to obtain the catalyst precursor;

[0018] S3. The catalyst precursor is calcined to obtain a Pd single-atom catalyst.

[0019] Preferably, in step S1:

[0020] The Pd salt is palladium nitrate;

[0021] The EDTA salt is EDTA-2Na.

[0022] Preferably, in step S2, the mixing temperature is 90–100°C;

[0023] In step S3:

[0024] The calcination is carried out in a protective atmosphere;

[0025] The calcination temperature is 100–300℃, and the holding time is 2–4 hours.

[0026] Preferably, the alkaline substance is at least one selected from K2CO3, NaHCO3, triethylamine, diisopropylethylamine, and diisopropylaminolithium.

[0027] Preferably, the ratio of the Pd single-atom catalyst to 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one is (30-50) mg: 1 mmol;

[0028] The molar ratio of the alkaline substance to 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one is 100% to 300%.

[0029] The molar ratio of 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one and 1-cyclopropionylpiperazine is 1:(0.8-1.2);

[0030] The gas pressure of the carbon monoxide is 1 to 10 atm.

[0031] Preferably, the reaction temperature is 20–120°C.

[0032] Preferably, after the reaction, a post-processing is also performed;

[0033] The post-processing includes: solid-liquid separation to remove the catalyst, and then removing the solvent from the resulting separated liquid to obtain olaparib.

[0034] The present invention provides a method for synthesizing olaparib using 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, carbon monoxide, and 1-cyclopropaneylpiperazine as reactants in the presence of a Pd single-atom catalyst and K₂CO₃. Based on the Pd single-atom catalyst, it exhibits good selectivity for phthalazine, an NH substrate, enabling a one-step synthesis of olaparib. This solves the problem of existing techniques requiring multiple steps to synthesize olaparib using cyclopropane carbonyl chloride, a Cl-CH₃ substrate. Furthermore, the olaparib synthesized in this invention achieves a yield of over 95%, eliminates the need for traditional column chromatography, and fully meets the purity standards of the Chinese Pharmacopoeia. The synthesis method is simple. Compared to traditional methods, the olaparib synthesis method provided by this invention can be carried out in a normal pressure carbon monoxide atmosphere, synthesizing the target product in one step. The preparation method is faster, more efficient, environmentally friendly, and milder. The high yield and simplified purification process facilitate large-scale industrial production.

[0035] Experimental results show that the product yield of the synthesis method of the present invention reaches over 95%, and the purity reaches over 97%. Attached Figure Description

[0036] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0037] Figure 1 The image shows a SEM image of the 5% Pd / C single-atom catalyst obtained in Example 1.

[0038] Figure 2 The 1H NMR spectrum of olaparib obtained in Example 1;

[0039] Figure 3 The image shows the carbon NMR spectrum of olaparib obtained in Example 1. Detailed Implementation

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0041] In this article, the technical features described in an open-ended manner include both closed technical solutions composed of the listed features and open technical solutions that include the listed features.

[0042] The term “and / or” as used herein includes any and all combinations of one or more of the related listed items.

[0043] In this document, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when a range refers to an integer, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0044] In this article, when referring to units for data ranges, if the unit is only followed by the right endpoint, it indicates that the units for the left and right endpoints are the same. For example, 5–15 mg / mL means that the units for the left endpoint “5” and the right endpoint “15” are both mg / mL.

[0045] This invention provides a method for synthesizing olaparib, comprising the following steps:

[0046] Under the action of a Pd single-atom catalyst and alkaline substances, 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, carbon monoxide and 1-cyclopropylformylpiperazine react to generate olaparib.

[0047] in,

[0048] The Pd single-atom catalyst includes a support and Pd single atoms supported on the support.

[0049] This invention provides a method for the efficient synthesis of olaparib directly from a simple phthalazine raw material. The process uses a Pd single-atom catalyst, which not only achieves high yield and selectivity, but also allows for direct filtration of the solid catalyst after the reaction to avoid contamination of the product by the heavy metal Pd, without the need for complex column chromatography separation.

[0050] Regarding Pd single-atom catalysts :

[0051] In this invention, the Pd single-atom catalyst is a supported catalyst, comprising a support and Pd single atoms supported on the support. Preferably, the support is at least one selected from activated carbon, iron oxide, alumina, cerium oxide, zirconium oxide, titanium oxide, manganese oxide, and silicon dioxide, and more preferably activated carbon.

[0052] In this invention, the mass fraction of Pd single atoms in the Pd single-atom catalyst is preferably 2% to 10%, specifically 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, and more preferably 4% to 8%. The mass fraction refers to the ratio of the mass of a Pd single atom to the total mass of the Pd single-atom catalyst.

[0053] In this invention, the Pd single-atom catalyst is prepared by the following method:

[0054] S1. Mix Pd salt, EDTA salt and solvent to obtain an EDTA solution containing Pa ions;

[0055] S2. The Pa-containing EDTA solution is mixed with the support and the solvent is removed to obtain the catalyst precursor;

[0056] S3. The catalyst precursor is calcined to obtain a Pd single-atom catalyst.

[0057] Regarding step S1:

[0058] The Pd salt is preferably palladium nitrate, which can be hydrated or non-hydrated, more preferably Pd(NO3)2·2H2O. The EDTA salt is preferably EDTA-2Na. The solvent is preferably at least one selected from water, dimethyl carbonate (DMC), 1,4-dioxane, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and toluene. The molar ratio of the Pd salt to the EDTA salt is preferably 1:5. The volume ratio of the Pd salt to the solvent is preferably 1 mol:10 mL. The concentration of the resulting EDTA solution containing Pa ions can specifically be 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, or 15 mg / mL.

[0059] Regarding step S2:

[0060] The carrier is preferably at least one selected from activated carbon, iron oxide, aluminum oxide, cerium oxide, zirconium oxide, titanium oxide, manganese oxide, and silicon dioxide, and more preferably activated carbon. The preferred ratio of the carrier to the Pa-containing EDTA solution obtained in step S1 is 500 mg: 30 mg.

[0061] The preferred mixing temperature for the Pa-ion-containing EDTA solution with the support is 90–100°C, specifically 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, or 100°C. During the mixing process, stirring is preferably performed to evaporate the solvent until it is completely evaporated. Afterward, drying is carried out to obtain the Pd atom catalyst precursor.

[0062] Regarding step S3:

[0063] The calcination is preferably carried out in a protective atmosphere. This invention does not have any particular limitation on the type of gas providing the protective atmosphere; any conventional protective gas in the art, such as nitrogen, helium, or argon, is acceptable. The calcination temperature is preferably 100–300°C, specifically 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, 190°C, 200°C, 210°C, 220°C, 230°C, 240°C, 250°C, 260°C, 270°C, 280°C, 290°C, or 300°C. The holding time for calcination is preferably 2–4 hours, specifically 2 hours, 3 hours, or 4 hours. The heating rate for calcination is preferably 4–6°C / min, specifically 4°C / min, 5°C / min, or 6°C / min, more preferably 5°C / min. After calcination, a Pd single-atom catalyst is obtained. In the obtained Pd single-atom catalyst, the Pd element is dispersed on the support in the form of single atoms.

[0064] In this invention, the preferred ratio of the Pd single-atom catalyst to 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one is (30-50) mg:1 mmol, specifically 30 mg:1 mmol, 35 mg:1 mmol, 40 mg:1 mmol, 45 mg:1 mmol, or 50 mg:1 mmol.

[0065] Regarding alkaline substances :

[0066] In this invention, the alkaline substance is preferably at least one selected from K2CO3, NaHCO3, triethylamine, diisopropylethylamine, and diisopropylaminolithium, and more preferably K2CO3.

[0067] In this invention, the molar ratio of the alkaline substance to 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one is preferably 100% to 300%, specifically 100%, 109%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, and 300%.

[0068] Regarding synthesis reactions :

[0069] In this invention, 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, carbon monoxide, and 1-cyclopropionylpiperazine are used as reactants for the synthesis reaction. The reaction route is as follows:

[0070]

[0071] In this invention, the molar ratio of 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one and 1-cyclopropionylpiperazine is preferably 1:(0.8-1.2), specifically 1:0.8, 1:0.9, 1:1.0, 1:1.1, or 1:1.2. The carbon monoxide is preferably carbon monoxide gas. The gas pressure of the carbon monoxide is preferably 1-10 atm, specifically 1 atm, 2 atm, 3 atm, 4 atm, 5 atm, 6 atm, 7 atm, 8 atm, 9 atm, or 10 atm.

[0072] In this invention, the reaction is preferably carried out in a solvent medium. The solvent is preferably at least one selected from water, dimethyl carbonate (DMC), 1,4-dioxane, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), and toluene. The preferred ratio of the solvent to 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one is (2-5) mL:1 mmol, specifically 2 mL:1 mmol, 3 mL:1 mmol, 4 mL:1 mmol, or 5 mL:1 mmol.

[0073] In this invention, the reaction temperature is preferably 20–120°C, specifically 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, or 120°C. The reaction time is preferably 1–12 hours, specifically 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In this invention, the reaction is preferably accompanied by stirring. The stirring speed is preferably 600–700 rpm, specifically 600 rpm, 650 rpm, or 700 rpm.

[0074] In this invention, the above-mentioned synthesis method preferably includes the following steps: adding 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, 1-cyclopropionylpiperazine, Pd single-atom catalyst, solvent and alkaline substance to a container, then purging the air in the container and introducing carbon monoxide gas, stirring the reaction to generate olaparib.

[0075] In this invention, after the above reaction, the resulting reaction solution is preferably post-treated. The post-treatment includes: solid-liquid separation to remove the catalyst, followed by solvent removal from the separated solution to obtain olaparib. In this invention, the Pd single-atom catalyst used is a solid-phase catalyst; therefore, simple solid-liquid separation after the reaction is sufficient to remove the catalyst, avoiding contamination of the product by the heavy metal Pd, and eliminating the need for complex column chromatography separation. The method of solid-liquid separation is not particularly limited and can be any conventional solid-liquid separation method in the art, such as filtration. After the above solid-liquid separation, solvent removal is performed. The solvent removal process includes extraction. The extractant used is preferably at least one of dichloromethane and anhydrous ethanol. After extraction, the extracts are combined, anhydrous sodium sulfate is added to remove water, the mixture is filtered again, the solvent is evaporated, and the mixture is vacuum dried to obtain olaparib.

[0076] The present invention provides a method for synthesizing olaparib using 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, carbon monoxide, and 1-cyclopropaneylpiperazine as reactants in the presence of a Pd single-atom catalyst and K₂CO₃. Based on the Pd single-atom catalyst, it exhibits good selectivity for phthalazine, an NH substrate, enabling a one-step synthesis of olaparib. This solves the problem of existing techniques requiring multiple steps to synthesize olaparib using cyclopropane carbonyl chloride, a Cl-CH₃ substrate. Furthermore, the olaparib synthesized in this invention achieves a yield of over 95%, eliminates the need for traditional column chromatography, and fully meets the purity standards of the Chinese Pharmacopoeia. The synthesis method is simple. Compared to traditional methods, the olaparib synthesis method provided by this invention can be carried out in a normal pressure carbon monoxide atmosphere, synthesizing the target product in one step. The preparation method is faster, more efficient, environmentally friendly, and milder. The high yield and simplified purification process facilitate large-scale industrial production.

[0077] Compared with the prior art, the present invention has the following beneficial effects:

[0078] (1) The synthesis process of this invention is simple to operate, with a yield of over 95%. The subsequent processing is simple and does not require a complicated column chromatography process to separate and purify the product.

[0079] (2) Compared with traditional methods, the method of the present invention uses water as solvent, K2CO3 as base, and Pd single atom as catalyst to synthesize the target product in one step under normal pressure carbon monoxide atmosphere. The preparation method is faster, more efficient, more environmentally friendly and milder.

[0080] To further understand the present invention, preferred embodiments of the present invention are described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, and are not intended to limit the scope of the claims of the present invention.

[0081] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. All instruments are conventionally selected in the art.

[0082] Example 1

[0083] 1. Preparation of Pd single-atom catalysts

[0084] S1. Pd(NO3)2·2H2O, EDTA-2Na, and solvent H2O are mixed to obtain a Pd-EDTA solution. The molar ratio of Pd salt to EDTA salt is 1:5, the volume ratio of Pd salt to solvent is 1 mol:10 mL, and the concentration of the obtained Pd-EDTA solution is 10 mg / mL.

[0085] S2. Add activated carbon powder to the Pd-EDTA solution obtained in step S1, heat to 100℃ and stir continuously to evaporate the solvent until the solvent is completely evaporated, then dry to obtain the catalyst precursor. The ratio of activated carbon powder to the Pd-EDTA solution obtained in step S1 is 500 mg: 30 mL.

[0086] S3. The catalyst precursor obtained in step S2 is calcined in a nitrogen atmosphere at a temperature of 200°C, with a heating rate of 5°C / min and a time of 4h, to obtain a 5% Pd / C single-atom catalyst.

[0087] The microstructure of the obtained 5% Pd / C single-atom catalyst was analyzed by scanning electron microscopy (SEM), and the results are shown in [link to SEM]. Figure 1 , Figure 1 The image shows a SEM image of the 5% Pd / C single-atom catalyst obtained in Example 1. It can be seen that the palladium element in the 5% Pd / C single-atom catalyst provided by the present invention is dispersed on the carbon support in the form of single atoms.

[0088] 2. Synthesis of Olaparib

[0089] The synthesis route is as follows:

[0090]

[0091] The specific process is as follows:

[0092] First, 379 mg (1 mmol) of 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one and 154 mg (1 mmol) of 1-cyclopropionylpiperazine were added to the reaction flask, followed by 40 mg of 5% Pd / C catalyst, 2 mL of water, and 414 mg (3 mmol) of K₂CO₃. The air in the reaction flask was then purged and carbon monoxide (CO pressure 1 atm) was introduced. A balloon was attached to the flask and the flask was sealed. A magnetic stirrer was turned on, and the reaction was carried out in a water bath at 80 °C for 8 h. After the reaction was stopped, the reaction solution was filtered to remove the solid-phase catalyst. Extraction was performed with dichloromethane (20 mL × 2 times). The filtrate and extract were combined, and anhydrous sodium sulfate was added to remove water. The mixture was filtered again, the solvent was evaporated, and the solution was dried under vacuum to obtain 0.981 mmol of pure olaparib compound, with a yield of 98.1% and a purity of 99.2%.

[0093] The nuclear magnetic resonance hydrogen spectrum of the obtained olaparib product ( 1 H NMR) and carbon nuclear magnetic resonance (NMR) 13 CNMR) respectively as Figure 2-3 As shown; 1 H NMR and 13 The C NMR data are as follows:

[0094] 1 H NMR (500MHz, DMSO-D6) δ12.60 (s, 1H), 8.22 (dd, J = 7.8, 1.5Hz, 1H), 7.91 (d, J=8.0Hz,1H),7.85–7.72(m,2H),7.40(ddd,J=8.2,5.1,2.2Hz,1H),7.37(s, 1H),7.18(t,J=9.0Hz,1H),4.29(s,2H),3.71(s,1H),3.66(s,1H),3.56(s, 2H),3.51(s,1H),3.43(s,1H),3.38(s,1H),3.14(s,1H),0.74–0.62(m,3H).

[0095] 13 C NMR (126MHz, DMSO-D6) δ171.86,164.62,159.97,157.90,155.95,145.38,135.33,133.96,132.33,132.27,132.02, 129.59,129.54,128.39,126.59,125.90,124.17,124.03,116.52,116.35,39.97(dt,J=42.2,20.8Hz),10.90,7.68.

[0096] Example 2

[0097] 1. Preparation of Pd single-atom catalysts

[0098] The process was carried out in accordance with Example 1, except that the activated carbon support was replaced with cerium oxide (CeO2), resulting in a 5% Pd / CeO2 single-atom catalyst.

[0099] 2. Synthesis of Olaparib

[0100] Using the 5% Pd / CeO2 single-atom catalyst described above, the synthesis was carried out according to the synthesis process in Example 1, resulting in 0.952 mmol of pure olaparib compound with a yield of up to 95.2% and a purity of 97.4%.

[0101] Example 3

[0102] 1. Preparation of Pd single-atom catalysts

[0103] The process was carried out in accordance with Example 1, except that the activated carbon support was replaced with iron oxide (Fe2O3), resulting in a 5% Pd / Fe2O3 single-atom catalyst.

[0104] 2. Synthesis of Olaparib

[0105] Using the 5% Pd / Fe2O3 single-atom catalyst described above, the synthesis was carried out according to the synthesis process in Example 1, resulting in 0.956 mmol of pure olaparib compound with a yield of up to 95.6% and a purity of 98.4%.

[0106] Comparative Example 1

[0107] The same method was implemented as in Example 1, except that the Pd single-atom catalyst was replaced with a homogeneous (CH3COO)2Pd catalyst.

[0108] The synthesis route is as follows:

[0109]

[0110] The specific process is as follows:

[0111] First, 379 mg (1 mmol) of 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one and 154 mg (1 mmol) of 1-cyclopropionylpiperazine were added to the reaction flask. Then, 20 μmol of (CH3COO)2Pd catalyst, 2 mL of water, and 414 mg (3 mmol) of K2CO3 were added. The air in the reaction flask was then purged and carbon monoxide (CO pressure 1 atm) was introduced. A balloon was attached to the mouth of the flask and sealed. The magnetic stirrer was turned on, and the reaction was carried out in a water bath at 80 °C for 8 h. After the reaction was stopped, the organic phase was extracted with dichloromethane. The filtrate and extract were combined, and the organic solution of olaparib was obtained by column chromatography. The solvent was removed by rotary evaporation and the solution was dried under vacuum to obtain 0.245 mmol of pure olaparib compound, with a yield of only 24.5% and a purity of 98%.

[0112] Comparative Example 2

[0113] The synthesis was carried out using a 10% nano-Pd / C single-atom catalyst (a Pd / C catalyst with added Pd nanoparticles, which is a known substance) according to the synthesis process in Example 1 (the synthesis route is shown below). The result was 0.323 mmol of pure olaparib compound, with a yield of only 32.3% and a purity of 94.3%.

[0114]

[0115] In summary, this invention uses 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, carbon monoxide, and 1-cyclopropanoylpiperazine as reactants, reacting them in the presence of a Pd single-atom catalyst and K₂CO₃ to synthesize olaparib in a single step. Furthermore, the post-processing is simple, requiring no column chromatography separation, and the product yield reaches over 95% with a purity of over 97%, enabling the efficient acquisition of a high-quality product.

[0116] This document uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of these embodiments are merely to aid in understanding the method and core ideas of the present invention, including the best mode, and to enable any person skilled in the art to practice the present invention, including manufacturing and using any device or system, and implementing any combined method. It should be noted that those skilled in the art can make various improvements and modifications to the present invention without departing from its principles, and these improvements and modifications also fall within the scope of protection of the claims. The scope of protection of this patent is defined by the claims and may include other embodiments that can be conceived by those skilled in the art. If these other embodiments have structural elements similar to those expressed in the claims, or if they include equivalent structural elements that are not substantially different from those expressed in the claims, then these other embodiments should also be included within the scope of the claims.

Claims

1. A method for synthesizing olaparib, characterized in that, Includes the following steps: In the presence of a Pd single-atom catalyst and the alkaline substance K2CO3, 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one, carbon monoxide and 1-cyclopropionylpiperazine react to generate olaparib. in, The Pd single-atom catalyst comprises a support and Pd single atoms supported on the support; wherein the support is at least one selected from activated carbon, iron oxide, aluminum oxide, cerium oxide, zirconium oxide, titanium oxide, manganese oxide, and silicon dioxide. Following the reaction, a post-processing step is performed, which includes: solid-liquid separation to remove the catalyst, followed by solvent removal from the resulting separated liquid to obtain olaparib.

2. The synthesis method according to claim 1, characterized in that, The mass fraction of Pd single atoms in the Pd single-atom catalyst is 2% to 10%.

3. The synthesis method according to claim 1, characterized in that, The Pd single-atom catalyst was prepared by the following method: S1. Mix Pd salt, EDTA salt and solvent to obtain an EDTA solution containing Pd ions; S2. The Pa-containing EDTA solution is mixed with the support and the solvent is removed to obtain the catalyst precursor; S3. The catalyst precursor is calcined to obtain a Pd single-atom catalyst.

4. The synthesis method according to claim 3, characterized in that, In step S1: The Pd salt is palladium nitrate; The EDTA salt is EDTA-2Na.

5. The synthesis method according to claim 3, characterized in that, In step S2, the mixing temperature is 90~100℃; In step S3: The calcination is carried out in a protective atmosphere; The calcination temperature is 100~300℃, and the holding time is 2~4h.

6. The synthesis method according to claim 1, characterized in that, The ratio of the Pd single-atom catalyst to 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one is (30~50) mg:1 mmol; The molar ratio of the alkaline substance to 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one is 100%~300%; The molar ratio of 4-(4-fluoro-3-iodobenzyl)phthalazine-1(2H)-one and 1-cyclopropionylpiperazine is 1:(0.8~1.2); The gas pressure of the carbon monoxide is 1~10 atm.

7. The synthesis method according to claim 1, characterized in that, The reaction temperature is 20~120℃.

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