A method for preparing high-purity olaparib
By improving the synthetic route of olaparib and employing the Wittig reaction and acyl chloride treatment, the problems of low purity and yield in the existing technology have been solved, and high-purity and high-yield olaparib preparation has been achieved, which is suitable for industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HEFEI CHUANGXIN MEDICINE TECH CO LTD
- Filing Date
- 2023-09-15
- Publication Date
- 2026-06-30
Smart Images
Figure QLYQS_1 
Figure BDA0004449859610000011 
Figure BDA0004449859610000012
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing high-purity olaparib. Background Technology
[0002] Olaparib (trade name: ynparza) is a poly(ADP-ribose) polymerase (PARP) inhibitor developed by AstraZeneca. It was approved by the FDA on December 19, 2014, for the treatment of ovarian and breast cancer with BRCA gene defects. The chemical name of olaparib is 1-(cyclopropanoyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine, with the following structural formula:
[0003]
[0004] Currently, the main synthetic routes and preparation methods for olaparib are as follows:
[0005] Route 1 (Reference J. Med. Chem., 2008, 51: 6581-6591):
[0006]
[0007] In this route, compound IV undergoes cyanohydrolysis and hydrazine hydrazine cyclization in a single step to yield compound V. However, in the actual synthesis process, incomplete cyanohydrolysis and hydrazine cyclization byproducts are present, resulting in low purity and yield. Furthermore, the reaction process is difficult to control during production. The condensation of compound V with cyclopropionylpiperazine uses HBTU and DIPEA, both of which are expensive. The yield of olaparib is only 38%, and purification is difficult, which is not conducive to industrial production.
[0008] Route 2 (CN103408552A):
[0009]
[0010] This route involves reacting phthalide with 2-fluoro-5-carboxybenzonitrile under sodium methoxide conditions to give 5-(2,3-dihydro-1,3-dioxo-1H-inden-2-yl)-2-fluorobenzonitrile. Then, under sodium hydroxide conditions, the cyano group is hydrolyzed to a carboxyl group, yielding a mixture of 2,3-dihydro-1,3-dioxo-1H-inden-2-yl)-2-fluorobenzoic acid and 5-(2-(2-carboxyphenyl)-2-oxoethyl-2-fluorobenzoic acid). This mixture is then reacted with hydrazine hydrate to give intermediate IV. While this route yields two products via cyano hydrolysis, and both can be converted to intermediate IV by hydrazine hydrate, the reaction is difficult to monitor, hindering large-scale production control.
[0011] Therefore, it is necessary to improve the preparation method of olaparib and provide a method for preparing high-purity olaparib suitable for industrial production. Summary of the Invention
[0012] This invention addresses the problems of existing technologies by providing a method for preparing high-purity olaparib. The method uses dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphate as a starting material. Compound 2 undergoes a Wittig reaction to generate compound 3. Compound 3 reacts with hydrazine hydrate to generate compound 4. Compound 4 is hydrolyzed and acidified to obtain compound 5. Compound 5 reacts with thionyl chloride to obtain compound 6. Compound 6 is then condensed with compounds 7 and 9 to obtain olaparib. This invention utilizes readily available raw materials, simple operation and post-processing, mild reaction conditions, a total yield of up to 90%, and a purity >99%. It is environmentally friendly and suitable for industrial production.
[0013] To achieve the above objectives, this invention provides a method for preparing high-purity olaparib, the reaction route of which is as follows:
[0014]
[0015] In a preferred embodiment, the preparation method includes the following steps:
[0016] 1) Using compound 1 ((3-oxo-1,3-dihydroisobenzofuran-1-yl)dimethyl phosphate) as a starting material, it reacts with compound 2 (2-fluoro-5-carboxymethyl benzoate) under the action of pyridine to generate compound 3 (2-fluoro-5-{[(1Z)-3-oxo-1,3-dihydro-2-benzofuran-1-yl]methyl}benzoate);
[0017] 2) Compound 3 reacts with hydrazine hydrate and acetic acid to give compound 4 (methyl 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoate);
[0018] 3) Compound 4 was hydrolyzed with sodium hydroxide to give compound 5 (2-fluoro-5-[(4-oxo-3,4-dihydrophthalic-1-yl)methyl]benzoic acid);
[0019] 4) Compound 5 reacts with an acyl chloride reagent to give compound 6 (2-fluoro-5-[(4-oxo-3,4-dihydrophthalic-1-yl)methyl]benzoyl chloride);
[0020] 5) Compound 8 (cyclopropionic acid) reacts with an acyl chloride reagent to give compound 9 (cyclopropionic acid chloride);
[0021] 6) Compounds 6, 7 (piperazine) and 9 were reacted with a condensing agent to obtain crude olaparib (compound 10), which was then purified to obtain high-purity olaparib.
[0022] In a preferred embodiment, in step 1), reaction solvent 1 is also added, wherein the reaction solvent 1 is ethyl acetate, the volume-to-mass ratio of reaction solvent 1 to compound 1 is 5-20 mL: 1 g, the molar ratio of compound 1 to compound 2 and pyridine is 1:1-1.5:1-1.5, preferably 1:1.1:1.1, and the reaction temperature is 0-40°C.
[0023] In a preferred embodiment, in step 2), reaction solvent 2 is added, wherein the reaction solvent 2 is methanol, the volume-to-mass ratio of reaction solvent 2 to compound 3 is 5-15 mL:1 g, the molar ratio of compound 3 to hydrazine hydrate is 1:1-3, the molar ratio of acetic acid to compound 3 is 3-7:1, and the reaction temperature is 30-60℃.
[0024] In a preferred embodiment, in step 3), a reaction solvent 3 is added, wherein the reaction solvent 3 is water, the volume-to-mass ratio of the reaction solvent 3 to the compound 4 is 5-15 mL:1 g, the molar ratio of the compound 4 to sodium hydroxide is 1:2-6, and the reaction temperature is 60-90°C.
[0025] In a preferred embodiment, in step 4), reaction solvent 4 is added, wherein the reaction solvent 4 is tetrahydrofuran, the volume-to-mass ratio of reaction solvent 4 to compound 5 is 4-10 mL: 1 g, the acyl chloride reagent is thionyl chloride, the molar ratio of compound 5 to acyl chloride reagent is 1:1-5, and the reaction conditions are reflux reaction for 3-7 h.
[0026] In a preferred embodiment, in step 5), a reaction solvent 5 is added, wherein the reaction solvent 5 is tetrahydrofuran; the volume-to-mass ratio of the reaction solvent 5 to compound 8 is 2-8 mL:1 g, the acyl chloride reagent is thionyl chloride, and the molar ratio of compound 8 to the acyl chloride reagent is 1:1-5, more preferably 1:1.5, and the reaction conditions are reflux reaction for 3-7 h.
[0027] In a preferred embodiment, in step 6), a reaction solvent 6 and an acid-binding agent are further added. The reaction solvent is at least one selected from acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, and toluene, preferably tetrahydrofuran, N,N-dimethylformamide, or N,N-dimethylacetamide, and most preferably tetrahydrofuran. The volume-to-mass ratio of reaction solvent 6 to compound 7 is 1-60 mL:1 g, more preferably 10-20 mL:1 g. The acid-binding agent is selected from potassium carbonate, triethylamine, and DIPEA. The compound 6, 7 and 9 contain at least one of pyridine, more preferably triethylamine; the molar ratio of the acid-binding agent to compound 7 is 1-3:1; the molar ratio of compound 6, compound 7 and compound 9 is 1:1-2:1-3; the condensing agent is selected from at least one of HOBT, HBTU, DCC and CDI, more preferably DCC; the molar ratio of the condensing agent to compound 7 is 1-5:1; the reaction temperature is -5-10℃, preferably 0-3℃; the dropping rate of the solution of compound 6 and compound 9 is 0.5-1.5 mL / min, preferably 1 mL / min.
[0028] In a preferred embodiment, in step 6), the crystallization solvent is selected from at least one of anhydrous ethanol, acetonitrile, n-propanol, acetone, and water; the volume-to-mass ratio of the crystallization solvent to the compound is 10-40 mL: 1 g.
[0029] In a preferred embodiment, the refining process in step 6) is as follows: the crude olaparib is redissolved in a crystallization solvent, stirred and heated to reflux, cooled, and crystallized; the crystallization solvent is selected from at least one of anhydrous ethanol, acetonitrile, n-propanol, acetone, and water, more preferably a mixed solvent of acetonitrile and acetone, or a mixed solvent of n-propanol, acetone, and water, and most preferably a mixed solvent of n-propanol, acetone, and water; in the mixed solvent of n-propanol, acetone, and water, the volume ratio of n-propanol, acetone, and water is 28:14-28:1.4-14, more preferably 28:17:6.
[0030] In a preferred embodiment, the preparation method specifically involves the following process:
[0031] 1) Compound 1 and Compound 2 were mixed in reaction solvent 1, pyridine was added dropwise and the reaction was kept at a constant temperature. The mixture was then concentrated, washed and dried to obtain Compound 3.
[0032] 2) Compound 3 was suspended in reaction solvent 2, hydrazine hydrate was added dropwise and the temperature was raised to react. Acetic acid was added and the reaction was continued at the temperature. The mixture was concentrated, washed and dried to obtain compound 4.
[0033] 3) Mix compound 4, sodium hydroxide and reaction solvent 3, heat to react, adjust pH to 3-4, stir to precipitate crystals, filter, and dry to obtain compound 5;
[0034] 4) Compound 5 was suspended in reaction solvent 4, and after adding an acyl chloride reagent, the mixture was refluxed, concentrated, washed, and dried to obtain compound 6;
[0035] 5) Compound 8 was suspended in reaction solvent 5, and after adding an acyl chloride reagent, the mixture was refluxed, concentrated, washed, and dried to obtain compound 9;
[0036] 6) Dissolve compounds 6 and 9 in reaction solvent 6 to prepare solutions of compound 6 with a mass-volume concentration of 0.1-0.3 g / mL and solutions of compound 9 with a mass-volume concentration of 0.1-0.3 g / mL. Dissolve compound 7, condensing agent, and acid-binding agent in reaction solvent 6. Add solutions of compound 6 and compound 9 dropwise and keep the reaction at a constant temperature. Add water to the reaction solution, stir and let stand. Separate the aqueous layer, wash, dry and concentrate the organic layer, add a crystallization solvent to dissolve and crystallize, filter and dry to obtain crude olaparib. After purification, obtain high-purity olaparib.
[0037] The solutions of compound 6 and compound 9 should be added at a slow and consistent rate to ensure reaction efficiency.
[0038] The beneficial effects of this invention are:
[0039] 1. This invention provides a method for preparing high-purity olaparib. The starting materials (3-oxo-1,3-dihydroisobenzofuran-1-yl) dimethyl phosphate (compound 1) and methyl 2-fluoro-5-carboxybenzoate (compound 2) are readily available and can be purchased commercially or prepared according to conventional chemical synthesis methods in the art.
[0040] 2. The process route of this invention is simple, the reaction conditions are mild, the controllability is strong, the yield is high, the cost is low, it is environmentally friendly, and it is suitable for industrial production.
[0041] 3. Step 1 of this invention is a typical Wittig reaction. The process is mature and the yield is high. Although there are isomers in the product, subsequent reactions can yield chiral products without affecting the product quality.
[0042] 4. In steps 2 and 3 of this invention, the reaction is first cyclized with hydrazine hydrate and then hydrolyzed, which avoids the defects of incomplete hydrolysis of cyano and incomplete cyclization of hydrazine hydrate byproducts in the one-pot cooking process, and the reaction process is not easy to control.
[0043] 5. In the synthesis step of olaparib in this invention, compounds 5 and 8 are chlorinated with thionyl chloride and then condensed with piperazine under condensing agent conditions, avoiding the use of HBTU and DIPEA in the traditional route, which greatly reduces production costs and improves purity and yield. Detailed Implementation
[0044] It is worth noting that the raw materials used in this invention are all commercially available products, and their sources are not specifically limited; unless otherwise specified, the methods of this invention are conventional methods in the field.
[0045] Example 1: Synthesis of Compound 3
[0046] (24.2 g, 0.100 mol) of compound 1 and (20.0 g, 0.110 mol) of compound 2 were mixed in 240 mL of ethyl acetate, stirred and cooled to 0-10 °C, and (8.7 g, 0.11 mol) of pyridine was added dropwise. After the addition was completed, the mixture was kept at 20-30 °C for 4-6 hours. After the reaction was completed, the ethyl acetate was concentrated, and the concentrate was mixed with 240 mL of water at room temperature, filtered, and dried to obtain 28.6 g of compound 3 (dry product), with a yield of 96%.
[0047] The results of the 1H NMR spectrum analysis are as follows: 1 H NMR (400MHz, MeOD), δ (ppm): 4.212 (s, 3H), 4.368 (s, 1H), 7.231-7.272 (t, J=8.2Hz, 1H), 7.339-7.417 ( m, 2H), 7.808-7.919 (m, 2H), 7.910-7.923 (d, J=5.2Hz, 1H), 8.222-8.247 (dd, J1=1.6Hz, J2=6.8Hz, 1H).
[0048] ESI-HRMS showed the molecular ion peak at m / z = 299.06 [M+H]. + The corresponding molecular weight is consistent with the theoretically calculated value (298.27) of the provided structural formula.
[0049] Example 2, Synthesis of Compound 4
[0050] 20.0 g (0.067 mol) of compound 3 was suspended in 160 mL of methanol, and 4.5 g (0.080 mol) of hydrazine hydrate was added dropwise. After the addition was completed, the temperature was raised to 60 °C and the reaction was maintained for 2 hours. Then, 20.1 g (0.335 mol) of acetic acid was added and the reaction was maintained for another 20 hours. After the reaction was completed, the solvent was removed by concentration. The concentrate was concentrated to dryness with 40 mL of water. The concentrate was then added to 100 mL of methanol and stirred at room temperature for 1 hour. The mixture was filtered and dried to obtain 19.5 g of compound 4 (dry product), with a yield of 93%.
[0051] The results of the 1H NMR spectrum analysis are as follows: 1H NMR (400MHz, MeOD), δ (ppm): 4.228 (s, 3H), 4.311 (s, 2H), 7.207-7.249 (t, J=8.4Hz, 1H), 7.351-7.430 ( m, 2H), 7.812-7.933 (m, 2H), 7.901-7.919 (d, J=7.2Hz, 1H), 8.218-8.245 (dd, J1=1.8Hz, J2=7.2Hz, 1H)
[0052] ESI-HRMS showed a molecular ion peak at m / z = 313.09 [M+H]. + The corresponding molecular weight is consistent with the theoretically calculated value (312.30) of the provided structural formula.
[0053] Example 3: Synthesis of Compound 5
[0054] (18.0 g, 0.058 mol) of compound 4, (9.3 g, 0.233 mol) of sodium hydroxide, and 180 mL of water were mixed and heated to 80 °C for 2 hours. The mixture was then cooled to 10-30 °C, and 2 mol / L hydrochloric acid was added to adjust the pH to 3-4. The mixture was stirred and crystallized for 1 hour. After filtration and drying, 16.3 g of compound 5 was obtained, with a yield of 95%.
[0055] The results of the 1H NMR spectrum analysis are as follows: 1 H NMR (400MHz, MeOD), δ (ppm): 4.319 (s, 2H), 7.198-7.236 (t, J=7.6Hz, 1H), 7.349-7.418 (m, 2H), 7.819-7.928 (m, 2H), 7.919-7.946 (d, J=10.8Hz, 1H), 8.224-8.246 (dd, J1=1.2Hz, J2=6.4Hz, 1H)
[0056] ESI-HRMS showed the molecular ion peak at m / z = 299.08 [M+H]. + The corresponding molecular weight is consistent with the theoretically calculated value (298.27) of the provided structural formula.
[0057] Example 4: Synthesis of Compound 10 (Olaparib)
[0058] Preparation of tetrahydrofuran solution of compound 6: 15.0 g (0.050 mol) of compound 5 was suspended in 105 mL of tetrahydrofuran, and 9.0 g (0.076 mol) of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed for 6 hours. After the reaction was completed, the reaction solvent was concentrated. The concentrate was further concentrated to dryness with 30 mL of tetrahydrofuran to obtain compound 6. Compound 6 was dissolved in 90 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 6 with a concentration of 0.18 g / mL, which was then used for later use.
[0059] Preparation of tetrahydrofuran solution of compound 9: (6.5 g, 0.076 mol) of compound 8 was suspended in 26 mL of tetrahydrofuran, and (13.6 g, 0.114 mol) of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed for 4 hours. After the reaction was completed, the reaction solvent was concentrated, and the concentrate was further concentrated to dryness with 20 mL of tetrahydrofuran to obtain compound 9. The prepared compound 9 was dissolved in 90 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 9 with a concentration of 0.09 g / mL, which was then used for later use.
[0060] (4.3 g, 0.050 mol) of compound 7, (19.8 g, 0.096 mol) of dicyclohexylcarbodiimide (DCC), and (9.7 g, 0.096 mol) of triethylamine were dissolved in 60 mL of tetrahydrofuran. The mixture was cooled to 0-3 °C, and the prepared tetrahydrofuran solutions of compounds 6 and 9 were slowly added dropwise simultaneously at a rate of approximately 1 mL / min. After the addition was complete, the mixture was kept at this temperature for 8 hours. Once the reaction was complete, 60 mL of water was added to the reaction mixture, and the mixture was stirred and allowed to stand. The aqueous layer was separated, and the organic layer was washed twice with 10% sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was concentrated. The mixture was then dissolved and crystallized in 90 mL of anhydrous ethanol, filtered, and dried to obtain 20.2 g of olaparib (93% yield, 99.5% purity, 0.20% dimer impurities).
[0061] The results of the 1H NMR spectrum analysis are as follows: 1 H NMR (400MHz, MeOD), δ (ppm): 0.713-0.769 (m, 4H), 1.904-1.989 (d, J=34Hz, 1H), 3.166-3.747 (m, 8H), 4.336 (s, 2H), 7.218-7.264 (t, J=9.2Hz, 1H), 7.368-7.465 (m, 2H), 7.813-7.916 (m, 2H), 7.958-7.977 (d, J=7.6Hz, 1H), 8.254-8.276 (dd, J1=1.2Hz, J2=6.4Hz, 1H).
[0062] ESI-HRMS showed the molecular ion peak at m / z = 435.18 [M+H]. +The corresponding molecular weight is consistent with the theoretically calculated value (434.47) of the provided structural formula.
[0063] Example 5: Synthesis of Compound 10 (Olaparib)
[0064] Preparation of tetrahydrofuran solution of compound 6: 15.0 g (0.050 mol) of compound 5 was suspended in 105 mL of tetrahydrofuran, and 9.0 g (0.076 mol) of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed for 6 hours. After the reaction was completed, the reaction solvent was concentrated. The concentrate was further concentrated to dryness with 30 mL of tetrahydrofuran to obtain compound 6. Compound 6 was dissolved in 90 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 6 with a concentration of 0.18 g / mL, which was then used for later use.
[0065] Preparation of tetrahydrofuran solution of compound 9: (6.5 g, 0.076 mol) of compound 8 was suspended in 26 mL of tetrahydrofuran, and (13.6 g, 0.114 mol) of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed for 4 hours. After the reaction was completed, the reaction solvent was concentrated, and the concentrate was further concentrated to dryness with 20 mL of tetrahydrofuran to obtain compound 9. The prepared compound 9 was dissolved in 90 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 9 with a concentration of 0.09 g / mL, which was then used for later use.
[0066] (4.3 g, 0.050 mol) of compound 7, (19.8 g, 0.096 mol) of dicyclohexylcarbodiimide (DCC), and (9.7 g, 0.096 mol) of triethylamine were dissolved in 60 mL of tetrahydrofuran. The mixture was cooled to 0-3 °C, and the prepared tetrahydrofuran solutions of compounds 6 and 9 were added dropwise over 10 minutes while maintaining the temperature at 0-3 °C. After the addition was complete, the mixture was kept at this temperature for 8 hours. Once the reaction was complete, 60 mL of water was added to the reaction mixture, and the mixture was stirred and allowed to stand. The aqueous layer was separated, and the organic layer was washed twice with 10% sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to remove the solvent, dissolved in 90 mL of anhydrous ethanol, and crystallized. The crystals were filtered, dried, and 18.8 g of olaparib was obtained, with a yield of 85% (purity 97.1%, dimer impurities 2.1%).
[0067] Example 6: Synthesis of Compound 10 (Olaparib)
[0068] Preparation of tetrahydrofuran solution of compound 6: 15.0 g (0.050 mol) of compound 5 was suspended in 105 mL of tetrahydrofuran, and 9.0 g (0.076 mol) of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed for 6 hours. After the reaction was completed, the reaction solvent was concentrated. The concentrate was further concentrated to dryness with 30 mL of tetrahydrofuran to obtain compound 6. Compound 6 was dissolved in 90 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 6 with a concentration of 0.18 g / mL, which was then used for later use.
[0069] Preparation of tetrahydrofuran solution of compound 9: (6.5 g, 0.076 mol) of compound 8 was suspended in 26 mL of tetrahydrofuran, and (13.6 g, 0.114 mol) of thionyl chloride was added dropwise. After the addition was complete, the mixture was refluxed for 4 hours. After the reaction was completed, the reaction solvent was concentrated, and the concentrate was further concentrated to dryness with 20 mL of tetrahydrofuran to obtain compound 9. The prepared compound 9 was dissolved in 90 mL of tetrahydrofuran to obtain a tetrahydrofuran solution of compound 9 with a concentration of 0.09 g / mL, which was then used for later use.
[0070] (4.3 g, 0.050 mol) of compound 7, (19.8 g, 0.096 mol) of dicyclohexylcarbodiimide (DCC), and (9.7 g, 0.096 mol) of triethylamine were dissolved in 60 mL of tetrahydrofuran. The mixture was cooled to 5–10 °C, and the prepared tetrahydrofuran solutions of compounds 6 and 9 were slowly added dropwise simultaneously at a rate of approximately 1 mL / min while maintaining the temperature at 5–10 °C. After the addition was complete, the mixture was kept at this temperature for 8 hours. Once the reaction was complete, 60 mL of water was added to the reaction mixture, and the mixture was stirred and allowed to stand. The aqueous layer was separated, and the organic layer was washed twice with 10% sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to remove the solvent, dissolved in 90 mL of anhydrous ethanol to crystallize, filtered, and dried to obtain 19.8 g of dried olaparib, with a yield of 89% (purity 98.3%, dimer impurities 0.66%).
[0071] Example 7: Refining of Compound 10 (Olaparib)
[0072] 4.0 g of compound 10 (purity 99.5%, dimer impurity 0.20%) was added to 50 mL of anhydrous ethanol, stirred and heated to reflux. After the solution was clear, it was filtered while hot. The filtrate was cooled to 30-40℃ and a large amount of solid was precipitated. Then it was cooled to 10-15℃ and stirred for 2 hours, filtered, and dried to obtain 3.4 g of compound 10 dry product, with a yield of 85% (purity 99.7%, dimer impurity 0.18%).
[0073] Example 8: Refining of Compound 10 (Olaparib)
[0074] 4.0 g of compound 10 (purity 99.5%, dimer impurity 0.20%) was added to 50 mL of acetonitrile, stirred and heated to reflux. After the solution was clear, it was filtered while hot. The filtrate was cooled to 30-40℃ and a large amount of solid was precipitated. Then it was cooled to 10-15℃ and stirred for 2 hours, filtered, and dried to obtain 3.32 g of compound 10 dry product, with a yield of 83% (purity 99.8%, dimer impurity 0.15%).
[0075] Example 9: Refining of Compound 10 (Olaparib)
[0076] 4.0 g of compound 10 (purity 99.5%, dimer impurity 0.20%) was added to a mixture of 25 mL acetonitrile and 25 mL acetone. The mixture was stirred and heated to reflux. After the solution was clear, it was filtered while hot. The filtrate was cooled until a large amount of solid precipitated. Then the temperature was lowered to 10-15℃ and stirred for 2 hours. The mixture was then filtered and dried to obtain 3.4 g of dry compound 10, with a yield of 85% (purity 99.8%, dimer impurity 0.10%).
[0077] Example 10: Refining of Compound 10 (Olaparib)
[0078] 4.0 g of compound 10 (purity 99.5%, dimer impurity 0.20%) was added to a mixture of 28 mL n-propanol, 17 mL acetone and 6 mL water. The mixture was stirred and heated to reflux. After the solution was clear, it was filtered while hot. The filtrate was cooled and a large amount of solid was precipitated. The temperature was then lowered to 10-15 °C and stirred for 2 hours before filtration and drying. 3.64 g of compound 10 was obtained, with a yield of 91% (purity 99.9%, dimer impurity 0.04%).
[0079] The present invention is not limited to the technical means disclosed above, but also includes technical solutions composed of any combination of the above technical features. The above descriptions are specific embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications are also considered within the scope of protection of the present invention.
Claims
1. A method for preparing high-purity olaparib, characterized in that, The reaction route is as follows: Includes the following steps: 1) Using compound 1 as a raw material, compound 2 reacts with compound 2 in the presence of pyridine to produce compound 3; 2) Compound 3 reacts with hydrazine hydrate and acetic acid to give compound 4; 3) Compound 4 was hydrolyzed with sodium hydroxide to give compound 5; 4) Compound 5 reacts with an acyl chloride reagent to give compound 6; 5) Compound 8 reacts with an acyl chloride reagent to give compound 9; 6) Compounds 6, 7 and 9 were reacted with a condensing agent to obtain crude olaparib, which was then purified to obtain high-purity olaparib.
2. The preparation method according to claim 1, characterized in that, In step 1), reaction solvent 1 is added, wherein the reaction solvent 1 is ethyl acetate, the volume-to-mass ratio of reaction solvent 1 to compound 1 is 5-20 mL: 1 g, the molar ratio of compound 1 to compound 2 and pyridine is 1:1-1.5:1-1.5, and the reaction temperature is 0-40℃.
3. The preparation method according to claim 1, characterized in that, In step 2), reaction solvent 2 is added, wherein the reaction solvent 2 is methanol, the volume-to-mass ratio of reaction solvent 2 to compound 3 is 5-15 mL:1 g, the molar ratio of compound 3 to hydrazine hydrate is 1:1-3, the molar ratio of acetic acid to compound 3 is 3-7:1, and the reaction temperature is 30-60℃.
4. The preparation method according to claim 1, characterized in that, In step 3), reaction solvent 3 is added, wherein the reaction solvent 3 is water, the volume-to-mass ratio of reaction solvent 3 to compound 4 is 5-15 mL:1 g, the molar ratio of compound 4 to sodium hydroxide is 1:2-6, and the reaction temperature is 60-90℃.
5. The preparation method according to claim 1, characterized in that, In step 4), reaction solvent 4 is added, wherein the reaction solvent 4 is tetrahydrofuran, and the volume-to-mass ratio of reaction solvent 4 to compound 5 is 4-10 mL: 1 g. The acyl chloride reagent is thionyl chloride, and the molar ratio of compound 5 to acyl chloride reagent is 1:1-5. The reaction conditions are reflux reaction for 3-7 h.
6. The preparation method according to claim 1, characterized in that, In step 5), reaction solvent 5 is added, wherein the reaction solvent 5 is tetrahydrofuran; the volume-to-mass ratio of reaction solvent 5 to compound 8 is 2-8 mL: 1 g, the acyl chloride reagent is thionyl chloride, the molar ratio of compound 8 to acyl chloride reagent is 1:1-5, and the reaction conditions are reflux reaction for 3-7 h.
7. The preparation method according to claim 2, characterized in that, In step 6), reaction solvent 6 and acid-binding agent are also added. The reaction solvent is at least one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, and toluene. The volume-to-mass ratio of reaction solvent 6 to compound 7 is 1-60 mL:1 g. The acid-binding agent is selected from at least one of potassium carbonate, triethylamine, DIPEA, and pyridine. The molar ratio of acid-binding agent to compound 7 is 1-3:
1. The molar ratio of compound 6, compound 7, and compound 9 is 1:1-2:1-3. The condensing agent is selected from at least one of HOBT, HBTU, DCC, and CDI. The molar ratio of condensing agent to compound 7 is 1-5:
1. The reaction temperature is -5-10℃. The dropping rate of the solutions of compound 6 and compound 9 is 0.5-1.5 mL / min.
8. The preparation method according to claim 1, characterized in that, The refining process in step 6) is as follows: the crude olaparib is redissolved in a crystallization solvent, stirred and heated to reflux, cooled and crystallized; the crystallization solvent is selected from at least one of anhydrous ethanol, acetonitrile, n-propanol, acetone and water; the volume-to-mass ratio of the crystallization solvent to the compound is 10-40 mL: 1 g.
9. The preparation method according to claim 1, characterized in that, The specific process of the preparation method is as follows: 1) Compound 1 and Compound 2 were mixed in reaction solvent 1, pyridine was added dropwise and the reaction was kept at a constant temperature. The mixture was then concentrated, washed and dried to obtain Compound 3. 2) Compound 3 was suspended in reaction solvent 2, hydrazine hydrate was added dropwise and the temperature was raised to react. Acetic acid was added and the reaction was continued at the temperature. The mixture was concentrated, washed and dried to obtain compound 4. 3) Mix compound 4, sodium hydroxide and reaction solvent 3, heat to react, adjust pH to 3-4, stir to precipitate crystals, filter, and dry to obtain compound 5; 4) Compound 5 was suspended in reaction solvent 4, and after adding an acyl chloride reagent, the mixture was refluxed, concentrated, washed, and dried to obtain compound 6; 5) Compound 8 was suspended in reaction solvent 5, and after adding an acyl chloride reagent, the mixture was refluxed, concentrated, washed, and dried to obtain compound 9; 6) Dissolve compounds 6 and 9 in reaction solvent 6 to prepare solutions of compound 6 with a mass-volume concentration of 0.1-0.3 g / mL and solutions of compound 9 with a mass-volume concentration of 0.1-0.3 g / mL. Dissolve compound 7, condensing agent, and acid-binding agent in reaction solvent 6. Add solutions of compound 6 and compound 9 dropwise and keep the reaction at a constant temperature. Add water to the reaction solution, stir and let stand. Separate the aqueous layer, wash, dry and concentrate the organic layer, add a crystallization solvent to dissolve and crystallize, filter and dry to obtain crude olaparib. After purification, obtain high-purity olaparib.