Preparation method of olaparib intermediate

Abstract

The invention discloses a method for preparing an olaparib key intermediate compound as shown in a formula (1). The method comprises the following steps: (a) reacting a compound as shown in a formula (2) with a compound as shown in a formula (3) to generate a compound as shown in a formula (4); (b) carrying out intramolecular cyclization on the compound as shown in the formula (4) under the catalysis of acid to generate a compound as shown in a formula (5); (c) hydrolyzing the compound as shown in the formula (5) in an alkali solution, and acidifying to obtain a compound as shown in a formula (1); wherein in the compounds as shown in the formula (3), the formula (4) and the formula (5), R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, t-butyloxycarbonyl, methylsulfonyl, benzenesulfonyl or p-toluenesulfonyl. The invention also discloses a compound shown in a formula (4) or a formula (5). The method is high in yield, mild in reaction condition, easy to purify and suitable for industrial large-scale production. # imgabs0 #

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of September 15, 2021, an application number of 202111081997.4, and an invention title of "Preparation Method of an Olaparib Intermediate". Technical Field

[0002] The present invention belongs to the technical field of pharmaceutical synthesis, and specifically relates to a preparation method of an olaparib intermediate. Background Art

[0003] Olaparib, chemically named 1-(cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine, has a structure as shown in 6. It was initially developed by KuDOS Pharmaceuticals and then continued to be developed by AstraZeneca after acquisition. It has obtained priority review qualifications from the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), and was approved for marketing in Europe on December 18, 2014, and in the US on December 19, 2014. The trade name is Lynparza TM , and is used to treat advanced ovarian cancer in women associated with BRCA gene defects in ovarian cancer.

[0004]

[0005] Olaparib is a novel oral poly(ADP-ribose) polymerase [PARP] inhibitor that acts on BRCA1 or BRCA2 mutations. It takes advantage of the defects in the DNA repair pathway to preferentially kill cancer cells. The intrinsic mechanism of chemotherapy sensitivity lies in the important role of BRCA proteins in DNA homologous recombination. For patients lacking recombination, they rely on the PARP single-strand repair signaling pathway. PARP inhibitors prevent the DNA damage self-repair ability of tumor cells and have a killing effect on tumor cells. As a PARP inhibitor, olaparib has shown better tumor suppression effects in phase I clinical trials and randomized trials compared with liposomal doxorubicin.

[0006] 5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1) is a key intermediate for the synthesis of olaparib. Compound 1 reacts with cyclopropylcarbonyl piperazine under the action of a condensing agent, a base, and a solvent to form olaparib (6):

[0007]

[0008] For the synthesis of the key intermediate 1, WO2004080976, US20050059663 and CN1788000B disclose that o-carboxybenzaldehyde 7 reacts with dimethyl phosphite to form a phosphonate compound 8, which then undergoes a Wittig reaction with 4-fluoro-3-cyanobenzaldehyde to form 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuran-ylidene)methyl]benzonitrile (2); Intermediate 2 is first hydrolyzed in an alkaline solution and then cyclized with hydrazine hydrate to form the key intermediate 1:

[0009]

[0010] When this route is used for the hydrolysis and cyclization reactions of intermediate 2, the reaction conditions are harsh, the reaction is difficult to proceed completely, and during the reaction process, impurities with similar properties are generated, and it is difficult to remove them completely during post-treatment; the reaction time is long, and the reaction aids sodium hydroxide and the reactant hydrazine hydrate both need to be greatly in excess to react more completely, resulting in low production efficiency.

[0011] CN104649979B discloses another method for preparing the key intermediate 1, which is to first cyclize intermediate 2 with hydrazine hydrate to form a phthalazinone intermediate 12, and then hydrolyze it to hydrolyze the cyano group to a carboxylic acid to obtain the key intermediate 1:

[0012]

[0013] This route is prone to the formation of hydrazide impurities and defluorination impurities during the reaction. Since the impurities have similar properties to the main product, it is difficult to remove them completely during post-treatment, affecting the product quality. Summary of the Invention

[0014] Aiming at the above-mentioned defects of the prior art, an object of the present invention is to provide a method for preparing olaparib key intermediate 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1) with high yield, mild reaction conditions, easy purification and suitable for industrial scale-up production.

[0015] Another object of the present invention is to provide two new intermediates for the preparation of olaparib.

[0016] The object of the present invention is achieved by the following technical solutions:

[0017] On the one hand, the present invention provides a method for preparing a compound represented by formula (1), comprising the following steps:

[0018]

[0019] (a) Reacting a compound represented by formula (2) with a compound represented by formula (3) to form a compound represented by formula (4);

[0020] (b) Intramolecular cyclization of the compound represented by formula (4) is carried out under acid catalysis to form the compound represented by formula (5);

[0021] (c) The compound represented by formula (5) is hydrolyzed in an alkaline solution and then acidified to obtain the compound represented by formula (1);

[0022] Among the compounds represented by formula (3), formula (4) and formula (5), R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, mesyl, benzenesulfonyl or p-toluenesulfonyl.

[0023] Preferably, in step (a), the reaction is carried out in a polar aprotic solvent.

[0024] More preferably, in step (a), the polar aprotic solvent is selected from one or more of methyl tert-butyl ether, isopropyl ether, dibutyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, DMF, DMSO and NMP.

[0025] Preferably, in step (b), the acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, glacial acetic acid and phosphoric acid.

[0026] Preferably, in step (c), the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.

[0027] Preferably, in step (c), the hydrolysis is carried out at a temperature of 60-80 °C.

[0028] Preferably, in step (c), the hydrolysis is carried out in a mixed solvent of water and another solvent; more preferably, the other solvent is selected from one or more of methanol, ethanol, tetrahydrofuran and isopropanol; further preferably, the volume ratio of water to the other solvent is 1:0.2-5. The inventors unexpectedly found that using a mixed solvent can further reduce the generation of impurities in the reaction.

[0029] Preferably, in step (c), the acidification is carried out by dropping hydrochloric acid, sulfuric acid or glacial acetic acid into the mixture after the hydrolysis reaction is completed.

[0030] On the other hand, the present invention provides a compound represented by formula (4) or formula (5):

[0031]

[0032] Among them, R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, mesyl, benzenesulfonyl or p-toluenesulfonyl.

[0033] Compared with the synthetic routes disclosed in the prior art documents, the preparation method using the route of the present invention can proceed more completely, produce fewer impurities, and the impurities are easily removed completely in the post-treatment, and it is easy to obtain qualified products. The method for preparing the key intermediate 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1) of olaparib of the present invention has a high yield, mild reaction conditions, the product is easy to purify, and the product purity is high, which is suitable for industrial scale-up production. Detailed implementation manners

[0034] The present invention will be further described below in conjunction with specific embodiments. These embodiments are only for explaining the present invention and do not mean to limit the content of the present invention in any way.

[0035] Example 1 :

[0036] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone acetylhydrazone (19)

[0037]

[0038] Add tetrahydrofuran (60 ml), acetylhydrazine (10.05 g, 135.0 mmol) and glacial acetic acid (0.68 g, 11.3 mmol) to a 250 ml round-bottom flask. After stirring evenly, add 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuran-1-ylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol), stir evenly, and heat up to 60 °C for reaction for 15 hours. After the reaction is completed, slowly add water (120 ml) dropwise while reducing the temperature of the reaction solution to 15-25 °C. Continue stirring for 30 minutes, stir evenly, filter, and wash with an appropriate amount of water. The filter cake is dried to obtain 37.3 g of a white solid product, with a yield of 97.2%. 1 HNNR(600MHz,DMSO-d6+D2O)δ:7.60-7.55(3H,m),7.48-7.44(2H,m),7.20(1H,t,J=9.0Hz),7.13(1H,m),3.33(1H,d,J=13.8Hz),3.07(1H,d,J=13.8Hz),2.03(3H,s).MS(ESI):m / z=322.1[(M-H2O+H) + ,362.1[(M+Na) + .

[0039] Step B: Synthesis of 2-fluoro-5-[(3-acetyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (28)

[0040]

[0041] Add tetrahydrofuran (45 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone acetylhydrazone (19) (15 g, 44.2 mmol) to a 250 ml three-necked flask. After stirring evenly, add glacial acetic acid (3.98 g, 66.3 mmol), and heat to 60 °C and stir for 8 hours. After the reaction is completed, take 1 ml of the reaction solution, purify it by silica gel column to obtain a white solid product, and perform structure identification. 1 HNNR (400 MHz, CDCl3) δ: 8.52 - 8.50 (1H, m), 7.82 - 7.77 (2H, m), 7.66 - 7.64 (1H, m), 7.58 - 7.55 (2H, m), 7.20 - 7.16 (1H, m), 4.35 (2H, s), 2.69 (3H, s). MS (ESI): m / z = 322.1 [(M + H) + . The reaction solution is directly subjected to the next reaction.

[0042] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0043]

[0044] Add a solution of sodium hydroxide (8.83 g, 221 mmol) dissolved in water (50 ml) to the reaction solution of 2-fluoro-5-[(3-acetyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (28) in Step B, and reflux for 15 hours. After the reaction is completed, slowly add concentrated hydrochloric acid to the reaction solution to adjust the pH value to 2 - 3. The solid product precipitates, the reaction solution slowly cools to room temperature, continue to stir for 1 hour, filter, wash the solid cake with an appropriate amount of water, and dry the wet solid in a blast drying oven at 90 °C to obtain a white solid product (12.85 g). Calculated, the overall yield of the two steps of Step B and Step C is 92.3%. The product is detected by liquid chromatography, the purity is greater than 99%, and the maximum single impurity content is 0.05%, meeting the quality standard requirements. 1 HNNR (400 MHz, DMSO-d6) δ: 13.21 (1H, bs), 12.59 (1H, s), 8.28 - 8.26 (1H, m), 7.99 - 7.81 (4H, m), 7.60 - 7.56 (1H, m), 7.24 (1H, dd, J = 10.4, 8.4 Hz), 4.36 (2H, s). MS (ESI): m / z = 299.1 [(M + H) + .

[0045] Example 2 :

[0046] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone benzoylhydrazone (21)

[0047]

[0048] Add dioxane (60 ml), benzoylhydrazine (18.4 g, 135.0 mmol) and p-toluenesulfonic acid (1.9 g, 11.3 mmol) to a 250 ml round-bottom flask. After stirring evenly, add 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuran-1-ylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol). After stirring evenly, heat the reaction solution to 80 - 90 °C and react for 12 hours. After the reaction is completed, slowly add water (120 ml) dropwise while reducing the temperature of the reaction solution to 15 - 25 °C. Continue stirring for 30 minutes. After stirring evenly, filter and wash with an appropriate amount of water. Dry the filter cake to obtain 43.4 g of a white solid product with a yield of 95.6%. MS(ESI): m / z = 402.1[(M + H) + , 424.1[(M + Na) + .

[0049] Step B: Synthesis of 2-fluoro-5-[(3-benzoyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (29)

[0050]

[0051] Add tetrahydrofuran (30 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone benzoylhydrazone (21) (12 g, 29.9 mmol) to a 250 ml three-necked flask. After stirring evenly, add methanesulfonic acid (4.31 g, 44.9 mmol) and stir at 60 °C for 8 hours. After the reaction is completed, take 0.5 ml of the reaction solution, purify it by silica gel column to obtain a white solid product, and perform structure identification. MS(ESI): m / z = 384.3[(M + H) + . The reaction solution is directly used for the next step of the reaction.

[0052] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0053]

[0054] To the reaction solution of 2-fluoro-5-[(3-benzoyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (29) in step B, a solution of lithium hydroxide monohydrate (6.28 g, 149.5 mmol) dissolved in water (60 ml) was added, and the mixture was refluxed for 12 hours. After the reaction was completed, concentrated hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH value to 2 - 3. The solid product precipitated, and the reaction solution was slowly cooled to room temperature. Stirring was continued for 1 hour, followed by filtration. The solid cake was washed with an appropriate amount of water, and the wet solid was dried in a blast drying oven at 90 °C to obtain a white solid product (8.40 g). Calculated, the overall yield of the two steps of step B and step C was 94.2%. The product was detected by liquid chromatography, with a purity greater than 99%, and the maximum single impurity content was 0.06%, meeting the quality standard requirements. 1 HNNR(400MHz,DMSO-d6)δ:13.21(1H,bs),12.59(1H,s),8.28 - 8.26(1H,m),7.99 - 7.81(4H,m),7.60 - 7.56(1H,m),7.24(1H,dd,J=10.4,8.4Hz),4.36(2H,s).MS(ESI):m / z=299.1[(M+H) + 。

[0055] Example 3 :

[0056] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-methoxycarbonylhydrazone (23) 2

[0057]

[0058] Isopropyl ether (60 ml), methoxycarbonylhydrazine (12.2 g, 135.0 mmol), and trifluoroacetic acid (1.29 g, 11.3 mmol) were added to a 250 ml round-bottom flask. After stirring evenly, 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuran-ylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol) was added. After stirring evenly, the reaction solution was heated to 60 - 68 °C and reacted for 16 hours. After the reaction was completed, most of the solvent was removed by distillation, and then water (120 ml) was slowly added dropwise while the temperature of the reaction solution was lowered to 15 - 25 °C. Stirring was continued for 30 minutes. After stirring evenly, filtration was carried out, and the filter cake was washed with an appropriate amount of water. The filter cake was dried to obtain 37.7 g of a white solid product with a yield of 93.8%. MS(ESI): m / z = 356.1[(M+H) + ,378.1[(M+Na) + 。

[0059] Step B: Synthesis of 2-Fluoro-5-[(3-methoxycarbonyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (30)

[0060]

[0061] Add methanol (40 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-methoxycarbonylhydrazone (23) (15 g, 42.2 mmol) into a 250 ml three-necked flask. After stirring evenly, add trifluoromethanesulfonic acid (8.75 g, 63.3 mmol), and stir at 60 °C for 10 hours. After the reaction is completed, take 0.5 ml of the reaction solution, purify it by silica gel column to obtain a white solid product, and conduct structure identification. MS(ESI): m / z = 337.1 [(M+H) + . The reaction solution is directly used for the next reaction.

[0062] Step C: Synthesis of 5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0063]

[0064] Add a solution of potassium hydroxide (9.47 g, 168.8 mmol) dissolved in water (40 ml) to the reaction solution of 2-fluoro-5-[(3-methoxycarbonyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (30) in Step B, and reflux for 12 hours. After the reaction is completed, slowly add concentrated hydrochloric acid to the reaction solution to adjust the pH value to 2 - 3. The solid product precipitates. The reaction solution is slowly cooled to room temperature, and stirring is continued for 1 hour. Filter, wash the solid cake with an appropriate amount of water, and dry the wet solid product in a blast drying oven at 90 °C to obtain a white solid product (11.66 g). Calculated, the overall yield of the two steps of Step B and Step C is 92.6%. The product is detected by liquid chromatography, with a purity greater than 99%, and the maximum single impurity content is 0.06%, meeting the quality standard requirements. 1 HNNR(400MHz,DMSO-d6)δ:13.21(1H,bs),12.59(1H,s),8.28 - 8.26(1H,m),7.99 - 7.81(4H,m),7.60 - 7.56(1H,m),7.24(1H,dd,J = 10.4,8.4Hz),4.36(2H,s).MS(ESI): m / z = 299.1 [(M+H) + .

[0065] Example 4 :[[]]

[0066] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone tert-butoxycarbonylhydrazone (25)

[0067]

[0068] Add DMF (60 ml), tert-butoxycarbonylhydrazine (17.84 g, 135.0 mmol) and concentrated sulfuric acid (0.55 g, 5.6 mmol) into a 250 ml round-bottom flask. After stirring evenly, add 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuran-ylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol). After stirring evenly, heat the reaction solution to 60 - 70 °C and react for 10 hours. After the reaction is completed, slowly add water (200 ml) dropwise while reducing the temperature of the reaction solution to 15 - 25 °C. Continue to stir for 30 minutes. After stirring evenly, filter and wash with an appropriate amount of water. Dry the filter cake to obtain 43.46 g of a white solid product with a yield of 96.7%. MS(ESI): m / z = 298.1 [(M - Boc + H)] + , 397.1 [(M + H) + .

[0069] Step B: Synthesis of 2-fluoro-5-[(3-tert-butoxycarbonyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (31)

[0070]

[0071] Add isopropanol (40 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone tert-butoxycarbonylhydrazone (25) (15 g, 37.7 mmol) into a 250 ml three-necked flask. After stirring evenly, add acetic acid (3.4 g, 56.6 mmol) and stir at 60 °C for 8 hours. After the reaction is completed, take 0.5 ml of the reaction solution, purify it by silica gel column to obtain a white solid product, and conduct structure identification. MS(ESI): m / z = 298.2 [(M - Boc + H) + , 398.2 [(M + H) + . Directly carry out the next step reaction on the reaction solution.

[0072] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0073]

[0074] To the reaction solution of 2-fluoro-5-[(3-tert-butoxycarbonyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (31) in step B, add a solution of sodium hydroxide (7.54 g, 188.8 mmol) dissolved in water (30 ml). Heat the mixture to 80 °C and carry out a gentle reflux reaction for 12 hours. After the reaction is completed, slowly add concentrated hydrochloric acid dropwise to the reaction solution to adjust the pH value to 2 - 3. A solid product will precipitate. Let the reaction solution cool slowly to room temperature and continue stirring for 1 hour. Then filter, wash the solid cake with an appropriate amount of water, and dry the wet solid in a forced-air oven at 90 °C to obtain a white solid product (10.61 g). Calculated, the overall yield of the two steps of step B and step C is 94.2%. The product is detected by liquid chromatography, with a purity greater than 99%, and the maximum single impurity content is 0.06%, meeting the quality standard requirements. 1 HNNR(400MHz,DMSO-d6)δ:13.21(1H,bs),12.59(1H,s),8.28 - 8.26(1H,m),7.99 - 7.81(4H,m),7.60 - 7.56(1H,m),7.24(1H,dd,J=10.4,8.4Hz),4.36(2H,s).MS(ESI):m / z=299.1[(M + H) + .

[0075] Example 5 :

[0076] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-benzenesulfonylhydrazone (27)

[0077]

[0078] Add DMSO (60 ml), benzenesulfonylhydrazide (23.25 g, 135.0 mmol), and p-toluenesulfonic acid (1.9 g, 11.3 mmol) to a 250 ml round-bottom flask. After stirring evenly, add 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuran-ylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol). After stirring evenly, heat the reaction solution to 80 - 90 °C and react for 12 hours. After the reaction is completed, slowly add water (120 ml) dropwise while reducing the temperature of the reaction solution to 15 - 25 °C. Continue stirring for 30 minutes. After stirring evenly, filter and wash with an appropriate amount of water. Dry the filter cake to obtain 47.4 g of a white solid product with a yield of 95.8%. MS(ESI): m / z = 438.1[(M + H) + , 460.1[(M + Na) + .

[0079] Step B: Synthesis of 2-Fluoro-5-[(3-phenylsulfonyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (32)

[0080]

[0081] Add ethanol (50 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone phenylsulfonylhydrazone (27) (20 g, 45.7 mmol) into a 250 ml three-necked flask. After stirring evenly, add sulfuric acid (6.7 g, 68.6 mmol), and stir at 60 °C for 8 hours. After the reaction is completed, take 0.5 ml of the reaction solution, purify it by silica gel column to obtain a white solid product, and perform structure identification. MS (ESI): m / z = 420.1 [(M+H) + . The reaction solution is directly used for the next reaction.

[0082] Step C: Synthesis of 5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0083]

[0084] Add a solution of sodium hydroxide (9.15 g, 228.5 mmol) dissolved in water (30 ml) to the reaction solution of 2-fluoro-5-[(3-phenylsulfonyl-4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzonitrile (32) in Step B, and reflux for 15 hours. After the reaction is completed, slowly add concentrated hydrochloric acid to the reaction solution to adjust the pH value to 2-3. The solid product precipitates, and the reaction solution is slowly cooled to room temperature and stirred for 1 hour. Filter, wash the solid cake with an appropriate amount of water, and dry the wet solid in a blast drying oven at 90 °C to obtain a white solid product (12.52 g). Calculated, the overall yield of the two steps of Step B and Step C is 91.8%. The product is detected by liquid chromatography, with a purity greater than 99% and the maximum single impurity content of 0.07%, meeting the quality standard requirements. 1 HNNR (400 MHz, DMSO-d6) δ: 13.21 (1H, bs), 12.59 (1H, s), 8.28 - 8.26 (1H, m), 7.99 - 7.81 (4H, m), 7.60 - 7.56 (1H, m), 7.24 (1H, dd, J = 10.4, 8.4 Hz), 4.36 (2H, s). MS (ESI): m / z = 299.1 [(M+H) + .

[0085] Comparative Example 1: Prepare 5-[(3,4-Dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1) according to the method of Example 4 of Patent CN104649979B

[0086]

[0087] (A) Preparation of Compound 12

[0088] 2-Fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2) (20 g, 75.40 mmol) and tetrahydrofuran (200 mL) were stirred in nitrogen at room temperature for 30 minutes. Hydrazine monohydrate (4.40 mL, 90.53 mmol) was added, followed by tetrahydrofuran (4 mL) to wash the pipeline. The reaction mixture was stirred at room temperature for 1 hour and 45 minutes. Acetic acid (1.10 ml, 19.20 mmol) was added, and the reaction mixture was heated to 60 °C and stirred overnight while maintaining the temperature. The reaction mixture was cooled to 50 °C, and water (200 ml) was added dropwise. The temperature was maintained at 45 °C during the addition process. The reaction mixture was cooled to 20 °C, filtered, washed with water (30 ml) and tetrahydrofuran (30 ml), and the wet solid was dried under vacuum at a temperature below 40 °C to obtain a white solid product (12, 18.2 g, yield 86.4%). The product was detected by liquid chromatography, with a purity greater than 99%, the content of impurity 33 being 0.18%, and this impurity was difficult to remove in the subsequent treatment process.

[0089]

[0090] (B) Preparation of Compound (1)

[0091] The obtained solid product 12 (9.60 g, 34.37 mmol) was taken, and water (40 ml) was added and stirred at 20 °C. Sodium hydroxide solution (2.0 mol / L, 36 ml, 72.0 mmol) was added, and the reaction mixture was heated to 90 °C and stirred overnight. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with water (10 ml). The filtrates were combined, heated to 60 °C, and hydrochloric acid (2.0 mmol / L, 56 ml, 112.0 mmol) was added dropwise over 40 minutes. The resulting suspension was cooled to 50 °C, filtered, and the solid was washed with water (57 ml). The wet solid was dried under vacuum at a temperature below 60 °C to obtain a white solid product 1 (9.76 g, yield 95.2%). The product was detected by liquid chromatography, with a purity greater than 99%, the content of impurity 33 being 0.13%, and the content of the newly generated impurity 34 being 0.27%.

[0092]

[0093] In order to reduce the content of each impurity to below the standard limit (0.1%), various methods were tried for purification. Among them, the following method had relatively good purification effect and relatively small product loss, but there was still a large amount of product loss:

[0094] The solid product (9.0 g) was heated and dissolved in DMF (90 mL) until clear, cooled to 0 °C, and the solid was filtered. The wet solid was washed with DMF (10 mL). The product was sampled and tested, and impurity 33 was reduced to 0.06%, while impurity 34 was hardly reduced. Since the residual DMF in the wet product could not be removed, the wet product was added to water (50 mL), heated to 50 °C, stirred and slurried for 5 hours, cooled to room temperature, filtered, rinsed, and then vacuum dried below 40 °C to obtain a white solid product (12, 6.69 g, yield 74.3%). The solubility of the product was poor. Recrystallization purification using DMF as the solvent resulted in large losses, a reduced yield, and a cumbersome post-treatment process. Impurity 33 could meet the limit requirement of less than 0.1%, but impurity 34 did not meet the standard.

[0095] The difference between impurity 34 and the product was too small, and it would continue to derivatize in the subsequent reaction process. The resulting derivative impurity 35 was also difficult to remove in the post-treatment process. When various solvents were selected for recrystallization, this impurity was hardly reduced, and a qualified product with impurities less than 0.1% could not be obtained.

[0096]

Claims

1. A compound represented by formula (4): Among them, R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, mesyl, benzenesulfonyl or p-toluenesulfonyl.

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