A preparation method of olaparib intermediate

Abstract

The present invention discloses a method for preparing a key intermediate compound of olaparib shown in formula (1), comprising the following steps: (a) reacting a compound shown in formula (2) with a compound shown in formula (3) to generate a compound shown in formula (4); (b) causing the compound shown in formula (4) to undergo intramolecular ring closure under acid catalysis to generate a compound shown in formula (5); (c) hydrolyzing the compound shown in formula (5) in an alkaline solution, and then acidifying to obtain a compound shown in formula (1); wherein, in the compounds shown in formula (3), formula (4) and formula (5), R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl, mesyl, benzenesulfonyl or p-toluenesulfonyl. A compound shown in formula (4) or formula (5) is also disclosed. The method has high yield, mild reaction conditions, easy purification, and is suitable for industrial scale-up production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for preparing an olaparib intermediate. Background Art

[0002] Olaparib, chemically named 1-(cyclopropylcarbonyl)-4-[5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoyl]piperazine, has a structure shown in Figure 6. It was originally created by KuDOS Pharmaceuticals and then acquired by AstraZeneca, which continued to develop it. It has been granted priority review by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) and was approved for marketing in Europe and the United States on December 18, 2014 and December 19, 2014, respectively. Trade name Lynparza TM , for the treatment of women with advanced ovarian cancer associated with defects in the BRCA gene.

[0003]

[0004] Olaparib is a new oral poly (ADP-ribose) polymerase (PARP) inhibitor that acts on BRCA1 or BRCA2 mutations. It uses 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 with recombination deficiency, it depends on the PARP single-strand repair signaling pathway. PARP inhibitors prevent the self-repair ability of tumor cells due to DNA damage and have a killing effect on tumor cells. As a PARP inhibitor, Olaparib has achieved better tumor inhibition effects compared with liposomal doxorubicin in phase I clinical trials and randomized trials.

[0005] 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1) is a key intermediate in the synthesis of olaparib. Compound 1 reacts with cyclopropylcarboxypiperazine in the presence of a condensing agent, a base and a solvent to produce olaparib (6):

[0006]

[0007] Regarding the synthesis of key intermediate 1, WO2004080976, US20050059663 and CN1788000B disclose that o-carboxybenzaldehyde 7 is reacted with dimethyl phosphite to generate phosphine ester compound 8, which is then reacted with 4-fluoro-3-cyanobenzaldehyde to generate 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2); intermediate 2 is first hydrolyzed in alkaline solution and then ring-closed with hydrazine hydrate to generate key intermediate 1:

[0008]

[0009] In this route, when the intermediate 2 is subjected to hydrolysis and ring-closure reaction, the reaction conditions are harsh, the reaction is difficult to be carried out thoroughly, and impurities with similar properties are generated during the reaction, which are difficult to remove completely in post-treatment; the reaction time is long, and both the reaction aid sodium hydroxide and the reactant hydrazine hydrate need to be greatly excessive in order to react thoroughly, and the production efficiency is not high.

[0010] CN104649979B discloses another method for preparing the key intermediate 1, which is to firstly close the intermediate 2 with hydrazine hydrate to generate the phthalazinone intermediate 12, and then hydrolyze the cyano group to a carboxylic acid to obtain the key intermediate 1:

[0011]

[0012] This reaction route is prone to the formation of hydrazide impurities and defluorination impurities. Since the impurities have similar properties to the main product, they are difficult to remove completely during post-processing, affecting product quality. Summary of the invention

[0013] In view of the above-mentioned defects of the prior art, an object of the present invention is to provide a method for preparing 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1), a key intermediate of olaparib, which has high yield, mild reaction conditions, is easy to purify, and is suitable for industrial scale-up production.

[0014] Another object of the present invention is to provide two novel intermediates for preparing Olaparib.

[0015] The objective of the present invention is achieved through the following technical solutions:

[0016] In one aspect, the present invention provides a method for preparing a compound represented by formula (1), comprising the following steps:

[0017]

[0018] (a) reacting a compound represented by formula (2) with a compound represented by formula (3) to produce a compound represented by formula (4);

[0019] (b) causing the compound represented by formula (4) to undergo intramolecular ring closure under acid catalysis to generate a compound represented by formula (5);

[0020] (c) hydrolyzing the compound represented by formula (5) in an alkaline solution and then acidifying to obtain the compound represented by formula (1);

[0021] Among them, in the compounds represented by formula (3), formula (4) and formula (5), R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.

[0022] Preferably, in step (a), the reaction is carried out in a polar aprotic solvent.

[0023] 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.

[0024] 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.

[0025] Preferably, in step (c), the base is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.

[0026] Preferably, in step (c), the hydrolysis is carried out at a temperature of 60-80°C.

[0027] 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 to 5. The inventors unexpectedly found that the use of a mixed solvent can further reduce the generation of impurities in the reaction.

[0028] Preferably, in step (c), the acidification is carried out by dropwise adding hydrochloric acid, sulfuric acid or glacial acetic acid to the mixture after the hydrolysis reaction.

[0029] In another aspect, the present invention provides a compound represented by formula (4) or formula (5):

[0030]

[0031] Wherein, R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.

[0032] Compared with the synthetic routes disclosed in the prior art literature, the preparation method using the route of the present invention can be more thoroughly reacted, less impurities are generated, and the impurities are easily removed in post-treatment, and qualified products are easily obtained. The method of preparing the key intermediate olaparib 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1) of the present invention has high yield, mild reaction conditions, easy purification of the product, high product purity, and is suitable for industrial scale-up production. DETAILED DESCRIPTION

[0033] The present invention will be further described below in conjunction with specific examples. These examples are only for explaining the present invention and are not intended to limit the content of the present invention in any way.

[0034] Example 1 :

[0035] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone acetylhydrazone (19)

[0036]

[0037] Tetrahydrofuran (60 ml), acetic acid hydrazide (10.05 g, 135.0 mmol) and glacial acetic acid (0.68 g, 11.3 mmol) were added to a 250 ml round-bottom flask, and after stirring, 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol) was added, and the mixture was stirred evenly. The mixture was heated to 60°C and reacted for 15 hours. After the reaction was completed, water (120 ml) was slowly added dropwise, and the reaction liquid temperature was lowered to 15-25°C. Stirring was continued for 30 minutes, and after stirring evenly, the mixture was filtered and washed with an appropriate amount of water. The filter cake was 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(1 H,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) + ].

[0038] Step B: Synthesis of 2-fluoro-5-[(3-acetyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (28)

[0039]

[0040] Tetrahydrofuran (45 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone acetylhydrazone (19) (15 g, 44.2 mmol) were added to a 250 ml three-necked flask, stirred evenly, and then glacial acetic acid (3.98 g, 66.3 mmol) was added, heated to 60°C and stirred for 8 hours. After the reaction was completed, 1 ml of the reaction solution was taken and purified by silica gel column to obtain a white solid product, and the structure was identified. 1 HNNR(400MHz, 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 was directly used for the next reaction.

[0041] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0042]

[0043] A solution of sodium hydroxide (8.83 g, 221 mmol) dissolved in water (50 ml) was added to the reaction solution of 2-fluoro-5-[(3-acetyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (28) in step B, and the mixture was refluxed for 15 hours. After the reaction, concentrated hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH value to 2-3, and a solid product was precipitated. The reaction solution was slowly cooled to room temperature, stirred for 1 hour, filtered, and the solid filter cake was washed with an appropriate amount of water. The solid wet product was dried in a 90° C. blast oven to obtain a white solid (12.85 g). The reaction yield of step B and step C was calculated to be 92.3%. The product was tested by liquid chromatography, and the purity was greater than 99%, and the maximum single impurity content was 0.05%, which met 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) + ].

[0044] Example 2 :

[0045] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone benzoylhydrazone (21)

[0046]

[0047] Add dioxane (60 ml), benzohydrazide (18.4 g, 135.0 mmol) and p-toluenesulfonic acid (1.9 g, 11.3 mmol) to a 250 ml round-bottom flask, stir well, then add 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol), stir well, and heat the reaction solution to 80-90°C and react for 12 hours. After the reaction is complete, slowly add water (120 ml) dropwise, and at the same time lower the temperature of the reaction solution to 15-25°C. Continue stirring for 30 minutes, stir well, filter, and wash with an appropriate amount of water. The filter cake is dried 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) + ].

[0048] Step B: Synthesis of 2-fluoro-5-[(3-benzoyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (29)

[0049]

[0050] Tetrahydrofuran (30 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone benzoylhydrazone (21) (12 g, 29.9 mmol) were added to a 250 ml three-necked flask, stirred evenly, and then methanesulfonic acid (4.31 g, 44.9 mmol) was added, and stirred at 60°C for 8 hours. After the reaction was completed, 0.5 ml of the reaction solution was taken and purified by silica gel column to obtain a white solid product, and the structure was identified. MS (ESI): m / z = 384.3 [(M+H) + ]. The reaction solution was directly used for the next reaction.

[0051] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0052]

[0053] To the reaction solution of 2-fluoro-5-[(3-benzoyl-4-oxo-3,4-dihydrobenzopyridazin-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, concentrated hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH value to 2-3, and a solid product was precipitated. The reaction solution was slowly cooled to room temperature, and stirring was continued for 1 hour. The solid filter cake was washed with an appropriate amount of water, and the solid wet product was dried in a 90° C. blast oven to obtain a white solid (8.40 g). The reaction yield of step B and step C was calculated to be 94.2%. The product was tested by liquid chromatography, and the purity was greater than 99%, and the maximum single impurity content was 0.06%, which met 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) + ].

[0054] Example 3 :

[0055] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-methoxycarbonylhydrazone (23)

[0056]

[0057] Add isopropyl ether (60 ml), methoxycarbonylhydrazine (12.2 g, 135.0 mmol) and trifluoroacetic acid (1.29 g, 11.3 mmol) to a 250 ml round-bottom flask, stir well, then add 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol), stir well, and then heat the reaction solution to 60-68°C and react for 16 hours. After the reaction is completed, most of the solvent is distilled off, and then water (120 ml) is slowly added dropwise, and the temperature of the reaction solution is lowered to 15-25°C. Continue stirring for 30 minutes, stir well, filter, and wash with an appropriate amount of water. The filter cake is 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) + ].

[0058] Step B: Synthesis of 2-fluoro-5-[(3-methoxycarbonyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (30)

[0059]

[0060] Methanol (40 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-methoxycarbonylhydrazone (23) (15 g, 42.2 mmol) were added to a 250 ml three-necked flask, stirred evenly, and then trifluoromethanesulfonic acid (8.75 g, 63.3 mmol) was added, and stirred at 60°C for 10 hours. After the reaction was completed, 0.5 ml of the reaction solution was taken and purified by silica gel column to obtain a white solid product, and the structure was identified. MS (ESI): m / z = 337.1 [(M+H) + ]. The reaction solution was directly used for the next reaction.

[0061] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0062]

[0063] A solution of potassium hydroxide (9.47 g, 168.8 mmol) dissolved in water (40 ml) was added to the reaction solution of 2-fluoro-5-[(3-methoxycarbonyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (30) in step B, and the mixture was refluxed for 12 hours. After the reaction, concentrated hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH value to 2-3, and a solid product was precipitated. The reaction solution was slowly cooled to room temperature, stirred for 1 hour, filtered, and the solid filter cake was washed with an appropriate amount of water. The solid wet product was dried in a 90° C. blast oven to obtain a white solid (11.66 g). The yield of the two-step reaction of step B and step C was calculated to be 92.6%. The product was detected by liquid chromatography, and the purity was greater than 99%, and the maximum single impurity content was 0.06%, which met 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) + ].

[0064] Example 4 :

[0065] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-tert-butoxycarbonylhydrazone (25)

[0066]

[0067] DMF (60 ml), tert-butyloxycarbonylhydrazine (17.84 g, 135.0 mmol) and concentrated sulfuric acid (0.55 g, 5.6 mmol) were added to a 250 ml round-bottom flask. After stirring, 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol) was added. After stirring, the reaction solution was heated to 60-70°C and reacted for 10 hours. After the reaction was completed, water (200 ml) was slowly added dropwise, and the temperature of the reaction solution was lowered to 15-25°C. Stirring was continued for 30 minutes. After stirring, the mixture was filtered and washed with an appropriate amount of water. The filter cake was dried 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) + ].

[0068] Step B: Synthesis of 2-fluoro-5-[(3-tert-butoxycarbonyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (31)

[0069]

[0070] Isopropanol (40 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-tert-butoxycarbonylhydrazone (25) (15 g, 37.7 mmol) were added to a 250 ml three-necked flask, stirred evenly, and then acetic acid (3.4 g, 56.6 mmol) was added and stirred at 60°C for 8 hours. After the reaction was completed, 0.5 ml of the reaction solution was taken and purified by silica gel column to obtain a white solid product, and the structure was identified. MS (ESI): m / z = 298.2 [(M-Boc+H) + ],398.2[(M+H) + ]. The reaction solution was directly used for the next reaction.

[0071] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0072]

[0073] A solution of sodium hydroxide (7.54 g, 188.8 mmol) dissolved in water (30 ml) was added to the reaction solution of 2-fluoro-5-[(3-tert-butoxycarbonyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (31) in step B, and the temperature was raised to 80° C. and the reaction was carried out under microreflux 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, and a solid product was precipitated. The reaction solution was slowly cooled to room temperature, and stirring was continued for 1 hour. The solid filter cake was washed with an appropriate amount of water, and the solid wet product was dried in a 90° C. blast oven to obtain a white solid (10.61 g). The yield of the two-step reaction of step B and step C was calculated to be 94.2%. The product was detected by liquid chromatography, and the purity was greater than 99%, and the maximum single impurity content was 0.06%, which met 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) + ].

[0074] Example 5 :

[0075] Step A: Synthesis of (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-benzenesulfonylhydrazone (27)

[0076]

[0077] DMSO (60 ml), benzenesulfonyl hydrazide (23.25 g, 135.0 mmol) and p-toluenesulfonic acid (1.9 g, 11.3 mmol) were added to a 250 ml round-bottom flask. After stirring, 2-fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2) (30.0 g, 113.1 mmol) was added. After stirring, the reaction solution was heated to 80-90°C and reacted for 12 hours. After the reaction was completed, water (120 ml) was slowly added dropwise, and the temperature of the reaction solution was lowered to 15-25°C. Stirring was continued for 30 minutes. After stirring, the mixture was filtered and washed with an appropriate amount of water. The filter cake was dried 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) + ].

[0078] Step B: Synthesis of 2-fluoro-5-[(3-benzenesulfonyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (32)

[0079]

[0080] Add ethanol (50 ml) and (3-cyano-4-fluorobenzyl)-(2-carboxyphenyl)-methanone-benzenesulfonylhydrazone (27) (20 g, 45.7 mmol) into a 250 ml three-necked flask, stir evenly, then add sulfuric acid (6.7 g, 68.6 mmol), stir at 60°C for 8 hours. After the reaction is completed, take 0.5 ml of the reaction solution, purify it with a silica gel column to obtain a white solid product, and identify its structure. MS (ESI): m / z = 420.1 [(M+H) + ]. The reaction solution was directly used for the next reaction.

[0081] Step C: Synthesis of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1)

[0082]

[0083] A solution of sodium hydroxide (9.15 g, 228.5 mmol) dissolved in water (30 ml) was added to the reaction solution of 2-fluoro-5-[(3-benzenesulfonyl-4-oxo-3,4-dihydrobenzopyridazin-1-yl)methyl]benzonitrile (32) in step B, and the mixture was refluxed for 15 hours. After the reaction, concentrated hydrochloric acid was slowly added dropwise to the reaction solution to adjust the pH value to 2-3, and a solid product was precipitated. The reaction solution was slowly cooled to room temperature, stirred for 1 hour, filtered, and the solid filter cake was washed with an appropriate amount of water. The solid wet product was dried in a 90° C. blast oven to obtain a white solid (12.52 g). The yield of the two-step reaction of step B and step C was calculated to be 91.8%. The product was tested by liquid chromatography, and the purity was greater than 99%, and the maximum single impurity content was 0.07%, which met 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) + ].

[0084] Comparative Example 1: Preparation of 5-[(3,4-dihydro-4-oxo-1-phthalazinyl)methyl]-2-fluorobenzoic acid (1) according to the method of Example 4 of Patent CN104649979B

[0085]

[0086] (A) Preparation of Compound 12

[0087] 2-Fluoro-5-[(3-oxo-1(3H)-isobenzofuranylidene)methyl]benzonitrile (2) (20 g, 75.40 mmol) and tetrahydrofuran (200 mL) were stirred at room temperature in nitrogen for 30 minutes. Hydrazine monohydrate (4.40 mL, 90.53 mmol) was added, followed by tetrahydrofuran (4 mL) to clean the pipe. 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. 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. The reaction mixture was cooled to 20°C, filtered, washed with water (30 ml) and tetrahydrofuran (30 ml), and the wet solid was dried in vacuo below 40°C to obtain an off-white solid product (12, 18.2 g, yield 86.4%). The product was tested by liquid chromatography and found to have a purity greater than 99% and an impurity 33 content of 0.18%. This impurity is difficult to remove in subsequent processing steps.

[0088]

[0089] (B) Preparation of Compound (1)

[0090] Take the obtained solid product 12 (9.60g, 34.37mmol), add water (40ml) and stir at 20℃. Then add sodium hydroxide solution (2.0mol / L, 36ml, 72.0mmol), heat the reaction mixture to 90℃ and stir overnight. The reaction solution is cooled to room temperature, filtered, the filter cake is washed with water (10ml), the filtrate is combined, the temperature is raised to 60℃, hydrochloric acid (2.0mmol / L, 56ml, 112.0mmol) is added dropwise, and the addition is completed in 40 minutes. The obtained suspension is cooled to 50℃, filtered, and the solid is washed with water (57ml). The solid wet product is vacuum dried below 60℃ to obtain an off-white solid product 1 (9.76g, yield 95.2%). The product is tested by liquid chromatography, and the purity is greater than 99%, the content of impurity 33 is 0.13%, and the content of newly generated impurity 34 is 0.27%.

[0091]

[0092] In order to reduce the content of each impurity to below the standard limit (0.1%), a variety of purification methods were tried. Among them, the purification effect was relatively good using the following method, and the product loss was relatively small, but there was still a large amount of product loss:

[0093] The solid product (9.0g) was heated and dissolved in DMF (90mL), cooled to 0°C, and the solid was filtered. The solid wet product was washed with DMF (10ml). Product sampling and testing showed that impurity 33 was reduced to 0.06%, and impurity 34 was substantially not reduced. Because the residual DMF in the wet product could not be removed, the wet product was put into water (50ml), heated to 50°C and stirred for 5 hours, cooled to room temperature, filtered, rinsed, and vacuum dried again below 40°C to obtain a white solid product (12, 6.69g, yield 74.3%). The product has poor solubility, and DMF is used as a solvent for recrystallization and purification, which results in large losses, reduced yields, and troublesome post-processing. Impurity 33 can be made to reach the limit requirement of less than 0.1%, but impurity 34 cannot be qualified.

[0094] Impurity 34 is too different from the product and will continue to be derived in the subsequent reaction process. The resulting derivative impurity 35 is also difficult to remove in the post-processing process. Various solvents are selected for recrystallization, and the impurity is hardly reduced, and a qualified product with an impurity of less than 0.1% cannot be obtained.

[0095]

Claims

1. A method for preparing a compound represented by formula (1), comprising the following steps: (a) reacting a compound represented by formula (2) with a compound represented by formula (3) to produce a compound represented by formula (4); (b) causing the compound represented by formula (4) to undergo intramolecular ring closure under acid catalysis to generate a compound represented by formula (5); (c) hydrolyzing the compound represented by formula (5) in an alkaline solution and then acidifying to obtain the compound represented by formula (1); Among them, in the compounds represented by formula (3), formula (4) and formula (5), R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.

2. The method according to claim 1, wherein in step (a), the reaction is carried out in a polar aprotic solvent.

3. The method according to claim 2, wherein 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.

4. The method according to claim 1, wherein 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.

5. The method according to claim 1, wherein in step (c), the alkali is selected from one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.

6. The method according to claim 1, wherein in step (c), the hydrolysis is carried out at a temperature of 60-80°C.

7. The method according to claim 1, wherein in step (c), the hydrolysis is carried out in a mixed solvent of water and another solvent.

8. The method according to claim 7, wherein in step (c), the additional solvent is selected from one or more of methanol, ethanol, tetrahydrofuran, and isopropanol.

9. The method according to claim 7, wherein in step (c), the volume ratio of water to another solvent is 1:0.2-5.

10. The method according to claim 1, wherein in step (c), the acidification is carried out by dropwise adding hydrochloric acid, sulfuric acid or glacial acetic acid to the mixture after the hydrolysis reaction.

11. A compound represented by formula (5): in, R is formyl, acetyl, propionyl, butyryl, benzoyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methanesulfonyl, benzenesulfonyl or p-toluenesulfonyl.

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