Intermediate compound of PARP inhibitor and preparation method and application thereof

Abstract

The present invention provides intermediates (compound formula I and compound formula II) of PARP inhibitors (such as olaparib, 1-cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxy-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-2,5-diazabicyclo[2,2,1]heptane-2-yl)ethane-1,2-dione, etc.), preparation methods and use of the intermediates in preparing PARP inhibitors or key intermediates of PARP inhibitors (compound formula A), which overcome the problems of high production cost, harsh reaction conditions and many reaction by-products in the existing preparation process and are suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical synthesis, and in particular to an intermediate of a PARP inhibitor and a preparation method and application thereof. Background Art

[0002] PARP is the abbreviation of "poly (ADP-ribose) polymerase". Tumor cells use PARP enzymes to repair DNA damage, including those caused by chemotherapy. Researchers are studying whether drugs that inhibit the PARP enzyme can also weaken this self-repair mechanism and make tumor cells more sensitive to treatment, accelerating tumor cell death. PARP inhibitors are a family of pharmacological inhibitors of poly (ADP-ribose) polymerase, which are important for promoting DNA repair, controlling RNA transcription, regulating cell death and immune response. Therefore, PARP inhibitors have been developed for a variety of indications, the most important of which is for the treatment of tumors. Several forms of BRCA-deficient tumor cells are more dependent on the repair function of PARP than normal cells, making PARP an attractive target for tumor treatment.

[0003] Known PARP inhibitors include olaparib, 1-cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-2,5-diazabicyclo[2,2,1]heptane-2-yl)ethane-1,2-dione, etc. 2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (compound formula A) having the following structure is a key intermediate for synthesizing the above PARP inhibitors:

[0004]

[0005] PCT patent applications WO2004080976A1 and WO2005053662A1 disclose methods for preparing various phthalazinone derivatives, their activities in inhibiting PARP, and their corresponding uses in treating cancer, and disclose the following method for preparing compound A:

[0006]

[0007] This method uses 2-fluoro-5-formylbenzonitrile, which is relatively expensive and has high cost. In addition, when the cyano group is hydrolyzed, the temperature is high, which easily causes the lactone ring to open, and there are many impurities, which is not suitable for industrial production.

[0008] The following preparation method of compound A is disclosed in Chinese patents CN101528714A and CN101821242A of Kudos Pharmaceuticals Co., Ltd.:

[0009]

[0010] This method improves the problem of cyano hydrolysis lactone ring opening in the prior art, but 2-fluoro-5-formylbenzonitrile is still used in the route, which is relatively expensive and has a high cost. In addition, the coupling reaction using heavy metal cuprous as a catalyst in the synthesis of 2-fluoro-5-formylbenzonitrile has a high temperature and produces many by-products, which is not suitable for industrial production.

[0011] In summary, the existing preparation process is not suitable for the industrial-scale preparation of the intermediate compound A of the PARP inhibitor. Therefore, it is urgent to develop a process with low cost and suitable for industrial production, which has significant economic and social benefits. Summary of the invention

[0012] In order to solve the above technical problems, the present invention provides intermediate compounds of formula I and formula II of PARP inhibitors (such as olaparib, 1-cyclopropyl-2-((1S,4S)-5-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)-2,5-diazabicyclo[2,2,1]heptane-2-yl)ethane-1,2-dione, etc.) and preparation methods thereof, as well as the use of the intermediates in the preparation of PARP inhibitors or PARP inhibitor key intermediate compounds of formula A, which overcome the problems of high production cost, harsh reaction conditions and many reaction by-products in the existing preparation process and are suitable for industrial production.

[0013] In order to achieve the technical purpose of the present invention, the present invention provides the following technical solutions:

[0014] The first aspect of the present invention provides a compound of formula II,

[0015]

[0016] Wherein, X is a halogen, preferably Cl or Br, most preferably Cl;

[0017] Preferably, the compound of formula II can be:

[0018]

[0019] The second aspect of the present invention provides a compound of formula I,

[0020]

[0021] Wherein, X is a halogen, preferably Cl or Br, most preferably Cl;

[0022] Preferably, the compound of formula I can be:

[0023] The third aspect of the present invention provides a method for preparing the compound of formula II.

[0024] The compound of formula II is prepared by subjecting the compound of formula I to hydrazine hydrolysis reaction in a solvent, and the reaction equation is as follows:

[0025]

[0026] Wherein, X is a halogen, preferably Cl or Br, most preferably Cl;

[0027] Preferably, the solvent may be one or more of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, ethyl acetate, and toluene;

[0028] Preferably, the hydrazine can be one of 80% hydrazine hydrate, 50% hydrazine hydrate, hydrazine hydrochloride, and hydrazine sulfate;

[0029] Preferably, the reaction temperature is 55-65°C;

[0030] Preferably, the above reaction equation can be:

[0031]

[0032] or

[0033]

[0034] The fourth aspect of the present invention provides a method for preparing the compound of formula I, comprising the following steps: preparing the compound from o-carboxybenzaldehyde, a phosphite diester, and 4-fluoro-3-halobenzaldehyde in a solvent under alkaline conditions by a coupling reaction and a wittit condensation reaction in one pot, wherein the reaction equation is as follows:

[0035]

[0036] Where R is C 1 -C 8 alkyl, preferably methyl, ethyl, isopropyl or tert-butyl, more preferably methyl or ethyl; X is halogen, preferably Cl or Br, most preferably Cl;

[0037] Preferably, the solvent may be one or more of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, ethyl acetate, and toluene;

[0038] Preferably, the base can be one or more of sodium tert-amylate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, and triethylamine;

[0039] Preferably, the molar ratio of the o-carboxybenzaldehyde to 4-fluoro-3-halobenzaldehyde may be 1.0:1.0-1.2;

[0040] Preferably, the molar ratio of the o-carboxybenzaldehyde to the phosphite diester may be 1.0:1.4-1.7, more preferably 1.0:1.5-1.7;

[0041] Preferably, the above reaction equation can be:

[0042]

[0043] or

[0044]

[0045] The fifth aspect of the present invention provides a method for preparing compound A, comprising the following steps: the compound II can react with magnesium in a solvent to generate a Grignard reagent, and then react with carbon dioxide to prepare compound A by a Grignard reaction method, wherein the reaction equation is as follows:

[0046]

[0047] Wherein, X is a halogen, preferably Cl or Br, most preferably Cl;

[0048] Preferably, the solvent may be one or more of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, and methyl tert-butyl ether;

[0049] Preferably, the reaction pH may be 3 to 4;

[0050] Preferably, the above reaction equation can be:

[0051]

[0052] or

[0053]

[0054] The present invention also provides a method for preparing the compound of formula A, characterized in that it comprises the following steps:

[0055] Step 1, coupling reaction and wittit condensation reaction: o-carboxybenzaldehyde reacts with a phosphorous acid diester in a solvent in the presence of a base to generate an intermediate solution, and the intermediate solution is then condensed with 4-fluoro-3-halobenzaldehyde under alkaline conditions to generate a compound of formula I;

[0056] Step 2, hydrazine reaction: Compound I reacts with hydrazine in a solvent to form compound II;

[0057] Step 3, Grignard reaction: Compound II reacts with magnesium in a solvent to generate a Grignard reagent, which then reacts with carbon dioxide to form compound A;

[0058] The reaction equation is as follows:

[0059]

[0060] Where R is C 1 -C 8 alkyl, preferably methyl, ethyl, isopropyl or tert-butyl, more preferably methyl, ethyl, most preferably; X is halogen, preferably Cl or Br, most preferably Cl;

[0061] Preferably, step one comprises the following steps: adding a phosphite diester, a base and an organic solvent into a reactor, reacting at 20 to 30° C. for 15 to 30 minutes; adding o-carboxybenzaldehyde to generate an intermediate solution of a coupling reaction, washing and separating the solution after the reaction is completed, adding 3-halogen-4-fluorobenzaldehyde and a base to the organic phase, stirring, generating a Wittit condensation reaction, filtering and drying.

[0062] Preferably, step 2 comprises the following steps: under nitrogen protection, suspending compound I in a solvent, controlling the temperature at 10-30° C., adding hydrazine hydrate, stirring, adding acetic acid, stirring at 55-65° C. for 9 hours, adding water for crystallization, cooling, filtering and drying.

[0063] Preferably, step three comprises the following steps: slowly adding the solution solvent of compound formula II into the solvent of suspended magnesium chips, stirring at 20-50° C. until the magnesium chips substantially disappear, cooling to -5--15° C., introducing excess carbon dioxide, adding acid dropwise to adjust pH to 3-4, stirring, filtering, and drying.

[0064] Preferably, the intermediate of formula I has two cis and trans isomers, and the ratio of the cis and trans isomers is 1:5 to 2:5.

[0065] Preferably, the above reaction equation can be:

[0066]

[0067] or

[0068]

[0069] The present invention also provides the use of the compound of formula I and / or the compound of formula II in the preparation of PARP inhibitors.

[0070] Preferably, the compound of formula I may be compound of formula Ia or compound of formula Ib; preferably, the compound of formula II may be compound of formula IIa or compound of formula IIb

[0071] Preferably, the PARP inhibitor is Olaparib or a structurally similar compound thereof; the structural analogue can be selected from the compounds in CN103237799A (such as the target compounds in Examples 1 and 2, etc.).

[0072] Preferably, the PARP inhibitor is Olaparib, which is prepared using the following reaction formula:

[0073]

[0074] The beneficial technical effects of the present invention are as follows:

[0075] 1. Using cheap and readily available 4-fluoro-3-halobenzaldehyde as a raw material, a coupling reaction is carried out with o-carboxylic acid benzaldehyde to obtain compound I with a purity of up to 99.9%;

[0076] 2. Compound I undergoes hydrazinolysis reaction to generate compound II with a chemical purity of up to 99.8%, and then undergoes Grignard reaction with magnesium strip to obtain compound A with a purity of up to 99.6%;

[0077] 3. The preparation method of the compound of formula A of the present invention reduces production costs, is easy to operate, has simple post-treatment, has few impurities, has high industrial operation feasibility, is conducive to large-scale industrial production, and has significant economic and social benefits.

[0078] The reagents and raw materials used in the present invention are commercially available. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] Figure 1 The hydrogen nuclear magnetic resonance spectrum of compound formula Ia is shown;

[0080] Figure 2 The hydrogen nuclear magnetic resonance spectrum of compound formula IIa is shown;

[0081] Figure 3 The hydrogen nuclear magnetic resonance spectrum of the compound of formula Ib is shown;

[0082] Figure 4 The hydrogen nuclear magnetic resonance spectrum of compound formula IIb is shown;

[0083] Figure 5 The hydrogen nuclear magnetic resonance spectrum of compound A is shown. DETAILED DESCRIPTION

[0084] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0085] Example 1-2: Preparation of Compound I

[0086]

[0087] Embodiment 1:

[0088] Step 1: Synthesis of (R / Z)-3-(3-chloro-4-fluorobenzylidene)isobenzofuran-1(3H)-one (Compound Formula Ia)

[0089] Under mechanical stirring, add 16.5kg (1.5eq, 150mol) of dimethyl phosphite, 16.5kg (1.5eq, 150mol) of sodium tert-amyl alcohol and 150L of methyltetrahydrofuran to a three-necked flask, and react at 30°C for 15min; add 15.0kg (1.0eq, 100mol) of o-carboxybenzaldehyde, and after the reaction, wash with 75L of water and 75L of 20% potassium bicarbonate solution in sequence. Separate the liquid, add 15.8kg (1.0eq, 100mol) of 3-chloro-4-fluorobenzaldehyde to the organic phase, and then dropwise add 12.1kg (1.2eq, 120mol) of triethylamine, stir at 50°C for 6h, filter, and dry at 50°C to obtain 25.6kg of white solid, which is compound formula Ia (there are two cis-trans isomers in a ratio of about 2:5), with a yield of 93.23% and a purity of 99.85%.

[0090] 1 HNMR (400 MHz, DMSO-d 6 )δ: 6.934 (s, 1H, trans isomer), 6.983 (s, 0.25H, cis isomer), 7.454-7.517 (m, 2H), 7.540-7.577 (m, 1H), 7.664-7.714 (s, 1H, trans isomer), 7.730-7.733 (m, 0.25H, cis isomer), 7.757-7.796 (m, 1H), 7.877-7.915 (m, 1H), 7.946-7.971 (m, 1H), 8.055 (d, J = 7.6 Hz, 1H), 19 FNMR (376 MHz, DMSO-d 6 )δ: -104.671 (s, 1F, trans isomer), -104.987 (s, 0.24F, cis isomer).

[0091] Step 2: Synthesis of 4-(3-chloro-4-fluorobenzyl)phthalic acid oxazine-1(2H)-one (compound formula IIa)

[0092] Under nitrogen protection, 25.0 kg (1.0 eq, 91 mol) of (R / Z)-3-(3-chloro-4-fluorobenzylidene)isobenzofuran-1(3H)-one (compound formula Ia) was suspended in 250 L of tetrahydrofuran, the temperature was controlled at 10°C, 7.1 kg (1.2 eq, 142 mol) of 80% hydrazine hydrate was added, stirred for 2 h, 9.6 kg (1.7 eq, 160 mol) of acetic acid was added, stirred at 55°C for 9 h, 250 L of water was added for crystallization, and then the reaction solution was cooled to 10°C, the solid was filtered, and dried at 50°C to obtain 25.0 kg of white solid, which is compound formula IIa, with a yield of 95.17% and a purity of 99.75%.

[0093] 1 HNMR (400 MHz, DMSO-d 6 )δ:4.299(s,2H),7.283(s,1H),7.303(s,1H),7.533-7.552(m,1H),7.784-7.824(m, 1H),7.855-7.896(m,1H),7.947-7.967(m,1H),8.243-8.265(m,1H),12.597(s,1H), 19 FNMR (376 MHz, DMSO-d 6 )δ:-108.533(s,1F).

[0094] Step 3: Synthesis of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (Compound Formula A)

[0095] 25.0 kg (1.0 eq, 86 mol) of 4-(3-chloro-4-fluorobenzyl)phthalic acid azine-1(2H)-one (compound formula IIa) was dissolved in 250 L of tetrahydrofuran, and then slowly added dropwise to a suspension of 5.0 kg (2.4 eq, 208 mol) of magnesium chips in tetrahydrofuran, stirred at 20°C until the magnesium chips were substantially eliminated, cooled to -15°C, introduced with excess carbon dioxide, and acid was added dropwise to adjust the pH to 4, stirred for 1 h, filtered, washed with water, and dried at 60°C to obtain 25.45 kg of a white solid, i.e., compound formula A, with a yield of 99.22% and a purity of 99.57%.

[0096] 1 HNMR (400 MHz, DMSO-d 6)δ:4.344(s,2H),7.22(dd,J=8.8Hz,J=2.0Hz,1H),7.557-7.588(m,1H),7.807(t,J=7.2Hz,2H),7.8 55(t,J=12Hz,1H),7.958(d,J=8.0Hz,1H),8.255(d,J=7.6Hz,1H),12.601(s,1H),13.253(brs,1H), 19 FNMR (376 MHz, DMSO-d 6 )δ:-102.725(s,1F).

[0097] Example 2

[0098] Step 1: Synthesis of (R / Z)-3-(3-chloro-4-fluorobenzylidene)isobenzofuran-1(3H)-one (Compound Formula Ia)

[0099] Under mechanical stirring, add 16.5g (1.5eq, 150mmol) of dimethyl phosphite, 16.5g (1.5eq, 150mmol) of sodium tert-amyl alcohol and 150ml of toluene to a three-necked flask, and react at 20°C for 30min; add 15.0g (1.0eq, 100mmol) of o-carboxybenzaldehyde, and after the reaction, wash with 75ml of water and 75ml of 20% potassium bicarbonate solution in turn. Separate the liquid, add 15.8g (1.0eq, 100mmol) of 3-chloro-4-fluorobenzaldehyde to the organic phase, and then dropwise add 12.1g (1.2eq, 120mmol) of triethylamine, stir at 40°C for 8h, filter, and dry at 50°C to obtain 25.1g of white solid, which is compound Ia (there are two cis-trans isomers in a ratio of about 1:5), with a yield of 91.38% and a purity of 99.87%.

[0100] Step 2: Synthesis of 4-(3-chloro-4-fluorobenzyl)phthalic acid oxazine-1(2H)-one (compound formula IIa)

[0101] Under nitrogen protection, 25.0 g (1.0 eq, 91 mmol) of (R / Z)-3-(3-chloro-4-fluorobenzylidene)isobenzofuran-1(3H)-one (compound formula Ia) was suspended in 250 ml of tetrahydrofuran, and the temperature was controlled at 30°C. 7.1 g (1.2 eq, 142 mmol) of 50% hydrazine hydrate was added, and the mixture was stirred for 2 h. 9.6 g (1.7 eq, 160 mmol) of acetic acid was added, and the mixture was stirred at 65°C for 9 h. 250 ml of water was added for crystallization, and the reaction solution was then cooled to 10°C. The solid was filtered and dried at 50°C to obtain 24.8 g of a white solid, which was compound formula IIa. The yield was 94.40% and the purity was 99.76%.

[0102] Step 3: Synthesis of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (Compound Formula A)

[0103] 25.0 g (1.0 eq, 86 mmol) of 4-(3-chloro-4-fluorobenzyl)phthalic acid azine-1(2H)-one (compound formula IIa) was dissolved in 250 ml of tetrahydrofuran, and then slowly added dropwise to a suspension of 5.0 g (2.4 eq, 208 mmol) of magnesium chips in tetrahydrofuran, stirred at 50°C until the magnesium chips basically disappeared, cooled to -5°C, introduced an excess of carbon dioxide, and acid was added dropwise to adjust the pH to 3, stirred for 1 hour, filtered, washed with water, and dried at 60°C to obtain 25.1 g of a white solid, which is compound formula A, with a yield of 97.86% and a purity of 99.63%.

[0104] Example 3-4: Preparation of Compound A

[0105]

[0106] Example 3

[0107] Step 1: Synthesis of (R / Z)-3-(3-bromo-4-fluorobenzylidene)isobenzofuran-1(3H)-one (Compound Formula Ib)

[0108] Under mechanical stirring, add 20.6g (1.5eq, 150mmol) of diethyl phosphite, 16.5g ((1.5eq, 150mmol)) of sodium tert-amyl alcohol and 150ml of methyltetrahydrofuran to a three-necked flask, and react at 20°C for 30min; add 15.0g (1.0eq, 100mmol) of o-carboxybenzaldehyde, and after the reaction, wash with 75ml of water and 75ml of 20% potassium bicarbonate solution in turn. Separate the liquid, add 20.3g (1.0eq, 100mmol) of 3-bromo-4-fluorobenzaldehyde to the organic phase, and then dropwise add 12.1g (1.2eq, 120mmol) of triethylamine, stir at 40°C for 8h, filter, and dry at 50°C to obtain 30.2g of white solid, compound formula Ib (there are two cis-trans isomers with a ratio of about 2:5), with a yield of 94.01% and a purity of 99.88%).

[0109] 1 HNMR (400 MHz, DMSO-d 6)δ: 6.928 (s, 1H, trans isomer), 6.985 (s, 0.49H, cis isomer), 7.450-7.524 (m, 2H, trans isomer), 7.593-7.630 (m, 0.49H, cis isomer), 7.661-7.750 (s, 2H), 7.793-7.833 (m, 1H), 7.867-7.912 (m, 1.5H, isomer mixture), 7.950-7.969 (m, 1.5H, isomer mixture), 8.041-8.096 (m, 2H), 19 FNMR (376 MHz, DMSO-d 6 )δ: -96.684 (s, 1F, major isomer), -96.978 (s, 0.34F, minor isomer).

[0110] Step 2: Synthesis of 4-(3-bromo-4-fluorobenzyl)phthalic acid oxazine-1(2H)-one (compound formula IIb)

[0111] Under nitrogen protection, 30.0 g (1.0 eq, 94 mmol) of (R / Z)-3-(3-bromo-4-fluorobenzylidene)isobenzofuran-1(3H)-one (compound formula Ⅰb) was suspended in 250 ml of tetrahydrofuran, and the temperature was controlled at 25°C. 7.1 g (1.2 eq, 147 mmol) of 80% hydrazine hydrate was added, and the mixture was stirred for 2 h. 10.0 g (1.7 eq, 167 mmol) of acetic acid was added, and the mixture was stirred at 60°C for 9 h. 250 ml of water was added for crystallization, and the reaction solution was then cooled to 10°C. The solid was filtered and dried at 50°C to obtain 30.0 g of a white solid, which was compound formula Ⅱb. The yield was 95.79% and the purity was 99.79%.

[0112] 1 HNMR (400 MHz, DMSO-d 6 )δ:4.305(s,2H),7.247-7.351(m,2H),7.664-7.686(m,1H),7.792-7.832(m,1H) ,7.884-7.905(m,1H),7.591-7.975(m,1H),8.245-7.905(m,1H),12.590(s,1H), 19 FNMR (376 MHz, DMSO-d 6 )δ:-100.568(s,1F).

[0113] Step 3: Synthesis of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (Compound Formula A)

[0114] 30.0 g (1.0 eq, 90 mmol) of 4-(3-bromo-4-fluorobenzyl)phthalic acid azine-1(2H)-one (compound formula IIb) was dissolved in 250 ml of tetrahydrofuran, and then slowly added dropwise to a suspension of 5.2 g (2.4 eq, 216 mmol) of magnesium chips in tetrahydrofuran, stirred at 30°C until the magnesium chips basically disappeared, cooled to -10°C, introduced an excess of carbon dioxide, and acid was added dropwise to adjust the pH to 3.5. The mixture was stirred for 1 hour, filtered, washed with water, and dried at 60°C to obtain 26.50 g of a white solid, compound formula A, with a yield of 98.73% and a purity of 99.67%.

[0115] Example 4

[0116] Step 1: Synthesis of (R / Z)-3-(3-bromo-4-fluorobenzylidene)isobenzofuran-1(3H)-one (Compound Formula Ib)

[0117] Under mechanical stirring, add 20.6g (1.5eq, 150mmol) of diethyl phosphite, 10.2g (1.5eq, 150mmol) of sodium ethoxide and 150ml of methyltetrahydrofuran to a three-necked flask, and react at 30℃ for 15min; add 15.0g (1.0eq, 100mmol) of o-carboxybenzaldehyde, and after the reaction, wash with 75ml of water and 75ml of 20% potassium bicarbonate solution in sequence. Separate the liquid, add 20.3g (1.0eq, 100mmol) of 3-bromo-4-fluorobenzaldehyde to the organic phase, and then dropwise add 12.1g (1.2eq, 120mmol) of triethylamine, stir at 50℃ for 6h, filter, and dry at 50℃ to obtain 29.8g of white solid, compound formula Ib (there are two cis-trans isomers with a ratio of about 1:5), with a yield of 93.39% and a purity of 99.87%.

[0118] Step 2: Synthesis of 4-(3-bromo-4-fluorobenzyl)phthalic acid oxazine-1(2H)-one (compound formula IIb)

[0119] Under nitrogen protection, 30.0 g (1.0 eq, 94 mmol) of (R / Z)-3-(3-bromo-4-fluorobenzylidene)isobenzofuran-1(3H)-one (compound formula Ⅰb) was suspended in 250 ml of tetrahydrofuran, and the temperature was controlled at 30°C. 7.1 g (1.2 eq, 147 mmol) of 80% hydrazine hydrate was added, and the mixture was stirred for 2 h. 10.0 g (1.7 eq, 167 mmol) of acetic acid was added, and the mixture was stirred at 55°C for 9 h. 250 ml of water was added for crystallization, and the reaction solution was then cooled to 10°C. The solid was filtered and dried at 50°C to obtain 29.5 g of a white solid, which is compound formula Ⅱb. The yield was 94.19% and the purity was 99.76%.

[0120] Step 3: Synthesis of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (Compound Formula A)

[0121] 30.0 g (1.0 eq, 90 mmol) of 4-(3-bromo-4-fluorobenzyl)phthalic acid azine-1(2H)-one (compound formula IIb) was dissolved in 250 ml of tetrahydrofuran, and then slowly added dropwise to a suspension of 5.2 g (2.4 eq, 216 mmol) of magnesium chips in tetrahydrofuran, stirred at 40°C until the magnesium chips basically disappeared, cooled to -10°C, introduced an excess of carbon dioxide, and acid was added dropwise to adjust the pH to 3-4. The mixture was stirred for 1 hour, filtered, washed with water, and dried at 60°C to obtain 25.50 g of a white solid, compound formula A, with a yield of 94.97% and a purity of 99.88%.

[0122] Example 5-7: Preparation of Olaparib and its intermediate B

[0123]

[0124] Example 5

[0125] 2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (A) (0.17 mol) obtained in Example 1, tert-butyl 1-piperazinecarboxylate (0.21 mol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.22 mol) and N,N-diisopropylethylamine (0.38 mol) were added to dimethylacetamide (40 ml) and stirred for 18 hours. Water (100 ml) was added and the reaction mixture was heated to 100° C. for 1 hour. The suspension was cooled to room temperature, filtered and dried to obtain a white solid, which was dissolved in a 6M HCl and ethanol solution (2:1, 50 ml) and stirred for 1 hour. The reaction was concentrated, basified to pH 9 with ammonia and the product extracted into dichloromethane (2 x 50 ml); the organic layers were combined, washed with water (2 x 50 ml), dried over MgSO4 and evaporated in vacuo to give compound B.

[0126] Example 6

[0127] 2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (A) (0.17 mol) obtained in Example 3, tert-butyl 1-piperazinecarboxylate (0.21 mol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) (0.22 mol) and N,N-diisopropylethylamine (0.38 mol) were added to dimethylacetamide (40 ml) and stirred for 16 hours. Water (100 ml) was added and the reaction mixture was heated to 102° C. for 1 hour. The suspension was cooled to room temperature, filtered and dried to obtain a white solid, which was dissolved in a 6M HCl and ethanol solution (2:1, 50 ml) and stirred for 1 hour. The reaction was concentrated, basified to pH 9 with ammonia and the product extracted into dichloromethane (2 x 50 ml); the organic layers were combined, washed with water (2 x 50 ml), dried over MgSO4 and evaporated in vacuo to give compound B.

[0128] Example 7

[0129] A pre-mixed solution of triethylamine (0.5 ml) and cyclopropanecarbonyl chloride (0.31 ml) in dichloromethane (1.2 ml) was added dropwise to a suspension of compound B (1.3 g) obtained in Example 5 in dichloromethane (15 ml), while maintaining the temperature below 20° C. The solution was then stirred at 10-15° C. for 15 min, and then washed with water (8 ml), 5% sodium carbonate (8 ml) solution and water (8 ml) in sequence. The organic phase was dried over anhydrous magnesium sulfate (0.5 g), filtered, concentrated, added with ethanol (10 ml), dissolved, cooled to 8° C., and filtered to obtain Olaparib with a yield of 90% and a purity of 99.34%.

Claims

1. A method for preparing a compound of formula A, characterized in that: The steps include: Step 1, coupling reaction and Wittig condensation reaction: o-carboxybenzaldehyde reacts with a phosphite diester in the presence of a base in a solvent to generate an intermediate solution, wherein the base is sodium tert-amyl alcohol or sodium ethoxide; the intermediate solution is then condensed with 4-fluoro-3-halobenzaldehyde under alkaline conditions to generate a compound of formula I, wherein the base in the alkaline conditions is triethylamine; Step 2, hydrazinolysis reaction: Compound I reacts with hydrazine in a solvent to form compound II; Step 3, Grignard reaction: Compound II reacts with magnesium in a solvent to generate a Grignard reagent, which then reacts with carbon dioxide to form compound A; The reaction equation is as follows: Wherein, R is methyl or ethyl; X is Cl or Br; In step 1, the solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, and toluene; In step 2, the reaction temperature is 55-65° C.; the hydrazine is one of 80% hydrazine hydrate, 50% hydrazine hydrate, hydrazine hydrochloride, and hydrazine sulfate; the solvent is tetrahydrofuran and / or methyltetrahydrofuran; In step 3, the solvent is tetrahydrofuran and / or methyltetrahydrofuran; and the pH of the reaction is 3-4.

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