Method for producing olaparib precursor and method for producing olaparib

Abstract

Provided is a method for producing an olaparib precursor, said method comprising the step of performing the following steps (a) to (c) continuously without isolating a reaction intermediate. (a) Reacting dimethyl(3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate and 2-fluoro-5-formylbenzoic acid in DMF, acetonitrile, or THF and in the presence of diazabicycloundecene. (b) Reacting the reaction mixture obtained in the reaction of (a) with hydrazine. (c) Adjusting the reaction liquid obtained in the reaction of (b) to a pH of not more than 4, to obtain 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazine-1-ylmethyl)-benzoic acid, which is an olaparib precursor.

Description

Method for producing olaparib precursor and method for producing olaparib

[0001] The present invention relates to a method for producing a precursor of olaparib and a method for producing olaparib. This application claims priority based on Japanese Patent Application No. 2024-147316, filed on August 29, 2024, the contents of which are incorporated herein by reference.

[0002] PARP inhibitors are drugs that inhibit the function of PARP, an enzyme that repairs damaged DNA, and are used as anticancer drugs. Olaparib is known as a representative PARP inhibitor, and various methods for producing it have been investigated (see, for example, Patent Documents 1 and 2).

[0003] Patent No. 5719471 Chinese Patent Application Publication No. 110790710

[0004] In the field of pharmaceuticals, regulatory authorities in Europe and the United States have issued instructions to pharmaceutical manufacturers regarding risk assessments of impurity contamination, and it is necessary to minimize impurity contamination. Furthermore, in order to improve pharmaceutical production efficiency, it is necessary to reduce the number of reaction steps. From this perspective, there is room for improvement in the manufacturing method of olaparib described in the above patent document.

[0005] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method for producing a highly pure olaparib precursor, and a further object of the present invention is to provide a method for producing olaparib that enables high-quality olaparib to be easily produced using the obtained olaparib precursor.

[0006] In order to solve the above problems, one aspect of the present invention includes the following aspects.

[0007] [1] A method for producing a precursor of olaparib, comprising the steps of (a) to (c) below, successively carrying out the steps without isolating reaction intermediates: (a) reacting dimethyl(3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate with 2-fluoro-5-formylbenzoic acid in the presence of diazabicycloundecene in DMF, acetonitrile, or THF; (b) reacting the reaction mixture obtained in the reaction (a) with hydrazine; and (c) adjusting the reaction solution obtained in the reaction (b) to a pH of 4 or less to obtain the precursor of olaparib, 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)benzoic acid.

[0008] [2] The method for producing an olaparib precursor according to [1], wherein the reaction (a) is carried out in DMF.

[0009] [3] The method for producing an olaparib precursor according to [1] or [2], wherein in (c), the pH of the reaction solution is adjusted to 1 to 2.

[0010] [4] A method for producing the olaparib precursor according to any one of [1] to [3], comprising the steps of: dissolving the crude crystals containing the olaparib precursor obtained in (c) and sodium hydroxide in DMF; adding acetic acid or formic acid to the solution obtained in the dissolving step to adjust the pH to 4 to 6; and filtering out the resulting crystals.

[0011] [5] A method for producing olaparib, comprising a step of amide condensing the olaparib precursor produced by the method for producing an olaparib precursor according to any one of [1] to [4] with 1-(cyclopropylcarbonyl)piperazine or 1-(cyclopropylcarbonyl)piperazine hydrochloride in DMF or acetonitrile to obtain olaparib.

[0012] [6] The method for producing olaparib according to [5], wherein the olaparib precursor and 1-(cyclopropylcarbonyl)piperazine are subjected to amide condensation in the step of obtaining olaparib.

[0013] [7] The method for producing olaparib according to [5] or [6], wherein the amide condensation uses a water-soluble carbodiimide and one alcohol selected from the group consisting of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and ethyl(hydroxyimino)cyanoacetate as an amide condensation agent.

[0014] [8] A method for producing olaparib according to any one of [5] to [7], comprising a step of dissolving at least a portion of the first olaparib having a first crystalline form in a solvent and crystallizing it to obtain a second olaparib having a second crystalline form.

[0015] [9] A method for producing olaparib according to [8], comprising the steps of heating and dissolving the olaparib in a mixed solvent of methanol and water (methanol:water = 80:20 to 70:30 (volume ratio)) to obtain an olaparib solution, cooling the olaparib solution to room temperature and then adding water dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution to methanol:water = 33:67 to 43:57, stirring the olaparib solution at room temperature for 19 to 26 hours to crystallize it, and filtering and drying the obtained crystals to obtain H-type crystals of olaparib.

[0016]

[10] The method for producing olaparib according to [8], comprising the steps of heating and dissolving the DMF clathrate of olaparib in a mixed solvent of methanol and water (methanol:water = 85:15 to 65:35 (volume ratio)) to obtain an olaparib solution, adding water dropwise to the heated olaparib solution to adjust the volume ratio of the mixed solvent in the olaparib solution to methanol:water = 28:72 to 46:54, and then stirring for more than 0 hours and not more than 2 hours, cooling the olaparib solution to room temperature and crystallizing for 1 to 19 hours, and filtering and drying the obtained crystals to obtain the type A crystals of olaparib.

[0017]

[11] A method for producing olaparib according to [8], comprising the steps of heating and dissolving the DMF clathrate of olaparib in a mixed solvent of methanol and water (methanol:water = 80:20 to 70:30 (volume ratio)) to obtain an olaparib solution, cooling the olaparib solution to room temperature and then adding water dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution to methanol:water = 33:67 to 43:57, stirring the olaparib solution at room temperature for 1 to 2 hours to crystallize it, and filtering and drying the obtained crystals to obtain E-form crystals of olaparib.

[0018]

[12] The method for producing olaparib according to [8], comprising the steps of heating and dissolving the olaparib in isopropyl alcohol to obtain an olaparib solution, cooling the olaparib solution to 0°C to 20°C and then adding water dropwise, stirring the olaparib solution at 0°C to cause crystallization, and filtering and drying the obtained crystals to obtain the IPA clathrate of olaparib.

[0019]

[13] The method for producing olaparib according to [8], comprising the steps of heating the H-type crystals of olaparib in a mixed solvent of methanol and water (methanol:water = 80:20 to 70:30 (volume ratio)) to obtain an olaparib dispersion, cooling the olaparib dispersion to room temperature over 30 minutes or more, and then adding water dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution to methanol:water = 33:67 to 43:57, stirring the olaparib dispersion at room temperature to crystallize, and filtering and drying the obtained crystals to obtain the L-type crystals of olaparib.

[0020]

[14] The method for producing olaparib according to any one of [5] to [7], comprising the steps of preparing an olaparib solution in which the olaparib is dissolved, and spray-drying the olaparib solution to obtain amorphous olaparib.

[0021] According to the present invention, a method for producing a highly pure olaparib precursor can be provided. In addition, a method for producing olaparib that uses the obtained olaparib precursor and enables high-quality olaparib to be easily produced can be provided.

[0022] Figure 1 is an XRD chart of the obtained DMF clathrate crystals. Figure 2 is an XRD chart of the obtained hydrate crystals. Figure 3 is an XRD chart of the obtained A-type crystals. Figure 4 is an XRD chart of the obtained E-type crystals. Figure 5 is an XRD chart of the obtained IPA clathrate crystals. Figure 6 is an XRD chart of the obtained L-type crystals. Figure 7 is an XRD chart of the obtained olaparib powder.

[0023] In this specification, when a numerical range is described as, for example, "A to B," it means a numerical range including A, which is the lower limit, and B, which is the upper limit.

[0024] The method for producing an olaparib precursor of this embodiment includes the steps of (a) to (c) below, which are carried out consecutively without isolating the reaction intermediates: (a) reacting dimethyl(3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate with 2-fluoro-5-formylbenzoic acid in the presence of diazabicycloundecene in DMF, acetonitrile, or THF; (b) reacting the reaction mixture obtained in the reaction (a) with hydrazine; and (c) adjusting the reaction solution obtained in the reaction (b) to a pH of 4 or less to obtain 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)benzoic acid, the olaparib precursor.

[0025] Furthermore, the method for producing olaparib according to the present embodiment includes a step of amide condensing the olaparib precursor produced by the method for producing an olaparib precursor according to the present embodiment with 1-(cyclopropylcarbonyl)piperazine or 1-(cyclopropylcarbonyl)piperazine hydrochloride in DMF to obtain olaparib.

[0026] In addition, DMF represents N,N-dimethylformamide, and THF represents tetrahydrofuran.

[0027] <<Method for Producing Olaparib Precursor>> In the method for producing an olaparib precursor of this embodiment, as shown in the following chemical formula (I), the above steps (a) to (c) are carried out consecutively without isolating the reaction intermediate (compound Xa in formula (I)). Therefore, according to the method for producing an olaparib precursor of this embodiment, the target olaparib precursor (2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid, compound X3, can be obtained with fewer steps than the step of isolating an intermediate.

[0028]

[0029] Note that the intermediate (compound Xa) represented by the above chemical formula (I) is one of the compounds that the inventors envision as being present in the reaction system, and does not necessarily mean that the reaction in the method for producing an olaparib precursor of this embodiment must proceed via compound Xa as an intermediate. Even if another compound is produced in the reaction system as an intermediate, as long as the target compound X3 can be obtained by performing the above steps (a) to (c) in one pot, this corresponds to the method for producing an olaparib precursor of this embodiment.

[0030] (Step (a)) In step (a), diazabicycloundecene (DBU®) is used as a base to react the starting material dimethyl(3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate (Compound X) with 2-fluoro-5-formylbenzoic acid. This produces a bond at the formyl group of 2-fluoro-5-formylbenzoic acid from Compound X, and then -P═O(OMe) is obtained via a betaine intermediate. ２ It is believed that the group is eliminated and condensed to give the intermediate compound Xa.

[0031]

[0032] In step (a), DMF, acetonitrile, or THF can be used as the solvent. These solvents may be used in combination with other organic solvents used in organic synthesis, as long as the effects of the invention are not impaired. DMF is preferred as the solvent used in step (a). That is, in step (a), it is preferred to react compound X with 2-fluoro-5-formylbenzoic acid in DMF in the presence of diazabicycloundecene.

[0033] (Step (b)) The reaction mixture of step (a) contains compound Xa, which is a condensation product of compound X and 2-fluoro-5-formylbenzoic acid. In step (b), it is believed that the lactone ring of compound Xa reacts with hydrazine to open the ring and produce compound Xb, an intermediate.

[0034]

[0035] The hydrazine used may be 100% or may be a hydrazine solution. The hydrazine solution may be an aqueous solution. The concentration of the aqueous hydrazine solution may be 50% by mass or more, 60% by mass or more, or 80% by mass or more.

[0036] (Step (c)) In step (c), the intermediate in the reaction system is treated with acid to obtain 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)-benzoic acid (compound X3). Compound X3 is a precursor of the desired olaparib. It is believed that the intermediate ring-opened in step (b) forms an imine intramolecularly under acidic conditions to produce compound X3.

[0037] During the acid treatment, the reaction solution is adjusted to a weak to strong acidity. At this time, the target pH of the reaction solution is 4 or less, preferably a pH of 1 to 2. In order to suppress side reactions and the generation of impurities, the acid treatment is preferably carried out at a temperature in the range of 20°C to 30°C.

[0038] When the pH of the reaction solution is relatively high (for example, pH 4), it may be difficult to obtain the target compound X3. In this case, the reaction solution may be appropriately heated to promote the reaction. The heating temperature may be 30° C. or higher and 80° C. or lower.

[0039] After step (c), compound X3 is crystallized by adding water to the reaction solution and stirring. The crystals formed in the system are filtered off, thereby obtaining the target compound X3 in high purity and high yield. That is, by performing steps (a) to (c) above consecutively without isolating the reaction intermediate, the target compound X3 can be obtained in high yield and high purity.

[0040] The purity of the obtained compound X3 can be confirmed by HPLC. The obtained compound X3 is subjected to HPLC analysis, and the area ratio of compound X3 to the total peak area value of the obtained chromatogram (HPLC area ratio (Area%)) is determined to calculate the purity. Note that the purity of olaparib described below and the progress of the reaction during the synthesis reaction can also be confirmed using a similar analytical method.

[0041] The HPLC analysis conditions can be, for example, as follows:

[0042] <Analysis conditions> Column: Inertsil ODS-3 (4.6 mm x 250 mm, 3 μm) Column temperature: 25°C Mobile phase A: 10 mM ammonium acetate aqueous solution (pH 4.5) Mobile phase B: acetonitrile Gradient (volume ratio): Condition 1 (0 → 3 min) Mobile phase A:mobile phase B = 90:10 Condition 2 (3 → 12 min) Mobile phase A:mobile phase B = 25:75 Condition 3 (12 → 16 min) Mobile phase A:mobile phase B = 25:75 Condition 4 (16 → 17 min) Mobile phase A:mobile phase B = 90:10 Condition 5 (17 → 25 min) Mobile phase A:mobile phase B = 90:10 Detector: UV 254 nm

[0043] The concentration of the mobile phase is changed continuously at a constant rate, as described above under "gradient." Under condition 1, the volume ratio of mobile phase A to mobile phase B is constant at 90:10. Under condition 2, the ratio is changed continuously at a constant rate from 90:10 to 25:75. Conditions 3, 4, and 5 can be understood in the same way as condition 2.

[0044] (Purification) The obtained olaparib precursor may be further purified. That is, when the crystals filtered from the reaction solution in the above-mentioned step (c) are designated as "crude crystals containing compound X3," an olaparib precursor having a higher purity than the crude crystals can be obtained by going through the steps of dissolving the crude crystals and sodium hydroxide in DMF, adding acetic acid to the solution obtained in the dissolving step to adjust the pH to 4 to 6, and filtering the resulting crystals.

[0045] In the dissolving step, the solution may be heated appropriately. The heating temperature may be, for example, 20°C or higher and 60°C or lower.

[0046] The above purification procedure, from the dissolving step to the filtration step, is counted as one operation, and may be carried out multiple times.

[0047] <<Method for Producing Olaparib>> In the method for producing olaparib of this embodiment, as shown in the following chemical formula (II), an olaparib precursor (compound X3) and 1-(cyclopropylcarbonyl)piperazine or 1-(cyclopropylcarbonyl)piperazine hydrochloride are subjected to amide condensation in DMF to obtain the target product, olaparib (4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one, compound A).

[0048]

[0049] In the method for producing olaparib, it is preferable to use a water-soluble carbodiimide (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, WSCD) as an amide condensing agent and one alcohol selected from the group consisting of 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), and ethyl (hydroxyimino)cyanoacetate (Oxyma). The chemical formulas of each compound are shown below.

[0050]

[0051] In the above reaction, 1-(cyclopropylcarbonyl)piperazine is preferred over 1-(cyclopropylcarbonyl)piperazine hydrochloride, as the use of 1-(cyclopropylcarbonyl)piperazine to produce olaparib results in higher purity compared to the use of 1-(cyclopropylcarbonyl)piperazine hydrochloride.

[0052] In the above reaction, an amine such as N,N-diisopropylethylamine (DIPEA) may be used in combination.

[0053] The purity of the obtained olaparib can be confirmed by HPLC measurement under the above <Analysis Conditions>.

[0054] The produced olaparib (compound A) is obtained as a composition of such high purity that in addition to olaparib, compound X1, which is particularly difficult to separate from olaparib, can be detected in trace amounts. In this embodiment, compound X1 is used as a labeled compound and can be used as an indicator of the purity of olaparib.

[0055] The method for producing olaparib according to this embodiment can also be said to produce a composition containing olaparib and an impurity represented by compound X1. In this case, the composition contains 99.8% or more of olaparib and more than 0% but less than 0.05% of compound X1 relative to the total composition. The numerical values ​​representing the content are area percentages determined by the above-mentioned HPLC analysis. In many cases, the content of compound X1 in the above composition is below the lower detection limit of HPLC. The sample concentration during HPLC measurement is 250 ppm. The sample was prepared by accurately weighing 5 mg of the object to be measured and dissolving it in 20 mL of 50% by volume aqueous acetonitrile solution.

[0056]

[0057] (Crystal Form Control) The crystalline form of a pharmaceutical (drug) is known to have a significant impact on drug quality. For example, even for the same drug, different crystalline forms can have different physical properties such as melting point, dissolution rate, and hygroscopicity, which can affect formulation preparation conditions and pharmacokinetics. Therefore, a single crystalline form is required for olaparib as a drug substance, but until now, there has been insufficient research into control methods to obtain a single crystalline form.

[0058] In the method for producing olaparib of this embodiment, the crystalline form can be controlled by a step of dissolving at least a portion of the first olaparib having a first crystalline form in a solvent and crystallizing it to obtain a second olaparib having a second crystalline form.

[0059] The crystal type of each crystal can be confirmed by performing XRD measurement under the conditions shown in Table 1 below. From the obtained measurement results, the crystal type is identified by referring to known XRD data. For information on the crystal type, reference can be made to, for example, Japanese Patent No. 5248513 (A-type crystal), Japanese Patent No. 5593229 (L-type crystal), International Publication No. 2017 / 140283 (clathrate), Chinese Patent Application Publication No. 114249695 (DMF hydrate crystal), and European Patent Application Publication No. 3184513 (hydrate crystal, amorphous).

[0060]

[0061] Olaparib is available in various crystalline forms as a drug substance depending on the process used to obtain it. In this specification, amorphous form, which does not have a crystalline structure, is also included as one of the crystalline forms of Olaparib.

[0062] Olaparib having a crystalline structure can be in the form of a solvate, clathrate, or unsolvate depending on the presence or absence of a solvent in the crystalline structure and the location of the solvent within the crystalline structure. That is, in this embodiment, "crystals of olaparib" include crystalline polymorphs of olaparib as well as solvates, clathrates, and unsolvates of olaparib having a crystalline structure.

[0063] A solvate is a state in which a compound and a solvent are regularly arranged in a fixed ratio. H-type crystals are hydrates.

[0064] A clathrate is a crystal in which a solvent is contained in the gaps of the crystal lattice of a compound at a constant or arbitrary equivalent amount. In general, the XRD data of a clathrate and a solvate containing the same solvent are different. In addition, a solvate generally shows a different XRD pattern when the solvent is different.

[0065] The content and amount of the solvent in the clathrate crystal was determined from the proton ratio by subjecting the obtained clathrate crystal to NMR measurement under the following measurement conditions.

[0066] < １ H-NMR measurement conditions> Measurement solvent: deuterated dimethyl sulfoxide (DMSO-d6) Measurement frequency: 400 MHz Internal standard substance: tetramethylsilane

[0067] Furthermore, it can be confirmed by thermogravimetry that the non-solvates do not contain solvents (organic solvents, water). Forms A, E, and L of olaparib are non-solvates.

[0068] For example, after the step of obtaining olaparib in the above production method, the resulting crystals are filtered to obtain a DMF clathrate of olaparib (first olaparib). This clathrate is dissolved in a solvent containing alcohol and crystallized to obtain a second olaparib having a second crystalline form.

[0069] In this case, a mixed solvent of alcohol and water may be used as the alcohol-containing solvent, and the mixing ratio (volume ratio) of the mixed solvent used may be alcohol:water=80:20 to 70:30.

[0070] Examples of alcohols that can be used in the mixed solvent include methanol, ethanol, propanol, and isopropanol (IPA). The type of alcohol to be used can be determined by conducting a preliminary experiment.

[0071] The DMF clathrate of olaparib obtained by the above production method is heated and dissolved in a mixed solvent of methanol and water, the resulting solution is cooled to room temperature, and water is added dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution. The solution is stirred at room temperature for 19 to 26 hours to crystallize, and the resulting crystals are filtered and dried to obtain H-type crystals of olaparib. In this embodiment, "room temperature" refers to a temperature range of 25°C ± 5°C. The same applies hereinafter.

[0072] When obtaining H-type crystals, the volume ratio of the mixed solvent of methanol and water may be 80:20 to 70:30 methanol:water, or 78:22 to 73:27 methanol:water. For example, a mixed solvent of 75:25 methanol:water can be used. Furthermore, when the olaparib solution is cooled to room temperature and water is added dropwise, the volume ratio of the mixed solvent in the olaparib solution may be 33:67 to 43:57 methanol:water, or 35:65 to 40:60 methanol:water. For example, a mixed solvent of 38:62 methanol:water can be used.

[0073] Alternatively, the DMF clathrate of olaparib obtained by the above production method can be heated and dissolved in a mixed solvent of methanol and water to obtain a solution, water can be added dropwise to the heated solution to adjust the volume ratio of the mixed solvent in the olaparib solution, and the mixture can be stirred for more than 0 hours and not more than 2 hours. The solution can then be cooled to room temperature and crystallized for 1 to 19 hours, and the resulting crystals can be filtered and dried to obtain type A crystals of olaparib.

[0074] When obtaining Type A crystals, the volume ratio of the methanol:water mixed solvent may be 85:15 to 65:35, 82:18 to 65:35, or 82:18 to 68:32. For example, a methanol:water mixed solvent of 80:20, 70:30, or 75:25 may be used. Furthermore, when the olaparib solution is cooled to room temperature and water is added dropwise, the volume ratio of the mixed solvent in the olaparib solution may be 28:72 to 46:54, 31:69 to 46:54, or 31:69 to 43:57. For example, a methanol:water mixed solvent of 32.8:67.2, 35:65, or 41:59 may be used.

[0075] The DMF clathrate of olaparib obtained by the above production method is heated and dissolved in a mixed solvent of methanol and water, the resulting solution is cooled to room temperature, and water is added dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution. The solution is then stirred at room temperature for 1 to 2 hours to crystallize, and the resulting crystals are filtered and dried to obtain E-type crystals of olaparib.

[0076] When obtaining E-type crystals, the volume ratio of the mixed solvent of methanol and water may be 80:20 to 70:30 methanol:water, or 78:22 to 73:27 methanol:water. For example, a 75:25 methanol:water mixed solvent can be used. Furthermore, when the olaparib solution is cooled to room temperature and water is added dropwise, the volume ratio of the mixed solvent in the olaparib solution may be 33:67 to 43:57 methanol:water, or 35:65 to 40:60 methanol:water. For example, a 38:62 methanol:water mixed solvent can be used.

[0077] As described above, if the DMF clathrate is dissolved by heating in a mixed solvent of methanol and water, the resulting solution is cooled to room temperature, water is added dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution, and the solution is stirred at room temperature for 19 to 26 hours to obtain type H crystals, or for 1 to 2 hours to obtain type E crystals. If the stirring time is 2 to 19 hours, a mixed crystal of type H crystals and type E crystals is obtained.

[0078] Furthermore, an IPA clathrate of olaparib can be obtained by dissolving the olaparib obtained by the above production method in isopropyl alcohol by heating, cooling the resulting solution to 0°C to 20°C, adding water dropwise, stirring the solution at 0°C to cause crystallization, and filtering and drying the resulting crystals. It has been confirmed that when a mixed solvent of IPA and water is used as the solvent for dissolving olaparib, a mixed crystal of IPA clathrate and H-type crystals can be obtained.

[0079] Furthermore, the H-type crystals of olaparib obtained by the above production method are heated in a mixed solvent of methanol and water, the resulting dispersion is cooled to room temperature over 30 minutes or more, water is then added dropwise, the dispersion is stirred at room temperature to cause crystallization, and the resulting crystals are filtered and dried to obtain L-type crystals of olaparib.

[0080] When obtaining type L crystals from type H crystals, the volume ratio of the mixed solvent of methanol and water may be 80:20 to 70:30 methanol:water, or 78:22 to 73:27 methanol:water. For example, a mixed solvent of 75:25 methanol:water can be used. Furthermore, when the olaparib solution is cooled to room temperature and then water is added dropwise, the volume ratio of the mixed solvent in the olaparib solution may be 33:67 to 43:57 methanol:water, or 35:65 to 40:60 methanol:water. For example, a mixed solvent of 38:62 methanol:water can be used.

[0081] In the method for obtaining each crystal of olaparib by crystallization as described above, the temperature at which the starting material, olaparib, is heated in the mixed solvent is not particularly limited as long as the mixed solvent does not evaporate. The heating temperature is preferably 55°C or higher, and may be 60°C or higher, for example.

[0082] The filtered crystals may be washed with an aqueous alcohol solution. For example, a 10 to 20% by volume aqueous methanol solution can be used as the washing solution. For example, a 12% by volume aqueous methanol solution can be used as the washing solution.

[0083] The obtained crystals can be dried by heating, blowing air, reducing pressure, or a combination thereof. During drying, it is preferable to heat the crystals to a temperature of 40° C. or higher but lower than 50° C.

[0084] Furthermore, a solution is prepared by dissolving the olaparib obtained by the above-mentioned production method in a solvent (a step of preparing a solution), and the obtained solution is spray-dried to obtain amorphous olaparib (a step of obtaining an amorphous form).

[0085] The fact that the solid obtained after spray drying is amorphous can be confirmed from the results of the above XRD measurement, which show a broad spectrum with no identifiable peaks.

[0086] By the above-mentioned operations, the crystal form of olaparib can be converted to the desired crystal form.

[0087] According to the method for producing an olaparib precursor configured as described above, a highly pure olaparib precursor can be easily obtained.

[0088] Furthermore, according to the method for producing olaparib configured as described above, high-quality olaparib can be easily produced using the olaparib precursor obtained by the above method.

[0089] Although the preferred embodiments of the present invention have been described above, the present invention is not limited to these examples. Each combination shown in the above examples is merely an example, and various modifications are possible within the scope of the gist of the present invention.

[0090] The present invention will be described below with reference to examples, but the present invention is not limited to these examples.

[0091] (Abbreviations) DMF: N,N-dimethylformamide, DBU: diazabicycloundecene, WSCD: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide, HOBt: 1-hydroxybenzotriazole, DIPEA: N,N-diisopropylethylamine, THF: tetrahydrofuran, IPA: isopropyl alcohol, HPLC: high performance liquid chromatography

[0092] In the following description, the starting materials for the reactions and the compounds to be synthesized are appropriately designated by names such as Compound A, as in the above-described embodiment.

[0093] In addition, with regard to the molar yields described in each example, all results exceeding 100% in measurement are expressed as 100%. The reason why the molar yields exceed 100% is thought to be because the obtained products contain by-products.

[0094] Example 1: Production of olaparib precursor. Comparison with known production method In Example 1, the difference in effect between the present invention and known production methods was investigated.

[0095] Example 1-1 Compound X (15.1 g), 2-fluoro-5-formylbenzoic acid (10 g), and DMF (50 mL) were combined, stirred, and cooled to −8° C. Then, diazabicycloundecene (18.1 g) was added dropwise over 0.5 hours, and the mixture was washed with 5 mL of DMF.

[0096] The resulting reaction solution was stirred at 0° C. for 21 hours and then cooled to −8° C. Hydrazine monohydrate (4.5 g) was further added dropwise, and the mixture was stirred at 0° C. for 1 hour.

[0097] Next, concentrated hydrochloric acid (15.8 mL) was added dropwise to the reaction solution to adjust the pH to 1.3 (actual measured value), and the temperature was then raised to 20°C and the mixture was stirred at 20°C for 5 hours.

[0098] Next, water (120 mL) was added dropwise to the reaction solution, and the mixture was stirred at 20°C for 23 hours to allow crystallization. The resulting crystals were filtered and washed with 20 mL of water. The washed crystals were dried in vacuo at 40°C for 19 hours to obtain compound X3 (dry yield 16.6 g, molar yield 94%, purity 95.9%). The HPLC analysis results of the obtained compound X3 are shown in Table 2 below.

[0099] In the table, "RT" means elution time (minutes), and "RRT" means relative retention time. Furthermore, "content" in the table means the content of each peak determined by HPLC analysis.

[0100]

[0101] Example 1-2 Compound X (1.5 g), 2-fluoro-5-formylbenzoic acid (1.0 g), and THF (6 mL) were combined, stirred, and cooled to −8° C. Diazabicycloundecene (1.8 g) was added dropwise to the resulting THF solution over 0.5 hours.

[0102] The resulting reaction solution was stirred at 26° C. for 15 hours and then cooled to −5° C. Hydrazine monohydrate (0.45 g) was further added dropwise, and the mixture was stirred at 0° C. for 1 hour.

[0103] Next, concentrated hydrochloric acid (1.6 mL) was added dropwise to the reaction solution to adjust the pH to 1.5 (actual measured value), and the temperature was then raised to 25°C and the mixture was stirred at 25°C for 3 hours.

[0104] Next, water (12 mL) was added dropwise to the reaction solution, and the mixture was stirred at 25°C for 21 hours to allow crystallization. The resulting crystals were filtered and washed with 2 mL of water. The washed crystals were dried in vacuo at 40°C for 18 hours to obtain compound X3 (dry yield 2.0 g, molar yield 100%, purity 88.3%).

[0105] Example 1-3 Compound X3 (dry yield 1.8 g, molar yield 100%, purity 91.0%) was obtained in the same manner as in Example 1-2, except that the solvent used was acetonitrile instead of THF.

[0106] Comparative Example 1 In the comparative example, the method described in Chinese Patent No. 110790710 was used as a known manufacturing method.

[0107] Compound X (2.6 g, 0.011 mol) and 2-fluoro-5-formylbenzoic acid (2.1 g, 0.012 mol) were dissolved in THF (25 ml). The resulting THF solution was cooled to 0°C, and then triethylamine (1.0 ml, 0.007 mol) was added dropwise. After the addition of triethylamine, the mixture was warmed to 25°C and stirred for 5 hours.

[0108] The reaction solution was then heated to 70° C. and stirred for 24 hours at 70° C. After 24 hours, 57% of the raw material Compound X remained in the reaction solution.

[0109] Hydrazine hydrate (5.1 ml, 0.107 mol) was added to the reaction solution at 70°C, and the mixture was stirred for 5 hours, after which the temperature was lowered to room temperature. The reaction solution contained 7% of the raw material Compound X and approximately 30% of the target compound X3. The reaction solution separated into two layers: a THF layer and a water layer.

[0110] Next, concentrated hydrochloric acid (7 mL) was added dropwise to the reaction solution to adjust the pH to 2-3, and the temperature was raised to 25°C and stirred at 25°C for 12 hours. The resulting crystals were filtered and washed sequentially with ethyl acetate (10 mL) and water (10 mL). The washed crystals were dried in vacuo at 40°C overnight to obtain compound X3 (dry yield 0.16 g, molar yield 5%, purity 9.9%) as a yellow solid. The HPLC analysis results of the obtained compound X3 are shown in Table 3 below.

[0111]

[0112] From the above, it was found that in Examples 1-1 to 1-3, compound X3 of high quality was obtained in good yield compared to Comparative Example 1.

[0113] Example 2: pH during acid cyclization reaction In Example 2, the pH adjusted after adding hydrazine was changed to confirm the effect, which relates to the conditions of step (c) described in the above embodiment.

[0114] Example 2-1 Compound X (1.5 g), 2-fluoro-5-formylbenzoic acid (1.0 g), and DMF (6 mL) were combined, stirred, and cooled to −10° C. Then, diazabicycloundecene (1.8 g) was added dropwise.

[0115] The resulting reaction solution was stirred at 0° C. for 17 hours and then cooled to −10° C. Hydrazine monohydrate (0.45 g) was further added dropwise, and the mixture was stirred at 0° C. for 2 hours.

[0116] Next, concentrated hydrochloric acid (0.8 mL, 1.5 equivalents) was added dropwise to the reaction solution to adjust the pH to 3.5 (actual measured value), and the temperature was raised to 80° C. and the mixture was stirred at 80° C. for 2 hours.

[0117] The reaction solution was then cooled to 18°C, and water (12 mL) was added dropwise thereto. The mixture was stirred at 22°C for 21 hours to allow crystallization. The resulting crystals were filtered and washed with 2 mL of water. The washed crystals were dried in vacuo at 40°C for 18 hours to obtain compound X3 (dry yield 1.9 g, molar yield 100%, purity 94.0%). The HPLC analysis results of the obtained compound X3 are shown in Table 4 below.

[0118]

[0119] Example 2-2 The amounts of the reagents other than concentrated hydrochloric acid used for pH adjustment were the same as in Example 2-1. Compound X, 2-fluoro-5-formylbenzoic acid, and DMF were mixed, stirred, and cooled to -4°C. Diazabicycloundecene was then added dropwise, and the resulting reaction solution was stirred at 0°C for 17 hours and then cooled to -5°C. Hydrazine monohydrate was then added dropwise, and the mixture was stirred at 0°C for 1 hour.

[0120] Next, concentrated hydrochloric acid (1.1 mL, 2.0 equivalents) was added dropwise to the reaction solution to adjust the pH to 2.5 (actual measured value), and the temperature was then raised to 25°C and the mixture was stirred at 25°C for 68 hours.

[0121] Next, water was added dropwise to the reaction solution, and the mixture was stirred at 25°C for 23 hours to allow crystallization. The resulting crystals were filtered and washed with 2 mL of water. The washed crystals were dried in vacuo at 40°C for 21 hours to obtain compound X3 (dry yield 1.7 g, molar yield 95%, purity 96.0%). The HPLC analysis results of the obtained compound X3 are shown in Table 5 below.

[0122]

[0123] Example 2-3 The amounts of the reagents other than concentrated hydrochloric acid used for pH adjustment were the same as in Example 2-1. Compound X, 2-fluoro-5-formylbenzoic acid, and DMF were mixed, stirred, and cooled to -5°C. Diazabicycloundecene was then added dropwise, and the resulting reaction solution was stirred at 0°C for 22 hours and then cooled to -6°C. Hydrazine monohydrate was then added dropwise, and the mixture was stirred at 0°C for 2 hours.

[0124] Next, concentrated hydrochloric acid (1.3 mL, 2.5 equivalents) was added dropwise to the reaction solution to adjust the pH to 1.5 (actual measured value), and the temperature was then raised to 25°C and the mixture was stirred at 25°C for 18 hours.

[0125] Next, water was added dropwise to the reaction solution, and the mixture was stirred at 25°C for 23 hours to allow crystallization. The resulting crystals were filtered and washed with 2 mL of water. The washed crystals were dried in vacuo at 40°C for 23 hours to obtain compound X3 (dry yield 1.7 g, molar yield 93%, purity 95.1%). The HPLC analysis results of the obtained compound X3 are shown in Table 6 below.

[0126]

[0127] Example 2-4 Compound X (15.1 g), 2-fluoro-5-formylbenzoic acid (10 g), and DMF (50 mL) were combined, stirred, and cooled to −8° C. Then, diazabicycloundecene (18.1 g) was added dropwise, and the mixture was washed with 5 mL of DMF.

[0128] The resulting reaction solution was stirred at 0° C. for 18 hours and then cooled to −7° C. Hydrazine monohydrate (4.5 g) was further added dropwise, and the mixture was stirred at 0° C. for 1 hour.

[0129] Next, concentrated hydrochloric acid (24.8 mL, 4 equivalents) was added dropwise to the reaction solution to adjust the pH to 0.5 (actual measured value), and the temperature was raised to 24°C, followed by stirring at 24°C for 2 hours.

[0130] Next, water (120 mL) was added dropwise to the reaction solution, and the mixture was stirred at 20°C for 18 hours to allow crystallization. The resulting crystals were filtered and washed with 20 mL of water. The washed crystals were dried in vacuo at 40°C for 23 hours to obtain compound X3 (dry yield 16.6 g, molar yield 94%, purity 94.0%). The HPLC analysis results of the obtained compound X3 are shown in Table 7 below.

[0131]

[0132] As a result of the evaluation, it was found that the optimum pH for the acid cyclization reaction in step (c) was 1.5 (Example 2-3). At pH 3.5 (Example 2-1), the product contained diazabicycloundecene salt, and the content was low. At pH 2.5 (Example 2-2), the rate of the cyclization reaction was very slow. At pH 0.5 (Example 2-4), the amount of the impurity RT11.3 produced increased, and the HPLC purity decreased.

[0133] Example 3: Purification of olaparib precursor In Example 3, the olaparib precursor produced in Example 1 was purified.

[0134] Example 3-1 Compound X3 (16.6 g) was dissolved in 3% aqueous sodium hydroxide solution (85.7 g), and then DMF (41.5 mL) was added to the resulting aqueous solution, followed by heating at 60° C. for 2 hours.

[0135] After heating, acetic acid (4.8 mL) was added dropwise to the reaction solution, which was then cooled to 20°C and stirred at 20°C for 18 hours to cause crystallization.

[0136] The resulting crystals were filtered and washed with 34 mL of water, and then dried under vacuum at 40° C. for 24 hours to obtain compound X3 (dry yield 14.6 g, molar yield 88%, purity 99.4%).

[0137] The obtained compound X3 (14.5 g) was dissolved again in 3% aqueous sodium hydroxide solution (74.8 g), and then DMF (36.3 mL) was added to the obtained aqueous solution, followed by heating at 60° C. for 2 hours.

[0138] After heating, acetic acid (4.2 mL) was added dropwise to the reaction solution, which was then cooled to 22°C and stirred at 20°C for 20 hours to cause crystallization.

[0139] The resulting crystals were filtered and washed with 29 mL of water. The washed crystals were dried in vacuum at 40° C. for 21 hours to obtain compound X3 (dry yield 12.9 g, molar yield 88%, purity 100%). The HPLC analysis results of the obtained compound X3 are shown in Table 8 below.

[0140]

[0141] [Example 3-2] Compound X3 (0.5 g) was dissolved in 3% aqueous sodium hydroxide solution (2.58 g), and then DMF (1.3 mL) was added to the resulting aqueous solution, followed by heating at 60°C for 1 hour.

[0142] After heating, formic acid (0.10 mL) was added dropwise to the reaction solution, which was then cooled to 20° C. and stirred at 20° C. for 17 hours to cause crystallization.

[0143] The resulting crystals were filtered and washed with 3 mL of water. The pH of the filtrate was 4.5. The washed crystals were dried in vacuo at 40° C. for 28 hours to obtain compound X3 (dry yield 0.46 g, molar yield 92%, purity 98.5%). The HPLC analysis results of the obtained compound X3 are shown in Table 9 below.

[0144]

[0145] [Example 3-3] Compound X3 (0.5 g) was dissolved in 3% aqueous sodium hydroxide solution (2.58 g), and then DMF (1.3 mL) was added to the resulting aqueous solution, followed by heating at 60°C for 2 hours.

[0146] After heating, formic acid (0.19 mL) was added dropwise to the reaction solution, which was then cooled to 20° C. and stirred at 20° C. for 17 hours to cause crystallization.

[0147] The resulting crystals were filtered and washed with 3 mL of water. The pH of the filtrate was 4.0. The washed crystals were dried in vacuo at 40°C for 28 hours to obtain compound X3 (dry yield 0.47 g, molar yield 94%, purity 97.4%). The HPLC analysis results of the obtained compound X3 are shown in Table 10 below.

[0148]

[0149] [Example 3-4] Compound X3 (0.5 g) was dissolved in 3% aqueous sodium hydroxide solution (2.58 g), and then DMF (1.3 mL) was added to the resulting aqueous solution, followed by heating at 60°C for 4 hours.

[0150] After heating, acetic acid (0.12 mL) was added dropwise to the reaction solution, which was then cooled to 20°C and stirred at 20°C for 19 hours to allow crystallization.

[0151] The resulting crystals were filtered and washed with 2 mL of water. The pH of the filtrate was 5.0. The washed crystals were dried in vacuo at 40°C for 22 hours to obtain compound X3 (dry yield 0.40 g, molar yield 80%, purity 99.4%). The HPLC analysis results of the obtained compound X3 are shown in Table 11 below.

[0152]

[0153] [Example 3-5] Compound X3 (0.5 g) was dissolved in 3% aqueous sodium hydroxide solution (2.58 g), and then DMF (1.3 mL) was added to the resulting aqueous solution, followed by heating at 60°C for 4 hours.

[0154] After heating, acetic acid (0.19 mL) was added dropwise to the reaction solution, which was then cooled to 20°C and stirred at 20°C for 19 hours to cause crystallization.

[0155] The resulting crystals were filtered and washed with 2 mL of water. The pH of the filtrate was 4.0. The washed crystals were dried in vacuo at 40°C for 22 hours to obtain compound X3 (dry yield 0.40 g, molar yield 80%, purity 99.4%). The HPLC analysis results of the obtained compound X3 are shown in Table 12 below.

[0156]

[0157] As a result of the evaluation, it was confirmed that a highly pure olaparib precursor can be obtained by simple purification procedures.

[0158] Example 4: Preparation of olaparib In Example 4, olaparib was prepared using the olaparib precursor produced in Example 3.

[0159] [Example 4-1] Compound X3 (12 g), WSCD (15.4 g), HOBt.H ２ O (1.23 g) and DMF (18 mL) were combined and stirred. 1-(Cyclopropylcarbonyl)piperazine (6.51 g) was added dropwise, and the mixture was washed with DMF (18 mL).

[0160] Then, diisopropylethylamine (10.5 mL) was added and washed with 4 mL of DMF.

[0161] After stirring at 20°C for 18 hours, water (72 mL) was added dropwise, and the mixture was stirred at 20°C for 18 hours to allow crystallization. The resulting crystals were filtered and washed with water (36 mL). The washed crystals were dried under vacuum at 40°C for 20 hours to obtain crystals of DMF clathrate of olaparib (yield 17.2 g, molar yield 89%, purity 99.96%).

[0162] FIG. 1 is an XRD chart of the obtained DMF clathrate crystals.

[0163] [Example 4-2] Compound X3 (1 g), WSCD (1.3 g), HOBt.H ２ O (0.1 g) and DMF (1 mL) were combined and stirred. After the whole was cooled to 0°C, 1-(cyclopropylcarbonyl)piperazine (0.54 g) was added dropwise, and DMF (2 mL) was added for washing.

[0164] After stirring at 25°C for 1 hour without adding diisopropylethylamine, water (6 mL) was added dropwise and stirred at 25°C for 2 hours to allow crystallization. The resulting crystals were filtered and washed with water (2 mL). The washed crystals were dried under vacuum at 40°C for 25 hours to obtain crystals of DMF clathrate of olaparib (yield 1.6 g, molar yield 98%, purity 98.6%).

[0165] [Example 4-3] Compound X3 (0.5 g), 1-(cyclopropylcarbonyl)piperazine hydrochloride (0.34 g), WSCD (0.64 g), HOBt.H ２ O (0.05 g) and DMF (18 mL) were mixed and stirred. Further, DMF (1.5 mL) was added and stirred.

[0166] Diisopropylethylamine (0.44 mL) was then added.

[0167] After stirring at 27°C for 15 hours, water (3 mL) was added dropwise, and the mixture was stirred at 23°C for 6 hours to allow crystallization. The resulting crystals were filtered and washed with water (1 mL). The washed crystals were dried under vacuum at 40°C for 23 hours to obtain crystals of DMF clathrate of olaparib (yield 0.76 g, molar yield 96%, purity 98.2%). The HPLC analysis results of the obtained DMF clathrate are shown in Table 13 below.

[0168]

[0169] [Example 4-4] Compound X3 (1.0 g), WSCD (1.3 g), HOBt.H ２ O (0.10 g) and acetonitrile (3 mL) were combined and stirred, and then 1-(cyclopropylcarbonyl)piperazine (0.54 g) was added dropwise.

[0170] After stirring at 30°C for 19 hours, water (6 mL) was added dropwise, and the mixture was stirred at 30°C for 28 hours to allow crystallization. The resulting crystals were filtered and washed with water (2 mL). The washed crystals were dried under vacuum at 40°C for 20 hours to obtain crystals of acetonitrile clathrate of olaparib (yield 1.5 g, molar yield 98%, purity 99.45%).

[0171] The XRD chart of the obtained acetonitrile clathrate crystals showed the same pattern as the XRD chart of the DMF clathrate shown in FIG.

[0172] From Examples 4-1 and 4-2, it was found that the reaction proceeded regardless of the presence of diisopropylethylamine, and a DMF clathrate with a purity of 98.6% or more was obtained in a yield of 89% or more.

[0173] Furthermore, from Examples 4-1 and 4-3, it was found that by producing olaparib using 1-(cyclopropylcarbonyl)piperazine, olaparib of higher purity can be obtained compared to when the hydrochloride salt of 1-(cyclopropylcarbonyl)piperazine is used.

[0174] Example 5: Conversion of crystalline form In Example 5, the crystalline form of olaparib was converted using the olaparib produced in Example 4.

[0175] Example 5-1 Preparation of Hydrate (H-Type Crystals) from DMF Clathrate Olaparib DMF clathrate (15 g), methanol (112.5 mL), and water (37.5 mL) were combined, stirred, and dissolved by heating to 60° C. The resulting solution was filtered to remove dust, and the filtrate was cooled to 30° C. over 30 minutes, and water (150 mL) was added dropwise to the filtrate.

[0176] After stirring at 20°C for 20 hours to allow crystallization, the resulting crystals were filtered and washed with a mixed solvent of methanol (30 mL) and water (13 mL). The washed crystals were dried in vacuo at 40°C for 19 hours to obtain olaparib hydrate (H-type crystals) (yield 13.0 g, molar yield 87%, purity 98.6%).

[0177] FIG. 2 is an XRD chart of the obtained hydrate (H-type crystals).

[0178] Example 5-2 Preparation of Hydrate (H-Type Crystals) from DMF Clathrate Olaparib DMF clathrate (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and dissolved by heating to 60° C. The resulting solution was filtered to remove dust, cooled to 30° C. over 30 minutes, and water (10 mL) was added dropwise.

[0179] After stirring at 20°C for 26 hours to allow crystallization, the crystals were filtered off and washed with a mixed solvent of methanol (2 mL) and water (13 mL). The washed crystals were dried in vacuo at 40°C for 19 hours to obtain olaparib hydrate (H-type crystals) (yield 0.8 g, molar yield 75%).

[0180] Example 5-3: Conversion of DMF clathrate to type A crystals Olaparib DMF clathrate (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. Water (10 mL) was added dropwise to the resulting solution, which was then stirred at 60°C for 30 minutes to cause crystallization. It was confirmed that the resulting crystals were precipitated during the dropwise addition of water and the subsequent stirring.

[0181] The solution was then cooled to 30°C over 30 minutes and stirred for 19 hours. The crystals were filtered and washed with 12.5% ​​by volume aqueous methanol solution (2 mL). The washed crystals were dried in vacuo at 40°C for 17 hours to obtain olaparib type A crystals (yield 0.9 g, molar yield 91%).

[0182] FIG. 3 is an XRD chart of the obtained A-type crystals.

[0183] Example 5-4: Conversion of DMF clathrate to type A crystals Olaparib DMF clathrate (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, cooled to 50°C, and water (10 mL) was added dropwise. The mixture was stirred at 50°C for 30 minutes to cause crystallization. It was confirmed that the resulting crystals were also precipitated during the dropwise addition of water and the subsequent stirring.

[0184] The solution was then cooled to 30°C over 30 minutes and stirred for 1 hour. The crystals were filtered and washed with 12.5% ​​by volume aqueous methanol solution (2 mL). The washed crystals were dried in vacuo at 40°C for 21 hours to obtain olaparib type A crystals (yield 0.9 g, molar yield 94%).

[0185] Example 5-5: Conversion of DMF clathrate to A-type crystals DMF clathrate of olaparib (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, and then water (10 mL) was added dropwise to the filtrate heated to 60°C, followed by stirring at 60°C for 2 hours to cause crystallization. It was confirmed that the resulting crystals were precipitated during the dropwise addition of water and the subsequent stirring.

[0186] The solution was then cooled to 30°C over 30 minutes and stirred for 1 hour. The crystals were filtered and washed with 12.5% ​​by volume aqueous methanol solution (2 mL). The washed crystals were dried in vacuo at 40°C for 16 hours to obtain olaparib type A crystals (yield 0.8 g, molar yield 91%).

[0187] Example 5-6: Conversion of DMF clathrate to type A crystals DMF clathrate of olaparib (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, and then water (10 mL) was added dropwise to the filtrate heated to 60°C. It was confirmed that the resulting crystals were precipitated during the dropwise addition of water and the subsequent stirring.

[0188] The solution was cooled to 30°C over 30 minutes and stirred for 1 hour. The crystals were filtered and washed with 12.5% ​​by volume aqueous methanol solution (2 mL). The washed crystals were dried in vacuo at 40°C for 16 hours to obtain olaparib type A crystals (yield 0.9 g, molar yield 96%).

[0189] Example 5-7: Conversion of DMF clathrate to type A crystals DMF clathrate of olaparib (5 g), methanol (35 mL), and water (15 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, and then water (50 mL) was added dropwise to the filtrate heated to 60°C, followed by stirring at 60°C for 30 minutes to cause crystallization. It was confirmed that the resulting crystals were precipitated during the dropwise addition of water and the subsequent stirring.

[0190] The solution was then cooled to 30°C over 30 minutes and stirred at 30°C for 18 hours to allow crystallization. The crystals were separated by filtration and washed with 12.5% ​​by volume aqueous methanol solution (10 mL). The washed crystals were dried in vacuo at 50°C for 22 hours to obtain olaparib type A crystals (yield 4.3 g, molar yield 92%).

[0191] Example 5-8: Conversion of DMF clathrate to type A crystals DMF clathrate of olaparib (5 g), methanol (45 mL), and water (15 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, and then water (50 mL) was added dropwise to the filtrate heated to 60°C, followed by stirring at 60°C for 30 minutes to cause crystallization. It was confirmed that the resulting crystals were precipitated during the dropwise addition of water and the subsequent stirring.

[0192] The solution was then cooled to 30°C over 30 minutes and stirred at 30°C for 18 hours to allow crystallization. The crystals were separated by filtration and washed with 12.5% ​​by volume aqueous methanol solution (10 mL). The washed crystals were dried in vacuo at 50°C for 23 hours to obtain olaparib type A crystals (yield 4.3 g, molar yield 93%).

[0193] Example 5-9: Conversion of DMF clathrate to Type A crystals DMF clathrate of olaparib (5 g), methanol (38 mL), and water (13 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, and then water (65 mL) was added dropwise to the filtrate heated to 60°C, followed by stirring at 60°C for 30 minutes to cause crystallization. It was confirmed that the resulting crystals were precipitated during the dropwise addition of water and the subsequent stirring.

[0194] The solution was then cooled to 30°C over 30 minutes and stirred at 30°C for 4 hours to allow crystallization. The resulting crystals were filtered and washed with a 12.5% ​​by volume aqueous methanol solution (10 mL). The washed crystals were dried in vacuo at 50°C for 66 hours to obtain olaparib type A crystals (yield 4.3 g, molar yield 94%).

[0195] Example 5-10: Conversion of DMF clathrate to type A crystals DMF clathrate of olaparib (1 g), methanol (8 mL), and water (2 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, and then water (10 mL) was added dropwise to the filtrate heated to 60°C, followed by stirring at 60°C for 30 minutes to cause crystallization. It was confirmed that the resulting crystals were precipitated during the dropwise addition of water and subsequent stirring.

[0196] The solution was then cooled to 30°C over 30 minutes and stirred at 30°C for 1 hour to allow crystallization. The crystals were separated by filtration and washed with 12.5% ​​by volume aqueous methanol solution (2 mL). The washed crystals were dried in vacuo at 40°C for 15 hours to obtain olaparib type A crystals (yield 0.8 g, molar yield 83%).

[0197] Example 5-11: Conversion of DMF clathrate to E-form crystals DMF clathrate of olaparib (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, cooled to 30°C over 2 hours, and water (10 mL) was added dropwise. It was confirmed that crystals precipitated during the process of cooling the solution from 60°C to 30°C.

[0198] After stirring for 1 hour, the crystals were filtered off and washed with 12.5% ​​by volume aqueous methanol solution (2 mL), and then dried under vacuum at 40°C for 15 hours to obtain olaparib type E crystals (yield 0.9 g, molar yield 92%).

[0199] FIG. 4 is an XRD chart of the obtained E-type crystals.

[0200] Example 5-12: Conversion of DMF clathrate to E-form crystals DMF clathrate of olaparib (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, cooled to 30°C over 30 minutes, and water (10 mL) was added dropwise. It was confirmed that crystals were precipitated during the process of cooling the solution from 60°C to 30°C.

[0201] After stirring for 2 hours, the crystals were filtered off and washed with 12.5% ​​by volume aqueous methanol solution (2 mL), and then dried under vacuum at 40°C for 3 hours to obtain olaparib type E crystals (yield 0.9 g, molar yield 91%).

[0202] Example 5-13: Conversion of DMF clathrate to E-form crystals DMF clathrate of olaparib (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, cooled to 30°C over 30 minutes, and water (10 mL) was added dropwise. It was confirmed that crystals precipitated during the process of cooling the solution from 60°C to 30°C.

[0203] After stirring for 1 hour, the crystals were filtered off and washed with 12.5% ​​by volume aqueous methanol solution (2 mL), and then dried in vacuum at 40°C for 3 hours to obtain olaparib type E crystals (yield 0.9 g, molar yield 92%).

[0204] Example 5-14: Conversion of DMF clathrate to E-form crystals DMF clathrate of olaparib (1 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, cooled to 20°C over 30 minutes, and water (10 mL) was added dropwise. It was confirmed that crystals precipitated during the process of cooling the solution from 60°C to 20°C.

[0205] After stirring for 1 hour, the crystals were filtered off and washed with 12.5% ​​by volume aqueous methanol solution (2 mL), and then dried under vacuum at 40°C for 17 hours to obtain olaparib type E crystals (yield 0.8 g, molar yield 90%).

[0206] Example 5-15: Conversion of DMF clathrate to IPA clathrate The DMF clathrate of olaparib (5 g) and IPA (150 mL) were combined, stirred, and heated to 80°C to dissolve. The resulting solution was cooled to 0°C, and water (300 mL) was added. It was confirmed that crystals were precipitated during the process of cooling the solution from 80°C to 0°C.

[0207] After stirring at 0°C for 1 hour to allow crystallization, the resulting crystals were filtered and washed with water (50 mL). The washed crystals were dried in vacuo at 40°C for 17 hours to obtain crystals of IPA clathrate of olaparib (yield 3.5 g).

[0208] Figure 5 is an XRD chart of the obtained IPA clathrate crystals. Figures 1 and 5 reveal that the DMF clathrate and the IPA clathrate have the same crystal structure.

[0209] Note that IPA clathrate was also obtained when the cooling temperature of the above solution was changed from 0° C. to 20° C. 15 mL of IPA was added to 500 mg of olaparib, and the mixture was heated to 80° C. to dissolve it. The mixture was then cooled to 20° C., and 30 mL of water was added dropwise. The mixture was stirred at 20° C. for 1 hour and filtered to obtain crystals of IPA clathrate of olaparib (yield 0.3 g, molar yield 64%).

[0210] Example 5-16: Conversion of IPA clathrate to hydrate (H-type crystals) IPA clathrate of olaparib (9 g), methanol (68 mL), and water (23 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was filtered to remove dust, and the filtrate was cooled to 30°C over 30 minutes, and water (10 mL) was added dropwise to the filtrate. It was confirmed that crystals were precipitated during the process of cooling the solution from 60°C to 30°C.

[0211] After stirring for 24 hours, the crystals were filtered off and washed with 12.5% ​​by volume aqueous methanol solution (2 mL), and then dried under vacuum at 40°C for 21 hours to obtain olaparib hydrate (H-type crystals) (yield: 8.2 g, molar yield: 91%).

[0212] Example 5-17: Conversion of hydrate (H-type crystals) to L-type crystals Olaparib hydrate (H-type crystals) (1.0 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60° C. The resulting dispersion was allowed to cool to 30° C. over 30 minutes, and water (10 mL) was added dropwise.

[0213] After stirring for 24 hours to allow crystallization, the resulting crystals were filtered and washed with 12.5% ​​by volume aqueous methanol solution (2 mL). The washed crystals were dried in vacuo at 40°C for 21 hours to obtain olaparib type L crystals (yield 1.0 g, molar yield 97%).

[0214] Example 5-18: Conversion of hydrate (H-type crystals) to L-type crystals Olaparib hydrate (H-type crystals) (1.0 g), methanol (7.5 mL), and water (2.5 mL) were combined, stirred, and heated to 60° C. The resulting solution was allowed to cool to 30° C. over 30 minutes, and water (10 mL) was added dropwise.

[0215] After stirring for 1 hour to allow crystallization, the resulting crystals were filtered and washed with 12.5% ​​by volume aqueous methanol solution (2 mL). The washed crystals were dried in vacuo at 40°C for 18 hours to obtain olaparib type L crystals (yield 0.9 g, molar yield 96%).

[0216] Example 5-19: Conversion of hydrate (H-type crystals) to amorphous Olaparib hydrate (10 g), methanol (300 mL), and ethanol (100 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was spray-dried using a spray dryer (Buchi, B-290) under the following conditions: (Spray conditions) Inlet temperature: 150°C, atomization gas flow rate: 600 L / hr, flow rate: 6.7 mL / min

[0217] The collected solid was dried under vacuum at 40°C for 18 hours to give olaparib powder (5.3 g).

[0218] Figure 7 is an XRD chart of the obtained olaparib powder. The results in Figure 7 show that it has an amorphous structure.

[0219] Example 5-20: Conversion of E-type crystals to amorphous Olaparib E-type crystals (1.0 g), methanol (30 mL), and ethanol (10 mL) were combined, stirred, and heated to 60°C to dissolve. The resulting solution was spray-dried using a spray dryer (Buchi, B-290) under the following conditions: (Spray conditions) Inlet temperature: 150°C, atomization gas flow rate: 600 L / hr, flow rate: 4.0 mL / min

[0220] The collected solid was dried under vacuum at 40°C for 18 hours to obtain olaparib powder (0.28 g). The results of XRD measurement of the olaparib powder showed that the obtained olaparib powder had an amorphous structure.

[0221] From the above results, it was confirmed that the crystalline form of the obtained olaparib can be converted by a simple method.

[0222] From the above results, it was confirmed that the present invention is useful.

Claims

1. A method for producing a precursor of olaparib, comprising the steps of (a) to (c) below, successively carrying out the steps without isolating the reaction intermediates: (a) reacting dimethyl(3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate with 2-fluoro-5-formylbenzoic acid in the presence of diazabicycloundecene in DMF, acetonitrile, or THF; (b) reacting the reaction mixture obtained in the reaction (a) with hydrazine; and (c) adjusting the reaction solution obtained in the reaction (b) to a pH of 4 or less to obtain the precursor of olaparib, 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazin-1-ylmethyl)benzoic acid.

2. The method for producing an olaparib precursor according to claim 1, wherein the reaction (a) is carried out in DMF.

3. The method for producing an olaparib precursor according to claim 1 or 2, wherein in (c), the pH of the reaction solution is adjusted to 1 to 2.

4. A method for producing the olaparib precursor according to claim 1 or 2, comprising the steps of: dissolving the crude crystals containing the olaparib precursor obtained in (c) and sodium hydroxide in DMF; adding acetic acid or formic acid to the solution obtained in the dissolving step to adjust the pH to 4 to 6; and filtering out the resulting crystals.

5. A method for producing olaparib, comprising the step of subjecting the olaparib precursor produced by the method for producing an olaparib precursor according to claim 1 or 2 to amide condensation with 1-(cyclopropylcarbonyl)piperazine or 1-(cyclopropylcarbonyl)piperazine hydrochloride in DMF or acetonitrile to obtain olaparib.

6. The method for producing olaparib according to claim 5, wherein in the step of obtaining olaparib, the olaparib precursor is subjected to amide condensation with 1-(cyclopropylcarbonyl)piperazine.

7. The method for producing olaparib according to claim 5, wherein the amide condensation uses a water-soluble carbodiimide and one alcohol selected from the group consisting of 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, and ethyl(hydroxyimino)cyanoacetate as an amide condensation agent.

8. A method for producing olaparib according to claim 5, comprising dissolving at least a portion of the first olaparib having the first crystalline form in a solvent and crystallizing the solution to obtain the second olaparib having the second crystalline form.

9. A method for producing olaparib according to claim 8, comprising the steps of: heating and dissolving the olaparib in a mixed solvent of methanol and water (methanol:water = 80:20 to 70:30 (volume ratio)) to obtain an olaparib solution; cooling the olaparib solution to room temperature and then adding water dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution to methanol:water = 33:67 to 43:57; stirring the olaparib solution at room temperature for 19 to 26 hours to cause crystallization; and filtering and drying the obtained crystals to obtain H-form crystals of olaparib.

10. A method for producing olaparib according to claim 8, comprising the steps of: heating and dissolving the DMF clathrate of olaparib in a mixed solvent of methanol and water (methanol:water = 85:15 to 65:35 (volume ratio)) to obtain an olaparib solution; adding water dropwise to the heated olaparib solution to adjust the volume ratio of the mixed solvent in the olaparib solution to methanol:water = 28:72 to 46:54, and stirring for more than 0 hours and not more than 2 hours; cooling the olaparib solution to room temperature and stirring for 1 to 19 hours to cause crystallization; and filtering and drying the obtained crystals to obtain Form A crystals of olaparib.

11. A method for producing olaparib according to claim 8, comprising the steps of: heating and dissolving the DMF clathrate of olaparib in a mixed solvent of methanol and water (methanol:water = 80:20 to 70:30 (volume ratio)) to obtain an olaparib solution; cooling the olaparib solution to room temperature and then adding water dropwise to adjust the volume ratio of the mixed solvent in the olaparib solution to methanol:water = 33:67 to 43:57; stirring the olaparib solution at room temperature for 1 to 2 hours to crystallize it; and filtering and drying the obtained crystals to obtain Form E crystals of olaparib.

12. A method for producing olaparib according to claim 8, comprising the steps of: heating and dissolving the olaparib in isopropyl alcohol to obtain an olaparib solution; cooling the olaparib solution to 0°C and then adding water dropwise; stirring the olaparib solution at 0°C to cause crystallization; and filtering and drying the obtained crystals to obtain the IPA clathrate of olaparib.

13. A method for producing olaparib according to claim 8, comprising the steps of: heating the H-form crystals of olaparib in a mixed solvent of methanol and water (methanol:water = 80:20 to 70:30 (volume ratio)) to obtain an olaparib dispersion; cooling the olaparib dispersion to room temperature over 30 minutes or more, and then adding water dropwise to adjust the volume ratio of the mixed solvent in the olaparib dispersion to methanol:water = 33:67 to 43:57; stirring the olaparib dispersion at room temperature to cause crystallization; and filtering and drying the obtained crystals to obtain the L-form crystals of olaparib.

14. The method for producing olaparib according to claim 5, comprising the steps of: preparing an olaparib solution by dissolving the olaparib; and spray-drying the olaparib solution to obtain amorphous olaparib.

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