Novel synthesis method of 18f-rucaparib

Abstract

The present invention relates to a method for efficiently preparing rucaparib for a PET image. More specifically, the present invention relates to an improved preparation method for synthesizing [18F]-rucaparib in excellent yield by means of a pathway for synthesizing a pinacol boronate derivative, which is a key intermediate, by using, as a starting material, a 2-iodoaniline derivative prepared by a novel synthesis method.

Description

A novel synthesis method for 18F-rucaparib

[0001] The present invention relates to an efficient method for producing rucaparib for PET imaging. More specifically, the present invention relates to a method for producing rucaparib in excellent yield through a route for synthesizing a pinacol boronate derivative, a key intermediate, using a 2-iodoaniline derivative produced by a novel synthetic method as a starting material. 18 [F]-Relates to an improved manufacturing method for synthesizing rucaparib.

[0002] Rucaparib (trade name: Rubraca) is an anticancer drug approved by the US FDA in late 2016 for the treatment of ovarian cancer through poly(ADP-ribose) polymerase (PARP) inhibition. Following its 2016 FDA approval, it was also approved for use in Europe in 2017, and has been used as a PARP inhibitor in the US and five European countries (the UK, Germany, France, Italy, and Spain) since 2018. Furthermore, rucaparib was approved for prostate cancer in 2020, and is in extensive preclinical trials for several other cancer types, including breast cancer.

[0003]

[0004] However, since the anticancer effects of rucaparib have been observed to be somewhat different in some patients, efforts are ongoing to identify the clear mechanism of action of rucaparib. Specifically, for more accurate and effective patient treatment, a new method to determine the expression rate of rucaparib as a PARP inhibitor, the degree of accumulation in cancer cells, and the degree of inhibitor binding to the binding pocket of the PARP enzyme is required. To this end, many studies have been conducted on the synthesis of rucaparib and derivatives with various forms of radioactive isotopes, as follows.

[0005]

[0006] In particular, many studies have been conducted to use rucaparib derivatives, which were recently introduced as F-18, for positron emission tomography (PET), and in 2021, the Gourverneur group [ 18 A synthetic method for [F]-rucaparib has been developed (Org. Lett. 2021, 23, 7290-7294). However, since the synthetic method relies on the existing rucaparib synthesis route, significant improvements in synthetic efficiency are needed.

[0007] Accordingly, in order to solve the above problem, the inventors of the present invention have developed a route for synthesizing a pinacol boronate derivative, which is a key intermediate, using a 2-iodoaniline derivative prepared by a novel synthetic method, as a starting material, unlike the previous synthetic route. 18 The present invention was completed by discovering that the synthesis of F]-rucaparib has excellent advantages in terms of economy and yield.

[0008] The purpose of the present invention is to achieve excellent synthetic yield and reproducibility [ 18 To provide an improved manufacturing method of F]-rucaparib.

[0009] Another object of the present invention is to provide a method for producing a starting material that is economically superior to existing synthetic methods.

[0010] In order to achieve the above purpose, in one specific example of the present invention, a compound of the following chemical formula (7) is provided. 18 As a method for manufacturing F]-rucaparib,

[0011] (a) a step of converting a compound of chemical formula (1) into a compound of chemical formula (2);

[0012] (b) a step of reacting a compound of chemical formula (2) with a compound of chemical formula (3) and converting it into a compound of chemical formula (4) in the presence of a catalyst;

[0013] (c) a step of converting the compound of chemical formula (4) into a compound of chemical formula (5) by reduction reaction and then lactam cyclization reaction;

[0014] (d) a step of converting the compound of chemical formula (5) into the compound of chemical formula (6) by reacting it with bis(pinacolato)diboron; and

[0015] (e) a step of converting the compound of formula (6) into the compound of formula (7) by fluorination and deprotection. 18 Provided is a method for preparing F]-rucaparib:

[0016] Chemical formula (1)

[0017]

[0018] Chemical formula (2)

[0019]

[0020] Chemical formula (3)

[0021]

[0022] Chemical formula (4)

[0023]

[0024] Chemical formula (5)

[0025]

[0026] Chemical formula (6)

[0027]

[0028] Chemical formula (7)

[0029]

[0030] Here,

[0031] X is H, Cl or Br;

[0032] R1 is straight-chain or branched C1-C5 alkyl;

[0033] P1 is an amine protecting group selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc).

[0034] In addition, in one specific embodiment of the present invention, the above-described [ 18 In the manufacturing method of F]-rucaparib, a novel manufacturing method of a compound of the following chemical formula (1) is provided.

[0035] (a-1) a step of obtaining a compound of chemical formula (9) by nitrating a compound of chemical formula (8); and

[0036] (a-2) A method for producing a compound of chemical formula (9) comprising the additional step of reacting the compound with sodium nitrite, iodizing the compound, and then reducing the nitro group. 18 Provided is a method for preparing F]-rucaparib:

[0037] Chemical formula (1)

[0038]

[0039] Chemical formula (8)

[0040]

[0041] Chemical formula (9)

[0042]

[0043] Here,

[0044] R1 is straight-chain or branched C1-C5 alkyl;

[0045] X is H, Cl or Br.

[0046] In one specific example of the present invention, the novel method for preparing a compound of formula (1) may further include a step of protecting an amine group prior to nitration reaction of the compound of formula (8).

[0047] In addition, in one specific example of the present invention, the novel method for preparing a compound of formula (1) may additionally include a step of deprotecting an amine group simultaneously with or after the above-described nitration reaction.

[0048] As used herein, the term "C1-C5 alkyl" means a hydrocarbon having 1 to 5 carbon atoms, and "straight-chain or branched" means that the hydrocarbon contains normal, secondary, or tertiary carbon atoms. Specifically, examples of suitable "C1-C5 alkyl" include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl, 1-butyl, 2-methyl-1-propyl, and 3-pentyl.

[0049] In one specific embodiment of the present invention, the step of converting to the compound of formula (4) is preferably performed in the presence of a dehydrating agent. The use of such a dehydrating agent can facilitate the overall reaction by removing water molecules generated during the formation of the imine intermediate.

[0050] In one specific embodiment of the present invention, preferred examples of the dehydrating agent include, but are not limited to, one or more compounds selected from the group consisting of TiCl4, MgSO4, and Na2SO4. In addition, in one specific embodiment of the present invention, the step of converting into the compound of the above chemical formula (3) may be performed by reacting with molecular sieves or using azeotropic distillation using a Dean-Stark distiller or the like.

[0051] In a preferred embodiment of the present invention, the catalyst used in the step of converting into the compound of the above formula (4) is MCN or N-heterocyclic carbene, wherein M is an alkali metal or NR4 + , and R is H or a straight-chain or branched C1-C5 alkyl. The catalyst promotes the reaction in which the imine intermediate generated during the reaction forms an indole skeleton through cyclization.

[0052] In one embodiment of the present invention, examples of preferred N-heterocyclic carbenes include, but are not limited to, compounds selected from the group consisting of imidazolium, triazolium, and thiazolium.

[0053] As used herein, the term "protecting group" refers to a moiety of a compound that completely masks or alters the properties of a functional group or the properties of a compound. The chemical substructures of protecting groups are very diverse. One function of protecting groups is to act as intermediates in the synthesis of the parent drug substance. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991), and "Protective Groups in Organic Chemistry", Peter G. M. Wuts and Theodora W. Greene, 4th Ed., 2006. Protecting groups are often used to mask the reactivity of specific functional groups, thereby enhancing the efficiency of the desired chemical reaction. Protection of a functional group of a compound alters physical properties other than the reactivity of the protected functional group, such as polarity, hydrophobicity, hydrophilicity, and other properties that can be measured by conventional analytical tools. Chemically protected intermediates may themselves be biologically and chemically active or inactive. An "amine protecting group" refers to a protecting group useful for protecting an amine group (-NH2).

[0054] In one specific embodiment of the present invention, preferred examples of the "amine protecting group" include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc), and a protecting group that can play a role chemically equivalent to the above protecting group is included in the scope of the present invention.

[0055] In one specific example of the present invention, P1 of the compound of the above chemical formula (6) is preferably t-butyloxycarbonyl (Boc).

[0056] In one specific embodiment of the present invention, the reduction reaction of step (c) is preferably performed in the presence of nickel boride and cobalt boride.

[0057] In one specific example of the present invention, the reduction reaction of step (c) is preferably performed in the presence of a metal hydride selected from the group consisting of DIBAL-H, L-selectride, NaBH4, and borane.

[0058] In one specific embodiment of the present invention, the lactam cyclization reaction of step (c) may be performed under basic conditions. Various inorganic and organic bases may be used as the base to provide basic conditions.

[0059] Meanwhile, in the previously known synthesis method of rucaparib, a 2-iodoaniline derivative, a compound of the following chemical formula (10) that can be purchased commercially, was used as a starting material, but in this case, there was a disadvantage in that the unit price of the starting material was very high.

[0060] Accordingly, in one specific example of the present invention, in order to compensate for these shortcomings, a method for producing a compound of the following chemical formula (10) is provided.

[0061] (a) a step of nitrating a compound of the following chemical formula (11) to obtain a compound of the following chemical formula (12); and

[0062] (b) A method for preparing a compound of formula (10) is provided, comprising the steps of reacting a compound of formula (12) with sodium nitrite, iodinating the compound, and then reducing a nitro group.

[0063] Chemical formula (10)

[0064]

[0065] Chemical formula (11)

[0066]

[0067] Chemical formula (12)

[0068]

[0069] Here,

[0070] R1 is straight-chain or branched C1-C5 alkyl;

[0071] X1 is a halogen.

[0072] In one specific example of the present invention, the novel method for preparing a compound of formula (1) may further include a step of protecting an amine group prior to nitration reaction of the compound of formula (11). Preferred amine protecting groups that can be used in the present invention include, but are not limited to, protecting groups selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), trifluoroacetyl, benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc).

[0073] In addition, in one specific example of the present invention, the novel method for preparing a compound of formula (1) may additionally include a step of deprotecting an amine group simultaneously with or after the above-described nitration reaction.

[0074] In one specific embodiment of the present invention, the present invention [ 18 As a novel intermediate that can be used in the production of F]-rucaparib, a compound of the following chemical formula (4) is provided:

[0075] Chemical formula (4)

[0076]

[0077] Here,

[0078] X is H, Cl or Br,

[0079] R1 is straight-chain or branched C1-C5 alkyl;

[0080] P1 is an amine protecting group selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc).

[0081] In one specific embodiment of the present invention, the present invention [ 18 As a novel intermediate that can be used in the production of F]-rucaparib, a compound of the following chemical formula (5) is provided:

[0082] Chemical formula (5)

[0083]

[0084] Here,

[0085] X is Cl;

[0086] P1 is an amine protecting group selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc).

[0087] Any suitable solvent may be used in the methods of the present invention. Representative solvents include, but are not limited to, pentane, pentanes, hexane, hexanes, heptanes, heptanes, petroleum ether, cyclopentane, cyclohexane, benzene, toluene, xylene, dichloromethane, trifluoromethylbenzene, halobenzenes such as chlorobenzene, fluorobenzene, dichlorobenzene, and difluorobenzene, methylene chloride, chloroform, acetone, ethyl acetate, diethyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, dibutyl ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, dioxane (1.4 dioxane), N-methyl pyrrolidinone (NMP), DMF, alcohols such as methanol, ethanol, propanol, butanol, or mixtures thereof.

[0088] The reaction mixture of each step of the present invention may be at any suitable pressure. For example, the reaction mixture may be at atmospheric pressure. The reaction mixture may also be exposed to any suitable environment, such as atmospheric gas or an inert gas such as nitrogen or argon.

[0089] The reaction of each step of the present invention can be carried out at any suitable temperature. For example, the temperature of the mixture during the reaction can be -78°C to 100°C, or -50°C to 150°C, or -25°C to 100°C, or 0°C to 100°C, or room temperature to 100°C, or 50°C to 100°C.

[0090] According to the present invention, it is possible to achieve excellent synthetic yield and reproducibility [ 18 An improved method for manufacturing F]-rucaparib is provided.

[0091] In addition, a method for manufacturing starting materials with excellent economic efficiency, unlike existing synthetic methods, is provided.

[0092] Figure 1 is an NMR spectrum of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (compound 2).

[0093] The present invention will be described in more detail with reference to the following examples. However, the following examples are intended to aid understanding of the present invention, and the scope of the present invention is not limited to the following examples.

[0094] General procedure

[0095] Unless otherwise noted, all reactions were performed in oven-dried glassware under an argon atmosphere. Unless otherwise noted, all reactions were magnetically stirred and monitored by analytical thin layer chromatography (TLC) using silica gel glass plates (0.25 mm) pre-coated with F254 indicator and visualized with UV light (254 nm). Flash column chromatography was performed using silica gel 60 (230-400 mesh) with the indicated eluent. Commercial grade reagents were used without further purification. Unless otherwise noted, yields refer to chromatographically and spectroscopically pure compounds. 1 H NMR and 13 C NMR spectra were recorded on 500 MHz and 125 MHz spectrometers, respectively. Tetramethylsilane (δ TMS : 0.0 ppm) and residual NMR solvent (CDCl3(δ H : 7.26ppm, δ C : 77.16ppm) or (CD3)2SO (δ H : 2.50ppm, δ C : 39.52ppm) respectively 1 H NMR and 13C NMR spectra were used as internal standards. Proton spectra were expressed as δ (proton position, multiplicity, coupling constant J, number of protons). Multiplicities were expressed as s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), m (multiplet), and br (broad). High-resolution mass spectra (HRMS) were recorded on a quadrupole time-of-flight mass spectrometer (QTOF-MS) using electrospray ionization (ESI) as the ionization method.

[0096] The main reagents used include TiCl4, NaBH4, and methanol (MeOH: For analysis, ACS grade, Carlo Erba Reagents).

[0097]

[0098] Synthesis Example 1: Synthesis of 2-iodoaniline derivative (chemical formula (1))

[0099] Manufacturing Example 1: Methyl 2-amino-5-halo-3-nitrobenzoate (5)

[0100]

[0101] Methyl 2-amino-5-halobenzoate (3; 50 mmol) was dissolved in sulfuric acid (90 mL), and the temperature was lowered to 0°C. Nitric acid (60%; 60 mmol) was slowly added dropwise, and the mixture was stirred for 2 hours while the progress of the reaction was observed via TLC. After the compound was completely consumed, ice water was slowly added dropwise to the reaction mixture to form a yellow precipitate. The obtained precipitate was filtered, washed with distilled water, and dried to obtain compound 5.

[0102] Manufacturing Example 1-1: Methyl 2-amino-5-bromo-3-nitrobenzoate (5a) Methyl 2-amino-5-halobenzoate (3; 50 mmol) was dissolved in sulfuric acid (90 mL), and the temperature was lowered to ℃. Nitric acid (60%; 60 mmol) was slowly added dropwise, and the mixture was stirred for 2 hours while the progress of the reaction was observed via TLC. After the compound was completely consumed, ice water was slowly added dropwise to the reaction mixture to form a yellow precipitate. The obtained precipitate was filtered, washed with distilled water, and dried to obtain compound 5.

[0103] Manufacturing Example 1-1: Methyl 2-amino-5-bromo-3-nitrobenzoate (5a)

[0104]

[0105] Compound 5a (3.8 g, 14 mmol, 28%) as a yellow solid was obtained through the above process using methyl 2-amino-5-bromobenzoate (3a).

[0106] 1 H NMR (500 MHz, CDCl3) δ8.50 (s, 1H), 8.32 (s, 1H), 3.93 (s, 3H).

[0107] Manufacturing Example 1-2: Methyl 2-amino-5-chloro-3-nitrobenzoate (5b)

[0108]

[0109] Compound 5b (3.6 g, 15.5 mmol, 31%) as a yellow solid was obtained through the above process using methyl 2-amino-5-chlorobenzoate (3b).

[0110] 1 H NMR (500 MHz, CDCl3) 8.38 (d, J = 2.7 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H).

[0111] Manufacturing Example 1-3: Methyl 2-amino-5-fluoro-3-nitrobenzoate (5c)

[0112]

[0113] Compound 5c (2.7 g, 12.5 mmol, 25%) as a yellow solid was obtained through the above process using methyl 2-amino-5-fluorobenzoate (3c).

[0114] 1 H NMR (500 MHz, CDCl3)δ8.32 (br. s., 2H), 8.15 (m, 1H), 8.03 (dd,J=8.3, 3.3 Hz, 1H), 3.94 (s, 3H).

[0115] Manufacturing Example 2: Methyl 2-amino-5-halo-3-nitrobenzoate (5)

[0116]

[0117] Methyl 2-amino-5-halobenzoate (3; 50 mmol) was dissolved in dichloromethane (500 mL), and the temperature of the reaction mixture was lowered to 0°C. Trifluoroacetic anhydride (TFAA; 10 mL, 75 mmol) was added, and the mixture was stirred for 30 minutes, and the progress of the reaction was observed via TLC. After compound 3 was completely consumed, distilled water was added dropwise to the reaction mixture, and then extracted using dichloromethane. The obtained organic layer was dried over MgSO4 and concentrated to obtain a mixture of amide compounds, which was used in the next reaction without further separation.

[0118] Sulfuric acid (90 mL) was added to the mixture and the temperature was lowered to 0°C. Nitric acid (60%; 60 mmol) was slowly added dropwise and the mixture was stirred for 2 hours while the progress of the reaction was observed via TLC. After the compound was completely consumed, ice water was slowly added dropwise to the reaction mixture and extracted using ethyl acetate. The obtained organic layer was dried over MgSO4 and concentrated to obtain a mixture of nitro compounds 4, which were used in the next reaction without further separation.

[0119] A mixture of nitro compound 4 was dissolved in methanol (350 mL), 6 N HCl aqueous solution (150 mL, 90 mmol) was added, and the mixture was stirred at 70°C for 12 hours while the progress of the reaction was observed by TLC. After compound 4 was completely consumed, distilled water cooled to 0°C was added dropwise to the reaction mixture to produce a yellow precipitate. The obtained precipitate was filtered, washed with distilled water, and dried to obtain compound 5.

[0120] Manufacturing Example 2-1: Methyl 2-amino-5-bromo-3-nitrobenzoate (5a)

[0121]

[0122] Compound 5a (12.5 g, 45.5 mmol, 91%) as a yellow solid was obtained through the above process using methyl 2-amino-5-bromobenzoate (3a).

[0123] 1 H NMR (500 MHz, CDCl3) δ8.50 (s, 1H), 8.32 (s, 1H), 3.93 (s, 3H).

[0124] Manufacturing Example 2-2: Methyl 2-amino-5-chloro-3-nitrobenzoate (5b)

[0125]

[0126] Compound 5b (10.5 g, 45.5 mmol, 91%) as a yellow solid was obtained through the above process using methyl 2-amino-5-chlorobenzoate (3b).

[0127] 1 H NMR (500 MHz, CDCl3) 8.38 (d, J = 2.7 Hz, 1H), 8.21 (d, J = 2.6 Hz, 1H), 3.93 (s, 3H).

[0128] Manufacturing Example 2-3: Methyl 2-amino-5-fluoro-3-nitrobenzoate (5c)

[0129]

[0130] Compound 5c (8.8 g, 41 mmol, 82%) as a yellow solid was obtained through the above process using methyl 2-amino-5-fluorobenzoate (3c).

[0131] 1 H NMR (500 MHz, CDCl3)δ8.32 (br. s., 2H), 8.15 (m, 1H), 8.03 (dd,J=8.3, 3.3 Hz, 1H), 3.94 (s, 3H).

[0132] Manufacturing Example 3: Methyl 3-amino-5-halo-2-iodobenzoate (chemical formula 1)

[0133]

[0134] Nitro compound 5 (40 mmol) was dissolved in acetic acid (120 mL), and the temperature was lowered to 12°C. Sulfuric acid (24 mL) was slowly added dropwise, followed by sodium nitrite (3.3 g, 48 mmol). After stirring for 1 hour, potassium iodide aqueous solution (80 mL, 56 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was heated to 25°C and stirred for 12 hours. After the reaction was completed, distilled water was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was sequentially extracted with a saturated aqueous solution of NaHCO3, a saturated aqueous solution of NaHSO3, and a saturated aqueous solution of NaCl. The obtained organic layer was dried over MgSO4 and concentrated to obtain a mixture of iodinated benzene compounds 6, which was then used in the next reaction without further separation.

[0135] A mixture of iodinated benzene compounds 6 was dissolved in ethanol (400 mL) and heated to 60°C. 35% HCl (67 mL) was added to the reaction mixture while stirring vigorously, followed by the addition of iron powder (45 g, 800 mmol). The reaction was stirred for 10 minutes and the progress of the reaction was observed by TLC. After compound 6 was completely consumed, the reaction mixture was filtered through Celite to remove insoluble solids and washed with ethyl acetate. The resulting filtrate was concentrated, and a saturated aqueous solution of NH4Cl was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was dried over MgSO4, concentrated, and purified by silica-based column chromatography using a mixed solution of ethyl acetate and hexane (10:1) as an eluent to obtain iodinated aniline compound 1.

[0136] Manufacturing Example 3-1. Methyl 3-amino-5-bromo-2-iodobenzoate (1a)

[0137]

[0138] Compound 1a (8.0 g, 22.4 mmol, 56%), a brown liquid, was obtained through the above process using compound 5a.

[0139] 1 H NMR (500 MHz, CDCl3)δ7.16 (d,J=2.1 Hz, 1H), 6.98 (d,J=2.3 Hz, 1H), 4.47 (br. s., 2H), 3.92 (s, 3H).

[0140] Manufacturing Example 3-2. Methyl 3-amino-5-chloro-2-iodobenzoate (1b)

[0141]

[0142] Compound 1b (5.1 g, 16.5 mmol, 33%), a brown liquid, was obtained through the above process using compound 5b.

[0143] 1H NMR (500 MHz, CDCl3)δppm 7.16 (d,J=2.1 Hz, 1 H), 6.98 (d,J=2.3 Hz, 1H), 4.47 (br. s., 2H), 3.92 (s, 3H).

[0144] Manufacturing Example 3-3. Methyl 3-amino-5-fluoro-2-iodobenzoate (1c)

[0145]

[0146] Compound 1c (7.7 g, 26 mmol, 65%), a brown liquid, was obtained through the above process using compound 5c.

[0147] 1 H NMR (500 MHz, CDCl3)δ6.82 (dd,J=8.7, 2.7 Hz, 1H), 6.59 (dd,J=9.9, 2.7 Hz, 1H), 4.52 (br. s., 2H).

[0148] Synthesis Example 2. Synthesis of 2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-4-methoxycarbonyl-indole-3-acetonitrile (10)

[0149] Manufacturing Example 1: (E)-2-Amino-6-methoxycarbonylcinnamyl nitrile (7)

[0150]

[0151] Acrylonitrile (2.0 mL, 30 mmol) was added to a solution of aminoaryl iodide compound 1 (10 mmol), bis(tri-tert-butylphosphine)palladium (510 mg, 1.0 mmol), and triethylamine (4.2 mL, 30 mmol) in toluene (100 mL), and the reaction progress was monitored by TLC while stirring at 80°C. After compound 1 was completely consumed, the temperature of the reaction mixture was lowered to 20°C, the insoluble solid was filtered through Celite, and the filtrate was concentrated. A saturated aqueous solution of NH4Cl was added dropwise to the obtained mixture, and the obtained mixture was extracted with ethyl acetate. The obtained organic layer was dried over MgSO4, concentrated, and purified by silica-based column chromatography using a mixed solution of ethyl acetate and hexane (1:5) as an eluent to obtain compound 7.

[0152] Manufacturing Example 1-1: (E)-2-Amino-4-bromo-6-methoxycarbonylcinnamyl nitrile (7a)

[0153]

[0154] Using compound 1a as a starting material, compound 7a (1.55 g, 5.5 mmol, 55%) as a light yellow solid was obtained through the above process.

[0155] 1 H NMR (500 MHz, CDCl3) δ7.75 (d,J= 17.1 Hz, 1H), 7.47 (d,J= 1.8 Hz, 1H), 7.06 (d,J= 1.8 Hz, 1H), 5.77 (d,J= 17.1 Hz, 1H), 4.07 (br, 2H), 3.88 (s, 3H).

[0156] Manufacturing Example 1-2. (E)-2-Amino-4-chloro-6-methoxycarbonylcinnamyl nitrile (7b)

[0157]

[0158] Using compound 1b as a starting material, compound 7b (2.22 g, 9.4 mmol, 94%) as a light yellow solid was obtained through the above process.

[0159] 1 H NMR (500 MHz, DMSO-d6) δ7.62 (d,J= 16.9 Hz, 1H), 6.95 (d,J= 2.0 Hz, 1H), 6.90 (d,J= 2.0 Hz, 1H), 5.94 (br, 2H), 5.86 (d,J= 16.9 Hz, 1H), 3.79 (s, 3H).

[0160] Manufacturing Example 1-3. (E)-2-Amino-6methoxycarbonylcinnamyl nitrile (7d)

[0161]

[0162] Using compound 1d as a starting material, compound 7d (1.7 g, 8.4 mmol, 84%) as a pale yellow solid was obtained through the above process.

[0163] 1 H NMR (500 MHz, CDCl3)δ7.83 (d,J= 17.1 Hz, 1H), 7.35 (dd,J= 7.6, 1.1 Hz, 1H), 7.19 (t,J= 7.9, 1H), 6.90 (dd,J= 8.1, 0.9 Hz, 1H), 5.78 (d,J= 17.1 Hz, 1H), 4.02 (br, 2H), 3.88 (s, 3H).

[0164] Manufacturing Example 2: 2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-4-methoxycarbonyl-indole-3-acetonitrile (10)

[0165]

[0166] The imine formation reaction was carried out by azeotropic distillation using titanium tetrachloride (1.0 M dichloromethane solution, 3.5 mL, 3.5 mmol) or a Dean-Stark distiller in a dichloromethane (50 mL) solution of 2-aminocinnamyl nitrile compound 7 (5.0 mmol), aldehyde compound 8 (1.3 g, 5.0 mmol) and triethylamine (2.1 mL, 15 mmol), and the progress of the reaction was monitored by TLC and 1 H NMR analysis was performed. After compounds 7 and 8 were completely consumed, distilled water was added dropwise to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The resulting organic layer was dried over MgSO4 and concentrated to obtain a mixture of compound 9, which was used in the next reaction without further purification.

[0167] After dissolving aldimine 9 in dimethylformamide (50 mL), 4 Å molecular sieves (2.0 g) and sodium cyanide (49 mg, 1.0 mmol) were added to the mixed solution, and the reaction progress was observed by TLC while stirring at 20°C. After compound 9 was completely consumed, the insoluble solid was removed by filtration and washed with ethyl acetate. The obtained filtrate was concentrated and purified by silica-based column chromatography using a mixed solution of ethyl acetate and hexane (1:2) as an eluent to obtain compound 10.

[0168] Manufacturing Example 2-1: 2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-6-bromo-4-methoxycarbonyl-indole-3-acetonitrile (10a)

[0169]

[0170] Compound 10a (1.76 g, 3.8 mmol, 75%) as a light yellow solid was obtained through the above process using a Dean-Stark distillation method using compound 7a as a starting material.

[0171] 1 H NMR (500 MHz, CDCl3)δ8.54 (m, 1H), 7.94 (d,J= 1.7 Hz, 1H) 7.73 (d,J= 1.7 Hz, 1H), 7.50 (br, 2H), 7.38 (d,J= 7.6 Hz, 2H), 4.50 (s, 2H), 4.08 (s, 2H), 4.03 (s, 3H), 2.88 (d,J= 9.5 Hz, 3H), 1.51 (d,J= 13.9 Hz, 9H).

[0172] Manufacturing Example 2-2: 2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-6-chloro-4-methoxycarbonyl-indole-3-acetonitrile (10b)

[0173]

[0174] Compound 10b (1.76 g, 3.8 mmol, 75%) as a pale yellow solid was obtained through the above process including the imine formation process using titanium tetrachloride using compound 7b as a starting material.

[0175] 1 H NMR (500 MHz, CDCl3)δ9.69 (m, 1H), 7.75 (d,J =1.8 Hz, 1H), 7.49 (m, 2H), 7.38 (m, 2H), 7.18 (m, 1H), 4.41 (m, 2H), 4.04 (br, 2H), 3.98 (s, 3H), 2.84 (br, 3H), 1.50 (m, 9H).

[0176] Manufacturing Example 2-3: 2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl-4-methoxycarbonyl-indole-3-acetonitrile (10d)

[0177]

[0178] Compound 10d (1.8 g, 4.2 mmol, 84%) as a pale yellow solid was obtained through the above process including the imine formation process using titanium tetrachloride using compound 7d as a starting material.

[0179] 1 H NMR (500 MHz, CDCl3)δppm 8.51 (br, 1H), 7.84 (d,J= 7.5 Hz, 1H), 7.60 (d,J= 0.9 Hz, 1H), 7.53 (br, 2H), 7.38 (d,J= 8.1 Hz, 2H), 7.28 (m, 3H), 4.50 (br, 2H), 4.12 (s, 2H), 4.03 (s, 3H), 2.88 (d,J= 11.7 Hz, 3H), 1.51 (d,J= 11.7 Hz, 9H).

[0180] Synthesis Example 3: 2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (11)

[0181]

[0182] Indole-3-acetonitrile compound 10 (0.50 mmol), nickel chloride hexahydrate (NiCl2·6H2O; 120 mg, 0.50 mmol) or cobalt chloride hexahydrate (CoCl2·6H2O; 120 mg, 0.50 mmol) was added sodium borohydride (133 mg, 3.5 mmol) to a methanol solution at 0°C, and the mixture was stirred at 60°C while monitoring the progress of the reaction using TLC. After compound 10 was completely consumed, the temperature of the reaction mixture was lowered to 20°C, diethylenetriamine (0.55 mL, 5.0 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes and concentrated. A saturated aqueous solution of NaHCO3 was added dropwise to the mixture, and the resulting mixture was extracted using ethyl acetate. The obtained organic layer was dried over MgSO4 and concentrated, and then separated and purified by silica-based column chromatography using a mixed solution of dichloromethane and methanol (20:1) as a developing solution to obtain indoloazepinone compound 11.

[0183] Manufacturing Example 3-1: 8-Bromo-2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (11a)

[0184]

[0185] Using compound 10a as a starting material, compound 11a (77 mg, 0.16 mmol, 32%) as a pale yellow solid was obtained through the above process.

[0186] 1H NMR (500 MHz, DMSO-d6)δ11.76 (s, 1H), 8.27 (t,J= 5.7 Hz, 1H), 7.74 (d,J= 1.7 Hz, 1H), 7.68 (m, 1H), 7.63 (d,J =1.0 Hz, 2H), 7.37 (d,J) =7.6 Hz, 2H), 4.43 (br, 2H), 3.38 (br, 2H), 3.04 (br, 3H), 2.79 (br, 3H), 1.42 (d,J =19.1 Hz, 9H).

[0187] Manufacturing Example 3-2: 8-Chloro-2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (11b)

[0188]

[0189] Using compound 10b as a starting material, compound 11b (170 mg, 0.39 mmol, 78%) as a pale yellow solid was obtained through the above process.

[0190] 1 H NMR (500 MHz, DMSO-d6)δ11.74 (s, 1H), 8.26 (t,J=5.7 Hz, 1H), 7.63 (m, 3H), 7.55 (d,J =2.0 Hz, 1H), 7.37 (d,J =7.6 Hz, 2H), 4.43 (s, 2H), 3.39 (br, 2H), 3.04 (br, 2H), 2.80 (s, 3H), 1.43 (d,J =16.6 Hz, 9H).

[0191] Manufacturing Example 3-3: 2-(4-((N-tert-butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one(11d)

[0192]

[0193] Using compound 10d as a starting material, the above process was carried out to obtain compound 11d (175 mg, 0.43 mmol, 86%) as a pale yellow solid.

[0194] 1 H NMR (500 MHz, CD3OD) δ 7.79 (d,J =7.6 Hz, 1H), 7.61 (m, 3H), 7.38 (d,J =8.1 Hz, 2H), 7.24 (t,J =7.8 Hz, 1H), 4.50 (s, 2H), 3.55 (d,J=5.0 Hz, 2H), 3.16 (m, 2H), 2.88 (br, 3H), 1.49 (br, 9H).

[0195] Synthesis Example 4: Synthesis of pinacol borate (2)

[0196] Manufacturing Example 4-1: Synthesis of pinacol borate 2 using compound 11a

[0197]

[0198] Indoloazepinone 11a (48 mg, 0.10 mmol), Pd(dppf)Cl2 (2.2 mg, 3.0 μmol), bis(pinacolato)diboron (38 mg, 0.15 mmol), and potassium acetate (29 mg, 0.30 mmol) were dissolved in dimethylformamide (1.0 mL). The reaction mixture was stirred at 80°C and the progress of the reaction was monitored by TLC. After 18 h, the temperature of the reaction mixture was lowered to 20°C and the insoluble solid was removed using Celite filtration. The filtrate was concentrated and purified by silica-based column chromatography using a mixed solution of dichloromethane and methanol (20:1) as an eluent to obtain pinacol borate compound 2 (27 mg, 0.050 mmol, 50%) as an ivory solid.

[0199] 1H NMR (500 MHz, CD3OD) δ8.24 (s, 1H), 8.00 (s, 1H), 7.59 (d,J =5.8 Hz, 2H), 7.33 (d,J =7.2 Hz, 2H), 4.45 (br, 2H), 3.51 (br, 2H), 3.11 (br, 2H), 2.84 (br, 3H), 1.47 (d,J =18.5 Hz, 9H) 1.35 (br, 12H).

[0200] Manufacturing Example 4-2: Synthesis of pinacol borate (2) using compound 11b

[0201]

[0202] Indoloazepinone 11b (44 mg, 0.10 mmol), Pd(OAc)2 (0.67 mg, 3.0 μmol), XPhos (2.9 mg, 6.0 μmol), bis(pinacolato)diboron (38 mg, 0.15 mmol), and potassium acetate (29 mg, 0.30 mmol) are dissolved in 1,4-dioxane (1.0 mL). The reaction mixture is stirred at 80°C and the progress of the reaction is monitored by TLC. After compound 11b is completely consumed, the temperature of the reaction mixture is lowered to 20°C and the insoluble solid is removed using Celite filtration. After concentrating the filtrate, the residue was separated and purified by silica-based column chromatography using a mixed solution of dichloromethane and methanol (20:1) as a developing solution, to obtain pinacol borate compound 2 (46 mg, 0.087 mmol, 87%) as an ivory solid.

[0203] Spectroscopic data for compound 2 were obtained with the same results as those obtained with compound 11a.

[0204] Manufacturing Example 4-3: Synthesis of pinacol borate (2) using compound 11d

[0205]

[0206] To a solution of bis(pinacolato)diboron (102 mg, 0.40 mmol), (1,5-cyclooctadiene)(methoxy)iridium dimer ([Ir(COD)OMe]2; 6.6 mg, 0.010 mmol), and tetramethylphenanthroline (Me4Phen; 4.7 mg, 0.020 mmol) in tetrahydrofuran (0.5 mL) was added pinacolborane (3.6 μL, 0.025 mmol), stirred at 80 °C for 30 min, and then a solution of indoloazepinone 11d (40 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) was added. The reaction mixture was stirred and the progress of the reaction was monitored by TLC. After 18 hours, the temperature of the reaction mixture was lowered to 20°C and the insoluble solid was removed using Celite filtration. The filtrate was concentrated and purified by silica-based column chromatography using a mixed solution of dichloromethane and methanol (20:1) as the developing solution, obtaining pinacol borate compound 2 (7.9 mg, 0.015 mmol, 15%).

[0207] Synthesis Example 5: [ 18 Synthesis of F]-rucaparib

[0208]

[0209] [#222] ... 18 F]-rucaparib was finally synthesized (yield 40%).

Claims

1. A compound of the following chemical formula (7) [ 18 As a method for manufacturing F]-rucaparib, (a) a step of converting a compound of chemical formula (1) into a compound of chemical formula (2); (b) a step of reacting a compound of chemical formula (2) with a compound of chemical formula (3) and converting it into a compound of chemical formula (4) in the presence of a catalyst; (c) a step of converting the compound of chemical formula (4) into a compound of chemical formula (5) by reduction reaction and then lactam cyclization reaction; (d) a step of converting the compound of chemical formula (5) into the compound of chemical formula (6) by reacting it with bis(pinacolato)diboron; and (e) a step of converting the compound of formula (6) into the compound of formula (7) by fluorination and deprotection. 18 Method for manufacturing F]-rucaparib: Chemical formula (1) Chemical formula (2) Chemical formula (3) Chemical formula (4) Chemical formula (5) Chemical formula (6) Chemical formula (7) Here, X is H, Cl or Br; R1 is straight-chain or branched C1-C5 alkyl; P1 is an amine protecting group selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc).

2. In the first paragraph, the step of converting into the compound of the chemical formula (4) is performed in the presence of a dehydrating agent. 18 F]-Method for manufacturing rucaparib.

3. In the second paragraph, the dehydrating agent is at least one compound selected from the group consisting of TiCl4, MgSO4 and Na2SO4, or a molecular sieve [ 18 F]-Method for manufacturing rucaparib.

4. In the first paragraph, the step of converting into the compound of the chemical formula (4) is performed through azeotropic distillation. 18 F]-Method for manufacturing rucaparib.

5. In the first paragraph, the catalyst is MCN or N-heterocyclic carbene [ 18 Method for manufacturing F]-rucaparib: Here, M is an alkali metal or NR4 + and; R is H or straight-chain or branched C1-C5 alkyl.

6. In paragraph 5, the N-heterocyclic carbene is selected from the group consisting of imidazolium, triazolium, and thiazolium. 18 F]-Method for manufacturing rucaparib.

7. In the first paragraph, the reduction reaction of step (c) is a reaction performed in the presence of nickel boride and cobalt boride. 18 F]-Method for manufacturing rucaparib.

8. In the first paragraph, the reduction reaction of step (c) is performed in the presence of a metal hydride selected from the group consisting of DIBAL-H, L-selectride, NaBH4 and borane. 18 F]-Method for manufacturing rucaparib.

9. In paragraph 1, as a method for producing a compound of the following chemical formula (1), (a-1) a step of obtaining a compound of chemical formula (9) by nitrating a compound of chemical formula (8); and (a-2) A method for producing a compound of chemical formula (9) comprising the additional step of reacting the compound with sodium nitrite, iodizing the compound, and then reducing the nitro group. 18 Method for manufacturing F]-rucaparib: Chemical formula (1) Chemical formula (8) Chemical formula (9) Here, R1 is straight-chain or branched C1-C5 alkyl; X is H, Cl or Br.

10. In the 9th paragraph, a step of protecting an amine group is additionally included before nitration reaction of the compound of the above chemical formula (8). 18 F]-Method for manufacturing rucaparib.

11. In the 10th paragraph, a step of deprotecting an amine group is additionally included simultaneously with or after the nitration reaction. 18 F]-Method for manufacturing rucaparib.

12. A method for producing a compound of the following chemical formula (10), (a) a step of nitrating a compound of the following chemical formula (11) to obtain a compound of the following chemical formula (12); and (b) A method for producing a compound of chemical formula (10), comprising the steps of reacting a compound of chemical formula (12) with sodium nitrite, iodizing the compound, and then reducing the nitro group: Chemical formula (10) Chemical formula (11) Chemical formula (12) Here, R1 is straight-chain or branched C1-C5 alkyl; X1 is a halogen.

13. A method for producing a compound of formula (10), further comprising a step of protecting an amine group prior to nitration reaction of the compound of formula (11) in claim 12.

14. A method for producing a compound of formula (10), further comprising a step of deprotecting an amine group simultaneously with or after the nitration reaction in claim 13. 15.[ 18 A compound of the following chemical formula (4) used in the manufacture of F]-rucaparib: Chemical formula (4) Here, X is H, Cl or Br, R1 is straight-chain or branched C1-C5 alkyl; P1 is an amine protecting group selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc). 16.[ 18 A compound of the following chemical formula (5) used in the manufacture of F]-rucaparib: Chemical formula (5) Here, X is Cl, P1 is an amine protecting group selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, diisopropylmethoxycarbonyl, t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethoxycarbonyl (Teoc), and aryloxycarbonyl (Alloc).

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