WO2025023769A1 - Novel synthesis method of 18f-rucaparib - Google Patents

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

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

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

However, since a somewhat different anticancer effect of rucaparib has been observed for some patients, efforts are being made to identify the clear mechanism of action of rucaparib. Specifically, for more accurate and effective patient treatment, a new method was required to identify the expression rate of PARP inhibitors by rucaparib, the degree of accumulation in cancer cells, and the degree of inhibitor binding to the binding pocket of the PARP enzyme. To this end, many studies have been conducted on the synthesis of rucaparib and derivatives introduced with various forms of radioactive isotopes, as follows.

In particular, many studies have been conducted to utilize rucaparib derivatives, of which F-18 has been recently introduced, for positron emission tomography (PET), and in 2021, the Gourverneur group developed a synthetic method for [ ¹⁸ F]-rucaparib (Org. Lett. 2021, 23, 7290-7294). However, since the above synthetic method relies on the existing fair synthesis route of rucaparib, much improvement is needed in terms of synthetic efficiency.

Accordingly, the inventors of the present invention have discovered that, in order to solve the above problems, when [18F]-rucaparib is synthesized through a route that uses a 2-iodoaniline derivative prepared by a novel synthetic method, different from previous synthetic routes, as a starting material to synthesize a pinacol boronate derivative, which is a key ^intermediate , it has excellent advantages in terms of cost efficiency and yield, thereby completing the present invention.

An object of the present invention is to provide an improved method for producing [ ¹⁸ F]-rucaparib which can achieve excellent synthetic yield and reproducibility.

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

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

(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 process for preparing [ ¹⁸ F]-rucaparib is provided, comprising the step of converting a compound of formula (6) into a compound of formula (7) by fluorination and deprotection:

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;

R ₁ is straight-chain or branched C ₁ -C ₅ alkyl;

P ₁ 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).

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

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

(a-2) Provided is a method for preparing [ ¹⁸ F]-rucaparib, which further comprises the step of reacting a compound of chemical formula (9) with sodium nitrite, performing iodination, and then reducing a nitro group:

Chemical formula (1)

Chemical formula (8)

Chemical formula (9)

Here,

R ₁ is straight-chain or branched C ₁ -C ₅ alkyl;

X is H, Cl or Br.

In one specific embodiment 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).

In addition, in one specific embodiment 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.

As used herein, the term "C ₁ -C ₅ 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 "C ₁ -C ₅ alkyl" include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl, 1-butyl, 2-methyl-1-propyl, and 3-pentyl.

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

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 TiCl ₄ , MgSO ₄ , and Na ₂ SO ₄ . In addition, in one specific embodiment of the present invention, the step of converting into the compound of the chemical formula (3) may be performed by reacting with molecular sieves, or using an azeotropic distillation method using a Dean-Stark distiller, etc.

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 ^{NR 4+} _, and R is H or a straight-chain or branched C ₁ -C ₅ alkyl. The catalyst promotes the reaction in which an imine intermediate generated during the reaction forms an indole skeleton through cyclization.

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.

As used herein, the term "protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of a compound as a whole. 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, e.g., "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 utilized to mask the reactivity of a particular functional group, thereby aiding in the efficiency of the desired chemical reaction. Protection of a functional group of a compound alters other physical properties of the protected functional group other than its reactivity, such as polarity, hydrophobicity, hydrophilicity, and other properties that can be measured by conventional analytical tools. A chemically protected intermediate may itself be biologically and chemically active or inactive. An "amine protecting group" refers to a protecting group useful for protecting an amine group (-NH ₂ ).

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 groups is included in the scope of the present invention.

In one specific example of the present invention, P ₁ of the compound of the above chemical formula (6) is preferably t-butyloxycarbonyl (Boc).

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.

In one specific embodiment 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, NaBH ₄ and borane.

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

Meanwhile, in the existing 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.

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.

(a) a step of obtaining a compound of chemical formula (12) by nitrating a compound of chemical formula (11); and

(b) A method for producing a compound of formula (10) is provided, comprising the steps of reacting a compound of formula (12) with sodium nitrite, performing iodination, and then reducing a nitro group:

Chemical formula (10)

Chemical formula (11)

Chemical formula (12)

Here,

R ₁ is straight-chain or branched C ₁ -C ₅ alkyl;

X ₁ is a halogen.

In one specific embodiment 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, a protecting group 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).

In addition, in one specific embodiment 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.

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

Chemical formula (4)

Here,

X is H, Cl or Br,

R ₁ is straight-chain or branched C ₁ -C ₅ alkyl;

P ₁ 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).

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

Chemical formula (5)

Here,

X is Cl;

P ₁ 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).

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.

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.

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.

According to the present invention, an improved method for preparing [ ¹⁸ F]-rucaparib is provided, which can achieve excellent synthetic yield and reproducibility.

In addition, a method for producing starting materials with excellent economic efficiency, unlike existing synthetic methods, is provided.

Figure 1 is the 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-1 H -azepino[5,4,3-cd]indol-6-one (compound 2).

The present invention will be described in more detail by the following examples. However, the following examples are provided to help understand the present invention, and the scope of the present invention is not limited to the following examples.

General procedure

Unless otherwise stated, all reactions were carried out in oven-dried glassware under an argon atmosphere. Unless otherwise indicated, 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 eluents. Commercial grade reagents were used without further purification. Unless otherwise stated, yields refer to chromatographically and spectroscopically pure compounds. ¹ H NMR and ¹³ C NMR spectra were recorded on a 500 MHz and 125 MHz spectrometer, respectively. Tetramethylsilane (δ _TMS : 0.0 ppm) and residual NMR solvent (CDCl ₃ (δ _H : 7.26 ppm, δ _C : 77.16 ppm) or (CD ₃ ) ₂ SO (δ _H : 2.50 ppm, δ _C : 39.52 ppm) were used as internal standards for ¹ H NMR and ¹³ C NMR spectra, respectively. 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.

The main reagents used include TiCl ₄ , NaBH ₄ , and methanol (MeOH: For analysis, ACS grade, Carlo Erba Reagents).

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

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

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, and 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 generate a yellow precipitate, and the obtained precipitate was filtered, washed with distilled water, and then dried to obtain compound 5.

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, and 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 generate a yellow precipitate. The obtained precipitate was filtered, washed with distilled water, and then dried to obtain compound 5.

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

Using methyl 2-amino-5-bromobenzoate (3a), the above process was carried out to obtain compound 5a (3.8 g, 14 mmol, 28%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.32 (s, 1H), 3.93 (s, 3H).

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

Using methyl 2-amino-5-chlorobenzoate (3b), the above process was carried out to obtain compound 5b (3.6 g, 15.5 mmol, 31%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J =2.7 Hz, 1H), 8.21 (d, J =2.6 Hz, 1H),3.93 (s, 3H).

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

Using methyl 2-amino-5-fluorobenzoate (3c), the above process was carried out to obtain compound 5c (2.7 g, 12.5 mmol, 25%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.32 (br. s., 2H), 8.15 (m, 1H), 8.03 (dd, J =8.3, 3.3 Hz, 1H), 3.94 (s, 3H).

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

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 MgSO ₄ and concentrated to obtain a mixture of amide compounds, which was used in the next reaction without further separation.

Sulfuric acid (90 mL) was added to the mixture and the temperature was lowered to 0℃. Nitric acid (60%; 60 mmol) was slowly added dropwise, and the reaction was stirred for 2 hours while observing the progress of the reaction 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 MgSO ₄ and concentrated to obtain a mixture of nitro compounds 4, which was used in the next reaction without further separation.

After dissolving the mixture of nitro compound 4 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 observing the progress of the reaction by TLC. After compound 4 was completely consumed, distilled water cooled to 0°C was added dropwise to the reaction mixture to generate a yellow precipitate. The obtained precipitate was filtered, washed with distilled water, and then dried to obtain compound 5.

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

Using methyl 2-amino-5-bromobenzoate (3a), the above process was carried out to obtain compound 5a (12.5 g, 45.5 mmol, 91%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.50 (s, 1H), 8.32 (s, 1H), 3.93 (s, 3H).

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

Using methyl 2-amino-5-chlorobenzoate (3b), the above process was carried out to obtain compound 5b (10.5 g, 45.5 mmol, 91%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.38 (d, J =2.7 Hz, 1H), 8.21 (d, J =2.6 Hz, 1H),3.93 (s, 3H).

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

Using methyl 2-amino-5-fluorobenzoate (3c), the above process was carried out to obtain compound 5c (8.8 g, 41 mmol, 82%) as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.32 (br. s., 2H), 8.15 (m, 1H), 8.03 (dd, J =8.3, 3.3 Hz, 1H), 3.94 (s, 3H).

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

After dissolving the nitro compound 5 (40 mmol) in acetic acid (120 mL), the temperature was lowered to 12°C. Sulfuric acid (24 mL) was slowly added dropwise, followed by slow addition of 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 extraction was performed using ethyl acetate. The obtained organic layer was sequentially extracted with a saturated aqueous solution of NaHCO ₃ , a saturated aqueous solution of NaHSO ₃ , and a saturated aqueous solution of NaCl. The obtained organic layer was dried over MgSO ₄ and concentrated to obtain a mixture of iodinated benzene compounds 6 , which was then used in the next reaction without additional separation.

A mixture of iodinated benzene compounds 6 is dissolved in ethanol (400 mL) and heated to 60°C. While stirring the reaction mixture vigorously, 35% HCl (67 mL) is added, followed by iron powder (45 g, 800 mmol). The mixture is stirred for 10 minutes and the progress of the reaction is observed by TLC. After compound 6 is completely consumed, the reaction mixture is filtered through celite to remove insoluble solids and washed with ethyl acetate. The obtained filtrate is concentrated, and a saturated NH ₄ Cl aqueous solution is added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer is dried over MgSO ₄ , concentrated, and separated and purified by silica-based column chromatography using a mixed solution of ethyl acetate and hexane (10:1) as a developing solution to obtain iodinated aniline compound 1.

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

Using compound 5a, the above process was performed to obtain compound 1a (8.0 g, 22.4 mmol, 56%) as a brown liquid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.16 (d, J =2.1 Hz, 1H), 6.98 (d, J =2.3 Hz, 1H), 4.47 (br. s., 2H), 3.92 (s, 3H) ).

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

Using compound 5b, the above process was performed to obtain compound 1b (5.1 g, 16.5 mmol, 33%) as a brown liquid.

¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 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).

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

Using compound 5c, the above process was followed to obtain compound 1c (7.7 g, 26 mmol, 65%) as a brown liquid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 6.82 (dd, J =8.7, 2.7 Hz, 1H), 6.59 (dd, J =9.9, 2.7 Hz, 1H), 4.52 (br. s., 2H).

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

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

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 mixture was stirred at 80°C. The progress of the reaction was observed by TLC. 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. To the obtained mixture, a saturated aqueous solution of NH ₄ Cl was added dropwise, and the obtained mixture was extracted using ethyl acetate. The obtained organic layer was dried over MgSO ₄ , concentrated, and separated and purified by silica-based column chromatography using a mixed solution of ethyl acetate and hexane (1:5) as a developing solution to obtain compound 7.

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

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

^1H NMR (500 MHz, CDCl ₃ ) δ 7.75 (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).

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

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

^1H NMR (500 MHz, DMSO- d ₆ ) δ 7.62 (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).

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

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.

^1H NMR (500 MHz, CDCl ₃ ) δ 7.83 (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).

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

2-Aminocinnamyl nitrile compound 7 (5.0 mmol), aldehyde compound 8 (1.3 g, 5.0 mmol), and triethylamine (2.1 mL, 15 mmol) were mixed in dichloromethane (50 mL) and 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 distillation, and the progress of the reaction was observed by TLC and ¹ H NMR analysis. After compounds 7 and 8 were completely consumed, distilled water was added dropwise to the reaction mixture, and the obtained mixture was extracted using dichloromethane. The obtained organic layer was dried over MgSO ₄ and concentrated to obtain a mixture of compound 9, which was used in the next reaction without further purification.

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 filtered off and washed with ethyl acetate. The obtained filtrate was concentrated, and then the mixture was separated and purified by silica-based column chromatography using a mixed solution of ethyl acetate and hexane (1:2) as a developing solution to obtain compound 10.

Manufacturing Example 2-1: 2-(4-((Nt ert -butoxycarbonyl)-(N-methyl)-aminomethyl)phenyl)-6-bromo-4-methoxycarbonyl-indole-3-acetonitrile (10a)

Using compound 7a as a starting material, compound 10a (1.76 g, 3.8 mmol, 75%) was obtained as a pale yellow solid through the above process via azeotropic distillation using a Dean-Stark distiller.

^1H NMR (500 MHz, CDCl ₃ ) δ 8.54 (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).

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

Using compound 7b as a starting material, 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.

^1H NMR (500 MHz, CDCl ₃ ) δ 9.69 (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).

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

Using compound 7d as a starting material, the above process including the imine formation process using titanium tetrachloride was performed to obtain compound 10d (1.8 g, 4.2 mmol, 84%) as a pale yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 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) ).

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)

Indole-3-acetonitrile compound 10 (0.50 mmol), nickel chloride hexahydrate (NiCl ₂ 6H ₂ O; 120 mg, 0.50 mmol) or cobalt chloride hexahydrate (CoCl ₂ 6H ₂ O; 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, and the progress of the reaction was observed by 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, the reaction mixture was stirred for 30 minutes, and then concentrated. A saturated aqueous solution of NaHCO ₃ was added dropwise to the mixture, and the resulting mixture was extracted using ethyl acetate. The obtained organic layer was dried over MgSO ₄ 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.

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)

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.

^1H NMR (500 MHz, DMSO- d ₆ ) δ 11.76 (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) ).

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)

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.

^1H NMR (500 MHz, DMSO- d ₆ ) δ 11.74 (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).

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)

Using compound 10d as a starting material, compound 11d (175 mg, 0.43 mmol, 86%) as a pale yellow solid was obtained through the above process.

¹ H NMR (500 MHz, CD ₃ OD) 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).

Synthesis Example 4: Synthesis of pinacol borate (2)

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

Indoloazepinone 11a (48 mg, 0.10 mmol), Pd(dppf)Cl ₂ (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 the product was 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 (27 mg, 0.050 mmol, 50%) as an ivory solid.

¹ H NMR (500 MHz, CD ₃ OD) δ 8.24 (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).

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

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.

The spectroscopic data for compound 2 were obtained with the same results as those obtained from compound 11a.

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

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 (Me ₄ Phen; 4.7 mg, 0.020 mmol) in tetrahydrofuran (0.5 mL) was added pinacolborane (3.6 μL, 0.025 mmol), and the mixture was stirred at 80 °C for 30 minutes, after which a solution of indoloazepinone 11d (40 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) was added. The progress of the reaction was monitored by TLC while stirring the reaction mixture. 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 a developing solution to obtain pinacol borate compound 2. (7.9 mg, 0.015 mmol, 15%).

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

[ ^18F ]-rucaparib was finally synthesized (40% yield) using pinacol borate (2) prepared in Synthetic Example 4 according to the method disclosed in the paper of the aforementioned Governor Group (Org. Lett. 2021, 23, 7290-7294).

Claims (16)

A method for producing [ ¹⁸ F]-rucaparib, a compound of the following chemical formula (7), (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 method for preparing [ ¹⁸ F]-rucaparib, comprising the step of converting a compound of chemical formula (6) into a compound of chemical formula (7) by fluorination and deprotection: 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; R ₁ is straight-chain or branched C ₁ -C ₅ alkyl; P ₁ 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). A method for producing [ ¹⁸ F]-rucaparib, wherein the step of converting into the compound of the chemical formula (4) in the first paragraph is performed in the presence of a dehydrating agent. A method for producing [ ¹⁸ F]-rucaparib in claim 2, wherein the dehydrating agent is at least one compound selected from the group consisting of TiCl ₄ , MgSO _{4 ,} and Na ₂ SO ₄ , or a molecular sieve. A method for producing [ ¹⁸ F]-rucaparib, wherein the step of converting into the compound of the chemical formula (4) in claim 1 is performed through an azeotropic distillation method. In the first aspect, a method for producing [ ¹⁸ F]-rucaparib, wherein the catalyst is MCN or N-heterocyclic carbene: Here, M is an alkali metal or NR ₄₊ ^; R is H or straight-chain or branched C ₁ -C ₅ alkyl. A method for preparing [ ¹⁸ F]-rucaparib in claim 5, wherein the N-heterocyclic carbene is selected from the group consisting of imidazolium, triazolium, and thiazolium. A method for producing [ ¹⁸ F]-rucaparib in claim 1, wherein the reduction reaction of step (c) is a reaction performed in the presence of nickel boride and cobalt boride. A method for producing [ 18 F]-rucaparib in claim 1, wherein 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, NaBH ₄ and borane. In the first paragraph, 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 [ ¹⁸ F]-rucaparib, further comprising the step of reacting a compound of chemical formula (9) with sodium nitrite, performing iodination, and then reducing a nitro group: Chemical formula (1)

Chemical formula (8)

Chemical formula (9)

Here, R ₁ is straight-chain or branched C ₁ -C ₅ alkyl; X is H, Cl or Br. A method for producing [ ¹⁸ F]-rucaparib, wherein the method further comprises a step of protecting an amine group prior to nitration of the compound of the chemical formula (8) in claim 9. A method for producing [ ¹⁸ F]-rucaparib, wherein the method further comprises a step of deprotecting an amine group simultaneously with or after the nitration reaction in claim 10. A method for producing a compound of the following chemical formula (10), (a) a step of obtaining a compound of chemical formula (12) by nitrating a compound of chemical formula (11); 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, performing iodination, and then reducing a nitro group: Chemical formula (10)

Chemical formula (11)

Chemical formula (12)

Here, R ₁ is straight-chain or branched C ₁ -C ₅ alkyl; X ₁ is a halogen. 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. A method for producing a compound of formula (10), wherein the method further comprises a step of deprotecting an amine group simultaneously with or after the nitration reaction in claim 13. [ ¹⁸ F] - Compound of the following chemical formula (4) used in the manufacture of rucaparib: Chemical formula (4)

Here, X is H, Cl or Br, R ₁ is straight-chain or branched C ₁ -C ₅ alkyl; P ₁ 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). [ ¹⁸ F] - Compound of the following chemical formula (5) used in the manufacture of rucaparib: Chemical formula (5)

Here, X is Cl, P ₁ 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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