Method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile

Abstract

The present invention relates to a method for efficiently preparing 2-amino-4-fluoro-6- methoxycarbonylcinnamonitrile. More specifically, the present invention relates to an improved preparation method for synthesizing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, which is a key intermediate in preparing rucaparib with excellent yield through a novel synthesis route using, as a starting material, alkyl 5-fluoro-2-methyl-3-nitrobenzoate rather than a conventional 2-iodoaniline derivative.

Description

Method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile

[0001] The present invention relates to an efficient method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile. More specifically, the present invention relates to an improved method for synthesizing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, a key intermediate in the preparation of rucaparib, in excellent yield through a novel synthetic route starting from alkyl 5-fluoro-2-methyl-3-nitrobenzoate, rather than a conventional 2-iodoaniline derivative.

[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] Currently, rucaparib is synthesized from compound (1), a meta-fluorobenzoate derivative, over a total of six steps with a low yield of 5.2% (Scheme 1 (a)). However, to improve the low synthesis yield, which is a drawback of the conventional method, the inventors of the present invention have developed a novel synthetic method for rucaparib, which utilizes the imino-Stetter reaction using a cyanide catalyst as a core reaction (Scheme 1 (b); see KR 10-2021-0101907).

[0005] In the above-described synthetic method, 2-aminocinnamonitrile (3), one of the starting materials for the imino-Stetter reaction, was synthesized from a 2-iodoaniline derivative (2) through the Heck reaction. However, the starting material, 2-iodoaniline derivative (2), although commercially available, is very expensive (approximately $4,000 / g), and therefore, the development of a more economical synthetic method is required.

[0006]

[0007] Scheme 1

[0008] Accordingly, the inventors of the present invention have discovered that, in order to solve the above-mentioned problem, when synthesizing the key intermediate 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile in excellent yield through a novel synthetic route using alkyl 5-fluoro-2-methyl-3-nitrobenzoate as a starting material instead of the 2-iodoaniline derivative (2), it has excellent advantages in terms of economy and yield, thereby completing the present invention.

[0009] The purpose of the present invention is to provide an improved method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, which can achieve excellent synthetic yield and reproducibility.

[0010] Another object of the present invention is to provide a novel intermediate used in the production of 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile.

[0011] In order to achieve the above purpose, in one specific example of the present invention, a method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, a compound of the following chemical formula (1), is provided.

[0012] (a) a step of converting a compound of chemical formula (2) into a compound of chemical formula (3);

[0013] (b) a step of converting the compound of formula (3) into the compound of formula (4) through an elimination reaction; and

[0014] (c) A method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile is provided, comprising the step of reducing the nitro group of the compound of formula (4) to convert it into the compound of formula (1):

[0015] Chemical formula (1)

[0016]

[0017] Chemical formula (2)

[0018]

[0019] Chemical formula (3)

[0020]

[0021] Chemical formula (4)

[0022]

[0023] Here,

[0024] X is a leaving group;

[0025] R1 is straight-chain or branched C1-C5 alkyl.

[0026] 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.

[0027] Examples of leaving groups that can be used in the present invention include halogen, tosylate, mesylate, triflate, acetate, trifluoromethylacetate, aryloxide, -NO2, -N(C 1-5 alkyl)(C 1-5 alkyl)-O - , -CN, -N + (C 1-5 alkyl)(C 1-5 alkyl)(C1-5 alkyl), -C(O)(C 1-6 alkyl), -C(O)(aryl), -C(O)O(C 1-5 Includes, but is not limited to, -C(O)O(alkyl), -C(O)O(aryl), etc.

[0028] In one embodiment of the present invention, the preferred leaving group is -N + R2R3-O - , -N + R2R3R4 or -CN, wherein R2, R3 and R4 are each independently a straight-chain or branched C1-C5 alkyl.

[0029] In a preferred embodiment of the present invention, step (a) comprises:

[0030] (a-1) A step of converting a compound of chemical formula (2) into a compound of chemical formula (5);

[0031] (a-2) a step of converting a compound of chemical formula (5) into a compound of chemical formula (6); and

[0032] (a-3) A method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile is provided, comprising the step of oxidizing a compound of chemical formula (6) to form an N-oxide derivative of a compound of chemical formula (7):

[0033] Chemical formula (2)

[0034]

[0035] Chemical formula (5)

[0036]

[0037] Chemical formula (6)

[0038]

[0039] Chemical formula (7)

[0040]

[0041] Here,

[0042] R1, R2 and R3 are each independently straight-chain or branched C1-C5 alkyl.

[0043] In one specific example of the present invention, the step of converting into the compound of the formula (5) is preferably a method of synthesizing an enamine derivative by using a reaction between DMF and dimethyl acetal (DMF-DMA). From the obtained enamine derivative, a tertiary amine derivative, which is a compound of the formula (6), is synthesized through a Strecker reaction, and the compound of the formula (6) can be oxidized to convert into an N-oxide derivative, which is a compound of the formula (7).

[0044] The converted N-oxide derivative can then be converted into the compound of the above-described chemical formula (4) through a Cope elimination reaction under basic conditions, with the entire N-oxide group acting as a leaving group. In this case, the ratio of the formed geometric isomers, trans and cis, was confirmed to be approximately 2:1, and these can be easily separated through recrystallization after a subsequent reduction reaction of the nitro group.

[0045] Therefore, the present invention is advantageous in that it can separate the final compound by recrystallization without purification of the intermediate, and it does not use a transition metal such as Pd used in a conventional reaction, so it is advantageous in that it can be applied to a process for mass production.

[0046] In a preferred embodiment of the present invention, step (a) comprises:

[0047] (a-4) A step of converting a compound of chemical formula (2) into a compound of chemical formula (5);

[0048] (a-5) a step of converting a compound of chemical formula (5) into a compound of chemical formula (6); and

[0049] (a-6) A method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile is provided, which comprises the step of reacting a compound of chemical formula (6) with MeI to form a quaternary ammonium salt of a compound of chemical formula (10):

[0050] Chemical formula (2)

[0051]

[0052] Chemical formula (5)

[0053]

[0054] Chemical formula (6)

[0055]

[0056] Chemical formula (10)

[0057]

[0058] Here, R1, R2 and R3 are each independently a straight-chain or branched C1-C5 alkyl, and R4 is methyl.

[0059] In one specific example of the present invention, when the compound of the above chemical formula (6) is reacted with MeI to form a quaternary ammonium salt, which is a compound of the above chemical formula (10), the resulting quaternary ammonium salt can then be converted into the compound of the above chemical formula (4) through a Hofmann elimination reaction in which the entire quaternary ammonium group acts as a leaving group.

[0060] In a preferred embodiment of the present invention, step (a) comprises:

[0061] (a-7) a step of converting a compound of chemical formula (2) into a compound of chemical formula (8); and

[0062] (a-8) A method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile is provided, comprising the step of converting a compound of formula (8) into a compound of formula (9):

[0063] Chemical formula (2)

[0064]

[0065] Chemical formula (8)

[0066]

[0067] Chemical formula (9)

[0068]

[0069] Here,

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

[0071] In one specific example of the present invention, in the step of converting the compound of the above-described chemical formula (2) into the compound of the chemical formula (8), it is preferable to use NBS. Thereafter, the compound can be converted into the compound of the chemical formula (9) by reacting it with malononitrile under basic conditions.

[0072] The compound of chemical formula (9) can then be converted into the compound of chemical formula (4) through an elimination reaction, specifically, heating with an organic base such as TEA, or reaction with Xantphos / Ni(cod)2 / styrene, etc. are preferred, but are not limited to these.

[0073] In one specific embodiment of the present invention, a compound of the following formula (3) is provided, which is an important intermediate used in the preparation of 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile:

[0074] Chemical formula (3)

[0075]

[0076] Here,

[0077] R1 is straight-chain or branched C1-C5 alkyl;

[0078] X is -N + R2R3-O - , -N + R2R3R4 or -CN,

[0079] R2, R3 and R4 are each independently straight-chain or branched C1-C5 alkyl.

[0080] In addition, in one specific embodiment of the present invention, a compound of the following chemical formula (6) is provided, which is an important intermediate used in the preparation of 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile:

[0081] Chemical formula (6)

[0082]

[0083] Here,

[0084] R1 is straight-chain or branched C1-C5 alkyl;

[0085] R2 and R3 are each independently straight-chain or branched C1-C5 alkyl.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] According to the present invention, an improved method for preparing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile is provided, which can achieve excellent synthetic yield and reproducibility.

[0090] In addition, according to the present invention, a novel intermediate used in the production of 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile is provided.

[0091] 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.

[0092] General procedure

[0093] Unless otherwise stated, all reactions were performed in oven-dried glassware under an argon atmosphere. Unless otherwise stated, 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 stated, 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.

[0094] Synthesis Example 1: Synthesis of 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile (1)

[0095] Manufacturing Example 1: Synthesis of methyl 2-(2-cyano-2-(dimethylamino)ethyl)-5-fluoro-3-nitrobenzoate (4)

[0096]

[0097] Methyl 5-fluoro-2-methyl-3-nitrobenzoate (2, 4.3 g, 20 mmol) was dissolved in N,N-dimethylformamide (200 mL), and triethylamine (1.4 mL, 10 mmol) and N,N-dimethylformamide dimethylacetal (13.3 mL, 100 mmol) were sequentially added, followed by 100 o The progress of the reaction was observed by TLC analysis while stirring at C. After compound 2 was completely consumed, the reaction mixture was concentrated to obtain a mixture of enamine compounds 3, which were used in the next reaction without further post-treatment.

[0098] A mixture of enamine compounds 3 was dissolved in isopropyl alcohol (200 mL), and trimethylsilyl cyanide (5.0 mL, 40 mmol) was added, followed by 20 oThe progress of the reaction was observed by TLC analysis while stirring at C. After compound 3 was completely consumed, the reaction mixture was concentrated, and ethanol was added dropwise to the reaction mixture to form a brown precipitate. The resulting precipitate was filtered to obtain compound 4 (4.4 g, 15 mmol, 75% yield in 2 steps) as a brown solid.

[0099] 1 H NMR (500 MHz, CDCl3)δ7.85 (dd,J= 8.2, 2.9 Hz, 1H), 7.67 (dd,J= 7.3, 2.9 Hz, 1H), 3.97 (s, 3H), 3.88 (t,J= 7.6 Hz, 1H), 3.81 (dd,J= 13.6, 7.5 Hz, 1H), 3.42 (dd,J= 13.6, 7.8 Hz, 1H), 2.30 (s, 6H).

[0100] Manufacturing Example 2: 2-Amino-4-fluoro-6-methoxycarbonylcinnamonitrile (1)

[0101]

[0102] Compound 4 (2.95 g, 10 mmol) was dissolved in dichloromethane (100 mL) and then 0 o Cool to C. Add meta-chloroperoxybenzoic acid (70%, 2.7 g, 11 mmol) to the cooled reaction solution and then 0 o The progress of the reaction was observed by TLC while stirring at C. After compound 4 was completely consumed, potassium carbonate (4.1 g, 30 mmol) was added to the reaction mixture at 0 o After adding in C 20 o The formation of compound 5 was observed by TLC while stirring at C for 1 hour. Afterwards, the reaction mixture was filtered through Celite to remove insoluble solids and concentrated to obtain a mixture of compound 5, which was used in the next reaction without further post-treatment.

[0103] After dissolving the mixture of compound 5 and zinc powder (6.5 g, 100 mmol) in methanol (100 mL), acetic acid (5.7 mL, 100 mmol) was added at room temperature and stirred for 60 o The progress of the reaction was monitored by TLC while stirring at C. After compound 5 was completely consumed, the reaction mixture was filtered through Celite to remove insoluble solids and concentrated. A saturated aqueous solution of NH4Cl was added dropwise to the mixture, and the resulting mixture was extracted using ethyl acetate. The obtained organic layer was washed with a 1 N aqueous solution of HCl, dried over MgSO4, and concentrated. The reaction mixture was dissolved again in ethyl acetate, and hexane was added dropwise to form a yellow precipitate, which was filtered to obtain compound 1 (1.32 g, 6.0 mmol, 60% yield in 2 steps) as a yellow solid.

[0104] 1 H NMR (500 MHz, CDCl3) δ7.77 (d,J= 17.1 Hz, 1H), 7.05 (dd,J= 8.8, 2.5 Hz, 1H), 6.60 (dd,J= 9.7, 2.5 Hz, 1H), 5.74 (d,J= 16.9 Hz, 1H), 4.13 (br, 2H), 3.88 (s, 3H).

[0105] Synthesis Example 2: Synthesis of 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile (1)

[0106]

[0107] Compound 4 (2.95 g, 10 mmol) was dissolved in dichloromethane (100 mL), and methyl iodide (12.5 mL, 200 mmol) was added, followed by 20 o The progress of the reaction was observed by TLC while stirring at C. When compound 4 was completely consumed, the reaction mixture was condensed and used in the next reaction without further post-treatment. After adding silver(I) oxide (6.95 g, 30 mmol) and H2O to the obtained reaction mixture, 50o The formation of compound 5 was observed by TLC while stirring at C. The reaction mixture was then filtered through Celite to remove insoluble solids and concentrated to obtain a mixture of compound 5, which was used in the next reaction without further post-treatment.

[0108] After dissolving the mixture of compound 5 and zinc powder (6.5 g, 100 mmol) in methanol (100 mL), acetic acid (5.7 mL, 100 mmol) was added at room temperature and stirred for 60 o The progress of the reaction was observed by TLC while stirring at C. After compound 5 was completely consumed, the reaction mixture was filtered through Celite to remove insoluble solids and concentrated. A saturated aqueous solution of NH4Cl (100 mL) was added dropwise to the mixture, and the resulting mixture was extracted using ethyl acetate (100 mL). The obtained organic layer was washed twice with a 1 N aqueous solution of HCl, dried over MgSO4, and concentrated. The reaction mixture was dissolved again in ethyl acetate, and hexane was added dropwise to form a yellow precipitate, which was filtered to obtain compound 1 (0.99 g, 4.5 mmol, 45% yield in 2 steps) as a yellow solid.

[0109] 1 H NMR (500 MHz, CDCl3) δ7.77 (d,J= 17.1 Hz, 1H), 7.05 (dd,J= 8.8, 2.5 Hz, 1H), 6.60 (dd,J= 9.7, 2.5 Hz, 1H), 5.74 (d,J= 16.9 Hz, 1H), 4.13 (br, 2H), 3.88 (s, 3H).

[0110] Synthesis Example 3: Synthesis of 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile (1)

[0111] Manufacturing Example 1: Methyl 2-(2,2-dicyanoethyl)-5-fluoro-3-nitrobenzoate (7)

[0112]

[0113] Methyl 5-fluoro-2-methyl-3-nitrobenzoate (2, 4.3 g, 20 mmol) was dissolved in 1,2-dichloroethane (DCE; 200 mL), N-bromosuccinimide (NBS; 18 g, 100 mmol), and 1,1'-azobis-(cyclohexane-1-carbonitrile) (ACHN; 2.4 g, 10 mmol). The reaction mixture was stirred at 90°C and the progress of the reaction was monitored by TLC. After compound 2 was completely consumed, the reaction mixture was cooled to 20°C, and a saturated aqueous solution of Na2S2O3 was added dropwise to the reaction mixture to remove the remaining N-bromosuccinimide. The reaction mixture was then extracted with dichloromethane. The obtained organic layer was dried over MgSO4 and concentrated to obtain a mixture of compound 6, which was used in the next reaction without further treatment.

[0114] A mixture of compound 6 and malononitrile (1.45 g, 22 mmol) was dissolved in tetrahydrofuran (200 mL), and triethylamine (5.6 mL, 40 mmol) was added, followed by 20 o The progress of the reaction was observed by TLC analysis while stirring at C. After compound 6 was completely consumed, the reaction mixture was concentrated, and ethanol was added dropwise to the reaction mixture to form a brown precipitate. The resulting precipitate was filtered to obtain compound 7 (3.3 g, 12 mmol, 60% yield in 2 steps) as a brown solid.

[0115] 1 H NMR (500 MHz, CDCl3)δ7.89 (dd,J= 8.2, 2.9 Hz, 1H), 7.71 (dd,J= 7.3, 2.9 Hz, 1H), 3.97 (s, 3H), 3.88 (t,J= 7.6 Hz, 1H), 3.25 (t,J= 7.6) Hz, 1H).

[0116] Manufacturing Example 2: 2-Amino-4-fluoro-6-methoxycarbonylcinnamonitrile (1)

[0117]

[0118] Compound 7 (2.77 g, 10 mmol) was dissolved in N,N-dimethylformamide (100 mL), then triethylamine (2.8 mL, 20 mmol) was added and 100 o The progress of the reaction was observed by TLC while stirring at C. After compound 7 was completely consumed, the reaction mixture was concentrated to obtain a mixture of compound 5, which was used in the next reaction without further post-treatment.

[0119] After dissolving the mixture of compound 5 and zinc powder (6.5 g, 100 mmol) in methanol (100 mL), acetic acid (5.7 mL, 100 mmol) was added at room temperature and stirred for 60 o The progress of the reaction was monitored by TLC while stirring at C. After compound 5 was completely consumed, the reaction mixture was filtered through Celite to remove insoluble solids and concentrated. A saturated aqueous solution of NH4Cl was added dropwise to the mixture, and the resulting mixture was extracted using ethyl acetate. The obtained organic layer was washed with a 1 N aqueous solution of HCl, dried over MgSO4, and concentrated. The reaction mixture was dissolved again in ethyl acetate, and hexane was added dropwise to form a yellow precipitate, which was filtered to obtain compound 1 (1.32 g, 6.0 mmol, 60% yield in 2 steps) as a yellow solid.

[0120] 1 H NMR (500 MHz, CDCl3) δ7.77 (d,J= 17.1 Hz, 1H), 7.05 (dd,J= 8.8, 2.5 Hz, 1H), 6.60 (dd,J= 9.7, 2.5 Hz, 1H), 5.74 (d,J= 16.9 Hz, 1H), 4.13 (br, 2H), 3.88 (s, 3H).

[0121] Manufacturing Example 3: 2-Amino-4-fluoro-6-methoxycarbonylcinnamonitrile (1)

[0122]

[0123] Compound 7 (2.77 g, 10 mmol) was dissolved in toluene (100 mL), and then Xantphos (10 mol%), Ni(cod)2 (10 mol%), and styrene (10 mmol) were added under an argon flow, and the reaction mixture was stirred at 120 o The progress of the reaction was observed by TLC and GC while stirring at C. After compound 7 was completely consumed, the reaction mixture was concentrated to obtain a mixture of compound 5, which was used in the next reaction without further post-treatment.

[0124] After dissolving the mixture of compound 5 and zinc powder (6.5 g, 100 mmol) in methanol (100 mL), acetic acid (5.7 mL, 100 mmol) was added at room temperature and stirred for 60 o The progress of the reaction was monitored by TLC while stirring at C. After compound 5 was completely consumed, the reaction mixture was filtered through Celite to remove insoluble solids and concentrated. A saturated aqueous solution of NH4Cl was added dropwise to the mixture, and the resulting mixture was extracted using ethyl acetate. The obtained organic layer was washed with a 1 N aqueous solution of HCl, dried over MgSO4, and concentrated. The reaction mixture was dissolved again in ethyl acetate, and hexane was added dropwise to form a yellow precipitate, which was filtered to obtain compound 1 (1.10 g, 5.0 mmol, 2-step yield 50%) as a yellow solid.

[0125] 1 H NMR (500 MHz, CDCl3) δ7.77 (d,J= 17.1 Hz, 1H), 7.05 (dd,J= 8.8, 2.5 Hz, 1H), 6.60 (dd,J= 9.7, 2.5 Hz, 1H), 5.74 (d,J= 16.9 Hz, 1H), 4.13 (br, 2H), 3.88 (s, 3H).

Claims

1. A method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, a compound of the following chemical formula (1), (a) a step of converting a compound of chemical formula (2) into a compound of chemical formula (3); (b) a step of converting the compound of formula (3) into the compound of formula (4) through an elimination reaction; and (c) A method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, comprising the step of reducing a nitro group of a compound of chemical formula (4) to convert it into a compound of chemical formula (1): Chemical formula (1) Chemical formula (2) Chemical formula (3) Chemical formula (4) Here, X is a leaving group; R1 is straight-chain or branched C1-C5 alkyl.

2. In the first paragraph, the leaving group X is -N + R2R3-O - , -N + A method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, wherein R2R3R4 or -CN, wherein R2, R3 and R4 are each independently a straight-chain or branched C1-C5 alkyl.

3. In paragraph 1, step (a) is, (a-1) A step of converting a compound of chemical formula (2) into a compound of chemical formula (5); (a-2) a step of converting a compound of chemical formula (5) into a compound of chemical formula (6); and (a-3) A method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, comprising the step of oxidizing a compound of chemical formula (6) to form an N-oxide derivative of a compound of chemical formula (7): Chemical formula (2) Chemical formula (5) Chemical formula (6) Chemical formula (7) Here, R1, R2 and R3 are each independently a straight-chain or branched C1-C5 alkyl.

4. In paragraph 1, step (a) is, (a-4) A step of converting a compound of chemical formula (2) into a compound of chemical formula (5); (a-5) a step of converting a compound of chemical formula (5) into a compound of chemical formula (6); and (a-6) A method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, comprising the step of reacting a compound of chemical formula (6) with MeI to form a quaternary ammonium salt, which is a compound of chemical formula (10): Chemical formula (2) Chemical formula (5) Chemical formula (6) Chemical formula (10) Here, R1, R2 and R3 are each independently a straight-chain or branched C1-C5 alkyl, and R4 is methyl.

5. In paragraph 1, step (a) is, (a-7) a step of converting a compound of chemical formula (2) into a compound of chemical formula (8); and (a-8) A method for producing 2-amino-4-fluoro-6-methoxycarbonylcinnamonitrile, comprising the step of converting a compound of chemical formula (8) into a compound of chemical formula (9): Chemical formula (2) Chemical formula (8) Chemical formula (9) Here, R1 is straight-chain or branched C1-C5 alkyl.

6. Compound of the following chemical formula (3): Chemical formula (3) Here, R1 is straight-chain or branched C1-C5 alkyl; X is -N + R2R3-O - , -N + R2R3R4 or -CN, R2, R3 and R4 are each independently straight-chain or branched C1-C5 alkyl.

7. Compound of the following chemical formula (6): Chemical formula (6) Here, R1 is straight-chain or branched C1-C5 alkyl; R2 and R3 are each independently straight-chain or branched C1-C5 alkyl.

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