Process for the production of 2-(halomethyl)naphthalenes and 2-naphthaleneacetonitriles

Abstract

The present invention safely and inexpensively produces 2-(halogenated methyl)naphthalene and 2-naphthaleneacetonitrile with high selectivity and good yield. 2-(Halogenated methyl)naphthalene is produced by halogenating 2-methylnaphthalene in a solvent selected from halogenated hydrocarbons, aliphatic esters, and aliphatic hydrocarbons, under light irradiation, with a halogenating agent. This compound can be derived into various pharmaceuticals or intermediates thereof (e.g., 2-naphthaleneacetonitrile).

Description

Technical Field

[0001] The present invention relates to a method for manufacturing 2-(halomethyl)naphthalene and 2-naphthylacetonitrile, which are useful as synthetic intermediates for pharmaceuticals and the like. Background Technology

[0002] 2-(halomethyl)naphthalene is useful as a synthetic starting material or intermediate for various pharmaceuticals, pesticides, and chemicals. Additionally, naphthalene compounds with similar chemical structures to 2-(halomethyl)naphthalene are also expected to be used as synthetic starting materials or intermediates for various pharmaceuticals, pesticides, and chemicals. For example, 2-(halomethyl)naphthalene and 2-naphthylacetonitrile, which have similar chemical structures, are useful as synthetic starting materials or intermediates for drugs treating attention deficit hyperactivity disorder (ADHD). Specifically, 2-(halomethyl)naphthalene and 2-naphthylacetonitrile, for example, can be suitable as synthetic starting materials or intermediates for (1R,5S)-1-(naphth-2-yl)-3-azabicyclo[3.1.0]hexane (common name: celefaldine).

[0003] Previously, batch reaction methods were known as a method for producing 2-(halomethyl)naphthalene. For example, a known method involves adding 2-methylnaphthalene, N-bromosuccinimide, dichloromethane, benzene, and triphenylmethyltetrafluoroborate to a batch reaction vessel and carrying out a photoreaction at room temperature under light irradiation, thereby producing 2-(bromomethyl)naphthalene (Non-Patent Literature 1). A photoreaction refers to a chemical reaction in which molecules absorb energy through light irradiation, becoming excited to a higher energy level, and the excited molecules initiate a reaction. Photoreactions are also known as photochemical reactions.

[0004]

[0005] However, the method in Non-Patent Literature 1 involves a reaction using benzene as a solvent, which is extremely difficult to ensure safety when used industrially. Furthermore, the yield of the obtained 2-(bromomethyl)naphthalene is also unsatisfactory industrially. Therefore, a safer and more productive industrial manufacturing method is desired.

[0006] In recent years, continuous halogenation reaction methods have been known to improve productivity. For example, the following method is known: in a flow-through photochemical reactor, a solution of 4-tert-butyltoluene and N-bromosuccinimide mixed with acetonitrile solvent is irradiated with light, thereby continuously producing 4-tert-butylbenzyl bromide (Non-Patent Literature 2).

[0007]

[0008] However, as illustrated in Comparative Example 1 below, it can be seen that even if the substrate of Non-Patent Document 2, namely 4-tert-butyltoluene, is replaced with 2-methylnaphthalene for manufacturing, it is not possible to obtain 2-(bromomethyl)naphthalene as the target compound with high selectivity, and the undesirable 1-bromo-2-methylnaphthalene is generated as the main product.

[0009] Therefore, in order to produce 2-(halomethyl)naphthalene in high yield, a method for halogenating the 2-methyl group of 2-methylnaphthalene with high selectivity is desired.

[0010] In addition, Non-Patent Document 3 describes a technique for producing 2-naphthylacetonitrile by cyaniding 2-(halomethyl)naphthyl.

[0011] Existing technical documents

[0012] Non-patent literature

[0013] Non-patent literature 1: Adv. Synth. Catal. (2018) 4197-4204

[0014] Non-patent literature 2: JOC.(2014)223-229

[0015] Non-patent literature 3: Tetrahedron Letters 56(2015)2054-2058 Summary of the Invention

[0016] The problem that the invention aims to solve

[0017] The objective of this invention is to provide a method for the safe and inexpensive production of 2-(halomethyl)naphthalene and a method for the production of 2-naphthylacetonitrile with high selectivity and good yield.

[0018] Methods for solving problems

[0019] The inventors conducted in-depth research and discovered that by reacting 2-methylnaphthalene with a halogenating agent in a specific organic solvent under light irradiation, 2-(halogenated methyl)naphthalene and 2-naphthylacetonitrile can be obtained safely and inexpensively with high selectivity and good yield, thus completing this invention. Furthermore, this invention has the following characteristics.

[0020] [1] A method for manufacturing 2-(halogenated methyl)naphthalene of general formula (1) includes a halogenation step of reacting 2-methylnaphthalene with a halogenating agent in an organic solvent selected from halogenated hydrocarbons, aliphatic esters and aliphatic hydrocarbons under light irradiation.

[0021]

[0022] (In the formula, X represents a halogen atom.)

[0023] [2] In the manufacturing method described in [1] above, the halogenating agent is a brominating agent.

[0024] [3] The manufacturing method according to [1] or [2] is wherein the light irradiation is performed using light with a wavelength of 280 nm to 700 nm.

[0025] [4] The manufacturing method according to any one of [1] to [3], wherein the reaction is carried out in the range of -20°C to 100°C.

[0026] [5] The manufacturing method according to any one of [1] to [4], wherein the reaction is carried out in the absence of additives.

[0027] [6] The manufacturing method according to any one of [1] to [5], wherein the reaction is carried out by a flow synthesis reaction.

[0028] [7] A method for manufacturing 2-naphthylacetonitrile, comprising:

[0029] A halogenation process in which 2-methylnaphthalene reacts with a halogenating agent in an organic solvent selected from halogenated hydrocarbons, aliphatic esters, and aliphatic hydrocarbons under light irradiation; and

[0030] A cyanidation process in which 2-(halogenated methyl)naphthalene, represented by general formula (1) obtained in the halogenation process, is reacted with a cyaniding agent in a solvent.

[0031]

[0032] (In the formula, X represents a halogen atom.)

[0033] Invention Effects

[0034] According to the method for producing 2-(halomethyl)naphthalene of the present invention, 2-(halomethyl)naphthalene can be produced safely and inexpensively with high selectivity and good yield. Furthermore, according to the method for producing 2-naphthoacetonitrile of the present invention, 2-naphthoacetonitrile can be produced safely and inexpensively with high selectivity and good yield. Attached Figure Description

[0035] Figure 1 A system diagram of a flow synthesis reactor illustrating an example of an embodiment of the method for producing 2-(halomethyl)naphthalene according to the present invention.

[0036] Figure 2 A system diagram of a flow synthesis reactor illustrating an example (cyanidation step) of a method for manufacturing 2-naphthylacetonitrile according to the present invention. Detailed Implementation

[0037] The present invention will now be described in detail.

[0038] [Method for manufacturing 2-(halomethyl)naphthalene]

[0039] The method for manufacturing 2-(halomethyl)naphthalene of the present invention is as follows: 2-methylnaphthalene is selectively halogenated at the 2-position by reacting it with a halogenating agent in an organic solvent selected from halogenated hydrocarbons, aliphatic esters and aliphatic hydrocarbons under light irradiation, thereby manufacturing 2-(halomethyl)naphthalene (hereinafter sometimes referred to as halogenated naphthalene) of general formula (1). (This step is sometimes referred to as "halogenation step of the present invention").

[0040]

[0041] (In the formula, X represents a halogen atom.)

[0042] "Halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom. The "halogen atom" is preferably a chlorine atom, bromine atom, or iodine atom, and from the point of view of reactivity, bromine atom is particularly preferred.

[0043] <<Halogenation Process>>

[0044] As an example of implementing the halogenation process of the present invention, a method can be described as follows: In a batch reactor, 2-methylnaphthalene, a halogenating agent, and an organic solvent are mixed and subjected to light irradiation under reaction conditions to induce a reaction. Alternatively, methods such as... Figure 1 The following method using a flow synthesis reactor is shown: while irradiating the transmissive flow-through reactor 3 equipped with the light irradiation mechanism 4 of the present invention, a mixture of 2-methylnaphthalene (2MN) prepared in the preparation tank 1 with an organic solvent and a halogenating agent is continuously pumped by a pump 2, and the 2-methylnaphthalene is continuously subjected to a halogenation reaction in the flow-through reactor 3. The reaction liquid containing 2-(halogenated methyl)naphthalene flowing out of the flow-through reactor 3 is recovered by a recovery tank 5.

[0045] From the viewpoint of reactivity and selectivity, the halogenation process of the present invention is preferably carried out by using a flow synthesis reactor. This flow synthesis reactor will be described later.

[0046] <2-methylnaphthalene>

[0047] 2-methylnaphthalene used as a raw material for the manufacture of 2-(halogenated methyl)naphthalene can be a commercially available product or 2-methylnaphthalene obtained by known methods or methods based thereon.

[0048] <Organic Solvents>

[0049] The organic solvents used in this invention are selected from halogenated hydrocarbons, aliphatic esters, and aliphatic hydrocarbons, which can be used alone or in any proportion of two or more. From a reactivity point of view, the use of halogenated hydrocarbons or aliphatic esters alone is particularly preferred.

[0050] Halogenated hydrocarbons are aliphatic hydrocarbons that are substituted with one or more halogen atoms. Examples of halogenated aliphatic hydrocarbons with 1 to 10 carbon atoms are typically used, preferably with 1 to 8 carbon atoms, and particularly preferably with 1 to 6 carbon atoms.

[0051] Examples of halogenated hydrocarbons include dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, tetrachloroethylene, dichloroethane, and 1,1,2,2-tetrachloroethane. From the viewpoints of reactivity, selectivity, safety, and ease of acquisition, dichloromethane and dichloroethane are preferred, and dichloromethane is particularly preferred.

[0052] Aliphatic esters are aliphatic hydrocarbons having one or more ester bonds, and examples include aliphatic esters with 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and particularly preferably 1 to 6 carbon atoms.

[0053] Examples of aliphatic esters include acetate esters such as methyl acetate, ethyl acetate, and propyl acetate. From the viewpoints of reactivity, selectivity, and ease of acquisition, methyl acetate and ethyl acetate are preferred, and from the viewpoint of safety, methyl acetate is particularly preferred.

[0054] Aliphatic hydrocarbons are cyclic or chain-like aliphatic hydrocarbons, and examples include aliphatic hydrocarbons with 5 to 12 carbon atoms, preferably 5 to 10 carbon atoms, and particularly preferably 5 to 8 carbon atoms.

[0055] Examples of cyclic aliphatic hydrocarbons include cyclopentane, cyclohexane, cycloheptane, cyclooctane, methylcyclopentane, ethylcyclopentane, methylcyclohexane, ethylcyclohexane, 1,2-dimethylcyclohexane, 1,3-dimethylcyclohexane, 1,4-dimethylcyclohexane, isopropylcyclohexane, n-propylcyclohexane, tert-butylcyclohexane, n-butylcyclohexane, and isobutylcyclohexane. From the viewpoint of reactivity, cyclopentane, cyclohexane, cycloheptane, and cyclooctane are preferred, and cyclopentane, cyclohexane, and cycloheptane are particularly preferred.

[0056] Examples of chain-like aliphatic hydrocarbons include n-pentane, n-hexane, n-heptane, and n-octane. From a reactivity point of view, n-hexane and n-heptane are preferred.

[0057] From the viewpoint of productivity and reactivity, the amount of organic solvent used relative to 2-methylnaphthalene is typically 1 to 200 times by weight, preferably 2 to 150 times by weight, and particularly preferably 3 to 100 times by weight.

[0058] In this invention, it is generally preferred that the 2-methylnaphthalene and the halogenating agent, which will be used as raw materials, are dissolved in an organic solvent to form a homogeneous solution for reaction. However, depending on the circumstances, it is acceptable if the aforementioned raw materials are not completely dissolved and are in the form of a slurry.

[0059] <Halogenating Agents>

[0060] There are no particular limitations on the halogenating agent as long as it can halogenate 2-methylnaphthalene. Examples of halogenating agents include brominating agents, iodizing agents, and chlorinating agents; from a reactivity point of view, brominating agents are preferred. Two or more halogenating agents can be used in any proportion, but from a cost and reactivity point of view, using one is preferred.

[0061] Examples of brominating agents include N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N,N,N',N'-tetrabromobenzene-1,3-disulfonamide, and molecular bromine. From the viewpoint of reactivity, N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin are preferred, with N-bromosuccinimide being particularly preferred.

[0062] Examples of chlorinating agents include N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin and molecular chlorine, with N-chlorosuccinimide being preferred from a reactivity point of view.

[0063] Examples of iodizing agents include N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin and molecular iodine. From the viewpoint of reactivity, N-iodosuccinimide is preferred.

[0064] The amount of halogenating agent used varies depending on the halogenating agent used. There is no particular limitation as long as the amount is sufficient to halogenate 2-methylnaphthalene. Generally, the lower limit of the halogen atom content of the halogenating agent relative to 1 mol of 2-methylnaphthalene is usually above 1 mol, the upper limit is below 10 mol, preferably below 5 mol, and particularly preferably below 2 mol.

[0065] <Other Additives>

[0066] In this invention, additives such as catalysts and photosensitizers can be used as needed. However, in this invention, the reaction can proceed well even without the specific use of additives, so it is generally preferred to carry out the reaction in the absence of additives.

[0067] If a photosensitizer is used as an additive, well-known photosensitizers such as benzophenone, 4,4-bis(dimethoxy)thiobenzophenone, 4,4-bis(dimethylamino)benzophenone, 4,4-bis(dimethylamino)thiobenzophenone and 4,4-bis(dimethoxy)benzophenone can be used alone or in any proportion of two or more of these.

[0068] From a reactivity standpoint, the amount of photosensitizer used is typically 0.01 mol% to 10 mol% relative to 1 mol of 2-methylnaphthalene.

[0069] <Reaction Conditions>

[0070] (Reaction temperature)

[0071] From the viewpoints of reactivity and productivity, the lower limit of the reaction temperature for the halogenation process of the present invention is generally -20°C or higher, preferably -10°C or higher, and particularly preferably 0°C or higher, while the upper limit is generally 100°C or lower, preferably 90°C or lower, and particularly preferably 80°C or lower. If the reaction temperature is too low, reactivity may decrease; conversely, if it is too high, side reactions, yield, and selectivity may occur.

[0072] (Reaction pressure)

[0073] The halogenation process of this invention can be carried out under normal pressure or pressure, for example, the lower limit is usually 0.1 MPa or more, the upper limit is usually 1 MPa or less, preferably 0.8 MPa or less, and particularly preferably 0.6 MPa or less. In this invention, the pressure can be adjusted by applying back pressure to the flow path of the reactor using a back pressure valve or the like, thereby enabling efficient reaction.

[0074] (Reaction time)

[0075] The reaction time in the halogenation process of this invention refers to the residence time (residence time) of the raw material mixture (a mixture of 2-methylnaphthalene, a halogenating agent, and an organic solvent) in the photochemical reactor used in this invention. The reaction time varies depending on the reaction temperature and pressure, typically ranging from 0.1 minutes to 240 minutes, and preferably from 1 minute to 120 minutes. It should be noted that when using a flow synthesis reactor or similar device as a photochemical reactor for continuous reactions, the reaction time refers to the residence time of the raw material mixture under light irradiation.

[0076] (Reaction atmosphere)

[0077] The halogenation process of this invention can be carried out under a nitrogen atmosphere or an oxygen-containing atmosphere such as air. From the viewpoint of reactivity, it is preferable to carry out the halogenation process under an oxygen-containing atmosphere.

[0078] (wavelength of light)

[0079] The wavelength of the light used for irradiation can be appropriately selected according to the organic solvent used. From the viewpoint of reactivity and selectivity, wavelengths typically range from 270 nm to 800 nm, preferably from 280 nm to 700 nm, more preferably from 290 nm to 600 nm, and particularly preferably from 300 nm to 550 nm. It should be noted that, in this invention, the wavelength of light refers to the emission wavelength of the light source.

[0080] (Radiation beam of light)

[0081] The light beam emitted in this invention is typically 1 J / s to 4000 J / s, and from the viewpoint of reactivity, it is preferably 2 J / s to 3000 J / s, and particularly preferably 3 J / s to 2000 J / s.

[0082] (Reaction method)

[0083] In this invention, 2-methylnaphthalene is reacted with a halogenating agent under light irradiation in the aforementioned specific organic solvent, but the reaction method is not particularly limited. From a reactivity point of view, industrially, a flow synthesis reactor (flow-through reactor) equipped with a light irradiation mechanism is preferred for implementation. For example, such as Figure 1 As shown, a mixture of 2-methylnaphthalene (2MN), a halogenating agent, and an organic solvent is prepared in preparation tank 1. The mixture is then supplied to a flow synthesis reactor (flow-through reactor) 3 using pump 2. Under the desired light irradiation using light irradiation mechanism 4, the halogenation reaction is carried out in the flow synthesis reactor 3. The reaction solution is then recovered using recovery tank 5.

[0084] (Photochemical reactor)

[0085] The material of the photochemical reactor used in this invention is not particularly limited, as long as it has excellent chemical resistance and can transmit light from a light source. Examples include glass and transparent synthetic resins with chemical resistance. Furthermore, the size of the photochemical reactor can be appropriately selected according to the production scale.

[0086] There are no particular limitations on the type of photochemical reactor; either batch reactors or flow synthesis reactors can be used.

[0087] (Batch reactor)

[0088] Batch reactors can be reactors equipped with flow paths for introducing and discharging substrates, jackets for temperature control, and agitators.

[0089] (Flow synthesis reactor)

[0090] Flow synthesis reactors typically use tubular reactors. The size of the tube can be appropriately selected according to the production scale; for example, the inner diameter is usually 1 mm to 20 mm. The length of the tube can be appropriately selected according to the desired residence time. As for the shape of the tube, straight, curved, or spiral shapes are commonly mentioned, with spiral shapes being particularly preferred from a reactivity point of view.

[0091] In addition, a temperature control mechanism can be provided in the flow synthesis reactor.

[0092] The introduction and discharge of substrates into the flow synthesis reactor can be quantitatively controlled using syringe pumps, diaphragm pumps, mass control devices, etc. Additionally, a back pressure valve and an online analysis device can be installed in the flow path from the reaction liquid outlet of the flow synthesis reactor.

[0093] (Light irradiation mechanism)

[0094] In this invention, a light irradiation mechanism for irradiating the photochemical reactor is preferred.

[0095] For example, when the photochemical reactor is a flow synthesis reactor, it is preferable to form a structure capable of subjecting the tubular portion undergoing the reaction to a specified light irradiation, such as... Figure 1 As shown, a light irradiation mechanism with a light source is installed inside the spiral tubular reactor.

[0096] <Post-processing>

[0097] 2-(halomethyl)naphthalene, the target compound, is separated from the reaction solution obtained through the halogenation process of this invention using conventional methods. Separation can be performed, for example, by neutralizing the obtained reaction solution with water or an alkaline aqueous solution, separating the liquid from the liquid, concentrating the resulting organic layer to precipitate the target compound, and performing solid-liquid separation. If necessary, known purification methods such as recrystallization or column chromatography can also be used.

[0098] <Uses of 2-(Halomethyl)naphthalene>

[0099] The 2-(halomethyl)naphthalene obtained by the present invention can be used as a raw material for various pharmaceuticals or intermediates thereof. For example, cyaniding the 2-(halomethyl)naphthalene obtained by the present invention can produce 2-naphthylacetonitrile, which is useful as a synthetic starting material or synthetic intermediate for, for example, celecoxib, a drug for the treatment of attention deficit hyperactivity disorder (ADHD).

[0100] [Method for manufacturing 2-naphthylacetonitrile]

[0101] 2-Naphthylacetonitrile can be manufactured by reacting 2-(halomethyl)naphthalene obtained by the above method with a cyaniding agent in a solvent (hereinafter, this step is sometimes referred to as "the cyanidation step of the present invention").

[0102] <<Cyanide Process>>

[0103] As an example of implementing the cyanidation process of the present invention, a method can be listed whereby 2-(halomethyl)naphthalene, a cyaniding agent, and a solvent are mixed in a batch reactor and the reaction is carried out under reaction conditions. Alternatively, the following methods can be listed: Figure 2 As shown, a pump 7 continuously feeds a mixture of 2-(halomethyl)naphthalene, solvent, and cyaniding agent prepared in preparation tank 6 into flow-through reactor 8. The cyanidation reaction of 2-(halomethyl)naphthalene is continuously carried out in flow-through reactor 8, and the reaction liquid containing 2-naphthaleneacetonitrile flowing out of flow-through reactor 8 is recovered by recovery tank 9.

[0104] In addition, the cyanidation process can be carried out according to methods known in non-patent literature 3, etc.

[0105] <Solvent>

[0106] As a solvent, aqueous solvents such as water, organic solvents such as alcohols and nitriles can be used alone or in any proportion of two or more of these. From the viewpoint of cost and reactivity, a mixture of water and nitriles is preferred as a solvent.

[0107] As an aqueous solvent, it can be: pure water, deionized water, and industrial water; or a solvent in which suitable hydrophilic organic solvents such as ketones, alcohols, and glycol ethers are mixed. From the perspective of cost and reactivity, water is preferred.

[0108] As the alcohol, aliphatic alcohols with 1 to 10 carbon atoms, preferably 1 to 8, and particularly preferably 1 to 6 carbon atoms can be used. Examples of alcohols include methanol, ethanol, propanol, butanol, pentanol, and hexanol. From the viewpoint of cost and reactivity, methanol and ethanol are preferred.

[0109] Nitriles refer to organic compounds having a structure represented by RC≡N (where R is an aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, and particularly preferably 1 to 6 carbon atoms), and examples include acetonitrile and propionitrile. From the viewpoint of reactivity, acetonitrile is preferred.

[0110] From the viewpoint of cost and reactivity, the organic solvent is preferably a nitrile, and particularly preferably acetonitrile.

[0111] From the viewpoint of productivity and reactivity, the amount of solvent used relative to 2-(halomethyl)naphthalene is typically 1 to 200 times by weight, preferably 2 to 150 times by weight, and particularly preferably 3 to 100 times by weight.

[0112] <Cyanide>

[0113] Examples of cyaniding agents include inorganic cyaniding agents such as sodium cyanide, potassium cyanide, and lithium cyanide, and organic cyaniding agents such as tetrabutylammonium cyanide. From a reactivity point of view, inorganic cyaniding agents are preferred. Sodium cyanide and potassium cyanide are preferred as inorganic cyaniding agents, and sodium cyanide is particularly preferred from a reactivity point of view.

[0114] From a reactivity point of view, the amount of cyaniding agent used relative to 1 mol of 2-(halomethyl)naphthalene is usually 1 mol to 10 mol, preferably 1 mol to 5 mol, and particularly preferably 1 mol to 2 mol.

[0115] <Reaction Conditions>

[0116] (Reaction temperature)

[0117] From the viewpoint of reactivity and productivity, the lower limit of the reaction temperature of the cyanidation process of the present invention is generally 0°C or higher, preferably 20°C or higher, and particularly preferably 40°C or higher, and the upper limit is generally 100°C or lower, preferably 90°C or lower, and particularly preferably 80°C or lower.

[0118] (Reaction time)

[0119] The reaction time of the cyanidation process of the present invention is typically 0.1 hours to 24 hours, preferably 1 hour to 12 hours.

[0120] (Reaction pressure)

[0121] The lower limit of the reaction pressure in the cyanidation process of the present invention is generally above 0.1 MPa, and the upper limit is generally below 1 MPa.

[0122] (Supply Methods)

[0123] The order in which 2-(halomethyl)naphthalene, the cyaniding agent, and the solvent are supplied can be appropriately selected. In the case of using a batch reactor, for example, a mixture of 2-(halomethyl)naphthalene and the solvent can be used as a pretreatment solution, and a mixture of the cyaniding agent and the solvent can be supplied to carry out the reaction under the reaction conditions.

[0124] When using a flow synthesis reactor, the raw materials can be supplied either all at once or in multiple batches. For example, a mixture of 2-(halomethyl)naphthalene, a cyaniding agent, and a solvent can be supplied to the flow synthesis reactor under reaction conditions and the reaction can proceed. Alternatively, a mixture of cyaniding agent and solvent can be supplied to the flow synthesis reactor while circulating the mixture of 2-(halomethyl)naphthalene and solvent in the flow synthesis reactor and the reaction can proceed.

[0125] <Reaction Mode>

[0126] The reaction can be carried out through either a batch reaction or a flow reaction, as described above.

[0127] <Reactor>

[0128] The reactor can be either a flow synthesis reactor or a batch reactor as described above.

[0129] <Post-processing>

[0130] 2-Naphthylacetonitrile, the target compound, is separated from the reaction solution obtained through the cyanidation process of this invention using conventional methods. Separation can be performed, for example, by neutralizing, separating, concentrating, or filtering the obtained reaction solution, or by known purification methods such as crystallization or column chromatography.

[0131] Example

[0132] Next, the present invention will be further described in detail through examples, but the following examples are not limited to the scope of the invention. In the following examples and comparative examples, unless otherwise stated, the reaction time is the light irradiation time. In addition, the conversion rate and selectivity are calculated according to the following formulas. In the formula, A(C) represents the area ratio (%) of the analytical result of compound C under analytical condition 1. For example, A(2MN) represents the area ratio (%) of the 2MN area value of the analytical result under analytical condition 1 to the total area value.

[0133] [Formula for calculating conversion rate]

[0134]

[0135] [Formula for calculating the selection rate]

[0136]

[0137] [abbreviation]

[0138] In this specification, the abbreviations refer to the following compounds.

[0139] 2MN: 2-Methylnaphthalene

[0140] 2XMN: 2-(halomethyl)naphthalene

[0141] 2BMN: 2-(bromomethyl)naphthalene

[0142] 2DBMN: 2-(dibromomethyl)naphthalene

[0143] 1BMN: 1-Bromo-2-methylnaphthalene

[0144] 1B2BMN: 2-(bromomethyl)-1-bromonaphthalene

[0145] NpAN: 2-Naphthylacetonitrile

[0146] DCM: Dichloromethane

[0147] DCE: Dichloroethane

[0148] MeCN: Acetonitrile

[0149] c-Hex: Cyclohexane

[0150] AT: Acetone

[0151] AcOMe: Methyl acetate

[0152] IPA: Isopropyl alcohol

[0153] NBS: N-bromosuccinimide

[0154] DMDBH: 1,3-Dibromo-5,5-dimethylhydantoin

[0155] [Flow Synthesis Reactor]

[0156] In the embodiments and comparative examples, the following methods are used: Figure 1 The commercially available flow synthesis reactor shown is a "Photo Flow System T-1" manufactured by Asahi Labs Trading Co., Ltd., with a capacity of 6 mL.

[0157] [light source]

[0158] In the examples and comparative examples, the light sources used for illumination are shown in Table 1. It should be noted that the range of emission wavelengths includes a measurement error of approximately ±10 nm.

[0159] [Table 1]

[0160]

[0161] [Analysis Methods]

[0162] In the following examples and comparative examples, the apparatus and conditions used in the analysis of the reaction solutions are shown in Tables 2 and 3.

[0163] [Analytical Method 1 (HPLC)]

[0164] [Table 2]

[0165]

[0166] [Analytical Method 2 (HPLC)]

[0167] [Table 3]

[0168]

[0169] [Example 1]

[0170] A mixed solution (2MN: 0.1 mol / L, NBS: 0.105 mol / L) of 2MN and NBS dissolved in DCM was supplied to a flow synthesis reactor with a jacket temperature maintained at 20°C under air atmosphere and illumination by light source 1 for a reaction time of 25 minutes, allowing the solution to circulate and react. A diaphragm pump was used to maintain the supply rate of the mixed solution at 240 μL / min.

[0171] The results of the analysis of the obtained reaction solution using analytical method 1 are shown in Table 4. The obtained reaction solution contains 2BMN (chemical purity 94.2%, selectivity 100.0%).

[0172] 2BMN:

[0173] 1 H-NMR (400MHz, CDCL3): δ7.84-7.80(m,4H),7.52-7.48(m,3H),4.67(s,2H)

[0174] [Examples 2-4]

[0175] In Example 1, the type of organic solvent, the concentration of 2MN, and the amount of halogenating agent were changed as shown in Table 4, but the reaction was carried out in the same manner as in Example 1. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 4.

[0176] [Comparative Examples 1-3]

[0177] In Example 1, the type of organic solvent, the concentration of 2MN, and the amount of halogenating agent were changed as shown in Table 4, but the reaction was carried out in the same manner as in Example 1. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 4.

[0178] [Table 4]

[0179]

[0180] As can be seen from Examples 1-4 and Comparative Examples 1-3 in Table 4, 2BMN can be obtained with high conversion and high selectivity by using halogenated hydrocarbons or aliphatic hydrocarbons as organic solvents.

[0181] When MeCN, used in Non-Patent Literature 2, was employed as the organic solvent to obtain 2BMN, 2BMN, the target compound, was unexpectedly not obtained (Comparative Example 1). When AT was used as the organic solvent, a large amount of 1BMN with a brominated naphthalene ring was generated, indicating poor selectivity (Comparative Example 2). When IPA was used as the organic solvent, the reaction did not proceed (Comparative Example 3).

[0182] [Examples 5-6]

[0183] In Example 1, the type and amount of halogenating agent were changed as shown in Table 5, and the reaction was otherwise carried out in the same manner as in Example 1. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 5.

[0184] [Table 5]

[0185]

[0186] As can be seen from Examples 5-6 in Table 5, even when using brominating agents other than NBS, 2BMN can be obtained with high conversion rate and high selectivity.

[0187] [Examples 7-8]

[0188] In Example 1, the light source was changed as shown in Table 6, and the reaction was otherwise carried out in the same manner as in Example 1. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 6.

[0189] [Table 6]

[0190]

[0191] As can be seen from Examples 7-8 in Table 6, even with changes in the light source, 2BMN can be obtained with high conversion rate and high selectivity.

[0192] [Examples 9-10]

[0193] In Example 1, the reaction temperature and residence time were varied as shown in Table 7, but the reaction was otherwise performed in the same manner as in Example 1. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 7.

[0194] [Table 7]

[0195]

[0196] As can be seen from Examples 9-10 in Table 7, regardless of whether the reaction temperature is low or high, 2BMN can be obtained with high conversion rate and high selectivity by appropriately changing the reaction time.

[0197] [Examples 11-13]

[0198] In Example 1, the solvent type and reaction time were changed as shown in Table 8, but the reaction was otherwise performed in the same manner as in Example 1. The resulting reaction solution was analyzed in the same manner as in Example 1, and the results are shown in Table 8.

[0199] [Table 8]

[0200]

[0201] As can be seen from Examples 11-13 in Table 8, 2BMN can be obtained with high conversion and high selectivity even when using methyl acetate solvent.

[0202] [Example 14]

[0203] In Example 12, the reaction atmosphere was changed as shown in Table 9, but the reaction was otherwise carried out in the same manner as in Example 12. The resulting reaction solution was analyzed using analytical method 2, and the results are shown in Table 9.

[0204] [Table 9]

[0205]

[0206] As can be seen from Examples 12 and 14 in Table 9, 2BMN can be obtained with high conversion rate and high selectivity by carrying out the reaction in an oxygen-containing atmosphere.

[0207] [Examples 15-21]

[0208] In Example 12, the 2MN concentration, the amount of halogenating agent used, the reaction temperature, and the reaction time were varied as shown in Table 10, but the reaction was carried out in the same manner as in Example 12. The resulting reaction solution was analyzed in the same manner as in Example 12, and the results are shown in Table 10.

[0209] [Table 10]

[0210]

[0211] As can be seen from Examples 15-21 in Table 10, 2BMN can be obtained with high selectivity and high efficiency by appropriately changing the reaction temperature and reaction time.

[0212] [Example 22]

[0213] A mixed solvent of 32 mL acetonitrile and 8 mL water was added to a closed glass reactor equipped with a condenser, a heating jacket, and a stirrer. Then, 8.00 g (36.18 mmol) of 2BMN and 2.12 g (43.42 mmol) of sodium cyanide were added. The jacket temperature was raised to 60 °C with stirring, and the reaction was carried out at this temperature for 4 hours.

[0214] The results of analysis of the obtained reaction solution using analytical method 2 showed that the obtained reaction solution contained NpAN as the main product (conversion rate 99.1%).

[0215] NpAN:

[0216] 1H-NMR (400MHz, CDCL3): δ7.87-7.83(m,4H),7.54-7.50(m,2H),7.39(dd,J=6.5Hz,10.5Hz,1H),3.92(s,2H)

[0217] Industrial availability

[0218] According to the method for producing 2-(halomethyl)naphthalene of the present invention, 2-(halomethyl)naphthalene, useful as a synthetic raw material or synthetic intermediate for pharmaceuticals, can be safely and inexpensively produced from 2-methylnaphthalene with high conversion and high selectivity and efficiency. Furthermore, according to the method for producing 2-naphthoacetonitrile of the present invention, 2-naphthoacetonitrile, useful as a synthetic raw material or synthetic intermediate for pharmaceuticals, can be safely and inexpensively produced from 2-methylnaphthalene with high conversion and high selectivity and high yield. The 2-(halomethyl)naphthalene and 2-naphthoacetonitrile obtained in the present invention can be used as synthetic raw materials or synthetic intermediates for various pharmaceuticals, and are therefore industrially useful.

[0219] Symbol Explanation

[0220] 1. Preparation tank

[0221] 2 pumps

[0222] 3. Flow-through reactor

[0223] 4. Light Irradiation Mechanism

[0224] 5 Recycling Tanks

[0225] 6. Preparation tank (cyanidation process)

[0226] 7 pumps (cyanidation process)

[0227] 8. Flow-through reactor (cyanidation process)

[0228] 9. Recovery tank (cyanidation process)

Claims

1. A method for manufacturing 2-(halogenated methyl)naphthalene of general formula (1), comprising a halogenation step of reacting 2-methylnaphthalene with a halogenating agent in an organic solvent selected from halogenated hydrocarbons, aliphatic esters and aliphatic hydrocarbons under light irradiation at -20°C to 55°C. In the formula, X represents a halogen atom. The halogenated hydrocarbon is dichloromethane or dichloroethane. The aliphatic ester is methyl acetate or ethyl acetate. The aliphatic hydrocarbon is n-pentane, n-hexane, n-heptane, or n-octane. The halogenation process is carried out using a flow synthesis reactor.

2. The manufacturing method according to claim 1, wherein, The halogenating agent is a brominating agent.

3. The manufacturing method according to claim 1, wherein, The light irradiation is performed using light with a wavelength of 280nm to 700nm.

4. The manufacturing method according to claim 2, wherein, The light irradiation is performed using light with a wavelength of 280nm to 700nm.

5. The manufacturing method according to any one of claims 1 to 4, wherein, The reaction was carried out in the absence of additives.

6. A method for manufacturing 2-naphthylacetonitrile, comprising: A halogenation process in which 2-methylnaphthalene reacts with a halogenating agent in an organic solvent selected from halogenated hydrocarbons, aliphatic esters, and aliphatic hydrocarbons under light irradiation at a temperature of -20°C to 55°C; and A cyanidation process in which 2-(halogenated methyl)naphthalene, represented by general formula (1) obtained in the halogenation process, is reacted with a cyaniding agent in a solvent. In the formula, X represents a halogen atom. The halogenated hydrocarbon is dichloromethane or dichloroethane. The aliphatic ester is methyl acetate or ethyl acetate. The aliphatic hydrocarbon is n-pentane, n-hexane, n-heptane, or n-octane. The halogenation process is carried out using a flow synthesis reactor.

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