[Technical Field]
[0001]
The present invention relates to methods for producing 2-
(halogenated methyl)naphthalenes and 2-naphthylacetonitrile
10 useful as synthetic intermediates for pharmaceuticals and the
like.
[Background Art]
[0002]
2-(Halogenated methyl)naphthalenes are useful as
15 synthetic raw materials or synthetic intermediates for various
pharmaceuticals, agrochemicals, chemical products and the like.
Naphthalene compounds having chemical structures similar to 2-
(halogenated methyl)naphthalenes are also expected to be used
as synthetic raw materials or synthetic intermediates for
20 various pharmaceuticals, agrochemicals and chemical products.
For example, 2-(halogenated methyl)naphthalenes, and 2-
naphthylacetonitrile having a chemical structure similar
thereto are useful as synthetic raw materials or synthetic
intermediates for therapeutic drugs for attention deficit
25 hyperactivity disorder (ADHD). Specifically, for example, 2-
(halogenated methyl)naphthalenes and 2-naphthylacetonitrile can
be preferably used as synthetic raw materials or synthetic
intermediates for (1R,SS)-1-(naphthalen-2-yl)-3-
azabicyclo[3.1.0]hexane (common name: Centanafadine).
30 Batch reaction methods are known as conventional
production methods for producing 2-(halogenated
methyl)naphthalenes. For example, a method for producing 2-
(bromomethyl)naphthalene by placing 2-methylnaphthalene, Nbromosuccinimide,
dichloromethane, benzene and trityl
35 fluoroborate in a batch reactor, and then subjecting the
1
3
mixture to a photoreaction under light irradiation at room
temperature is known (Non-Patent Document 1) . Photoreaction
refers to all chemical reactions in which molecules are excited
to a higher energy level state by absorbing energy through
5 light irradiation, and the excited molecules cause a reaction,
and it is also called photochemical reaction.
10
[0003]
[0004]
NBS
TrBF4
Light
Benzene
Batch reactor
However, the method described in Non-Patent Document 1 is
a reaction using benzene solvent, and the industrial use of
benzene solvent is extremely difficult for safety reasons, and
the yield of the obtained 2-(bromomethyl)naphthalene is also
not industrially satisfactory. Therefore, a safer, more
15 productive and industrial production method is desired.
In recent years, continuous halogenation reaction methods
for increasing productivity are known. For example, a method
for continuously producing 4-tert-butylbenzyl bromide by
subjecting a solution prepared by mixing 4-tertbutyltoluene and
20 N-bromosuccinimide in an acetonitrile solvent, to
photoirradiation in a flow photochemical reactor is known (NonPatent
Document 2).
[0005]
25 [0006]
NBS
Light
MeCN
Flow reactor
Br
However, as is clear from Comparative Example 1 below, it
was found that the replacement of 4-tert-butyltoluene, the
substrate described in Non-Patent Document 2, with 2-
2
4
methylnaphthalene did not yield the target compound 2-
(bromomethyl)naphthalene with high selectivity, but instead
undesirable 1-bromo-2-methylnaphthalene as the major product.
Therefore, for production of 2-(halogenated
5 methyl)naphthalenes in high yield, a production method that
enables highly selective halogenation of the methyl at the 2-
position of 2-methylnaphthalene is desired.
[0007]
Non-Patent Document 3 describes the production of 2-
10 naphthylacetonitrile by subjecting 2-(halogenated
methyl)naphthalenes to cyanation.
[Citation List]
[Non-Patent Document]
[0008]
15 [Non-Patent Document 1] Adv. Synth. Catal. (2018) 4197-4204
[Non-Patent Document 2] JOC. ( 2014) 223-22 9
[Non-Patent Document 3] Tetrahedron Letters 56 (2015) 2054-2058
[Summary of Invention]
[Problems to be solved by the Invention]
20 [0009]
The present invention aims to provide a method for
producing 2-(halogenated methyl)naphthalenes, and a method for
producing 2-naphthylacetonitrile therefrom, both safely and
inexpensively with high selectivity in good yield.
25 [Means of Solving the Problems]
[0010]
The present inventors have conducted intensive studies
and found that the reaction of 2-methylnaphthalene with a
halogenating agent in a specific organic solvent under light
30 irradiation yields 2-(halogenated methyl)naphthalenes and then·
2-naphthylacetonitrile therefrom, both safely and inexpensively
with high selectivity in good yield, which resulted in the
completion of the present invention. Accordingly, the present
invention is characterized by the following
35 [ 0 011]
3
5
[1] A method for producing a 2-(halogenated methyl)naphthalene
represented by general formula (1):
[0012]
X (1)
5 [0013]
wherein X is a halogen atom,
which comprises a halogenation process of reacting 2-
methylnaphthalene with a halogenating agent under light
irradiation, in an organic solvent selected from a halogenated
10 hydrocarbon, an aliphatic ester and an aliphatic hydrocarbon.
[2] The method according to the above [1], wherein the
halogenating agent is a brominating agent.
[3] The method according to [1] or [2], wherein the light
irradiation is performed using light with a wavelength of 280
15 nm to 700 nm.
[4] The method according to any one of [1] to [3], wherein the
reaction is carried out within the range of -20°C to 100°C.
[5] The method according to any one of [1] to [4], wherein the
reaction is carried out in the absence of an additive.
20 [6] The method according to any one of [1] to [5], wherein the
reaction is carried out by flow synthesis reaction.
[7] A method for producing 2-naphthylacetonitrile, which
comprises
a halogenation process of reacting 2-methylnaphthalene with a
25 halogenating agent under light irradiation, in an organic
solvent selected from a halogenated hydrocarbon, an aliphatic
ester and an aliphatic hydrocarbon; and
a cyanation process of reacting the 2-(halogenated
methyl)naphthalene obtained in the halogenation process and
30 represented by general formula (1):
[0014]
4
6
X (1)
[0015]
wherein X is a halogen atom,
with a cyanating agent, in a solvent.
5 [Effect of the Invention]
[0016]
According to the method for producing 2-(halogenated
methyl)naphthalenes of the present invention, 2-(halogenated
methyl)naphthalenes can be produced safely and inexpensively
10 with high selectivity in good yield. Moreover, according to
the method for producing 2-naphthylacetonitrile of the present
invention, 2-naphthylacetonitrile can be produced safely and
inexpensively with high selectivity in good yield.
[Brief Description of Drawings]
15 [0017]
[Figure 1]
Figure 1 is a system diagram of a flow synthesis reactor
showing one example of embodiments of the method for producing
2-(halogenated methyl)naphthalenes of the present invention.

[Claim 1]
A method for producing a 2-(halogenated
5 methyl)naphthalene represented by general formula (1):
X (1)
wherein X is a halogen atom,
which comprises a halogenation process of reacting 2-
methylnaphthalene with a halogenating agent under light
10 irradiation, in an organic solvent selected from a halogenated
hydrocarbon, an aliphatic ester and an aliphatic hydrocarbon.
[Claim 2]
The method according to claim 1, wherein the halogenating
agent is a brominating agent.
15 [Claim 3]
20
The method according to claim 1 or 2, wherein the light
irradiation is performed using light with a wavelength of 280
nm to 700 nm.
[Claim 4]
The method according to any one of claims 1 to 3, wherein
the reaction is carried out within the range of -20°C to 100°C.
[Claim 5]
The method according to any one of claims 1 to 4, wherein
the reaction is carried out in the absence of an additive.
25 [Claim 6]
The method according to any one of claims 1 to 5, wherein
the reaction is carried out by flow synthesis reaction.
[Claim 7]
A method for producing 2-naphthylacetonitrile, which
30 comprises
a halogenation process of reacting 2-methylnaphthalene with a
halogenating agent under light irradiation, in an organic
solvent selected from a halogenated hydrocarbon, an aliphatic
38
40
5
ester and an aliphatic hydrocarbon; and
a cyanation process of reacting the 2-(halogenated
methyl)naphthalene obtained in the halogenation process and
represented by general formula (1):
X (1)
wherein X is a halogen atom,
with a cyanating agent, in a solvent.