Specification
Title of the invention: High-purity 2-naphthylacetonitrile and its production method
Technical field
[0001]
The present invention relates to high-purity 2-naphthylacetonitrile useful as raw materials and intermediates for synthesizing various pharmaceuticals, agricultural chemicals, chemical products, etc., and a method for producing the same.
Background technology
[0002]
　2-Naphthylacetonitrile is useful as a synthetic raw material and synthetic intermediate for various pharmaceuticals, agricultural chemicals, and chemical products. Aromatic nitrile compounds having chemical structures similar to 2-naphthylacetonitrile are also expected to be used as raw materials and intermediates for synthesizing various pharmaceuticals, agricultural chemicals, and chemical products.
[0003]
For example, 2-naphthylacetonitrile is useful for depression (eg, major depressive disorder, bipolar disorder), fibromyalgia, pain (eg, neuropathic pain), sleep disorders, attention deficit disorder (ADD), attention deficit activity. disorders (ADHD), restless leg syndrome, schizophrenia, anxiety, obsessive-compulsive disorder, post-traumatic stress disorder, seasonal affective disorder (SAD), premenstrual imbalance, neurodegenerative diseases (e.g. Parkinson's disease, Alzheimer's disease) disease), diseases related to urinary incontinence and irritable bowel syndrome (IBS), drugs used for the prevention and treatment of diabetes, etc., erythropoietin (EPO) inducers, calcium antagonists, histamine receptor antagonists, tachykinin receptor antagonists 12-lipoxygenase inhibitors, protein kinase C (PKC) inhibitors, PDE IV inhibitors, etc.
[0004]
2-Naphthylacetonitrile is, in particular, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3. 1.0] hexane can be suitably used as a raw material or an intermediate for the production of hexane.
[0005]
As a method for producing 2-naphthylacetonitrile, for example, a method of producing 2-(bromomethyl)naphthalene by bromination of 2-methylnaphthalene and reacting it with potassium cyanide is known (Non-Patent Document 1). .
[0006]
[Chemical 1]

[0007]
However, this method is not preferable as an industrial production method due to the low yield, the generation of many by-products due to bromination, and the use of highly toxic compounds such as carbon tetrachloride and potassium cyanide.
[0008]
Furthermore, a method of synthesizing nitrile compounds from aromatic carboxylic acids, aromatic carboxylic acid derivatives, etc. has also been reported (Non-Patent Document 2).
Non-Patent Document 2 describes a method of dissolving carboxylic acid halides and sulfamides having various structures such as aromatic rings in sulfolane and reacting them to convert them into nitrile compounds.
However, the method of Non-Patent Document 2 has a low yield depending on the substrate, and further improvement is required as an industrial production method.
[0009]
Non-Patent Document 3 reports a method for synthesizing aromatic carboxylic acids and aromatic thioamides from aromatic ketones by the Wilgerott reaction.
However, these methods do not yield sufficient yields, and since sulfur is used in the Wilgerott reaction, the resulting aromatic carboxylic acid, etc. is thought to contain a large amount of sulfur, so it is not suitable as an industrial production method. , further improvement is required.
In addition, 2-naphthylacetonitrile obtained by these methods is considered to contain about several percent of by-products such as sulfur, amide compounds, and thioamide compounds, judging from these production methods and their yields.
prior art documents
patent literature
[0010]
Patent Document 1: WO2007/016155
Patent Document 2: WO2015/089111
Patent Document 3: WO2015/102826
Non-patent literature
[0011]
Non-Patent Document 1: Tetrahedron Letters 56 (2015) 2054-2058
Non-Patent Document 2: Tetrahedron Letters, Vol.23, No.14, pp.1505-1508, 1982
Non-Patent Document 3: Synthetic Communications, Vol.33, No.1, pp.59-63, 2003
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0012]
The present invention provides a method for producing high-purity 2-naphthylacetonitrile that has few impurities, is safe and highly efficient, and can be produced inexpensively on an industrial scale.
Means to solve problems
[0013]
In order to solve the above problems, the present inventors have developed aromatic carboxylic acid compounds such as 2-naphthylacetic acid from relatively inexpensive and versatile aromatic ketone compounds such as 2′-acetonaphthone by utilizing Willgerott rearrangement. Furthermore, a method for producing an aromatic nitrile compound such as 2-naphthylacetonitrile in high yield and high purity from the aromatic carboxylic acid compound was found (International Application No. PCT/JP2019/018065).
Here, in general, raw materials and intermediates for the synthesis of pharmaceuticals are required to have a high degree of purity so that the impurities contained in them do not cause unexpected side effects. Impurities include, for example, by-products generated during their manufacture. In some cases, by-products can be removed in the refining or manufacturing process of the target drug. is desired to be further reduced, and high-purity raw materials and intermediates for synthesizing pharmaceuticals with fewer impurities are desired.
As a result of studies by the present inventors, they have found that 2-naphthylacetonitrile obtained by the production method described in the international application contains less by-products than conventionally known methods, and have arrived at the present invention.
In addition, the present inventors further studied the manufacturing method.
[0014]
That is, the gist of the present invention is as follows.
[1] The HPLC purity of 2-naphthylacetonitrile is 95 area % or more, contains one or more selected from naphthalene compounds represented by the following formulas (a) to (j) as impurities, and contains each naphthalene compound High-purity 2-naphthylacetonitrile, the amounts of which are respectively as follows:
[0015]
[Chemical 2]

[0016]
[2] The composition according to [1], which contains one or more selected from naphthalene compounds represented by the following formulas (a) to (d) as impurities, and the content of each naphthalene compound is as follows. High purity 2-naphthylacetonitrile.
[0017]
[Chemical 3]

[0018]
[3] The high-purity 2- according to [1], which contains a naphthalene compound represented by the following formula (c) as an impurity, and the content of the naphthalene compound represented by the formula (c) is 1 area % or less. Naphthylacetonitrile.
[0019]
[Chemical 4]

[0020]
[4] General formula (5) below
[0021]
[Chemical 5]

[0022]
(In general formula (5), X represents a halogen atom.)
and a reaction raw material 2 containing sulfamide and a second organic solvent are mixed at 15°C to 90°C, and the temperature is raised to 80°C. A method for producing high-purity 2-naphthylacetonitrile, wherein the reaction is performed at ~180°C to obtain 2-naphthylacetonitrile.
[5] The high-purity 2-naphthylacetonitrile according to [4], characterized in that the reaction raw material 1 is added to the reaction raw material 2 at 15°C to 90°C, and the temperature is raised to react at 80°C to 180°C. manufacturing method.
[6] For 1 mol of sulfamide, the above general formula (5)
[0023]
[Chemical 6]

[0024]
The production of high-purity 2-naphthylacetonitrile according to [5], characterized in that the reaction raw material 1 is added to the reaction raw material 2 so that the amount of the acid halogen compound represented by is 0.0027 mol/min or more. Method.
[7] Reaction raw material 1 is obtained by mixing 2-naphthylacetic acid, a halogenating agent and a first organic solvent, optionally in the presence of a catalyst, [4]-[6] A method for producing high-purity 2-naphthylacetonitrile according to any one of.
[8] A method for producing high-purity 2-naphthylacetonitrile, characterized by including the following steps 1 and 2.
Step 1:
A step of hydrolyzing an amide compound obtained by subjecting 2'-acetonaphthone to a Wilgerott reaction in the presence of an additive, if necessary, and then liberating 2-naphthylacetic acid to obtain 2-naphthylacetic acid;
Step 2:
A reaction raw material 1 containing 2-naphthylacetic acid obtained in step 1, a halogenating agent and a first organic solvent, and a reaction raw material 2 containing sulfamide and a second organic solvent are mixed and reacted to give 2-naphthyl. Obtaining acetonitrile.
[9] of [4] to [7], wherein the first organic solvent is a hydrocarbon solvent, an amide solvent, a sulfone solvent, or a mixed solvent thereof, and the second organic solvent is a sulfone solvent; A method for producing high-purity 2-naphthylacetonitrile according to any one.
[0025]
In addition, the present invention relates to the following.
[1A] High-purity 2-naphthylacetonitrile having an HPLC purity of 95 area % or more, and containing the naphthalene compounds represented by the following formulas (a) to (i) as follows.
[0026]
[Chemical 7]

[0027]
[2A] A method for producing high-purity 2-naphthylacetonitrile, comprising the following steps 1A and 2A.
Step 1A:
A step of hydrolyzing an amide compound obtained by subjecting 2'-acetonaphthone to a Wilgerott reaction in the presence of an additive, if necessary, and then neutralizing it to obtain 2-naphthylacetic acid;
Step 2A:
2-naphthylacetic acid obtained in step 1A, a halogenating agent and the following general formula (7)
R 1SO 2R 2 (7)
(In the formula, R 1 and R 2 each independently represent a chlorine atom, hydroxyl group, amino group, isocyanate group or p-tolyl group.)
A step of reacting a compound represented by optionally in the presence of a catalyst in an organic solvent to obtain 2-naphthylacetonitrile.
[0028]
[3A] The above step 2A is
2-naphthylacetic acid obtained in step 1A, a halogenating agent, a first organic solvent and, if necessary, a reaction raw material 1 mixed with a catalyst, the compound represented by the general formula (7), and a second organic The method for producing high-purity 2-naphthylacetonitrile according to [2A], which is a step of obtaining 2-naphthylacetonitrile by mixing and reacting reaction raw materials 2 mixed with a solvent.
[0029]
[4A] The high-purity 2-naphthylacetonitrile according to [3A], wherein the first organic solvent is a hydrocarbon solvent, a sulfone solvent, or a mixture thereof, and the second organic solvent is a sulfone solvent. manufacturing method.
[0030]
[5A] The above step 2A is
2-naphthylacetic acid obtained in step 1A, a halogenating agent, a first organic solvent and, if necessary, a reaction raw material 1 mixed with a catalyst, the compound represented by the general formula (7), and a second organic [3A], characterized in that the reaction raw material 2 mixed with a solvent is mixed at 15 ° C. to 90 ° C., and then the temperature is raised and reacted at 80 ° C. to 180 ° C. to obtain 2-naphthylacetonitrile. A method for producing high-purity 2-naphthylacetonitrile.
[0031]
[6A] Step 2A is
2-naphthylacetic acid obtained in step 1A, a halogenating agent, a first organic solvent and, if necessary, a reaction raw material 1 mixed with a catalyst, the compound represented by the general formula (7) and the second organic A step of adding to reaction raw material 2 mixed with a solvent and reacting to obtain 2-naphthylacetonitrile,
With respect to 1 mol of the compound represented by the general formula (7) contained in the reaction raw material 2, the following general formula (5)
[0032]
[Chemical 8]

[0033]
(In general formula (5), X represents a halogen atom.)
The method for producing high-purity 2-naphthylacetonitrile according to [3A], wherein the reaction raw material 1 is added to the reaction raw material 2 so that the amount of the acid halogen compound represented by is 0.0027 mol/min or more. .
[0034]
[7A] In the above step 1A, after the hydrolysisThe reaction product obtained by the above is brought into contact with a hydrocarbon solvent, the hydrocarbon solvent is present during the neutralization, or the reaction product obtained by the neutralization is brought into contact with the hydrocarbon solvent. The method for producing high-purity 2-naphthylacetonitrile according to [2A].
Effect of the invention
[0035]
According to the present invention, it is possible to provide high-purity 2-naphthylacetonitrile with few impurities, which is useful as raw materials and intermediates for the synthesis of various pharmaceuticals, agricultural chemicals, and chemical products, especially as raw materials and intermediates for the synthesis of pharmaceuticals. In addition, it is possible to provide a method for producing high-purity 2-naphthylacetonitrile that is safe, highly efficient, and industrially mass-produced at low cost. Furthermore, by using 2-naphthylacetonitrile of the present invention, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane and the like can be obtained industrially and in large quantities at low cost. Pharmaceuticals can be manufactured.
Brief description of the drawing
[0036]
1] FIG. 1 is a diagram showing the HPLC analysis results of 2-naphthylacetonitrile obtained in Example 1. [FIG.
2] FIG. 2 is a diagram showing the HPLC analysis results of 2-naphthylacetonitrile obtained in Example 3. [FIG.
MODE FOR CARRYING OUT THE INVENTION
[0037]
The present invention will be described in detail below.
High-purity 2-naphthylacetonitrile of the present invention
The high-purity 2-naphthylacetonitrile of the present invention contains less specific by-products (impurities) than before. Specifically, the HPLC purity of 2-naphthylacetonitrile is 95 area % or more, and the contents of the naphthalene compounds represented by the following formulas (a) to (j) are as shown in Table 1.
[0038]
[table 1]

[0039]
The compounds represented by the above formulas (a), (b), (c), (d) and (h) are impurities that are difficult to remove by purification operations such as solid-liquid separation by crystallization and column purification. And from the viewpoint of refining cost, it is preferable to suppress the production amount.
The compounds represented by the above formulas (e), (f), (g), (i) and (j) are highly reactive and may cause side reactions, so they should not remain in 2-naphthylacetonitrile. is preferred.
The HPLC purity of the high-purity 2-naphthylacetonitrile of the present invention is preferably 97 area% or more, more preferably 98 area% or more, and particularly preferably 99 area% or more.
The content of the naphthalene compound represented by the formula (a) is preferably 0.25 area % or less, more preferably 0.2 area % or less, still more preferably 0.15 area % or less, and particularly preferably 0.25 area % or less. It is 1 area % or less.
The content of the naphthalene compounds represented by the above formulas (b) and (d) is preferably 0.08 area% or less, more preferably 0.05 area% or less, and still more preferably 0.03 area% or less. , and particularly preferably 0.01 area % or less.
The content of the naphthalene compound represented by the above formula (c) is preferably 0.8 area % or less, more preferably 0.5 area % or less, still more preferably 0.3 area % or less, and particularly preferably 0.5 area % or less. It is 1 area % or less.
The content of the naphthalene compounds represented by formulas (e), (f) and (h) is preferably 0.03 area % or less, more preferably 0.02 area % or less, and still more preferably 0.02 area % or less. 01 area % or less, particularly preferably 0.005 area % or less.
The content of the naphthalene compound represented by the formula (g) is preferably 0.08 area % or less, more preferably 0.05 area % or less, still more preferably 0.03 area % or less, and particularly preferably 0.05 area % or less. 01 area % or less.
The content of the naphthalene compounds represented by the above formulas (i) and (j) is preferably 0.03 area % or less, more preferably 0.02 area % or less, still more preferably 0.01 area % or less, especially Preferably, it is 0 area %.
The content of the naphthalene compound represented by the following formula is preferably 0.08 area % or less, more preferably 0.05 area % or less, still more preferably 0.03 area % or less, and particularly preferably 0.01 area %. area % or less.
[0040]
[Chemical 9]

[0041]
Since the high-purity 2-naphthylacetonitrile of the present invention has a low content of impurities, it can be used as it is as a raw material or intermediate for synthesizing pharmaceuticals without purification. useful as raw materials and intermediates for the synthesis of
Of the impurities in the high-purity 2-naphthylacetonitrile of the present invention, the naphthalene compound represented by the above formula (c), which has the highest content, can be suppressed from being produced by the production method of the present invention, which will be described later.
Table 2 shows the relative retention times (RRT) of the naphthalene compounds represented by the above formulas (a) to (h). Note that the relative retention time may differ by about ±0.05 depending on the HPLC measurement conditions.
[0042]
[Table 2]

[0043]
In the present invention, the purity and impurity content of 2-naphthylacetonitrile can be measured by the peak area ratio in high performance liquid chromatography (HPLC), which is a well-known method in the field of analytical chemistry. The HPLC measurement conditions can be selected as appropriate, but are preferably the conditions shown below.
Analytical instrument: Agilent HPLC (1200 series)
Column: Zorbax Eclipse Plus Phenyl-Hexyl, 5 μm, 250 mm × 4.6 mm
　Mobile phase A: 0.1% by volume trifluoroacetic acid aqueous solution
　Mobile phase B: acetonitrile
Gradient: 0 minutes (B: 30%) - 15 minutes (B: 60%) - 20 minutes (B: 95%) - 30 minutes (B: 95%)
　Flow rate: 1.0 mL/min
　Injection volume: 5 μL
　Detection wavelength: 280 nm
　Column temperature: 40℃
[0044]
The color tone of the high-purity 2-naphthylacetonitrile of the present invention is white to brown, preferably white to light brown. The water content of the high-purity 2-naphthylacetonitrile of the present invention is usually 2.0% by weight or less, preferably 1.5% by weight or less, and more preferably 1.0% by weight or less.
In addition, the high-purity 2-naphthylacetonitrile of the present invention uses sulfur and organic solvents in the manufacturing process, but the content of these is also small. The sulfur content of the high-purity 2-naphthylacetonitrile of the present invention is usually 0.5 area% or less, preferably 0.3 area% or less, more preferably 0.1 area% or less, particularly preferably 0.05 area%. It is below. The content of organic solvents such as sulfolane and toluene is usually 0.5% by weight or less, preferably 0.3% by weight or less, more preferably 0.1% by weight or less, and particularly preferably 0.05% by weight or less. .
As described above, the high-purity 2-naphthylacetonitrile of the present invention has a high HPLC purity of 95 area% or more, more preferably 98 area% or more, and contains impurities than 2-naphthylacetonitrile produced by a conventionally known method. Since the amount is small, high reactivity can be expected when used as a raw material or intermediate for synthesizing pharmaceuticals. In addition, the high-purity 2-naphthylacetonitrile of the present invention has excellent solubility and a high dissolution rate in organic solvents. Therefore, the high-purity 2-naphthylacetonitrile of the present invention is useful as a raw material or intermediate for the synthesis of pharmaceuticals that are industrially produced in large quantities.
[0045]
Method for producing high-purity 2-naphthylacetonitrile of the present invention
The method for producing high-purity 2-naphthylacetonitrile of the present invention includes a step of obtaining 2-naphthylacetic acid represented by the following formula (3) from 2'-acetonaphthone represented by the following formula (2) (step 1); A step of obtaining 2-naphthylacetonitrile represented by the following formula (1) from 2-naphthylacetic acid (Step 2).
[0046]
[Chemical 10]

[0047]
<>
Step 1 is a step of subjecting 2′-acetonaphthone represented by formula (2) to a Willgerott reaction and then hydrolyzing the resulting compound to obtain 2-naphthylacetic acid represented by formula (3). .
As used herein, the Willgerott reaction means the Willgerott reaction and the Willgerott-Kindler reaction.
[0048]
[Willgerott reaction]
The Wilgerott reaction can be carried out by reacting sulfur compounds such as sodium sulfide (Na 2S.9H 2O) and ammonium sulfide ((NH 4) 2S) on 2'-acetonaphthone under heating.
[Wilgerott-Kinderler Reaction]
The Wilgerott-Kindler reaction can be performed by reacting 2'-acetonaphthone with sulfur and a secondary amine such as dialkylamine or morpholine under heating.
[0049]

(2'-acetonaphthone)
2'-acetonaphthone may be commercially available or obtained by a known method.
(Sulfur compound)
One type of sulfur compound may be used alone, or two or more types may be used in any combination and ratio.
The amount of sulfur compound used is not particularly limited as long as it is an effective amount for the Wilgerott reaction of 2'-acetonaphthone. The amount of the sulfur compound to be used is generally 1 mol-5 mol, preferably 1 mol-3 mol, per 1 mol of 2'-acetonaphthone.
(sulfur)
The amount of sulfur used is not particularly limited as long as it is effective for the reaction, but it is usually 1 mol to 5 mol, preferably 1 mol to 3 mol, per 1 mol of 2'-acetonaphthone.
(secondary amine)
As the secondary amine, morpholine is preferable for industrial production because the reaction can be efficiently performed without a solvent.
The amount of secondary amine used is not particularly limited as long as it is an amount effective for the reaction. The amount of the secondary amine to be used is generally 1 mol-6 mol, preferably 2 mol-4 mol, per 1 mol of 2'-acetonaphthone.
(solvent)
Step 1 can be carried out without solvent or in an organic solvent inert to the reaction.
Examples of organic solvents include dioxane and N,N-dimethylformamide. One of these organic solvents may be used alone, or two or more thereof may be used in any combination and ratio. Moreover, when performing reaction using a sulfur compound, reaction can be performed also in presence of aqueous solvents, such as water.
[0050]
(Additive)
In step 1, additives may be used as necessary.
Additives include dehydrating agents such as zeolite, molecular sieves, magnesium sulfate, and sodium sulfate. One dehydrating agent may be used alone, or two or more may be used in any combination and ratio. By controlling the amount of water in the reaction system using a dehydrating agent, the reaction can proceed efficiently.
The amount of dehydrating agent used is not particularly limited as long as dehydration proceeds efficiently, but it is usually 1 mol to 5 mol, preferably 1.5 mol to 4 mol, per 1 mol of 2'-acetonaphthone.
Examples of additives include organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, and trifluoroacetic acid. An organic acid may be used individually by 1 type, and may use 2 or more types by arbitrary combinations and ratios. As the organic acid, p-toluenesulfonic acid and methanesulfonic acid are particularly preferred. By using these additives, by-products, especially the following formula
[0051]
[Chemical 11]

[0052]
The formation of the ketothioamide compound represented by is suppressed, and the reaction can proceed efficiently.
The amount of organic acid used is usually 0.01 mol to 5 mol, preferably 0.05 mol to 3 mol, per 1 mol of 2'-acetonaphthone.
In addition, in order to control the amount of water in the reaction system to be small, the reaction may be performed while dehydrating by distillation.
[0053]

(Reaction method)
The production method of the present invention may be batch type or continuous type, but is usually carried out in batch type.
(reaction temperature)
The reaction temperature is usually 90°C to 150°C, preferably 100°C to 140°C, particularly preferably 110°C to 130°C.
(reaction pressure)
The reaction is usually carried out at normal pressure, but even if pressurizedgood.
(reaction time)
The reaction time can be appropriately selected depending on the progress of the reaction, and is usually 1 to 24 hours, preferably 2 to 12 hours.
[0054]

[Hydrolysis]
After the Willgerott reaction, the resulting compound may be subjected to hydrolysis after being separated from the reaction system, or may be subjected to subsequent hydrolysis without separation.
[0055]
In the present invention, after the Willgerott reaction, the resulting compound can be hydrolyzed with a base.
(base)
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkaline earth metal hydrogen carbonates such as calcium hydrogen carbonate; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide and alkali metal alkoxides such as Industrially, it is preferable to use alkali metal hydroxides such as sodium hydroxide and potassium hydroxide in terms of cost and availability. One base may be used alone, or two or more bases may be used in any combination and ratio.
The amount of base used is not particularly limited as long as it is an effective amount for hydrolyzing the compound obtained after the Wilgerott reaction. The amount of the base to be used is generally 1 mol to 10 mol, preferably 1 mol to 5 mol, per 1 mol of the compound obtained after the Willgerrott reaction.
(solvent)
The hydrolysis may be carried out without a solvent or in a solvent such as water, but from the viewpoint of excellent agitation and uniformity, it is preferably carried out in a solvent.
(reaction temperature)
The hydrolysis reaction temperature is not particularly limited as long as it is a temperature at which hydrolysis proceeds. The hydrolysis temperature is usually 80°C to 115°C, preferably 85°C to 110°C.
(reaction pressure)
Hydrolysis is usually performed at normal pressure, but it may be pressurized.
[0056]
[Release reaction]
The reaction product obtained by hydrolysis (eg, 2-naphthylacetic acid or a salt thereof) is reacted with an acid to liberate 2-naphthylacetic acid represented by formula (3).
(acid)
Acids such as hydrochloric acid, sulfuric acid and hydrobromic acid can be used to liberate 2-naphthylacetic acid.
One type of acid may be used alone, or two or more types may be used in any combination and ratio. Industrially, hydrochloric acid is preferable from the viewpoint of reaction efficiency, cost, and the like.
The amount of acid used is not particularly limited as long as it is an effective amount for neutralization. The amount of acid to be used is generally 1 mol to 20 mol, preferably 3 mol to 10 mol, per 1 mol of the reaction product obtained by hydrolysis.
[0057]

(liquid)
The pH of the mixed solution during the liberation reaction of 2-naphthylacetic acid is usually 0-5, preferably 0-3.
(reaction temperature)
The temperature of the liberation reaction is not particularly limited as long as it is the temperature at which the liberation proceeds. The temperature of the liberation reaction is usually 50°C to 90°C, preferably 60°C to 80°C.
(reaction time)
The reaction time is usually 10 minutes to 5 hours, preferably 30 minutes to 2 hours.
(reaction pressure)
The reaction pressure is usually normal pressure, but it may be pressurized.
(supply method)
As for the supply method, the acid may be supplied to the reactor using the reaction product obtained by hydrolysis as a bed liquid, or the reaction product obtained by hydrolysis may be supplied to the reactor using an acid as a bed liquid. Alternatively, the reaction product obtained by hydrolysis and the acid may be supplied at the same time.
[0058]

2-Naphthylacetic acid can be extracted and recovered from the reaction product obtained by the liberation reaction using an organic solvent.
(organic solvent)
Organic solvents include hydrocarbon solvents capable of dissolving 2-naphthylacetic acid. Examples of hydrocarbon solvents include alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene, ethylbenzene and tert-butylbenzene; trifluoromethylbenzene, nitrobenzene, Aromatic halogenated hydrocarbon solvents such as chlorobenzene, chlorotoluene, and bromobenzene can be mentioned. As the hydrocarbon solvent, from the viewpoint of cost, alicyclic hydrocarbon solvents and aromatic hydrocarbon solvents are preferred, and cyclohexane, toluene and xylene are particularly preferred.
The hydrocarbon solvent can be used alone or in combination of two or more at any ratio.
The amount of the organic solvent used is usually 1 to 20 times the volume of 2-naphthylacetic acid, preferably 1.5 to 10 times the volume, and particularly preferably 3 to 5 times the volume.
[0059]
(Purification method)
Since sulfur and sulfur compounds are used in step 1, the resulting reaction product usually contains several mol% or more of sulfur. Sulfur is an impurity in 2-naphthylacetic acid, which is the target product of Step 1, and may reduce the reaction efficiency when chemical reactions are performed using 2-naphthylacetic acid as a raw material, so it should be removed as much as possible. is preferred.
In the present invention, the reaction product obtained by hydrolysis is contacted with a hydrocarbon solvent after the hydrolysis, the hydrocarbon solvent is present during the liberation, or the reaction product obtained by the liberation The sulfur content of 2-naphthylacetic acid obtained in step 1 can be reduced by contacting a hydrocarbon solvent with. When contacting with a hydrocarbon solvent, water, an aqueous solution, or the like may be present as necessary. When contacting with a hydrocarbon solvent, the amount of the hydrocarbon solvent to be used is usually 1-fold to 30-fold, preferably 3-fold to 20-fold, particularly preferably 5-fold to 2-naphthylacetic acid. Use 15 times the capacity.
[0060]
In the present invention, toluene is particularly preferred as the hydrocarbon solvent because sulfur removal and 2-naphthylacetic acid extraction can be performed with a single solvent.
Thus, in step 1 of the present invention, 2-naphthylacetic acid obtained by contacting with a hydrocarbon solvent or the like has a sulfur content of 0.001 mol% to 1 mol%, preferably 0.001 mol% to It is 0.5 mol % and has a purity of 98 mol % or higher, preferably 99 mol % or higher.
(Isolation method)
An organic solvent capable of dissolving 2-naphthylacetic acid (e.g., toluene, xylene, cyclohexane, etc.) is added to the reaction product obtained by the liberation reaction, and the reaction product is washed once or more with an appropriate washing liquid such as water or an aqueous solution. It may be washed twice and isolated using known methods. For example, by stirring under acidic conditions (e.g., pH 3 or less) and heating (e.g., 50° C. to 90° C.), washing as necessary, separating the aqueous layer, concentrating, etc., and then cooling, 2-Naphthylacetic acid can be precipitated and recovered as a solid.
The 2-naphthylacetic acid obtained in step 1 is useful as a raw material for synthesis of various industrial products and pharmaceuticals, and as an intermediate for synthesis, and can be subjected to step 2 of the present invention.
[0061]
<>
[0062]
[Chemical 12]

[0063]
(Wherein, X is a halogen atom.)
[0064]
Step 2 is a step of obtaining 2-naphthylacetonitrile represented by formula (1) including the following two reactions I and II.
Reaction I: A compound represented by Formula (5) by mixing 2-naphthylacetic acid represented by Formula (4) and a halogenating agent in a first organic solvent, optionally in the presence of a catalyst. A reaction to obtain a reaction raw material 1 containing
Reaction II: Reaction to obtain 2-naphthylacetonitrile by mixing reaction raw material 1 containing the compound represented by formula (5) and reaction raw material 2 containing sulfamide and a second organic solvent.
[0065]
[Reaction I]
2-naphthylacetic acid represented by formula (3) and a halogenating agent are mixed in a first organic solvent in the presence of a catalyst if necessary to react a compound represented by formula (5) This is a reaction to obtain raw material 1.
[0066]
[Chemical 13]

[0067]
(Wherein, X is a halogen atom.)
[0068]

(2-naphthylacetic acid)
For 2-naphthylacetic acid, the one obtained in step 1 above or a commercially available one can be used.
[0069]
(halogenating agent)
The halogenating agent is not particularly limited as long as it can halogenate 2-naphthylacetic acid. As the halogenating agent, a chlorinating agent and a brominating agent are preferable, and a chlorinating agent is more preferable.
Chlorinating agents include thionyl chloride, oxalyl chloride, sulfuryl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, and the like.
Brominating agents include thionyl bromide and phosphorus tribromide.
Among these, thionyl chloride, phosphoryl chloride, phosphorus pentachloride, thionyl bromide, and phosphorus tribromide are preferred, and thionyl chloride is particularly preferred, from the viewpoint of cost, versatility, reactivity, and the like. One of these halogenating agents may be used alone, or two or more thereof may be used in any combination and ratio.
The amount of the halogenating agent to be used is not particularly limited as long as it is an amount capable of halogenating 2-naphthylacetic acid. It is preferable to use 1 mol or more.
The upper limit of the amount used is not particularly limited, but from the viewpoint of cost, productivity, etc., it is preferably 3 mol or less per 1 mol of 2-naphthylacetic acid.
[0070]
(catalyst)
Reaction I can be carried out in the presence of a catalyst if necessary. The catalyst is not particularly limited as long as it promotes the reaction, but the reaction is preferably carried out in the presence of a catalyst in order to increase the reactivity.
Examples of the catalyst include tertiary amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidinone. - dimethylformamide is preferred.
The amount of catalyst used is not particularly limited as long as it is an effective amount for functioning as a catalyst. The amount of catalyst used is preferably 0.0001 mol to 1 mol, more preferably 0.001 mol to 0.1 mol, per 1 mol of 2-naphthylacetic acid.
[0071]
(First organic solvent)
The first organic solvent is not particularly limited as long as the reaction proceeds.
Examples of the first organic solvent include hydrocarbon solvents, amide solvents, sulfoxide solvents, and sulfone solvents. One of these organic solvents may be used alone, or two or more thereof may be used in any combination and ratio.
Examples of hydrocarbon solvents include chain aliphatic hydrocarbons such as hexane and heptane; cyclic aliphatic hydrocarbons such as cyclohexane, methylcyclohexane and cycloheptane; benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzene and the like; Aromatic hydrocarbon; Aromatic halogenated hydrocarbons such as trifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene and bromobenzene can be used.
As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidinone can be used, preferably N,N-dimethylformamide.
As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethylsulfoxide can be used.
As the sulfone solvent, for example, aprotic sulfones such as ethylmethylsulfone, ethylisopropylsulfone, 3-methylsulfolane and sulfolane can be used, preferably sulfolane.
The first organic solvent is preferably a hydrocarbon solvent, an amide solvent, or a sulfone solvent, more preferably a hydrocarbon solvent or an amide solvent, from the viewpoint of excellent operability, productivity, etc., and cost, etc., and among these, toluene and xylene. , chlorobenzene and N,N-dimethylformamide are more preferred, and toluene is particularly preferred.
In addition, it should be excellent in reactivity, operability, productivity, etc., and costFrom a viewpoint, it is also preferable to use a mixture of a hydrocarbon solvent and an amide solvent as the first organic solvent, and a mixture of toluene and N,N-dimethylformamide is particularly preferable. The mixing ratio (volume ratio) of the hydrocarbon solvent and the amide solvent can be appropriately selected within the range of 1:99 to 99:1.
The amount of the first organic solvent to be used is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more from the viewpoint of operability, per 1 kg of 2-naphthylacetic acid. From the viewpoint of performance and cost, it is usually 50 L or less, preferably 30 L or less, more preferably 20 L or less, still more preferably 10 L or less, particularly preferably 4.5 L or less, and most preferably 4 L or less.
(Inorganic additive)
In reaction I, inorganic additives (e.g., diatomaceous earth, anhydrous silicic acid, silicon dioxide, sodium sulfate, magnesium sulfate, sodium chloride, magnesium chloride, calcium carbonate, magnesium carbonate, etc.) may be added as necessary. . By using an inorganic additive, the reaction can proceed smoothly.
[0072]

(reaction temperature)
The reaction temperature is usually 15°C to 70°C, preferably 20°C to 65°C, and particularly preferably 30°C to 60°C. If the reaction temperature is too low, the progress of the reaction may slow down and the productivity may decrease.
(reaction time)
The reaction time is usually 0.5 hours to 30 hours, preferably 1 hour to 15 hours, particularly preferably 2 hours to 10 hours.
(reaction pressure)
The reaction pressure is usually normal pressure, but the reaction may be carried out under increased pressure.
[0073]

When the reaction solution obtained in Reaction I containing the compound represented by formula (5) is used in Reaction II, the reaction solution may be used as it is, or a concentrated solution obtained by concentrating the reaction solution may be used. Alternatively, the reaction solution may be mixed with water or an alkaline aqueous solution for neutralization, and the organic layer obtained by liquid separation may be used. You may use what was obtained by processing. Further, the product obtained in Reaction I may be purified by known purification means such as column chromatography. In the production method of the present invention, from the viewpoint of cost and productivity, it is preferable to use the reaction liquid or the concentrated liquid as it is in Reaction II.
[0074]
[Reaction II]
A reaction to obtain 2-naphthylacetonitrile represented by formula (1) by mixing the compound represented by formula (5), sulfamide and a second organic solvent.
[0075]
[Chemical 14]

[0076]
(Wherein, X is a halogen atom.)
This reaction II can suppress the formation of the naphthalene compound (by-product) described in the section "High-purity 2-naphthylacetonitrile of the present invention".
[0077]

(Compound represented by formula (5))
As the compound represented by formula (5), the one obtained in Reaction I can be used, and the concentrated solution obtained by concentrating the reaction solution obtained in Reaction I is used from the viewpoint of productivity. preferable.
(Sulfamide)
Commercially available sulfamide can be used.
The amount of sulfamide used is generally preferably 1 mol or more per 1 mol of 2-naphthylacetic acid. The amount of sulfamide to be used is generally 1 mol-5 mol, preferably 1.02 mol-3 mol, more preferably 1.03 mol-2 mol, particularly preferably 1.05 mol-1.5 mol, per 1 mol of 2-naphthylacetic acid.
(Second organic solvent)
As the second organic solvent, the same solvent as the first organic solvent can be used, but a sulfone solvent is preferred, and sulfolane is preferred from the viewpoint of reactivity, productivity, and the like.
Furthermore, it is also preferable to use a mixture of a hydrocarbon solvent and a sulfone solvent as the second organic solvent, and a mixture of toluene and sulfolane is particularly preferable. The mixing ratio (volume ratio) of the hydrocarbon solvent and the sulfone solvent can be appropriately selected within the range of 1:99 to 99:1.
The amount of the second organic solvent to be used is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more from the viewpoint of operability, per 1 kg of 2-naphthylacetic acid. From the viewpoint of performance and cost, it is usually 50 L or less, preferably 30 L or less, more preferably 20 L or less, still more preferably 4.5 L or less, and particularly preferably 4 L or less.
(Inorganic additive)
In reaction II, inorganic additives (e.g., diatomaceous earth, anhydrous silicic acid, silicon dioxide, sodium sulfate, magnesium sulfate, sodium chloride, magnesium chloride, calcium carbonate, magnesium carbonate, etc.) may be added as necessary. . By using an inorganic additive, the reaction can proceed smoothly.
[0078]

(reaction temperature)
The reaction temperature may vary depending on the organic solvent and catalyst used, but the lower limit is usually 80° C. or higher, preferably 85° C. or higher, particularly preferably 90° C. or higher, from the viewpoint of quality, reactivity, etc., and the upper limit is is usually 180° C. or lower, preferably 150° C. or lower, more preferably 120° C. or lower, particularly preferably 110° C. or lower, from the viewpoints of quality, reactivity, cost, and the like.
If the reaction temperature is too low, the progress of the reaction may slow down and productivity may decrease.
In this embodiment, after mixing the reactant 1 and the reactant 2, the temperature may be raised to react at 80°C to 180°C. may be mixed and reacted. Further, the reaction raw material 2 may be added to the reaction raw material 1 and mixed, or the reaction raw material 1 may be added to the reaction raw material 2 and mixed.
(reaction time)
The reaction time of the reaction raw material 1 and the reaction raw material 2 may vary depending on the halogenating agent, organic solvent, catalyst, etc. used, but can be appropriately selected depending on the progress of the reaction, usually 0.5 hours to 48 hours, preferably 1 hour to 24 hours, particularly preferably 2 hours to 12 hours. The reaction time means the time from the start of mixing of the reaction raw materials 1 and 2 to the post-treatment when the reaction proceeds from the start of mixing of the raw materials 1 and 2 .
(reaction pressure)
The pressure during the reaction is usually normal pressure, but may be pressurized.
[0079]
(Reaction method)
The production method of the present invention may be batch type or continuous type, but is usually carried out in batch type.
(supply order)
The supply order of the reaction raw materials 1 and 2 can be selected as appropriate. For example, in one reactor, the reaction raw material 1 may be used as a bed liquid and the reaction raw material 2 may be supplied and mixed, or the reaction raw material 2 may be used as a bed liquid and the reaction raw material 1 may be supplied and mixed, The reactants 1 and 2 may be supplied simultaneously and mixed.
By setting the temperature of the mixture of the reaction raw materials 1 and 2 to a relatively low temperature with respect to the reaction temperature, the generation of by-products due to overreaction is suppressed, and even in industrial scale mass synthesis, higher purity can be obtained. 2-Naphthylacetonitrile can be efficiently produced at low cost.
(supply method)
The supply method includes, for example, a method of adding the entire amount of the reaction raw material 1 to the reaction raw material 2 at once, a method of dividing the reaction raw material 1 into two or more portions and adding the reaction raw material 1 in two or more portions at intervals of time, or dropping. A method of intermittently or continuously adding a constant amount by, for example,
In the present invention, in order to suppress the production of by-products, a method of adding in two or more portions or a method of intermittently or continuously adding a fixed amount by dropping or the like is preferable. In this case, with respect to 1 mol of sulfamide contained in the reaction raw material 2, the amount of the acid halogen compound represented by the general formula (5) contained in the reaction raw material 1 (addition amount per minute) is 0. The reactant 1 is added to the reactant 2 at a concentration of 0.0027 mol/min or more, preferably 0.0035 mol/min or more, and particularly preferably 0.0069 mol/min or more. By setting the addition amount to 0.0027 mol/min or more, the amount of the acid halogen compound represented by the general formula (5) in the reaction liquid in which the reaction raw materials 1 and 2 are mixed is kept within an appropriate range. Since it can be controlled, it is thought that the production of by-products can be suppressed. In particular, it is believed that the formation of the naphthalene compound represented by formula (c) can be suppressed.
In this case, the time for adding the reaction raw material 1 to the reaction raw material 2 can be appropriately selected depending on the amount of the reaction raw material 1 added, but it is usually 5 minutes or more, preferably 10 minutes or more.
If the amount added is less than 0.0027 mol/min, the production of by-products may increase. Also, if the addition time is too short, there is a risk that a large amount of gas, which is a by-product of the reaction between the reaction raw materials 1 and 2, may be generated rapidly.
(Temperature of mixed liquid)
The temperature of the mixture obtained by mixing the reaction raw material 1 and the reaction raw material 2 may vary depending on the organic solvent, catalyst, etc. used, but the lower limit is usually 10° C. or higher, preferably 10° C. or higher, from the viewpoint of quality, reactivity, etc. It is 15° C. or higher, particularly preferably 20° C. or higher, and the upper limit is usually 100° C. or lower, preferably 95° C. or lower, particularly preferably 90° C. or lower, from the viewpoint of quality, reactivity, cost, and the like.
If the temperature of the mixture obtained by mixing the reaction raw material 1 and the reaction raw material 2 is lower than 15°C, the mixing may be insufficient and the reaction efficiency may decrease. The production of by-products may increase. In particular, when the temperature of the mixed liquid is high, the compound represented by formula (5) reacts with the reaction product, and impurities such as the compound represented by formula (c) are likely to be generated. The yield and quality of 2-naphthylacetonitrile represented by may decrease.
[0080]
[Chemical 15]

[0081]

The reaction solution containing 2-naphthylacetonitrile obtained in step 2 may be subjected to treatments such as neutralization, liquid separation and filtration, or may be subjected to simple treatment such as concentration and crystallization with an organic solvent such as toluene and heptane. The desired 2-naphthylacetonitrile may be isolated by separation means. Further, by adding a poor solvent such as water to the reaction solution containing the desired 2-naphthylacetonitrile, the nitrile compound can be precipitated as crystals.
For example, the obtained reaction solution is cooled, an organic solvent such as toluene is added, the organic layer is washed with water and a base, the organic layer obtained by washing is concentrated, and the concentration residue is an organic solvent such as methanol. is added to replace the solvent, cooled, the precipitated 2-naphthylacetonitrile is collected by filtration, and the resulting wet crystals are dried to obtain 2-naphthylacetonitrile as a solid.
In addition, the 2-naphthylacetonitrile obtained in the present invention has a high purity (HPLC) of preferably 98 area% or more, particularly preferably 99 area% or more, but if necessary, recrystallization, column chromatography It may be further purified by known purification means such as activated carbon treatment.
[0082]
In addition, each compound in the present invention may form a solvate such as a hydrate or an organic solvate, and its form is not particularly limited as long as it does not inhibit the reaction.
[0083]
In the production method of the present invention, the following steps are particularly preferred as steps 1 and 2.
[0084]
Step 1: Step of reacting 2'-acetonaphthone, sulfur and morpholine followed by hydrolysis to obtain 2-naphthylacetic acid
[0085]
[Chemical 16]

[0086]
Step 2: A reaction raw material 1 containing a mixture of 2-naphthylacetic acid, thionyl chloride, toluene and, if necessary, a catalyst, and a reaction raw material 2 containing a mixture of sulfamide and sulfolane are mixed at 15° C. to 90° C., and then the temperature is raised. A step of reacting at 80° C. to 180° C. to obtain 2-naphthylacetonitrile, or a step of adding the above reaction raw material 1 to the above reaction raw material 2 and reacting at 80° C. to 180° C. to obtain 2-naphthylacetonitrile. The reaction raw material 1 is added to the reaction raw material 2 so that the amount of the acid chloride compound contained in the reaction raw material 1 is 0.0027 mol/min or more with respect to 1 mol of sulfamide contained in the reaction raw material 2. Addition process
By this step 2, the above "high performance of the present inventionPurity of 2-naphthylacetonitrile” can suppress the formation of the naphthalene compound (by-product), particularly the naphthalene compound represented by formula (c).
[0087]
[Chemical 17]

Example
[0088]
The present invention will be described in more detail below with reference to examples, but the present invention is not limited by these examples.
In addition, in the following examples and comparative examples, commercially available 2'-acetonaphthone was used. Further, the purity of the obtained compound was measured by HPLC under the following analysis conditions.
[0089]
(HPLC analysis conditions)
Analytical instrument: Agilent HPLC (1200 series)
Column: Zorbax Eclipse Plus Phenyl-Hexyl, 5 μm, 250 mm × 4.6 mm
　Mobile phase A: 0.1% by volume trifluoroacetic acid aqueous solution
　Mobile phase B: acetonitrile
Gradient: 0 minutes (B: 30%) - 15 minutes (B: 60%) - 20 minutes (B: 95%) - 30 minutes (B: 95%)
　Flow rate: 1.0 mL/min
　Injection volume: 5 μL
　Detection wavelength: 280 nm
　Column temperature: 40℃
[0090]
Example 1
(1) Synthesis of 2-naphthylacetic acid
[0091]
[Chemical 18]

[0092]
24 kg of 2'-acetonaphthone, 5.65 kg of sulfur (1.25 molar times relative to 2'-acetonaphtone), and 2.68 kg of p-toluenesulfonic acid monohydrate ( 0.1 mol times for 2′-acetonaphthone) and 36.9 kg of morpholine (3 mol times for 2′-acetonaphthone) were added and stirred, followed by reaction at 115° C. to 120° C. for 3 hours. Here, it was confirmed by HPLC that a thioamide form was produced.
After cooling the reaction solution to 70° C. to 80° C., a 20% by weight aqueous solution of sodium hydroxide (a mixture of 16.9 kg of sodium hydroxide and 67.7 kg of water) After adding 43.2 kg of water, the temperature was raised and the mixture was reacted at 90° C. to 105° C. for 4 hours (hydrolysis).
The resulting reaction solution was cooled to 65° C. to 75° C., 24 kg of water and 83.2 kg of toluene were added, stirred at 65° C. to 75° C., allowed to stand, and then the resulting upper layer was discarded (unreacted sulfur removal). The remaining lower layer (206.35 kg) was added to a mixture of 208.05 kg of toluene and 80.8 kg of 35% strength by weight hydrochloric acid. Further, 2.4 kg of water was added to the reaction vessel containing the lower layer to wash it, and the liquid obtained after washing was also added to the mixed liquid. The mixture containing the reaction solution thus obtained was stirred at 65° C. to 75° C. and allowed to stand (extraction of 2-naphthylacetic acid), and the obtained lower layer was discarded. 121.0 kg of water was added to the remaining upper layer, stirred at 65° C. to 75° C., allowed to stand still, and the lower layer was discarded. Further, 121 kg of water was added to the remaining upper layer, stirred at 65° C. to 75° C., allowed to stand, and the lower layer was discarded.
After concentrating the remaining upper layer, it was cooled to 10°C or less. The precipitated crystals of 2-naphthylacetic acid were collected by centrifugation and washed with 20.8 kg of toluene to obtain wet crystals. The obtained wet crystals were dried under reduced pressure at 60° C. to obtain 19.70 kg of 2-naphthylacetic acid.
1H-NMR (400MHz, CDCl3) δ 3.80 (2H, s), 7.40 (1H, dd, J = 8.4, 3.0Hz), 7.43-7.49 (2H, m), 7.73 (1H, s), 7.78-7.82 (3H, m)
[0093]
(2) Synthesis of 2-naphthylacetonitrile
[0094]
[Chemical 19]

[0095]
18.7 kg of 2-naphthylacetic acid obtained in (1) above, 40.55 kg of toluene, and 73.08 g of N,N-dimethylformamide were added to a nitrogen-purged reaction vessel. Furthermore, the equipment used for the above addition was washed with 16.2 kg of toluene, and the liquid obtained after washing was also added to the reaction vessel. To the resulting solution was added 12.5 kg of thionyl chloride (1.05 mol times that of 2-naphthylacetic acid) and reacted at 35° C. to 45° C. for 5 hours. After cooling to 20° C.-30° C., it was filtered. The resulting filtrate was mixed with the washing liquid obtained by washing the filtration residue with 8.15 kg of toluene, and 23.6 kg of sulfolane (1 volume of 2-naphthylacetic acid) was added thereto, followed by concentration under reduced pressure. to prepare an acid chloride solution.
11.6 kg of sulfamide (1.2 mol times that of 2-naphthylacetic acid), 58.9 kg of sulfolane (2.5 times mol of 2-naphthylacetic acid) and an inorganic system were added to another reaction vessel that was purged with nitrogen. After adding 18.7 kg of the agent and stirring, the temperature was raised to 95° C. to 105° C. to prepare a sulfamide solution.
At 95°C to 105°C, the acid chloride solution was added dropwise to the sulfamide solution over 2 hours. Further, the reaction vessel containing the acid chloride solution was washed with 1.62 kg of toluene, and the liquid obtained after washing was also added to the reaction vessel, followed by reaction at 95° C. to 105° C. for 7 hours.
The resulting reaction solution was cooled to 25°C, 65 kg of toluene and 74.8 kg of water were added, stirred at 20°C to 30°C, allowed to stand, and the lower layer was discarded. 35.5 kg of water and 5.61 kg of potassium carbonate were added to the remaining upper layer, the equipment used in the above reaction was washed with 15 kg of water, and the liquid obtained after washing was also added to the mixed liquid containing the above upper layer. . The resulting mixture was stirred at 20° C. to 30° C. and allowed to stand, and the lower layer was discarded. 37.4 kg of water was added to the remaining upper layer, stirred at 20° C. to 30° C., allowed to stand, and the lower layer was discarded. After concentrating the remaining upper layer, 104 kg of methanol was added and further concentrated. 44.4 kg of methanol was added to the obtained concentrate and concentrated. 0.374 kg of activated carbon and 45.1 kg of methanol were added to the obtained concentrate at 35° C., stirred, and then filtered. The filtration residue was washed with 14.95 kg of methanol, and the filtrate and the liquid after washing were mixed.
After holding the resulting mixed solution at 30° C. to 40° C. for about 90 minutes, it is cooled, and 74.8 kg of water (4 times the volume of 2-naphthylacetic acid) is added at a temperature of around 10° C., and the mixture is stirred for 4 hours. Stirred. The precipitated crystals were collected by centrifugation, and the collected wet crystals were washed with an aqueous methanol solution (mixed solution of 14.8 kg of methanol and 18.7 kg of water). The obtained wet crystals were dried under reduced pressure in an atmosphere of 60° C. to obtain 15.2 kg of 2-naphthylacetonitrile crystals (purity: 99.50 area %).
1H-NMR (400 MHz, CDCl 3 ) δ 3.92 (2H, s), 7.37-7.40 (1H, m), 7.49-7.54 (2H, m), 7.83-7. 85 (4H, m)
[0096]
The HPLC analysis results of the obtained 2-naphthylacetonitrile are shown in Table 3 and Figure 1. In Table 3, RRT is the relative retention time when the retention time of 2-naphthylacetonitrile is 1.00.
[0097]
[Table 3]

[0098]
Also, from the HPLC analysis results, no compounds of formulas (e) to (j) were detected in the obtained 2-naphthylacetonitrile.
The 1H-NMR measurement results of the compounds of formulas (a) to (d) are as follows.
[0099]
compounds of formula (a)
[0100]
[Chemical 20]

[0101]
1H-NMR (400MHz, CDCl 3) δ = 3.71 (s, 3H), 3.79 (s, 2H), 7.40-7.47 (m, 3H), 7.73 (s, 1H) , 7.79-7.83 (m, 3H)
[0102]
compounds of formula (b)
[0103]
[Chemical 21]

[0104]
LC/MS 215 (m/z, Pos)
1H-NMR (400MHz, CDCl 3) δ = 1.26 (t, J = 7.2Hz, 3H), 3.78 (s, 2H), 4.17 (q, J = 7.2Hz, 2H), 7.41-7.49 (m, 3H), 7.74 (s, 1H), 7.79-7.82 (m, 3H)
[0105]
compounds of formula (c)
[0106]
[Chemical 22]

[0107]
LC/MS 354 (m/z, Pos)
1H-NMR (400MHz, dmso-d 6) δ = 4.03 (s, 4H), 7.41 (dd, J = 8.4, 1.6Hz, 2H), 7.48-7.50 (m , 4H), 7.75 (s, 2H), 7.82-7.90 (m, 6H), 11.12 (s, 1H)
[0108]
compounds of formula (d)
[0109]
[Chemical 23]

[0110]
LC/MS 503 (m/z, Pos)
1H-NMR (400MHz, CDCl 3) δ = 1.27 (s, 9H), 3.54 (s, 2H), 3.59 (s, 2H), 7.04 (d, J = 8.8Hz, 1H), 7.11 (d, J = 2.0Hz, 1H), 7.21 (dd, J = 8.4, 2.4Hz, 1H), 7.29-7.34 (m, 2H), 7.42-7.49 (m, 4H), 7.59 (s, 1H), 7.63 (s, 1H), 7.76-7.79 (m, 6H)
[0111]
Example 2
75.02 g of 2-naphthylacetic acid synthesized according to the method of Example 1 (1), 263 mL of toluene (3.5 times the volume of 2-naphthylacetic acid), and N,N-dimethyl were placed in a nitrogen-purged reaction vessel. 0.29 g of formamide (0.01 mol times that of 2-naphthylacetic acid) was added, the temperature was raised to 35° C. to 45° C., and 50.3 g of thionyl chloride (1.05 mols of 2-naphthylacetic acid) was added. times) were added. After reacting for 3 hours, the reaction mixture was concentrated to prepare a reaction raw material 1 containing 2-naphthylacetic chloride.
46.49 g of sulfamide (1.2 mol-fold relative to 2-naphthylacetic acid), 74.99 g of inorganic additive (1-fold mol relative to 2-naphthylacetic acid), and 263 mL of sulfolane were placed in another nitrogen-purged reaction vessel. (3.5 times the volume of 2-naphthylacetic acid) was added, and the temperature was raised (preparation of reaction raw material 2). After dropping the reaction material 1 containing 2-naphthyl acetic acid chloride into the reaction material 2 at 95° C. to 105° C. over 18 minutes, 7.5 mL of toluene (2-naphthyl The solution obtained by washing with acetic acid (0.1 times by volume) was further added to the reaction raw material 2 and reacted at 95° C. to 105° C. for 4 hours. The reaction solution was analyzed by HPLC, and after confirming the disappearance of the raw materials, it was cooled to 20° C. to 30° C., and 300 mL of water (4 times by volume with respect to 2-naphthylacetic acid) and 300 mL of toluene (with respect to 2-naphthylacetic acid) were added. 4 times the volume) was added and stirred, and then the aqueous layer was discarded. The remaining organic layer was washed with 225.08 g of a 10% by weight aqueous potassium carbonate solution (3 times the weight of 2-naphthylacetic acid) and 150 mL of water (2 times the volume of 2-naphthylacetic acid).
The obtained organic layer was concentrated, 525 mL of methanol (7 times the volume of 2-naphthylacetic acid) was added to the concentrated residue, and the mixture was concentrated again. Furthermore, after adding methanol to the resulting concentrated residue to adjust the liquid volume to 525 mL, 1.52 g of activated carbon (0.02 times the weight of 2-naphthylacetic acid) was added, and the mixture was heated at 50°C to 60°C. After stirring, it was filtered. The resulting filtration residue was washed with 75 mL of methanol (1 volume of 2-naphthylacetic acid).
After cooling the resulting filtrate to 5°C to 15°C, 300 mL of water (4 times the volume of 2-naphthylacetic acid) was added and stirred. The precipitated 2-naphthylacetonitrile was collected by filtration, and the obtained wet crystals were dried to obtain 60.38 g of 2-naphthylacetonitrile as a solid (purity: 99.85 area %).
Table 4 shows the HPLC analysis results of the reaction solution after reacting for 4 hours and the obtained 2-naphthylacetonitrile.
[0112]
[Table 4]

[0113]
Also, from the HPLC analysis results, the compounds of formulas (d) to (j) were not detected in the obtained 2-naphthylacetonitrile crystals.
[0114]
Example 3
[0115]
[Chemical 24]

[0116]
Combined in a nitrogen-substituted reaction vessel according to the method of Example 1 (1)25 g of 2-naphthylacetic acid formed, 75.88 g of toluene (3.5 times the volume of 2-naphthylacetic acid), and 0.0982 g of N,N-dimethylformamide (0.01 times the volume of 2-naphthylacetic acid). was added. To the resulting solution, 16.77 g of thionyl chloride (1.05 mol times that of 2-naphthylacetic acid) was added dropwise and reacted at 43° C. to 45° C. for 3 hours. 0.5 times the volume of 2-naphthylacetic acid) and 31.53 g of sulfolane (1 times the volume of 2-naphthylacetic acid) were added and concentrated under reduced pressure to prepare a reaction raw material 1 containing 2-naphthylacetic acid chloride.
15.5 g of sulfamide (1.2 mol times that of 2-naphthylacetic acid), 78.78 g of sulfolane (2.5 times mol of 2-naphthylacetic acid), and an inorganic system were added to another reaction vessel that had been purged with nitrogen. After adding 25.01 g of the agent and stirring, the temperature was raised to 75° C. to 85° C. (preparation of reaction raw material 2). This reaction raw material 2 was in a slurry state rather than a solution.
After the reaction material 1 containing 2-naphthylacetic acid chloride was added dropwise to the reaction material 2 at 75° C. to 85° C. over 10 hours, the temperature was further raised to 100° C. over 2 hours, and the reaction was allowed to proceed for 5 hours. .
The resulting reaction solution was cooled to 55° C. to 65° C., and 86.7 g of toluene (4 times the volume of 2-naphthylacetic acid) and 100.05 g of water (4 times the volume of 2-naphthylacetic acid) were added. After stirring, the mixture was allowed to stand, and the lower layer was discarded. To the remaining upper layer was added 75.01 g of a 5% by weight aqueous sodium hydrogencarbonate solution (three times the weight of 2-naphthylacetic acid), stirred at 55° C. to 65° C., allowed to stand, and the lower layer was discarded. 50.01 g of water (two times the weight of 2-naphthylacetic acid) was added to the remaining upper layer, stirred at 55° C. to 65° C., allowed to stand, and the lower layer was discarded. The remaining upper layer was concentrated, 138.44 g of methanol (7 times the volume of 2-naphthylacetic acid) was added to the concentrated residue, and the mixture was further concentrated. 59.34 g of methanol (3 times the volume of 2-naphthylacetic acid) was added to the obtained concentrated residue and concentrated, and 39.55 g of methanol (2 times the volume of 2-naphthylacetic acid) and 0.5 g of activated carbon (0.02 times the weight of 2-naphthylacetic acid) was added and filtered. The resulting filtrate was mixed with a washing solution obtained by washing the filtration residue with 19.78 g of methanol (1 volume of 2-naphthylacetic acid) to obtain a 2-naphthylacetonitrile solution.
The resulting 2-naphthylacetonitrile solution was heated to 40° C. to 50° C., and added with 0.1259 g of water (0.005 times the volume of 2-naphthylacetic acid) and 0.0248 g of potassium carbonate (relative to 2-naphthylacetic acid). After stirring for 1 hour, 100 g of water (4 times the volume of 2-naphthylacetic acid) was added dropwise over 1 hour. Then, it was cooled and stirred for 1 hour at a temperature of around 10°C. The precipitated crystals were centrifuged, and the recovered wet crystals were washed twice with an aqueous methanol solution (mixed solution of 27.71 g of methanol and 15.03 g of water). The obtained wet crystals were dried under reduced pressure in an atmosphere of 60° C. to obtain 19.09 g of 2-naphthylacetonitrile as crystals (yield 85%, purity 99.87 area %).
[0117]
The HPLC analysis results of the obtained 2-naphthylacetonitrile are shown in Table 5 and Figure 2.
[0118]
[Table 5]

[0119]
Also, from the HPLC analysis results, the compounds of formulas (b) and (e) to (j) were not detected in the obtained 2-naphthylacetonitrile crystals. According to this example, 2-naphthylacetonitrile containing less impurities such as compounds of formulas (a) and (c) than in Examples 1 and 2 was obtained. In particular, the 2-naphthylacetonitrile obtained in this example does not contain the compound of formula (c), and is useful as a starting material and intermediate for synthesizing pharmaceuticals.
Thus, after mixing the reaction raw material 1 containing 2-naphthyl acetic acid chloride and the reaction raw material 2 containing sulfamide at a relatively low temperature, the temperature is raised and the reaction is carried out to obtain a high-purity 2 containing less impurities. - naphthylacetonitrile is obtained.
[0120]
Example 4
10.03 g of 2-naphthylacetic acid synthesized according to the method of Example 1 (1), 35 mL of toluene (3.5 times the volume of 2-naphthylacetic acid), and N,N-dimethyl were placed in a nitrogen-purged reaction vessel. 42 µL of formamide (0.01 mol times that of 2-naphthylacetic acid) was added, the temperature was raised, and 6.72 g of thionyl chloride (1.05 mol times that of 2-naphthylacetic acid) was added at 35°C to 45°C. added. After reacting for 2 hours, it was cooled and filtered at room temperature, and the filter residue was washed with 5 mL of toluene. 10 mL of sulfolane (1 volume of 2-naphthylacetic acid) was added to the resulting filtrate and washing, and the mixture was concentrated to prepare a reaction raw material 1 containing 2-naphthylacetic acid chloride.
6.19 g of sulfamide (1.2 mol times relative to 2-naphthylacetic acid), 10.01 g of inorganic additive (1.0 mol times relative to 2-naphthylacetic acid), 25 mL of sulfolane (2.5 times the volume of 2-naphthylacetic acid) was added and the temperature was raised (preparation of reaction raw material 2). At 95° C. to 105° C., the reaction material 1 containing 2-naphthylacetic acid chloride was added dropwise to the reaction material 2 over 1 hour. 0.1 times by volume) was added, and the mixture was reacted at 95° C. to 105° C. for 4 hours. As a result of analyzing the reaction liquid by HPLC, it contained 96.27 area % of 2-naphthylacetonitrile and 0.39 area % of the compound of formula (c).
The reaction solution was cooled to 25° C., 40 mL of water (4 times the volume of 2-naphthylacetic acid) and 40 mL of toluene (4 times the volume of 2-naphthylacetic acid) were added and stirred, and then the lower layer was discarded. . The remaining organic layer was washed with 30.32 g of a 10% by weight potassium carbonate aqueous solution (3 times the weight of 2-naphthylacetic acid) and 20 mL of water (2 times the volume of 2-naphthylacetic acid).
The obtained organic layer was concentrated, 70 mL of methanol (7 times the volume of 2-naphthylacetic acid) was added to the concentrated residue, and the mixture was concentrated again. Furthermore, methanol is added to the resulting concentrated residue to adjust the liquid volume to 70 mL, 0.2 g of activated carbon (0.02 times the weight of 2-naphthylacetic acid) is added, and the mixture is stirred at 40°C to 50°C. After that, it was filtered, and the filter residue was washed with 10 mL of methanol (1 volume of 2-naphthylacetic acid).
After cooling the resulting filtrate to 5°C to 15°C, 40 mL of water (4 times the volume of 2-naphthylacetic acid) was added and stirred. The precipitated 2-naphthylacetonitrile was collected by filtration, and the obtained wet crystals were dried to obtain 8.11 g of 2-naphthylacetonitrile as a solid (purity: 99.30 area %).
Table 6 shows the HPLC analysis results of the reaction solution after reacting for 4 hours and the obtained 2-naphthylacetonitrile.
[0121]
[Table 6]

[0122]
Also, from the HPLC analysis results, the compounds of formulas (d) to (j) were not detected in the obtained 2-naphthylacetonitrile crystals.
[0123]
Example 5
The reaction was carried out in the same manner as in Example 4, except that the time for dropping the reaction raw material 1 was changed from 1 hour to 8 minutes.
As a result of measuring the reaction liquid obtained by reacting the reaction raw material 1 and the reaction raw material 2 for 4 hours by HPLC, it contained 95.94 area% of 2-naphthylacetonitrile and 0.30 area% of the compound of formula (c). was
[0124]
Example 6
The reaction was carried out in the same manner as in Example 4, except that the time for dropping the reaction raw material 1 was changed from 1 hour to 4 hours.
As a result of measuring the reaction liquid obtained by reacting the reaction raw material 1 and the reaction raw material 2 for 4 hours by HPLC, it contained 96.37 area% of 2-naphthylacetonitrile and 0.70 area% of the compound of formula (c). was
[0125]
Comparative example 1
2-naphthylacetonitrile was synthesized in the same manner as in Example 4, except that the time for dropping the reaction raw material 1 was changed from 1 hour to 10 hours.
As a result of measuring the reaction liquid obtained by reacting the reaction raw material 1 and the reaction raw material 2 for 4 hours by HPLC, it contained 92.75 area% of 2-naphthylacetonitrile and 1.16 area% of the compound of formula (c). was
Further, as a result of HPLC analysis of the obtained 2-naphthylacetonitrile, the content of 2-naphthylacetonitrile was 97.44 area% and the content of the compound of formula (c) was 0.47 area%.
[0126]
Table 7 shows the dropwise addition time and amount of reaction raw material 1, and the contents of 2-naphthylacetonitrile and the compound of formula (c) in the reaction solution obtained by reacting for 4 hours.
In Table 7, the amount of reaction raw material 1 added means the amount of acid chloride compound contained in reaction raw material 1 added (mol/min) per 1 mol of sulfamide contained in reaction raw material 2.
[0127]
[Table 7]

[0128]
As is clear from Table 7, the larger the addition amount (mol/min) of the acid chloride compound contained in the reaction raw material 1, the smaller the amount of the compound of formula (c) produced.
However, if the addition amount (mol/min) of the acid chloride compound contained in the reaction raw material 1 is too large, a large amount of hydrochloric acid gas may be generated as a by-product. Therefore, it is necessary to pay attention to safety, such as installing a processing device.
Industrial applicability
[0129]
According to the present invention, it is possible to provide high-purity 2-naphthylacetonitrile with few impurities, which is useful as raw materials and intermediates for the synthesis of various pharmaceuticals, agricultural chemicals, and chemical products, especially as raw materials and intermediates for the synthesis of pharmaceuticals. In addition, it is possible to provide a method for producing high-purity 2-naphthylacetonitrile that is safe, highly efficient, and industrially mass-produced at low cost. Furthermore, by using 2-naphthylacetonitrile of the present invention, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane and the like can be obtained industrially and in large quantities at low cost. Pharmaceuticals can be manufactured.
[0130]
This application is based on Japanese Patent Application No. 2019-196782 (filing date: October 29, 2019) filed in Japan, the contents of which are hereby incorporated by reference.

The scope of the claims

[Claim 1]
The HPLC purity of 2-naphthylacetonitrile is 95 area% or more, and one or more selected from naphthalene compounds represented by the following formulas (a) to (j) are included as impurities, and the content of each naphthalene compound is High purity 2-naphthylacetonitrile which is:
[Chemical 1]

[Claim 2]
High-purity 2 according to claim 1, wherein one or more selected from naphthalene compounds represented by the following formulas (a) to (d) are included as impurities, and the content of each naphthalene compound is as follows. - Naphthylacetonitrile.
[Chemical 2]

[Claim 3]
The high-purity 2-naphthylacetonitrile according to claim 1, which contains a naphthalene compound represented by the following formula (c) as an impurity, and the content of the naphthalene compound represented by the formula (c) is 1% by area or less.
[Chemical 3]

[Claim 4]
General formula (5) below
[Chemical 4]

(In general formula (5), X represents a halogen atom.)
and a reaction raw material 2 containing sulfamide and a second organic solvent are mixed at 15°C to 90°C, and the temperature is raised to 80°C. A method for producing high-purity 2-naphthylacetonitrile, wherein the reaction is performed at ~180°C to obtain 2-naphthylacetonitrile.
[Claim 5]
The method for producing high-purity 2-naphthylacetonitrile according to claim 4, characterized in that the reaction raw material 1 is added to the reaction raw material 2 at 15°C to 90°C, and the temperature is raised to react at 80°C to 180°C. .
[Claim 6]
For 1 mol of sulfamide, the general formula (5)
[Chemical 5]

The production of high-purity 2-naphthylacetonitrile according to claim 5, wherein the reaction raw material 1 is added to the reaction raw material 2 so that the amount of the acid halogen compound represented by is 0.0027 mol/min or more. Method.
[Claim 7]
The reaction raw material 1 is a mixture of 2-naphthylacetic acid, a halogenating agent and a first organic solvent, optionally in the presence of a catalyst.The method for producing high-purity 2-naphthylacetonitrile according to any one of claims 4 to 6, which is obtained by combining.
[Claim 8]
A method for producing high-purity 2-naphthylacetonitrile, characterized by including the following steps 1 and 2.
Step 1:
A step of hydrolyzing an amide compound obtained by subjecting 2'-acetonaphthone to a Wilgerott reaction in the presence of an additive, if necessary, and then liberating 2-naphthylacetic acid to obtain 2-naphthylacetic acid;
Step 2:
A reaction raw material 1 containing 2-naphthylacetic acid obtained in step 1, a halogenating agent and a first organic solvent, and a reaction raw material 2 containing sulfamide and a second organic solvent are mixed and reacted to give 2-naphthyl. Obtaining acetonitrile.
[Claim 9]
8. The method according to any one of claims 4 to 7, wherein the first organic solvent is a hydrocarbon solvent, an amide solvent, a sulfone solvent, or a mixed solvent thereof, and the second organic solvent is a sulfone solvent. A process for producing high-purity 2-naphthylacetonitrile as described.